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] This disclosure claims priority to an earlier application filed on December 29, 2021, with China National Intellectual Property Administration, patent application number 202111642855.0, entitled "A p38 MAPK / MK2 pathway modulator and its composition, preparation method and use", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the pharmaceutical field, specifically relating to a p38 MAPK / MK2 pathway modulator, its composition, preparation method, and uses. Background Technology

[0003] Biological signal transduction involves specific protein-protein interactions and post-translational modifications, regulating genetic and epigenetic processes in response to internal and external environmental influences. Mitogen-activated protein kinases (MAPKs) are a group of serine-threonine protein kinases that can be activated by various intracellular and extracellular stresses, serving as crucial signal transducers from the cell surface to the nucleus. Stress factors include cytokines, neurotransmitters, hormones, cellular stress, and cell adhesion.

[0004] As a subfamily of the MAPK family, p38 MAPK responds to cellular signals and inflammatory cytokines. Upon activation, p38 MAPK phosphorylates and activates various downstream protein kinases and transcription factors, thereby exerting complex biological effects. p38 MAPK comprises four members: p38α, p38β, p38γ, and p38δ. Among them, p38α is considered to play a crucial role in signaling pathways during inflammation, while the biological functions of other isoforms are not fully understood, although they exhibit pleiotropic effects. Studies have shown that p38β plays an important role in cell protection mechanisms, while mitogen-activated protein kinase 3 (MAP Kinase 3) mediates the effects of p38δ on the proliferation and survival of advanced colorectal cancer (CRC) cells. As an attractive target for drug development, several inhibitors of p38 MAPK have entered clinical trials, but none have yet been approved for marketing. According to publicly available information, some candidate compounds have failed in clinical trials. The main reasons for these failures include dosage limitations to avoid toxicity, insufficient exposure of the drug molecule to its target site, downregulation of anti-inflammatory pathways, redundancy in signaling networks, or inhibition of key proteins involved in feedback regulation of other MAPK pathways. Inhibition of feedback mechanisms may upregulate other pro-inflammatory pathways, leading to increased inflammation. Therefore, developing a safe and effective p38 MAPK inhibitor is currently a major challenge in drug development in this field.

[0005] p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152),924]. Therefore, selectively inhibiting the activation of downstream effectors of p38 MAPK is a major strategy to avoid side effects / insufficient efficacy due to overall inhibition of p38 MAPK. MAPK-activated protein kinase 2 (MK2) is a direct downstream substrate of p38 MAPK and can be activated by p38α and p38β. As the first discovered p38 MAPK substrate, MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thus 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 AU-rich elements in mRNA. In a mouse model of postoperative intestinal obstruction [The Journal of Surgical Research 2013(185),102], MK2 inhibitors reduced the expression of inflammatory factors such as MIP-1α, TNF-α, IL-6, and IL-1β, and also showed reduced infiltration of polymorphonuclear leukocytes, mast cells, and monocytes / macrophages, as well as improved intestinal smooth muscle contractility. In a mouse model of collagen-induced arthritis (CIA) [Journal of Immunology 2006(177),1913], knocking out the MK2 gene reduced the incidence of CIA. Compared with wild-type mice, MK2- / - and MK2+ / - mice showed reduced incidence and severity of CIA, and the expression of inflammatory factors TNF-α and IL-6 was also reduced to varying degrees. In a MK2 knockout hypercholesterolemia mouse model [Circ Res 2007(101), 1104], the mice showed reduced lipid deposition and macrophages in the large arteries, as well as reduced expression of inflammatory factors such as VCAM-1 and MCP-1. 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, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Selective inhibition of the p38 MAPK / MK2 pathway reduces the impact on other downstream pathways of p38MAPK, thereby reducing potential toxicity and inadequate efficacy in drug development; and addresses unmet clinical needs in disease areas related to the p38MAPK / MK2 pathway. Summary of the Invention

[0007] To address the problems existing in the prior art, this disclosure provides a compound as shown in Formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt, or prodrug thereof:

[0008]

[0009] Where W is CH or N; m is an integer from 0 to 5; n is an integer from 0 to 3;

[0010] Ring A is a 3-20 member nitrogen-containing heterocyclic group, except for those with the parent nucleus. In addition to the connected N atom, it may optionally contain one, two or more heteroatoms selected from O, N or S;

[0011] R 1 Selected from H, halogens, CN and C 1-6 alkyl;

[0012] R 2 Selected from -OR 81 -NH-C(O)R 82 -NHR 83 and -C(O)NHR 84 ;

[0013] R 3 Selected from H, C 1-10 Alkyl and C 3-20 cycloalkyl;

[0014] R 4 Selected from H, halogens and C 1-10 alkyl;

[0015] R 5 Each is independently selected from H, halogen, -OH, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, oxo (=O), -C(O)C 1-6Alkyl, hydroxyl substituted C 1-10 Alkyl, -C(O)OH, -C(O)NR 91a R 91b -S(O)2R 92 and -S(O)2NR 93a R 93b ;

[0016] R 6 Selected from H, halogens, and methyl groups;

[0017] R 7 Each is independently selected from H, halogen, unsubstituted or Ra-substituted C. 1-10 Alkyl and C 3-20 cycloalkyl; Ra is selected from halogens and C 3-20 cycloalkyl;

[0018] R 81 R 82 R 83 R 84 They are identical or different, and are independently selected from C that are unsubstituted or arbitrarily substituted by 1, 2, 3, 4 or 5 Rb. 6-14 Aryl-C 1-10 Alkyl, 5-14 membered heteroaryl-C 1-10 Alkyl, C 6-14 Aryl and 5-14 heteroaryl groups; each Rb may be the same or different, and each is independently selected from halogens, halogenated C-groups. 1-10 Alkyl, C 1-10 Alkyl and C 1-10 Alkoxy;

[0019] 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 3-20 Cycloalkyl.

[0020] According to the embodiments of this disclosure, W is CH or N; m is an integer from 0 to 5; n is an integer from 0 to 3;

[0021] Ring A is a 3-20 quintile nitrogen-containing heterocyclic group, which, in addition to the N atom attached to the parent nucleus, optionally contains one, two or more heteroatoms selected from O, N or S;

[0022] R 1 Selected from H, halogens, CN and C 1-6 alkyl;

[0023] R 2 Selected from -OR 81-NH-C(O)R 82 -NHR 83 and -C(O)NHR 84 ;

[0024] R 3 Selected from H, C 1-10 Alkyl and C 3-20 cycloalkyl;

[0025] R 4 Selected from H, halogens and C 1-10 alkyl;

[0026] R 5 Each is independently selected from H, halogen, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, oxo (=O), -C(O)C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, -C(O)OH, -C(O)NR 91a R 91b -S(O)2R 92 and -S(O)2NR 93a R 93b ;

[0027] R 6 Selected from H, halogens, and methyl groups;

[0028] R 7 Selected independently from H, halogen, and C. 1-10 Alkyl and C 3-20 cycloalkyl;

[0029] R 81 R 82 R 83 R 84 Same or different, selected independently 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; of which C 6-14 The aryl group or 5-14 heteroaryl group is unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogens, halogenated C-membered groups. 1-10 Alkyl, C 1-10 Alkyl and C 1-6 Alkyl substitution;

[0030] 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 3-20 Cycloalkyl.

[0031] According to the embodiments of this disclosure, W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3;

[0032] Ring A is a 3-12 member nitrogen-containing heterocyclic group, which, in addition to the N atom attached to the parent nucleus, optionally contains one, two or more heteroatoms selected from O, N or S;

[0033] R 1 Selected from H, halogens, CN and C 1-6 alkyl;

[0034] R 2 Selected from -OR 81 -NH-C(O)R 82 -NHR 83 and -C(O)NHR 84 ;

[0035] R 3 Selected from H, C 1-6 Alkyl and C 3-12 cycloalkyl;

[0036] R 4 Selected from H, halogens and C 1-6 alkyl;

[0037] R 5 Each is independently selected from H, halogen, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, oxo (=O), -C(O)C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, -C(O)OH, -C(O)NR 91a R 91b -S(O)2R 92 and -S(O)2NR 93a R 93b ;

[0038] R 6 Selected from H, halogens, and methyl groups;

[0039] R 7 Selected independently from H, halogen, and C. 1-6 Alkyl and C 3-12 cycloalkyl;

[0040] R 81 R 82 R 83 R 84 Same or different, selected independently from C6-14 Aryl-C 1-6 Alkyl, 5-14 membered heteroaryl-C 1-6 Alkyl, C 6-14 Aryl and 5-14 heteroaryl groups; wherein the aryl or heteroaryl groups are unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogens, halogenated C-membered groups. 1-6 Alkyl, C 1-6 Alkyl and C 1-3 Alkyl substitution;

[0041] 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 3-10 Cycloalkyl.

[0042] According to the embodiments of this disclosure, W is CH or N; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3;

[0043] Ring A is a 3-9 member nitrogen-containing heterocyclic group, which, in addition to the N atom attached to the parent nucleus, optionally contains one, two or more heteroatoms selected from O, N or S;

[0044] R 1 Selected from halogens;

[0045] R 2 Selected from -OR 81 -NH-C(O)R 82 -NHR 83 and -C(O)NHR 84 ;

[0046] R 3 Selected from C 1-3 Alkyl and C 3-6 cycloalkyl;

[0047] R 4 C 1-3 Alkyl or halogen;

[0048] 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, hydroxyl substituted C 1-3 Alkyl, -C(O)OH, -C(O)NR 91a R 91b -S(O)2R 92 and -S(O)2NR93a R 93b ;

[0049] R 6 Selected from H, halogens, and methyl groups;

[0050] R 7 Selected independently from H, halogens and C respectively 1-3 alkyl;

[0051] R 81 R 82 R 83 R 84 Same or different, selected independently from C 6-8 Aryl-C 1-3 Alkyl, 5-6 membered heteroaryl-C 1-3 Alkyl, C 6-8 Aryl, 5-6 heteroaryl; wherein the aryl or heteroaryl groups are unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogens or halogenated C. 1-3 Alkyl, C 1-3 Alkyl and C 1-3 Alkyl substitution;

[0052] 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. 1-3 Alkyl and C 3-7 Cycloalkyl.

