Acetylbenzylamine derivative as well as preparation method and application thereof

Abstract

The invention relates to an acetylbenzylamine derivative as well as a preparation method and application thereof, and particularly discloses a compound as shown in a formula I or pharmaceutically acceptable salt thereof. The compound has a good agonistic effect on a human somatostatin SSTR4 receptor; the compound can be used for preparing medicines for treating and / or preventing diseases related to the central nervous system. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application 2023107347549, filed on June 20, 2023. This application cites the entire text of the above Chinese patent application. Technical Field

[0002] The invention relates to an acetylbenzamide derivative, a preparation method and application thereof. Background Art

[0003] Somatostatin receptors (SSTRs) are a family of G protein-coupled receptors that mediate somatostatin and its analogs and have a variety of biological effects. Their physiological functions and mechanisms of action have long attracted much attention. Studies have shown that these specific membrane receptors on the cell membrane, including SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5, can play an important role in regulating GH secretion, inducing cell apoptosis, inhibiting tumor cell proliferation, inhibiting insulin action and inhibiting cell growth through cAMP, PTP and MAPK signaling pathways. They also show kinetic characteristics similar to those of other G protein-coupled receptors. Somatostatin (SST) is a cyclic polypeptide widely distributed in the central nervous system and peripheral tissues. It is a growth hormone-inhibiting releasing hormone isolated and purified from the hypothalamus of sheep by Brazeau et al. in 1973. It exists in the body in two forms: 14 peptides (SST-14) and 28 peptides (SST-28). The results show that SST, as a signal molecule, is mediated by the SST receptor family (somatostatin receptors, SSTRs) on the cell membrane. SST has only two forms, and the complexity of SST's physiological function is reflected by the complexity of its receptors. Therefore, the biological significance of SSTR is more important than SST to some extent.

[0004] There is 40% to 60% homology in the amino acid sequence between the subtypes of human somatostatin receptor (hSSTR), among which Taylor et al. confirmed that SSTR2 has two variants, SSTR2A and SSTR2B. Among the five subtypes, except for SSTR5, whose binding force to SST28 is 10 to 30 times that of SST14, all subtypes have high affinity to SST14 and SST28. Somatostatin is associated with the regulation of processes such as cell proliferation, glucose homeostasis, inflammation and pain. In this regard, it is believed that somatostatin or other members of the somatostatin peptide family inhibit pain and inflammatory processes via the SSTR4 pathway. The selective SSTR4 agonist J-2156 has been disclosed, for example, in Biomedicine & Pharmacotherapy, 117, (2019), 109056, and it is reported to have analgesic effects in animals. Other patents WO2016075239, WO2016075240, and WO2014184275 report the application of SSTR4 agonists in the field of analgesia.

[0005] Natural SST has a wide range of effects, low selectivity, and a short half-life (about 1 min). Therefore, a variety of somatostatin analogs (SSTA) have been artificially synthesized to enhance its effects and prolong its half-life. The synthesized SSTAs include octapeptide analogs octreotide (SMS201995), lanreotide (BIM2304), and vapreotide (RC-160); heptapeptide analogs include TT-232; hexapeptide analogs include seglitide (MK-678), etc. These octapeptide analogs have a plasma half-life of >90 min and high affinity for receptors, but are difficult to be orally absorbed and are not suitable for long-term chronic diseases, such as pain. Therefore, it is urgent to develop non-peptide SSTR4 agonists with high stability, high selectivity, and oral efficacy to meet clinical needs. Summary of the invention

[0006] The present invention aims to solve the technical problem that there are few agonists for human somatostatin IV type SSTR4 receptor, and thus provides an acetylbenzamide derivative, a preparation method and application thereof. The compound has a good agonistic effect on human somatostatin IV type SSTR4 receptor and can be used to prepare drugs for treating and / or preventing diseases related to the central nervous system.

[0007] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0008]

[0009] Wherein, the carbon atom with "*" indicates that when it is a chiral carbon atom, it is independently in S configuration, R configuration or a mixture thereof;

[0010] The definition of each substituent is selected from one of the following schemes 1-3:

[0011] Option 1: R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -C 2-6 Alkynyl, -C 2-6 Haloalkynyl, -C 3-6 Cycloalkyl, -C 3-6 Halogenated cycloalkyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, 1, 2 or 3 R a Replaced-C 1-6 Alkyl, 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, 1, 2 or 3 R a Replaced-C 2-6 Alkynyl; R 1 ,R 2 ,R 3 ,R 4 and R 5 At least one of them is -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 alkyl;

[0012] R a Independently -C 3-6 Cycloalkyl;

[0013] R 6 For -C 3-6 Cycloalkyl, 1, 2 or 3 R b Replaced-C 1-6 alkyl;

[0014] R b are independently halogen or -CN;

[0015] R 7 -H, -C1-6 Alkyl, -C 3-6 Cycloalkyl or -C substituted by 1, 2 or 3 CN 1-6 alkyl;

[0016] Option 2: R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -C 2-6 Alkynyl, -C 2-6 Haloalkynyl, -C 3-6 Cycloalkyl, -C 3-6 Halogenated cycloalkyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, 1, 2 or 3 R a Replaced-C 1-6 Alkyl, 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, 1, 2 or 3 R a Replaced-C 2-6 Alkynyl;

[0017] R a Independently -C 3-6 Cycloalkyl;

[0018] R 6 For -C 3-6 Cycloalkyl, -C substituted by 1, 2 or 3 -CN 1-6 alkyl;

[0019] R 7 -H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl or -C substituted by 1, 2 or 3 CN 1-6 alkyl;

[0020] Option 3: R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -C2-6 Alkynyl, -C 2-6 Haloalkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -C 3-6 Cycloalkyl, -C 3-6 Halogenated cycloalkyl, 1, 2 or 3 R a Replaced-C 1-6 Alkyl, 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, 1, 2 or 3 R a Replaced-C 2-6 Alkynyl;

[0021] R a Independently -C 3-6 Cycloalkyl;

[0022] R 6 For -C 3-6 Cycloalkyl, 1, 2 or 3 R b Replaced-C 1-6 alkyl;

[0023] R b are independently halogen or -CN;

[0024] R 7 -C substituted by 1, 2 or 3 CN 1-6 Alkyl or -C 3-6 Cycloalkyl.

[0025] In a preferred embodiment, some groups in the compound as shown in Formula I are defined as follows (the groups not mentioned are the same as those described in any embodiment of the present application, hereinafter referred to as "in a preferred embodiment"). In Embodiments 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 1-6 Alkyl, -OC 1-6 Alkyl, substituted-C 1-6 Alkyl, and substituted -OC 1-6 -C in the alkyl group 1-6 Alkyl can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example, methyl.

[0026] In a preferred embodiment, in Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C1-6 Haloalkyl, and -OC 1-6 -C in haloalkyl 1-6 The haloalkyl group may independently be halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl, halo-isobutyl, halo-sec-butyl or halo-tert-butyl.

[0027] In a preferred embodiment, in Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 2-6 Alkynyl, and substituted -C 2-6 -C in alkynyl 2-6 Alkynyl groups independently may be -C 2-4 Alkynyl, e.g.

[0028] In a preferred embodiment, in Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 2-6 The haloalkynyl groups are independently -C 2-4 Haloalkynyl.

[0029] In a preferred embodiment, in Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 3-6 Cycloalkyl, -OC 3-6 -C in cycloalkyl 3-6 Cycloalkyl groups independently may be cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; for example, cyclopropyl or cyclobutyl.

[0030] In a preferred embodiment, in Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 3-6 Halogenated cycloalkyl, -OC 3-6 -C in halocycloalkyl 3-6 The halocycloalkyl groups independently may be halocyclopropyl, halocyclobutyl, halocyclopentyl and halocyclohexyl, for example halocyclobutyl.

[0031] In a preferred embodiment, in Scheme 1-3, R 6 In the -C 3-6Cycloalkyl groups independently may be cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; for example, cyclopropyl or cyclobutyl.

[0032] In a preferred embodiment, in Scheme 1-3, R 6 wherein the substituted -C 1-6 -C in the alkyl group 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0033] In a preferred embodiment, in Schemes 1 and 2, R 7 In the -C 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl.

[0034] In a preferred embodiment, in Scheme 1-3, R 7 In the -C 3-6 Cycloalkyl groups independently may be cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; for example, cyclopropyl or cyclobutyl.

[0035] In a preferred embodiment, in Scheme 1-3, R 7 In the case of -C 1-6 -C in the alkyl group 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0036] In a preferred embodiment, in Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the above, the halogen can independently be F, Cl, Br, I, for example, F or Cl.

[0037] In a preferred embodiment, in embodiments 1 and 3, R b In the above, the halogen can independently be F, Cl, Br, I, for example, F or Cl.

[0038] In a preferred embodiment, in Scheme 1-3, R a In the -C 3-6 The cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, for example cyclopropyl.

[0039] In a preferred embodiment, in Scheme 2, R 6 wherein the substituted -C 1-6 The number of CN in the alkyl group may be 1.

[0040] In a preferred embodiment, in Scheme 3, R7 wherein the substituted -C 1-6 The number of CN in the alkyl group may be 1.

[0041] In a preferred embodiment, in Scheme 1, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 Alkyl; R 1 , R 2 , R 3 , R 4 and R 5 Among them, one is -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 alkyl, and the rest are -H or halogen.

[0042] In a preferred embodiment, in Scheme 1, R a Independently -C 3-6 Cycloalkyl.

[0043] In a preferred embodiment, in Scheme 1, R 6 For 1, 2 or 3 R b Replaced-C 1-6 alkyl.

[0044] In a preferred embodiment, in Scheme 1, R b are independently halogen.

[0045] In a preferred embodiment, in Scheme 1, R 7 For -C 1-6 alkyl.

[0046] In a preferred embodiment, in Scheme 2, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl; preferably, R 1 , R 2 , R 3 , R4 and R 5 One of them is -H, halogen, -C 1-6 Alkyl or -OC 1-6 alkyl, the rest are H; more preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is -H, halogen or -C 1-6 Alkyl, the rest are H.

[0047] In a preferred embodiment, in Scheme 2, R 6 For -C 3-6 Cycloalkyl, -C substituted by 1, 2 or 3 -CN 1-6 alkyl.

[0048] In a preferred embodiment, in Scheme 2, R 7 For -C 1-6 alkyl.

[0049] In a preferred embodiment, in Scheme 3, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H or halogen; preferably, R 1 , R 2 , R 3 , R 4 and R 5 Among them, one is -H or halogen, and the rest are H.

[0050] In a preferred embodiment, in Scheme 3, R 6 For 1, 2 or 3 R b Replaced-C 1-6 alkyl.

[0051] In a preferred embodiment, in Scheme 3, R b are independently halogen or -CN.

[0052] In a preferred embodiment, in Scheme 3, R 7 -C substituted by 1, 2 or 3 CN 1-6 Alkyl or -C 3-6 Cycloalkyl.

[0053] In a preferred embodiment, in Scheme 1,

[0054] R 1 , R 2 , R 3 , R 4 and R 5are independently -H, halogen, -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 Alkyl; R 1 , R 2 , R 3 , R 4 and R 5 Among them, one is -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, the rest are -H or halogen;

[0055] R a Independently -C 3-6 Cycloalkyl;

[0056] R 6 For 1, 2 or 3 R b Replaced-C 1-6 alkyl;

[0057] R b are independently halogen;

[0058] R 7 For -C 1-6 alkyl.

[0059] In a preferred embodiment, in Scheme 2,

[0060] R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -C 1-6 Alkyl or -OC 1-6 alkyl;

[0061] R 6 For -C 3-6 Cycloalkyl, -C substituted by 1, 2 or 3 -CN 1-6 alkyl;

[0062] R 7 For -C 1-6 alkyl;

[0063] Preferably, R 1 , R 2 , R 3 , R 4 and R5 One of them is -H, halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl, the rest are H;

[0064] More preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is -H, halogen or -C 1-6 Alkyl, the rest are H.

[0065] In a preferred embodiment, in Scheme 3,

[0066] R 1 , R 2 , R 3 , R 4 and R 5 are independently -H or halogen;

[0067] R 6 For 1, 2 or 3 R b Replaced-C 1-6 alkyl;

[0068] R b are independently halogen;

[0069] R 7 -C substituted by 1, 2 or 3 CN 1-6 Alkyl or -C 3-6 Cycloalkyl;

[0070] Preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is -H or halogen, and the rest are H.

[0071] In a preferred embodiment, in Scheme 1, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, One of them is The rest are -H or halogen.

[0072] In a preferred embodiment, in Scheme 1, R 6 for For example

[0073] In a preferred embodiment, in Scheme 1, R7 for For example

[0074] In a preferred embodiment, in Scheme 2, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -CH 3 or -O-CH 3 ; preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is H, halogen, -CH 3 or -O-CH 3 , and the rest are H.

[0075] In a preferred embodiment, in Scheme 2, R 6 for For example

[0076] In a preferred embodiment, in Scheme 2, R 7 -CH 3 , Preferably For example

[0077] In a preferred embodiment, in Scheme 3, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H or halogen; preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is H or halogen, and the rest are H.

[0078] In a preferred embodiment, in Scheme 3, R 6 for (Preferably ).

[0079] In a preferred embodiment, in Scheme 3, R 7 for For example

[0080] In a preferred embodiment, the compound shown in formula I is a compound shown in formula IA:

[0081]

[0082] Among them, *, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The definition of is as above.

[0083] In a preferred embodiment, in Scheme 1, the compound shown in Formula I is a compound shown in Formula I-1A, I-1B or I-1C:

[0084]

[0085] Among them, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as above.

[0086] In a preferred embodiment, in Scheme 2, the compound shown in Formula I is a compound shown in Formula I-2A, I-2B or I-2C:

[0087]

[0088] Among them, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as above.

[0089] In a preferred embodiment, in Scheme 3, the compound shown in Formula I is a compound shown in Formula I-3A or I-3B:

[0090]

[0091] Among them, R 1 , R 2 , R 3 , R 4 and R 5 The definition of is as above.

[0092] The compound as shown in formula I is selected from any of the following compounds:

[0093]

[0094]

[0095] The present invention also provides a method for preparing the compound as shown in formula I, which comprises the following steps:

[0096] In a solvent, the compound represented by formula II and the compound represented by formula III are mixed to undergo a condensation reaction to obtain a compound represented by formula I;

[0097]

[0098] *、R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The definitions are as mentioned above.

[0099] The present invention also provides a compound as shown in formula II, or a salt thereof,

[0100]

[0101] *、R 1 , R 2 , R 3 , R 4 , R 5 and R 6 The definitions are as mentioned above.

[0102] The compound as shown in formula II is selected from any of the following compounds:

[0103]

[0104]

[0105] The present invention also provides a pharmaceutical composition, which comprises (a therapeutically effective amount of) the above compound as shown in Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

[0106] The selection of the pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and can generally be conventional fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc. in the art.

[0107] The present invention also provides a use of the compound shown in formula I, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of an SSTR4 receptor agonist.

[0108] The SSTR4 receptor agonist can be used to prepare medicines for treating and / or preventing diseases related to the central nervous system.

[0109] The SSTR4 receptor agonist can be used to prepare a drug for treating and / or preventing pain or osteoarthritis. The pain can be acute pain, neuropathic peripheral pain or chronic pain.

