A p38 mapk / mk2 pathway modulator, and compositions, methods of preparation and uses thereof

Abstract

The present disclosure discloses a compound as shown in formula I, its racemate, stereoisomer, tautomer, isotopically labeled, solvate, pharmaceutically acceptable salt or prodrug thereof, and its composition, preparation method and application. The compound has good regulation effect on p38MAPK / MK2 pathway, and has good selectivity, good pharmacokinetics and other properties. In addition, it can be used for treating diseases related to p38 kinase inhibitor mediation, and preparing drugs for such diseases or diseases.

Description

[0001] The present disclosure claims the priority of the prior application with the patent application number 202111640112.X, filed on December 29, 2021, with the State Intellectual Property Office of China, and entitled “A p38 MAPK / MK2 Pathway Modulator and Compositions, Preparation Methods and Uses Thereof”. The entire contents of the prior application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure belongs to the field of medicine, and particularly relates to a p38 MAPK / MK2 pathway modulator and compositions, preparation methods and uses thereof. BACKGROUND

[0003] Biological signal transduction involves specific protein-protein interactions and post-translational modifications, and regulates genetic and epigenetic processes to respond to internal and external environmental effects. Mitogen-activated protein kinase (MAPK) is a group of serine-threonine protein kinases that can be activated by different intracellular and extracellular stresses, and is an important transmitter of signals from the cell surface to the inside of the nucleus. Stress factors include cytokines, neurotransmitters, hormones, cell stress and cell adhesion, etc.

[0004] As a subfamily of the MAPK family, p38 MAPK is activated in response to extracellular signals and inflammatory cytokines, and after being activated, p38 MAPK phosphorylates and activates various downstream protein kinases and transcription factors, thereby exerting complex biological effects. p38 MAPK includes four members, namely p38α, p38β, p38γ and p38δ. Among them, p38α is believed to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isoforms have not yet been fully discovered, but they have pleiotropic effects. Studies have shown that p38β plays an important role in cell protection mechanisms, and mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates the role of p38δ in the proliferation and survival of advanced colorectal cancer (CRC) cells. As an attractive target in the field of drug development, p38 MAPK has multiple inhibitor drugs entering clinical research, and no drug has been approved for marketing so far. According to public information, some candidate compounds have failed in clinical research, and the main reasons for clinical failure include dose limitation to avoid toxicity, leading to insufficient exposure of drug molecules at the action target, down-regulation of anti-inflammatory pathways, signal network redundancy, or inhibition of key proteins involved in other MAPK pathways feedback regulation, etc., and inhibition of the feedback mechanism may up-regulate other pro-inflammatory pathways, leading to increased inflammation. Therefore, developing a safe and effective p38 MAPK inhibitor is currently the main challenge faced by drug development in this field.

[0005] p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013 (152), 924], so selectively inhibiting the activation of p38 MAPK downstream effectors is the main strategy to avoid side effects / insufficient efficacy caused by the overall inhibition of p38 MAPK. MAPK-activated protein kinase 2 (MK2) is a direct substrate of p38 MAPK downstream, which can be activated by p38α and p38β. As the first discovered substrate of p38 MAPK, MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thereby playing an important role in the regulation of multiple inflammatory diseases. Studies have shown that MK2 can increase the expression of inflammatory factors such as TNF-α, IL-6, IL-8 and COX-2 by stabilizing the AU-rich element of mRNA. In the postoperative ileus model of mice [The Journal of surgical research 2013 (185), 102], MK2 inhibitors can reduce the expression of inflammatory factors such as MIP-1α, TNF-α, IL-6 and IL-1β, and at the same time, the infiltration of polymorphonuclear leukocytes, mast cells and mononuclear macrophages is reduced and the contractile performance of intestinal smooth muscle is improved. In the collagen-induced arthritis (CIA) model of mice [Journal of immunology 2006 (177), 1913], knocking out the MK2 gene can reduce the incidence of collagen-induced arthritis. Compared with wild-type mice, MK2- / - and MK2+ / - mice have reduced incidence and severity of collagen-induced arthritis, and the expression of inflammatory factors TNF-α and IL-6 is also reduced to varying degrees. In the MK2 knockout hypercholesterolemia mouse model [Circ Res 2007 (101), 1104], the lipid deposition and macrophages of the large artery of the mice are reduced, and the expression of inflammatory factors such as VCAM-1 and MCP-1 is also reduced. In addition, studies have shown that inhibiting MK2 can be used for the development of anti-tumor drugs [Cancer cell 2007 (11), 175].

[0006] Many diseases are associated with the p38 MAPK / MK2 pathway, including (but not limited to) autoimmune and inflammatory diseases (such as rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergy and asthma, Alzheimer's disease, and hormone-related diseases, etc. Selective inhibition of the p38 MAPK / MK2 pathway reduces the impact on other downstream pathways of p38 MAPK, thereby reducing potential toxic side effects and insufficient drug efficacy in drug development; and meets the unmet clinical needs in the field of diseases associated with the p38 MAPK / MK2 pathway. SUMMARY

[0007] The present disclosure provides a compound as shown in Formula I, its racemate, stereoisomer, tautomer, isotopically labeled, solvate, pharmaceutically acceptable salt or prodrug thereof:

[0008]

[0009] wherein W is CH or N;

[0010] m is an integer from 0 to 5;

[0011] n is an integer from 0 to 3;

[0012] Ring A is C 3-20 cycloalkyl, 3-20 membered heterocyclyl, the carbon atom in ring A is connected to the parent core, and the 3-20 membered heterocyclyl contains 1, 2 or more O, N or S atoms;

[0013] R 1 is selected from H, halogen, CN and C 1-6 alkyl;

[0014] R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;

[0015] R 3 is selected from H, C 1-10 alkyl and C 3-20 cycloalkyl;

[0016] R 4 is selected from H, halogen and C 1-10 alkyl;

[0017] R 5 are each independently selected from H, halogen, -OH, -C 1-6alkyl, -C 1-6 alkoxy, oxo (=0), -C(O)C 1-6 alkyl, -C(O)OH, -C(O)NR 91a R 91b , -S(O)2R 92 and -S(O)2NR 93a R 93b ;

[0018] R 6 is selected from H, halogen and methyl;

[0019] R 7 are each independently selected from H, halogen, C 1-10 alkyl and C 3-20 cycloalkyl; Rais halogen or C 3-20 cycloalkyl;

[0020] R 81 , R 82 , R 83 , R 84 are identical or different, independently of each other, selected from C 6-14 aryl-C 1-10 alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; each Rbis identical or different, independently of each other, selected from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl and C 1-10 alkoxy;

[0021] R 91a , R 91b , R 92 , R 93a , R 93b are identical or different, independently of each other, selected from H, C 1-6 alkyl and C 3-20 cycloalkyl.

[0022] According to embodiments of the present disclosure, W is CH or N; m is an integer from 0 to 5; n is an integer from 0 to 3;

[0023] Ring A is C 3-20 cycloalkyl, 3-20 membered heterocyclyl, containing 1, 2 or more O, N or S atoms in the 3-20 membered heterocyclyl, the carbon atoms of which are attached to the core;

[0024] R 1 is selected from H, halogen, CN and C 1-6 alkyl;

[0025] R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 , and -C(O)NHR 84 ;

[0026] R 3 is selected from H, C 1-10 alkyl, and C 3-20 cycloalkyl;

[0027] R 4 is selected from H, halogen, and C 1-10 alkyl;

[0028] R 5 are each independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, oxo (=O), -C(O)C 1-6 alkyl, -C(O)OH, -C(O)NR 91a R 91b , -S(O)2R 92 , and -S(O)2NR 93a R 93b ;

[0029] R 6 is selected from H, halogen, and methyl;

[0030] R 7 are each independently selected from H, halogen, C 1-10 alkyl, and C 3-20 cycloalkyl;

[0031] R 81 , R 82 , R 83 , R 84 are identical or different, independently of each other, selected from C 6-14 aryl-C 1-10 alkyl, 5-14 membered heteroaryl-C 1-10 alkyl, C 6-14 aryl, and 5-14 membered heteroaryl; wherein C 6-14 aryl, 5-14 membered heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4, or 5 substituents independently of each other selected from halogen, halogenated C 1-10 alkyl, C 1-10 alkyl, and C 1-6 alkoxy;

[0032] R 91a , R 91b , R 92 , R 93a , R 93bidentically or differently, independently of one another, selected from H, C 1-6 alkyl and C 3-20 cycloalkyl.

[0033] According to embodiments of the present disclosure,

[0034] W is CH or N;

[0035] m is 0, 1, 2, 3, 4 or 5;

[0036] n is 0, 1, 2 or 3;

[0037] Ring A is C 3-12 cycloalkyl, 3-12-membered heterocyclyl, which contains 1, 2 or more O, N or S atoms, the carbon atoms of which are attached to the core, and

[0038] R 1 is selected from H, halogen, CN and -C 1-6 alkyl;

[0039] R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;

[0040] R 3 is selected from H, C 1-6 alkyl and C 3-12 cycloalkyl;

[0041] R 4 is selected from H, halogen and C 1-6 alkyl;

[0042] R 5 are each independently selected from halogen, -OH, -C 1-6 alkyl, -C 1-6 alkoxy, oxo (=O), -C(O)C 1-6 alkyl, -C(O)OH, -C(O)NR 91a R 91b , -S(O)2R 92 and -S(O)2NR 93a R 93b ;

[0043] R 6 is selected from H, halogen and methyl;

[0044] R 7 are each independently selected from H, halogen, C 1-6 alkyl and C 3-12 cycloalkyl;

[0045] R 81 , R 82 , R 83 , R 84 are identical or different, independently of each other, selected from the group consisting of C 6-14 alkyl, 5-14 membered heteroaryl-C 1-6 alkyl, 5-14 membered heteroaryl-C 1-6 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein C 6-14 aryl, 5-14 membered heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of halogen, halogen-C 1-6 alkyl, C 1-6 alkyl and C 1-3 alkoxy;

[0046] R 91a , R 91b , R 92 , R 93a , R 93b are identical or different, independently of each other, selected from the group consisting of H, C 1-3 alkyl and C 3-10 cycloalkyl.

[0047] According to an embodiment of the present disclosure,

[0048] W is CH or N;

[0049] m is 0, 1, 2, 3, 4 or 5;

[0050] n is 0, 1, 2 or 3;

[0051] Ring A is C 3-9 cycloalkyl, 3-9 membered heterocyclyl, containing 1, 2 or more O, N or S atoms in the 3-9 membered heterocyclyl, the carbon atoms of which are attached to the mother nucleus;

[0052] R 1 is halogen;

[0053] R 2 is selected from the group consisting of -OR 81 , -NH-C(O)R 82 , -NHR 83 and -C(O)NHR 84 ;

[0054] R 3 is C 1-3 alkyl and C 3-6 cycloalkyl;

[0055] R 4 is C 1-3 alkyl;

[0056] R5 are each independently selected from the group consisting of halogen, -OH, -C 1-3 alkyl, -C 1-3 alkoxy, oxo (=0), -C(O)C 1-3 alkyl, -C(O)OH, -C(O)NR 91a R 91b , -S(O)2R 92 and -S(O)2NR 93a R 93b ;

[0057] R 6 is selected from the group consisting of H, halogen and methyl;

[0058] R 7 are each independently selected from the group consisting of H, halogen and C 1-3 alkyl;

[0059] R 81 , R 82 , R 83 , R 84 are the same or different, independently of each other, selected from the group consisting of C 6-8 aryl-C 1-3 alkyl, 5-6 membered heteroaryl-C 1-3 alkyl, C 6-14 aryl and 5-14 membered heteroaryl; wherein C 6-14 aryl, 5-14 membered heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently of each other selected from the group consisting of halogen, halogen-C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy;

[0060] R 91a , R 91b , R 92 , R 93a , R 93b are the same or different, independently of each other, selected from the group consisting of H, C 1-3 alkyl and C 3-6 cycloalkyl.

[0061] According to an embodiment of the present disclosure,

[0062] W is CH or N;

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

[0064] n is 0 or 1 ;

[0065] Ring A is selected from piperidinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, azetidinyl, tetrahydropyrrolyl, thietanyl, tetrahydro-2H-thiopyranyl;

[0066] R 1 is Cl or Br;

[0067] R 2 is selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 , and -C(O)NHR 84 ;

[0068] R 3 is methyl or cyclopropyl;

[0069] R 4 is methyl;

[0070] R 5 are each independently selected from F, -OH, methyl, methoxy, oxo (=O), -C(O)C 1-3 alkyl, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -S(O)2CH3, -S(O)2CH2CH3, and -S(O)2-cyclopropane;

[0071] R 6 is selected from H, F, and Cl;

[0072] R 7 is H;

[0073] R 81 , R 82 , R 83 , R 84 are the same or different, each being independently selected from phenylmethyl, pyridinylmethyl, pyridinylethyl, phenyl, and pyridyl, which are unsubstituted or optionally substituted with 1, 2, or 3 Rb; each Rbis the same or different, each being independently selected from F, Cl, and CF3.

[0074] According to embodiments of the present disclosure, ring A can be selected from:

[0075]

[0076] According to embodiments of the present disclosure, the structure formed by R5and ring A can be selected from:

[0077]

[0078]

[0079] In a preferred embodiment, the compound of formula I has the structure of formula la or lb:

[0080]

[0081] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, W, m, n have the definitions described above, and the bolded chemical bond indicates the presence of an axial chirality in the compound.

[0082] In a preferred embodiment, the compound of formula I has the structure of formula II:

[0083]

[0084] wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , W, m, n and ring A independently of each other have the definitions described above;

[0085] R 10 is selected from the group consisting of H, halogen, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen, OH, NH2: C 1-10 alkyl, C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkenyloxy, C 2-10 alkynyl, C 2-10 alkynyloxy;

[0086] each R 11 is identical or different, independently of one another, selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-10 alkyl;

[0087] p is an integer from 0 to 4.

[0088] According to an embodiment of the present disclosure, R 10 is selected from the group consisting of H, halogen, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen, OH, NH2: C 1-6 alkyl, C 1-6 alkoxy, halogenated C1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkenyloxy group, C 2-6 alkynyl group, C 2-6 alkynyloxy group;

[0089] Each R 11 They are either the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0090] p can be 0, 1, 2, 3, or 4.

[0091] According to the implementation scheme of this disclosure, R 10 Selected from H, halogens, C 1-3 Alkyl, Halogenated C 1-3 Alkyl group; p is 0, 1, or 2;

[0092] Each R 11 They are either the same or different, and are independently selected from H, halogens, and C. 1-3 Alkyl, Halogenated C 1-3 alkyl.

[0093] According to the implementation scheme of this disclosure, R 10 Selected from H and methyl; p is 0, 1 or 2;

[0094] Each R 11 They are either the same or different, and are independently selected from F, Cl, and CF3.

[0095] In a more preferred embodiment, the compound of formula II has formula IIa or formula IIb:

[0096]

[0097] Among them, R 1 R 3 R 4 R 5 R 6 R 7 R 10 R 11 A, W, m, n, and p have the definitions described above, and the bolded chemical bonds indicate that the compound has axial chirality.

[0098] In some embodiments, the compound represented by formula I, Ia, Ib, II, IIa or IIb, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein W is N.

[0099] In some embodiments, a compound according to Formula I, Formula la, or Formula lb, racemates, stereoisomers, tautomers, isotopically labeled derivatives, solvates, pharmaceutically acceptable salts, or prodrugs thereof, wherein R 2 is -OR 81 ; R 83 is -OR 81 ; and R 83 and R 6-8 are the same or different, each being independently selected from the group consisting of C 1-3 aryl-C 1-3 alkyl, 5-6 membered heteroaryl-C 6-8 alkyl, C 6-8 aryl, and 5-6 membered heteroaryl; wherein C 1-3 aryl, 5-6 membered heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from each other halogen, halogen-C 1-3 alkyl, C 1-3 alkyl, and C 1-3 alkoxy; and the C 2 alkyl moiety is attached to O or NH.

[0100] In some embodiments, a compound according to Formula I, Formula la, or Formula lb, racemates, stereoisomers, tautomers, isotopically labeled derivatives, solvates, pharmaceutically acceptable salts, or prodrugs thereof, wherein R 81 ; R 81 is C6 aryl-C 1-3 alkyl or 6 membered heteroaryl-C 1-3 alkyl; wherein C6 aryl or 6 membered heteroaryl is unsubstituted or optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from each other halogen, halogen-C 1-3 alkyl, C 1-3 alkyl, and C 1-3 alkoxy; and the C 1-3 alkyl moiety is attached to O.

[0101] In some embodiments, a compound according to Formula I, Formula la, Formula lb, Formula II, Formula Ila, or Formula lib, racemates, stereoisomers, tautomers, isotopically labeled derivatives, solvates, pharmaceutically acceptable salts, or prodrugs thereof, wherein is R 5 is selected from the group consisting of halogen, -OH, -C 1-3 alkyl, -C 1-3 alkoxy, oxo (=0), -C(O)C 1-3 alkyl, -C(O)OH, -C(O)NR 91a R 91b , -S(O)2R 92 , and -S(O)2NR 93a R93b R 91a R 91b R 92 R 93a R 93b are the same or different, independently of each other, selected from the group consisting of H, C 1-3 alkyl and C 3-6 cycloalkyl.

