Penta- and hexa-membered compounds, intermediates thereof, preparation methods, compositions and applications

Abstract

The present invention discloses a pentad and hexaad compound, an intermediate, a preparation method, a composition and an application thereof. The pentad and hexaad compound of the present invention is a compound as shown in formula I. The compound of the present invention has a significant cAMP agonist effect at the cellular level.

Description

Technical Field

[0001] The invention relates to a pentahedral and hexaahedral compound, an intermediate, a preparation method, a composition and application thereof. Background Art

[0002] Diabetes is a metabolic disease characterized by high blood sugar. Due to factors such as insulin secretion defects or decreased physiological function of pancreatic B cells, long-term high blood sugar levels in the body can lead to chronic damage or dysfunction of organs and tissues such as the eyes, kidneys, heart, blood vessels, and nerves. According to different pathogenesis, diabetes can be mainly divided into type I diabetes and type II diabetes. Type II diabetes is caused by decreased pancreatic B cell function and insulin resistance, and is the main type of diabetes.

[0003] Glucagon-like peptide-1 receptor (GLP-1 receptor) is one of the effective targets for the treatment of type II diabetes. GLP-1 receptor belongs to the G protein-coupled receptor B family, has seven transmembrane domains, and its natural agonist ligand is glucagon-like peptide-1 (GLP-1). When GLP-1 receptor is activated, it can further activate downstream signaling pathways such as PKA, PI3K, and MAPK, promoting insulin release and reducing glucagon release, thereby lowering blood sugar levels.

[0004] The GLP-1 receptor agonists developed in the early stage are GLP-1 analogs, which are all peptide substances. Peptide GLP-1R agonists activate GLP-1 receptors by simulating natural GLP-1, enhancing insulin secretion and inhibiting glucagon secretion in a glucose concentration-dependent manner, and can delay gastric emptying, reduce food intake through central appetite suppression, thereby achieving the effect of lowering blood sugar. Current peptide substances include liraglutide, semaglutide, etc. Through genetic engineering methods and formulation improvements, long-acting, oral peptide drugs have been developed, but oral peptides are still subject to multiple unfavorable restrictions such as administration time, dosage, and gastrointestinal disturbance. In recent years, researchers have found that the function of GLP-1 receptors can also be regulated by small molecule compounds, and small molecule GLP-1 receptor agonists have been developed. However, the structural type of existing small molecule agonists is limited, and it is necessary to develop new structural types and agonists that are specific to GLP-1 receptors. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the relatively simple structure of GLP-1R agonist compounds in the prior art. To this end, the present invention provides a five-membered and six-membered compound, an intermediate thereof, a preparation method, a composition and an application.

[0006] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0007]

[0008] W is CH or N;

[0009] Z is CH or N;

[0010] n is 1, 2 or 3;

[0011] R 1 is unsubstituted or substituted with one or more R 1-1 Substituted 6-10 membered aryl;

[0012] Each R 1-1 are independently halogen, cyano, carboxyl, unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or unsubstituted or with one or more R 1-1-2 Substituted C1-C6 alkoxy;

[0013] Each R 1-1-1 and R 1-1-2 are independently halogen;

[0014] L1 is -(CH2) p -; p is 1, 2 or 3;

[0015] L2 is unsubstituted or replaced by one or more L 2-1 Substituted -(CH2) q -; q is 1, 2 or 3;

[0016] Each L 2-1 are independently unsubstituted or substituted with one or more L 2-1-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more L 2-1-2 substituted 6-10 membered aryl, unsubstituted or substituted with one or more L 2-1-3 substituted 5-10 membered heteroaryl or unsubstituted or substituted with one or more L 2-1-4 A substituted 3-6 membered cycloalkyl group; the heteroatom of the 5-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0017] Each L 2-1-1 , L 2-1-2 , L 2-1-3 and L 2-1-4 are independently cyano, carboxyl or phenyl;

[0018] L3 does not exist, or unsubstituted or replaced by one or more L 3-1 Replaced m is 1, 2 or 3; T is absent, O, NH or S;

[0019] Each L 3-1 are independently C1-C6 alkyl;

[0020] The ring Cy is unsubstituted or substituted with one or more Cy -1 substituted 6-10 membered heteroaromatic ring; the heteroatom of the 6-10 membered heteroaromatic ring is selected from one or more of N and O, and the number of heteroatoms is 1, 2 or 3; each Cy -1 are independently halogen or C1-C6 alkyl;

[0021] X and Y are independently -N(R 4 )-, -O-, -S- or unsubstituted or substituted by one or two R 5 Substituted -CH2-;

[0022] R 4 is hydrogen, 6-10 membered aryl or 5-10 membered heteroaryl or is unsubstituted or substituted by one or more R 4-1 Substituted C1-C6 alkyl; each R 4-1 are independently carboxyl, C1-C6 alkoxy or 6-10 membered aryl; the heteroatoms of the 5-10 membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0023] Each R 5 are independently unsubstituted or substituted with one or more R 5-1 Substituted C1-C6 alkyl; each R 5-1 are independently C1-C6 alkoxy or 6-10 membered aryl;

[0024] R 2 is hydrogen, unsubstituted or replaced by one or more R 2-1 Substituted C1-C6 alkyl or unsubstituted or with one or more R 2-2 Substituted C1-C6 alkoxy;

[0025] Each R 2-1 and R 2-2 are independently halogen, C1-C6 alkoxy, 3-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-1-1 substituted 5-10 membered heteroaryl; the heteroatom of the 3-6 membered heterocycloalkyl is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatom of the 5-6 membered heteroaryl is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0026] Each R 2-1-1 are independently C1-C6 alkyl;

[0027] Each R 3 are independently hydrogen, carboxyl, halogen, -C(=O)-NH2, cyano, unsubstituted or substituted with one or more R 3-1 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-2 Substituted C1-C6 alkoxy;

[0028] Each R 3-1 and R 3-2 are independently halogen.

[0029] In a preferred embodiment, a five-membered and six-membered compound as shown in Formula I or a pharmaceutically acceptable salt thereof; the definitions of certain groups may be as described below, and the definitions of other groups may be as described in any of the above embodiments (hereinafter referred to as "in a preferred embodiment").

[0030] In a preferred embodiment:

[0031] L2 is unsubstituted or replaced by one or more L 2-1 Substituted -(CH2) q -; q is 1, 2 or 3;

[0032] Each L 2-1 are independently unsubstituted or substituted with one or more L 2-1-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more L 2-1-2 Substituted 6-10 membered aryl or unsubstituted or substituted by one or more L 2-1-3 Substituted 5-10 membered heteroaryl; the heteroatom of the 5-10 membered heteroaryl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0033] Each L 2-1-1 , L 2-1-2 and L 2-1-3 are independently cyano, carboxyl or phenyl;

[0034] L3 does not exist, or unsubstituted or replaced by one or more L 3-1 Replaced m is 1, 2 or 3; T is absent, O, NH or S;

[0035] Each L 3-1 are independently C1-C6 alkyl.

[0036] In a preferred embodiment, R 1 In the above, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group.

[0037] In a preferred embodiment, each R 1-1In the above, the halogen may be fluorine, chlorine, bromine or iodine; for example, fluorine or chlorine.

[0038] In a preferred embodiment, each R 1-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.

[0039] In a preferred embodiment, each R 1-1 In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group.

[0040] In a preferred embodiment, each R 1-1-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0041] In a preferred embodiment, each R 1-1-2 In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0042] In a preferred embodiment, each L 2-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an isobutyl group or a tert-butyl group.

[0043] In a preferred embodiment, each L 2-1 In the above, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group.

[0044] In a preferred embodiment, each L 2-1 In the above, the 5-10 membered heteroaryl group may be a 5-6 membered heteroaryl group, such as furyl, thienyl or pyridyl.

[0045] In a preferred embodiment, each L 2-1 In the above, the 3-6 membered cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0046] In a preferred embodiment, each L 3-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.

[0047] In a preferred embodiment, in the ring Cy, the 6-10 heteroaromatic rings may be or a benzo 5-membered heterocyclic ring, Z1, Z2 and Z3 are independently N or CH, the heteroatom of the 5-membered heterocyclic ring is O, and the number of heteroatoms is 1 or 2; the benzo 5-membered heterocyclic ring is preferably Said Preferred is a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring or a triazine ring, for example a pyridine ring or a pyrazine ring.