[0110] The disease related to the central nervous system may be Alzheimer's disease, epilepsy or depression.

[0111] In the application, the SSTR4 receptor agonist can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of the SSTR4 receptor agonist.

[0112] The present invention also provides a compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof for preparing a drug for treating and / or preventing diseases related to the central nervous system.

[0113] The diseases related to the central nervous system are mediated through the SSTR4 pathway.

[0114] The disease may be Alzheimer's disease, epilepsy or depression.

[0115] The disease may be pain or osteoarthritis. The pain may be acute pain, neuropathic peripheral pain or chronic pain.

[0116] the term

[0117] Unless otherwise specified, the following terms appearing in the specification and claims of the present invention have the following meanings:

[0118] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0119] The end of the structural fragment It means that the structural fragment is connected to the rest of the molecule through this site.

[0120] A "-" at the end of a group means that the group is attached to the rest of the molecule through that site. For example, -CN refers to a cyano group.

[0121] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0122] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., 1-6 The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0123] The term "alkynyl" refers to a radical having the specified number of carbon atoms (e.g., C 2-6 alkynyl), a linear or branched, unsaturated, monovalent hydrocarbon radical having one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 Triple bond. Alkynyl groups include, but are not limited to: wait.

[0124] The term "cycloalkyl" refers to a cycloalkyl radical having the specified number of carbon atoms (e.g., 3-6 Cyclic, saturated, monovalent hydrocarbon group, which is a monocyclic ring. Cyclic alkyl groups include, but are not limited to: wait.

[0125] The term "haloalkyl" is an "alkyl" substituted with one or more (eg, 1, 2 or 3) halogens; the definition of the "alkyl" is the same as the term "alkyl".

[0126] The term "halocycloalkyl" is a "cycloalkyl" substituted with one or more (eg, 1, 2 or 3) halogens; the definition of the "cycloalkyl" is the same as the term "cycloalkyl".

[0127] The term "haloalkynyl" is an "alkynyl" substituted with one or more (eg, 1, 2 or 3) halogens; the "alkynyl" is defined as the term "alkynyl".

[0128] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0129] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives. For details, please refer to the "Pharmacopoeia of the People's Republic of China (2020 Edition)" and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0130] The term "treating" refers to removing the cause or alleviating the symptoms.

[0131] The term "prevention" refers to reducing the risk of developing a disease.

[0132] The term "patient" refers to any animal, usually a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0133] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0134] The reagents and raw materials used in the present invention are commercially available.

[0135] The positive and progressive effect of the present invention is that the compounds of the present application have a good agonistic effect on human somatostatin SSTR4 receptors and can be used to prepare drugs for treating and / or preventing diseases related to the central nervous system. BRIEF DESCRIPTION OF THE DRAWINGS

[0136] Figure 1 These are the results of a pharmacodynamic study on a rat sciatic nerve pain model.

[0137] Figure 2 These are the results of a pharmacodynamic study on the rat CFA pain model. DETAILED DESCRIPTION

[0138] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0139] Synthesis part:

[0140] Example 1 BX20-7-804

[0141] Step 1: Synthesis of intermediate A2

[0142] The synthetic route is shown below:

[0143]

[0144] Method: Compound A0 (3.0 g, 24.6 mmol) was dissolved in DMA (50 mL), and Cs 2 CO 3 (16 g, 49.1 mmol), KI (1.2 g, 7.4 mmol), N 2 , A1 (30 g, 245.7 mmol) was added, and the reaction mixture was heated to 150°C in a sealed tube and stirred for 12 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography (PE) to obtain a light yellow oily compound A2 (1.3 g, 32.5%). MS (ESI, m / z) 163.1 [M+H] + .

[0145] Step 2: Synthesis of intermediate S1

[0146] The synthetic route is shown below:

[0147]

[0148] Method: Compound SM1 (1.2 g, 9.5 mmol) was dissolved in toluene (30 mL), and A2 (1.3 g, 8.0 mmol), KHSO 4 (1.3 g, 9.5 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S1 (1.6 g, 64.0%). MS (ESI, m / z) 266.1 [M+H] + .

[0149] Step 3: Synthesis of intermediate S2

[0150] The synthetic route is shown below:

[0151]

[0152] Method: Compound S1 (1.6 g, 6.0 mmol) and SM2 (1.3 g, 6.6 mmol) were dissolved in THF (20 mL), cooled to -78 °C, and LiHMDS (7.2 mL, 1 M) was added dropwise. The reaction was maintained at -78 °C and stirred for 90 min. After the reaction, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow solid compound S2 (1.8 g, 65.5%). MS (ESI, m / z) 458.1 [M+H] + .

[0153] Step 4: Synthesis of S3

[0154] The synthetic route is shown below:

[0155]

[0156] Method: Dissolve NaOAc (3.2 g, 39 mmol) and HOAc (2.3 g, 39 mmol) in H 2 O (6.8 mL) to obtain solution A. Compound S2 (1.8 g, 3.9 mmol) was dissolved in DMF (20 mL) to obtain solution B. A was added to B, and then Mg (1.4 g, 59 mmol) was added. The reaction mixture was stirred at 25°C for 2 h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography to obtain a colorless oily compound S3 (1 g, 80.1%). MS (ESI, m / z) 318.1 [M+H] + .

[0157] Step 5: Synthesis of S4

[0158] The synthetic route is shown below:

[0159]

[0160] Method: Compound S3 (1 g, 3.2 mmol) was dissolved in MeOH (10 mL), HCl / 1,4-dioxane (8 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a light yellow solid compound S4 (900 mg, crude product). MS (ESI, m / z) 214.1 [M+H] + .

[0161] Step 6: Synthesis of BX20-7-804

[0162] The synthetic route is shown below:

[0163]

[0164] Method: Compound Int 1 (0.23 g, 1.4 mmol) was dissolved in DMF (5 mL), TEA (0.36 g, 3.6 mmol) and HATU (0.53 g, 1.4 mmol) were added in sequence, and S4 (0.30 g, 1.2 mmol) was added after stirring for 5 min. The reaction mixture was stirred at 25 ° C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and purified by preparative chromatography (ammonia system) to obtain a brown solid compound BX20-7-804 (90 mg, 18.2%). MS (ESI, m / z) 353.2 [M+H] + .

[0165] 1 H NMR (400 MHz, DMSO-d 6 )δ=8.70(d,J=8.0Hz,1H),7.46-7.44(m,1H),7.35-7.31(m,2H),7.03-7.00(m,1H) , 6.19-5.90(m,1H), 5.69-5.60(m,1H), 3.93-3.89(m,1H), 3.6-3.01(m,2H), 2.95-2 .90(m,2H), 2.46-2.41(m,1H), 2.34-2.27(m,1H), 2.22-2.18(m,1H), 1.82(t,J=8. 0Hz, 2H), 1.38 (t, J = 8.0Hz, 2H), 0.84-0.82 (m, 3H), 0.80-0.78 (m, 2H), 0.70 (s, 2H).

[0166] Example 2BX20-7-805

[0167] Step 1: Synthesis of intermediate A2

[0168] The synthetic route is shown below:

[0169]

[0170] Method: Compound A0 (4.0 g, 23.1 mmol) was dissolved in NMP (80 mL), and Cs 2 CO 3 (18.8 g, 57.7 mmol), A1 (5.6 g, 46.3 mmol), the reaction mixture was heated to 130 ° C and refluxed for 24 h. After the reaction, the filtrate was collected. Diluted with water, extracted with EA, and washed with brine. After reduced pressure concentration, it was purified by column chromatography to obtain a colorless transparent oil compound A2 (2.2 g, 44.7%). MS (ESI, m / z) 213.0 [M+H] + .

[0171] Step 2: Synthesis of intermediate A3

[0172] The synthetic route is shown below:

[0173]

[0174] Method: Compound A2 (2.2 g, 10.3 mmol) was dissolved in THF (30 mL), cooled to -78 °C, and n-BuLi (5.0 mL, 2.5 M) was added dropwise. The reaction was maintained at -78 °C and stirred for 1 h. DMF (1.5 g, 20.6 mmol) was then added dropwise. The reaction mixture was naturally heated to 25 °C and stirred for 3 h. After the reaction was completed, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oily compound A3 (1.3 g, 79.6%). MS (ESI, m / z) 163.1 [M+H] + .

[0175] Step 3: Synthesis of intermediate S1

[0176] The synthetic route is shown below:

[0177]

[0178] Method: Compound SM1 (1.2 g, 9.7 mmol) was dissolved in toluene (30 mL), and A3 (1.3 g, 8.1 mmol), KHSO 4 (1.3 g, 9.7 mmol), the reaction mixture was heated to 45°C and stirred for 16 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S1 (1.3 g, 60.5%). MS (ESI, m / z) 266.1 [M+H] + .

[0179] Step 4: Synthesis of intermediate S2

[0180] The synthetic route is shown below:

[0181]

[0182] Method: Compound S1 (1.3 g, 4.9 mmol) and SM2 (1.3 g, 6.6 mmol) were dissolved in THF (20 mL), cooled to -78 °C, and LiHMDS (6.0 mL, 1 M) was added dropwise. The reaction was maintained at -78 °C and stirred for 90 min. After the reaction, saturated NH 4The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow solid compound S2 (1.7 g, 75.9%). MS (ESI, m / z) 458.1 [M+H] + .

[0183] Step 5: Synthesis of S3

[0184] The synthetic route is shown below:

[0185]

[0186] Method: Dissolve NaOAc (3.0 g, 36 mmol) and HOAc (2.2 g, 36 mmol) in H 2 O (6.3mL) to obtain solution A. Compound S2 (1.7g, 3.6mmol) was dissolved in DMF (30mL) to obtain solution B. A was added to B, and then Mg (1.3g, 54mmol) was added. The reaction mixture was stirred at 25°C for 2h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography to obtain a colorless oil compound S3 (0.8g, 70.2%). MS (ESI, m / z) 318.1 [M+H] + .

[0187] Step 6: Synthesis of S4

[0188] The synthetic route is shown below:

[0189]

[0190] Method: Compound S3 (0.8 g, 2.5 mmol) was dissolved in MeOH (10 mL), HCl / 1,4-dioxane (6 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound S4 (720 mg, crude). MS (ESI, m / z) 214.1 [M+H] + .

[0191] Step 7: Synthesis of BX20-7-805

[0192] The synthetic route is shown below:

[0193]

[0194] Method: Compound Int 1 (0.23 g, 1.4 mmol) was dissolved in DMF (5 mL), TEA (0.36 g, 3.6 mmol) and HATU (0.55 g, 1.4 mmol) were added in sequence, and S4 (0.30 g, 1.2 mmol) was added after stirring for 5 min. The reaction mixture was stirred at 25 ° C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and purified by preparative chromatography (formic acid system) to obtain a white solid compound BX20-7-804 (300 mg, 70.9%). MS (ESI, m / z) 353.2 [M+H] + .

[0195] 1 H NMR (400 MHz, DMSO-d 6 )δ=8.83-8.80(m,1H), 7.33-7.29(m,1H), 7.16(s,1H), 7.08-7.03(m,2H), 6. 34-6.06(m,1H), 5.39-5.30(m,1H), 3.85-3.82(m,1H), 3.21-3.16(m,2H), 3. 12-3.07(m,2H), 2.67-2.59(m,1H), 2.38-2.36(m,2H), 1.91-1.88(m,2H), 1. 42-1.39(m,2H), 0.83(t,J=8.0Hz,3H), 0.8-0.77(m,2H), 0.66-0.62(m,2H).

[0196] Example 3 BX20-7-806

[0197] Step 1: Synthesis of intermediate A2

[0198] The synthetic route is shown below:

[0199]

[0200] Method: Compound A0 (4.0 g, 23.1 mmol) was dissolved in NMP (80 mL), and Cs 2 CO 3 (18.8 g, 57.7 mmol), A1 (5.6 g, 46.3 mmol), the reaction mixture was heated to 130 ° C and refluxed for 24 h. After the reaction, the filtrate was collected. Diluted with water, extracted with EA, and washed with brine. After reduced pressure concentration, it was purified by column chromatography to obtain a colorless transparent oil compound A2 (2.2 g, 44.7%). MS (ESI, m / z) 213.0 [M+H] + .

[0201] Step 2: Synthesis of intermediate A3

[0202] The synthetic route is shown below:

[0203]

[0204] Method: Compound A2 (2.2 g, 10.3 mmol) was dissolved in THF (30 mL), cooled to -78 °C, and n-BuLi (5.0 mL, 2.5 M) was added dropwise. The reaction was maintained at -78 °C and stirred for 1 h. DMF (1.5 g, 20.6 mmol) was then added dropwise. The reaction mixture was naturally heated to 25 °C and stirred for 3 h. After the reaction was completed, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oily compound A3 (1.0 g, 59.9%). MS (ESI, m / z) 163.1 [M+H] + .

[0205] Step 3: Synthesis of intermediate S1

[0206] The synthetic route is shown below:

[0207]

[0208] Method: Compound SM1 (0.9 g, 7.4 mmol) was dissolved in toluene (30 mL), and A3 (1.0 g, 6.2 mmol), KHSO 4 (1.0 g, 7.4 mmol), the reaction mixture was heated to 45°C and stirred for 16 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S1 (0.7 g, 42.6%). MS (ESI, m / z) 266.1 [M+H] + .

[0209] Step 4: Synthesis of intermediate S2

[0210] The synthetic route is shown below:

[0211]

[0212] Method: Compound S1 (0.7 g, 2.6 mmol) and SM2 (0.56 g, 2.9 mmol) were dissolved in THF (20 mL), cooled to -78 °C, and LiHMDS (3.2 mL, 1 M) was added dropwise. The reaction was maintained at -78 °C and stirred for 90 min. After the reaction, saturated NH 4The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow solid compound S2 (0.55 g, 45.6%). MS (ESI, m / z) 458.1 [M+H] + .

[0213] Step 5: Synthesis of S3

[0214] The synthetic route is shown below:

[0215]

[0216] Method: Dissolve NaOAc (0.98 g, 12 mmol) and HOAc (0.72 g, 12 mmol) in H 2 O (2.1mL) to obtain solution A. Compound S2 (0.55g, 1.2mmol) was dissolved in DMF (10mL) to obtain solution B. A was added to B, and then Mg (0.43g, 18mmol) was added. The reaction mixture was stirred at 25°C for 2h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography to obtain a colorless oily compound S3 (0.32g, 84.0%). MS (ESI, m / z) 318.1 [M+H] + .

[0217] Step 6: Synthesis of S4

[0218] The synthetic route is shown below:

[0219]

[0220] Method: Compound S3 (0.32 g, 1.0 mmol) was dissolved in MeOH (5 mL), HCl / 1,4-dioxane (2.5 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound S4 (0.2 mg, crude). MS (ESI, m / z) 214.1 [M+H] + .

[0221] Step 7: Synthesis of BX20-7-806

[0222] The synthetic route is shown below:

[0223]

[0224] Method: Compound Int 1 (0.16 g, 1.0 mmol) was dissolved in DMF (5 mL), TEA (0.25 g, 2.5 mmol) and HATU (0.41 g, 1.1 mmol) were added in sequence, and S4 (0.21 g, 0.8 mmol) was added after stirring for 5 min. The reaction mixture was stirred at 25 ° C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-804 (67 mg, 23.8%). MS (ESI, m / z) 353.2 [M+H] + .