[0053] According to the embodiments of this disclosure, W is CH or N; m is 0, 1, 2 or 3; n is 0 or 1;

[0054] Ring A is selected from the following structures:

[0055]

[0056] R 1 It is Cl or Br;

[0057] R 2 Selected from -OR 81 -NH-C(O)R 82 -NHR 83 and -C(O)NHR 84 ;

[0058] R 3 It is methyl or cyclopropyl;

[0059] R 4 It is methyl;

[0060] R5 Selected from F, -OH, methyl, methoxy, ethoxy, oxo (=O), -C(O)C 1-3 Alkyl, 2-hydroxyisopropyl, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -S(O)2CH3, S(O)2CH2CH3 and -S(O)2-cyclopropane;

[0061] R 6 Selected from H, F and Cl;

[0062] R 7 For H;

[0063] R 81 R 82 R 83 R 84 The same or different, independently selected from phenylmethyl, pyridylmethyl, pyridylethyl, phenyl and pyridyl groups that are unsubstituted or optionally substituted with 1, 2 or 3 Rb groups; each Rb is the same or different, independently selected from F, Cl and CF3.

[0064] According to the embodiments of this disclosure, the structure formed by R5 and ring A can be selected from:

[0065]

[0066]

[0067] In a preferred embodiment, the compound of formula I has the structure shown in formula Ia or Ib:

[0068]

[0069] 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 above, and the bolded chemical bonds indicate the presence of axial chirality in the compound.

[0070] In a preferred embodiment, the compound of formula I has the structure shown in formula II:

[0071]

[0072] Where R 1 R 3 R 4 R 5 R 6 R 7m, n, W and ring A have the definitions described above independently of each other;

[0073] R 10 Selected from H, halogens, unsubstituted groups, or optionally substituted with one, two, or more halogens, OH, or 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 group, C 2-10 alkynyl group and C 2-10 alkynyloxy group;

[0074] Each R 11 They are either the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl and Halogenated C 1-10 alkyl;

[0075] p is an integer between 0 and 4.

[0076] According to the implementation scheme of this disclosure, R 10 Selected from H, halogens, unsubstituted groups, or optionally substituted with one, two, or more halogens, OH, or NH2: C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkenyloxy group, C 2-6 alkynyl group and C 2-6 alkynyloxy group;

[0077] Each R 11 They are either the same or different, and are independently selected from H, halogens, and C. 1-6 Alkyl and Halogenated C 1-6 alkyl;

[0078] p can be 0, 1, 2, 3, or 4.

[0079] According to the implementation scheme of this disclosure, R 10 Selected from H, halogens, C 1-3 Alkyl and Halogenated C 1-3 Alkyl group; p is 0, 1, or 2;

[0080] Each R 11 They are either the same or different, and are independently selected from H, halogens, and C. 1-3 Alkyl and Halogenated C 1-3 alkyl.

[0081] According to the implementation scheme of this disclosure, R 10It is H or methyl; p is 0, 1 or 2;

[0082] Each R 11 They are either the same or different, and are selected independently from F, Cl and CF3.

[0083] In a more preferred embodiment, the compound of formula II has the structure shown in formula IIa or formula IIb:

[0084]

[0085] 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 the presence of axial chirality.

[0086] 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.

[0087] In some embodiments, the compound represented by Formula I, Formula Ia, or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt, or prodrug thereof, wherein R 2 For -OR 81 or -NHR 83 ;R 81 and R 83 Whether they are the same or different, they are independent of each other as C. 6-8 Aryl-C 1-3 alkyl- or 5-6-membered heteroaryl-C 1-3 Alkyl-; wherein C 6-8 Aryl, 5-6-membered heteroaryl groups are unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 independently selected from halogens, halogenated C 1-3 Alkyl, C 1-3 Alkyl and C 1-3 Alkoxy substitution, C 1-3 The alkyl moiety is attached to O or NH.

[0088] In some embodiments, the compound represented by Formula I, Formula Ia, or Formula Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt, or prodrug thereof, wherein R 2 For -OR 81 ;R 81 C6-8 Aryl-C 1-3 Alkyl or 5-6-membered heteroaryl-C 1-3 Alkyl; wherein C 6-8 The aryl group and the 5-6 heteroaryl group are unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogens, halogenated C-membered groups. 1-3 Alkyl, C 1-3 Alkyl and C 1-3 Alkoxy substitution; C 1-3 The alkyl moiety is attached to O. In some embodiments, the compound represented by formula I, Ia, or Ib, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt, or prodrug thereof, wherein R 2 For -OR 81 ;R 81 It is -CH2-pyridyl; wherein the pyridyl group is unsubstituted or optionally surrounded by 1, 2, 3, 4 or 5 C groups independently selected from halogens, halogenated C groups. 1-3 Alkyl, C 1-3 Alkyl and C 1-3 Alkyl-substituted.

[0089] 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 R 5 Each is independently selected from H, -OH, and -C. 1-6 Alkyl, -C 1-6 Alkoxy group, -C(O)C 1-6 Alkyl, hydroxyl substituted C 1-10 Alkyl, -C(O)OH, -C(O)NR 91a R 91b and -S(O)2R 92 ;R 91a R 91b and R 92 They are either the same or different, and are independently selected from H and C. 1-6 Alkyl and C 3-10 Cycloalkyl.

[0090] 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 R 1 It is a halogen.

[0091] 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 R 3 C 1-3 alkyl.

[0092] 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 R 4 Halogen or C 1-3 alkyl.

[0093] 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 R 6 It is H or halogen.

[0094] According to embodiments of this disclosure, the compounds of formula I include, but are not limited to, the following structures:

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] According to embodiments of this disclosure, the compounds represented by Formula I include, but are not limited to, the following structures:

[0103]

[0104]

[0105]

[0106]

[0107] This disclosure also provides a method for preparing a compound of formula I, comprising:

[0108] Option 1: Compound a1 and compound a2 undergo a coupling reaction to obtain compound I.

[0109] The reaction formula is as follows:

[0110]

[0111] 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 have the definitions described above independently of each other;

[0112] Option 2: When W is N and R7 is H, compound b1 reacts with compound b2 to obtain compound II;

[0113] The reaction formula is as follows:

[0114]

[0115] Where R 1 R 3 R 4 R 5 R 6 R 7 R 10 R 11 m, n, p and ring A have the definitions described above independently of each other;

[0116] According to an embodiment of this disclosure, 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.

[0117] According to an embodiment of this disclosure, when R5 is OH, the OH in compound b2 can be protected by a silicon protecting group, which can be tert-butyldiphenylsilyl; the silicon protecting group will be removed in the reaction to obtain deprotected OH.

[0118] This disclosure also provides the use of at least one of the compounds of Formula I, their racemates, stereoisomers, tautomers, isotopic labels, solvates, pharmaceutically acceptable salts, or prodrug compounds in the preparation of pharmaceuticals.

[0119] According to embodiments of this disclosure, the medicament may be a drug for treating and / or preventing diseases associated with p38 kinase inhibitors, such as an MK2 inhibitor or a p38 MAPK / MK2 pathway modulator.

[0120] This disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of Formula I, a racemic mixture, a stereoisomer, a tautomer, an isotope label, a solvate, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0121] According to embodiments of this disclosure, the pharmaceutical composition further includes at least one pharmaceutically acceptable carrier.

[0122] According to embodiments of this disclosure, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0123] The carrier includes disintegrants such as methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium carboxymethylcellulose, polyvinylpyrrolidone, carboxypropylcellulose, starch, etc.; lubricants including calcium stearate, zinc stearate, magnesium stearate, sodium stearoyl fumarate, etc.; binders including gelatin, polyethylene glycol, sugar, gum, starch, hydroxypropyl cellulose, etc.; diluents including mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, and starch; and surfactants including polysorbate 80, sodium lauryl sulfate, talc, and silica. The compositions disclosed herein can be formulated using methods known in the art to provide immediate, sustained, or delayed release of the active ingredient upon administration to a patient.

[0124] This disclosure also provides the use of compounds of Formula I, their racemates, stereoisomers, tautomers, isotopic labels, solvates, pharmaceutically acceptable salts or prodrug compounds thereof, in the treatment and / or prevention of diseases mediated by p38 kinase inhibitors.

[0125] This disclosure also provides methods for treating and / or preventing diseases mediated by p38 kinase inhibitors, including administering to a patient a therapeutic or preventative amount of at least one of a compound of Formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt, or prodrug compound thereof.

[0126] According to embodiments of this disclosure, the diseases can be those related to the p38 MAPK / MK2 pathway, such as autoimmune diseases 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, allergies and asthma, Alzheimer's disease, and hormone-related diseases.

[0127] Beneficial effects

[0128] The disclosed compounds exhibit good regulatory activity and selectivity towards the p38 MAPK / MK2 pathway. Furthermore, the disclosed compounds demonstrate favorable pharmacokinetic and other properties. Additionally, the disclosed compounds can be used to treat diseases mediated by p38 kinase inhibitors, and to prepare medicaments for such conditions or diseases.

[0129] Terminology Definitions and Explanations

[0130] Unless otherwise stated, the definitions of groups and terms recorded in this disclosure and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this disclosure and / or claims.

[0131] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to describing each integer value in the numerical range "1-20", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Furthermore, when certain numerical ranges are defined as "numbers", it should be understood that they describe the two endpoints of the range, each integer within the range, and each decimal within the range. For example, "numbers from 0 to 10" should be understood to describe not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0132] It should be understood that in this article, when describing one, two or more, "more" should refer to integers greater than 2, such as 3 or greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0133] It should be understood that the term "optionally containing one, two or more heteroatoms selected from O, N or S" indicates either the absence of heteroatoms or the presence of one, two or more heteroatoms selected from O, N or S.

[0134] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0135] Term "C" 1-10 "Alkyl" should be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms. For example, it refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, where "C" represents a carbon atom. 1-6"Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0136] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Preferably, alkoxy groups (C-) contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. 1-12 Alkoxy groups, more preferably alkoxy groups containing 1 to 6 carbon atoms (C 1-6 Alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0137] Term "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-8 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C... 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0138] Term "C" 2-10 "Alkyne" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C"). 2-8 "Alkyne group" has 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0139] Term "C" 3-20 "Cycloalkyl" should be understood to refer to saturated monovalent monocyclic, bicyclic (such as fused, spiro, or bridged) hydrocarbon rings or tricyclic alkanes having 3 to 20 carbon atoms, preferably "C". 3-12 "Cycloalkyl", more preferably "C" 3-8 cycloalkyl. The term "C" 3-12 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The C... 3-12 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0140] The term "3-20-membered nitrogen-containing heterocyclic group" refers to a saturated or unsaturated nitrogen-containing non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic (such as fused rings, spirocyclic rings, bridged rings) or tricyclic ring system, and contains at least one nitrogen atom. It may also contain, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O and S, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2- states. Preferably, the heterocyclic group may be selected from "3-12-membered nitrogen-containing heterocyclic groups". The term "3-12-membered nitrogen-containing heterocyclic group" means a saturated or unsaturated nitrogen-containing non-aromatic ring or ring system, containing at least one nitrogen atom, and containing, for example, heteroatoms selected from O and S. The heterocyclic group is connected to the parent nucleus via an N atom and can be connected to the rest of the molecule via any one of the carbon atoms or other nitrogen atoms (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl; 5-membered rings, such as pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl; or 6-membered rings, such as piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopentano[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl. Alternatively, it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-12-membered nitrogen-containing heterocyclic group is linked to other groups to form the compounds of this disclosure, the N atom on the 3-12-membered nitrogen-containing heterocyclic group can be linked to the parent nucleus, and the carbon atom can be linked to other groups. For example, when the 3-12-membered nitrogen-containing heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be linked to the parent nucleus. Or when the 3-12-membered nitrogen-containing heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring can be linked to the parent nucleus.