[0048] In a preferred embodiment, each Cy -1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; and also a methyl group.

[0049] In a preferred embodiment, each Cy -1 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0050] In a preferred embodiment, R 4 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; and also such as a methyl group, an ethyl group or an isopropyl group.

[0051] In a preferred embodiment, R 4 In the above, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group.

[0052] In a preferred embodiment, R 4 In the above, the 5-10 membered heteroaryl group may be a 5-6 membered heteroaryl group, such as furyl, thienyl or pyridyl.

[0053] In a preferred embodiment, R 4 In the above, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

[0054] In a preferred embodiment, each R 4-1 In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group; and also a methoxy group.

[0055] In a preferred embodiment, each R 4-1 In one preferred embodiment, each R 5 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; and also such as a methyl group, an ethyl group or an isopropyl group.

[0056] In a preferred embodiment, each R 5 In the above, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, ethyl.

[0057] In a preferred embodiment, each R 5-1 In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group; and also a methoxy group.

[0058] In a preferred embodiment, each R 5-1 In the above, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group.

[0059] In a preferred embodiment, R 2 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; and also such as a methyl group or an ethyl group.

[0060] In a preferred embodiment, R 2 In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group.

[0061] In a preferred embodiment, each R 2-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine; for example, fluorine or chlorine.

[0062] In a preferred embodiment, each R 2-1 In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group; and also a methoxy group.

[0063] In a preferred embodiment, each R 2-1 In the above, the heteroatom of the 3-6 membered heterocycloalkyl is N, S or O, and the number of the heteroatom is 1; for example, oxetane.

[0064] In a preferred embodiment, each R 2-1 In the above, the 5-10 membered heteroaryl group may be a 5-6 membered heteroaryl group, the heteroatom of the 5-10 membered heteroaryl group is preferably N, and the number of heteroatoms of the 5-10 membered heteroaryl group is preferably 1, 2 or 3; for example, the 5-10 membered heteroaryl group is imidazolyl.

[0065] In a preferred embodiment, each R 2-2 In the above, the halogen may be fluorine, chlorine, bromine or iodine; for example, fluorine or chlorine.

[0066] In a preferred embodiment, each R 2-2In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group; and also a methoxy group.

[0067] In a preferred embodiment, each R 2-2 In the above, the heteroatom of the 3-6 membered heterocycloalkyl is N, S or O, and the number of the heteroatom is 1.

[0068] In a preferred embodiment, each R 2-2 In the above, the 5-10 membered heteroaryl group may be a 5-6 membered heteroaryl group, the heteroatom of the 5-10 membered heteroaryl group is preferably N, and the number of heteroatoms of the 5-10 membered heteroaryl group is 1, 2 or 3; for example, the 5-10 membered heteroaryl group is imidazolyl.

[0069] In a preferred embodiment, each R 2-1-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; and also such as an ethyl group or a methyl group.

[0070] In a preferred embodiment, each R 3 In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0071] In a preferred embodiment, each R 3 In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group.

[0072] In a preferred embodiment, each R 3 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.

[0073] In a preferred embodiment, each R 3-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0074] In a preferred embodiment, each R 3-2 In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0075] In a preferred embodiment, W is N.

[0076] In a preferred embodiment, Z is CH.

[0077] In a preferred embodiment, n is 1.

[0078] In a preferred embodiment, R 1 is unsubstituted or substituted with one or more R1-1 Substituted phenyl.

[0079] In a preferred embodiment, each R 1-1 are independently halogen or cyano.

[0080] In a preferred embodiment, p is 1 or 2, preferably 1.

[0081] In a preferred embodiment, q is 2 or 3, preferably 2.

[0082] In a preferred embodiment, m is 1.

[0083] In a preferred embodiment, T is O or NH.

[0084] In a preferred embodiment, the ring Cy is unsubstituted or substituted with a Cy -1 A substituted pyridine ring, pyrazine ring or benzo 5-membered heterocyclic ring; the heteroatom of the 5-membered heterocyclic ring is O, and the number of heteroatoms is 1 or 2.

[0085] In a preferred embodiment, each Cy -1 are independently halogen.

[0086] In a preferred embodiment, each L 2-1 are independently unsubstituted or substituted with one or more L 2-1-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more L 2-1-2 Substituted phenyl, unsubstituted or replaced by one or more L 2-1-3 substituted 5-6 membered heteroaryl or unsubstituted or substituted by one or more L 2-1-4 The substituted 3-6 membered cycloalkyl group; the heteroatom of the 5-6 membered heteroaryl group is N, O or S, and the number of heteroatoms is 1; the heteroatom of the 3-6 membered heterocycloalkyl group is selected from one or more of N, O and S, and the number of heteroatoms is 1.

[0087] In a preferred embodiment, each L 2-1 are independently unsubstituted or substituted with one or more L 2-1-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more L 2-1-2 Substituted phenyl or unsubstituted or with one or more L 2-1-3 substituted 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl is N, O or S, and the number of heteroatoms is 1; preferably, each L 2-1 are independently methyl, ethyl or isopropyl.

[0088] In a preferred embodiment, L3 is absent, or unsubstituted or replaced by one or more L 3-1 Replaced m is 1, 2 or 3; T is absent, O or NH.

[0089] In a preferred embodiment, L3 is absent, unsubstituted or replaced by one or more L 3-1 Replaced m is 1, 2 or 3; T is absent, O or NH.

[0090] In a preferred embodiment, R 4 It is an unsubstituted C1-C6 alkyl group.

[0091] In a preferred embodiment, each R 4-1 are independently carboxyl, C1-C6 alkoxy or phenyl.

[0092] In a preferred embodiment, each R 5 and are independently unsubstituted C1-C6 alkyl.

[0093] In a preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 Substituted C1-C6 alkyl.

[0094] In a preferred embodiment, each R 2-1 is independently C1-C6 alkoxy, 3-6 membered heterocycloalkyl or unsubstituted or substituted with one or more R 2-1-1 substituted 5-6 membered heteroaryl; the heteroatom of the 3-6 membered heterocycloalkyl is N, S or O, and the number of heteroatoms is 1; the heteroatom of the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1, 2 or 3.

[0095] In a preferred embodiment, each R 3 are independently carboxyl.

[0096] In a preferred embodiment, R 1 is phenyl or is replaced by one or two R 1-1 Substituted phenyl.

[0097] In a preferred embodiment, R 1 For one or two R 1-1 Substituted phenyl.

[0098] In a preferred embodiment, X is -N(R 4 )-, -O-, -S- or unsubstituted or substituted by one or two R 5 Substituted -CH2-, R 4 is hydrogen, phenyl or unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl; each R 4-1 are independently carboxyl, C1-C6 alkoxy or phenyl; each R 5 are independently C1-C6 alkyl.

[0099] In a preferred embodiment, X is -N(R 4 )-, -O- or -S-, R 4 is hydrogen or unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl; each R 4-1 are independently carboxyl, C1-C6 alkoxy or phenyl.

[0100] In a preferred embodiment, Y is -N(R 4 )-, -O- or -S-, R 4 is hydrogen, unsubstituted C1-C6 alkyl, -CH2COOH or phenyl; preferably, Y is -N(R 4 )-or-O-, R 4 is hydrogen or unsubstituted C1-C6 alkyl.

[0101] In a preferred embodiment, T is O.

[0102] In a preferred embodiment, the ring Cy is a pyridine ring.

[0103] In a preferred embodiment, each R 2-1 are independently C1-C6 alkoxy or 3-6 membered heterocycloalkyl; the heteroatom of the 3-6 membered heterocycloalkyl is O, and the number of heteroatoms is 1; preferably, each R 2-1 are independently 3-6 membered heterocycloalkyl.

[0104] In a preferred embodiment, R 3 It is a carboxyl group.

[0105] In a preferred embodiment, X is -N(R 4 )-, -O-, -S- or unsubstituted or substituted by one or two R 5 Substituted -CH2-; each R 5 are independently C1-C6 alkyl; R 4 is hydrogen, phenyl, unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl; R 4-1 is C1-C6 alkoxy or carboxyl; R 4 Preferred is a phenyl group or a C1-C6 alkyl group which is unsubstituted or substituted by a carboxyl group.