[0102] In some embodiments, the compound of Formula I, Formula la, Formula lb, Formula II, Formula Ila, or Formula lib, racemates, stereoisomers, tautomers, isotopically labeled is R 5 is selected from the group consisting of F, -OH, methyl, methoxy, -C(O)C 1-3 alkyl, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -S(O)2CH3, -S(O)2CH2CH3, and -S(O)2-cyclopropane.

[0103] In some embodiments, the compound of Formula I, Formula la, Formula lb, Formula II, Formula Ila, or Formula lib, racemates, stereoisomers, tautomers, isotopically labeled

[0104]

[0105] In some embodiments, the compound of Formula I, Formula la, Formula lb, Formula II, Formula Ila, or Formula lib, racemates, stereoisomers, tautomers, isotopically labeled 1 is halogen.

[0106] In some embodiments, the compound of Formula I, Formula la, Formula lb, Formula II, Formula Ila, or Formula lib, racemates, stereoisomers, tautomers, isotopically labeled 3 is C 1-3 alkyl.

[0107] In some embodiments, the compound of Formula I, Formula la, Formula lb, Formula II, Formula Ila, or Formula lib, racemates, stereoisomers, tautomers, isotopically labeled 4 is halogen or C 1-3 alkyl.

[0108] In some embodiments, the compound of Formula I, Formula la, Formula lb, Formula II, Formula Ila, or Formula lib, racemates, stereoisomers, tautomers, isotopically labeled derivatives, solvates, pharmaceutically acceptable salts, or prodrugs thereof, wherein R 6 is H or halogen.

[0109] According to embodiments of the present disclosure, the compound of Formula I has the following structure:

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] wherein the * in the structure of compound 10 and 63 indicates the presence of cis-trans structure, and the * is one of cis or trans. According to embodiments of the present disclosure, the compound of Formula I has the following structure:

[0122]

[0123]

[0124] wherein the * in the structure of compound 10-P1 or 10-P2 and 63-P1 or 63-P2 indicates the presence of cis-trans structure, and the * is one of cis or trans.

[0125] The present disclosure also provides a method for preparing a compound of Formula I, comprising:

[0126] Scheme 1: Compound a1 and compound a2 undergo a coupling reaction to obtain a compound of Formula I.

[0127] The reaction scheme is as follows:

[0128]

[0129] wherein Y is Cl or Br; W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n and ring A independently of each other have the definitions described above.

[0130] Scheme II: when W is N and R7 is H, compound b1 is reacted with compound b2 to obtain a compound of formula I;

[0131] The reaction is as follows:

[0132]

[0133] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n and ring A independently of each other have the definitions described above.

[0134] According to an embodiment of the present disclosure, the reaction is carried out in the presence of an inorganic base; the inorganic base is selected from one of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.

[0135] According to an embodiment of the present disclosure, when R5 is OH, the OH in compound b2 can be protected by a silicon protecting group, which can be a tert-butyldiphenylsilyl group; the silicon protecting group is removed in the reaction to obtain a deprotected OH.

[0136] The present disclosure also provides use of at least one of the compounds of formula I, its racemate, stereoisomer, tautomer, isotopically-labeled, solvate, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a medicament.

[0137] According to an embodiment of the present disclosure, the medicament can be a medicament for treating and / or preventing a disease related to p38 kinase inhibitors, for example, an MK2 inhibitor or a p38 MAPK / MK2 pathway modulator.

[0138] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of formula I, its racemate, stereoisomer, tautomer, isotopically-labeled, solvate, pharmaceutically acceptable salt or prodrug compound thereof.

[0139] According to embodiments of the present disclosure, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0140] According to embodiments of the present disclosure, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0141] The carrier includes a disintegrant, such as methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, carboxypropylcellulose, starch, etc.; a lubricant, including calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, etc.; a binder, including gelatin, polyethylene glycol, sugar, gum, starch, hydroxypropylcellulose, etc.; a diluent, including mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, and starch; a surfactant, including polysorbate 80, sodium dodecyl sulfate, talc, and silicon dioxide. The composition of the present disclosure can be formulated by using methods known in the art, so as to provide the effect of immediate release, sustained release, or delayed release of the active ingredient after administration to a patient.

[0142] The present disclosure also provides the use of a compound represented by Formula I, a racemate, a stereoisomer, a tautomer, an isotopically-labeled material, a solvate, a pharmaceutically acceptable salt, or a prodrug compound thereof, in the treatment and / or prevention of a disease mediated by a p38 kinase inhibitor.

[0143] The present disclosure also provides a method for treating and / or preventing a disease mediated by a p38 kinase inhibitor, comprising administering to a patient a therapeutically or prophylactically effective amount of at least one of a compound represented by Formula I, a racemate, a stereoisomer, a tautomer, an isotopically-labeled material, a solvate, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0144] According to embodiments of the present disclosure, the disease can be a disease associated with the p38 MAPK / MK2 pathway, such as autoimmune and inflammatory diseases (e.g., rheumatoid arthritis, hidradenitis suppurativa, psoriasis, inflammatory bowel disease, idiopathic dermatitis, systemic lupus erythematosus, etc.), bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergy and asthma, Alzheimer's disease, and hormone-related diseases.

[0145] Advantages

[0146] The compounds of the present disclosure have good modulation of the p38 MAPK / MK2 pathway and good selectivity. In addition, the compounds of the present disclosure have good pharmacokinetic properties, etc. Furthermore, the compounds of the present disclosure can be used for treating diseases mediated by a p38 kinase inhibitor, and for preparing a medicament for such diseases or conditions.

[0147] Definitions and explanations of terms

[0148] Unless otherwise indicated, the definitions of groups and terms in the present disclosure and claims, including the definitions of examples, illustrative examples, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and incorporated with each other in any manner. The group definitions and compound structures after such combination and incorporation should be understood as within the scope recited in the present disclosure and / or claims.

[0149] Unless otherwise indicated, numerical ranges recited in the specification and claims, such as those quantifying relative amounts of components, are inclusive of the recited integer values. For example, a numerical range of "1-20" is intended to include every integer value between and including 1 and 20. In addition, when a certain numerical range is defined as "a number", it should be understood that both endpoints of the range, every integer within the range, and every decimal within the range are recited. For example, "a number from 0 to 10" should be understood to recite not only every integer from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least every integer multiplied by 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

[0150] It should be understood that herein, in describing one, two, or more, "more" should mean greater than 2, such as an integer of 3 or more, such as 3, 4, 5, 6, 7, 8, 9, or 10.

[0151] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0152] The term "C 1-10 The term "alkyl" is understood to mean a straight or branched chain saturated monovalent hydrocarbon group having from 1 to 10 carbon atoms. For example, straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms are meant, "C 1-6 The term "alkyl" is understood to mean a straight or branched chain saturated monovalent hydrocarbon group having from 1 to 10 carbon atoms. For example, straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms are meant, "C

[0153] The term "alkoxy" denotes -O-(alkyl), wherein alkyl is as defined herein. Preferred is an alkoxy group containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (C 1-12 alkoxy), more preferred is an alkoxy group containing 1 to 6 carbon atoms (C 1-6 alkoxy). Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0154] The term "C 2-10 alkenyl" is to be understood as preferably denoting a straight-chained or branched one- valent hydrocarbon group which contains one or more double bonds and which has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-8 alkenyl". C 2-10 alkenyl" is to be understood as preferably denoting a straight-chained or branched one- valent hydrocarbon group which contains one or more double bonds and which has 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. 2, 3, 4, 5 or 6 carbon atoms (i.e. C 2-6 alkenyl", 2 or 3 carbon atoms (i.e. C 2-3Alkynyl" is understood to preferably mean a straight-chain or branched univalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C2-C8-alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C2-C6-alkynyl"), 2 or 3 carbon atoms ("C2-C3-alkynyl"). Alkynyl groups are, in particular, C2-C6-alkynyl. Examples are acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,1-dimethyl- prop-2-ynyl, 1-ethylprop-1-ynyl, 1-propylprop-1-ynyl, 1-isopropylprop-1-ynyl.

[0155] The term "C 2-10 Alkynyl" is understood to preferably mean a straight-chain or branched univalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C2-C8-alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C2-C6-alkynyl"), 2 or 3 carbon atoms ("C2-C3-alkynyl"). Alkynyl groups are, in particular, C2-C6-alkynyl. Examples are acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,1-dimethyl- prop-2-ynyl, 1-ethylprop-1-ynyl, 1-propylprop-1-ynyl, 1-isopropylprop-1-ynyl. 2-8 Alkynyl" is understood to preferably mean a straight-chain or branched univalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C2-C8-alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C2-C6-alkynyl"), 2 or 3 carbon atoms ("C2-C3-alkynyl"). Alkynyl groups are, in particular, C2-C6-alkynyl. Examples are acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,1-dimethyl- prop-2-ynyl, 1-ethylprop-1-ynyl, 1-propylprop-1-ynyl, 1-isopropylprop-1-ynyl. 2-6 Alkynyl" is understood to preferably mean a straight-chain or branched univalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C2-C8-alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C2-C6-alkynyl"), 2 or 3 carbon atoms ("C2-C3-alkynyl"). Alkynyl groups are, in particular, C2-C6-alkynyl. Examples are acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,1-dimethyl- prop-2-ynyl, 1-ethylprop-1-ynyl, 1-propylprop-1-ynyl, 1-isopropylprop-1-ynyl. 2-3alkynyl groups). Said alkynyl groups are, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, said alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0156] The term "C 3-20 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, spiro, bridged) or tricyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C 3-12 Cycloalkyl", more preferably "C 3-8 Cycloalkyl". The term "C 3-12 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, spiro, bridged) or tricyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Said C 3-12 Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic, bicyclic (e.g. fused, spiro, bridged) or tricyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C

[0157] The term "3-20 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic (e.g., fused, spiro, bridged) or tricyclic ring system, and contains at least one, e.g., 1, 2, 3, 4, 5 or more, heteroatoms selected from O, S, and N, wherein N and S can also be optionally oxidized to various oxidation states to form a nitrogen oxide, -S(O)-, or -S(O)2- state. Preferably, the heterocyclyl group can be selected from "3-12 membered heterocyclyl". The term "3-12 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S, and N. The heterocyclyl group can be attached to the remainder of the molecule by any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl group can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl group can include, but is not limited to: a 3-membered ring, such as an oxiranyl group; a 4-membered ring, such as an azetidinyl, oxetanyl group; a 5-membered ring, such as a tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl group; or a 6-membered ring, such as a tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl group; or a 7-membered ring, such as a diazepanyl group. Optionally, the heterocyclyl group can be benzo-fused. The heterocyclyl group can be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl group can be partially unsaturated, i.e., it can contain one or more double bonds, such as, but not limited to, a dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, l,2,3,5-tetrahydrooxazolyl, or 4H-[l,4]thiazinyl group, or it can be benzo-fused, such as, but not limited to, a dihydroisoquinolinyl group. The 3-12 membered heterocyclyl group can be attached to other groups through a carbon atom on the 3-12 membered heterocyclyl group or through a heteroatom on the 3-12 membered heterocyclyl ring when the 3-12 membered heterocyclyl group is attached to other groups to form a compound of the disclosure. For example, when the 3-12 membered heterocyclyl group is selected from a piperazinyl group, the nitrogen atom on the piperazinyl group can be attached to other groups. Or when the 3-12 membered heterocyclyl group is selected from a piperidinyl group, the nitrogen atom on the piperidinyl ring and the carbon atom ortho to the nitrogen atom can be attached to other groups.

[0158] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0159] The term "fused" refers to a ring system in which two rings share two ring atoms.

[0160] The term "bridged" refers to a ring system in which two rings share three or more ring atoms.

[0161] The term "C 6-14 aryl-C 1-10 alkyl" means a C 6-14 aryl-substituted C 1-10 alkyl, the point of attachment being at the C 1-10 alkyl.

[0162] The term "5-14 membered heteroaryl-C 1-10 alkyl" means a C 1-10 alkyl, the point of attachment being at the C 1-10 alkyl.

[0163] The term "aryl" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing a pair of adjacent carbon atoms) ring having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to a heteroaryl, heterocyclyl, or cycloalkyl ring as described herein, where the ring that is connected to the parent structure is the aryl ring, non-limiting examples of which include:

[0164] The aryl group can be substituted or unsubstituted.

[0165] The term "heteroaryl" means a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl rings fused to an aryl, heterocyclyl, or cycloalkyl ring as described herein, where the ring that is connected to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0166] The heteroaryl group can be substituted or unsubstituted.

[0167] The terms "alkyl," "alkoxy," "cycloalkyl," "heterocyclyl," "aryl," and "heteroaryl" and the like as used herein can be substituted or unsubstituted; when substituted, it can be substituted at any available attachment point with one or more of the same or different substituents, preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0168] Pharmaceutically acceptable salts of the compounds described in this disclosure may be inorganic or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form inner salts.

[0169] The compounds disclosed herein may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures and other mixtures, as well as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure.

[0170] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that no configuration has been specified. Indicates absolute configuration, that is, if chiral isomers exist in the chemical structure, the bonds... It can be Or simultaneously include Two configurations, This indicates the presence of axial chirality.

[0171] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0172] Furthermore, the compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactamimide isomerization. All tautomer forms of all compounds disclosed herein are within the scope of this disclosure. The name of a compound named in a single manner does not exclude any tautomer.

[0173] This disclosure also includes compounds of this disclosure with the same structure as those described herein, but with one or more atoms replaced by isotopes having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure.

[0174] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare compounds in their deuterated form, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0175] The "therapeutic effective amount" of this disclosure refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians seek in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). For the purposes of this disclosure, "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0176] The term "pharmaceutically acceptable" is used herein to describe and

[0177] The term "patient" as used herein refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, goats, horses, or primates, most preferably humans. DETAILED DESCRIPTION

[0178] The technical solutions of the present disclosure will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained the present disclosure, and should not be interpreted as limiting the scope of protection of the present disclosure. Any technology achieved based on the above description of the present disclosure is covered within the scope intended to be protected by the present disclosure.

[0179] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0180] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shift (δ) is given in units of 10 -6 (ppm). The NMR was measured by Bruker ASCEND TM -400 nuclear magnetic instrument, and the measuring solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0181] The MS was measured by Agilent 6110, Agilent 1100, Agilent 6120, and Agilent G6125B liquid chromatograph-mass spectrometer.

[0182] The HPLC was measured by Shimadzu HPLC-2010C high performance liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um chromatographic column).

[0183] The chiral HPLC analysis was measured by THARSFC X5.

[0184] The thin layer chromatography silica gel plate was Yantai Qingdao GF254 silica gel plate, and the specification of the silica gel plate used in the thin layer chromatography (TLC) was 0.15mm-0.2mm, and the specification of the thin layer chromatography separation and purification product was 0.4mm-0.5mm.

[0185] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0186] High performance liquid preparation uses Waters 2767, Waters 2545, and Innovative constant LC3000 preparation chromatograph.

[0187] Chiral preparation column chromatography uses Shimadzu LC-20AP, THAR SF C PREP 80.

[0188] CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

[0189] Pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0190] Microwave reaction uses Biotage initiator+ microwave reactor.

[0191] In the experimental examples, unless otherwise specified, the reactions were carried out under argon or nitrogen atmosphere.

[0192] Argon or nitrogen atmosphere refers to connecting a about 1 liter volume of argon or nitrogen balloon to the reaction bottle.

[0193] Hydrogen atmosphere refers to connecting a about 1 liter volume of hydrogen balloon to the reaction bottle.

[0194] In the experimental examples, unless otherwise specified, the reaction temperature is room temperature, and the temperature range is 20-30℃.

[0195] The asterisk (*) in the chemical structure formula in the reaction scheme indicates that there is cis-trans isomerism at the specific ring structure position (those skilled in the art can understand that there is cis-trans isomerism in the substituted cycloalkane structure), and the exemplary cis-trans isomerism is as follows:

[0196] The * is one of cis or trans.

[0197] Those skilled in the art should understand that the chiral compounds separated can be distinguished by the order of retention time in the chiral chromatographic column, therefore, the chiral compounds separated according to the order of retention time are distinguished by the number suffix P1, P2. That is, the suffix P1 corresponds to the chiral structure separated first, and the suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of the compound is listed in the reaction formula, it does not mean that it corresponds one by one to the compound with the number suffix P1, P2, and only indicates the two existing forms of absolute configuration. The absolute configuration of the compound with the number suffix P1, P2 is subject to the absolute configuration corresponding to the specific retention time.

[0198] Synthesis of intermediate compound A-5

[0199]

[0200] First step: synthesis of compound A-5b

[0201] Sulfoxyl chloride (22.43 g, 188.5 mmol) was slowly added dropwise to a solution of compound A-5a (20 g, 125 mol) in ethanol (60 mL), and the reaction mixture was carried out at 60 °C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent to obtain compound A-5b (20 g) as a crude product, which was directly used in the next step. MS m / z (ESI): 187.9 [M+1] + .

[0202] Second step: synthesis of compound A-5c

[0203] Compound A-5b (16 g, 85.6 mmol) was dissolved in ethanol (60 mL), and sodium borohydride (6.48 g, 171.2 mmol) was slowly added portionwise to the solution at 0 °C. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 5) to obtain compound A-5c (16 g, yield: 73.5%). MS m / z (ESI): 146.1 [M+1] + .