[0225] 1 H NMR (400 MHz, DMSO-d 6 )δ=8.70(d,J=8.00Hz,1H), 7.39(d,J=8.0Hz,2H), 7.05(d,J=8.0Hz,2H), 6.28-6.00(m,1H), 5.34-5.23(m,1H), 3.86-3.81(m,1H), 3.05-3.00(m,2H ), 2.95-2.90(m,2H), 2.45-2.43(m,1H), 2.28-2.19(m,2H), 1.83(t,J=8. 0Hz,2H), 1.40-1.37(m,2H), 0.82(t,J=8.0Hz,3H), 0.78-0.75(m,2H), 0.6 -0.61(m,2H).

[0226] Example 4 BX20-7-810

[0227] Step 1: Synthesis of intermediate A3

[0228] The synthetic route is shown below:

[0229]

[0230] Method: Dissolve compound A1 (4.0 g, 17.0 mmol) in CHCl 3 (50 mL), A2 (44.0 g, 71.0 mmol), P-TsOH·H 2 O (4.5 g, 33 mmol), the reaction mixture was heated to 65 ° C and refluxed for 12 h. After the reaction, it was diluted with water and extracted with DCM. The organic phase was collected, washed with saturated NaCl, and washed with anhydrous NaSO 4 After drying, the residue was concentrated under reduced pressure and purified by column chromatography to obtain a light yellow oily compound A3 (2.8 g, 59.7%). MS (ESI, m / z) 277.0 [M+H] + .

[0231] Step 2: Synthesis of Intermediate A0

[0232] The synthetic route is shown below:

[0233]

[0234] Method: Compound A3 (2.8 g, 10.0 mmol) was dissolved in DMF (30 mL), and TEA (2.5 g, 24.6 mmol), CuI (0.16 g, 0.8 mmol), (PPh 3 ) 2 PdCl 2 (0.29 g, 0.4 mmol). 2 , A4 (12 mL, 12 mmol) was added to the reaction mixture. The reaction mixture was heated to 80 °C and stirred for 12 h. After the reaction, it was diluted with water and extracted with EA. The organic phase was collected, washed with saturated NaCl, and washed with anhydrous NaSO 4 After drying, the product was concentrated under reduced pressure and purified by column chromatography to obtain a light yellow oily compound A0 (1.4 g, 97.2%). MS (ESI, m / z) 145.1 [M+H] + .

[0235] Step 3: Synthesis of intermediate S1

[0236] The synthetic route is shown below:

[0237]

[0238] Method: Compound SM1 (1.4 g, 11.7 mmol) was dissolved in toluene (20 mL), and A0 (1.4 g, 9.7 mmol), KHSO 4 (1.6 g, 11.7 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S1 (1.6 g, 66.7%). MS (ESI, m / z) 248.1 [M+H] + .

[0239] Step 4: Synthesis of intermediate S2

[0240] The synthetic route is shown below:

[0241]

[0242] Method: Compound S1 (1.6 g, 6.5 mmol) and SM2 (1.4 g, 7.1 mmol) were dissolved in THF (20 mL), cooled to -78 °C, and LiHMDS (8.0 mL, 1 M) was added dropwise. The reaction was maintained at -78 °C and stirred for 90 min. After the reaction, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to form a light yellow oily compound S2 (1.1 g, 59.2%). MS (ESI, m / z) 440.1 [M+H] + .

[0243] Step 5: Synthesis of S3

[0244] The synthetic route is shown below:

[0245]

[0246] Method: Dissolve NaOAc (2.0 g, 24.0 mmol) and HOAc (1.4 g, 24.0 mmol) in H 2 O (4.2mL) to obtain solution A. Compound S2 (1.1 g, 2.4 mmol) was dissolved in DMF (20 mL) to obtain solution B. A was added to B, and then Mg (0.86 g, 36.0 mmol) was added. The reaction mixture was stirred at 25°C for 2 h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography to obtain a white solid compound S3 (0.6 g, 83.5%). MS (ESI, m / z) 300.1 [M+H] + .

[0247] Step 6: Synthesis of S4

[0248] The synthetic route is shown below:

[0249]

[0250] Method: Compound S3 (0.6 g, 2.0 mmol) was dissolved in DCM (10 mL), HCl / 1,4-dioxane (10 mL) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and purified by column chromatography to obtain a light yellow solid compound S4 (0.11 g, 28.2%). MS (ESI, m / z) 196.1 [M+H] + .

[0251] Step 7: Synthesis of BX20-7-810

[0252] The synthetic route is shown below:

[0253]

[0254] Method: Compound Int 1 (0.11 g, 0.7 mmol) was dissolved in DMF (3 mL), TEA (0.17 g, 1.7 mmol) and HATU (0.26 g, 0.7 mmol) were added in sequence, and S4 (0.11 g, 0.6 mmol) was added after stirring for 5 min. The reaction mixture was stirred at 25 ° C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-810 (90 mg, 26.9%). MS (ESI, m / z) 335.2 [M+H] + .

[0255] 1 H NMR (400 MHz, DMSO-d 6 )δ=8.77(d,J=8.00Hz,1H),7.47-7.45(m,2H),7.42-7.40(m,2H),6.35-6.07(m,1H),5.41-5.32(m,1H),3.05-3.01(m,2H),2 .95-2.90(m,2H), 2.44(s,1H), 2.33-2.20(m,2H), 2.04(s,3H), 1.87-1.80(m,2H), 1.42-1.35(m,2H), 0.82(t,J=8.0Hz,3H).

[0256] Example 5 BX20-7-814

[0257] Step 1: Synthesis of intermediate S2

[0258] The synthetic route is shown below:

[0259]

[0260] Method: Compound S1 (8 g, 29.6 mmol) was dissolved in THF (60 mL) and N 2 , cooled to -30°C, SM1 (44.4 mL, 44.4 mmol) was added dropwise, and the reaction mixture was stirred at -30 to -20°C for 2 h. After the reaction, the reaction mixture was added dropwise to ice-saturated NH 4 The reaction mixture was quenched in Cl, extracted with EA, and the organic phase was dried. After concentration under reduced pressure, it was purified by column chromatography to obtain a white solid compound S2 (5.12 g, 84.8%). MS (ESI, m / z) 205 [M+H] + .

[0261] Step 2: Synthesis of intermediate S3

[0262] The synthetic route is shown below:

[0263]

[0264] Method: Ph 3 THF (100 mL) was added to PMeBr (13.9 g, 39 mmol) and stirred thoroughly to replace N 2 , cool to -78°C, add KHMDS (39 mL, 39 mmol) dropwise, warm to room temperature and stir for 2 h, then cool to -78°C again, add S2 (5.3 g, 26 mmol, diluted with 10 mL THF), warm to room temperature and react overnight. After the reaction, add the reaction solution to 200 mL of saturated NH 4 The mixture was quenched with Cl solution and extracted with EA. The organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oily compound S2 (3.2 g, 60.8%).

[0265] Step 3: Synthesis of S4

[0266] The synthetic route is shown below:

[0267]

[0268] Method: Compound SM2 (1.46 g, 15.7 mol) was dissolved in EtOH (30 mL), stirred until dissolved, TEA (4.5 g, 44.5 mmol) and compound S3 (2.9 g, 14.3 mmol) were added under ice bath, and reacted at room temperature for 16 h. After the reaction, vacuum distillation was performed to dryness, and column chromatography was performed. The light yellow oily compound S4 (1.69 g, 45.6%) was obtained by column chromatography purification. MS (ESI, m / z) 260 [M+H] + .

[0269] Step 4: Synthesis of Y-4

[0270] The synthetic route is shown below:

[0271]

[0272] Method: Compound S4 (0.8 g, 3.1 mmol) was dissolved in MeOH (5 mL), referred to as solution A; LiOH·H 2 O (0.13 g, 3.1 mmol) was added H 2 O (2 mL) was dissolved and recorded as solution B. Solution B was added to solution A, and the temperature was raised to 60°C and stirred for 12 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure, and washed with PE and acetonitrile in turn to obtain a white solid compound Y-4 (0.6 g, crude product). MS (ESI, m / z) 170 [M+H] +.

[0273] Step 5: Synthesis of intermediate S5

[0274] The synthetic route is shown below:

[0275]

[0276] Method: Compound SM3 (27.4 g, 0.23 mol) was dissolved in toluene (400 mL), and SM4 (20 g, 0.19 mol), KHSO 4 (30.8 g, 0.23 mol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S5 (25 g, 63.4%). MS (ESI, m / z) 210 [M+H] + .

[0277] Step 6: Synthesis of intermediate S6

[0278] The synthetic route is shown below:

[0279]

[0280] Method: Compound S5 (25 g, 0.12 mol) and SM5 (25.3 g, 0.13 mol) were dissolved in THF (250 mL) and N 2 The temperature was lowered to -78°C, and LiHMDS (143 mL, 1 M in THF, 0.14 mol) was added dropwise. The reaction was stirred at -78°C for 90 min. After the reaction, 150 saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow solid compound S6 (32 g, 66.7%). MS (ESI, m / z) 402 [M+H] + .

[0281] Step 7: Synthesis of S7

[0282] The synthetic route is shown below:

[0283]

[0284] Method: Dissolve NaOAc (71.5 g, 0.87 mol) and HOAc (52.4 g, 0.87 mmol) in H 2O (150mL) to obtain solution A. Compound S6 (35g, 87.2mmol) was dissolved in DMF (350mL) to obtain solution B. A was added to B, and then Mg (31.8g, 1.31mol) was added. The reaction mixture was stirred at 25°C for 2h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography to obtain yellow oily compound S7 (26.4g, 99.9%). MS (ESI, m / z) 262 [M+H] + .

[0285] Step 8: Synthesis of X-1

[0286] The synthetic route is shown below:

[0287]

[0288] Method: Compound S7 (26.4 g, 20.6 mmol) was dissolved in MeOH (10 mL), and HCl / 1,4-dioxane (253 mL, 4 M) was added dropwise. The reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with EA to obtain a white solid compound X-1 (2.7 g). The mother liquor was then deionized to obtain a non-white solid S4 (8.7 g). A total of S4 (11.4 g, 58.3%) was obtained. MS (ESI, m / z) 158 [M+H] + .

[0289] Step 9: Synthesis of BX20-7-814

[0290] The synthetic route is shown below:

[0291]

[0292] Wherein, * indicates that the chiral carbon is racemic.

[0293] Method: Compound Y-4 (0.3 g, 1.8 mmol) was dissolved in DMF (5 mL) and stirred to dissolve. DIPEA (0.58 g, 4.5 mmol) was added in turn and stirred to dissolve. EDCI (0.58 g, 3.0 mmol) was added and stirred to dissolve. HOBT (0.24 g, 1.8 mmol) was added and stirred to dissolve. After stirring for 10 min, X-1 (0.29 g, 1.5 mmol) was added. The reaction mixture was stirred at 25 ° C for 6 h. After the reaction was completed, the reaction solution was added to ice water to quench, extracted with EA, washed with concentrated brine, and dried over anhydrous sodium sulfate. After concentration, the yellow solid compound BX20-7-814 (racemic, 92 mg, 19.9%) was obtained after purification by preparative chromatography (ammonia system). MS (ESI, m / z) 309 [M+H] + .

[0294] 1 H NMR(400MHz,Chloroform-d)δ9.80(dd,J=17.3,8.5Hz,1H),7.43–7.30(m,5H),6.00(tdd,J=56.0,4.6,2.1Hz,1H),5.51–5.22(m,1H),3.41–3.18(m,4H), 2.86–2.58(m,2H),2.15–2.08(m,2H),1.47–1.35(m,1H),0.94–0.79(m,1H), 0.72–0.57(m,1H),0.54–0.43(m,1H),0.43–0.32(m,1H),0.15–0.03(m,1H).

[0295] Example 6BX20-7-815

[0296] Step 1: Synthesis of intermediate S1

[0297] The synthetic route is shown below:

[0298]

[0299] Method: Compound SM1 (11 g, 90.76 mmol) was dissolved in toluene (190 mL), and SM2 (8.03 g, 75.63 mmol), KHSO 4 (12.36 g, 90.76 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S1 (14.1 g, 89.07%). MS (ESI, m / z) 210 [M+H] + .

[0300] Step 2: Synthesis of intermediate S2

[0301] The synthetic route is shown below:

[0302]

[0303] Method: Compound S1 (2 g, 9.56 mmol) was dissolved in CH 2 Cl 2 (200 mL), cooled to -78°C, SM3 (96, 0.5 M) was added dropwise, and the reaction was maintained at -78°C with stirring for 120 min. After the reaction, saturated NH 4The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to form a colorless oily compound S2 (1.15 g, 47.88%). MS (ESI, m / z) 252 [M+H] + .

[0304] Step 3: Synthesis of X3

[0305] The synthetic route is shown below:

[0306]

[0307] Method: Compound S2 (1.15 g, 4.57 mmol) was dissolved in DCM (12 mL), HCl / 1,4-dioxane (11.5 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound X3 (852 mg, crude product). MS (ESI, m / z) 131 [M+H] + .

[0308] Step 4: Synthesis of BX20-7-815

[0309] The synthetic route is shown below:

[0310]

[0311] Method: Compound Int 1 (500 mg, 3.18 mmol) was dissolved in DMF (14 mL), and TEA (965 mg, 9.54 mmol) and HATU (1.33 g, 3.5 mmol) were added in sequence. After stirring for 5 min, X3 (852 mg, 4.66 mmol) was added, and the reaction mixture was stirred at 25 ° C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and purified by preparative chromatography (ammonia system) to obtain a brown solid compound BX20-7-815 (142 mg, 15.59%). MS (ESI, m / z) 287 [M+H] + .

[0312] 1 H NMR (400 MHz, DMSO-d 6)pppm 0.28-0.41(m,3H)0.50(d,J=7.83Hz,3H)0.72(t,J=7.43Hz,3H)0.84-0.94(m,2H)1.06-1.22(m,1H)1.33-1.57(m,2H)3.05-3.20(m,1H)3.82 -4.12(m,4H)4.12-4.33(m,1H)6.13-6.21(m,1H)7.10-7.52(m,5H)7. 16-7.19(m,1H)8.55-8.88(m,3H)8.69-8.69(m,1H)8.71-8.71(m,1H).

[0313] Example 7BX20-7-819

[0314] Step 1: Synthesis of intermediate S1

[0315] The synthetic route is shown below:

[0316]

[0317] Method: Compound SM1 (11 g, 90.76 mmol) was dissolved in Tol (190 mL), and SM2 (8.0 g, 75.63 mmol), KHSO 4 (12.4 g, 90.76 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S1 (14.1 g, 89.07%), MS (ESI, m / z) 210 [M+H] + .

[0318] Step 2: Synthesis of intermediate S2

[0319] The synthetic route is shown below:

[0320]

[0321] Method: Compound S1 (7 g, 33.44 mmol) was dissolved in THF (70 mL), cooled to -78 °C, n-BuLi (52.5, 1.5 M) was added dropwise, stirred for 90 min, MeCN (2.8 g, 66.89 mmol) was added dropwise, and the reaction was maintained at -78 °C for 2 h. After the reaction, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to form a colorless oily compound S2 (2.4 g, 28.19%). MS (ESI, m / z) 251 [M+H] + .