[0106] In a preferred embodiment, X is -N(R 4 )-, -O- or -S-, R 4 is hydrogen, phenyl, unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl; R 4-1 is C1-C6 alkoxy or carboxyl; R 4 Preferably, phenyl or unsubstituted or carboxy-substituted C1-C6 alkyl; preferably, X is -N(R4 )-or-O-, R 4 It is methyl.

[0107] In a preferred embodiment, for

[0108] Or X is -O-, Y is -N(R 4 )-OR 4 is hydrogen or unsubstituted C1-C6 alkyl, L2 is unsubstituted or replaced by one or more L 2-1 Substituted -(CH2) q -; q is 2; each L 2-1 are independently methyl, ethyl or isopropyl.

[0109] In a preferred embodiment, the compound as shown in Formula I is as shown in Formula Ia, Ib, Ic or Id:

[0110]

[0111] In a preferred embodiment, R 1 for

[0112] In a preferred embodiment, R 1 for

[0113] In a preferred embodiment, L3 is absent, Preferably, there is no r and R 1 Connected, s is connected to ring Cy.

[0114] In a preferred embodiment, L3 is Preferably r and R 1 Connected, s is connected to ring Cy.

[0115] In a preferred embodiment, ring Cy is

[0116] In a preferred embodiment, X is

[0117] In a preferred embodiment, Y is Preferably

[0118] In a preferred embodiment, L1 is -CH2-.

[0119] In a preferred embodiment, L2 is -CH(Bn)-, -CH2-, -CH(CH2CH3)-, -CH2-CH2-, -CH(CH3)-CH2-, -CH(CH2CH3)-CH2-, -C(CH3)2-CH2-, -CH(Ph)-CH2- or -CH(Bn)-CH2-, preferably -CH2-, c-CH(CH2CH3)-d, -CH2-CH2-, c-CH(CH3)-CH2-d, d-CH(CH3)-CH2-c, c-CH(CH2CH3)-CH2-d, d-CH(CH2CH3)-CH2-c, cC(CH3)2-CH2-d, dC(CH3)2-CH2-c, c-CH(Ph)-CH2-d, d-CH(Ph)-CH2-c, c-CH(Bn)-CH2-d or d-CH(Bn)-CH2-c, and -CH2-CH2-, c-CH(CH3)-CH2-d, d-CH(CH3)-CH2-c, c-CH(CH2CH3)-CH2-d, d-CH(CH2CH3)-CH2-c, Among them, c is connected to X and d is connected to Y.

[0120] In a preferred embodiment, L2 is -CH2-CH2-, -CH(CH3)-CH2-, -CH(CH2CH3)-CH2-, -C(CH3)2-CH2-, -CH(Ph)-CH2- or -CH(Bn)-CH2-.

[0121] In a preferred embodiment, R 2 for In a preferred embodiment, R 2 for Preferably In a preferred embodiment, for

[0122] Preferably

[0123]

[0124]

[0125] More preferably

[0126]

[0127] The a-end ring is connected to Cy, and the b-end is connected to L1.

[0128] In a preferred embodiment, for

[0129] Preferably

[0130]

[0131] The a-end ring is connected to Cy, and the b-end is connected to L1.

[0132] In a preferred embodiment, for

[0133] In a preferred embodiment, for

[0134] The present invention also provides any one of the compounds shown below:

[0135]

[0136]

[0137]

[0138]

[0139] The present invention provides a compound as shown in formula IA, Among them, W, Z, n, L1, L2, L3, X, Y, R 1 , R 2 , R 3 , R 4 and R 5 As mentioned above; R 6 It is a C1-C6 alkyl group.

[0140] In a preferred embodiment, each R 6In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; and also a methyl group.

[0141] The present invention also provides a compound as shown in formula IB,

[0142]

[0143] Wherein, R is halogen or R 1 ; X, R 1 , L3, L2 and R 4 The definition of is as described above; when R is halogen, X is O.

[0144] In a preferred embodiment, in R, the halogen may be fluorine, chlorine, bromine or iodine, such as chlorine.

[0145] The present invention also provides a compound as shown below:

[0146]

[0147]

[0148]

[0149] The present invention also provides a compound as shown in formula IC,

[0150]

[0151] Among them, R 2 , R 6 , R 4 , L1, L2, Y, Z and n are as defined above. In a preferred embodiment, the compound shown in formula IC is any of the following compounds:

[0152]

[0153] The present invention also provides a compound as shown in formula II-D:

[0154]

[0155] Among them, R 2 , R 6 , R 4 , Cy, L1, L2, X, Y, W, Z and n are as defined above, X 1 is halogen, preferably Cl.

[0156] In a preferred embodiment, the compound shown in formula II-D is any of the following compounds:

[0157]

[0158] The present invention also provides a pharmaceutical composition, which comprises a substance Z and a pharmaceutical excipient, wherein the substance Z is the compound shown in formula I as described above or a pharmaceutically acceptable salt thereof.

[0159] The present invention also provides a use of a substance Y in the preparation of a cAMP agonist or a drug for treating and / or preventing a cAMP-related disease, wherein the substance Y is a compound as shown in formula I as described above, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0160] The present invention also provides a method for treating and / or preventing cAMP-related diseases, which comprises administering an effective amount of substance Z to a patient, wherein substance Z is a compound as shown in formula I as described above or a pharmaceutically acceptable salt thereof.

[0161] In a preferred embodiment, the cAMP-related disease may be a related disease caused by diabetes or diabetic complications. The diabetes is preferably type 2 diabetes, gestational diabetes, hyperglycemia, insulin resistance or malnutrition-related diabetes. The related diseases caused by diabetic complications are preferably diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, sclerosis and hepatocellular carcinoma), cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, endothelial dysfunction, poor vascular compliance, vascular restenosis, congestive heart failure, myocardial infarction, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, hypertension, stroke, angina pectoris, inflammatory bowel disease, Alzheimer's disease, schizophrenia or impaired cognitive function. Vascular restenosis is preferably restenosis after angioplasty. Inflammatory bowel disease is preferably ulcerative colitis. Colitis is preferably ulcerative colitis.

[0162] The present invention also provides a method for preparing the compound represented by formula IA as described above, which is any one of the following methods:

[0163] Method 1: It comprises the following steps: in a solvent, a compound represented by formula ID and a compound represented by formula IE are subjected to a condensation reaction as shown in the following formula in the presence of a base (preferably potassium carbonate or cesium carbonate);

[0164]

[0165] Among them, Y is Or O, W, Z, n, L1, L2, L3, X, R 1 , R2 , R 4 and R 6 As mentioned above, R 7 is a halogen;

[0166] Preferably, R 7 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example chlorine;

[0167] Method 2: It includes the following steps:

[0168]

[0169] Among them, L3' is L3-H, L3 is or unsubstituted or replaced by one or more L 3-1 Replaced R 1 , L3, ring Cy, X, Y, L1, L2, W, Z, n, R 2 , R 6 , L 3-1 , m and T are as described above.

[0170] The present invention also provides a method for preparing the compound represented by the above formula IB, which comprises the following steps: in a solvent, the compound represented by the formula IF and the compound represented by the formula IF are subjected to a coupling reaction as shown in the following formula in the presence of a palladium salt (preferably bisdibenzylideneacetone palladium or palladium acetate), a phosphorus ligand (preferably 1,1'-binaphthyl-2,2'-bisdiphenylphosphine or 2-(di-tert-butylphosphine)-1,1'-binaphthyl) and a base (preferably Cs2CO3);

[0171]

[0172] Among them, X is or O, R, L2, L3 and R 4 As mentioned above, R 8 It is a halogen.

[0173] In a preferred embodiment, R 8 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example chlorine.

[0174] The present invention also provides a method for preparing the compound of formula IC as described above, which comprises the following steps: in a solvent, the compound of formula IF and the compound of formula IH are subjected to a coupling reaction as shown in the following formula in the presence of a base (preferably Cs2CO3);

[0175]

[0176] Among them, Y is or O, W is N, Z, n, L1, L2, R2 , R 4 and R 6 As mentioned above, R 7 It is a halogen.

[0177] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0178] The terms "compound" and "pharmaceutically acceptable salt" may exist in the form of a single tautomer or a mixture thereof if tautomers exist, preferably in a form in which the more stable tautomer is predominant.

[0179] If a group has two bonds to other groups, when the connection direction is not specified, it means that both connection modes are possible. For example, in this application, for It can be It can also be The a-end is connected to the ring Cy, and the b-end is connected to L1.