[0204] Third step: synthesis of compound A-5

[0205] Sulfoxyl chloride (1.77 g, 0.015 mol) was slowly added to a solution of compound A-5c (1.8 g, 0.0124 mol) and N,N-dimethylformamide (5 drops) in dichloromethane (50 mL) at room temperature, and the reaction mixture was carried out at room temperature for 1 hour. After the reaction was completed, ammonium chloride solution (100 mL, 4 M) was added to the reaction solution to adjust the pH value to neutral, then water (20 mL) was added and extracted with dichloromethane (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 5 / 1) to obtain compound A-5 (1.8 g, yield: 84.68%). 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 2.4 Hz, 1H), 7.26 (ddd, J = 9.1, 8.0, 2.6 Hz, 1H), 4.72 (d, J = 2.1 Hz, 2H).

[0206] Synthesis of intermediate compound A:

[0207]

[0208] First Step: Synthesis of Compound A-2

[0209] A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (141 mL, 141 mmol) was slowly added to a solution of compound A-1 (20 g, 141 mmol) in tetrahydrofuran (500 mL) at -78 °C. After the reaction solution was stirred at -78 °C for 1 h, acetyl chloride (6.6 g, 844 mmol) was slowly added dropwise. The resulting mixture was stirred at -78 °C for another 1 h. After the reaction was completed, the reaction solution was slowly poured into saturated aqueous ammonium chloride solution (500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound A-2 (6.6 g, yield: 30%). MS m / z (ESI): 185.1 [M+1] + .

[0210] Second Step: Synthesis of Compound A-4

[0211] A solution of compound A-2 (8.98 g, 48.7 mmol) and compound A-3 (4.63 g, 32.5 mmol) in 1,4-dioxane (150 mL) was heated to 90 °C and stirred for 3.5 h. After the reaction solution was naturally cooled to room temperature, methanesulfonic acid (3.12 g, 32.5 mmol) was added, and then the reaction was heated to 50 °C and stirred for another 3 h. After the reaction was completed, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was collected and dried to give compound A-4 (5.6 g, yield: 69%). MS m / z (ESI): 251.0 [M+1] + .

[0212] Third Step: Synthesis of Compound A-6

[0213] To a solution of compound A-5 (4.01 g, 24.6 mmol) in N,N-dimethylformamide (80 mL) was added compound A-4 (5.6 g, 22.3 mmol), potassium carbonate (7.69 g, 55.7 mmol) and 18-crown-6 (1.18 g, 4.4 mmol). The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound A-6 (8.4 g, yield 80%) as a crude product which was used directly in the next step. MS m / z (ESI): 378.0 [M+1] + .

[0214] Fourth Step: Synthesis of compound A-8

[0215] To a solution of compound A-6 (8.4 g, 22.2 mmol) and tributyl(1-ethoxyvinyl)tin (compound A-7) (10.21 g, 24.2 mmol) in 1,4-dioxane (100 mL) was added dichlorobis(triphenylphosphine)palladium (1.56 g, 2.22 mmol) and the reaction was heated to 130°C and stirred for 4 hours. Then the reaction was filtered and the filtrate was directly concentrated under reduced pressure. To the residue was added tetrahydrofuran (100 mL) and 5 mL of concentrated hydrochloric acid was added dropwise and stirred for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (ethyl acetate) to give compound A-8 (5 g, yield: 60%). MS m / z (ESI): 386.0 [M+1] + .

[0216] Fifth Step: Synthesis of compound A-9

[0217] To a solution of compound A-8 (5 g, 13 mmol) and N-chlorosuccinimide (1.9 g, 14.3 mmol) in isopropanol (100 mL) was added acetic acid (2 mL) dropwise and the reaction was stirred at 60°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (ethyl acetate) to give compound A-9 (3.6 g, yield: 70%). MS m / z (ESI): 420.0 [M+1] + .

[0218] Sixth Step: Synthesis of compound A

[0219] N, N-dimethylformamide dimethyl acetal (0.85 g, 7.2 mmol) was added to a solution of compound A-9 (1.3 g, 3.1 mmol) in N, N-dimethylformamide (15 mL), and the reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 50 / 1) to give compound A (900 mg, yield: 78%). MS m / z (ESI): 474.9 [M+H] + .

[0220] Synthesis of intermediate compound B:

[0221]

[0222] First step: Synthesis of compound B-2

[0223] Diphenyl phosphorazide (23.5 g, 0.085 mol) was added to a mixture of compound B-1 (10 g, 0.057 mol) and triethylamine (17.3 g, 0.17 mol) in tert-butanol / toluene (50 mL / 50 mL), and the reaction mixture was stirred at 110 °C for 16 hours. After the reaction was completed, the reaction mixture was poured into water, and extracted with dichloromethane (200 mL x 3). The combined organic phase was washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound B-2 (3.6 g, yield: 25%). MS m / z (ESI): 247.0 [M+1] + .

[0224] Second step: Synthesis of compound B-3

[0225] Compound B-2 (3.6 g, 14.5 mol) was added to a mixture of trifluoroacetic acid / dichloromethane (15 mL / 30 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound B-3 crude (3.1 g). MS m / z (ESI): 147.0 [M+1] + .

[0226] Third step: Synthesis of compound B-4

[0227] Silver sulfate (6.61 g, 0.02 mol) and iodine (5.38 g, 0.02 mol) were added to a solution of compound B-3 (3.1 g, 0.02 mol) in ethanol (50 mL), and the reaction was stirred at 50 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound B-4 (4.9 g, yield: 65%). MS m / z (ESI): 272.7 [M+1] + .

[0228] Fourth step: synthesis of compound B-6

[0229] Methylboronic acid (530 mg, 8.8 mmol), cesium carbonate (8.96 g, 27.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (450 mg, 0.55 mmol) were sequentially added to a solution of compound B-4 (1.5 g, 5.5 mmol) in 1,4-dioxane (30 mL) under nitrogen protection, and the reaction mixture was subjected to 100 °C for 1.5 hours. After the reaction was completed, sodium bicarbonate aqueous solution was added to the reaction solution for dilution, and extraction was performed with ethyl acetate (50 mL x 3). The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain compound B-6 (0.43 g, yield: 48%). MS m / z (ESI): 161.0 [M+1] + .

[0230] Fifth step: synthesis of compound B-7

[0231] Compound B-6 (1.2 g, 6.88 mmol) was added to a solution of compound A-5 (850 mg, 5.29 mmol) in anhydrous 1,4-dioxane (8 mL), and the reaction mixture was heated to 110 °C and stirred at this temperature for 1 hour. After the reaction solution was naturally cooled to 50 °C, methyl sulfonic acid (285 mg, 2.96 mmol) was added, and then the reaction was continued at 50 °C for 1 hour. After the reaction was completed, water (50 mL) was added to the reaction solution for dilution, and extraction was performed with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (dichloromethane) to obtain compound B-7 (530 mg, yield: 66%). MS m / z (ESI): 269.0 [M+1] + .

[0232] Sixth step: synthesis of compound B-8

[0233] Potassium carbonate (1.14 g, 8.28 mmol), 18-crown-6 (175 mg, 0.66 mmol) were added to a solution of compound A-5 (702 mg, 4.30 mmol) and compound B-7 (890 mg, 3.31 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was heated to 40°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound B-8 (1.5 g, purity: 84%, yield: 96%) as a crude product, which was directly used in the next reaction. MS m / z (ESI): 395.8 [M+1] + .

[0234] Seventh step: synthesis of compound B-9

[0235] Compound A-7 (2.01 g, 5.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (257 mg, 0.37 mmol) were added to a solution of compound B-8 (1.45 g, 3.70 mmol) in 1,4-dioxane (20 mL), and the reaction mixture was stirred at 130°C for 1.5 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to give compound B-9 (3.9 g) as a crude product, which was directly used in the next reaction. MS m / z (ESI): 431.9 [M+1] + .

[0236] Eighth step: synthesis of compound B-10

[0237] Compound B-9 (1.45 g, 3.40 mmol) was added to a solution of tetrahydrofuran (15 mL) and concentrated hydrochloric acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to give B-10 (910 mg, yield: 66%). MS m / z (ESI): 403.9 [M+1] + .

[0238] Ninth step: synthesis of compound B-11

[0239] N-chlorosuccinimide (330 mg, 2.48 mmol) and glacial acetic acid (0.2 mL) were added to a solution of compound B-10 (910 mg, 2.25 mmol) in isopropanol (12 mL) successively, and the reaction mixture was stirred at 60 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain compound B-11 (1.13 g). MS m / z (ESI): 437.8 [M+1] + .

[0240] Tenth step: synthesis of compound B

[0241] N,N-dimethylformamide dimethyl acetal (600 mg, 5.0 mmol) was added to a solution of compound B-11 (1.08 g, 2.5 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was naturally cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound B (900 mg, yield: 72%). MS m / z (ESI): 492.7 [M+1] + .

[0242] Synthesis of compound 1 of example 1

[0243]

[0244] First step: synthesis of compound 1-2

[0245] Compound A (200 mg, 0.42 mmol) was added to a solution of compound 1-1 (191.5 mg, 0.84 mmol) and potassium carbonate (232.9 mg, 1.684 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was heated to 60 °C and stirred at the temperature for 18 hours. After the reaction was completed, the reaction solution was naturally cooled to room temperature, diluted with ethyl acetate (40 mL), and then washed with saturated brine (20 mL x 5). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (methanol / dichloromethane = 1 / 10) to obtain compound 1-2 (200 mg, yield: 71%). MS m / z (ESI): 661.0 [M+23] + .

[0246] Second step: synthesis of compound 1-3

[0247] Compound 1-2 (280 mg) was added to trifluoroacetic acid / dichloromethane (3 mL / 6 mL) mixed solution, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (methanol / dichloromethane = 1:10) to obtain compound 1-3 (220 mg, yield: 84%). MS m / z (ESI): 538.7 [M+1] + .

[0248] Third step: Synthesis of compound 1

[0249] Paraformaldehyde (55 mg) and glacial acetic acid (0.1 mL) were added to a methanol (5 mL) solution of compound 1-3 (110 mg), and after stirring at room temperature for 0.5 hours, sodium cyanoborohydride (39 mg) was added and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by high performance liquid chromatography (preparative column: Xbridge-C18; 150 x 21.2 mm, 5 μm; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 15-40%) to obtain compound 1 (25.5 mg, yield: 22%). MS m / z (ESI): 553.0 [M+1] + . 1 H NMR (400 MHz, CD3OD): δ 8.90 (d, J = 5.2 Hz, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.80-7.72 (m, 1H), 6.86 (s, 1H), 5.54 (d, J = 1.6 Hz, 2H), 3.42-3.33 (m, 2H), 3.22-3.10 (m, 1H), 2.84 (t, J = 11.2 Hz, 2H), 2.70 (s, 3H), 2.32-2.22 (m, 3H), 2.20 (s, 3H), 2.19-2.12 (m, 1H), 2.08 (s, 3H).

[0250] Synthesis of compound 2, 2-P1 and 2-P2 of example 2

[0251]

[0252] To a solution of compound 1-3 (90 mg, 0.16 mmol) and triethylamine (67.59, 0.67 mmol) in dichloromethane (8 mL) was added acetic anhydride (51.15 mg, 0.50 mmol) and the reaction was stirred at room temperature for 12 h. After completion of the reaction, the reaction was concentrated under reduced pressure, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) and preparative HPLC (column: Xbridge-Gemini-C18, 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid) gradient: 30-60%) to give compound 2 (43.8 mg, yield: 43.77%). MS m / z (ESI): 580.8 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ 8.88 (d, J = 5.3 Hz, 1H), 8.83 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.42 (s, 1H), 8.29 (dd, J = 5.3, 2.3 Hz, 1H), 7.81-7.72 (m, 1H), 6.84 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 4.69-4.57 (m, 1H), 4.06 (d, J = 11.8 Hz, 1H), 3.31-3.16 (m, 2H), 2.84 (t, J = 12.7 Hz, 1H), 2.19 (s, 3H), 2.17-2.05 (m, 8H), 2.04-1.83 (m, 2H).

[0253] Compound 2 was separated by supercritical fluid preparative chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250 mm x 20 mm, 5 μm; mobile phase: 40% methanol (methanol / carbon dioxide, 0.2% ammonia); total flow rate: 12.5 g / min) to give compound 2-P1 (19.4 mg) and compound 2-P2 (18.6 mg).

[0254] Compound 2-P1:

[0255] MS m / z (ESI): 581.1 [M+H] + ; SFC: retention time = 4.08 min, UV = 214 nm; 1H NMR (400 MHz, CD3OD) δ 8.83 (d, J = 5.2 Hz, 1H), 8.79 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.25 (dd, J = 5.3, 2.3 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.64 - 4.50 (m, 1H), 4.06 - 3.97 (m, 1H), 3.21 (ddd, J = 15.4, 11.1, 7.8 Hz, 2H), 2.80 (t, J = 12.8 Hz, 1H), 2.15 (s, 3H), 2.11 - 2.05 (m, 5H), 2.04 (s, 3H), 2.01 - 1.86 (m, 2H).

[0256] Compound 2-P2:

[0257] MS m / z (ESI): 581.1 [M+H] + ; SFC: Retention time = 5.51 min, UV = 214 nm; 1 H NMR (400 MHz, CD3OD) δ 8.83 (dd, J = 5.3, 0.6 Hz, 1H), 8.79 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 8.25 (dd, J = 5.3, 2.2 Hz, 1H), 7.76 - 7.66 (m, 1H), 6.81 (s, 1H), 5.49 (d, J = 2.0 Hz, 2H), 4.58 (ddd, J = 13.0, 5.4, 3.2 Hz, 1H), 4.00 (dd, J = 18.6, 12.5 Hz, 1H), 3.26 - 3.15 (m, 2H), 2.87 - 2.74 (m, 1H), 2.15 (s, 3H), 2.10 (m, 5H), 2.04 (m, 3H), 1.99 - 1.84 (m, 2H).

[0258] Synthesis of compound 3 and 3-P1 and 3-P2 of example 3

[0259]

[0260] Compound 3-1 (134 mg, 1.05 mmol) and potassium carbonate (218 mg, 1.57 mmol) were added to a solution of compound A (250 mg, 0.52 mmol) in N,N-dimethylformamide (5 mL). The reaction was heated to 60 °C and stirred at this temperature for 16 h. After the reaction was completed, the reaction was poured into water and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by removing the solvent under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Xbridge-C18, 150 x 21.2 mm, 5 μm; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%) to give compound 3 (121.2 mg, yield: 47%). MS m / z (ESI): 540.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J = 5.2 Hz, 1H), 8.83 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.34 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 8.11-8.04 (m, 1H), 6.79 (s, 1H), 5.45 (d, J = 1.5 Hz, 2H), 3.96-3.87 (m, 2H), 3.43 (td, J = 11.6, 2.4 Hz, 2H), 3.15-3.04 (m, 1H), 2.05 (s, 3H), 1.93 (s, 3H), 1.91-1.79 (m, 4H).

[0261] Compound 3 was resolved by supercritical fluid preparative chromatography (equipment: SFC Thar prep 80; column: chiralpak-AD; mobile phase: 40% isopropyl alcohol (isopropyl alcohol / carbon dioxide, 0.2% ammonia water), flow rate: 12.5 g / min) to give compound 3-P1 (62.1 mg, yield 21%) and compound 3-P2 (59.1 mg, yield 20%).

[0262] Compound 3-P1:

[0263] MS m / z (ESI): 540.2 [M+1] + ; SFC: retention time = 3.42 min, UV = 214 nm; 1H NMR (400 MHz, CD3OD): δ 8.88 (d, J = 5.3 Hz, 1H), 8.84 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.41 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.80-7.71 (m, 1H), 6.85 (s, 1H), 5.54 (d, J = 1.8 Hz, 2H), 4.12-4.03 (m, 2H), 3.62 (dt, J = 13.0, 6.7 Hz, 2H), 3.27-3.17 (m, 1H), 2.20 (s, 3H), 2.12-1.95 (m, 7H).

[0264] Compound 3-P2:

[0265] MS m / z (ESI): 540.2 [M+1] + ; SFC: Retention time = 4.64 min, UV = 214 nm; 1 H NMR (400 MHz, CD3OD): δ 8.88 (d, J = 5.3 Hz, 1H), 8.84 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.41 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.80-7.71 (m, 1H), 6.85 (s, 1H), 5.54 (d, J = 1.8 Hz, 2H), 4.12-4.03 (m, 2H), 3.62 (dt, J = 13.0, 6.7 Hz, 2H), 3.27-3.17 (m, 1H), 2.20 (s, 3H), 2.12-1.95 (m, 7H).

[0266] Synthesis of compound 4 of example 4

[0267]

[0268] Potassium carbonate (87.32 mg, 0.63 mmol) and compound 4-1 (63.44 mg, 0.42 mmol) were added to a solution of compound A (100 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by high performance liquid preparative chromatography (column: Xbridge-C18, 150 x 21.2 mm, 5 μm; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-60%) to obtain compound 4 (36.6 mg, yield: 31.7%). MS m / z (ESI): 525.8 [M+1] + . 1 H NMR (400 MHz, CD3OD): δ 8.83 (dd, J = 5.2, 0.9 Hz, 1H), 8.80 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.26 (dd, J = 5.2, 0.9 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.81 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.23 - 4.14 (m, 1H), 4.133.99 (m, 2H), 3.94 - 3.86 (m, 1H), 3.85 - 3.76 (m, 1H), 2.39 (ddd, J = 13.5, 6.7, 1.4 Hz, 2H), 2.15 (s, 3H), 2.04 (d, J = 0.7 Hz, 3H).