[0322] Step 3: Synthesis of X-4

[0323] The synthetic route is shown below:

[0324]

[0325] Method: Compound S2 (2.4 g, 9.43 mmol) was dissolved in MeOH (23 mL), HCl / 1,4-dioxane (23 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a yellow solid compound X-4 (1.5 g, crude product). MS (ESI, m / z) 147 [M+H] + .

[0326] Step 4: Synthesis of BX20-7-819

[0327] The synthetic route is shown below:

[0328]

[0329] Method: Dissolve Y-5 (465 mg, 2.96 mmol) in DMF (10 mL), add DIEA (637 mg, 4.93 mmol), EDCI (945 mg, 4.93 mmol), HOBT (400 mg, 2.96 mmol) in sequence, stir for 10 min, then add X-4 (450 mg, 2.46 mmol), and stir the reaction mixture at 25 °C for 2 h. After the reaction, drop the reaction mixture into ice H 2 O was diluted and extracted with EA, the organic phase was dried and concentrated under reduced pressure, and purified by preparative chromatography (NH 4 HCO 3 System) to obtain a white solid compound BX20-7-821 (77 mg, 10.95%). MS (ESI, m / z) 286.2 [M+H] + .

[0330] 1H NMR(400MHz,DMSO-d6)ppm 0.83(t,J=7.43Hz,3H),1.28-1.46(m,2H),1.83(quin,J=6.85Hz,2H),2.08-2.18(m,1H),2.18-2.24(m,1H),2.40-2.46(m,1H),2.75-2.97(m ,3H),2.98-3.11(m,3H),5.20(td,J=8.71,5.28Hz,1H),7.24-7.30(m, 1H), 7.35 (t, J = 7.43Hz, 2H), 7.41-7.47 (m, 2H), 8.62 (d, J = 8.61Hz, 1H).

[0331] Example 8 BX20-7-820

[0332] Step 1: Synthesis of intermediate S2

[0333] The synthetic route is shown below:

[0334]

[0335] Method: Compound S1 (10.0 g, 81.9 mmol) was dissolved in DCM (300 mL) and N 2 Then, DMAP (2.0 g, 16.4 mmol) and Et 3 N (33.1 g, 327.6 mmol), SM1 (22.2 g, 245.5 mmol), naturally warm to room temperature and react for 16 hours. After the reaction is completed under TLC control, filter and collect the filtrate. The filtrate is extracted with saturated sodium chloride, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a colorless oily compound S2 (9.4 g, 65.2%).

[0336] Step 2: Synthesis of intermediate S3

[0337] The synthetic route is shown below:

[0338]

[0339] Method: Compound SM2 (5.5 g, 58.7 mmol) was dissolved in anhydrous ethanol (100 mL) and N 2 , TEA (16.8 g, 165.5 mmol) and S2 (9.4 g, 53.4 mmol) were added in turn under ice bath, and the temperature was naturally raised to room temperature for reaction for 16 h. After the reaction, the mixture was concentrated under reduced pressure, extracted with water and DCM, and the organic phase was collected and dried. After concentration under reduced pressure, the mixture was purified by column chromatography to obtain a light yellow oily compound S3 (10.3 g, 82.8%). MS (ESI, m / z) 234 [M+H]+ .

[0340] Step 3: Synthesis of intermediate S4

[0341] The synthetic route is shown below:

[0342]

[0343] Method: Compound S3 (10.3 g, 44.2 mmol) was dissolved in THF (200 mL) and N 2 , cool to below -80°C, add LiHMDS (119 mL, 119 mmol) dropwise, maintain the reaction at -78°C with stirring for 0.5 h, naturally warm to -30°C with stirring for 2 h, cool to -78°C again, add SM3 (29.7 g, 247.5 mmol) dropwise, maintain the reaction at -78°C for 4 h. After the reaction, add saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a brown compound S4 (4.85 g, 40.3%). MS (ESI, m / z) 273 [M+H] + .

[0344] Step 4: Synthesis of Y-9

[0345] The synthetic route is shown below:

[0346]

[0347] Method: Compound S4 (3.2 g, 11.7 mmol) was dissolved in MeOH (15 mL), referred to as solution A. LiOH·H 2 O (0.49 g, 11.7 mmol) was dissolved in water (4 mL), which was recorded as solution B. Solution B was added to solution A, and the temperature was raised to 60°C and stirred for 16 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain brown oil compound Y-9 (1.67 g, crude product). MS (ESI, m / z) 169 [M+H] + .

[0348] Step 5: Synthesis of BX20-7-820

[0349] The synthetic route is shown below:

[0350]

[0351] Method: Compound Y-9 (1.67 g, 9.9 mmol) was dissolved in DMF (20 mL) and stirred to dissolve. DIPEA (3.22 g, 24.9 mmol), EDCI (3.18 g, 16.6 mmol), and HOBT (1.34 g, 9.9 mmol) were added in sequence. After stirring for 10 min, X-2 (1.75 g, 8.3 mmol) was added. The reaction mixture was stirred at 25 ° C for 3 h. After the reaction, the reaction solution was added to ice water for quenching, extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative chromatography (formic acid system) to obtain a yellow solid compound BX20-7-820 (260 mg, 9.6%). MS (ESI, m / z) 326 [M+H] + .

[0352] 1 H NMR (400 MHz, DMSO-d 6 )δ9.23(d,J=8.9Hz,0H),7.50(tdd,J=7.1,5.3,2.1Hz,2H),7.38–7.10(m,2H),6.23(tdd,J=55.2,5.0,3.1Hz,1H),5.35(dddd,J=20 .8,11.7,8.0,3.4Hz,1H),3.31–3.01(m,4H),2.76(dq,J=13.5,6.8,6.1Hz,1H),2.51(d,J=1.9Hz,4H),1.95(dp,J=28.3,7.2Hz,2H).

[0353] Example 9BX20-7-821

[0354] Step 1: Synthesis of intermediate S1

[0355] The synthetic route is shown below:

[0356]

[0357] Method: Compound SM1 (10 g, 81.89 mmol) was dissolved in DMA (167 mL), and Cs 2 CO 3 (53.36 g, 163.77 mmol), KI (4.08 g, 24.57 mmol), N 2 SM2 (33.16 g, 245.66 mmol) was added, and the reaction mixture was heated to 150°C in a sealed tube and stirred for 12 h. After the reaction, the filtrate was filtered and collected. After concentration under reduced pressure, the mixture was purified by column chromatography to obtain a light yellow oily compound S1 (14 g, 97.03%). MS (ESI, m / z) 177 [M+H] +.

[0358] Step 2: Synthesis of intermediate S2

[0359] The synthetic route is shown below:

[0360]

[0361] Method: Compound SM3 (10.9 g, 89.96 mmol) was dissolved in toluene (292 mL), and S1 (13.21 g, 74.97 mmol), KHSO 4 (12.25 g, 89.96 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S2 (15.47 g, 73.86%). MS (ESI, m / z) 280 [M+H] + .

[0362] Step 3: Synthesis of intermediate S3

[0363] The synthetic route is shown below:

[0364]

[0365] Method: Compound S2 (2.5 g, 8.95 mmol) and SM4 (1.89 g, 9.85 mmol) were dissolved in THF (20 mL), cooled to -78 °C, and LiHMDS (10.8 mL, 1 M in THF) was added dropwise. The reaction was maintained at -78 °C and stirred for 90 min. After the reaction, saturated NH 4 Cl solution was quenched. Extracted with EA, the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain pale yellow solid compound S3 (3.7 g, 87.7%). MS (ESI, m / z) 472 [M+H] + .

[0366] Step 4: Synthesis of S4

[0367] The synthetic route is shown below:

[0368]

[0369] Method: Dissolve NaOAc (6.44 g, 78.5 mmol) and HOAc (4.71 g, 78.5 mmol) in H 2O (13.7 mL) to obtain solution A. Compound S2 (3.7 g, 7.85 mmol) was dissolved in DMF (40 mL) to obtain solution B. A was added to B, and then Mg (2.86 g, 117.7 mmol) was added. The reaction mixture was stirred at 25°C for 2 h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography to obtain yellow oily compound S4 (1.78 g, 68.46%). MS (ESI, m / z) 332 [M+H] + .

[0370] Step 5: Synthesis of S5

[0371] The synthetic route is shown below:

[0372]

[0373] Method: Compound S4 (1.78 g, 5.37 mmol) was dissolved in MeOH (17 mL), HCl / 1,4-dioxane (13 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a light yellow solid compound S5 (1.2 mg, 84.51%). MS (ESI, m / z) 228 [M+H] + .

[0374] Step 6: Synthesis of BX20-7-821

[0375] The synthetic route is shown below:

[0376]

[0377] Method: Y-5 (358 mg, 2.3 mmol) was dissolved in DMF (7 mL), and DIEA (490 mg, 3.8 mmol), EDCI (727 mg, 3.8 mmol), and HOBT (307 mg, 2.3 mmol) were added in sequence. After stirring for 10 min, S5 (500 mg, 1.9 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. After the reaction, the reaction solution was dropped into ice H 2 After dilution with O, EA extraction was performed, the organic phase was dried and concentrated under reduced pressure, and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-821 (394 mg, 56.71%). MS (ESI, m / z) 367.2 [M+H] + .

[0378] 1H NMR (400MHz, DMSO-d6)d=0.82(t,J=7.24Hz,3H),1.38(quin,J=7.24Hz,2H),1.57-1.71(m,1H),1.74-1.86( m,3H),2.06(dd,J=9.59,8.02Hz,2H),2.20(dd,J=10.96,5.09Hz,1H),2.26-2.36(m,1H),2.38-2.47(m,3H) ,2.92(q,J=6.65Hz,2H),3.03(q,J=6.65Hz,2H),4.73(t,J=7.04Hz,1H),5.61-5.82(m,1H),5.94-6.31(m,1 H), 6.85 (d, J = 8.22Hz, 1H), 6.96 (t, J = 7.43Hz, 1H), 7.20-7.32 (m, 1H), 7.44 (d, J = 7.43Hz, 1H), 8.68 (s, 1H).

[0379] Example 10BX20-7-822

[0380] Step 1: Synthesis of intermediate S3

[0381] The synthetic route is shown below:

[0382]

[0383] Method: Compound S1 (8.0 g, 74 mmol) was dissolved in DCM (100 mL), pyridine (19.1 g, 242 mmol) was added, the temperature was lowered to -78 °C, Tf 2 O (16.2 mL). After the addition, the reaction solution was heated to 0°C and stirred for 1 hour. The reaction solution was poured into a 0.1N HCl solution to quench, extracted with DCM three times, and the organic phases were combined and washed twice with a 0.1N HCl solution, washed with water, washed with concentrated brine, dried, and purified by a short silica gel column to obtain a light yellow transparent liquid compound S2 (11.0 g, crude product), which was used directly in the next step. S2 (11.0 g, crude product) and A1 (6.0 g, 50 mmol) were dissolved in DMF (100 mL) and Cs 2 CO 3 (40 g, 123 mmol), the reaction solution was stirred at 60°C for 3 hours. After the reaction, it was filtered, water was added and extracted with EA, the organic phase was washed with concentrated brine, dried and concentrated, and purified by column chromatography to obtain a light yellow transparent liquid S3 (6.3 g, 59.4%). MS (ESI, m / z) 213 [M+H] + .

[0384] Step 2: Synthesis of intermediate S4

[0385] The synthetic route is shown below:

[0386]

[0387] Method: Compound A1 (2.2 g, 18.5 mol) was dissolved in toluene (100 mL), and S3 (3.0 g, 14.2 mmol) and KHSO were added. 4 (2.5 g, 18.5 mmol), the reaction mixture was stirred at 45°C for 16 h. After the reaction, the mixture was filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (PE: EA = 10: 1 to 3: 1) to obtain a light yellow oily compound S4 (3.9 g, 87.2%). MS (ESI, m / z) 316 [M+H] + .

[0388] Step 3: Synthesis of intermediate S5

[0389] The synthetic route is shown below:

[0390]

[0391] Method: Compound S4 (3.9 g, 12.4 mmol) and A2 (2.9 g, 15.1 mmol) were dissolved in THF (100 mL) and N 2 The temperature was then lowered to -78°C, and LiHMDS (15.5 mL, 1 M in THF) was slowly added dropwise. The reaction was maintained at -78°C with stirring for 90 min. After the reaction was completed, saturated NH 4 The mixture was quenched with Cl solution. EA was extracted, the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography (PE:EA=10:1-1:1) to obtain yellow oily compound S5 (4.6 g, 75.0%). MS (ESI, m / z) 508 [M+H] + .

[0392] Step 4: Synthesis of S6

[0393] The synthetic route is shown below:

[0394]

[0395] Method: Dissolve NaOAc (7.4 g, 90 mmol) and HOAc (5.4 g, 90 mmol) in H 2O (17mL), which is solution A. Compound S5 (4.6g, 9mmol) was dissolved in DMF (25mL), added to solution A, and magnesium wire (3.24g, 135mmol) was slowly added. The reaction mixture was stirred at 25°C for 3h. After the reaction, it was filtered, extracted with EA after adding water, and the organic phase was washed with concentrated brine, dried and concentrated, and purified by column chromatography (PE:EA=5:1~1:1) to obtain a white solid compound S6 (3.2g, 96.7%). MS (ESI, m / z) 368 [M+H] + .

[0396] Step 5: Synthesis of X-7-2

[0397] The synthetic route is shown below:

[0398]

[0399] Method: Compound S6 (3.2 g, 8.7 mmol) was dissolved in DCM (50 mL), HCl / 1,4-dioxane (22 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 1 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound X-7-2 (2.3 g, 88.2%). MS (ESI, m / z) 264 [M+H] + .

[0400] Step 6: Synthesis of BX20-7-822

[0401] The synthetic route is shown below:

[0402]

[0403] Method: Dissolve Y-5 (200 mg, 1.27 mmol) in DMF (5 mL), add DIPEA (490 mg, 3.81 mmol), EDCI (487 mg, 2.54 mmol) and HOBT (223 mg, 1.65 mmol), stir for 15 minutes, then add X-7-2 (380 mg, 1.27 mmol), and continue to stir at room temperature for 12 hours. After the reaction, the reaction solution was added to ice water to quench, extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative chromatography (ammonia system) to obtain a light yellow solid compound BX20-7-822 (130 mg, 25.4%). MS (ESI, m / z) 403 [M+H] + .

[0404] 1 H NMR (400 MHz, CDCl 3)δ9.52(d,J=8.8Hz,1H),7.35–7.26(m,2H),7.04–7.00(m,1H),6.70–6.68(m,1 H),6.02(td,J=56.0,2.0Hz,1H),5.85–5.75(m,1H),4.74–4.65(m,1H),3.34–3. 21(m,4H),3.16–3.06(m,2H),2.88–2.67(m,3H),2.52(dd,J=12.4,3.6Hz,1H), 2.17–2.06(m,3H),1.79–1.68(m,1H),1.54–1.43(m,1H),0.91(t,J=7.6Hz,3H).