[0141] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0142] The term "ring-chain" refers to a ring system in which two rings share two cyclic atoms.

[0143] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0144] Term "C"6-14 Aryl-C 1-10 "alkyl" refers to the C 6-14 aryl-substituted C 1-10 Alkyl group, with the linkage site at C 1-10 alkyl.

[0145] The term "5-14 heteroaryl-C" 1-10 "alkyl" refers to C-membered compounds substituted with 5-14 heteroaryl groups. 1-10 Alkyl group, with the linkage site at C 1-10 alkyl.

[0146] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described herein, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0147] The aryl group can be substituted or unsubstituted.

[0148] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 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, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0149] The heteroaryl group can be substituted or unsubstituted.

[0150] The terms “alkyl,” “alkoxy,” “cycloalkyl,” “heterocyclic,” “aryl,” and “heteroaryl” used herein may be substituted or unsubstituted; when substituted, they may be substituted at any usable linking point, and the substituents are preferably independently selected independently from one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] "Pharmaceutical acceptable" in this disclosure means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0160] In this disclosure, "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred. Detailed Implementation

[0161] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0162] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0163] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The measurements are given in units of ppm. NMR determinations were performed using Bruker Ascend. TM The NMR spectrometer was set to -400, and the solvents used for determination were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0164] MS measurements were performed using an Agilent 6110, Agilent 1100, Agilent 6120, or Agilent G6125B liquid chromatography-mass spectrometry system.

[0165] HPLC determinations were performed using a Shimadzu HPLC-2010C high-performance liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um column).

[0166] Chiral HPLC analysis was performed using THARSFC X5.

[0167] The silica gel plates used for thin-layer chromatography are GF254 silica gel plates from Yantai Qingdao. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0168] Column chromatography typically uses Qingdao marine silica gel 200-300 mesh as the carrier.

[0169] High-performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2545, and the innovative Hengtong LC3000 preparative chromatograph.

[0170] Chiral preparative column chromatography was performed using Shimadzu LC-20AP and THARSFC PREP 80.

[0171] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0172] The pressurized hydrogenation reaction uses a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0173] The microwave reaction uses a Biotage initiator+ type microwave reactor.

[0174] Unless otherwise specified in the experimental examples, the reactions were carried out under an argon or nitrogen atmosphere.

[0175] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of about 1 liter.

[0176] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 liter.

[0177] Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, ranging from 20℃ to 30℃.

[0178] Synthesis of intermediate compound A-5

[0179]

[0180] Step 1: Synthesis of compound A-5b

[0181] Thionyl chloride (22.43 g, 188.5 mmol) was slowly added dropwise to an ethanol (60 mL) solution of compound A-5a (20.00 g, 125 mol), and the reaction mixture was incubated at 60 °C for 3 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure to remove the solvent, yielding crude compound A-5b (20.00 g), which was used directly in the next reaction step.

[0182] MS m / z (ESI): 187.9 [M+1] + .

[0183] Step 2: Synthesis of compound A-5c

[0184] Compound A-5b (16.00 g, 85.6 mmol) was dissolved in ethanol (60 mL), and sodium borohydride (6.48 g, 171.2 mmol) was slowly added to the solution in portions at 0 °C. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to give compound A-5c (16.00 g, yield: 73.5%).

[0185] MS m / z (ESI): 146.1 [M+1] + .

[0186] Step 3: Synthesis of compound A-5

[0187] At room temperature, thionyl chloride (1.77 g, 0.015 mol) was slowly added to a solution of compound A-5c (1.80 g, 0.012 mol) and N,N-dimethylformamide (5 drops) in dichloromethane (50 mL), and the reaction 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 to neutral, then water (20 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) to give compound A-5 (1.80 g, yield: 84.68%).

[0188] 1 H NMR (400MHz, CDCl3) δ8.35 (d, J = 2.4Hz, 1H), 7.26 (ddd, J = 9.1, 8.0, 2.6Hz, 1H), 4.72 (d, J = 2.1Hz, 2H).

[0189] Synthesis of Compound A

[0190]

[0191] Step 1: Synthesis of compound A-2

[0192] At -78°C, a tetrahydrofuran solution (141 mL, 141 mmol) of bis(trimethylsilyl)aminolithium was slowly added to a tetrahydrofuran solution (500 mL) of compound A-1 (20 g, 141 mmol). The reaction mixture was stirred at -78°C for 1 hour, followed by the slow addition of acetyl chloride (6.6 g, 844 mmol). The resulting mixture was stirred at -78°C for another hour. After the reaction was complete, the reaction mixture was slowly poured into a saturated ammonium chloride aqueous solution (500 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:0–2:1) to give compound A-2 (6.6 g, yield: 30%).

[0193] MS m / z (ESI): 185.1 [M+1] + .

[0194] Step 2: Synthesis of compound A-4

[0195] 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 hours. After the reaction mixture cooled naturally to room temperature, methanesulfonic acid (3.12 g, 32.5 mmol) was added, and the reaction was heated to 50 °C and stirred for another 3 hours. After the reaction was complete, the reaction mixture was cooled naturally to room temperature and filtered. The filter cake was collected and dried to give compound A-4 (5.60 g, yield: 69%).

[0196] MS m / z(ESI): 251.0 [M+1] + .

[0197] Step 3: Synthesis of compound A-6

[0198] Compound A-5 (4.01 g, 24.6 mmol) was added to a mixture of compound A-4 (5.60 g, 22.3 mmol), potassium carbonate (7.69 g, 55.7 mmol), and 18-crown-6 (1.18 g, 4.4 mmol) in N,N-dimethylformamide (80 mL). The reaction was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude compound A-6 (8.40 g, 80% yield), which was used directly in the next reaction.

[0199] MS m / z(ESI): 378.0 [M+1]+ .

[0200] Step 4: Synthesis of compound A-8

[0201] Di(triphenylphosphine)palladium dichloride (1.56 g, 2.22 mmol) was added to a solution of compound A-6 (8.4 g, 22.2 mmol) and tributyl(1-ethoxyethylene)tin (compound A-7) (10.21 g, 24.2 mmol) in 1,4-dioxane (100 mL). The reaction mixture was heated to 130 °C and stirred for 4 hours. The reaction mixture was then filtered, and the filtrate was directly concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), and then 5 mL of concentrated hydrochloric acid was added dropwise while stirring 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%).

[0202] MS m / z(ESI): 386.0 [M+1] + .

[0203] Step 5: Synthesis of compound A-9

[0204] Acetic acid (2 mL) was added dropwise to a solution of compound A-8 (5 g, 13 mmol) and N-chlorosuccinimide (1.90 g, 14.3 mmol) in isopropanol (100 mL). The reaction 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 (ethyl acetate) to give compound A-9 (3.60 g, yield: 70%).

[0205] MS m / z(ESI): 420.0 [M+1] + .

[0206] Step 6: Synthesis of Compound A

[0207] N,N-Dimethylformamide dimethyl acetal (0.85 g, 7.2 mmol) was added to a solution of compound A-9 (1.30 g, 3.1 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 1:0–50:1) to give compound A (900 mg, yield: 78%).

[0208] MS m / z(ESI): 474.9 [M+H] + .

[0209] Synthesis of intermediate compound B:

[0210]

[0211] Step 1: Synthesis of compound B-2

[0212] Diphenyl azidophosphate (23.5 g, 0.085 mol) was added to a mixed solution 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). The reaction mixture was incubated at 110 °C for 16 hours. After the reaction was complete, the reaction mixture was poured into water and extracted with dichloromethane (200 mL × 3). The combined organic phases were washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0–10:1) to give compound B-2 (3.6 g, yield: 25%).

[0213] MS m / z(ESI): 247.0 [M+1] + .

[0214] Step 2: Synthesis of compound B-3

[0215] Compound B-2 (3.6 g, 14.5 mol) was added to a mixed solution 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 solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain crude compound B-3 (3.1 g).

[0216] MS m / z(ESI): 147.0 [M+1] + .

[0217] Step 3: Synthesis of compound B-4

[0218] Silver sulfate (6.61 g, 0.02 mol) and iodine (5.38 g, 0.02 mol) were added to an ethanol (50 mL) solution of compound B-3 (3.1 g, 0.02 mol). The reaction mixture was stirred at 50 °C for 16 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0–10:1) to give compound B-4 (4.9 g, yield: 65%). MS m / z (ESI): 272.7 [M+1] + .

[0219] Step 4: Synthesis of compound B-6

[0220] Under nitrogen protection, methylboric acid (530 mg, 8.8 mmol), cesium carbonate (8.96 g, 27.5 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (450 mg, 0.55 mmol) were sequentially added to a 1,4-dioxane (30 mL) solution of compound B-4 (1.5 g, 5.5 mmol). The reaction mixture was incubated at 100 °C for 1.5 hours. After the reaction was complete, the reaction solution was diluted with an aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:3) to give compound B-6 (0.43 g, yield: 48%).

[0221] MS m / z(ESI): 161.0 [M+1] + .

[0222] Step 5: Synthesis of compound B-7

[0223] Compound B-6 (1.20 g, 6.88 mmol) was added to an anhydrous 1,4-dioxane (8 mL) solution of compound A-2 (850 mg, 5.29 mmol). The reaction mixture was heated to 110 °C and stirred at this temperature for 1 hour. After the reaction mixture cooled naturally to 50 °C, methanesulfonic acid (285 mg, 2.96 mmol) was added, and the reaction was continued at 50 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane) to give compound B-7 (530 mg, yield: 66%).

[0224] MS m / z(ESI): 269.0 [M+1] + .