[0269] Synthesis of compound 6 of example 5

[0270]

[0271] Potassium carbonate (116 mg, 0.84 mmol) and compound 6-1 (62 mg, 0.42 mmol) were added to a solution of compound A (100 mg, 0.21 mmol) in N,N-dimethylformamide (3 mL), the reaction mixture was heated to 60 °C and stirred at this temperature for 16 h. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by removing the solvent under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Xbridge-C18, 150 x 21.2 mm, 5 μm; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 50-70%) to give compound 6 (35.3 mg, yield: 32%). MS m / z (ESI): 524.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J = 5.2 Hz, 1H), 8.86 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 8.14-8.07 (m, 1H), 6.83 (s, 1H), 5.49 (s, 2H), 3.40-3.33 (m, 1H), 2.10 (s, 3H), 2.08-2.00 (m, 2H), 1.96 (s, 3H), 1.94-1.86 (m, 2H), 1.83-1.72 (m, 2H), 1.71-1.59 (m, 2H).

[0272] Synthesis of compound 7 of example 6

[0273]

[0274] Potassium carbonate (186.25 mg, 1.35 mmol) and compound 7-1 (81.2 mg, 0.67 mmol) were added to a solution of compound A (160 mg, 0.34 mmol) in N,N-dimethylformamide (2 mL), and the reaction mixture was heated to 60 °C and stirred at this temperature for 18 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (30 mL x 5), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (Gemini-C18, 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid) = 45-60%; UV: 214 nm) to give compound 7 (43 mg, yield: 25.2%). MS m / z (ESI): 496.0 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 8.85 (s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H), 8.14-8.08 (m, 2H), 6.83 (s, 1H), 5.50 (s, 2H), 2.33-2.24 (m, 1H), 2.09 (s, 3H), 1.96 (s, 3H), 1.18-1.15 (m, 1H), 1.12-1.06 (m, 3H).

[0275] Synthesis of compound 8 of example 7

[0276]

[0277] Potassium carbonate (87.32 mg, 0.63 mmol) and compound 8-1 (56.7 mg, 0.42 mmol) were added to a solution of compound A (100 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated to 80 °C and stirred at this temperature for 12 h. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Xbridge-C18, 150 x 21.2 mm, 5 um; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-60%) to give compound 8 (52.9 mg, yield: 47.8%). MS m / z (ESI): 509.8 [M+1] + . 1H NMR (400 MHz, CD3OD) δ 8.83-8.78 (m, 2H), 8.44 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.22 (d, J = 5.3 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 2.0 Hz, 2H), 3.91-3.79 (m, 1H), 2.57-2.44 (m, 2H), 2.41-2.31 (m, 2H), 2.15 (s, 3H), 2.13-2.06 (m, 1H), 2.06-2.03 (m, 3H), 1.99-1.89 (m, 1H).

[0278] Synthesis of compound 9 of example 8

[0279]

[0280] First Step: Synthesis of compound 9-2

[0281] Sodium borohydride (200 mg, 5 mmol) was slowly added to a solution of compound 9-1 (1 g, 10 mmol) in methanol (15 mL) under ice-bath. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 9-2 (560 mg, yield: 57%). 1 H NMR (400 MHz, CDCl3): δ 4.28-4.18 (m, 1H), 2.79-2.69 (m, 2H), 2.62-2.51 (m, 1H), 2.37-2.26 (m, 2H).

[0282] Second Step: Synthesis of compound 9-4

[0283] Compound 9-3 (1.56 g, 5.68 mmol) was added to a solution of compound 9-2 (460 mg, 4.74 mmol) and imidazole (644 mg, 9.47 mmol) in dichloromethane (15 mL), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction was diluted with water (30 mL) and extracted with dichloromethane (20 mL x 3), and the combined organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 9-4 (1.2 g, yield: 80%). MS m / z (ESI): 358.0 [M+23] + .

[0284] Third Step: Synthesis of compound 9-5

[0285] Compound 9-4 (100 mg, 0.29 mmol) in methanol (27 mg, 0.89 mmol) was added dropwise hydrochloric ether solution (2.0 M, 5 mL), the reaction mixture was stirred at room temperature for 16 hours, the reaction was concentrated under reduced pressure, added to the ammonia methanol solution (7.0 M, 5 mL), the reaction was continued at room temperature for 3 hours. After the reaction was completed, the reaction was directly concentrated under reduced pressure to obtain compound 9-5 (41 mg, yield 39%) crude, which was directly used in the next step. MS m / z (ESI): 353.0 [M+1] + .

[0286] Fourth step: synthesis of compound 9

[0287] Compound 9-5 (39 mg, 0.110 mmol) was added to compound A (35 mg, 0.073 mmol) in N,N-dimethylformamide (5 mL), the reaction was heated to 100°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by thin plate chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 9 (8.7 mg, yield: 15%). MS m / z (ESI): 525.7 [M+1] + ; 1 H NMR (400 MHz, CD3OD): δ 8.82-8.77 (m, 2H), 8.46-8.41 (m, 2H), 8.24 (d, J = 5.2 Hz, 1H), 7.74-7.67 (m, 1H), 6.82 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.25-4.21 (m, 1H), 3.26-3.24 (m, 1H), 2.75-2.62 (m, 2H), 2.51-2.31 (m, 2H), 2.16 (s, 3H), 2.05 (s, 3H).

[0288] Synthesis of compound 10, 10-P1 & compound 10-P2 of example 9

[0289]

[0290] First step: synthesis of compound 10-2

[0291] To a solution of compound 10-1 (500 mg, 5.2 mmol) in toluene (15 mL) was added titanium tetrachloride (6.3 mL, 6.3 mmol) and methyl lithium lithium chloride complex (2.0 M, 3.2 mL, 6.3 mmol) slowly at -5 °C, the reaction system was naturally warmed to room temperature and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into saturated aqueous ammonium chloride solution (30 mL) to quench, extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 10-2 (230 mg) as a crude product, which was directly used in the next step.

[0292] Second step: synthesis of compound 10-3

[0293] Hydroxylamine aqueous solution (50%, 2 mL) was added to a solution of compound 10-2 (160 mg, 1.44 mmol) in ethanol (5 mL), the reaction was heated to 75 °C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to give compound 10-3 (300 mg) as a crude product, which was directly used in the next step. MS m / z (ESI): 145.1 [M+H] + .

[0294] Third step: synthesis of compound 10-4

[0295] Under nitrogen protection at room temperature, Raney nickel (400 mg) was added to a solution of compound 10-3 (200 mg, 1.39 mmol) in methanol (8 mL). The reaction was carried out under normal pressure for 12 hours under hydrogen atmosphere at room temperature. After the reaction was completed, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to give compound 10-4 (160 mg) as a crude product, which was directly used in the next step. MS m / z (ESI): 129.1 [M+H] + .

[0296] Fourth step: synthesis of compounds 10-P1 and 10-P2

[0297] Compound 10-4 (160 mg, 1.11 mmol) and potassium carbonate (262 mg, 1.89 mmol) were added to a solution of compound A (300 mg, 0.63 mmol) in N,N-dimethylformamide (15 mL), the reaction was heated to 90 °C and stirred at this temperature for 12 h. After the reaction was completed, the reaction mixture was poured into water (30 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with water (20 mL x 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by high performance liquid preparative chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-55%, column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 10 (70 mg).

[0298] The compound 10 was chiral split by supercritical fluid preparative chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250mm*20mm, 5 μm; mobile phase: 40% ethanol (ethanol / carbon dioxide, 0.2% ammonia water); flow rate: 12.5 g / min) to give compound 10-P1 (15.7 mg, yield: 4.6%) and 10-P2 (17.2 mg, yield: 5.1%).

[0299] Compound 10-P1:

[0300] MS m / z (ESI): 539.8 [M+1] + ; SFC: Retention time = 2.66 min, UV = 214 nm; 1 H NMR (400 MHz, CD3OD): δ 8.79 (d, J = 5.1 Hz, 2H), 8.48-8.42 (m, 2H), 8.23 (d, J = 5.3 Hz, 1H), 7.75-7.67 (m, 1H), 6.81 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 3.41-3.30 (m, 1H), 2.63-2.50 (m, 2H), 2.39-2.44 (m, 2H), 2.15 (s, 3H), 2.05 (s, 3H), 1.44 (s, 3H).

[0301] Compound 10-P2:

[0302] MS m / z (ESI): 539.8 [M+1] + ; SFC: Retention time = 3.22 min, UV = 214 nm; 1H NMR (400 MHz, CD3OD): δ 8.79 (d, J = 5.2 Hz, 2H), 8.49-8.42 (m, 2H), 8.23 (d, J = 5.3 Hz, 1H), 7.68-7.72 (m, 1H), 6.82 (d, J = 0.6 Hz, 1H), 5.49 (d, J = 1.9 Hz, 2H), 3.38-3.31 (m, 1H), 2.55 (dd, J = 10.7, 9.7 Hz, 2H), 2.47-2.36 (m, 2H), 2.15 (s, 3H), 2.05 (s, 3H), 1.44 (s, 3H).

[0303] Synthesis of compound 14, 14-G1 and 14-G2 of example 10

[0304]

[0305] First step: synthesis of compound 14-2

[0306] To a solution of compound 14-1 (2.0 g, 16.20 mmol) in toluene (50 mL) was added titanium tetrachloride (19.4 mL, 19.40 mmol, 1 M) and methyl lithium (9.7 mL, 19.40 mmol, 2 M) slowly at -5 °C, after the addition was completed, the reaction was allowed to warm to room temperature naturally and stirred at room temperature for 3 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 2) to give compound 14-2 (1.0 g, yield: 40%). 1 H NMR (400 MHz, CDCl3) δ 2.87-2.33 (m, 1H), 2.05-1.80 (m, 2H), 1.79-1.53 (m, 3H), 1.39 (m, 3H), 1.28-1.19 (m, 3H).

[0307] Second step: synthesis of compound 14-3

[0308] Hydroxylamine aqueous solution (50%, 0.5 mL) was added to a solution of compound 14-2 (200 mg, 1.4 mmol) in ethanol (5 mL), the reaction was heated to 75 °C and stirred at this temperature for 16 hours, after the reaction was completed, the reaction was directly concentrated under reduced pressure to give crude compound 14-3 (300 mg), which was directly used in the next step reaction. MS m / z (ESI): 173.1 [M+H] + .

[0309] Step 3: Synthesis of compound 14-4

[0310] Raney nickel (40 mg) was added to a solution of compound 14-3 (300 mg, 1.70 mmol) in methanol (10 mL) under nitrogen protection, the reaction was carried out at room temperature and normal pressure hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain compound 14-4 (300 mg) crude product, which was directly used in the next step. MS m / z (ESI): 157.1 [M+H] + .

[0311] Step 4: Synthesis of compound 14-G1 and 14-G2

[0312] Compound 14-4 (200 mg, 1.2 mmol) and potassium carbonate (34 mg, 2.50 mmol) were added to a solution of compound A (304 mg, 0.64 mmol) in N,N-dimethylformamide (10 mL), the reaction was heated to 90°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction mixture was poured into water (50 mL), extracted with dichloromethane (30 mL x 3), the combined organic phase was washed with water (20 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by high performance liquid preparative chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 35-45%, column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain two groups of compounds 14-G1 (10 mg, yield: 1.20%) and compound 14-G2 (20 mg, yield: 2.34%).

[0313] Compound 14-G1:

[0314] MS m / z (ESI): 568.7 [M+H] + ; HPLC: Retention time = 5.00 min, UV = 214 nm; 1 H NMR (400 MHz, CD3OD) δ 8.92 - 8.81 (m, 2H), 8.49 (d, J = 2.3 Hz, 1H), 8.41 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 7.81 - 7.70 (m, 1H), 6.85 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 3.02 - 2.93 (m, 1H), 2.20 (s, 3H), 2.11 - 2.01 (m, 5H), 1.94 - 1.78 (m, 4H), 1.67 (dd, J = 12.6, 3.9 Hz, 2H), 1.31 (s, 3H).

[0315] Compound 14-G2:

[0316] MS m / z (ESI): 568.1 [M+H] + ; HPLC: Ret Time = 5.31 min, UV = 214 nm; 1 H NMR (400 MHz, CD3OD): δ 8.91 - 8.82 (m, 2H), 8.52 - 8.44 (m, 2H), 8.33 (d, J = 5.4 Hz, 1H), 7.81 - 7.70 (m, 1H), 6.86 (s, 1H), 5.54 (d, J = 1.8 Hz, 2H), 2.92 (ddd, J = 12.6, 7.8, 3.3 Hz, 1H), 2.23 - 2.04 (m, 8H), 1.83 (t, J = 13.6 Hz, 4H), 1.63 - 1.52 (m, 2H), 1.26 (s, 3H).

[0317] Synthesis of compound 16, 16-P1 and 16-P2 of example 11

[0318]

[0319] First Step: Synthesis of compound 16-2

[0320] Under ice-bath, trimethylsilyl cyanide (11.89 g, 119.8 mmol) and zinc iodide (0.82 g, 2.56 mmol) were added to compound 16-1 (6 g, 85.6 mmol) in tetrahydrofuran (100 mL) successively. The reaction was allowed to warm to room temperature naturally and stirred at room temperature for 40 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 16-2 (5.2 g, yield: 59.5%). 1 H NMR (400 MHz, CDCl3) δ 3.55 (s, 1H), 2.71-2.57 (m, 2H), 2.42-2.28 (m, 2H), 2.05-1.88 (m, 2H).

[0321] Second Step: Synthesis of compound 16-3

[0322] Compound 16-2 (5.2 g, 53.5 mmol) was added to hydrochloric acid ethanol solution (4 M, 25 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the obtained residue was slurried with diethyl ether (20 mL), filtered, and the filter cake was collected and dried to obtain compound 16-3 (2.8 g, yield: 32.9%). MS m / z (ESI): 144.0 [M+1] +1 . 1H NMR (400 MHz, DMSO-d6): δ 11.13 (d, J = 111.0 Hz, 2H), 4.54 (q, J = 7.0 Hz, 2H), 2.43-2.20 (m, 2H), 1.98-1.65 (m, 2H), 1.49-1.31 (m, 3H).

[0323] Third Step: Synthesis of compound 16-4

[0324] Compound 16-3 (2.8 g, 19.6 mmol) was added to the ammonia ethanol solution (2 M, 30 mL), the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction liquid was filtered, the filtrate was concentrated under reduced pressure, the obtained residue was slurried with diethyl ether (15 mL), filtered, the filter cake was collected and dried to obtain compound 16-4 (1.4 g, yield: 56.1%). MS m / z (ESI): 115.1 [M+1] + .

[0325] Fourth Step: Synthesis of compound 16

[0326] Compound 16-4 (144.21 mg, 1.26 mmol) and potassium carbonate (261.92 mg, 1.895 mmol) were added to a solution of compound A (300 mg, 0.63 mmol) in N,N-dimethylformamide (5 mL), the reaction was stirred under microwave (90 °C) conditions for 2 hours. After the reaction was completed, the reaction liquid was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) and further purified by high performance liquid chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid), gradient: 40-60%) to obtain compound 16 (60 mg). MS m / z (ESI): 525.8 [M+1] + . 1 H NMR (400 MHz, CD3OD): δ 8.92 (d, J = 5.2 Hz, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.76-7.67 (m, 1H), 6.81 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 2.77-2.66 (m, 2H), 2.37 (dd, J = 10.5, 9.1 Hz, 2H), 2.16 (s, 3H), 2.04 (d, J = 5.9 Hz, 3H), 2.02-1.94 (m, 2H).

[0327] Compound 16 was purified by supercritical fluid chiral preparative chromatography (Equipment: SFC Thar prep 80; Column: CHIRALPAK AD-H 250mm*20mm, 5μιη; Mobile phase: 40% Ethanol (Ethanol / Carbon dioxide, 0.2% ammonia); Flow rate: 12.5 g / min) to give compound 16-P1 (21.8 mg) and 16-P2 (22 mg).

[0328] Compound 16-P1:

[0329] MS m / z (ESI): 525.8 [M+1] +1 Chiral HPLC: Ret Time = 6.36 min, UV = 214 nm. 1 H NMR (400 MHz, CD3OD) δ 8.92 (d, J = 5.2 Hz, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.71 (ddd, J = 9.7, 8.6, 2.4 Hz, 1H), 6.81 (d, J = 0.6 Hz, 1H), 5.49 (d, J = 2.0 Hz, 2H), 2.77 - 2.67 (m, 2H), 2.38 (dt, J = 11.8, 8.8 Hz, 2H), 2.16 (s, 3H), 2.05 (d, J = 0.5 Hz, 3H), 2.03 - 1.94 (m, 2H).

[0330] Compound 16-P2:

[0331] MS m / z (ESI): 525.8 [M+1] +1 Chiral HPLC: Ret Time = 16.05 min, UV = 214 nm. 1 H NMR (400 MHz, CD3OD) δ 8.92 (d, J = 5.2 Hz, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.81 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 2.0 Hz, 2H), 2.71 (ddd, J = 9.8, 7.2, 5.1 Hz, 2H), 2.38 (dd, J = 9.3, 3.4 Hz, 2H), 2.16 (s, 3H), 2.05 (d, J = 0.5 Hz, 3H), 2.03 - 1.94 (m, 2H).