[0180] If a linking group is indicated as "absent", the structures on both sides of the linking group are directly connected by a single bond, for example -ABC-. ​​When B does not exist, -ABC- is -AC-.

[0181] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0182] The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0183] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), wherein the heteroatoms may be connected to other groups as a linking group or may not be connected to other groups (e.g., piperidinyl may be The ring in the heterocycloalkyl group is a monocyclic ring, and each ring is saturated. The heterocycloalkyl group includes but is not limited to azetidinyl.

[0184] The term "cycloalkyl" refers to a saturated monocyclic group having a specified number of ring carbon atoms (e.g., C3-C6), the ring atoms of which are composed only of carbon atoms. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0185] The term "heteroaryl" refers to a cyclic group with a specified number of ring atoms (e.g., 5 to 9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, imidazolyl, etc.

[0186] The term "heteroaromatic ring" refers to a cyclic group with a specified number of ring atoms (e.g., 5 to 9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (complying with Huckel's rule). The heteroaromatic ring is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring.

[0187] The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site. For example, CH3-C(=O)- refers to acetyl.

[0188] In the structure fragment It means that the structural fragment is connected to other fragments in the molecule through this site. For example, It refers to the acetyl group.

[0189] The term "plurality" refers to 2, 3, 4 or 5.

[0190] When any variable (such as the group R 1-1 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other. 1-1 Substituted C6~C 10 Aryl refers to C6~C 10 The aromatic group will be 3 R 1-1 Replacement, 3 R's 1-1 The definitions are independent of each other and do not affect each other.

[0191] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, maleates, acetates, trifluoroacetates, sulfates, mesylates, and the like. See Handbook of Pharmaceutical Salts: Properties, Selection, and Mse (P. Heinrich Stahl, 2002) for details.

[0192] The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or Handbook of Pharmaceutical EMcipients (Raymond C Rowe, 2009).

[0193] The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that initiates a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

[0194] The term "prevention" refers to reducing the risk of developing a disease.

[0195] The term "patient" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0196] 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.

[0197] The reagents and raw materials used in the present invention are commercially available.

[0198] The positive and progressive effect of the present invention is that the compounds of the present invention have a significant cAMP agonist effect at the cellular level. DETAILED DESCRIPTION

[0199] 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.

[0200] Example 1 Preparation of Compound (I-1)

[0201] Step 1

[0202]

[0203] Take intermediate (3) (70 mg, 1.0 eq.), tert-butyl methyl (2-(methylamino)ethyl) carbamate (60 mg, 1.2 eq.), Pd2(dba)3 (bis(dibenzylideneacetonepalladium)) (24 mg, 0.1 eq.), BINAP (1,1'-binaphthyl-2,2'-bis(diphenylphosphine)) (33 mg, 0.2 eq.), Cs2CO3 (173 mg, 2.0 eq.) and mix them in a 5 mL eggplant-shaped bottle, add a magnetic stirrer, replace argon three times; place in an oil bath at 110°C and heat with stirring for 23.5 h; TLC monitoring shows that no raw material A remains. The reaction solution is cooled to room temperature, passed through a diatomaceous earth funnel, the filter cake is washed with a small amount of EA, and the combined filtrate is concentrated to obtain 190 mg of crude oil. Column packing: 2 cm diameter, 6 cm height; PE:DCM = 60:40-10:90, collect the product and concentrate to obtain 67 mg of pure product, yield: 61%. LC-MS: BE043-023-p; [M+1] + =415 purity 99%.

[0204]

[0205] Take the intermediate (6) (100 mg, 1.0 eq.) and dissolve it in 2 mL DCM (dichloromethane), add 180 μL TFA (trifluoroacetic acid) (10 eq.) to the reaction system, and react at room temperature under nitrogen protection; after 4 hours, add 90 μL (5.0 eq.) TFA; after 2 hours, TLC monitoring shows that the reaction is complete, add 5 mL DCM to dilute the reaction solution, add 2 mL of saturated sodium carbonate solution dropwise under magnetic stirring until the pH is ~ 10; transfer to a separatory funnel and let stand for stratification; the organic phase is concentrated under reduced pressure to obtain 58 mg of yellow oil; yield: 76%. LC-MS: [M+1] + =315, purity 95.8% (254nm).

[0206] Step 2

[0207]

[0208] Take (1a) (55 mg, 1.0 eq.) and dissolve it in 1.5 mL MeCN (acetonitrile), take intermediate (1) (49.5 mg, 1.0 eq.) and potassium carbonate (121 mg, 2.0 eq.) and add them to the reaction system. Use a water pump to replace nitrogen twice, and stir the reaction under magnetic stirring at 50°C for 11 hours. Cool the reaction solution to room temperature, add 1.5 mL pure water to dilute the reaction solution, add 2 mL EA to extract, combine the organic phases and wash with 1 mL saturated brine, and concentrate the organic phase to obtain 102 mg of yellow oily crude product. Silica gel column chromatography, elution polar DCM: MeOH 100:1~100:1.5, collect the product spots, and concentrate under reduced pressure to obtain 72 mg of pure product, with a yield of 73%; LC-MS: BE043-045-P, [M+1] + =561, purity 94.5% (254nm): 1 H-NMR (400MHz, CDCl3) δ8.01(s,1H),7.93(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.56(d,J =7.6Hz,1H),7.42(d,J=8.0Hz,1H),7.31(dd,J=14.4,8.8Hz,2H),5.98(d,J=7.8Hz,1H),5.9 2(d,J=8.0Hz,1H),5.33(s,2H),4.41(t,J=5.2Hz,2H),4.00-3.86(m,5H),3.59(t,J=5.2Hz, 4H), 3.20 (s, 3H), 3.06 (d, J = 7.2Hz, 1H), 2.87 (s, 3H), 2.67 (s, 2H), 2.34 (s, 3H), 1.62 (s, 4H).

[0209] Step 3

[0210]

[0211] Take (1b) (50 mg, 1.0 eq.) and dissolve it in 500 μL acetonitrile, add 100 μL pure water, and add 12 mg solid lithium hydroxide monohydrate under magnetic stirring; heat the reaction in an oil bath at 50°C for about 11 hours. TLC monitoring shows that there is no residual raw material. Cool to room temperature, add about 2 ml of EA to dilute, add 100 μL of saturated ammonium chloride solution to wash, add 1 mL of pure water to wash the organic phase, and concentrate the organic phase to obtain a crude product. Prepare a thin layer, load 45 mg, develop with DCM: MeOH 5:1, scrape off the product band, dissolve the product with DCM: MeOH = 10:1, filter, concentrate the filtrate, dissolve with DCM, filter, and concentrate the filtrate to obtain 19 mg of pure product, with a yield of 40%; LC-MS: [M+1] + =547, purity 96.3%. 1H-NMR (400MHz, MeOD): δ8.15(s,1H),7.93(d,J=8.4Hz,1H),7.63(d,J=8.4Hz,1H),7.57–7.46 (m,3H),7.35(t,J=8.0Hz,1H),6.09(d,J=8.0Hz,1H),5.98(d,J=7.6Hz,1H),5.48(s,2H),5.26 (s,2H),4.45(t,J=4.8Hz,2H),4.12(s,2H),3.64(dd,J=25.6,20.8Hz,5H),3.51–3.39(m,6H), 3.19(s,3H),2.95(s,5H),2.81(s,8H),2.54(s,3H),2.35(t,J=8.0Hz,6H),2.08–1.97(m,6H).

[0212] Example 2 Preparation of Compound (I-2)

[0213] Referring to Example 1, intermediate (2) (Refer to WO2019239319 for the synthesis of intermediate (2)) instead of intermediate (1) to prepare compound (I-2). LC-MS: [M+1] + =559, purity is >99.9%. 1 HNMR (400MHz, CDCl3) δ8.10 (s, 1H), 8.03 (d, J = 8.5Hz, 1H), 7.78 (d, J = 8.3Hz, 1H), 7.60 (t, J = 7. 6Hz,1H),7.45(d,J=8.4Hz,1H),7.34(t,J=8.5Hz,2H),6.01(d,J=7.7Hz,1H),5.96(d,J=8.2Hz, 1H),5.36(s,2H),5.13–5.05(m,1H),4.62-4.54(m,2H),4.49-4.43(m,1H),4.31-4.25(m,1H),4 .03(s,2H),3.70-3.55(m,2H),2.89(s,3H),2.75–2.67(m,3H),2.40(s,3H),2.33-2.29(m,1H).