[0225] Step 6: Synthesis of compound B-8

[0226] Potassium carbonate (1.14 g, 8.28 mmol) and 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). The reaction mixture was heated to 40 °C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound B-8 (1.5 g, purity: 84%, yield: 96%), which was used directly in the next reaction.

[0227] MS m / z(ESI): 395.8 [M+1] + .

[0228] Step 7: Synthesis of compound B-9

[0229] Compound A-7 (2.01 g, 5.55 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (257 mg, 0.37 mmol) were added to a solution of compound B-8 (1.45 g, 3.70 mmol) in 20 mL of 1,4-dioxane. The reaction was stirred at 130 °C for 1.5 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain crude compound B-9 (3.90 g), which was used directly in the next step.

[0230] MS m / z(ESI): 431.9 [M+1] + .

[0231] Step 8: Synthesis of compound B-10

[0232] Compound B-9 (1.45 g, 3.40 mmol) was added to a solution of tetrahydrofuran (15 mL) and concentrated hydrochloric acid (0.50 mL), and the reaction 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 residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to give B-10 (910 mg, yield: 66%).

[0233] MS m / z(ESI): 403.9 [M+1] + .

[0234] Step 9: Synthesis of compound B-11

[0235] N-chlorosuccinimide (330 mg, 2.48 mmol) and glacial acetic acid (0.20 mL) were added sequentially to a solution of compound B-10 (910 mg, 2.25 mmol) in isopropanol (12 mL). The reaction 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. The residue was purified by silica gel column chromatography (ethyl acetate) to give compound B-11 (1.13 g).

[0236] MS m / z(ESI): 437.8 [M+1] + .

[0237] Step 10: Synthesis of Compound B

[0238] 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). The reaction was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was allowed to cool to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give compound B (900 mg, yield: 72%).

[0239] MS m / z(ESI): 492.7 [M+1] + .

[0240] Example 1: Synthesis of compounds 2, 2-P1 and 2-P2

[0241]

[0242] Step 1: Synthesis of Compounds 2-3

[0243] Compound 2-1 (300 mg, 2.42 mmol), compound 2-2 (753 mg, 2.42 mmol), and N,N-diisopropylethylamine (627 mg, 4.85 mmol) were dissolved in acetonitrile (15 mL) and stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 4:1) to give compound 2-3 (620 mg, yield: 77.3%).

[0244] MS m / z(ESI): 330.0 [M+1] + .

[0245] Step 2: Synthesis of compounds 2-4

[0246] At room temperature, a 1,4-dioxane solution of hydrogen chloride (1.9 mL, 4 M) was slowly added to a solution of compound 2-3 (500 mg, 1.52 mmol) in dichloromethane (10 mL), and the reaction was allowed to proceed for 12 hours at room temperature. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain compound 2-4 (200 mg, crude product). This crude product was directly used for the next reaction. MS m / z (ESI): 130.1 [M+1] + .

[0247] Step 3: Synthesis of Compound 2

[0248] Compound A (100 mg, 0.21 mmol), compounds 2-4 (70 mg, 0.42 mmol), and potassium carbonate (87 mg, 0.63 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini-C18, 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-70%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 2 (40 mg, yield 35.0%).

[0249] MS m / z(ESI): 540.8 [M+1] + ; 1 H NMR(400MHz,CD3OD)δ8.84(s,1H),8.48(dd,J=12.2,4.1Hz,2H),8.41(s,1H),7.83–7.72(m,2H),6.7 9(s,1H),5.51(d,J=1.8Hz,2H),4.20–4.11(m,4H),2.17(d,J=3.7Hz,3H),1.99(s,3H),1.55(s,3H).

[0250] Compound A (300 mg, 0.63 mmol), compounds 2-4 (314 mg, 1.89 mmol), and potassium carbonate (175 mg, 1.26 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), 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 to 20 / 1) to obtain crude compound 2. Crude compound 2 was resolved by supercritical fluid chiral chromatography (equipment: SFC Har prep 80, column: CHIRALPAK WHELK-01 250 mm * 21.1 mm, 5 μm, mobile phase: 40% MeOH / CO2 (NH4OH 0.2%), total flow rate: 40 g / min) to obtain compound 2-P1 (29.1 mg, yield 8.5%) and compound 2-P2 (40.2 mg, yield 11.7%).

[0251] Compound 2-P1:

[0252] ESI-MS[M+H] + :541.2. SFC: Retention time = 4.84 min; 1 H NMR (400MHz, CD3OD) δ8.69(s,1H),8.42(d,J=5.2Hz,1H),8.39(d,J=2.4Hz,1H),8.30(s,1H),7.61(d,J=5.2Hz,1H),7.32( ddd,J=9.0,8.0,2.4Hz,1H),6.33(s,1H),5.38(t,J=2.2Hz,2H),4.15–4.03(m,4H),2.12(s,3H),1.83(s,3H),1.54(s,3H).

[0253] Compound 2-P2:

[0254] ESI-MS[M+H] + :541.0. SFC: Retention time = 6.79 min; 1H NMR (400MHz, CD3OD) δ8.71(s,1H),8.42(d,J=5.3Hz,1H),8.39(d,J=2.4Hz,1H),8.24(s,1H),7.62(d,J=5.3Hz,1H),7.32(d dd,J=9.0,8.0,2.4Hz,1H),6.35(s,1H),5.39(s,2H),4.12(dt,J=15.3,6.2Hz,4H),2.14(s,3H),1.87(s,3H),1.55(s,3H).

[0255] Example 2 Synthesis of Compound 6

[0256]

[0257] Step 1: Synthesis of Compound 6-2

[0258] S-methylisothiourea sulfate (799 mg, 4.25 mol) was added to 5 mL of an aqueous solution of compound 6-1 (500 mg, 5.74 mol), and the reaction mixture was stirred at 90 °C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was washed with ethanol to give compound 6-2 (900 mg, yield: 92.80%).

[0259] MS m / z (ESI): 130.2 [M+1] + .

[0260] Step 2: Synthesis of Compound 6

[0261] Compound 6-2 (383 mg, 1.68 mmol) and potassium carbonate (233 mg, 1.68 mmol) were added to a solution of compound A (200 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini-C18, 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-50%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 6 (60 mg, yield: 26.3%).

[0262] MS m / z (ESI): 541.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6): δ8.80(s,1H),8.61(d,J=2.3Hz,1H),8.52(d,J=5.0Hz,1H),8.28(s,1H),8.14-8.06(m,1H),7.51(d,J =5.0Hz,1H),6.83(s,1H),5.49(d,J=1.2Hz,2H),5.05-4.82(m,1H),4.50-4.25(m,1H),3.82-3.45(m,4H),2.10-1.85(m,8H).

[0263] Example 3 Synthesis of Compound 10

[0264]

[0265] Potassium carbonate (87.32 mg, 0.63 mmol) and compound 10-2 (54.4 mg, 0.42 mmol) were added to a solution of compound A (100 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 90 °C for 12 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 150 × 21.2 mm, 5 μm; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile term: acetonitrile-water (0.1% formic acid); gradient: 40-60%) to obtain compound 10 (30.5 mg, yield: 25.4%).

[0266] MS m / z (ESI): 540.8 [M+1] + ; 1 H NMR (400MHz, CD3OD): δ8.74(s,1H),8.48(d,J=5.1Hz,1H),8.44(d,J=2.3Hz,1H),8.25(s,1H),7.75-7.68(m,1H),7.58 (d,J=5.1Hz,1H),6.80(s,1H),5.48(d,J=1.5Hz,2H),3.85-3.78(m,4H),3.76-3.68(m,4H),2.13(s,3H),2.03(s,3H).

[0267] Example 4 Synthesis of Compound 11

[0268]

[0269] Step 1: Synthesis of Compound 11-2

[0270] Compound 11-1 (1 g, 9.90 mmol) and S-methylisothiourea sulfate (0.93 g, 4.95 mmol) were dissolved in water (15 mL), and the reaction mixture was stirred at 90 °C for 1 hour. Ethanol (20 mL) was added and stirred for 30 minutes. The mixture was filtered, and the filter cake was dried to give compound 11-2 (0.88 g, yield: 74.1%).

[0271] MS m / z (ESI): 144.1 [M+H] + .

[0272] Step 2: Synthesis of Compound 11

[0273] Compound A (119 mg, 0.25 mmol), compound 11-2 (200 mg, 1.40 mmol), and potassium carbonate (116 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at 90 °C for 12 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 10:1) after reduction. The crude product was then purified by preparative high performance liquid chromatography (column: Gemini-C18; 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-70%; column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 11 (37 mg, yield: 26.7%).

[0274] MS m / z (ESI): 555.2 [M+1] + ; 1 H NMR (400MHz, CD3OD) δ8.78(s,1H),8.49–8.46(m,2H),8.29(s,1H),7.78–7.72(m,1H),7.56(d,J=5.1Hz,1H),6.84(s,1H),5.53(d,J=1.9Hz,2 H),4.54(d,J=13.7Hz,2H),3.93–3.84(m,1H),3.36(s,1H),3.31(s,1H ), 2.17 (s, 3H), 2.07 (s, 3H), 1.98–1.90 (m, 2H), 1.50 (d, J = 10.7Hz, 2H).

[0275] Example 5: Synthesis of compounds 12, 12-P1, and 12-P2

[0276]

[0277] Step 1: Synthesis of Compound 12-2

[0278] At room temperature, S-methylisothiourea sulfate (351 mg, 1.86 mmol) was added to an aqueous solution (5.0 mL) of compound 12-1 (430 mg, 3.73 mmol). The reaction mixture was stirred at 90 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 12-2 (600 mg, crude product). The product was used directly in the next reaction without purification.

[0279] MS m / z (ESI): 158.1 [M+1] + .

[0280] Step 2: Synthesis of compounds 12-P1 and 12-P2

[0281] A solution of compound 12-2 (559 mg, 2.19 mmol), compound A (260 mg, 0.55 mmol), and potassium carbonate (302 mg, 2.19 mmol) in N,N-dimethylformamide (15 mL) was heated to 60 °C and reacted for 12 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), 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 a crude product with a purity of 80%. The crude product was purified by high performance liquid preparative chromatography (column: Gemini-C18; 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25℃; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 12 (45 mg, yield: 14.3%).

[0282] MS m / z (ESI): 569.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.62(d,J=2.3Hz,1H),8.51(d,J=5.0Hz,1H),8.28(s,1H),8.14–8.08(m,1H),7.49(d,J=5.0Hz,1H),6 .83(s,1H),5.48(s,2H),4.39(s,1H),4.28(d,J=12.3Hz,2H),3.50–3 .42(m,2H),2.06(s,3H),1.95(s,3H),1.52–1.43(m,4H),1.15(s,3H).