[0332] Synthesis of compound 33, 33-P1 or 33-P2

[0333]

[0334] First step: synthesis of compound 33-2

[0335] Trimethylsilyl cyanide (3.31 g, 33.3 mmol) and zinc iodide (0.23 g, 0.71 mmol) were added to a solution of compound 33-1 (2.0 g, 23.8 mmol) in tetrahydrofuran (25 mL) successively under ice-bath. The reaction was allowed to warm to room temperature naturally and stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 33-2 (1.5 g, yield: 32.7%). 1 H NMR (400 MHz, CDCl3): δ 2.11-2.05 (m, 2H), 2.04-1.96 (m, 2H), 1.89-1.73 (m, 4H), 0.25-0.22 (m, 9H).

[0336] Second step: synthesis of compound 33-3

[0337] Compound 33-2 (1.5 g, 8.2 mmol) was added to a solution of hydrochloric acid in ethanol (4 M, 15 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was slurried with diethyl ether (15 mL), filtered, and the filter cake was collected and dried to obtain compound 33-3 (0.8 g, yield: 58.5%). MS m / z (ESI): 158.1 [M+H] + .

[0338] Third step: synthesis of compound 33-4

[0339] Compound 33-3 (0.5 g, 3.2 mmol) was added to a solution of ammonia in ethanol (2 M, 15 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was slurried with diethyl ether (15 mL), filtered, and the filter cake was collected and dried to obtain compound 33-4 (0.23 g, yield: 50.8%). MS m / z (ESI): 129.1 [M+H] + .

[0340] Fourth step: synthesis of compound 33-P1 and compound 33-P2

[0341] Compound 33-4 (162 mg, 1.26 mmol) and potassium carbonate (262 mg, 1.9 mmol) were added to a solution of compound A (300 mg, 0.63 mmol) in N,N-dimethylformamide (15 mL), the reaction was heated to 90 °C and stirred at this temperature for 12 h. After the reaction was completed, the reaction was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the obtained residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) and high performance liquid preparation chromatography (column: Gemini-C18 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%) to obtain compound 33.

[0342] Compound 33 was resolved by supercritical fluid preparation chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H, 250 mm x 20 mm, 5 um; mobile phase: 40% isopropanol (isopropanol / carbon dioxide, 0.2% ammonia water); flow rate: 15 g / min) to obtain compound 33-P1 (11.3 mg) and compound 33-P2 (14.2 mg).

[0343] Compound 33-P1:

[0344] MS m / z (ESI): 539.8 [M+H] + ; SFC: Retention time = 6.67 min, UV = 214 nm; 1 H NMR (400 MHz, CD3OD) d 8.92 (d, J = 5.2 Hz, 1H), 8.84 (s, 1H), 8.56 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.81 - 7.71 (m, 1H), 6.86 (s, 1H), 5.53 (d, J = 1.9 Hz, 2H), 2.42 - 2.26 (m, 2H), 2.20 (s, 3H), 2.10 (s, 3H), 2.06 - 1.83 (m, 6H).

[0345] Compound 33-P2:

[0346] MS m / z (ESI): 539.8 [M+H] + ; SFC: Retention time = 11.99 min, UV = 214 nm; 1H NMR (400 MHz, CD3OD) δ 8.80 (d, J = 5.2 Hz, 1H), 8.72 (s, 1H), 8.44 (s, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.64 - 7.61 (m, 1H), 6.74 (s, 1H), 5.41 (d, J = 1.9 Hz, 2H), 2.42 - 2.23 (m, 2H), 2.08 (s, 3H), 1.98 (s, 3H), 1.93 - 1.72 (m, 6H).

[0347] Synthesis of compound 41, 41-P1 and compound 41-P2 of example 13

[0348]

[0349] First step: synthesis of compound 41-2

[0350] Hydroxylamine aqueous solution (50%, 5 mL) was added to a solution of 41-1 (5.0 g, 1.4 mmol) in ethanol (5 mL), the reaction was heated to 75 °C and stirred at this temperature for 12 hours, after the reaction was completed, the reaction liquid was directly concentrated under reduced pressure to obtain the crude compound 41-2 (5.8 g), which was directly used in the next step reaction. MS m / z (ESI): 160.1 [M+H] + .

[0351] Second step: synthesis of compound 41-3

[0352] Under the protection of nitrogen, Raney nickel (3.0 g) was added to a solution of compound 41-2 (5.8 g, 27.9 mmol) in methanol (50 mL), the reaction was carried out at room temperature and under normal pressure hydrogen atmosphere for 12 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was directly concentrated under reduced pressure to obtain compound 41-3 (5.2 g) crude product, which was directly used in the next step reaction. MS m / z (ESI): 200.1 [M+H] + .

[0353] Third step: synthesis of compound 41-4

[0354] Compound 41-3 (193 mg, 0.96 mmol) and potassium carbonate (201 mg, 1.45 mmol) were added to a solution of compound A (230 mg, 0.48 mmol) in N,N-dimethylformamide (10 mL), the reaction was heated to 90 °C and stirred at this temperature for 12 h. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 41-4 (90 mg, yield: 28%). MS m / z (ESI): 510.8 [M-Boc] + .

[0355] Fourth step: synthesis of compound 41-5

[0356] Trifluoroacetic acid (84 mg, 0.74 mmol) was slowly added to a solution of compound 41-4 (90 mg, 0.15 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 12 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain compound 41-5 (70 mg) as a crude product, which was directly used in the next step. MS m / z (ESI): 510.8 [M+H] + .

[0357] Fifth step: synthesis of compound 41, compound 41-P1 and compound 41-P2

[0358] Acetic anhydride (60 mg, 0.59 mmol) was slowly added to a solution of compound 41-5 (100 mg, 0.19 mmol) and triethylamine (59 mg, 0.59 mmol) in dichloromethane (8 mL), and the reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, then poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to high performance liquid chromatography (preparative column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 41 (50 mg).

[0359] Compound 41 was purified by supercritical fluid preparation chromatography (equipment: SFC Thar prep 80; column: CHIRALPAK AD-H 250 mm x 20 mm, 5 pm; mobile phase: 40% methanol (methanol / carbon dioxide, 0.2% ammonia); flow rate: 12.5 g / min) to give compound 41-P1 (19 mg in 17.6% yield) and compound 41-P2 (17 mg in 15.7% yield).

[0360] Compound 41-P1

[0361] MS m / z (ESI): 552.8 [M+H] + ; SFC: Retention time = 6.33 min, UV = 214 nm; 1 H NMR (400 MHz, CD3OD) δ 8.90 (dd, J = 5.2, 4.3 Hz, 1H), 8.81 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.30 (dd, J = 5.3, 1.1 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (s, 1H), 5.48 (d, J = 1.9 Hz, 2H), 4.57 (ddd, J = 14.7, 8.7, 4.3 Hz, 2H), 4.40 - 4.30 (m, 2H), 4.16 (ddd, J = 8.8, 5.9, 2.8 Hz, 1H), 2.15 (s, 3H), 2.03 (s, 3H), 1.87 (s, 3H).

[0362] Compound 41-P2

[0363] MS m / z (ESI): 552.8 [M+H] + ; SFC: Retention time = 13.32 min, UV = 214 nm; 1 H NMR (400 MHz, CD3OD) δ 8.90 (dd, J = 5.2, 4.4 Hz, 1H), 8.81 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.31 (dd, J = 5.2, 1.2 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.81 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.57 (ddd, J = 14.7, 8.8, 4.1 Hz, 2H), 4.40 - 4.30 (m, 2H), 4.17 (ddd, J = 8.9, 5.9, 2.9 Hz, 1H), 2.15 (s, 3H), 2.04 (s, 3H), 1.87 (s, 3H).

[0364] Example 14: Synthesis of compound 63, 63-P1 or 63-P2

[0365]

[0366] First Step: Synthesis of compound 63

[0367] Compound 10-4 (104 mg, 0.81 mmol) and potassium carbonate (168 mg, 1.2 mmol) were added to a solution of compound B (200 mg, 0.41 mmol) in N,N-dimethylformamide (15 mL), the reaction was heated to 90 °C and stirred at this temperature for 12 h. After the reaction was completed, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-65%, column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 63 (65 mg).

[0368] Compound 63 was purified by supercritical fluid preparative chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250 mm x 20 mm, 5 um; mobile phase: 40% ethanol (ethanol / carbon dioxide, 0.2% ammonia water), total flow rate: 40 g / min) to give compound 63-P1 (25.3 mg, yield: 11.2%) and compound 63-P2 (26.7 mg, yield: 11.8%).

[0369] Compound 63-P1:

[0370] MS m / z (ESI): 557.8 [M+1] + ; SFC: Retention time = 2.90 min, UV = 220 nm; 1H NMR (400 MHz, CD3OD) δ 8.89 (d, J = 5.3 Hz, 1H), 8.73 (d, J = 0.5 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.75 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.91 (s, 1H), 5.55 (d, J = 1.9 Hz, 2H), 3.42 (dd, J = 17.0, 8.6 Hz, 1H), 2.59 (dd, J = 15.0, 5.7 Hz, 2H), 2.53 - 2.44 (m, 2H), 2.25 (s, 3H), 2.16 (s, 3H), 1.48 (s, 3H).

[0371] Compound 63-P2:

[0372] MS m / z (ESI): 557.8 [M+1] + ; SFC: Retention time = 5.56 min, UV = 220 nm; 1 H NMR (400

[0373] MHz, CD3OD) δ 8.77 (d, J = 5.3 Hz, 1H), 8.61 (d, J = 0.6 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.63 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.78 (d, J = 0.6 Hz, 1H), 5.42 (d, J = 1.9 Hz, 2H), 3.31 (t, J = 8.3 Hz, 1H), 2.53 - 2.42 (m, 2H), 2.41 - 2.32 (m, 2H), 2.13 (s, 3H), 2.04 (s, 3H), 1.36 (s, 3H).

[0374] Synthesis of compound 58 of example 15

[0375]

[0376] First step: synthesis of compound 58-1

[0377] Triflic anhydride (2.37 g, 8.4 mmol) was slowly added to a solution of compound A-4 (1.2 g, 4.2 mmol) and triethylamine (1.27 g, 12.6 mmol) in dichloromethane (20 mL). The reaction was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 5) to obtain compound 58-1 (0.35 g, yield: 64%). MS m / z (ESI): 416.9 [M+1] +.

[0378] Step 2: Synthesis of compound 58-4

[0379] Compound 58-2 (205 mg, 1.45 mmol) was added to a solution of compound 58-1 (500 mg, 1.2 mmol) in 1,4-dioxane (10 mL), the reaction was heated to 90 °C and stirred at this temperature for 12 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 58-3 (1.3 g, yield: 71.4%). MS m / z (ESI): 409.9 [M+1] + .

[0380] Step 3: Synthesis of compound 58-4

[0381] Bis(triphenylphosphine)palladium dichloride (68 mg, 0.1 mmol) was added to a solution of compound 58-3 (200 mg, 0.48 mmol) and compound A-7 (704 mg, 1.95 mmol) in 1,4-dioxane / water (10 mL / 1 mL), the reaction was heated to 110 °C and stirred at this temperature for 3 h. After the reaction was completed, the reaction was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, the obtained residue was purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound 58-4 (0.11 g, yield: 48%). MS m / z (ESI): 446.1 [M+1] + .

[0382] Step 4: Synthesis of compound 58-5

[0383] Compound 58-4 (120 mg, 0.67 mmol) was dissolved in a solution of tetrahydrofuran / hydrochloric acid (5 mL / 1 mL), the reaction was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure, the obtained residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 58-5 (0.1 g, yield: 80.4%). MS m / z (ESI): 418.1 [M+1] + .

[0384] Step 5: Synthesis of compound 58-6

[0385] Compound 58-5 (100 mg, 0.24 mmol) was added to a solution of N,N- dimethylformamide dimethyl acetal (42 mg, 0.36 mmol) in N,N-dimethylformamide (10 mL), the reaction was heated to 100 °C and stirred at this temperature for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 58-6 (0.1 g, yield: 80%). MS m / z (ESI): 472.8 [M+1] + .

[0386] Sixth step: synthesis of compound 71

[0387] Compound 58-7 (108 mg, 0.84 mmol) and potassium carbonate (58 mg, 0.42 mmol) were added to a solution of compound 58-6 (100 mg, 0.21 mmol) in N,N- dimethylformamide (10 mL), the reaction was heated to 90 °C and stirred at this temperature for 16 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-70%) to obtain compound 71 (9.1 mg, yield: 7.9%). MS m / z (ESI): 538.1 [M+1] + ; 1 H NMR (400 MHz, CD3OD): δ 8.86 (d, J = 5.3 Hz, 1H), 8.80 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 7.48-7.39 (m, 1H), 7.07-6.98 (m, 2H), 6.23 (s, 1H), 4.67 (s, 2H), 4.11-4.04 (m, 2H), 3.66-3.57 (m, 2H), 3.25-3.14 (m, 1H), 2.19 (s, 3H), 2.10-1.96 (m, 4H), 1.94 (s, 3H).

[0388] Example 16 synthesis of compound 12

[0389]

[0390] First step: synthesis of compound 12-2

[0391] To a solution of compound 12-1 (234 mg, 2.0 mmol) in ethanol (5 mL) was added hydroxylamine aqueous solution (1 mL), the reaction mixture was heated to 75 °C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 12-2 (260 mg, crude). MS m / z (ESI): 151.0 [M+1] + .

[0392] Second Step: Synthesis of compound 12-3

[0393] To a solution of compound 12-2 (260 mg, 1.73 mmol) in methanol (10 mL) was added Raney nickel (508 mg), the reaction mixture was stirred under hydrogen atmosphere at normal pressure for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 12-3 (180 mg, crude). MS m / z (ESI): 135.1 [M+H] + .

[0394] Third Step: Synthesis of compound 12

[0395] To a solution of compound A (120 mg, 0.25 mmol) and compound 12-3 (68 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (104 mg, 0.75 mmol), the reaction mixture was heated to 90 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 12 (17.1 mg, yield 12.4%). MS m / z (ESI): 545.8 [M+1] + . 1H NMR (400 MHz, CD3OD) δ 8.86 (d, J = 5.3 Hz, 1H), 8.80 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 2.0 Hz, 2H), 3.70 - 3.59 (m, 1H), 3.08 - 2.91 (m, 4H), 2.15 (s, 3H), 2.04 (d, J = 0.5 Hz, 3H).

[0396] Synthesis of compound 37

[0397]

[0398] Potassium carbonate (252 mg, 1.82 mmol) was added to a solution of intermediate B (300 mg, 0.61 mmol) and intermediate 16-4 (139 mg, 1.2 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was heated to 90 °C under microwave conditions for 2 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 ~ 10:1) to obtain a crude product, which was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 37 (17.7 mg, yield: 5.1%). MS m / z (ESI): 543.7 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 8.86 (d, J = 5.3 Hz, 1H), 8.80 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 7.71 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.80 (d, J = 0.5 Hz, 1H), 5.49 (d, J = 2.0 Hz, 2H), 3.70 - 3.59 (m, 1H), 3.08 - 2.91 (m, 4H), 2.15 (s, 3H), 2.04 (d, J = 0.5 Hz, 3H).

[0399] Synthesis of compound 38

[0400]

[0401] Compound B (200 mg, 0.4 mmol) and compound 33-4 (400 mg 3 mmol) in N,N- dimethylformamide (15 mL) was added potassium carbonate (405 mg 3 mmol), the reaction mixture was heated to 90 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-10:1) to obtain a crude product, which was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 38 (22 mg, yield 15%). MS m / z (ESI): 558.1 [M+1] + . 1 HNMR (400 MHz, CD3OD) δ 8.98 (d, J = 5.3 Hz, 1H), 8.75 (s, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.76 (ddd, J = 9.6, 8.6, 2.4 Hz, 1H), 6.91 (s, 1H), 5.55 (d, J = 1.9 Hz, 2H), 2.41 - 2.30 (m, 2H), 2.26 (s, 3H), 2.16 (s, 3H), 2.04 - 1.89 (m, 6H).

[0402] Synthesis of compound 42 of example 19

[0403]

[0404] To a solution of compound 41-5 (35 mg, 0.068 mmol) and triethylamine (21 mg, 0.21 mmol) in dichloromethane (5 mL) was added propionyl chloride (13 mg, 0.14 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-36%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 42 (16.7 mg, yield: 42%). MS m / z (ESI): 556.8 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 9.01 - 8.89 (m, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.35 (dd, J = 5.2, 1.4 Hz, 1H), 7.80 - 7.72 (m, 1H), 6.84 (d, J = 1.9 Hz, 1H), 5.53 (d, J = 1.8 Hz, 2H), 4.60 (dt, J = 14.4, 8.7 Hz, 2H), 4.46 - 4.32 (m, 2H), 4.26 - 4.14 (m, 1H), 2.26 - 2.12 (m, 5H), 2.07 (d, J = 1.7 Hz, 3H), 1.10 (dt, J = 9.2, 7.6 Hz, 3H).