[0214] Example 3 Preparation of Compound (I-3)

[0215] Preparation of intermediate (14)

[0216]

[0217] Take the intermediate (7), benzyl bromide (100 μl, 3.0 eq.), cesium carbonate (440 mg, 5.0 eq.), and MeCN 2.2 ml and mix them in a 25 mL eggplant-shaped bottle. Heat the oil bath to 80°C for 18 h. TLC monitoring shows that no raw material remains. The reaction solution is cooled to room temperature, and the reaction solution is extracted with a syringe. It is filtered through a 0.22 μM organic microporous filter membrane, and the filtrate is concentrated under reduced pressure to obtain a crude product. 2 cm diameter silica gel column, 100-200 mesh silica gel, elution polar PE: EA (petroleum ether: ethyl acetate) = 10:1, collect the product spot, and obtain 60 mg of light yellow oil. LC-MS: [M+1] + =491

[0218] Referring to Example 1, intermediate (14) was used instead of intermediate (6) to prepare compound (I-3). LC-MS: [M+1] + =623, purity 97.2%. 1 H NMR (400MHz, CDCl3) δ8.03(d,J=0.8Hz,1H),7.96(dd,J=8.4,1.6Hz,1H),7.71(d,J=8.4Hz,1H),7.49(t,J=7.6H z,1H),7.36(dd,J=8.0,1.2Hz,1H),7.25-7.18(m,5H),7.08–7.00(m,2H),6.01(d,J=7.7Hz,1H),5.96(d,J=8.2 Hz,1H),5.31(s,2H),5.14(d,J=6.8Hz,1H),4.60(s,2H),4.47(t,J=5.2Hz,2H),3.97(s,3H),3.92(s,2H),3.63 (t,J=5.2Hz,2H),3.53(t,J=6.8Hz,2H),3.40(t,J=7.2Hz,2H),3.21(s,3H),2.86(s,3H),2.70(t,J=6.4Hz,2H).

[0219] Example 4 Preparation of Compound (I-4)

[0220] Step 1

[0221]

[0222] Take intermediate (3) (50 mg, 1.0 eq.), N-Boc-N-methylethylenediamine (36 mg, 1.1 eq.), BINAP (1,1'-binaphthyl-2,2'-bis(diphenylphosphine)) (23.7 mg, 0.2 eq.), cesium carbonate (124 mg, 2.0 eq.) and 2 mL of toluene in a 25 ml eggplant-shaped bottle, replace Ar with a water pump 3 times, add Pd2(dba)3 (bis(dibenzylideneacetonepalladium)) (17.4 mg), replace Ar with a water pump 3 times, stir in an oil bath at 110°C for 10.5 h, and TLC monitoring shows that no raw material remains. Cool to room temperature, pass the reaction solution through a diatomaceous earth funnel, wash the filter cake with EA, and concentrate the filtrate to obtain a crude product. The sample was dissolved in DCM and wet loaded on a 100-200 mesh silica gel column. Polar PE:EA=20:1-10:1 was used for elution. The product was collected to obtain 64 mg of a yellow oil with a yield of 84%. LC-MS: BE043-071-p, purity 93.5%.

[0223] Step 2: Referring to Example 1, intermediate (7) was used instead of intermediate (6) to prepare compound (I-4). LC-MS: [M+1] + =533, purity is 95.87% (254nm). 1 H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 8.00 (d, J = 8.4Hz, 1H), 7.78 (d, J = 7.9Hz, 1H), 7. 61(t,J=6.9Hz,1H),7.43(d,J=7.9Hz,1H),7.34(d,J=9.2Hz,1H),7.30(d,J=5.7Hz ,1H),6.03(d,J=7.6Hz,1H),6.01-5.90(m,1H),5.38(s,1H),4.52(s,2H),4.04(s, 2H),3.65(s,2H),3.39(s,2H),3.22(s,3H),2.81(s,2H),2.40(s,3H),2.09(s,1H).

[0224] Example 5 Preparation of Compound (I-5)

[0225] Referring to Example 1, compound (I-5) was prepared by replacing methyl (2-(methylamino)ethyl)carbamic acid tert-butyl ester with 2-(methylamino)ethylcarbamic acid tert-butyl ester. LC-MS: [M+1] + =533 purity 99% (254nm). 1HNMR(400MHz, DMSO-d6)δ8.13(s,1H),7.85(d,J=9.2Hz,1H),7.79(d,J=8.0Hz,1H)7.69–7.58(m,3H),7.40(t,J=7.9Hz,1H),6.13(d,J=8.1Hz,1H), 6.00(d,J=7.7Hz,1H),5.39(s,2H),4.50(s,2H),4.01(s,2H),3.63(d,J= 4.8Hz,2H),3.51(s,2H),3.15(s,3H),2.93(s,3H),2.70(t,J=8.7Hz,2H).

[0226] Example 6 Preparation of Compound (I-7)

[0227] Step 1

[0228]

[0229] Take N-Boc-N-methylethylenediamine (472 mg, 1.5 eq.), potassium carbonate (514 mg, 2.0 eq.), and MeCN 4 mL in an eggplant-shaped bottle, take bromoethyl methyl ether (239 mg, 1.0 eq.) and dissolve it in 1 mL MeCN, and add it dropwise to the reaction solution; react at 80 ° C for 3 hours, and TLC monitoring shows that no raw material remains. Cool to room temperature, pass through a diatomaceous earth funnel, and concentrate the filtrate to obtain a crude product. Column chromatography separation (separation conditions are not recorded) to obtain 241 mg of pure product, with a yield of 60%; HPLC: purity 88.9% (220nm).

[0230] Step 2

[0231]

[0232] Take intermediate (3) (163 mg, 1.0 eq.), intermediate (11-a) (144 mg, 1.1 eq.), BINAP (71 mg, 0.2 eq.), cesium carbonate (451 mg, 2.0 eq.) and 8 ml of toluene in a 25 ml eggplant-shaped bottle, replace nitrogen with a water pump 3 times, weigh the catalyst (51 mg, 0.1 eq.) and add it to the reaction solution, replace nitrogen with a water pump 3 times, react overnight (about 13.5 h) in an oil bath at 110°C, and no raw material remains after TLC monitoring. Cool to room temperature, pass the reaction solution through a diatomaceous earth funnel, rinse the filter cake with EA, and concentrate the organic phase to obtain a crude product. Silica gel column chromatography, elution polarity 20:1-10:1, collect product spots, and obtain 118 mg of pure product, with a yield of 26%. [M+1] + =459, purity 95.3%.

[0233] Referring to Example 1, intermediate (11) was used instead of intermediate (6) to prepare compound (I-7). LC-MS: [M+1] + =591, purity 97.8%. 1 H-NMR (400MHz, CDCl3) δ8.12(s,1H),8.04(d,J=8.4Hz,1H),7.77(d,J=8.4Hz,1H),7.59(t,J=7 .6Hz,1H),7.45(d,J=8.4Hz,1H),7.36(d,J=9.2Hz,1H),7.24(t,J=8.0Hz,1H),5.97(d,J=7.8Hz ,1H),5.95(d,J=8.3Hz,1H)5.36(s,2H),4.52(t,J=4.8Hz,2H),3.98(s,2H),3.67(d,J=4.8Hz, 2H),3.54(t,J=6.0Hz,4H),3.43–3.38(m,4H),3.26(d,J=7.6Hz,6H),1.70(s,2H),1.27(s,3H).

[0234] Example 7 Preparation of Compound (I-8)

[0235] Refer to Example 6 and refer to WO 2019239319 to synthesize intermediate (2) Compound (I-8) was prepared by replacing intermediate (1). LC-MS: [M+1] + =603, purity is 96.99%. 1H NMR (600MHz, DMSO-d6) δ8.23(s,1H),7.92(d,J=9.8Hz,1H),7.83(d,J=8.4Hz,1H),7.74(d,J=7.9Hz,1H),7.67(d,J=8.4Hz,1H),7.61(t, J=7.6Hz,1H),7.36(t,J=7.9Hz,1H),6.13(d,J=8.2Hz,1H),6.02(d,J=7.7Hz,1H),5.39(s,2H),5.06-5.02(m,1H),4.77(dd,J=15.3,7.6 Hz,1H),4.59(dd,J=15.4,2.8Hz,1H),4.48(td,J=8.0,5.8Hz,1H),4.30(dt,J=9.1,5.9Hz,1H),4.00(d,J=13.5Hz,1H),3.84(d,J=13.5H z,1H),3.59–3.50(m,4H),3.34(t,J=6.0Hz,2H),3.19(s,3H),2.71–2.66(m,1H),2.63(t,J=7.2Hz,1H),2.36-2.32(m,1H),2.31(s,3H).