[0405] Example 11BX20-7-823

[0406] Step 1: Synthesis of intermediate S1

[0407] The synthetic route is shown below:

[0408]

[0409] Method: Compound SM1 (10 g, 81.89 mmol) was dissolved in DMA (150 mL), and Cs 2 CO 3 (53.4 g, 163.77 mmol), KI (4.08 g, 24.57 mmol), N 2 , SM2 (99 g, 0.82 mol) was added, and the reaction mixture was heated to 150°C in a sealed tube and stirred for 12 h. After the reaction, the filtrate was filtered and collected. After concentration under reduced pressure, the organic phase was extracted with EA, and the organic phase was dried and concentrated, and then purified by column chromatography to obtain a light yellow oily compound S1 (4.6 g, 34.64%). MS (ESI, m / z) 163.1 [M+H] + .

[0410] Step 2: Synthesis of intermediate S2

[0411] The synthetic route is shown below:

[0412]

[0413] Method: Compound SM3 (4.13 g, 34.04 mmol) was dissolved in toluene (40 mL), and S1 (4.6 g, 28.36 mmol), KHSO 4(4.63 g, 34.04 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S2 (5.5 g, 73.04%). MS (ESI, m / z) 266.1 [M+H] + .

[0414] Step 3: Synthesis of intermediate S3

[0415] The synthetic route is shown below:

[0416]

[0417] Method: Compound S2 (2 g, 7.54 mmol) and SM4 (1.6 g, 8.29 mmol) were dissolved in THF (20 mL), cooled to -78 °C, and LiHMDS (9 mL, 1 M in THF) was added dropwise. The reaction was maintained at -78 °C and stirred for 90 min. After the reaction, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow solid compound S3 (2.4 g, 69.57%). MS (ESI, m / z) 458.1 [M+H] + .

[0418] Step 4: Synthesis of S4

[0419] The synthetic route is shown below:

[0420]

[0421] Method: Dissolve NaOAc (4.3 g, 52.5 mmol) and HOAc (3.2 g, 52.5 mmol) in H 2 O (10mL) to obtain solution A. Compound S2 (2.4 g, 5.25 mmol) was dissolved in DMF (24 mL) to obtain solution B. A was added to B, and then Mg (1.9 g, 78.68 mmol) was added. The reaction mixture was stirred at 25°C for 2 h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography to obtain yellow oily compound S4 (1.25 g, 75.30%). MS (ESI, m / z) 318.1 [M+H] + .

[0422] Step 5: Synthesis of S5

[0423] The synthetic route is shown below:

[0424]

[0425] Method: Compound S4 (1.25 g, 3.94 mmol) was dissolved in DCM (10 mL), HCl / 1,4-dioxane (10 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 2 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a non-white solid compound S5 (900 mg, 91.52%). MS (ESI, m / z) 214 [M+H] + .

[0426] Step 6: Synthesis of S6

[0427] The synthetic route is shown below:

[0428]

[0429] Method: t-BuOK (1.23 g, 11 mmol) was dissolved in THF (20 mL) and the system was replaced with N 2 The temperature was lowered to 0°C, SM5 (1.3 g, 10 mmol) was slowly added dropwise, and then SM6 (3.4 g, 20 mmol) was added. The mixture was stirred at 70°C for 24 h. After the reaction, the reaction solution was poured into water and extracted with EA. The organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow oily compound S6 (200 mg). MS (ESI, m / z) 173.1 [M+H] + .

[0430] Step 7: Synthesis of intermediate S7

[0431] The synthetic route is shown below:

[0432]

[0433] Method: Compound SM6 (4.1 g, 23.81 mmol) was dissolved in THF (60 mL) and N 2 , add LiHMDS (28.6 mL, 1 M) at -78 °C, stir at -78 °C for 30 min, add (CH 2 O) n (3.57 g, 120 mmol), the reaction was maintained at 25°C for 16 h. After the reaction, the mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by column chromatography (PE:EA=50:1) to obtain a light yellow liquid compound S7 (3.8 g, crude product).

[0434] Step 8: Synthesis of intermediate S8

[0435] The synthetic route is shown below:

[0436]

[0437] Method: Compound SM7 (3.8 g, 26.7 mmol) was dissolved in EtOH (20 mL), TEA (8.1 g, 80 mmol) and S7 (3.8 g, crude product) were added, and the reaction was maintained at 25°C for 16 h. After the reaction, the mixture was extracted with DCM, the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography (DCM: MeOH = 10: 1) to obtain yellow oily compound S8 (550 mg, 10.32%). MS (ESI, m / z) 200.1 [M+H] + .

[0438] Step 9: Synthesis of intermediate S9

[0439] The synthetic route is shown below:

[0440]

[0441] Method: Compound S8 (530 mg, 2.66 mmol) was dissolved in MeOH (4 mL) and LiOH·H 2 O (123 mg, 2.93 mmol) and H 2 O(1), the reaction mixture was stirred at 60°C for 16 h. After the reaction, it was concentrated under reduced pressure to obtain a pale yellow oily crude product, which was washed with PE and slurried with MeCN to obtain a white solid S9 (370 mg, 78.53%). MS (ESI, m / z) 172.1 [M+H] + .

[0442] Step 10: Synthesis of BX20-7-823

[0443] The synthetic route is shown below:

[0444]

[0445] Method: S9 (133 mg, 0.75 mmol) was dissolved in DMF (2 mL), and DIEA (176 mg, 1.36 mmol), EDCI (261 mg, 1.36 mmol), and HOBT (110 mg, 0.82 mmol) were added in sequence. After stirring for 10 min, S5 (170 mg, 0.68 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 h. After the reaction, the reaction solution was dropped into ice H 2 After dilution with O, EA extraction was performed, the organic phase was dried and concentrated under reduced pressure, and purified by preparative chromatography (ammonium bicarbonate system) to obtain a non-white solid compound BX20-7-823 (104 mg, 29.44%). MS (ESI, m / z) 367.2 [M+H] + .

[0446] 1 H NMR (400 MHz, DMSO-d 6 )pppm:0.69(d,J=6.65Hz,3H),0.72-0.79(m,3H),0.79-0.91(m,4H),1.58-1.71(m,1H),1.76 (t,J=6.85Hz,1H),1.87(t,J=6.85Hz,1H),2.08-2.19(m,1H),2.20-2.38(m,1H),2.51-2.59(m ,1H),2.85(q,J=6.65Hz,1H),2.95-3.11(m,3H),3.81-4.05(m,1H),5.47-5.75(m,1H),5.82- 6.25(m,1H),6.86-7.09(m,1H),7.24-7.34(m,2H),7.34-7.47(m,1H),8.58(d,J=9.78Hz,1H).

[0447] Example 12 BX20-7-824

[0448] Step 1: Synthesis of intermediate A2

[0449] The synthetic route is shown below:

[0450]

[0451] Method: Compound A0 (10.0 g, 71.4 mmol) was dissolved in DMA (150 mL), and Cs 2 CO 3 (46.5 g, 142.8 mmol), KI (3.6 g, 21.4 mmol), N 2 , A1 (85.7 g, 245.7 mmol) was added, and the reaction mixture was heated to 150°C in a sealed tube and stirred for 12 h. After the reaction, the mixture was filtered and the filtrate was collected. After concentration under reduced pressure, the mixture was purified by column chromatography to obtain a light yellow oily compound A2 (1.89 g, 14.7%). MS (ESI, m / z) 181 [M+H] + .

[0452] Step 2: Synthesis of intermediate S1

[0453] The synthetic route is shown below:

[0454]

[0455] Method: Compound SM1 (1.51 g, 12.5 mmol) was dissolved in toluene (40 mL), and A2 (1.89 g, 10.5 mmol), KHSO4 (1.7 g, 12.5 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S1 (2.23 g, 75.0%). MS (ESI, m / z) 284 [M+H] + .

[0456] Step 3: Synthesis of intermediate S2

[0457] The synthetic route is shown below:

[0458]

[0459] Method: Compound S1 (2.23 g, 7.9 mmol) and SM2 (1.67 g, 8.7 mmol) were dissolved in THF (20 mL), cooled to -78 °C, and LiHMDS (9.5 mL, 1 M) was added dropwise. The reaction was maintained at -78 °C and stirred for 90 min. After the reaction, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow solid compound S2 (2.94 g, 78.5%). MS (ESI, m / z) 476 [M+H] + .

[0460] Step 4: Synthesis of S3

[0461] The synthetic route is shown below:

[0462]

[0463] Method: Dissolve NaOAc (5.2 g, 63 mmol) and HOAc (3.8 g, 63 mmol) in H 2 O (11mL) to obtain solution A. Compound S2 (2.94g, 6.2mmol) was dissolved in DMF (30mL) to obtain solution B. A was added to B, and then Mg (2.3g, 94.7mmol) was added. The reaction mixture was stirred at 25°C for 2h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography to obtain a colorless oily compound S3 (1.1g, 53.2%). MS (ESI, m / z) 336 [M+H] + .

[0464] Step 5: Synthesis of S4

[0465] The synthetic route is shown below:

[0466]

[0467] Method: Compound S3 (1.1 g, 3.3 mmol) was dissolved in MeOH (10 mL), HCl / 1,4-dioxane (8 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound S4 (0.56 g, 72.7%). MS (ESI, m / z) 232 [M+H] + .

[0468] Step 6: Synthesis of BX20-7-824

[0469] The synthetic route is shown below:

[0470]

[0471] Method: Compound Int 1 (0.36 g, 2.3 mmol) was dissolved in DMF (6.8 mL) and stirred to dissolve. DIPEA (0.74 g, 5.7 mmol) was added in turn and stirred to dissolve. EDCI (0.73 g, 3.8 mmol) was added and stirred to dissolve. HOBT (0.31 g, 2.3 mmol) was added and stirred to dissolve. After stirring for 10 min, S4 (0.50 g, 1.9 mmol) was added. The reaction mixture was stirred at 25 ° C for 6 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-824 (260 mg, 37.0%). MS (ESI, m / z) 371 [M+H] + .

[0472] 1 H NMR (400 MHz, DMSO-d 6)δ8.73(d,J=9.5Hz,1H),7.49(dd,J=8.6,6.8Hz,1H),6.96(dd,J=11.3,2.5Hz,1H),6.86(td,J=8.5,2.5Hz,1H) ,6.27–5.95(m,2H),5.74(dddt,J=19.7,9.8,6.5,3.0Hz,1H),5.44(dq,J=17.3,1.8Hz,1H),5.34–5.26(m,1H),4 .71–4.61(m,2H),3.34(s,4H),3.03(q,J=6.7Hz,2H),2.92(q,J=6.7Hz,2H),2.44(dd,J=11.0,8.8Hz,1H),2.35 –2.24(m,1H),2.21(dd,J=10.9,5.1Hz,1H),1.82(p,J=6.9Hz,2H),1.38(p,J=7.3Hz,2H),0.82(t,J=7.4Hz,3H).

[0473] Example 13 BX20-7-825

[0474] Step 1: Synthesis of intermediate S2

[0475] The synthetic route is shown below:

[0476]

[0477] Method: Compound S1 (3.0 g, 24.6 mmol) was dissolved in DMA (50 mL), and Cs 2 CO 3 (16 g, 49.1 mmol), KI (1.2 g, 7.4 mmol), N 2 , A1 (30 g, 245.7 mmol) was added, and the reaction mixture was heated to 150°C in a sealed tube and stirred for 12 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, the compound S2 (1.3 g, 32.5%) was purified by column chromatography to obtain a light yellow oily compound S2 (1.3 g, 32.5%). MS (ESI, m / z) 163.1 [M+H] + .

[0478] Step 2: Synthesis of intermediate S3

[0479] The synthetic route is shown below:

[0480]

[0481] Method: Compound A2 (1.2 g, 9.5 mmol) was dissolved in toluene (30 mL), and S2 (1.3 g, 8.0 mmol), KHSO4 (1.3 g, 9.5 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S3 (1.6 g, 64.0%). MS (ESI, m / z) 266.1 [M+H] + .

[0482] Step 3: Synthesis of intermediate S4

[0483] The synthetic route is shown below:

[0484]

[0485] Method: Compound S3 (9.2 g, 34.7 mmol), [Bu 4 N][SiPh 3 F 2 ] (20.6 g, 38.2 mmol) was dissolved in THF (200 mL), cooled to -60 °C, and TMSCF was added dropwise 3 (14.8 g, 104.1 mmol), the reaction was maintained at -60 °C with stirring for 11.5 h. After the reaction was completed, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain yellow solid compound S4 (2 g, 17.2%). MS (ESI, m / z) 336 [M+H] + .

[0486] Step 4: Synthesis of X-7-5

[0487] The synthetic route is shown below:

[0488]

[0489] Method: Compound S4 (2 g, 6.0 mmol) was dissolved in MeOH (20 mL), HCl / 1,4-dioxane (15 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a light yellow solid compound X-7-5 (0.56 g, 35%). MS (ESI, m / z) 232 [M+H] + .

[0490] Step 5: Synthesis of BX20-7-825

[0491] The synthetic route is shown below:

[0492]

[0493] Method: Compound Int 1 (0.36 g, 2.3 mmol) was dissolved in DMF (6.8 mL) and stirred to dissolve. DIPEA (0.74 g, 5.7 mmol) was added in turn and stirred to dissolve. EDCI (0.73 g, 3.8 mmol) was added and stirred to dissolve. HOBT (0.31 g, 2.3 mmol) was added and stirred to dissolve. After stirring for 10 min, X-7-5 (0.50 g, 1.9 mmol) was added. The reaction mixture was stirred at 25 ° C for 6 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure and purified by preparative chromatography (ammonia system) to obtain a yellow solid compound BX20-7-825 (85 mg, 10.0%). MS (ESI, m / z) 371 [M+H] + .

[0494] 1 H NMR (400 MHz, DMSO-d 6 )δ9.04(d,J=9.9Hz,0H),7.59(d,J=7.7Hz,1H),7.45–7.31(m,2H),7.07(td,J=7.5,1.3Hz,1H),6.16–6.08(m,1H),4.01–3.88(m,1H),3 .04(dd,J=32.0,7.2Hz,4H),2.32(d,J=1.8Hz,1H),1.82(p,J=7.0Hz,2H),1.42(q,J=7.2Hz,2H),0.87–0.76(m,5H),0.70–0.54(m,2H).

[0495] Example 14 BX20-7-826

[0496] Step 1: Synthesis of intermediate S1

[0497] The synthetic route is shown below:

[0498]

[0499] Method: Compound SM1 (20 g, 163.8 mmol) was dissolved in DMF (400 mL), and SM2 (23.2 g, 172.0 mmol), K 2 CO 3 (45.3 g, 327.5 mmol), the reaction mixture was heated to 60 °C and stirred for 4 h. After the reaction, the reaction mixture was poured into 400 mL of H 2 O, extracted with EA, collected the organic phase, dried and concentrated under reduced pressure, and purified by column chromatography (PE:EA=10:1) to obtain a light yellow oily compound S1 (27.0 g, 93.56%). MS (ESI, m / z) 177 [M+H]+ .