[0405] Example 20 Synthesis of compound 43

[0406]

[0407] Isobutyryl chloride (25 mg, 0.23 mmol) was added dropwise to a solution of compound 41-5 (60 mg, 0.12 mmol) and triethylamine (36 mg, 0.35 mmol) in dichloromethane (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 43 (16.7 mg, yield: 12.5%). MS m / z (ESI): 580.8 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.94 (dd, J = 6.7, 5.3 Hz, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.41 (d, J = 4.1 Hz, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.81 - 7.72 (m, 1H), 6.85 (d, J = 2.6 Hz, 1H), 5.53 (s, 2H), 4.68 (t, J = 8.6 Hz, 1H), 4.60 (dd, J = 8.6, 5.8 Hz, 1H), 4.41 (t, J = 9.5 Hz, 1H), 4.36 - 4.27 (m, 1H), 4.25 - 4.13 (m, 1H), 2.60 (dd, J = 13.6, 6.8 Hz, 1H), 2.20 (d, J = 1.8 Hz, 3H), 2.07 (d, J = 2.0 Hz, 3H), 1.11 (dd, J = 6.8, 3.2 Hz, 3H), 1.05 (dd, J = 14.0, 6.8 3.2 Hz, 3H).

[0408] Synthesis of compound 44

[0409]

[0410] First Step: Synthesis of compound 44-2

[0411] Hydroxylamine aqueous solution (0.5 mL) was added to a solution of compound 44-1 (200 mg, 1.0 mmol) in ethanol, and the reaction mixture was heated to 80 °C and stirred for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 44-2 (300 mg, crude). MS m / z (ESI): 230.1 [M+H]+ .

[0412] Step 2: Synthesis of compound 44-3

[0413] Raney nickel (30 mg) was added to a solution of compound 44-2 (300 mg, 1.3 mmol) in methanol (10 mL), and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 12 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 44-3 (300 mg, crude). MS m / z (ESI): 214.1 [M+H] + .

[0414] Step 3: Synthesis of compound 44-4

[0415] Potassium carbonate (260 mg, 1.9 mmol) was added to a solution of compound 44-3 (200 mg, 0.93 mmol) and compound A (356 mg, 0.75 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated to 90 °C and stirred for 12 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 1:0 ~ 10:1) to give compound 44-4 (90 mg, yield: 13%). MS m / z (ESI): 525.0 [M-100] + .

[0416] Step 4: Synthesis of compound 44-5

[0417] Hydrogen chloride solution in 1,4-dioxane (4 M, 2 mL) was added to a solution of compound 44-4 (70 mg, 0.11 mmol) in dichloromethane (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give compound 44-5 (100 mg, crude). MS m / z (ESI): 525.2 [M+H] + .

[0418] Step 5: Synthesis of compound 44

[0419] Acetic anhydride (20 mg, 0.19 mmol) was added to a solution of compound 44-5 (70 mg, 0.13 mmol) and triethylamine (27 mg, 0.26 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 15-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 44 (10 mg, yield: 12.6%). MS m / z (ESI): [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.91 (d, J = 5.2 Hz, 1H), 8.85 (s, 1H), 8.49 (dd, J = 2.2, 1.1 Hz, 1H), 8.43 - 8.30 (m, 2H), 7.80 - 7.71 (m, 1H), 6.85 (s, 1H), 5.54 (s, 2H), 4.14 - 3.63 (m, 5H), 2.56 - 2.30 (m, 2H), 2.20 (s, 3H), 2.08 (dd, J = 11.2, 5.0 Hz, 6H).

[0420] Synthesis of compound 66, 66-P1, 66-P2, 66-P3 and 66-P4 of Example 22

[0421]

[0422] First step: synthesis of compound 66-2

[0423] Compound 66-1 (3 g, 23 mmol) was added to a solution of ammonia in ethanol (150 mL), and the reaction mixture was stirred at 90 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 66-2 (3 g, yield: 90%). MS m / z (ESI): 130.3 [M+1] + .

[0424] Second step: synthesis of compound 66-3

[0425] Compound 66-3 (5.78 g, 20.4 mmol) and sodium cyanide (2 g, 40.8 mmol) in dimethyl sulfoxide (40 mL) were heated to 110 °C and stirred at the temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 1:0 ~ 10:1) to obtain compound 66-4 (400 mg, yield: 13%). + .

[0426] Third Step: Synthesis of compound 66-4

[0427] Compound 66-3 (5.78 g, 20.4 mmol) and sodium cyanide (2 g, 40.8 mmol) in dimethyl sulfoxide (40 mL) were heated to 110 °C and stirred at the temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 1:0 ~ 10:1) to obtain compound 66-4 (400 mg, yield: 13%). 1 H NMR (400 MHz, CD3OD) δ 3.30-3.21 (m, 2H), 2.68 (s, 3H), 2.64-2.51 (m, 2H), 2.50-2.42 (m, 2H).

[0428] Fourth Step: Synthesis of compound 66-5

[0429] Hydroxylamine aqueous solution (1 mL) was added to a solution of compound 66-4 (400 mg, 2.89 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain compound 66-5 (350 mg, yield: 56%). MS m / z (ESI): 172.1 [M+1] + .

[0430] Fifth Step: Synthesis of compound 66-6

[0431] Raney nickel (1.2 g, 20 mmol) was added to a solution of compound 66-5 (350 mg, 2 mmol) and acetic acid (122 mg, 2 mmol) in methanol (15 mL), and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 66-6 (300 mg, yield: 89%). MS m / z (ESI): 156.2 [M+1] + .

[0432] Step 6: Synthesis of compound 66

[0433] Potassium carbonate (232 mg, 1.68 mmol) was added to a solution of compound 66-6 (196 mg, 1.26 mmol) and compound A (200 mg, 0.42 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 90 °C for 16 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 1:0 ~ 10:1) to obtain a crude product, which was separated by supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH / CO2(NH4OH 0.2%), total flow rate: 40 g / min) to obtain compound 66-P1 (16.3 mg, yield 6.8%), compound 66-P2 (7.4 mg, yield 3.1%), compound 66-P3 (14.7 mg, yield 6.1%), and compound 66-P4 (8.2 mg, yield 3.4%).

[0434] Compound 66-P1:

[0435] MS m / z (ESI): 566.8 [M+1] + Supercritical fluid chromatography SFC: retention time = 7.2 min, UV = 214 nm. 1 HNMR (400 MHz, CD3OD) δ 8.73 (d, J = 5.3 Hz, 2H), 8.40 - 8.34 (m, 2H), 8.17 (d, J = 5.3 Hz, 1H), 7.68 - 7.59 (m, 1H), 6.74 (s, 1H), 5.42 (d, J = 1.8 Hz, 2H), 3.69 - 3.59 (m, 1H), 3.01 (ddd, J = 17.8, 9.6, 8.3 Hz, 1H), 2.67 - 2.54 (m, 7H), 2.08 (s, 3H), 1.98 (s, 3H).

[0436] Compound 66-P2:

[0437] MS m / z (ESI): 566.8 [M+1] + Supercritical fluid chromatography SFC: retention time = 7.9 min, UV = 214 nm. 1H NMR (400 MHz, CD3OD) δ 8.88 (d, J = 5.3 Hz, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.43 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.81 - 7.72 (m, 1H), 6.85 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 3.91 (dt, J = 14.8, 7.2 Hz, 1H), 3.31 - 3.24 (m, 1H), 2.75 - 2.58 (m, 7H), 2.20 (s, 3H), 2.09 (s, 3H).

[0438] 14.8,7.2Hz,1H),3.31–3.24(m,1H),2.75–2.58(m,7H),2.20(s,3H),2.09(s,3H)。

[0439] Compound 66-P3:

[0440] MS m / z (ESI): 566.8 [M+1] + Supercritical fluid chromatography SFC: Retention time = 8.56 min, UV = 214 nm. 1 H NMR (400 MHz, CD3OD) δ 8.85 (d, J = 5.3 Hz, 1H), 8.85 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.43 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.81 - 7.72 (m, 1H), 6.85 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 3.91 (dt, J = 14.8, 7.2 Hz, 1H), 3.31 - 3.24 (m, 1H), 2.75 - 2.58 (m, 7H), 2.20 (s, 3H), 2.09 (s, 3H).

[0441] Compound 66-P4:

[0442] MS m / z (ESI): 566.8 [M+1] + Supercritical fluid chromatography SFC: Retention time = 9.8 min, UV = 214 nm.1H NMR (400 MHz, CD3OD) δ 8.76 (d, J = 5.2 Hz, 1H), 8.73 (s, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 8.17 (d, J = 5.3 Hz, 1H), 7.68 - 7.60 (m, 1H), 6.73 (s, 1H), 5.41 (d, J = 1.8 Hz, 2H), 3.86 - 3.73 (m, 1H), 3.18 - 3.10 (m, 1H), 2.65 - 2.55 (m, 7H), 2.08 (s, 3H), 1.97 (s, 3H).

[0443] Synthesis of Example 23 compound 69

[0444]

[0445] First Step: Synthesis of compound 69-2

[0446] Hydroxylamine aqueous solution (1 mL) was added to a solution of compound 69-1 (500 mg, 3.93 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 69-2 (610 mg, yield: 82.3%). MS m / z (ESI): 161.1 [M+1] + .

[0447] Second Step: Synthesis of compound 69-3

[0448] Raney nickel (670 mg, 11.42 mmol) was added to a mixture of compound 69-2 (610 mg, 3.81 mmol) in methanol and acetic acid (15 mL / 1 mL), and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 69-3 (500 mg, crude). MS m / z (ESI): 145.1 [M+1] + .

[0449] Third Step: Synthesis of compound 69-4

[0450] Potassium carbonate (174 mg, 1.26 mmol) was added to a solution of compound 69-3 (182 mg, 1.26 mmol) and compound A (150 mg, 0.32 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at 75 °C for 12 h. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to obtain compound 69-4 (100 mg, yield: 54%). MS m / z (ESI): 555.7 [M+1] + .

[0451] Fourth Step: Synthesis of compound 69

[0452] Potassium peroxodisulfate (331.6 mg, 0.54 mmol) was added to a solution of compound 69-4 (100 mg, 0.18 mmol) in methanol (5 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (20 mL), extracted with diethyl ether (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 2) to obtain a crude compound 69, which was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 69 (40 mg, yield: 35.9%). MS m / z (ESI): 587.7 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 5.2 Hz, 1H), 8.83 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H), 8.19 (d, J = 5.2 Hz, 1H), 8.07 (ddd, J = 10.0, 9.0, 2.4 Hz, 1H), 6.79 (s, 1H), 5.46 (d, J = 1.7 Hz, 2H), 3.35 - 3.32 (m, 1H), 3.27 (ddd, J = 9.5, 3.8, 1.7 Hz, 2H), 3.09 (dt, J = 6.9, 6.2 Hz, 2H), 2.45 - 2.34 (m, 2H), 2.32 - 2.20 (m, 2H), 2.06 (s, 3H), 1.93 (s, 3H).

[0453] Synthesis of compound 70, 70-P1, 70-P2, 70-P3 and 70-P4 of Example 24

[0454]

[0455] First step: synthesis of compound 70-2

[0456] Sodium borohydride (1.53 g, 40.4 mmol) was added to a solution of compound 70-1 (3.5 g, 36.8 mmol) in methanol (150 mL), and the reaction mixture was stirred at 0°C for 1 hour. After the reaction was completed, the reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 70-2 (3.4 g, yield: 76%).

[0457] Step 2: Synthesis of compound 70-3

[0458] p-Toluenesulfonyl chloride (7.34 g, 38.5 mmol) was added dropwise to a solution of compound 70-2 (3.4 g, 35 mmol), 4-dimethylaminopyridine (0.86 g, 7 mmol) and triethylamine (4.25 g, 42 mmol) in dichloromethane (50 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with hydrochloric acid (1 M), extracted with dichloromethane (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 10 / 1) to give compound 70-3 (5 g, yield: 54%). 1 H NMR (400 MHz, CDC13) δ 7.77 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.81 - 4.69 (m, 1H), 2.74 - 2.59 (m, 3H), 2.59 - 2.48 (m, 2H), 2.46 (s, 3H).

[0459] Step 3: Synthesis of compound 70-4

[0460] Potassium thioacetate (3.64 g, 31.8 mmol) was added to a solution of compound 70-3 (4 g, 15.91 mmol) in N,N-dimethylformamide (40 mL), and the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 3 / 1) to give compound 70-4 (2 g, yield: 72%). 1 H NMR (400 MHz, CDC13) δ 4.31 - 4.18 (m, 1H), 3.29 - 3.25 (m, 1H), 2.93 - 2.86 (m, 2H), 2.50 - 2.42 (m, 2H), 2.31 (s, 3H).

[0461] Step 4: Synthesis of compound 70-5

[0462] Potassium carbonate (890 mg, 6.44 mmol) was added to a solution of compound 70-4 (500 mg, 3.22 mmol) in methanol (10 mL), and the reaction mixture was stirred at 50 °C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), adjusted to pH = 4 with 1 N hydrochloric acid, and extracted with ethyl acetate (15 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 3 / 1) to give compound 70-5 (600 mg, yield: 74%). 1H NMR (400 MHz, CDCI3) δ 3.81 - 3.73 (m, 2H), 3.31 - 3.11 (m, 2H), 2.83 - 2.62 (m, 4H), 2.55 - 2.35 (m, 4H).

[0463] Step 5: Synthesis of compound 70-6

[0464] Hydrochloric acid (31.2 mL, 2M) was added to a solution of compound 70-5 (700 mg, 3.12 mmol) in tetrahydrofuran (15 mL), and zinc powder (2.04 g, 3.12 mmol) was added with stirring. The reaction mixture was stirred at 45 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (10 mL), extracted with ethyl acetate (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 70-6 (320 mg, yield: 81%). 1 H NMR (400 MHz, CDCI3) δ 3.80 - 3.74 (m, 1H), 3.22 - 3.30 (m, 1H), 2.95 - 2.79 (m, 2H), 2.45 - 2.30 (m, 2H), 1.90 (d, J = 7.2 Hz, 1H).

[0465] Step 6: Synthesis of compound 70-7

[0466] Methyl iodide (1.2 g, 8.5 mmol) was added to a solution of compound 70-7 (320 mg, 2.83 mmol) and potassium carbonate (781 mg, 5.6 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 4 / 1) to give compound 70-7 (350 mg, yield: 87%). 1 H NMR (400 MHz, CDCI3) δ 3.67 - 3.56 (m, 1H), 3.36 - 3.24 (m, 1H), 2.81 - 2.69 (m, 2H), 2.40 - 2.29 (m, 2H), 2.07 (s, 3H).

[0467] Step 7: Synthesis of compound 70-8

[0468] Hydroxylamine (649 mg, 19.65 mmol) was added to a solution of compound 70-7 (500 mg, 3.93 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 70 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 70-8 (600 mg, yield: 66%). MS m / z (ESI): 161.2 [M+1] + .

[0469] Eighth step: synthesis of compound 70-9

[0470] Aluminum nickel alloy (2.650 g, 31.2 mmol) was added to a solution of compound 70-8 (500 mg, 3.12 mmol) and acetic acid (2 mL) in methanol (10 mL), and the reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 70-9 (500 mg, yield: 77%). MS m / z (ESI): 145.2 [M+1] + .

[0471] Ninth step: synthesis of compound 70-10

[0472] Compound 70-9 (455 mg, 3.15 mmol) was added to a solution of compound A (500 mg, 1.05 mmol) and potassium carbonate (436 mg, 3.15 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was stirred at 90 °C for 12 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 5 / 4) to obtain compound 70-10 (350 mg, yield: 50%). MS m / z (ESI): 555.8 [M+1] + .

[0473] Tenth step: synthesis of compound 70

[0474] Potassium peroxymonosulfate (1127 mg, 1.83 mmol) was added to a solution of compound 70-10 (340 mg, 0.61 mmol) in methanol (20 mL), the reaction mixture was stirred at room temperature for 12 hours, after the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to obtain compound 70, compound 70 was separated by supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH / CO2(NH4OH 0.2%), total flow rate: 40g / min) to obtain compound 70-P1 (16.5 mg, yield 4.6%), compound 70-P2 (6.3 mg, yield 1.7%), compound 70-P3 (23.0 mg, yield 6.4%) and compound 70-P4 (6.9 mg, yield 1.9%).

[0475] Compound 70-P1:

[0476] MS m / z (ESI): 587.7 [M+1] + Supercritical fluid chromatography SFC: retention time = 7.59 min, UV = 214 nm. 1 HNMR (400MHz, CD3OD) δ 8.87-8.79 (m, 2H), 8.44 (s, 2H), 8.25 (d, J = 5.3 Hz, 1H), 7.73-7.67 (m, 1H), 6.81 (s, 1H), 5.49 (s, 2H), 4.09-3.98 (m, 1H), 3.90-3.79 (m, 1H), 2.99 (dt, J = 12.6, 9.4 Hz, 1H), 2.92-2.81 (m, 4H), 2.78-2.66 (m, 2H), 2.15 (s, 3H), 2.06 (d, J = 0.4 Hz, 3H).

[0477] Compound 70-P2:

[0478] MS m / z (ESI): 587.7 [M+1] + Supercritical fluid chromatography SFC: retention time = 7.96 min, UV = 214 nm. 1HNMR (400 MHz, CD3OD) δ 8.90 - 8.78 (m, 2H), 8.47 - 8.39 (m, 2H), 8.27 (d, J = 5.3 Hz, 1H), 7.73 - 7.67 (m, 1H), 6.80 (s, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.13 - 3.91 (m, 2H), 2.96 - 2.88 (m, 5H), 2.88 - 2.78 (m, 2H), 2.15 (s, 3H), 2.05 (s, 3H).