[0283] Compound 12 was resolved by supercritical fluid preparative chromatography (equipment: SFC Thar prep 80; column: CHIRALPAKAD-H, 250 mm × 20 mm, 5 μm; mobile phase: 40% ethanol (ethanol / carbon dioxide, 0.2% ammonia); flow rate: 12.5 g / min) to obtain compound 12-P1 (15.4 mg) and compound 12-P2 (15.8 mg).

[0284] Compound 12-P1:

[0285] MS m / z(ESI): 568.8 [M+1] + SFC: Retention time = 3.50 min; 1 H NMR (400MHz, CD3OD) δ8.73(s,1H),8.43(t,J=4.1Hz,2H),8.24(s,1H),7.75–7.67(m,1H),7.50(d,J=5.1Hz,1H),6.79(s,1H),5.48( d,J=1.8Hz,2H),4.33–4.24(m,2H),3.54(ddd,J=13.5,10.1,3.8Hz,2H),2.13(s,3H),2.02(s,3H),1.63-1.54(m,4H),1.22(s,3H).

[0286] Compound 12-P2:

[0287] MS m / z(ESI): 568.8 [M+1] + SFC: Retention time = 5.76 min; 1H NMR (400MHz, CD3OD) δ8.66(s,1H),8.36(dd,J=5.2,3.7Hz,2H),8.17(s,1H),7.67–7.59(m,1H),7.43(d,J=5.1Hz,1H),6.72(s,1H) ,5.40(d,J=1.8Hz,2H),4.21(dd,J=13.5,4.5Hz,2H),3.53–3.43(m,2H),2.05(s,3H),1.95(s,3H),1.56–1.47(m,4H),1.15(s,3H).

[0288] Example 6 Synthesis of Compound 13

[0289]

[0290] Step 1: Synthesis of Compound 13-2

[0291] An aqueous solution (50 mL) of 13-1 (1 g, 7.8 mmol) and S-methylisothiourea sulfate (730 mg, 3.90 mmol) was heated to 90 °C and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and 20 mL of ethanol was added to the residue. The mixture was stirred for 30 minutes, filtered, and the filter cake was dried to give compound 13-2 (0.5 g, yield: 36%).

[0292] 1 H NMR (400MHz, CD3OD) δ3.76–3.68 (m, 4H), 3.67–3.52 (m, 4H), 2.15 (d, J = 7.8Hz, 3H).

[0293] Step 2: Synthesis of Compound 13

[0294] A solution of compound A (100 mg, 0.21 mmol), compound 13-2 (72 mg, 0.42 mmol), and potassium carbonate (58 mg, 0.42 mmol) in N,N-dimethylformamide (10 mL) was heated to 90 °C and stirred for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini-C18, 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 30-50%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 13 (14.9 mg, yield: 12.2%). MS m / z(ESI): 582.1 [M+H]+ ; 1 H NMR (400MHz, CD3OD) δ8.80(s,1H),8.54(d,J=5.2Hz,1H),8.49(d,J=2.4Hz,1H),8.36(s,1H),7.76(ddd,J=9.6,8.6,2.4Hz,1H),7.67(d,J=5. 2Hz,1H),6.84(s,1H),5.53(d,J=1.9Hz,2H),4.03–3.96(m,2H),3.96– 3.89(m,2H),3.73–3.62(m,4H),2.19(s,3H),2.17(s,3H),2.07(s,3H).

[0295] Example 7 Synthesis of compounds 33, 33-P1 and 33-P2

[0296]

[0297] Step 1: Synthesis of Compound 33-2

[0298] Compound 33-1 (3.60 g, 23.75 mmol), compound 2-2 (7.37 g, 23.75 mmol), and N,N-diisopropylethylamine (6.14 g, 47.50 mmol) were added to acetonitrile (50 mL) and stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to give compound 33-2 (7.5 g, yield: 84.8%).

[0299] MS m / z(ESI): 358.2 [M+1] + .

[0300] Step 2: Synthesis of compound 33-3

[0301] At room temperature, a 26 mL (4 M) solution of dioxane containing hydrogen chloride was slowly added to a 100 mL (100 M) solution of compound 33-2 (7.5 g, 21 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to give compound 33-3 (6 g, crude product). The product was used directly in the next reaction without purification.

[0302] MS m / z (ESI): 158.1 [M+1] + .

[0303] Step 3: Synthesis of compound 33-4

[0304] A solution of compound A (500 mg, 1.05 mmol), compound 33-3 (4.07 g, crude), and potassium carbonate (1.45 g, 10.53 mmol) in N,N-dimethylformamide (10 mL) was heated to 90 °C and stirred for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), 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 = 1:0–20:1) to give compound 33-4 (150 mg, yield: 22.54%).

[0305] MS m / z(ESI): 568.8 [M+1] + .

[0306] Step 4: Synthesis of Compound 33

[0307] Compound 33-4 (150 mg, 0.27 mmol) and lithium hydroxide hydrate (37 mg, 0.81 mmol) were dissolved in 10 mL of a mixture of tetrahydrofuran and water (V:V = 1:1), and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, 1 M hydrochloric acid was added dropwise to the reaction solution until the pH reached 7. The mixture was filtered, and the filter cake was dried to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini-C18; 150 × 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 obtain compound 33 (23.2 mg, yield: 15.5%).

[0308] MS m / z (ESI): 554.6 [M+1] + ; 1 H NMR (400MHz, CD3OD) δ8.85(s,1H),8.49(t,J=4.2Hz,2H),8.41(s,1H),7.84(d,J=5.8Hz,1H),7.80–7.71(m,1H),6.81(s,1H), 5.52(d,J=1.7Hz,2H),4.50(td,J=9.1,3.3Hz,2H),4.42(td,J=8.9,6.0Hz,2H),3.70–3.63(m,1H),2.19(s,3H),2.03(s,3H).

[0309] Compound 33 (30 mg) from an amplified batch was separated into compound 33-P1 (12.6 mg) and compound 33-P2 (10.4 mg) by supercritical fluid chiral chromatography (equipment: SFC Thar prep80, column: CHIRALPAK AD-H 250 mm * 20 mm, 5 μm, mobile phase: 40% EtOH / CO2 (NH4OH 0.2%), total flow rate: 40 g / min).

[0310] Compound 33-P1:

[0311] MS m / z (ESI): 554.8 [M+1] + SFC: Retention time = 3.03 min; UV = 254 nm. 1 H NMR(400MHz, DMSO-d6)δ8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.1Hz,1H),8.23(s,1H),8.14–8.07(m,1H),7 .61(d,J=5.1Hz,1H),6.82(s,1H),5.48(d,J=1.1Hz,2H),4.31–4.08(m,4H),3.51(s,1H),2.07(s,3H),1.93(s,3H).

[0312] Compound 33-P2:

[0313] MS m / z (ESI): 554.8 [M+1] + SFC: Retention time = 3.57 min; UV = 254 nm. 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.1Hz,1H),8.23(s,1H),8.10(td,J=9.9,2.3 Hz,1H),7.61(d,J=5.1Hz,1H),6.82(s,1H),5.48(s,2H),4.29–4.15(m,4H),3.50(s,1H),2.07(s,3H),1.95(s,3H).

[0314] Example 8: Synthesis of compounds 35, 35-P1, and 35-P2

[0315] Route 1:

[0316]

[0317] Compound 33 (150 mg, 0.27 mmol), methylamine hydrochloride (109 mg, 1.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (155 mg, 0.81 mmol), 1-hydroxybenzotriazole (110 mg, 0.81 mmol), and triethylamine (82 mg, 0.81 mmol) were dissolved in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), 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 to 20:1) to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm mobile term: ACN--H2O (0.1% FA), gradient: 20-60, temperature: 45℃; pressure: 80 bar; wavelength: 214 / 254 nm; flow rate: 20 mL / min) to obtain compound 35 (2.7 mg, yield: 1.74%).

[0318] MS m / z(ESI): 567.7 [M+1] + ; 1 H NMR (400MHz, CD3OD) δ8.79(s,1H),8.50–8.45(m,2H),8.26(s,1H),7.75(s,1H),7.68(d,J=5.2Hz,1H),6. 83(s,1H),5.52(d,J=1.9Hz,2H),4.34–4.25(m,4H),3.96(s,1H),2.78(s,3H),2.17(s,3H),2.06(s,3H).

[0319] Route 2:

[0320]

[0321] Step 1: Synthesis of Compound 35-2

[0322] Compound 35-1 (1.7 g, 7.9 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (10 mL, 4 M), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 35-2 (1.5 g, crude product). MS m / z (ESI): 115.1 [M+1] + .

[0323] Step 2: Synthesis of Compound 35-3

[0324] Compound 35-2 (1.5 g, 9.96 mmol) was added to a solution of compound 2-2 (3.4 g, 10.96 mmol) and N,N-diisopropylethylamine (2.57 g, 19.92 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, 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 35-3 (3 g, yield: 84.5%). MS m / z (ESI): 357.0 [M+1] + .

[0325] Step 3: Synthesis of compound 35-4

[0326] Compound 35-3 (500 mg, 1.40 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (10 mL, 4 M), 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 to give compound 35-4 (300 mg, crude product). MS m / z (ESI): 157.1 [M+1] + .

[0327] Step 4: Synthesis of Compound 35

[0328] Compound 35-4 (300 mg, 1.92 mmol) was added to a solution of compound A (182.43 mg, 0.38 mmol) and potassium carbonate (530.94 mg, 3.84 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 90 °C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were 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 to 10:1) to obtain compound 35. Compound 35 was purified 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)). The mixture was separated to yield compound 35-P1 (48.6 mg, yield 4.5%) and compound 35-P2 (59.8 mg, yield 5.5%) by means of a flow rate of 0.2% (total flow rate: 40 g / min).

[0329] Compound 35-P1:

[0330] MS m / z(ESI): 568.2 [M+1] + SFC: Retention time = 2.76 min, UV = 254 nm. 1H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.0Hz,1 H),8.21(s,1H),8.16–8.06(m,1H),7.98(d,J=4.7Hz,1H),7.59(d,J=5.1Hz,1H ),6.82(s,1H),5.48(s,2H),4.21(t,J=8.6Hz,2H),4.12(dd,J=14.9,8.7Hz,2H ), 3.41 (td, J = 8.5, 4.2Hz, 1H), 2.61 (d, J = 4.6Hz, 3H), 2.08 (s, 3H), 1.95 (s, 3H).