[0500] Step 2: Synthesis of intermediate S2

[0501] The synthetic route is shown below:

[0502]

[0503] Method: Compound SM3 (22.95 g, 0.19 mol) was dissolved in toluene (500 mL), and S1 (27.8 g, 0.16 mol) and KHSO were added in sequence. 4 (25.78 g, 0.19 mol), the reaction mixture was stirred at 45°C for 16 h. After the reaction, the mixture was filtered, the filtrate was concentrated under reduced pressure and purified by column chromatography (PE: EA = 10: 1 to 3: 1) to obtain a light yellow oily compound S2 (18.4 g, 41.74%). MS (ESI, m / z) 280 [M+H] + .

[0504] Step 3: Synthesis of intermediate S3

[0505] The synthetic route is shown below:

[0506]

[0507] Method: Compound S2 (5.0 g, 17.9 mmol) and SM4 (3.8 g, 19.7 mmol) were dissolved in THF (50 mL) and N 2 The temperature was then lowered to -78°C, and LiHMDS (21.5 mL, 1 M in THF) was slowly added dropwise. The reaction was maintained at -78°C with stirring for 90 min. After the reaction was completed, saturated NH 4 The mixture was quenched with Cl solution. EA was extracted, the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography (PE:EA=3:1-1:2) to obtain a light yellow oily compound S3 (6.3 g, 74.64%). MS (ESI, m / z) 472 [M+H] + .

[0508] Step 4: Synthesis of S4

[0509] The synthetic route is shown below:

[0510]

[0511] Method: Dissolve NaOAc (11.0 g, 0.13 mol) and HOAc (8.0 g, 0.13 mol) in H 2O (23mL) to obtain solution A. Compound S3 (6.3g, 13.36mmol) was dissolved in DMF (63mL) to obtain solution B. A was added to B, and then Mg (4.9g, 0.2mol) was added. The reaction mixture was stirred at 25°C for 2h. After the reaction was completed, the filtrate was filtered and collected. After the filtrate was dried, it was directly concentrated under reduced pressure and purified by column chromatography (PE:EA=2:1~1:2) to obtain yellow oily compound S4 (3.1g, 69.98%). MS (ESI, m / z) 332 [M+H] + .

[0512] Step 5: Synthesis of S5

[0513] The synthetic route is shown below:

[0514]

[0515] Method: Compound S4 (3.1 g, 9.35 mmol) was dissolved in MeOH (30 mL), and HCl / 1,4-dioxane (23.4 mL, 4 M) was added dropwise. The reaction mixture was stirred at 25°C for 5 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound S5 (2.33 g, 99.99%). MS (ESI, m / z) 228 [M+H] + .

[0516] Step 6: Synthesis of BX20-7-826

[0517] The synthetic route is shown below:

[0518]

[0519] Method: Dissolve Y-5 (358 mg, 2.3 mmol) in DMF (10 mL), add DIPEA (735 mg, 5.7 mmol), EDCI (874 mg, 4.6 mmol) and HOBT (370 mg, 2.8 mmol), stir for 15 minutes, then add S5 (500 mg, 1.9 mmol), and continue to stir at room temperature for 12 hours. After the reaction, the reaction solution was added to ice water to quench, extracted with EA, washed with concentrated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-826 (400 mg, 57.5%). MS (ESI, m / z) 367 [M+H] + .

[0520] 1H NMR(400MHz,DMSO-d6)δ8.69(d,J=9.6Hz,1H),7.46–7.44(m,1H),7.31–7.26(m,1H),7.01–6 .96(m,2H),6.12(td,J=55.6,2.4Hz,1H),5.82–5.74(m,1H),3.92–3.85(m,2H),3.06–2.89(m ,4H),2.47–2.42(m,1H),2.35–2.31(m,1H),2.21(q,J=5.2Hz,1H),1.85–1.78(m,2H),1.42– 1.35(m,2H),1.30–1.22(m,1H),0.83(t,J=7.6Hz,3H),0.59–0.55(m,2H),0.37–0.34(m,2H).

[0521] Example 15 BX20-7-830

[0522] Step 1: Synthesis of intermediate S1

[0523] The synthetic route is shown below:

[0524]

[0525] Method: Compound SM2 (5.0 g, 40.3 mmol) was dissolved in toluene (50 mL), and SM1 (5.0 g, 40.3 mmol), KHSO 4 (6.6 g, 48 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a light yellow oily compound S1 (5.0 g, 54.6%). MS (ESI, m / z) 228 [M+H] + .

[0526] Step 2: Synthesis of intermediate S2

[0527] The synthetic route is shown below:

[0528]

[0529] Method: Compound S1 (1 g, 4.4 mmol) was dissolved in DCM (10 mL) and the system was replaced by N 2 The temperature was lowered to -78°C, SM3 (44 mL, 0.5 M in THF) was added dropwise, and the reaction was maintained at -78°C with stirring for 2 h. After the reaction, saturated NH 4The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow solid compound S2 (880 mg, 73.95%). MS (ESI, m / z) 270 [M+H] + .

[0530] Step 3: Synthesis of S3

[0531] The synthetic route is shown below:

[0532]

[0533] Method: Compound S2 (880 mg, 3.27 mmol) was dissolved in DCM (8.8 mL), HCl / 1,4-dioxane (8.17 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound S3 (600 mg, 91.07%). MS (ESI, m / z) 166 [M+H] + .

[0534] Step 4: Synthesis of BX20-7-830

[0535] The synthetic route is shown below:

[0536]

[0537] Method: Dissolve Y-5 (465 mg, 2.96 mmol) in DMF (10 mL), add DIPEA (1.10 g, 8.88 mmol), EDCI (1.13 g, 5.92 mmol) and HOBT (480 mg, 3.55 mmol), stir for 15 minutes, then add S3 (500 mg, 2.48 mmol), and continue to stir at room temperature for 12 hours. After the reaction, the reaction solution was added to ice water to quench, extracted with EA, washed with concentrated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-830 (380 mg, 50.41%). MS (ESI, m / z) 305 [M+H] + .

[0538] 1H NMR(400MHz, DMSO-d6)δ8.32(d,J=8.8Hz,1H),7.50–7.35(m,2H),7.16–7.09(m,2H),4.32–4.26(m,1H),3.10–2.90(m,4H),2.51 –2.41(m,1H),2.24–2.08(m,2H),1.93–1.83(m,2H),1.37–1.26(m,2H),1.13–1.06(m,1H),0.83–0.65(m,3H),0.53–0.27(m,4H).

[0539] Example 16BX20-7-833

[0540] Step 1: Synthesis of intermediate S3

[0541] The synthetic route is shown below:

[0542]

[0543] Method: Compound S1 (10.0 g, 87.7 mmol) was dissolved in ethanol (100 mL), and S2 (9.84 g, 105.2 mmol), Et 3 N (26.6 g, 263.1 mmol), the reaction mixture was stirred at room temperature for 16 h. After the reaction, the filtrate was filtered and collected, extracted with DCM three times, washed with concentrated brine, dried and concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow transparent liquid S3 (8.5 g, 56.6%). MS (ESI, m / z) 172 [M+H] + .

[0544] Step 2: Synthesis of intermediate S4

[0545] The synthetic route is shown below:

[0546]

[0547] Method: Compound S1 (8.5 g, 49.7 mmol) was dissolved in MeOH (50 mL) and water (10 mL), and LiOH·H 2 O (2.3 g, 54.7 mmol), the reaction was stirred at 60 ° C for 16 h. After the reaction, the reaction mixture was directly concentrated, washed with PE and MeCN in turn, and filtered to obtain a white solid S4 (9.0 g, crude product). MS (ESI, m / z) 144 [M+H] + .

[0548] Step 3: Synthesis of BX20-7-833

[0549] The synthetic route is shown below:

[0550]

[0551] Method: S4 (149 mg, 1.0 mmol) was dissolved in DMF (5 mL), and DIPEA (323 mg, 2.5 mmol), EDCI (382 mg, 2.0 mmol) and HOBT (162 mg, 1.2 mmol) were added. After stirring for 15 minutes, X-1 (135 mg, 0.63 mmol) was added, and the reaction was continued to stir at room temperature for 3 hours. After the reaction was completed, the reaction solution was added to ice water to quench, extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative chromatography (ammonia system) to obtain a light yellow oily compound BX20-7-833 (60 mg, 31.5%). MS (ESI, m / z) 303 [M+H] + .

[0552] 1 H NMR (400 MHz, CDCl 3 )δ8.74–8.63(m,1H),7.24–7.17(m,2H),6.93–6.87(m,2H),4.69(q,J=8 .8Hz,1H),3.89–3.88(t,J=2.0Hz,3H),3.26–3.21(m,3H),2.17–2.12(m ,1H),2.70–2.54(m,1H),2.43–2.36(m,1H),2.25–2.01(m,3H),1.35–1. 27(m,1H),1.07(t,J=7.2Hz,3H),0.48–0.34(m,3H),0.31–0.25(m,1H).

[0553] Example 17BX20-7-834

[0554] Step 1: Synthesis of intermediate S2

[0555] The synthetic route is shown below:

[0556]

[0557] Method: Compound SM1 (6.8 g, 56.5 mmol) was dissolved in toluene (100 mL), and S1 (5.0 g, 47.1 mmol), KHSO 4(7.7 g, 56.5 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After reduced pressure concentration, it was purified by column chromatography to obtain a brown oily compound S2 (4.45 g, 45.2%). MS (ESI, m / z) 210 [M+H] + .

[0558] Step 2: Synthesis of intermediate S3

[0559] The synthetic route is shown below:

[0560]

[0561] Method: Compound S2 (4.4 g, 21 mmol) was dissolved in DCM (40 mL) and N 2 , cool to -78°C. Add SM2 (63 mL, 63 mmol) dropwise, keep -78°C for 1 h. After the reaction, filter and collect the filtrate. After concentration under reduced pressure, purify by column chromatography to obtain a light brown oily compound S3 (4.8 g, 91.0%). MS (ESI, m / z) 252 [M+H] + .

[0562] Step 3: Synthesis of intermediate S4

[0563] The synthetic route is shown below:

[0564]

[0565] Method: Compound S3 (4.8 g, 19.1 mmol) was dissolved in MeOH (50 mL), HCl / 1,4-dioxane (48 mL, 191 mmol) was added dropwise, and the mixture was stirred at 25°C for 12 h. After the reaction, the mixture was concentrated under reduced pressure and dried by spin drying, and PE:EA=3:1 (50 mL) was added to slurry for 0.5 h, and the white solid compound S4 (2.6 g, 74.3%) was obtained by filtration. MS (ESI, m / z) 148 [M+H] + .

[0566] Step 4: Synthesis of BX20-7-834

[0567] The synthetic route is shown below:

[0568]

[0569] Method: Compound S5 (0.17 g, 0.96 mmol) was dissolved in DMF (4 mL) and stirred to dissolve. DIPEA (0.31 g, 2.4 mmol) was added in turn and stirred to dissolve. EDCI (0.31 g, 1.6 mmol) was added and stirred to dissolve. HOBT (0.13 g, 0.96 mmol) was added and stirred to dissolve. After stirring for 10 min, S4 (0.15 g, 0.8 mmol) was added. The reaction mixture was stirred at 25 ° C for 3 h. After the reaction was completed, the reaction solution was added to ice water to quench, extracted with EA, washed with concentrated brine, and dried over anhydrous sodium sulfate. After concentration, the white solid compound BX20-7-834 (70 mg, 29.1%) was obtained after purification by preparative chromatography (ammonia system). MS (ESI, m / z) 301 [M+H] + .

[0570] 1 H NMR(400MHz,Chloroform-d)δ8.23–8.02(m,1H),7.44–7.35(m,2H),7.35–7.29(m,2H),7.26–7.21(m,1H),4.60–4.49(m,1H),3.26–3.08(m,4H),2.7 6–2.67(m,1H),2.50–2.42(m,1H),2.25–2.09(m,1H),2.08–1.97(m,2H),1 .93-1.83(m,1H),1.21-1.11(m,1H),1.07–0.74(m,6H),0.63–0.32(m,4H).

[0571] Example 18 BX20-7-835

[0572] Step 1: Synthesis of intermediate S1

[0573] The synthetic route is shown below:

[0574]

[0575] Method: Compound SM2 (6.5 g, 54.1 mmol) was dissolved in toluene (100 mL), and SM1 (5.0 g, 41.6 mmol), KHSO 4 (7.4 g, 54.1 mmol), the reaction mixture was stirred at 45°C for 16 h. After the reaction, the filtrate was collected and concentrated under reduced pressure and purified by column chromatography to obtain a yellow oily compound S1 (7.85 g, 84.6%). MS (ESI, m / z) 224 [M+H] + .

[0576] Step 2: Synthesis of intermediate S2

[0577] The synthetic route is shown below:

[0578]

[0579] Method: Compound S1 (1.5 g, 6.7 mmol) was dissolved in DCM (20 mL) and the system was replaced by N 2 The temperature was lowered to -78°C, SM3 (34 mL, 1 M in THF) was added dropwise, and the reaction was maintained at -78°C with stirring for 1 h. After the reaction, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a light yellow oily compound S2 (1.4 g, 79.4%). MS (ESI, m / z) 266 [M+H] + .

[0580] Step 3: Synthesis of S3

[0581] The synthetic route is shown below:

[0582]

[0583] Method: Compound S2 (1.4 g, 5.3 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (13.3 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 1 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound S3 (880 mg, 83.7%). MS (ESI, m / z) 162 [M+H] + .

[0584] Step 4: Synthesis of BX20-7-835

[0585] The synthetic route is shown below:

[0586]

[0587] Method: Dissolve Y-5 (200 mg, 1.27 mmol) in DMF (6 mL), add DIPEA (490 mg, 3.81 mmol), EDCI (487 mg, 2.54 mmol) and HOBT (223 mg, 1.65 mmol), stir for 15 minutes, then add S3 (251 mg, 1.27 mmol), and continue to stir at room temperature for 3 hours. After the reaction, the reaction solution was added to ice water to quench, extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-835 (120 mg, 31.5%). MS (ESI, m / z) 301 [M+H] + .

[0588] 1 H NMR (400 MHz, CDCl 3 )δ7.36(d,J=7.6Hz,1H),7.20–7.13(m,1H),7.20–7.15(m,3H),4.99(d,J=6. 8Hz,1H),3.24–3.16(m,4H),2.70–2.64(m,1H),2.45–2.41(m,1H),2.39(s,3H ),2.10–2.01(m,1H),1.99–1.93(m,1H),1.71–1.60(m,1H),1.52–1.41(m,1H) ,1.23–1.16(m,1H),0.88–0.84(m,3H),0.56–0.42(m,2H),0.40–0.25(m,2H).

[0589] Example 19BX20-7-836

[0590] Step 1: Synthesis of intermediate S1

[0591] The synthetic route is shown below:

[0592]

[0593] Method: Compound SM2 (6.3 g, 52.1 mmol) was dissolved in toluene (100 mL), and SM1 (5.0 g, 40.3 mmol), KHSO 4 (7.1 g, 52.2 mmol), the reaction mixture was stirred at 45°C for 16 h. After the reaction, the filtrate was collected and concentrated under reduced pressure and purified by column chromatography to obtain a yellow oily compound S1 (4.0 g, 43.7%). MS (ESI, m / z) 228 [M+H] + .