[0479] Compound 70-P3:

[0480] MS m / z (ESI): 587.7 [M+1] + Supercritical fluid chromatography SFC: Retention time = 9.71 min, UV = 214 nm. 1 HNMR (400 MHz, CD3OD) δ 8.87 - 8.77 (m, 2H), 8.44 (d, J = 2.7 Hz, 2H), 8.25 (d, J = 5.3 Hz, 1H), 7.73 - 7.67 (m, 1H), 6.80 (d, J = 0.7 Hz, 1H), 5.49 (d, J = 1.9 Hz, 2H), 4.07 - 3.95 (m, 1H), 3.89 - 3.80 (m, 1H), 3.03 - 2.96 (m, 1H), 2.92 - 2.82 (m, 4H), 2.77 - 2.66 (m, 2H), 2.15 (s, 3H), 2.05 (d, J = 0.5 Hz, 3H).

[0481] Compound 70-P4:

[0482] MS m / z (ESI): 587.7 [M+1] + Supercritical fluid chromatography SFC: Retention time = 10.98 min, UV = 214 nm.1H NMR (400 MHz, CD3OD) δ 8.86 (d, J = 5.3 Hz, 1H), 8.80 (s, 1H), 8.48 - 8.38 (m, 2H), 8.27 (d, J = 5.3 Hz, 1H), 7.73 - 7.67 (m, 1H), 6.80 (s, 1H), 5.49 (d, J = 1.8 Hz, 2H), 4.12 - 3.90 (m, 2H), 2.99 - 2.78 (m, 7H), 2.15 (s, 3H), 2.04 (s, 3H).

[0483] Synthesis of Example 25 compound 76

[0484]

[0485] First step: synthesis of compound 76-2

[0486] Sulfuric chloride (813 g, 6.8 mmol) was added to a solution of compound 76-1 (800 mg, 4.6 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 60 °C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched by the addition of saturated sodium bicarbonate solution (10 mL), and concentrated under reduced pressure to remove ethanol. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was concentrated under reduced pressure to give compound 76-2 (900 mg, crude). MS m / z (ESI): 204.1 [M+H] + .

[0487] Second Step: Synthesis of compound 76-3

[0488] Sodium borohydride (334 mg, 8.8 mmol) was added to a solution of compound 76-2 (900 mg, 4.4 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 25 °C for 12 h. After the reaction was completed, the reaction solution was quenched by the addition of saturated ammonium chloride solution (5 mL) and concentrated under reduced pressure to remove ethanol. The residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was concentrated under reduced pressure to give compound 76-3 (600 mg, crude). MS m / z (ESI): 162.1 [M+H] + .

[0489] Third Step: Synthesis of compound 76-4

[0490] To a solution of compound 76-3 (100 mg, 0.62 mmol) in dichloromethane (10 mL) were added 2 drops of N,N-dimethylformamide and 0.1 mL of sulfuric chloride solution dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 76-4 (100 mg, crude).

[0491] Fourth Step: Synthesis of compound 76-5

[0492] Compound A-4 (143 mg, 0.55 mmol) was added to a solution of compound 76-4 (100 mg, 0.55 mmol) and potassium carbonate (154 mg, 1.11 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 65 °C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 2 / 1) to give compound 76-5 (100 mg, yield: 45%). MS m / z (ESI): 402.0 [M+H] + .

[0493] Step 5: Synthesis of compound 76-6

[0494] N-chlorosuccinimide (50 mg, 0.37 mmol) was added to a solution of compound 76-5 (100 mg, 0.25 mmol) in isopropanol (10 mL), and the reaction solution was stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 5 / 1) to give compound 76-6 (100 mg, yield: 92%). MS m / z (ESI): 435.9 [M+H] + .

[0495] Step 6: Synthesis of compound 76-7

[0496] N,N-dimethylformamide dimethyl acetal (55 mg, 0.46 mmol) was added to a solution of compound 76-6 (100 mg, 0.23 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 5 / 1) to give compound 76-7 (80 mg, yield: 71%). MS m / z (ESI): 491.0 [M+H] + .

[0497] Step 7: Synthesis of compound 76

[0498] Tetrahydro-pyran-4-carboxamidine (42 mg, 0.33 mmol) was added to a solution of compound 76-7 (80 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 90 °C for 16 h. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high pressure liquid preparative chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-70%, column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 76 (13.4 mg, yield: 14.7%). MS m / z (ESI): 556.1 558.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 3.9 Hz, 1H), 8.74 (s, 1H), 8.48 (d, J = 1.5 Hz, 1H), 8.31 (s, 1H), 8.21 (d, J = 3.5 Hz, 1H), 7.59 (dd, J = 8.8, 1.8 Hz, 1H), 6.42 (s, 1H), 5.43 (s, 2H), 4.11 (dd, J = 12.5, 6.0 Hz, 2H), 3.58 (t, J = 10.8 Hz, 2H), 3.19 (t, J = 10.6 Hz, 1H), 2.20 (s, 3H), 2.13-2.07 (m, 2H), 2.01-1.96 (m, 5H).

[0499] Synthesis of compound 77

[0500]

[0501] First step: synthesis of compound 77-2

[0502] Dichlorosulfoxide (813 mg, 6.83 mmol) was slowly added dropwise to a solution of compound 77-1 (800 mg, 4.56 mmol) in ethanol (15 mL), and the reaction mixture was stirred at 60 °C for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 77-2 (910 mg, crude). MS m / z (ESI): 203.9 [M+H] + .

[0503] Second step: synthesis of compound 77-3

[0504] Sodium borohydride (353.07 mg, 9.3 mmol) was added portionwise to a solution of compound 77-2 (910 mg, 4.6 mmol) in ethanol (15 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (50 mL), and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 77-3 (700 mg, crude). MS m / z (ESI): 162.0 [M+H] + .

[0505] Step 3: Synthesis of compound 77-4

[0506] To a solution of compound 77-3 (120 mg, 0.74 mmol) in dichloromethane (5 mL) were added 2 drops of N,N-dimethylformamide and 0.5 mL of a solution of thionyl chloride, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 77-4 (60 mg, crude). MS m / z (ESI): 180.7 [M+H] + .

[0507] Step 4: Synthesis of compound 77-5

[0508] Compound A-4 (110 mg, 0.42 mmol) was added to a solution of compound 77-4 (76 mg, 0.42 mmol) and potassium carbonate (117 mg, 0.85 mmol) in N,N-dimethylformamide (20 mL), and the reaction mixture was stirred at 60°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 77-5 (80 mg, yield 42%). MS m / z (ESI): 401.9 [M+H] + .

[0509] Step 5: Synthesis of compound 77-6

[0510] N-chlorosuccinimide (26 mg, 0.19 mmol) was added to a solution of compound 77-5 (80 mg, 0.91 mmol) in isopropanol (15 mL), and the reaction mixture was stirred at 60°C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0 / 1 ~ 1 / 0) to give compound 77-6 (80 mg, yield: 73%). MS m / z (ESI): 437.0 [M+H] + .

[0511] Step 6: Synthesis of compound 77-7

[0512] N,N-dimethylformamide dimethyl acetal (87 mg, 0.73 mmol) was added to a solution of compound 77-6 (80 mg, 0.18 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 50 / 1) to give compound 77-7 (35 mg, yield: 34%). MS m / z (ESI): 491.0 [M+H] + .

[0513] Step 7: Synthesis of compound 77

[0514] Tetrahydropyran-4-carboxamidine (18 mg, 0.14 mmol) was added to a solution of compound 77-7 (35 mg, 0.07 mmol) and potassium carbonate (29 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 90 °C for 12 h. After completion of the reaction, the reaction was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-70%, column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 77 (6.6 mg, yield: 14.2%). MS m / z (ESI): 556.0 558.0 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.88 (d, J = 5.3 Hz, 1H), 8.84 (s, 1H), 8.55 (d, J = 2.5 Hz, 1H), 8.41 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.97 (dd, J = 8.2, 2.5 Hz, 1H), 6.81 (s, 1H), 5.58 (s, 2H), 4.12 - 4.03 (m, 2H), 3.62 (dd, J = 17.8, 6.6 Hz, 2H), 3.27 - 3.14 (m, 1H), 2.20 (s, 3H), 2.09 - 1.96 (m, 7H).

[0515] Synthesis of compound 78, 78-P1 and 78-P2

[0516]

[0517] First step: synthesis of compound 78-1

[0518] Compound 69-3 (878 mg, 6.09 mmol) was added to a solution of compound B (500 mg, 1.01 mmol) and potassium carbonate (981 mg, 7.10 mmol) in acetonitrile (10 mL), and the reaction mixture was stirred at 75 °C for 12 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 20 / 1) to give compound 78-1 (100 mg, yield: 16%). MS m / z (ESI): 574.0 [M+1] + .

[0519] Second step: synthesis of compound 78

[0520] Potassium hydrogen persulfate (546 mg, 0.89 mmol) was added to a solution of compound 78-1 (170 mg, 0.30 mmol) in methanol (10 mL), and the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to give compound 78, which was separated by supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH / CO2(NH4OH 0.2%), total flow rate: 40 g / min) to give compound 78-P1 (15.6 mg, yield 8.26%) and compound 78-P2 (19.0 mg, yield 10%).

[0521] Compound 78-P1:

[0522] MS m / z (ESI): 606.0 [M+1] + . Super critical fluid chromatography SFC: retention time = 4.58 min, UV = 214 nm. 1 HNMR (400 MHz, CD3OD) δ 8.89 - 8.84 (m, 1H), 8.66 - 8.59 (m, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.54 - 7.52 (m, 1H), 6.58 (d, J = 0.6 Hz, 1H), 5.41 (d, J = 2.0 Hz, 2H), 3.30 -

[0523] 3.19 (m, 1H), 3.15 - 3.04 (m, 4H), 2.41 (dd, J = 12.0, 5.9 Hz, 4H), 2.15 (d, J = 0.4 Hz, 3H), 1.99 (s, 3H).

[0524] Compound 78-P2:

[0525] MS m / z (ESI): 606.0 [M+1] + . Chiral SFC: Retention time = 6.39 min, UV = 214 nm. 1 H NMR (400 MHz, CD3OD) δ 8.86 (d, J = 5.2 Hz, 1H), 8.62 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.54 - 7.52 (m, 1H), 6.58 (d, J = 0.5 Hz, 1H), 5.41 (d, J = 2.0 Hz, 2H), 3.30 - 3.20 (m, 1H), 3.16 - 3.04 (m, 4H), 2.41 (dd, J = 12.0, 5.9 Hz, 4H), 2.15 (s, 3H), 1.99 (s, 3H).

[0526] Synthesis of compound 82, 82-P1 and 82-P2 of example 28

[0527]

[0528] First step: synthesis of compound 82-2

[0529] Methylamine (2.38 g, 35.2 mmol) was added to a solution of compound 82-1 (3 g, 17.6 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.75 g, 35.2 mmol), 1-hydroxybenzotriazole (4.76 g, 35.2 mmol) and triethylamine (5.34 g, 52.8 mmol) in dichloromethane (50 mL), the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was diluted with water (150 mL), extracted with dichloromethane (100 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 5 / 2) to give compound 82-2 (1.1 g, yield: 30%). MS m / z (ESI): 184.1 [M+1] + .

[0530] Second step: synthesis of compound 82-3

[0531] Compound 82-2 (1.1 g, 6 mmol) was added to the ammonia ethanol solution (8.6 mL, 60 mmol), and the reaction mixture was placed in a sealed tube, heated to 90°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 82-3 (1 g, yield: 90%). MS m / z (ESI): 168.9 [M+1] + .

[0532] Third step: synthesis of compound 82-4

[0533] Trifluoroacetic anhydride (1.86 g, 8.8 mmol) was added to a solution of compound 82-3 (1 g, 5.9 mmol) and triethylamine (3 g, 29.5 mmol) in dichloromethane (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to obtain compound 82-4 (280 mg, yield: 28%). MS m / z (ESI): 150.9 [M+1] + .

[0534] Fourth step: synthesis of compound 82-5

[0535] Aqueous hydroxylamine solution (2 mL, 3.73 mmol) was added to a solution of compound 82-4 (280 mg, 1.86 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 82-5 (300 mg, yield: 79%). MS m / z (ESI): 184.0 [M+1] + .

[0536] Fifth step: synthesis of compound 82-6

[0537] Raney nickel (14 mg, 0.24 mmol) was added to a solution of compound 82-5 (300 mg, 1.6 mmol) and acetic acid (1 mL) in methanol (10 mL), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 82-6 (300 mg, yield: 98%). MS m / z (ESI): 168.2 [M+1] + .

[0538] Sixth step: synthesis of compound 82

[0539] Compound 82-6 (300 mg, 0.6 mmol) was added to a solution of compound A (211 mg, 1.2 mmol) and potassium carbonate (175 mg, 1.2 mmol) in N,N-dimethylformamide (10 mL), the reaction mixture was stirred at 90 °C for 12 h, after the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to obtain compound 82, compound 82 was further separated by supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH / CO2(NH4OH 0.2%), total flow rate: 40 g / min) to obtain compound 82-P1 (35.2 mg, yield 9.61%) and compound 82-P2 (36.6 mg, yield 10.61%).

[0540] Compound 82-P1:

[0541] MS m / z (ESI): 578.8 [M+1] + Supercritical fluid chromatography SFC: retention time = 2.37 min, UV = 254 nm. 1 H NMR (400 MHz, CD3OD) δ 8.89 - 8.83 (m, 2H), 8.49 (d, J = 2.3 Hz, 1H), 8.39 - 8.31 (m, 2H), 7.79 - 7.71 (m, 1H), 6.85 (s, 1H), 5.54 (d, J = 1.8 Hz, 2H), 2.77 (s, 3H), 2.43 (d, J = 12.0 Hz, 6H), 2.19 (s, 3H), 2.08 (s, 3H).

[0542] Compound 82-P2:

[0543] MS m / z (ESI): 578.8 [M+1] + Supercritical fluid chromatography SFC: retention time = 7.9 min, UV = 254 nm. 1 H NMR (400 MHz, CD3OD) δ 8.88 - 8.84 (m, 2H), 8.49 (d, J = 2.3 Hz, 1H), 8.38 - 8.32 (m, 2H), 7.79 - 7.71 (m, 1H), 6.85 (s, 1H), 5.53 (d, J = 1.8 Hz, 2H), 2.77 (s, 3H), 2.45 (s, 6H), 2.19 (s, 3H), 2.08 (s, 3H).

[0544] The following compounds were prepared according to the methods described in Examples 1-28 above:

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554] Compound C: was prepared according to the method of WO2021195475A1 Example 1.

[0555] Biological evaluation

[0556] Test Example 1. Determination of p38 MAPK / MK2 in vitro activity

[0557] The inhibition of p38 MAPK / MK2 by the compound was detected by Z-LYTE kinase detection kit (Thermo, PV3177). The test compound was dissolved in DMSO to 10 mM stock solution, and stored at -20°C for use. The starting concentration of the compound was 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, double duplicate wells; 50 mM HEPES pH 7.5, 10 mM MgCl2, 0.01% Brij-35, 1 mM EGTA was used as the reaction buffer to configure 2x active p38a / inactive MK2 / Ser / Thr 4 mixture, and the final 10 μL reaction system was carried out in a 384-well plate (Corning, 4514) containing 500 ng / mL inactive MK2 (abcam, 79910), 8 ng / mL active p38a (Carna, 04-152), 2 μM Ser / Thr 4; after 1 hour of reaction at 20°C, 5 μL of diluted 2048 times Development Reagent A was added, and after 1 hour of incubation at room temperature, 5 μL of termination buffer solution was added to terminate the reaction, and the enzyme-labeled instrument was detected (Ex. 400 nm, Em. 445 nm; Ex. 400 nm, Em. 520 nm). The concentration-effect curve was fitted by GraphPad Prism 8 software, and the compound concentration for 50% inhibition, IC50, was calculated 50 The results are shown in Table 1.

[0558] Table 1

[0559]

[0560]

[0561] From Table 1, it can be seen that the compound of the present disclosure has good inhibitory activity on p38 MAPK / MK2.

[0562] Test Example 2. In vitro activity determination of p38 MAPK / MK5

[0563] The inhibition of p38 MAPK / MK5 by the compound was detected by Z-LYTE kinase detection kit (Thermo, PV3177). The test compound was dissolved in DMSO to 10 mM stock solution, and stored at -20°C for use. The starting concentration of the compound was 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, double duplicate wells; 50 mM HEPES pH 7.5, 10 mM MgCl2, 0.01% Brij-35, 1 mM EGTA was used as the reaction buffer to configure 2x active p38a / inactive MK5 / Ser / Thr 4 mixture, and the final 10 μL reaction system was carried out in a 384-well plate (Corning, 4514) containing 10 μg / mL inactive MK5 (abcam, 217826), 1 ng / mL active p38a (Carna, 04-152), 2 μM Ser / Thr 4; after 4 hours of reaction at 20°C, 5 μL of diluted 2048 times Development Reagent A was added, and after 1 hour of incubation at room temperature, 5 μL of stop buffer solution was added to terminate the reaction, and the enzyme-labeled instrument was detected (Ex. 400 nm, Em. 445 nm; Ex. 400 nm, Em. 520 nm). The concentration-effect curve was fitted by GraphPad Prism 8 software, and the compound concentration for 50% inhibition was calculated, that is, IC 50 The results are shown in Table 2.