[0331] Compound 35-P2:

[0332] MS m / z(ESI): 568.2 [M+1] + SFC: Retention time = 3.2 min, UV = 254 nm. 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.61(d,J=2.3Hz,1H),8.54(d,J=5.1Hz,1 H),8.21(s,1H),8.15–8.08(m,1H),7.98(d,J=4.6Hz,1H),7.59(d,J=5.1Hz,1H ),6.82(s,1H),5.49(d,J=1.1Hz,2H),4.21(t,J=8.5Hz,2H),4.12(dd,J=14.8, 8.7Hz, 2H), 3.49–3.36 (m, 1H), 2.61 (d, J = 4.6Hz, 3H), 2.08 (s, 3H), 1.95 (s, 3H).

[0333] Example 9 Synthesis of Compound 38

[0334]

[0335] Step 1: Synthesis of Compound 38-2

[0336] Compound 38-1 (500 mg, 2.17 mmol), methylamine hydrochloride (161 mg, 2.39 mmol), HATU(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate) (1.65 g, 4.34 mmol), and N,N-diisopropylethylamine (840 mg, 6.51 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 16 hours under nitrogen protection. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, 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 = 1:0–20:1) to give compound 38-2 (550 mg, purity 75%, yield: 78.1%).

[0337] MS m / z(ESI): 265.0 [M+23] + .

[0338] Step 2: Synthesis of compound 38-3

[0339] A 1,4-dioxane solution of hydrogen chloride (3 mL, 4 M) was added to a dichloromethane solution of compound 38-2 (600 mg, 2.48 mmol) and stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain compound 38-3 (600 mg, crude product). The product was used directly for the next reaction without purification.

[0340] MS m / z (ESI): 143.1 [M+1] + .

[0341] Step 3: Synthesis of compound 38-4

[0342] Compound 38-3 (300 mg, 1.68 mmol), compound 2-2 (520 mg, 1.68 mmol), and N,N-diisopropylethylamine (434 mg, 3.35 mmol) were dissolved in acetonitrile (5 mL), and the reaction mixture was stirred at 40 °C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to give compound 38-4 (650 mg, yield: 80.7%).

[0343] MS m / z(ESI): 385.0 [M+1] + .

[0344] Step 4: Synthesis of compound 38-5

[0345] A 1,4-dioxane solution of hydrogen chloride (3 mL, 4 M) was added to a dichloromethane solution of compound 38-4 (550 mg, 1.43 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain compound 38-5 (500 mg, crude product). The product was used directly for the next reaction without purification.

[0346] MS m / z (ESI): 185.2 [M+1] + .

[0347] Step 5: Synthesis of Compound 38

[0348] Compound 38-5 (264 mg, 1.20 mmol), compound A (171 mg, 0.36 mmol), and potassium carbonate (247 mg, 1.79 mmol) were dissolved in N,N dimethylformamide (10 mL) and stirred at 65 °C for 16 hours. After the reaction was complete, the solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, 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 to 2:1) to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-50%; column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 38 (40 mg, yield: 18.6%).

[0349] MS m / z(ESI): 596.2 [M+1] + ; 1 H NMR (400MHz, CD3OD) δ8.79 (s, 1H), 8.49 (d, J = 3.1Hz, 1H), 8.48 (s, 1H), 8.3 1(s,1H),7.79–7.71(m,1H),7.60(d,J=5.2Hz,1H),6.84(s,1H),5.52(d,J= 1.9Hz,2H),2.99(t,J=12.3Hz,3H),2.73(s,3H),2.55–2.45(m,1H),2.18( s, 3H), 2.07 (s, 3H), 1.86 (d, J = 10.8Hz, 2H), 1.68 (dd, J = 25.0, 12.4Hz, 3H).

[0350] Example 10 Synthesis of compounds 41, 41-P1 and 41-P2

[0351]

[0352] Step 1: Synthesis of Compound 41-2

[0353] Compound 41-1 (400 mg, 2.33 mmol), compound 2-2 (723 mg, 2.33 mmol), and N,N-diisopropylethylamine (602 mg, 4.66 mmol) were dissolved in acetonitrile (20 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 4:1) to give compound 41-2 (600 mg, yield: 64.8%).

[0354] MS m / z(ESI): 377.9 [M+1] + .

[0355] Step 2: Synthesis of compound 41-3

[0356] A 1,4-dioxane solution (1.7 mL, 4 M) of hydrogen chloride was slowly added to a 10 mL solution of compound 41-2 (500 mg, 1.32 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain compound 41-3 (220 mg, crude product). The product was used directly for the next reaction without purification.

[0357] MS m / z(ESI): 178.0 [M+1] + .

[0358] Step 3: Synthesis of Compound 41

[0359] A solution of compound A (150 mg, 0.31 mmol), compound 41-3 (135 mg, crude), and potassium carbonate (128 mg, 0.93 mmol) in N,N-dimethylformamide (15 mL) was heated to 90 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini-C18, 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-50%; column temperature: 25 °C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 41 (41.6 mg, yield 21.9%).

[0360] MS m / z(ESI): 588.8 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ8.79(s,1H),8.58(d,J=2.4Hz,1H),8.55(d,J=5.1Hz,1H),8.22(s,1H),8.07(ddd,J=10.0,9.0,2.4H z,1H),7.64(d,J=5.1Hz,1H),6.80(s,1H),5.45(d,J=1.5Hz,2H),4.45–4.21(m,5H),3.02(s,3H),2.04(s,3H),1.92(s,3H).

[0361] Compound 41 from the amplified batch was subjected to... 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) resolved compounds 41-P1 (33.3mg, yield 10.5%) and 41-P2 (29.8mg, yield 9.3%).

[0362] Compound 41-P1:

[0363] MS m / z(ESI): 588.7 [M+1] + SFC: Retention time = 6.92 min, UV = 254 nm. 1 H NMR (400MHz, CD3OD) δ8.68(s,1H),8.42(d,J=5.2Hz,1H),8.36(d,J=2.4Hz,1H),8.20(s,1H),7.68–7.58(m,2H), 6.71(s,1H),5.40(d,J=1.9Hz,2H),4.42–4.29(m,4H),4.29–4.22(m,1H),2.90(s,3H),2.06(s,3H),1.93(s,3H).

[0364] Compound 41-P2:

[0365] MS m / z(ESI): 588.7 [M+1] + SFC: Retention time = 8.76 min, UV = 254 nm. 1H NMR (400MHz, CD3OD) δ8.68(s,1H),8.42(d,J=5.2Hz,1H),8.36(d,J=2.3Hz,1H),8.20(s,1H),7.69–7.59(m,2H),6.71(s ,1H),5.40(d,J=1.8Hz,2H),4.43–4.30(m,4H),4.26(d,J=8.2Hz,1H),2.89(d,J=5.7Hz,3H),2.06(s,3H),1.93(s,3H).

[0366] Example 11 Synthesis of Compound 45

[0367]

[0368] Step 1: Synthesis of Compound 45-2

[0369] Compound 45-1 (500 mg, 3.86 mmol), compound 2-2 (1.2 g, 3.86 mmol), and N,N-diisopropylethylamine (998 mg, 7.72 mmol) were dissolved in acetonitrile (15 mL) and stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0–4:1) to give compound 45-2 (1.2 g, yield: 88%).

[0370] MS m / z(ESI): 335.9 [M+1] + .

[0371] Step 2: Synthesis of Compound 45-3

[0372] A 1,4-dioxane solution of hydrogen chloride (1.8 mL, 4 M) was added to a 15 mL solution of compound 45-2 (800 mg, 2.38 mmol) in dichloromethane, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 45-3 (200 mg, crude product). The product was used directly for the next reaction without purification.

[0373] MS m / z(ESI): 136.1 [M+1] + .

[0374] Step 3: Synthesis of Compound 45

[0375] A solution of compound A (100 mg, 0.21 mmol), compound 45-3 (72 mg, 0.42 mmol), and potassium carbonate (87 mg, 0.63 mmol) in N,N-dimethylformamide (8 mL) was heated to 90 °C and stirred for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini-C18; 150 × 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 give compound 45 (20.2 mg, yield 16.6%).

[0376] MS m / z(ESI): 546.8 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.62(dd,J=8.6,3.7Hz,2H),8.26(s,1H),8.11(td,J=10.0,2.3Hz, 1H), 7.74 (d, J = 5.1Hz, 1H), 6.84 (s, 1H), 5.50 (s, 2H), 4.56 (t, J = 12.5Hz, 4H), 2.09 (s, 3H), 1.96 (s, 3H).

[0377] Example 12 Synthesis of compounds 34, 34-P1 and 34-P2

[0378]

[0379] Step 1: Synthesis of Compound 34-2

[0380] Isobutyl chloroformate (2.7 g, 19.78 mmol) was added to a tetrahydrofuran (50 mL) solution of compound 34-1 (2.0 g, 9.88 mmol) and N-methylmorpholine (1.5 g, 14.83 mmol). The reaction mixture was stirred at -10 °C for 1 hour, followed by the addition of a methanol solution of ammonia (20 mL), and stirring continued for 1.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0–1:1) to give compound 34-2 (2.1 g, yield: 84.41%). MS m / z (ESI): 145.1 [M+1] + .

[0381] Step 2: Synthesis of compound 34-3

[0382] A 15 mL, 4 M solution of 1,4-dioxane hydrogen chloride was added to a 15 mL solution of compound 34-2 (2.1 g, 10.43 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 34-3 (1.5 g, yield: 86.14%). MS m / z (ESI): 101.1 [M+1] + .

[0383] Step 3: Synthesis of compound 34-4

[0384] Compound 2-2 (3.1 g, 9.99 mmol) was added to a solution of compound 34-3 (1.0 g, 9.99 mmol) and N,N-diisopropylethylamine (2.58 g, 19.98 mmol) in acetonitrile (15 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0–1:1) to give compound 34-4 (1.0 g, yield: 26.32%). MS m / z (ESI): 342.9 [M+1] + .

[0385] Step 4: Synthesis of Compounds 34-5

[0386] A 1,4-dioxane solution of hydrogen chloride (3 mL, 4 M) was added to a dichloromethane solution of compound 34-4 (1.0 g, 2.92 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 34-5 (450 mg, yield: 97.55%). MS m / z (ESI): 143.0 [M+1] + .

[0387] Step 5: Synthesis of Compound 34

[0388] Compound 34-5 (449 mg, 3.16 mmol) was added to a solution of compound A (300 mg, 0.63 mmol) and potassium carbonate (523.84 mg, 3.79 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 90 °C for 16 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 (30 mL × 3). The combined organic phases were 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 to 10:1) to obtain compound 34. Compound 34 was purified by supercritical fluid chiral chromatography (equipment: SFC Tharprep80, column: CHIRALPAK AD-H 250 mm * 20 mm, 5 μm, mobile phase: 40%). EtOH / CO2 (NH4OH 0.2%), total flow rate: 40 g / min) was used to resolve compounds 34-P1 (40.5 mg, yield 11.3%) and 34-P2 (47.1 mg, yield 13.1%).