[0594] Step 2: Synthesis of intermediate S2

[0595] The synthetic route is shown below:

[0596]

[0597] Method: Compound S1 (1.5 g, 6.6 mmol) was dissolved in DCM (15 mL) and the system was replaced by N 2 The temperature was lowered to -78°C, SM3 (33 mL, 1 M in THF) was added dropwise, and the reaction was maintained at -78°C with stirring for 1 h. After the reaction, saturated NH 4 The solution was quenched with Cl solution, extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to obtain a white solid S2 (1.6 g, 90.0%). MS (ESI, m / z) 270 [M+H] + .

[0598] Step 3: Synthesis of S3

[0599] The synthetic route is shown below:

[0600]

[0601] Method: Compound S2 (1.6 g, 5.9 mmol) was dissolved in DCM (50 mL), HCl / 1,4-dioxane (14.8 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 1 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid S3 (1.16 g, crude product). MS (ESI, m / z) 166 [M+H] + .

[0602] Step 4: Synthesis of BX20-7-836

[0603] The synthetic route is shown below:

[0604]

[0605] Method: Dissolve Y-5 (200 mg, 1.27 mmol) in DMF (6 mL), add DIPEA (491 mg, 3.81 mmol), EDCI (487 mg, 2.54 mmol) and HOBT (228 mg, 1.65 mmol), stir for 15 minutes, then add S3 (256 mg, 1.27 mmol), and continue to stir at room temperature for 3 hours. After the reaction, the reaction solution was added to ice water to quench, extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-836 (191 mg, 62.5%). MS (ESI, m / z) 301 [M+H] + .

[0606] 1 H NMR (400 MHz, CDCl 3 )δ8.62(d,J=8.0Hz,1H),7.29(td,J=7.6Hz,2.0Hz,1H),7.24–7.18(m,1H),7.10 –7.00(m,2H),4.65-4.60(m,1H),3.25–3.12(m,4H),2.71–2.58(m,1H),2.45–2.4 1(dd,J=8.0Hz,3.6Hz,1H),2.11–1.96(m,3H),1.70–1.60(m,1H),1.51–1.42(m, 1H),1.30–1.21(m,1H),0.89–0.83(m,3H),0.56–0.41(m,3H),0.37–0.29(m,1H).

[0607] Example 20BX20-7-837

[0608] Step 1: Synthesis of intermediate S1

[0609] The synthetic route is shown below:

[0610]

[0611] Method: Compound SM2 (5.2 g, 42.7 mmol) was dissolved in toluene (50 mL), and SM1 (5 g, 35.6 mmol), KHSO 4 (5.8 g, 42.7 mmol), the reaction mixture was heated to 45°C and stirred for 24 h. After the reaction, the filtrate was filtered and collected. After concentration under reduced pressure, it was extracted with EA. The organic phase was dried and concentrated and purified by column chromatography to obtain a light yellow oily compound S1 (3.2 g, 37.34%). MS (ESI, m / z) 244.1 [M+H] + .

[0612] Step 2: Synthesis of intermediate S2

[0613] The synthetic route is shown below:

[0614]

[0615] Method: Compound S1 (1.5 g, 6.15 mmol) was dissolved in DCM (15 mL) and the system was replaced by N 2 The temperature was lowered to -78°C, SM3 (30.8 mL, 1 M in THF) was added dropwise, and the reaction was maintained at -78°C with stirring for 2 h. After the reaction, saturated NH 4 The mixture was quenched with Cl solution. The mixture was extracted with EA, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography to form a light yellow oily compound S2 (1.5 g, 85.23%). MS (ESI, m / z) 286.2 [M+H] + .

[0616] Step 3: Synthesis of S3

[0617] The synthetic route is shown below:

[0618]

[0619] Method: Compound S2 (1.5 g, 5.25 mmol) was dissolved in DCM (20 mL), HCl / 1,4-dioxane (13 mL, 4 M) was added dropwise, and the reaction mixture was stirred at 25°C for 2 h. After the reaction, the reaction solution was directly concentrated under reduced pressure and washed with PE:EA=3:1 to obtain a white solid compound S3 (1.1 g, 96.49%). MS (ESI, m / z) 182.1 [M+H] + .

[0620] Step 4: Synthesis of BX20-7-837

[0621] The synthetic route is shown below:

[0622]

[0623] Method: Y-5 (238 mg, 1.51 mmol) was dissolved in DMF (3 mL), and DIEA (533 mg, 4.13 mmol), EDCI (527 mg, 2.75 mmol), and HOBT (223 mg, 1.65 mmol) were added in sequence. After stirring for 10 min, S3 (300 mg, 1.38 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. After the reaction, the reaction solution was dropped into ice H 2After dilution with O, EA extraction was performed, the organic phase was dried and concentrated under reduced pressure, and purified by preparative chromatography (ammonia system) to obtain a white solid compound BX20-7-837 (199 mg, 45.09%). MS (ESI, m / z) 321.2 [M+H] + .

[0624] 1 H NMR(400MHz,CHLOROFORM-d)pppm:0.18-0.51(m,3H),0.52-0.61(m,1H),0.81-0.92( m,3H),1.33(dt,J=7.92,5.04Hz,1H),1.40-1.54(m,1H),1.67(dt,J=14.09,7.04Hz, 1H),1.95-2.14(m,3H),2.45(dd,J=11.93,3.72Hz,1H),2.69(dd,J=12.13,9.78Hz,1 H), 3.24 (t, J = 6.85Hz, 4H), 4.79-5.02 (m, 1H), 7.13-7.25 (m, 2H), 7.32-7.38 (m, 2H).

[0625] Comparative Example 1 Reference Compound 1 (801):

[0626] Reference compound 1 was synthesized by referring to the synthesis method of Example 204 of patent WO2021202781A1

[0627]

[0628] 1 H NMR (400 MHz, DMSO-d 6 )δ=8.86-8.83(m,1H), 8.20(s,1H), 7.55-7.51(m,2H), 7.26-7.21(m,2H), 6.33-6.06(m,1H), 5.40-5.35(m,1H), 3.18-3.17( m,2H), 3.09-3.07(m,2H), 2.63-2.58(m,1H), 2.40-2.34(m,2H), 1.93-1.86(m,2H), 1.42-1.38(m,2H), 0.82(t,J=8.0Hz,3H).

[0629] Comparative Example 2 Reference Compound 2 (802):

[0630] Reference compound 2 was synthesized by referring to the synthesis method of Example 180 of patent WO2021202781A1

[0631]

[0632] 1 H NMR (400MHz, DMSO-d6) δ8.77(d,J=9.3Hz,1H),7.54–7.28(m,5H),6.20(td,J=55.3,3.4Hz,1H),5.36(ddp,J=16.1,12.5,3.7Hz,1H),3.03(q ,J=6.7Hz,2H),2.92(q,J=6.7Hz,2H),2.48–2.40(m,1H),2.34–2.16(m,2H),1.82(p,J=6.9Hz,2H),1.46–1.29(m,2H),0.82(t,J=7.4Hz,3H).

[0633] Comparative Example 3 Reference Compound 3 (803):

[0634] Reference compound 3 was synthesized by referring to the synthesis method of Example 189 of patent WO2021202781A1

[0635]

[0636] MS (ESI, m / z) 327.2 [M+H]+.

[0637] 1H NMR (400MHz, DMSO-d6) δ = 8.73-8.71 (m, 1H), 7.46-7.44 (m, 1H), 7.35-7.31 (m, 1H), 7.06-6.98(m,2H), 6.24-5.96(m,1H), 5.76-5.68(m,1H), 3.84(s,3H), 3.0 6-3.01(m,2H), 2.95-2.90(m,2H), 2.44-2.43(m,1H), 2.35-2.28(m,1H), 2.23 -2.19(m,1H), 1.83-1.80(m,2H), 1.38(t,J=8.0Hz,2H), 0.82(t,J=8.0Hz,3H).

[0638] Comparative Example 4 Reference Compound 4 (816):

[0639] Reference compound 4 was synthesized by referring to the synthesis method of Example 201 of patent WO2021202781A1

[0640]

[0641] MS (ESI, m / z) 269.2 [M+H]+.

[0642] 1H NMR (400MHz, DMSO-d6)d=7.47-7.19(m,5H),6.37-5.97(m,1H),5.30(t,J=13.9Hz ,1H),3.25-3.10(m,1H),2.69-2.54(m,2H),2.39-2.11(m,5H),1.65-1.26(m,2H).

[0643] Biological test evaluation

[0644] The present invention is further described and explained below in conjunction with test examples.

[0645] Test Example 1 Determination of the agonist activity of the compounds of the present invention on human somatostatin type IV receptor SSTR4

[0646] 1. Purpose of the experiment

[0647] Cell-based human SSTR4 cAMP assay was used to determine the agonist effect of the test compound on SSTR4 receptor.

[0648] 2. Experimental materials and equipment

[0649] 2.1 Experimental reagents and consumables

[0650]

[0651]

[0652] 2.2 Experimental instruments and equipment

[0653] instrument brand model Multi-label microplate reader EnVision PerkinElmer 2203-1060

[0654] 3. Experimental Methods

[0655] 3.1 Cell culture and reagent preparation

[0656] 1) Cell line: Flp-In-CHO-SSTR4 (provided by Kanglong Pharmaceutical Technology Co., Ltd., constructed using the Flp-In system of Invitrogen)

[0657] 2) Complete medium: Complete medium: Ham's F-12K + 10% fetal bovine serum + 1x penicillin-streptomycin (PS) + 600 μg / mL hygromycin B

[0658] 3) Cell seeding medium: Ham's F-12K + 10% FBS

[0659] 4) Experimental buffer: 1X HBSS + 20mM HEPES + 0.1% BSA + 500μM IBMX

[0660] 3.2 Preparation of working solution of test compound

[0661] The test compound was dissolved in DMSO to prepare a 10 mM stock solution and diluted to a maximum starting concentration of 1000 nM during the experiment.

[0662] 3.3 EC of the test compound 50 Determination of value

[0663] 1) Flp-In-CHO-SSTR4 cell line was cultured in complete medium at 37°C, 5% CO 2 To 70% to 90% fusion degree.

[0664] 2) After TrypLE digestion, the cells were resuspended in inoculation medium and inoculated into a 384-well cell culture plate (PEculture384plate), with 7,000 cells per well, at 37°C, 5% CO 2 Incubate overnight.

[0665] 3) Prepare the positive control compound and the test compound working solution (8X).

[0666] 4) Take out the cell culture plate, centrifuge at 200g for 5 seconds at room temperature to remove the culture medium, then quickly add 15 μL of experimental buffer to each experimental well, and centrifuge at 200g for 5 seconds at room temperature to mix evenly.

[0667] 5) Add 2.5 μL of the 8X compound working solution diluted in step 3 to the corresponding test wells, centrifuge at 200 g for 5 seconds at room temperature, and incubate at 37°C for 10 minutes.

[0668] 6) Prepare 4 μM Forskolin working solution (8X).

[0669] 7) Take out the cell plate and equilibrate it to room temperature, then add 2.5 μL of the 8X Forskolin working solution prepared in step 6 to the corresponding test wells, 200g, RT, 5s, and stand at 37°C for 30min.

[0670] 8) Freeze-thaw Eu-cAMP tracer and Uliaght-anti cAMP, dilute Eu-cAMP tracer 50 times and Uliaght-anti cAMP 150 times with detection buffer.

[0671] 9) Add 10 μL Eu-cAMP tracer to all experimental wells, and add 10 μL Uliaght-anti cAMP to the remaining experimental wells.

[0672] 10) The reaction plate was centrifuged at 200 g for 30 seconds at room temperature, allowed to stand at 25°C for 1 hour, and data were collected using Envision.

[0673] 3.4 Data Analysis

[0674] Calculate compound EC using GraphPad nonlinear fitting formula 50 .

[0675] Z' factor = 1-3*(standard deviation Max + standard deviation Min) / (average value Max - average value Min)

[0676] Coefficient of variation Max = (standard deviation Max / average value Max) * 100%

[0677] Coefficient of variation Min = (standard deviation Min / average value Min) * 100%

[0678] S / B = Singal / Background signal value / background value

[0679] Negative control (Min): Assay buffer

[0680] Positive control (Max): 1,000nM of Somatostatin 14

[0681] The EC50 of the compound was calculated using the GraphPad nonlinear fitting formula:

[0682] Y=Bottom+(Top-Bottom) / (1+10^((LogEC50-X)*HillSlope))

[0683] X: log value of compound concentration; Y: Activation%.

[0684] 4. Experimental Results

[0685] Table 1 SSTR4 agonist activity assay

[0686]

[0687]

[0688]

[0689]

[0690]

[0691] 5. Experimental Conclusion

[0692] Results Table 1 shows that the above examples have good activity.

[0693] Test Example 2 Pharmacokinetics Determination in SD Rats

[0694] 1. Purpose of the experiment

[0695] SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 10 mg / kg.

[0696] 2. Test methods

[0697] 2.1. Test drugs

[0698] The examples and reference compounds of the present invention were prepared in-house.

[0699] 2.2. Experimental animals

[0700] Male SPF SD rats, weighing (200±20) g, from Sibeifu (Beijing) Biotechnology Co., Ltd., animal production license number SCXK (Beijing) 2022-0030.

[0701] 2.3. Preparation of experimental drugs

[0702] Drug preparation: The drug concentration was prepared to 1 mg / mL, and the solution was 0.5% CMC-Na solution.

[0703] Specific preparation: Weigh 15 mg of each drug using a 1 / 100000 precision balance and suspend evenly in 15 mL of 0.5% CMC-Na solution.

[0704] 2.4. Administration:

[0705] After 3-4 days of adaptive feeding, male SPF SD rats were gavaged and administered with a dose of 10 mg / kg and a dosing volume of 10 mL / kg.

[0706] Before (0h) and after administration, blood was collected from rats at 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, and 24h. Blood was collected by fundus puncture, and the blood volume was about 0.5mL, which was placed in a labeled EDTA-K2 anticoagulant tube. Immediately after blood collection, the blood collection tube was gently and completely inverted 3 times to mix with the anticoagulant, and immediately centrifuged at 4500rpm in an ice water bath at 4℃ for 10min. After the centrifugation operation was completed, the plasma was promptly dispensed into EP tubes with corresponding labels and stored in a -80℃ refrigerator.

[0707] 2.6. Sample testing

[0708] This experiment used a simple validated LC-MS / MS method to determine the concentrations of Example X and Example Y in plasma after administration.

[0709] 2.6.1. Sample processing: Take 2 μL of blank plasma in a 96-deep-well plate, add 400 μL of precipitant methanol, vortex for 10 min, centrifuge at 4000 rpm for 15 min, take 250 μL of supernatant in a 96-deep-well plate, and perform LC-MS / MS analysis with an injection volume of 5 μL.

[0710] 2.6.2. Liquid quality analysis:

[0711] 1) Liquid phase conditions

[0712] Chromatographic column: WATERS ACQUITY HSS T3, 2.1*100mm, 1.8μm; No.: 046

[0713] Pressure: 60Mpa

[0714] Pre-column: waters guard column

[0715] Column temperature: 40°C

[0716] Injection volume: 1 μL

[0717] Injector temperature: 4°C

[0718] Run time: 6 minutes

[0719] Flow rate: 0.6mL / min

[0720] Column pressure: 60Mpa

[0721] Needle washing solution: 50% acetonitrile water

[0722] Needle wash mode: Before and after aspiration

[0723] Mobile phase A: 0.1% formic acid in 5 mM ammonium acetate in water

[0724] Mobile phase B: 0.1% formic acid, 5 mM ammonium acetate, 90% acetonitrile in water

[0725] Elution program and mobile phase distribution ratio: Gradient elution is shown in Table 2 below.