[0236] Example 8 Preparation of Compound (I-9)

[0237] Referring to Example 1, methyl (3-(methylamino)propyl)carbamic acid tert-butyl ester was used instead of methyl (2-(methylamino)ethyl)carbamic acid tert-butyl ester to prepare compound (I-9). LC-MS: [M+1] + =561, purity is 99.9%. 1 HNMR (400MHz, CDCl3) δ8.20–8.00(m,2H),7.90-7.78(m,1H),7.65-7.56(m,1H),7.47–7.31(m,3H),6.09(d,J=7.6,1H),6.03(d,J=8Hz,1H),5.4 3(s,2H),4.63-4.45(m,2H),4.17-4.05(m,2H),3.71(s,3H),3.58-3.50 (m,2H),3.26(s,3H),2.96(s,3H),2.53-2.45(m,2H),0.92–0.82(m,2H).

[0238] Example 9 Preparation of Compound (I-10)

[0239] Step 1

[0240]

[0241] The intermediate (12) (200 mg, 1.0 eq.), ethyl bromide (163 mg, 3.0 eq.), and cesium carbonate (813 mg, 5.0 eq.) were added to 4 mL of MeCN and mixed in a microwave tube. A magnetic stirrer was added to seal the tube, and the tube was placed in an 80°C oil bath and heated and stirred for 19 h. TLC monitoring showed that no raw material A remained. The reaction solution was cooled to room temperature, passed through a diatomaceous earth funnel, and the filter cake was washed with a small amount of EA. The combined filtrate was concentrated to obtain a crude oil. The product was purified by silica gel column chromatography with EA:PE=1:1 and concentrated to obtain 87 mg of pure product. The yield was 41%. LC-MS: [M+1] + =449Purity:93.07%(254nm)

[0242] Step 2

[0243]

[0244] Compound (10a) (87 mg, 1.0 eq.) was placed in a 25 ml eggplant-shaped bottle, 3 mL of DCM was added to dissolve, 223 μl of TFA was added dropwise under magnetic stirring, and the mixture was stirred at room temperature for 2 h. TLC monitoring showed that no raw material A remained. Saturated sodium carbonate solution was added and stirred for 3 min. The pH was adjusted to 10, and the aqueous phase was extracted twice with 10 ml of DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 67 mg of a yellow oil with a yield of 100%, which was directly used in the next step of synthesis. LC-MS: [M+1] + =349.

[0245] Step 3

[0246]

[0247] Take intermediate (3) (51 mg, 1.0 eq.), compound (10b) (67 mg, 1.0 eq.), Pd2(dba)3 (17 mg, 0.1 eq.), BINAP (24 mg, 0.2 eq.), Cs2CO3 (125 mg, 2.0 eq.), add 3 mL of toluene and mix in a reaction bottle, add a magnetic stirrer, and replace nitrogen three times; place in a 110°C oil bath and heat and stir for 15 h; TLC monitoring shows that there is no residual raw material; the reaction solution is cooled to room temperature, passed through a diatomaceous earth funnel, the filter cake is washed with a small amount of EA, and the combined filtrate is concentrated to obtain a crude oil; purify by silica gel column chromatography, DCM:CH3OH=90:1~70:1, collect the product point and concentrate, and obtain 49 mg of pure product, yield: 44%. LC-MS: [M+1] + =575.

[0248] Step 4

[0249]

[0250] Compound (10c) (49 mg, 1.0 eq.) was dissolved in 1 mL MeCN, 400 μL pure water was added, and (22 mg, 6.0 eq.) solid lithium hydroxide monohydrate was added under magnetic stirring; the reaction was heated in an oil bath at 45°C for about 18 h, and TLC monitoring showed that no raw material remained; the reaction was cooled to room temperature, 3 mL of saturated ammonium chloride solution was added for washing, and 10 mL of EA was used for extraction twice, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phases were concentrated to obtain 50 mg of a yellow solid crude product. Preparative thin layer purification was performed, DCM: MeOH = 10:1 was used for development, the product band was scraped off, the product was dissolved in DCM: MeOH = 10:1, filtered, and the filtrate was concentrated, and DCM was added for dissolution, filtered, and the filtrate was concentrated to obtain 23 mg of a pure product with a yield of 48%; LC-MS: [M+1] + =561 purity 99% (254nm). 1 H NMR (400MHz, DMSO-d6) δ8.06(s,1H),7.86(d,J=8.8Hz,1H),7.77(d,J=8.5Hz,1H),7.68(d, J=7.9Hz,1H),7.57(t,J=7.9Hz,2H),7.30(t,J=7.9Hz,1H),6.03(d,J=7.8Hz,1H),5.93(d,J =7.6Hz,1H),5.31(s,2H),4.47(s,2H),3.89(s,2H),3.61(t,J=5.1Hz,2H),3.51(s,2H),3. 47(d,J=6.7Hz,2H),3.15(s,3H),2.78(s,3H),2.58(d,J=7.0Hz,2H),0.99(t,J=7.0Hz,3H).

[0251] Example 10 Preparation of Compound (I-11)

[0252] Intermediates (13)

[0253]

[0254] Intermediate (2) (10 mg, 1.0 eq.) was dissolved in 1 mL DMF (N,N-dimethylformamide), and N-Boc-N-methylethylenediamine (12 mg, 2.0 eq) was added. Cs2CO3 (11 mg, 1.0 eq) was added and stirred at room temperature for 12 h. TLC monitoring showed that no raw material remained. After the reaction was completed, the system was poured into a saturated ammonium chloride solution to quench, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined and washed with a saturated sodium chloride solution, the organic phases were separated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 20 mg of the product. LC-MS: [M+1] + =433.

[0255] Referring to Example 9, intermediate (13) was used instead of intermediate (12) to prepare compound (I-11). LC-MS: [M+1] + =575, purity 98.04% (254nm). 1 H NMR (400MHz, CDCl3) δ8.09(s,1H),8.04(d,J=8.5Hz,1H),7.78(d,J=8.4Hz,1H),7.60(t,J=7.5Hz,1H),7. 45(d,J=7.9Hz,1H),7.35(d,J=9.3Hz,1H),7.26(d,J=8.1Hz,1H),5.95(d,J=7.7Hz,1H),5.88(d,J=8.1Hz, 1H),5.33(s,2H),5.15-5.09(m,1H),4.67–4.55(m,2H),4.47(d,J=13.3Hz,1H),4.35-4.29(m,1H),4.16- 4.05(m,2H),3.59–3.45(m,2H),2.78(s,3H),2.76–2.64(m,4H),2.45-2.25(m,2H),1.17(t,J=6.8Hz,3H).

[0256] Example 11 Preparation of Compound (I-12)

[0257] Referring to Example 9, benzyl bromide was used instead of ethyl bromide to prepare compound (I-12). LC-MS: [M+1] + =623, purity 96% (254nm). 1H NMR(400MHz,d6-DMSO)δ8.06(s,1H),7.82(d,J=10.0Hz,1H),7.76(d,J=9.8Hz,1H) ,7.62(dd,J=16.3,7.5Hz,2H),7.52(t,J=7.6Hz,1H),7.28(dd,J=13.5,6.1Hz,6H) ,6.02(d,J=7.9Hz,1H), 5.93(d,J=7.6Hz,1H),5.21(s,2H),4.39(s,2H),3.88(s,2 H),3.68(s,2H),3.51(s,2H),3.43(s,2H),3.03(s,3H),2.77(s,3H),2.68(s,2H).