[0389] Compound 34-P1:

[0390] MS m / z(ESI):[M+1] + 553.8. SFC: Retention time = 3.81 min, UV = 214 nm. 1 H NMR (400MHz, CD3OD) δ8.74(s,1H),8.43(dd,J=3.8,1.3Hz,2H),8.24(s,1H),7.75–7.68(m,1H),7.63(d,J=5. 2Hz,1H),6.77(s,1H),5.47(d,J=1.8Hz,2H),4.35–4.17(m,4H),3.59–3.46(m,1H),2.12(s,3H),2.00(s,3H).

[0391] Compound 34-P2:

[0392] ESI-MS[M+H] + 553.8. SFC: Retention time = 4.6 min, UV = 214 nm. 1H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.43 (dd, J = 3.9, 1.1 Hz, 2H), 8.24 (s, 1H), 7.75–7.67 (m, 1H), 7.63 (d, J = 5.2 Hz, 1H), 6.77 (s, 1H), 5.47 (d, J = 1.6 Hz, 2H), 4.35–4.18 (m, 4H), 3.59–3.46 (m, 1H), 2.13 (s, 3H), 2.00 (s, 3H).

[0393] Example 13 Synthesis of compounds 29, 29-P1 and 29-P2

[0394]

[0395] Compounds 2-4 (303 mg, 1.83 mmol) were added to a solution of compound B (300 mg, 0.61 mmol) and potassium carbonate (168 mg, 1.22 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was heated to 90 °C and stirred for 16 hours. After the reaction was complete, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), 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 to 20 / 1) to obtain crude compound 29. Crude compound 29 was resolved by supercritical fluid chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK IC 250 mm * 4.6 mm, 5 μm, mobile phase: 40% MeOH / CO2 (NH4OH 0.2%), total flow rate: 40 g / min) to obtain compound 29-P1 (19.5 mg, yield 5.7%) and compound 29-P2 (22.6 mg, yield 6.6%).

[0396] Compound 29-P1:

[0397] ESI-MS[M+H] + :559.1. SFC: Retention time = 5.44 min, UV = 214 nm. 1 H NMR (400MHz, CD3OD) δ8.63(s,1H),8.44(dd,J=3.8,1.3Hz,2H),7.71(ddd,J=9.6,8.6,2.4Hz,1H),7.27(d,J=5.1 Hz,1H),6.85(d,J=0.5Hz,1H),5.49(d,J=1.9Hz,2H),4.09–3.91(m,4H),2.19(s,3H),2.10(s,3H),1.51(s,3H).

[0398] Compound 29-P2:

[0399] ESI-MS[M+H] + 559.1. SFC: Retention time = 15.16 min, UV = 214 nm. 1H NMR (400MHz, CD3OD) δ8.63(s,1H),8.44(dd,J=3.8,1.3Hz,2H),7.71(ddd,J=9.6,8.6,2.4Hz,1H),7.32–7 .21(m,1H),6.85(s,1H),5.49(d,J=1.9Hz,2H),4.10–3.93(m,4H),2.19(s,3H),2.10(s,3H),1.51(s,3H).

[0400] Based on the above embodiments, the following compounds were prepared:

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408] Biological evaluation

[0409] 1. Determination of in vitro activity of p38 MAPK / MK2

[0410] The inhibitory effect of the compounds on p38 MAPK / MK2 was detected using the Z-LYTE kinase assay kit (Thermo, PV3177). The test compounds were dissolved in DMSO to a 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound was 10 μM, serially diluted 5-fold with 1% DMSO, resulting in 8 concentrations in duplicate wells. 50 mM HEPES (pH 7.5), 10 mM MgCl2, 0.01% Brij-35, and 1 mM EGTA were used as reaction buffers to prepare 2x active p38a / inactive MK2 / Ser / Thr 4 mixtures. The final 10 μL reaction mixture 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), and 2 μM Ser / Thr 4. After reacting at 20°C for 1 hour, a 2048-fold diluted Development Reagent was added to each well. A. After incubation at room temperature for 1 hour, 5 μL of stop buffer was added to terminate the reaction. The results were detected using a microplate reader (Ex. 400 nm, Em. 445 nm; Ex. 400 nm, Em. 520 nm). Concentration-response curves were fitted using GraphPad Prism 8 software, and the concentration of the compound at which 50% inhibition occurred was calculated, i.e., the IC50 value. 50 The results are shown in Table 1.

[0411] Table 1

[0412] compound <![CDATA[p38 MAPK / MK2 IC 50 (nM)]]> Compound 2 4.75 Compound 2-P1 0.41 Compound 6 10.92 Compound 10 16.59 Compound 11 2.68 Compound 12 4.69 Compound 12-P2 0.55 Compound 13 10.04 Compound 29-P2 0.18 Compound 33 3.76 Compound 35 1.26 Compound 38 31.29 Compound 41 3.20 Compound 45 203.70 Compound 33-P2 2.11 Compound 34-P2 6.33 Compound 35-P2 1.24 Compound 41-P2 1.06

[0413] As shown in Table 1, the compounds disclosed herein exhibit good inhibitory activity against p38 MAPK / MK2.

[0414] 2. In vitro activity assay of p38 MAPK / MK5

[0415] The inhibitory effect of the compounds on p38 MAPK / MK5 was detected using the Z-LYTE kinase assay kit (Thermo, PV3177). The test compounds were dissolved in DMSO to a 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound was 10 μM, serially diluted 5-fold with 1% DMSO, resulting in 8 concentrations in duplicate wells. 50 mM HEPES (pH 7.5), 10 mM MgCl2, 0.01% Brij-35, and 1 mM EGTA were used as reaction buffers to prepare 2x active p38a / inactive MK5 / Ser / Thr 4 mixtures. The final 10 μL reaction mixture 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), and 2 μM Ser / Thr 4. After reacting at 20°C for 4 hours, a 2048-fold diluted Development Reagent was added to each well. A. After incubation at room temperature for 1 hour, 5 μL of stop buffer was added to terminate the reaction. The results were detected using a microplate reader (Ex. 400 nm, Em. 445 nm; Ex. 400 nm, Em. 520 nm). Concentration-response curves were fitted using GraphPad Prism 8 software, and the concentration of the compound at which 50% inhibition occurred was calculated, i.e., the IC50 value. 50 The results are shown in Table 2.

[0416] Table 2

[0417] compound <![CDATA[p38 MAPK / MK5 IC 50 (nM)]]> Compound 2 8443 Compound 6 2238 Compound 10 >10000 Compound 12 >10000 Compound 13 3206 Compound 41 8746

[0418] As shown in Table 2, the compounds disclosed herein exhibit inhibitory activity greater than 2 μM against p38 MAPK / MK5. This further demonstrates that the compounds disclosed herein possess good selectivity against p38 MAPK / MK2.

[0419] 3. Determination of in vitro activity of p38 MAPK / ATF2

[0420] The inhibitory effect of the compound on p38a-catalyzed ATF2 was detected using the HTRF method. The test compound was dissolved in DMSO to a 10 mM stock solution and stored at -20°C until use. The initial concentration of the compound was 10 μM, serially diluted 5-fold with 0.25% DMSO, in 8 wells, in duplicate. 40 mM Tris (pH 7.5), 20 mM MgCl2, 0.1 mg / mL BSA, and 50 μM DTT were used as reaction buffers to prepare working solutions for 3.5x p38a (MAPK14, Carna Biosciences, 04-152), 3.5x Human ATF2 Protein (Sino Biological, 11599-H20B), and 3.5x ATP. 10 mM EDTA was used to terminate the reaction. The final 14 μL reaction mixture was carried out in a 96-well plate (cisbio, 66PL96025) containing 0.29 ng / μL p38a, 0.29 μM Human ATF2 Protein, and 25 μM ATP. After reacting at 20℃ for 35 min, pre-prepared antibody solution (cibio, 63ADK015PEG, Phospho-ATF2 Eu Cryptate antibody, Phospho-ATF2 d2 antibody, diluted 40-fold with detection buffer) was added to each well and incubated overnight at room temperature. Detection was performed using an ELISA reader (HTRF compatible reader). Concentration-response curves were fitted using GraphPad Prism 8 software, and the concentration of the compound achieving 50% inhibition, i.e., IC50, was calculated. 50 The results are shown in Table 3.

[0421] Table 3

[0422]

[0423]

[0424] As shown in Table 3, the compounds disclosed herein exhibit inhibitory activity against p38 MAPK / ATF2 greater than 3.7 μM. This further demonstrates that the compounds disclosed herein possess good selectivity for p38 MAPK / MK2.

[0425] 4. In vitro activity assay of TNF-α in human PBMC cell supernatant

[0426] The inhibitory effect of the compound on TNF-α in human PBMC cell supernatant was detected using an ELISA kit (Beyotime, PI518). The test compound was dissolved in DMSO to a 10 mM stock solution and stored at -20°C until use. The initial compound concentration was 2 μM, with 5-fold serial dilutions, resulting in 6 concentrations. Cells were plated in double replicates, and ELISA was performed in single wells. The final DMSO concentration was 0.4%. The initial compound concentration, serial dilution factor, number of concentration gradients, and number of replicates can be adjusted according to the specific circumstances of the compound screening.

[0427] Fresh human peripheral blood mononuclear cells (PBMCs) (Sailor Biotech) were seeded at a density of 2*10^5 cells in 96-well plates (Corning, 3599). Each well contained 100 μL of RPMI-1640 (Gibco#A1049101) + 10% FBS (Gibco, 10099141C) and incubated overnight at 37°C with 5% CO2. The test compound was added to each well at a volume of 25 μL. After 1 hour, 5 μL of LPS was added to bring the final concentration to 100 ng / mL. Negative control wells did not contain LPS or the test compound, and positive control wells did not contain the test compound. The cells were incubated at 37°C with 5% CO2 for another 24 hours. The cell culture supernatant was collected by centrifugation at 500 rcf for 8 min. The concentration of TNF-α was measured according to the ELISA kit instructions. Concentration-response curves were fitted using GraphPad Prism 8 software, and the concentration of the compound at which 50% inhibition was achieved was calculated, i.e., IC50. 50 The results are shown in Table 4.