[0726] Table 2

[0727] Time / min A％ B％ 4.20 40 60 4.21 5 95 5.10 5 95 5.11 85 15 6.00 System Controller Stop

[0728] 2) Mass spectrometry conditions:

[0729] Ion detection method: Multiple reaction ion monitoring (MRM)

[0730] Ion polarity: positive ion

[0731] Ionization method: pneumatically assisted electrospray ionization (ESI)

[0732] CAD: 8

[0733] CUR: 40psi

[0734] GS1: 50psi

[0735] GS2: 50psi

[0736] TEM: 600℃

[0737] IS: 4500v

[0738] 3. Test results and analysis

[0739] The main pharmacokinetic parameters were calculated using WinNonlin 7.0. The results of the rat pharmacokinetic experiment are shown in Table 3 below.

[0740] Table 3 Results of rat pharmacokinetic test

[0741]

[0742] 4. Experimental conclusion

[0743] It can be seen from the rat pharmacokinetic test results in the table that the compounds of the examples of the present invention exhibit good absorption.

[0744] Test Example 3 Determination of analgesic effect in rat sciatica pain model

[0745] Objective: To evaluate the efficacy of the examples in the CCI model of sciatic nerve pain in Sprague-Dawley (SD) rats using a mechanical allodynia test.

[0746] Test drugs: Examples of the present invention and reference compounds, homemade. The drug concentration was prepared according to the dosing regimen to 6 mg / mL, and the prepared solution was 0.5% CMC-Na solution.

[0747] Methods: Male Sprague-Dawley rats aged 7 to 8 weeks were selected, and chronic sciatic nerve constriction injury (CCI) surgery was performed on the right foot of the animals on the first day. The model rats were adapted from the 11th to the 13th day, and the baseline animal mechanical pain perception (PWT) test was performed using Von Frey on the 14th day. According to the baseline grouping, animals with a mechanical pain threshold of less than 10g were screened and randomly divided into a solvent control group, a pregabalin group, a reference compound group 4, and an example group 5, with 8 animals in each group. Subsequently, the animals were weighed and administered a single oral gavage according to the test. All animals were tested for foot withdrawal threshold using Von Frey 2 hours, 4 hours, and 6 hours after administration. Grouping and administration are shown in Table 4.

[0748] Table 4 Experimental groups and dosage table

[0749]

[0750] Mechanical pain (PWT) test method:

[0751] The rats were placed in a transparent plastic cage with a wire mesh at the bottom, and the animals were allowed to acclimate to the environment for 10 minutes before the test. The von Frey cilia were used to stimulate the filaments from the minimum force (the stimulation site was the plantar surface), and the mechanical stimulation intensity was from small to large, vertically stimulating the plantar surface of the rat's left hind paw, and gradually increasing the pressure until the filament was in an "S" shape, which lasted for 6 to 8 seconds. Each strength was tested 3-5 times, with an interval of 10 seconds each time, and the rats were observed for any movements such as retracting their feet, shaking their legs, shaking their hind paws, or licking. If the rats quickly shook their legs or retracted their feet when the filaments were stimulated or removed, it was recorded as a positive reaction; the mechanical pain threshold of three positive reactions in the test was recorded, and the average of the three times was recorded as the pain threshold of the rat.

[0752] Results: As shown in Table 5, Figure 1 As shown, the results showed that Example 5 could inhibit the mechanical allodynia induced by the rat sciatic nerve pain model 2 hours after oral administration.

[0753] Table 5 Results of efficacy study of compounds in rat CCI pain model

[0754]

[0755] Note: *p<0.05, compared with the solvent control group using t test

[0756] Test Example 4 Determination of analgesic effect in rat CFA model

[0757] Objective: To evaluate the efficacy of the examples in the CFA model of Sprague-Dawley (SD) rats using the mechanical allodynia test.

[0758] Test drugs: Examples of the present invention and reference compounds, homemade. The drug concentration was prepared according to the dosing regimen to 6 mg / mL, and the prepared solution was 0.5% CMC-Na solution.

[0759] Method: 7-8 week old male SD rats were selected, 100 μL of CFA solution (CFA (Freund's complete adjuvant): physiological saline = 1:1, CFA stock solution (sigma)) was injected into the center of the left hind paw of the rats, 24 hours after modeling, animals with a foot withdrawal threshold of <5g were screened according to the basic value of mechanical pain, and divided into groups, 8 animals in each group, and the foot withdrawal threshold of the animals was tested using fibers 2 hours, 4 hours and 6 hours after a single oral administration of the example molecules. The grouping and administration method is shown in Table 6.

[0760] The mechanical pain perception (PWT) test method is the same as described in Test Example 3.

[0761] Table 6 Experimental groups and dosage table

[0762]

[0763] Table 7 Results of efficacy study of compounds in rat CFA inflammatory pain model

[0764]

[0765] Note: *p<0.05, compared with the solvent control group using t test

[0766] The results are shown in Table 7. Figure 2 As shown, the results showed that Example 15 30 mg / kg could inhibit mechanical allodynia induced by the CFA model in rats after oral administration for 2 hours, 4 hours, and 6 hours.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, in, The carbon atom with "*" indicates that when it is a chiral carbon atom, it is independently in S configuration, R configuration or a mixture thereof; The definition of each substituent is selected from one of the following schemes 1-3: Option 1: R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -C 2-6 Alkynyl, -C 2-6 Haloalkynyl, -C 3-6 Cycloalkyl, -C 3-6 Halogenated cycloalkyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, 1, 2 or 3 R a Replaced-C 1-6 Alkyl, 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, 1, 2 or 3 R a Replaced-C 2-6 Alkynyl; R 1 ,R 2 ,R 3 ,R 4 and R 5 At least one of them is -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 alkyl; R a Independently -C 3-6 Cycloalkyl; R 6 For -C 3-6 Cycloalkyl, 1, 2 or 3 R b Replaced-C 1-6 alkyl; R b are independently halogen or -CN; R 7 -H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl or -C substituted by 1, 2 or 3 CN 1-6 alkyl; Option 2: R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -C 2-6 Alkynyl, -C 2-6 Haloalkynyl, -C 3-6 Cycloalkyl, -C 3-6 Halogenated cycloalkyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, 1, 2 or 3 R a Replaced-C 1-6 Alkyl, 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, 1, 2 or 3 R a Replaced-C 2-6 Alkynyl; R a Independently -C 3-6 Cycloalkyl; R 6 For -C 3-6 Cycloalkyl, -C substituted by 1, 2 or 3 -CN 1-6 alkyl; R 7 -H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl or -C substituted by 1, 2 or 3 CN 1-6 alkyl; Option 3: R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -C 2-6 Alkynyl, -C 2-6 Haloalkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl, -C 3-6 Cycloalkyl, -C 3-6 Halogenated cycloalkyl, 1, 2 or 3 R a Replaced-C 1-6 Alkyl, 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, 1, 2 or 3 R a Replaced-C 2-6 Alkynyl; R a Independently -C 3-6 Cycloalkyl; R 6 For -C 3-6 Cycloalkyl, 1, 2 or 3 R b Replaced-C 1-6 alkyl; R b are independently halogen or -CN; R 7 -C substituted by 1, 2 or 3 CN 1-6 Alkyl or -C 3-6 Cycloalkyl.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) In scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 1-6 Alkyl, -OC 1-6 Alkyl, substituted-C 1-6 Alkyl, and substituted -OC 1-6 -C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example, methyl; (2) In schemes 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 1-6 Haloalkyl, and -OC 1-6 -C in haloalkyl 1-6 The haloalkyl groups are independently halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl, halo-isobutyl, halo-sec-butyl or halo-tert-butyl; (3) In Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 2-6 Alkynyl, and substituted -C 2-6 -C in alkynyl 2-6 Alkynyl is independently -C 2-4 Alkynyl, e.g. (4) In Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 2-6 The haloalkynyl groups are independently -C 2-4 Haloalkynyl; (5) In Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 3-6 Cycloalkyl, -OC 3-6 -C in cycloalkyl 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for example cyclopropyl or cyclobutyl; (6) In Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 In the -C 3-6 Halogenated cycloalkyl, -OC 3-6 -C in halocycloalkyl 3-6 Halocycloalkyl is independently halocyclopropyl, halocyclobutyl, halocyclopentyl and halocyclohexyl, for example halocyclobutyl; (7) In Scheme 1-3, R 6 In the -C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for example cyclopropyl or cyclobutyl; (8) In Scheme 1-3, R 6 wherein the substituted -C 1-6 -C in the alkyl group 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (9) In Schemes 1 and 2, R 7 In the -C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl; (10) In Scheme 1-3, R 7 In the -C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for example cyclopropyl or cyclobutyl; (11) In Scheme 1-3, R 7 In the case of -C 1-6 -C in the alkyl group 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (12) In Scheme 1-3, R 1 , R 2 , R 3 , R 4 and R 5 wherein the halogen is independently F, Cl, Br, I, such as F or Cl; (13) In Schemes 1 and 3, R b wherein the halogen is independently F, Cl, Br, I, such as F or Cl; (14) In Scheme 1-3, R a In the -C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, for example cyclopropyl; (15) In scheme 2, R 6 wherein the substituted -C 1-6 The number of CN in the alkyl group is 1; (16) In scheme 3, R 7 wherein the substituted -C 1-6 The number of CN in an alkyl group is 1.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: When the compound as shown in Formula I is selected from Scheme 1, the compound as shown in Formula I satisfies one or more of the following conditions: (1)R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 Alkyl; R 1 , R 2 , R 3 , R 4 and R 5 Among them, one is -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, the rest are -H or halogen; (2)R a Independently -C 3-6 Cycloalkyl; (3)R 6 For 1, 2 or 3 R b Replaced-C 1-6 alkyl; (4)R b are independently halogen; (5)R 7 For -C 1-6 alkyl; When the compound as shown in Formula I is selected from Scheme 2, the compound as shown in Formula I satisfies one or more of the following conditions: (1)R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl; preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is -H, halogen, -C 1-6 Alkyl or -OC 1-6 alkyl, the rest are H; more preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is -H, halogen or -C 1-6 Alkyl, the rest are H; (2)R 6 For -C 3-6 Cycloalkyl, -C substituted by 1, 2 or 3 -CN 1-6 alkyl; (3)R 7 For -C 1-6 alkyl; When the compound as shown in Formula I is selected from Scheme 3, the compound as shown in Formula I satisfies one or more of the following conditions: (1)R 1 , R 2 , R 3 , R 4 and R 5 are independently -H or halogen; preferably, R 1 , R 2 , R 3 , R 4 and R 5 Among them, one is -H or halogen, and the rest are H; (2)R 6 For 1, 2 or 3 R b Replaced-C 1-6 alkyl; (3)R b are independently halogen or -CN; (4)R 7 -C substituted by 1, 2 or 3 CN 1-6 Alkyl or -C 3-6 Cycloalkyl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I satisfies one of the following conditions: (1) In Scheme 1, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 Alkyl; R 1 , R 2 , R 3 , R 4 and R 5 Among them, one is -C 2-6 Alkynyl, -OC 3-6 Cycloalkyl, -OC 3-6 Halogenated cycloalkyl or 1, 2 or 3 R a Replaced-OC 1-6 Alkyl, the rest are -H or halogen; R a Independently -C 3-6 Cycloalkyl; R 6 For 1, 2 or 3 R b Replaced-C 1-6 alkyl; R b are independently halogen; R 7 For -C 1-6 alkyl; (2) In scheme 2, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl; preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is -H, halogen, -C 1-6 Alkyl or -OC 1-6 alkyl, the rest are H; more preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is -H, halogen or -C 1-6 Alkyl, the rest are H; R 6 For -C 3-6 Cycloalkyl, -C substituted by 1, 2 or 3 -CN 1-6 alkyl; R 7 For -C 1-6 alkyl; (3) In scheme 3, R 1 , R 2 , R 3 , R 4 and R 5 are independently -H or halogen; preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is -H or halogen, and the rest are H; R 6 For 1, 2 or 3 R b Replaced-C 1-6 alkyl; R b are independently halogen; R 7 -C substituted by 1, 2 or 3 CN 1-6 Alkyl or -C 3-6 Cycloalkyl.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: When the compound as shown in Formula I is selected from Scheme 1, the compound as shown in Formula I satisfies one or more of the following conditions: (1)R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, One of them is The rest are -H or halogen; (2)R 6 for For example (3)R 7 for For example When the compound as shown in Formula I is selected from Scheme 2, the compound as shown in Formula I satisfies one or more of the following conditions: (1)R 1 , R 2 , R 3 , R 4 and R 5 are independently -H, halogen, -CH3 or -O-CH3; preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is H, halogen, -CH3 or -O-CH3, and the rest are H; (2)R 6 for For example (3)R 7 -CH3, Preferably For example When the compound as shown in Formula I is selected from Scheme 3, the compound as shown in Formula I satisfies one or more of the following conditions: (1)R 1 , R 2 , R 3 , R 4 and R 5 are independently -H or halogen; preferably, R 1 , R 2 , R 3 , R 4 and R 5 One of them is H or halogen, and the rest are H; (2)R 6 for For example (3)R 7 for For example 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The compound shown in Formula I is a compound shown in Formula IA: Among them, *, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The definition as described in any one of claims 1-5.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The compound as shown in formula I satisfies one of the following conditions: (1) In Scheme 1, the compound represented by Formula I is a compound represented by Formula I-1A, I-1B or I-1C: Among them, R 1 , R 2 , R 3 , R 4 and R 5 The definition as described in any one of claims 1 to 5; (2) In Scheme 2, the compound represented by Formula I is a compound represented by Formula I-2A, I-2B or I-2C: Among them, R 1 , R 2 , R 3 , R 4 and R 5 The definition as described in any one of claims 1 to 5; (3) In Scheme 3, the compound represented by Formula I is a compound represented by Formula I-3A or I-3B: Among them, R 1 , R 2 , R 3 , R 4 and R 5 The definition as described in any one of claims 1-5.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I is selected from any of the following compounds:

9. A method for preparing the compound of formula I according to any one of claims 1 to 8, comprising the following steps: In a solvent, the compound represented by formula II and the compound represented by formula III are mixed to undergo a condensation reaction to obtain a compound represented by formula I; *、R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The definitions are as described in any one of claims 1 to 8.

10. A compound as shown in formula II or a salt thereof, *、R 1, R 2 , R 3 , R 4 , R 5 and R 6 The definitions are as described in any one of claims 1 to 8.

11. The compound of formula II or a salt thereof according to claim 10, characterized in that: The compound as shown in formula II is selected from any of the following compounds:

12. A pharmaceutical composition comprising (a therapeutically effective amount of) a compound of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

13. Use of the compound of formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12 in the preparation of an SSTR4 receptor agonist.

14. A compound of formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 12 for use in the preparation of a medicament for treating and / or preventing a disease related to the central nervous system.

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