[0258] Example 12 Preparation of Compound (I-13)

[0259] Compound (I-13) was prepared by using bromoethyl methyl ether instead of bromoethane in accordance with Example 9. LC-MS: [M+1] + =591. 1 H NMR (600MHz, DMSO-d6) δ8.23(s,1H),7.92(d,J=9.8Hz,1H),7.83(d,J=8.4Hz,1H),7.74(d,J=7.9Hz,1H),7.67(d,J=8.4Hz,1H),7.61(t, J=7.6Hz,1H),7.36(t,J=7.9Hz,1H),6.13(d,J=8.2Hz,1H),6.02(d,J=7.7Hz,1H),5.39(s,2H),5.06-5.02(m,1H),4.77(dd,J=15.3,7.6 Hz,1H),4.59(dd,J=15.4,2.8Hz,1H),4.48(td,J=8.0,5.8Hz,1H),4.30(dt,J=9.1,5.9Hz,1H),4.00(d,J=13.5Hz,1H),3.84(d,J=13.5H z,1H),3.59–3.50(m,4H),3.34(t,J=6.0Hz,2H),3.19(s,3H),2.71–2.66(m,1H),2.63(t,J=7.2Hz,1H),2.36-2.32(m,1H),2.31(s,3H).

[0260] Example 13 Preparation of Compound (I-14)

[0261] Step 1

[0262]

[0263] N-Boc-N-methylaminoethanol (248 mg, 1.5 eq.) and intermediate (1) (200 mg, 1.0 eq.) were dissolved in acetonitrile (5 mL), cesium carbonate (461 mg, 1.5 eq.) was added, and the mixture was stirred at room temperature overnight. TLC and LC-MS monitoring showed that a main product point was generated on TLC. The molecular weight of the target compound was observed on LC-MS, corresponding to the main product point. At the same time, some raw materials remained. The system was evaporated to dryness, diluted with EA (20 mL), quenched with saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with EA (10 mL*3). The organic phases were combined and washed with pure water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then evaporated to remove the solvent. The crude product was purified by silica gel column chromatography, PE:EA=10:1-5:1-3:1, to obtain 74 mg of the target compound, 84 mg of the recovered raw materials, 99% purity of the target compound, and a yield of 23.5%. LC-MS: [M+1] + =422 purity 98.18% (254nm)

[0264] Step 2

[0265]

[0266] Compound (14a) (70 mg, 1.0 eq.) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (370 μL, 30.0 eq.) was added by syringe, and the mixture was stirred at room temperature for 20 min. The reaction of the raw material was completed by TLC monitoring. 15 mL of dichloromethane was added to the system for dilution, and the mixture was washed with saturated sodium carbonate solution (20 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10 mL*2), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The crude product was directly used for the next step reaction. LC-MS: [M+1] + =548 purity 96.55% (254nm).

[0267] Step 3

[0268]

[0269] Compound (14b) (53 mg, 1.0 eq.) and intermediate (3) (44 mg, 1.0 eq.) were dissolved in toluene (PhMe) (2 mL), cesium carbonate (108 mg, 2.0 eq.) was added, nitrogen was replaced 3 times by a water pump, BINAP (21 mg, 0.2 eq.) and palladium acetate (15 mg, 0.1 eq.) were added, and nitrogen was replaced 3 times again. The system was moved to 110°C and heated under reflux and stirred to react overnight. After the reaction was completed, the temperature was cooled to room temperature, the system was filtered with diatomaceous earth, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE:EA=10:1-5:1-3:1-1:1) to obtain 72 mg of the target compound with a purity of 96% and a yield of 79.2%. LC-MS: [M+1] + =548 purity 96.55% (254nm).

[0270] Step 4

[0271]

[0272] Compound (14c) (72 mg, 1.0 eq.) was dissolved in acetonitrile (1.4 mL, 20 V), and lithium hydroxide aqueous solution was prepared. Lithium hydroxide monohydrate (28 mg, 5.0 eq.) was dissolved in pure water (280 μL, 4 V) and added to the system. The mixture was heated and stirred at 40 ° C overnight. The reaction was monitored by TLC and LC-MS. 15 mL of saturated ammonium chloride solution was quenched, EA was extracted (15 mL*3), the organic phases were combined and washed with pure water (20 mL*2), washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation. The preparative plate was purified and the system was developed (DCM: MeOH = 20:1) to obtain 36 mg of colorless oil with a purity of 98.7% and a yield of 51.4%. LC-MS: [M+1] + =534, purity 99.30% (254nm). 1 H NMR(600MHz,DMSO-d6)δ8.22(d,J=1.5Hz,1H),7.91(dd,J=10.0,1.5Hz,1H),7.86( dd,J=8.4,1.5Hz,1H),7.73–7.69(m,2H),7.65(t,J=7.6Hz,1H),7.47(t,J=7.9Hz,1 H),6.17(d,J=8.1Hz,1H),6.08(d,J=7.7Hz,1H),5.42(s,2H),4.82(s,2H),4.50(t ,J=5.2Hz,2H),3.69(t,J=5.7Hz,2H),3.66-3.63(m,4H),3.19(s,3H),2.98(s,3H).

[0273] Example 14 Preparation of Compound (I-15)

[0274] Step 1

[0275]

[0276] Intermediate (5) (500 mg, 1.0 eq.) and 4-cyano-2-fluorobenzyl alcohol (659 mg, 2.5 eq.) were dissolved in toluene (25 mL), cesium carbonate (1.42 g, 2.5 eq.) was added, nitrogen was replaced 3 times by a water pump, phosphine ligand (2-(di-tert-butylphosphino)-1,1'-binaphthyl) (CAS: 255836-67-0, 97 mg, 0.14 eq.) and palladium acetate (39 mg, 0.1 eq.) were added, and nitrogen was replaced 3 times again. The system was moved to 75°C and heated with stirring for 20 h. TLC and LC-MS monitoring showed that a main point was generated in the system, which corresponded to the molecular weight of the target compound. The system was cooled to room temperature, filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was evaporated to remove the solvent. Purification by silica gel column chromatography, PE:EA=(20:1→15:1) gave 448 mg of the target compound as a colorless oil with a purity of 98% and a yield of 64%. LC-MS: [M+1] + =402, purity 98% (254nm).

[0277] Step 2

[0278]

[0279] Compound (15a) (70 mg, 1.0 eq.) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (388 μL, 30.0 eq.) was added by syringe, and the mixture was stirred at room temperature for 20 min. The reaction of the raw material was completed as monitored by TLC, and the solvent was removed by rotary evaporation to obtain a crude product, which was directly used for the next step reaction.

[0280] Step 3

[0281]

[0282] The crude product was dissolved in acetonitrile (2mL), and an excess of potassium carbonate (96mg, 4.0eq.) was added. Compound C (49mg, 1.0eq.) was added and stirred at room temperature for overnight reaction. TLC and LC-MS monitoring showed that a small amount of raw materials remained, and the main product point corresponded to the molecular weight of the target compound. The system evaporated the solvent, diluted with ethyl acetate (10mL), quenched with saturated ammonium chloride solution (10mL), separated the organic phase, extracted the aqueous phase with EA (10mL*2), and then the organic phases were combined and washed with pure water (20mL), washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, and then evaporated to remove the solvent. Purification by silica gel column chromatography (PE:EA=5:1-1:1) gave 65mg of a colorless oil with a purity of 90% and a yield of 68%. LC-MS: [M+1]+ =548, purity 90.59%.

[0283] Step 4

[0284]

[0285] Compound (15c) (100 mg, 1.0 eq.) was dissolved in acetonitrile (2 mL, 20 V), and lithium hydroxide aqueous solution was prepared. Lithium hydroxide monohydrate (83 mg, 5.0 eq.) was dissolved in pure water (400 μL, 4 V) and added to the system. The mixture was heated and stirred at 40 ° C overnight. TLC and LC-MS monitored the reaction to be complete. 10 mL of saturated ammonium chloride solution was used for quenching, and EA was extracted (10 mL*3). The organic phases were combined and washed with pure water (15 mL*2), washed with saturated sodium chloride solution (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation. Purification was performed on a preparative plate, and the system was developed (DCM: MeOH = 30:1) to obtain 32 mg of a colorless oil with a purity of 98.5% and a yield of 32.9%. LC-MS: [M+1] + =534, purity 98.46% (254nm). 1 H NMR (400MHz, CDCl3) δ8.12(d,J=1.6Hz,1H),7.90(dd,J=10.0,1.5Hz,1H),7.81–7.58(m,5H),6.42(d,J=7.9Hz,1H),6.37(d,J=7.9Hz, 1H),5.38(s,2H),4.57(t,J=5.2Hz,2H),4.29(t,J=5.6Hz,2H),3.88(s,2H),3.60(t,J=5.1Hz,2H),2.77(t,J=5.6Hz,2H),2.24(s,3H).