[0428] Table 4

[0429] compound <![CDATA[TNF-αIC 50 (nM)]]> Compound 6 34.15 Compound 10 72.99 Compound 12 24.64 Compound 13 56.80 Compound 41 50 Compound 34-P2 96.39 Compound 35-P2 77.74 Compound 41-P1 38.18

[0430] As shown in Table 4, the compounds disclosed herein have a good inhibitory effect on TNF-α in human PBMC cells.

[0431] The embodiments of this disclosure have been described above. However, this disclosure is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this disclosure should be included within the protection scope of this disclosure.

Claims

1. A compound as shown in Formula I, a racemate, a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof: Formula I wherein: W is CH or N; m is an integer from 0 to 5; n is an integer from 0 to 3; R1 is H or CH3; R2 is H or CH3; R3 is H or CH3; R4 is H or CH3; R5 is H, OH, or CH3; R6 is H or CH3; R7 is H, OH, or CH3; R8 is H or CH3; R9 is H or CH3; R10 is H or CH3; R11 is H or CH3; R12 is H or CH3; R13 is H or CH3; R14 is H or CH3; R15 is H or CH3; R16 is H or CH3; R17 is H or CH3; R18 is H or CH3; R19 is H or CH3; R20 is H or CH3; R21 is H or CH3; R22 is H or CH3; R23 is H or CH3; R24 is H or CH3; R25 is H or CH3; R26 is H or CH3; R27 is H or CH3; R28 is H or CH3; R29 is H or CH3; R30 is H or CH3; R31 is H or CH3; R32 is H or CH3; R33 is H or CH3; R34 is H or CH3; R35 is H or CH3; R36 is H or CH3; R37 is H or CH3; R38 is H or CH3; R39 is H or CH3; R40 is H or CH3; R41 is H or CH3; R42 is H or CH3; R43 is H or CH3; R44 is H or CH3; R45 is H or CH3; R46 is H or CH3; R47 is H or CH3; R48 is H or CH3; R49 is H or CH3; R50 is H or CH3; R51 is H or CH3; R52 is H or CH3; R53 is H or CH3; R54 is H or CH3; R55 is H or CH3; R56 is H or CH3; R57 is H or CH3; R58 is H or CH3; R59 is H or CH3; R60 is H or CH3; R61 is H or CH3; R62 is H or CH3; R63 is H or CH3; R64 is H or CH3; R65 is H or CH3; R66 is H or CH3; R67 is H or CH3; R68 is H or CH3; R69 is H or CH3; R70 is H or CH3; R71 is H or CH3; R72 is H or CH3; R73 is H or CH3; R74 is H or CH3; R75 is H or CH3; R76 is H or CH3; R77 is H or CH3; R78 is H or CH3; R79 is H or CH3; R80 is H or CH3; R81 is H or CH3; R82 is H or CH3; R83 is H or CH3; R84 is H or CH3; R85 is H or CH3; R86 is H or CH3; R87 is H or CH3; R88 is H or CH3; R89 is H or CH3; R90 is H or CH3; R91 is H or CH3; R92 is H or CH3; R93 is H or CH3; R94 is H or CH3; R95 is H or CH3; R96 is H or CH3; R97 is H or CH3; R98 is H or CH3; R99 is H or CH3; R100 is H or CH3; R101 is H or CH3; R102 is H or CH3; R103 is H or CH3; R104 is H or CH3; R105 is H or CH3; R106 is H or CH3; R107 is H or CH3; R108 is H or CH3; R109 is H or CH3; R110 is H or CH3; R111 is H or CH3; R112 is H or CH3; R113 is H or CH3; R114 is H or CH3; R115 is H or CH3; R116 is H or CH3; R117 is H or CH3; R118 is H or CH3; R119 is H or CH3; R120 is H or CH3; R121 is H or CH3; R122 is H or CH3; R123 is H or CH3; R124 is H or CH3; R125 is H or CH3; R126 is H or CH3; R127 is H or CH3; R128 is H or CH3; R129 is H or CH3; R130 is H or CH3; R131 is H or CH3; R132 is H or CH3; R133 is H or CH3; R134 is H or CH3; R135 is H or CH3; R136 is H or CH3; R137 is H or CH3; R138 is H or CH3; R139 is H or CH3; R140 is H or CH3; R141 is H or CH3; R142 is H or CH3; R143 is H or CH3; R144 is H or CH3; R145 is H or CH3; R146 is H or CH3; R147 is H or CH3; R148 is H or CH3; R149 is H or CH3; R150 is H or CH3; R151 is H or CH3; R152 is H or CH3; R153 is H or CH3; R154 is H or CH3; R155 is H or CH3; R156 is H or CH3; R157 is H or CH3; R158 is H or CH3; R159 is H or CH3; R160 is H or CH3; R161 is H or CH3; R162 is H or CH3; R163 is H or CH3; R164 is H or CH3; R165 is H or CH3; R166 is H or CH3; R167 is H or CH3; R168 is H or CH3; R169 is H or CH3; R170 is H or CH3; R171 is H or CH3; R172 is H or CH3; R173 is H or CH3; R174 is H or CH3; R175 is H or CH3; R176 is H or CH3; R177 is H or CH3; R178 is H or CH3; R179 is H or CH3; R180 is H or CH3; R181 is H or CH3; R182 is H or CH3; R183 is H or CH3; R184 is H or CH3; R185 is H or CH3; R186 is H or CH3; R187 is H or CH3; R188 is H or CH3; R189 is H or CH3; R190 is H or CH3; R191 is H or CH3; R192 is H or CH3; R193 is H or CH3; R194 is H or CH3; R195 is H or CH3; R196 is H or CH3; R197 is H or CH3; R198 is H or CH3; R199 is H or CH3; R200 is H or CH3; R201 is H or CH3; R202 is H or CH3; R203 is H or CH3; R204 is H or CH3; R205 is H or CH3; R206 is H or CH3; R207 is H or CH3; R208 is H or CH3; R209 is H or CH3; R210 is H or CH3; R211 is H or CH3; R212 is H or CH3; R213 is H or CH3; R214 is H or CH3; R215 is H or CH3; R216 is H or CH3; R217 is H or CH3; R218 is H or CH3; R219 is H or CH3; R220 is H or CH3; R221 is H or CH3; R222 is H or CH3; R223 is H or CH3; R224 is H or CH3; R225 is H or CH3; R226 is H or CH3; R227 is H or CH3; R228 is H or CH3; R229 is H or CH3; R230 is H or CH3; R231 is H or CH3; R232 is H or CH3; R233 is H or CH3; R234 is H or CH3; R235 is H or CH3; R236 is H or CH3; R237 is H or CH3; R238 is H or CH3; R239 is H or CH3; R240 is H or CH3; R241 is H or CH3; R242 is H or CH3; R243 is H or CH3; R244 is H or CH3; R245 is H or CH3; R246 is H or CH3; R247 is H or CH3 wherein ​ Ring A is a 4-9 membered nitrogen-containing heterocyclyl, except for the N atom attached to the parent optionally contains 1, 2 or more heteroatoms selected from O, N or S in addition to the N atom attached to the parent R 1 selected from halogen; R 2 selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 , and -C(O)NHR 84 ; R 3 selected from C 1-3 alkyl and C 3-6 cycloalkyl; R 4 selected from the group consisting of halogen and C 1-3 alkyl; R 5 are each independently selected from the group consisting of halogen, -OH, -C 1-6 alkyl, -C 1-6 alkoxy, oxo (=0), -C(O)C 1-6 alkyl, hydroxy-substituted 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, halogen and methyl; R 7 are each independently selected from the group consisting of H, halogen, C 1-3 alkyl; R 81 , R 82 , R 83 , R 84 are identical or different and independently of each other selected from the group consisting of phenylmethyl, pyridinylmethyl, pyridinylethyl, phenyl and pyridyl, unsubstituted or optionally substituted by 1, 2 or 3 Rb; each Rb is identical or different and independently of each other selected from the group consisting of F, CI and CF3; R 91a , R 91b , R 92 , R 93a , R 93b are identical or different and independently of each other selected from the group consisting of H, C 1-6 alkyl and C 3-7 cycloalkyl.

2. The compound, racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, ​ ​ R 1 is CI or Br; R 2 selected from -OR 81 , -NH-C(O)R 82 , -NHR 83 , and -C(O)NHR 84 ; R 3 is methyl or cyclopropyl; R 4 is methyl; R 5 selected from F, -OH, methyl, methoxy, ethoxy, oxo (=0), -C(0)CH3, -C(0)OH, -C(0)NH2, -C(0)NHCH3, -S(0)2CH3, S(0)2CH2CH3, and -S(0)2-cyclopropane; 1-3 alkyl, 2-hydroxyisopropyl, -C(0)OH, -C(0)NH2, -C(0)NHCH3, -S(0)2CH3, S(0)2CH2CH3, and -S(0)2-cyclopropane; R 6 selected from H, F and CI; R 7 is H; R 81 , R 82 , R 83 , R 84 are identical or different and independently of each other selected from the group consisting of phenylmethyl, pyridinylmethyl, pyridinylethyl, phenyl and pyridyl, unsubstituted or optionally substituted by 1, 2 or 3 Rb; each Rb is identical or different and independently of each other selected from the group consisting of F, CI and CF3.

3. The compound of claim 1, racemate, stereoisomer, tautomer thereof, or pharmaceutically acceptable salt thereof, wherein, ​ 4. The compound of claim 1, racemate, stereoisomer, tautomer thereof, or pharmaceutically acceptable salt thereof, wherein, ​ wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A, W, m and n have the definitions given in claim 1. ​ wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, W and ring A independently of one another have the definitions given in claim 1 ; R 10 selected from H, C 1-6 alkyl; Each R 11 They are either the same or different, and are selected independently from F, Cl and CF3.

6. The compound, racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 5, wherein ​ wherein 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 given in claim 5.

7. The compound of claim 1, racemate, stereoisomer, tautomer thereof, or pharmaceutically acceptable salt thereof, wherein, ​ 8. The compound of claim 1, racemate, stereoisomer, tautomer thereof, or pharmaceutically acceptable salt thereof, wherein, ​ 9. A process for the preparation of a compound according to any one of claims 1 to 8, a racemate, a stereoisomer, a tautomer thereof or a pharmaceutically acceptable salt thereof, characterized in that, ​ ​ ​ wherein Y is CI 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 given in any one of claims 1 to 8; ​ ​ wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , m, n, p and ring A independently of each other have the definitions given in any of claims 1 to 8; ​ ​ ​ ​ ​ 12. Use according to claim 11, characterized in that, ​ 13. Use according to claim 12, characterized in that, ​ ​ ​

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