[0564] Table 2

[0565] Compound p38 MAPK / MK5 IC 50 (nM) Compound 3 9353 Compound 3-P1 3155 Compound 4 5729 Compound 6 3933 Compound 7 9321 Compound 8 4621 Compound 9 864 Compound 10 2894 Compound 10-P1 1980 Compound 14-G1 773.2 Compound 14-G2 2674 Compound 16-P1 8940 Compound 33-P1 679.5 Compound 42 2091 Compound 58 873.7 Compound 63-P1 5449

[0566] From Table 2, it can be seen that the p38 MAPK / MK5 inhibitory activity of the compound of the present disclosure is greater than 0.6 μM. This further indicates that the compound of the present disclosure has good selectivity for p38 MAPK / MK2.

[0567] Test Example 3. Determination of p38 MAPK / ATF2 in vitro activity

[0568] The inhibition of p38a catalyzed ATF2 by the compound was detected by HTRF method. The test compound was dissolved in DMSO to 10 mM stock solution, and stored at -20°C for use. The starting concentration of the compound was 10 μM, 0.25% DMSO, 5-fold dilution, 8 concentrations, double duplicate wells; 40 mM Tris pH 7.5, 20 mM MgCl2, 0.1 mg / mL BSA, 50 μM DTT were used as reaction buffer to prepare 3.5x p38a (MAPK14, Carna Biosciences, 04-152) protein working solution, 3.5x Human ATF2 Protein (Sino Biological, 11599-H20B) working solution and 3.5x ATP working solution, 10 mM EDTA was used to terminate the reaction, and the final 14 μL reaction system was carried out in a 96-well plate (cisbio, 66PL96025), containing 0.29 ng / μL p38a, 0.29 μM Human ATF2 Protein; 25 μM ATP. After 35 min of reaction at 20°C, the pre-prepared antibody solution (cibio, 63ADK015PEG, Phospho-ATF2 Eu Cryptate antibody, Phospho-ATF2 d2antibody, diluted 40 times with Detection buffer) was added to each well, and incubated at room temperature overnight, and then detected by microplate reader (HTRF compatible reader). The concentration-effect curve was fitted by GraphPad Prism 8 software, and the compound concentration for 50% inhibition was calculated, that is, IC 50 The results are shown in Table 3.

[0569] Table 3

[0570] Compound p38 MAPK / ATF2 IC 50 (nM) <!-- 70 -->]]> Compound 2-P1 902.7 Compound 3-P1 4715 Compound 4 28021 Compound 6 854.7 Compound 7 5389 Compound 8 1450 Compound 9 6976 Compound 10 4657 Compound 10-P1 1173 Compound 14-G1 15915 Compound 14-G2 8262 Compound 16-P1 8634 Compound 33-P1 >20000 Compound 41 >20000 Compound 63-P1 1250

[0571] From Table 3, it can be seen that the p38 MAPK / ATF2 inhibitory activity of the compound of the present disclosure is greater than 0.8 μM. This further indicates that the compound of the present disclosure has good selectivity for p38 MAPK / MK2.

[0572] Test Example 4. In vitro activity determination of TNF-α in the supernatant of human PBMC cells

[0573] The inhibition of TNF-α in the supernatant of human PBMC cells by the compound was detected by an Elisa detection kit (Biuntian, PI518). The test compound was dissolved in DMSO to a 10 mM stock solution and stored at -20°C for use. The initial concentration of the compound was 2 μM, 5-fold dilution, 6 concentrations, double-replicate wells for cell plating, single wells for Elisa detection, and the final concentration of DMSO was 0.4%. The initial concentration of the compound, the dilution factor, the number of gradient concentrations, and the number of replicate wells can also be changed according to the actual situation of the compound screening.

[0574] Fresh human peripheral blood mononuclear cells (PBMC) (Sailas Biological) were plated in a 96-well plate (Corning, 3599) at a concentration of 2*10^5 cells per well in 100 μL of RPMI-1640 (Gibco #A1049101) + 10% FBS (Gibco, 10099141C) and incubated overnight at 37°C, 5% CO2. The test compound was added to the 96-well culture plate at a volume of 25 μL / well, and after 1 h, 5 μL of LPS was added to a final concentration of 100 ng / mL. The negative control wells did not contain LPS or the compound, and the positive control wells did not contain the compound. The cells were incubated at 37°C, 5% CO2 for another 24 h, and then the cell culture supernatant was collected by centrifugation at 500 rcf for 8 min. The concentration of TNF-α was detected according to the operation manual of the Elisa kit. The concentration-effect curve was fitted by GraphPad Prism 8 software, and the compound concentration for 50% inhibition, IC50, was calculated. 50 The results are shown in Table 4.

[0575] Table 4

[0576] Compound TNF-α IC50 (nM) Compound 2 45.38 Compound 2-P1 10.39 Compound 3 41.40 Compound 3-P1 6.39 Compound 6 14.96 Compound 7 41.48 Compound 9 37.91 Compound 10 17.68 Compound 10-P1 7.58 Compound 14-G1 7.96 Compound 14-G2 4.84 Compound 16 29.15 Compound 16-P1 9.27 Compound 33-P1 22.79 Compound 37 0.61 Compound 38 0.21 Compound 41 98.84 Compound 63-P1 1.73 Compound 66-P2 24.62 Compound 70-P2 9.92 Compound 82-P2 17.27

[0577] As can be seen from Table 4, the compound of the present disclosure has a good inhibitory effect on TNF-α of human PBMC cells.

[0578] Test Example 5. In vitro CYP enzyme inhibition evaluation

[0579] The experiment adopts the cocktail method to study the inhibition of the CYP enzyme 1A2, 2B6, 2C8, 2C19, 2C9, 2D6 and 3A4 subtypes of the test compound, and the IC50 values of the activity of several CYP enzyme subtypes of the test compound are measured. The control compounds are: fluvoxamine (1A2), ketoconazole (2B6), montelukast sodium (2C8), tranylcypromine (2C19), sulfaphenazole (2C9), quinindium (2D6) and ketoconazole (3A4 / 5); the CYP enzyme probe substrates used are: phenacetin (1A2), bupropion (2B6), amodiaquine (2C8), mephenytoin (2C19), diclofenac sodium (2C9), dextromethorphan (2D6) and testosterone (3A4 / 5). The PBS buffer is a 50mM K2HPO4 buffer. The concentration of the test compound is 50μM, 12.5μM, 3.125μM, 0.781μM, 0.195μM, 0.0488μM, respectively. The corresponding probe substrate and microsomes are added to PBS, mixed uniformly, then the control compound / test compound / DMSO solution is added in the corresponding reaction system, pre-incubated at 37℃ water bath for 5min, 10mM NADPH solution is added, and placed in a 37℃ water bath for 10min, then the reaction is terminated by adding an internal standard acetonitrile solution. Centrifuge at 4000rpm, take the supernatant solution, add an equal volume of pure water, mix uniformly, and analyze the amount of each probe substrate reaction product by LC-MS / MS (AB Triple Quard 5500), and use the measured product generation amount to calculate the IC50 value by GraphPad Prism 5. The results are shown in Table 5:

[0580] Table 5

[0581]

[0582] From Table 5, it can be seen that the compounds 10-P1 and 63-P1 of the present disclosure have no inhibitory effect on in vitro CYP enzymes.

[0583] Test Example 6. Evaluation of in vitro time-dependent CYP3A4 enzyme inhibition

[0584] The experiment compares the IC50 value changes of the test compound on the CYP3A4 / 5 subtype enzyme activity inhibition under the above two conditions by pre-reaction of the test compound with the microsomal reaction system and the experimental conditions without pre-reaction, and calculates the corresponding IC50 shift value. The control compound is: Verapamil (CYP3A4 / 5), the probe substrate is: Testosterone (CYP3A4 / 5). PBS Buffer is 50mM K2HPO4 buffer. The concentration of the test compound is 50μM, 10μM, 2μM, 0.4μM, 0.08μM, 0.016μM respectively. The probe substrate and PBS solution are pre-prepared into a substrate solution (1990μL of PBS + 10μL of substrate). The microsomes are added to PBS, the samples without pre-reaction group are pre-incubated at 37℃ water bath for 30min, then the control compound / test compound / DMSO solution, 10mM NADPH solution and probe substrate solution are added in the corresponding reaction system, and placed in a 37℃ water bath for 10min, then the internal standard acetonitrile solution is added to terminate the reaction; the pre-reaction group samples are added with control compound / test compound / DMSO solution, 10mM NADPH solution in the corresponding system, mixed uniformly, placed in a 37℃ water bath for 30min, then the probe substrate solution is added, placed in a 37℃ water bath for 10min, then the internal standard acetonitrile solution is added to terminate the reaction. After centrifugation at 4000rpm, the supernatant solution is added with equal volume of pure water and mixed uniformly, and the amount of each probe substrate reaction product is analyzed by LC-MS / MS (AB Triple Quard 5500), and the measured product generation amount is used to calculate the IC50 by GraphPad Prism 5. The results are shown in Table 6:

[0585] Table 6

[0586]

[0587]

[0588] From Table 6, it can be seen that the compounds 10-P1 and 63-P1 of the present disclosure have no time-dependent CYP3A4 enzyme inhibition effect.

[0589] Test Example 7. In vitro liver microsomal stability evaluation

[0590] The control compound used in the experiment is: Ketanserin, the final concentration of microsomes in the experimental system is 0.5 mg / mL. PBS Buffer is 50 mM K2HPO4 buffer. The concentration of the test compound is 1 μM. Add microsomes to PBS, add control compound / test compound in the corresponding reaction system respectively, mix uniformly, pre-incubate in a 37°C water bath for 5 min, add 20 mM NADPH solution, start the reaction under the condition of 37°C water bath (for No NADPH samples, replace 20 mM NADPH solution with an equal volume of PBS solution). At reaction time points 0 min, 10 min, 30 min, 60 min and 90 min, respectively, take out 30 μL of reaction sample from each reaction system (for No NADPH samples, take samples at reaction time points 0 min and 90 min, respectively), immediately add 300 μL of internal standard acetonitrile solution to terminate the reaction. After centrifugation at 4000 rpm, mix equal volumes of pure water with the supernatant solution, and detect the amount of compound in each time point sample by LC-MS / MS (AB Triple Quard 5500) and calculate the T 1 / 2 The results are shown in Table 7:

[0591] Table 7

[0592]

[0593] As can be seen from Table 7, the compound 10-P1 of the present disclosure has good in vitro liver microsomal stability (human / mouse / rat).

[0594] Test Example 8. In vivo pharmacokinetic evaluation in mice

[0595] Weigh the compound and dissolve it in a mixed solvent of DMAC:Solutol:PBS=1:1:8. After intravenous / intragastric administration to mice, collect 30 μL of whole blood at 0.083, 0.25, 0.5, 1, 2, 4, 7 and 24 hours, and immediately anticoagulate with EDTA-K2. Then, centrifuge at 4000 rpm for 5 min at 4°C, take the supernatant, and freeze the sample in a -80°C refrigerator. After precipitation with a CH3CN precipitant containing an internal standard, centrifuge at 12700 rpm for 10 min, and take the supernatant for analysis by LC-MS / MS (AB Triple Quard 5500) to obtain the blood drug concentration, and calculate the parameters by a non-compartment model of Winnolin 8.1 version. The results are shown in Table 8:

[0596] Table 8

[0597]

[0598]

[0599] From Table 8, it can be seen that both the compound 10-P1 and the compound 63-P1 of the present disclosure have good exposure, in vivo clearance and bioavailability within the concentration dose and detection time range given. In intravenous injection administration, the in vivo clearance CL of the compound 10-P1 is 1241.95 mL / hr / kg, which is significantly better than the in vivo clearance CL of the compound C (2313.22 mL / hr / kg); in gavage administration, the blood drug exposure of the compound 10-P1 is 2120.68 hr*ng / mL, which is doubled compared with the blood drug exposure of the compound C; the in vivo clearance CL of the compound 63-P1 is 1492.93 mL / hr / kg, which is significantly better than the in vivo clearance CL of the compound C (2313.22 mL / hr / kg); in gavage administration, the blood drug exposure of the compound 63-P1 is 2596.40 hr*ng / mL, which is doubled compared with the blood drug exposure of the compound C. Therefore, it is shown that the compound of the present disclosure has good in vivo pharmacokinetics and is significantly better than the control compound C.

[0600] The above describes the embodiments of the present disclosure. However, the present disclosure is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present disclosure shall be included in the protection scope of the present disclosure.

Claims

1. A compound of Formula I, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in, W is either CH or N; m can be 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, or 3; Ring A is C 3-9 Cycloalkyl groups, 3-9 membered heterocyclic groups, wherein the carbon atom in ring A is connected to the parent nucleus, and the 3-9 membered heterocyclic group contains one, two or more O, N or S atoms; R 1 Selected from halogens; R 2 Selected from -OR 81 -NH-C(O)R 82 -NHR 83 and -C(O)NHR 84 ; R 3 Selected from C1-3 alkyl and C 3-6 cycloalkyl; R 4 Selected from C1-3 alkyl groups; R 5 Each is independently selected from halogens, -OH, and -C. 1-3 Alkyl, -C 1-3 Alkoxy, oxo (=O), -C(O)C 1-3 Alkyl, -C(O)OH, -C(O)NR 91a R 91b -S(O)2R 92 and -S(O)2NR 93a R 93b ; R 6 Selected from H, halogens, and methyl groups; R 7 Selected independently from H, halogen, and C. 1-3 alkyl; R 81 R 82 R 83 R 84 The same or different, independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, phenyl, pyridyl, whether unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 Rb; each Rb is the same or different, independently selected from F, Cl, CF3; R 91a R 91b R 92 R 93a R 93b They are either the same or different, and are independently selected from H and C. 1-6 Alkyl and C 3-6 Cycloalkyl.

2. The compound according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, W is either CH or N; m can be 0, 1, 2, or 3; n is 0 or 1; Ring A is selected from piperidinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxetane, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-oxetane[3.3]heptyl, 2-oxetane[3.5]nonyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, azacyclobutane, tetrahydropyrrole, thionecyclobutane, and tetrahydro-2H-thiaranyl. R 1 Selected from Cl and Br; R 2 Selected from -OR 81 -NH-C(O)R 82 -NHR 83 -C(O)NHR 84 ; R 3 Selected from methyl and cyclopropyl; R 4 Selected from methyl; R 5 Each is independently selected from F, -OH, methyl, methoxy, oxo (=O), and -C(O)C. 1-3 Alkyl, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2-cyclopropane; R 6 Selected from H, F, and Cl; R 7 Selected from H; R 81 R 82 R 83 R 84 The same or different, independently selected from unsubstituted or optionally substituted with 1, 2 or 3 Rb, phenylmethyl, pyridylmethyl, pyridylethyl, phenyl, pyridyl; each Rb is the same or different, independently selected from F, Cl, CF3.

3. The compound according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The ring A is selected from the following structures: 。 4. The compound according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The structure formed by R5 and ring A is selected from: 。 5. The compound according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound shown in Formula I has the structure shown in Formula Ia or Ib: Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 A, W, m, and n have the definitions described in claim 1.

6. The compound represented by Formula II, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: Where R 1 R 3 R 4 R 5 R 6 R 7 W, m, n and ring A independently have the definitions described in claim 1; R 10 Selected from H, C 1-6 alkyl; Each R 11 They are either the same or different, and are independently selected from F, Cl, and CF3.

7. The compound according to claim 6, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound shown in Formula ⅠI has the structure shown in Formula ⅠIa or ⅠIb: ； Among them, R 1 R 3 R 4 R 5 R 6 R 7 R 10 R 11 A, W, m, n, and p have the definitions described in claim 6.

8. The compound according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound has the following structure: In the structural formulas of compounds 10 and 63, the asterisk (*) indicates the presence of a cis-trans structure at that location, and the asterisk is either cis or trans.

9. The compound according to claim 1, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound shown in Formula I has the following structure: In the structural formulas of compounds 10-P1 or 10-P2 and 63-P1 or 63-P2, the asterisk (*) indicates the presence of a cis-trans structure at that location, and the asterisk is either cis or trans.

10. A method for preparing the compound according to any one of claims 1-9, its racemic mixture, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: Option 1: Compound a1 and compound a2 undergo a coupling reaction to obtain compound I. The reaction formula is as follows: Where Y is Cl or Br; W, R 1 R 2 R 3 R 4 R 5 R 6 R 7 m, n, and ring A independently have the definitions described in any one of claims 1-9; Option 2: When W is N and R7 is H, compound b1 reacts with compound b2 to obtain compound I. The reaction formula is as follows: Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 m, n, p and ring A independently have the definitions described in any one of claims 1-9; And / or, the reaction is carried out in the presence of an inorganic base; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide. And / or, when R 5 When the OH group is OH, the OH group in compound b2 is protected by a silicon protecting group, which is tert-butyldiphenylsilyl; the silicon protecting group is removed in the reaction to obtain deprotected OH.

11. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1-9, their racemic, stereoisomer, tautomer, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers.

12. Use of at least one of the compounds of any one of claims 1-9, their racemic, stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 11, in the preparation of a medicament; The drug is a drug for treating and / or preventing diseases associated with the p38 MAPK / MK2 pathway.

13. The use according to claim 12, characterized in that... The diseases mentioned include autoimmune and inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, and hormone-related diseases.

14. The use according to claim 13, characterized in that, The autoimmune diseases mentioned are selected from rheumatoid arthritis, psoriasis, inflammatory bowel disease, idiopathic dermatitis, and systemic lupus erythematosus; The inflammatory diseases mentioned are selected from hidradenitis suppurativa, allergies, and asthma; The neurological and neurodegenerative disease mentioned is Alzheimer's disease.

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