[0286] Example 15 Preparation of Compound (I-16)

[0287] Referring to Example 14, compound (16) was prepared by substituting intermediate (2) for intermediate (1). 1HNMR (400MHz, DMSO-d6) δ12.75 (s, 1H), 8.20 (s, 1H), 7.90 (d, J = 9.9Hz, 1H), 7.78 (d, 8.0Hz, 1H), 7.71 (d, 8. 0Hz, 1H),7.68–7.60(m,3H),6.42(d,7.9Hz,1H),6.39(d,J=7.8Hz,1H)5.39(s,2H),5.03–4.97(m,1H),4.77 (dd,J=15.2,7.5Hz,1H),4.60(dd,J=15.3,2.7Hz,1H),4.41(q,J=7.3Hz,1H),4.32–4.20(m,3H),4.00(d,J= 13.5Hz,1H),3.83(d,J=13.5Hz,1H),2.82-2.72(m,2H),2.63–2.52(m,1H),2.31-2.23(m,1H),2.23(s,3H).

[0288] Example 16 Preparation of Compound (I-17)

[0289] Step 1

[0290]

[0291] Intermediate (4) (400 mg, 1.0 eq.) and intermediate (1) (650 mg, 1.0 eq.) were dissolved in acetonitrile (20 mL), cesium carbonate (1.5 g, 2.0 eq.) was added, and the reaction was stirred at room temperature overnight. The system was filtered to remove the alkali, the filtrate was concentrated, diluted with ethyl acetate (50 mL), quenched with saturated ammonium chloride solution (30 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20 mL*2), the combined organic phases were washed with pure water (50 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Purification by silica gel column chromatography, PE:EA=(10:1→2:1) to obtain 110 mg of the target compound as a colorless oil with a purity of 98% and a yield of 11%. LC-MS: [M+1] + =402, purity 98% (254nm).

[0292] Step 2

[0293]

[0294] Compound (17a) (110 mg, 1.0 eq.) and 4-cyano-2-fluorobenzyl alcohol (98 mg, 2.5 eq.) were dissolved in toluene (3 mL), cesium carbonate (214 mg, 2.5 eq.) was added, nitrogen was replaced 3 times by a water pump, phosphine ligand (2-(di-tert-butylphosphine)-1,1'-binaphthyl) (CAS: 255836-67-0, 14 mg, 0.14 eq.) and palladium acetate (6 mg, 0.1 eq.) were added, and nitrogen was replaced 3 times again. The system was moved to 75 ° C and heated and stirred for 20 h. The system was cooled to room temperature, filtered with diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was evaporated to remove the solvent. Purification by silica gel column chromatography (PE: EA = 10: 1-5: 1) gave 125 mg of a colorless oil with a purity of 98.9% and a yield of 89.3%. LC-MS: [M+1] + =535, purity 98.92% (254nm).

[0295] Step 3

[0296]

[0297] Compound (17b) (60 mg, 1.0 eq.) was dissolved in acetonitrile (1.2 mL, 20 V), and lithium hydroxide aqueous solution was prepared. Lithium hydroxide monohydrate (24 mg, 5.0 eq.) was dissolved in pure water (240 μL, 4 V) and added to the system. The mixture was heated and stirred at 40 ° C overnight. The reaction was monitored by TLC and LC-MS. 10 mL of saturated ammonium chloride solution was quenched, EA was extracted (10 mL*3), the organic phases were combined and washed with pure water (15 mL*2), washed with saturated sodium chloride solution (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation. Purification was performed on a preparative plate, and the system was developed (DCM: MeOH = 30:1) to obtain 23 mg of a colorless oil with a yield of 39.6%. LC-MS: [M+1] + =521, purity 98.25% (254nm). 1H NMR (400MHz, CDCl3) δ8.23(s,1H),8.06(d,J=8.6Hz,1H),7.82(d,J=8.5Hz,1H),7.58(t,J =7.5Hz,1H),7.49(t,J=7.9Hz,1H),7.43(d,J=7.9Hz,1H),7.36(d,J=9.1Hz,1H),6.37(d, J=7.9Hz,1H),6.31(d,J=7.9Hz,1H),5.39(s,2H),5.01(s,2H),4.55(t,J=5.2Hz,2H),4.4 2–4.32(t,J=4.8Hz,2H),3.95–3.84(t,J=4.8Hz,2H),3.73(t,J=5.2Hz,2H),3.26(s,3H).

[0298] Example 17 Preparation of Compound (I-18)

[0299] Referring to Example 16, compound (18) was prepared by substituting intermediate (2) for intermediate (1). 1 HNMR (400 MHz, DMSO-d 6) δ12.90(brs,1H),8.28(d,J=1.6Hz,1H),7.90(dd,J=10.0,1.4Hz,1H),7.82(dd,J=8.4,1.6Hz,1H),7 .75–7.61(m,4H),6.46(d,7.9Hz,1H),6.41(d,7.9Hz,1H),5.43(s,2H),5.06-5.00(m,1H),4.92(d,J =12.6Hz,1H),4.82(d,J=12.6Hz,1H),4.70(dd,J=15.3,7.4Hz,1H),4.56(dd,J=15.3,2.9Hz,1H),4. 47–4.41(m,1H)4.37–4.26(m,3H),3.81(dd,J=5.5,3.7Hz,2H),2.66-2.57(m,1H),2.39-2.30(m,1H).

[0300] Example 18 Preparation of Compound (I-19)

[0301] Step 1

[0302]

[0303] Take isopropanolamine (3.0g, 1eq.) and dissolve it in DCM (10mL). Add di-tert-butyl dicarbonate (8.75g, 1eq.) DCM (15mL) dropwise at room temperature. Stir at room temperature for 4h. Monitor the reaction by TLC. The raw material reacts completely. Add saturated sodium bicarbonate aqueous solution for washing, water washing, salt washing, drying over anhydrous sodium sulfate, and rotary evaporation of DCM to obtain 5.02g of transparent oily substance, yield: 71.71%. 1 H NMR (400MHz, DMSO-d6) δ6.66(t,J=5.9Hz,1H),4.56(d,J=4.8Hz,1H),3.58(q d,J=6.2,4.8Hz,1H),2.91–2.78(m,2H),1.38(s,9H),0.99(d,J=6.2Hz,3H).

[0304]

[0305] Take the intermediate (3) (500 mg, 1 eq.), compound (15-a) (832 mg, 2.5 eq.), cesium carbonate (1.55 g, 2.5 eq.) and toluene (20 mL) and add them to a double-necked bottle, repeatedly replace nitrogen 3 times, then add palladium acetate (45 mg, 0.1 eq.), 2-(di-tert-butylphosphine)-1,1'-binaphthyl (105 mg, 0.15 eq.), repeatedly replace nitrogen 3 times, place at 78 ° C to react overnight, control the reaction by TLC, and the raw material reacts completely. After the reaction is completed, filter with diatomaceous earth, take the filtrate and evaporate it to obtain a crude product. Purify by column chromatography, take a small amount of DCM to dissolve, wet sample, column chromatography separation and purification (PE: EA = 30: 1) to obtain 550 mg of white paste, yield 71.89%. LC-MS: [M+23] + =424, purity: 99.64% (254nm). 1 H NMR (600MHz, DMSO-d6) δ7.94–7.86(m,1H),7.75–7.60(m,3H),6.96(t,J=6.0Hz,1H),6.45(dd,J=14.4,7.8Hz,1H),6.34(d,J=7.9Hz,1H), 5.50–5.42(m,2H),5.00(q,J=6.1Hz,1H),3.18(dt,J=12.9,6.2Hz,1H),3.06(dt,J=13.7,5.8Hz,1H),1.35(s,9H),1.14(d,J=6.2Hz,3H).

[0306]

[0307] Compound (15-b) (600 mg, 1.0 eq.) was dissolved in 8 mL of anhydrous THF, and NaH (180 mg, 5.0 eq.) was added. After reacting at room temperature for 40 min, iodomethane (846 mg, 4.0 eq.) was added to the system, and then the system was transferred to a 40°C oil bath for reaction for 4 h. After TLC monitoring, the reaction of the raw materials was complete. After the reaction was completed, dilute hydrochloric acid was added to the system to adjust the pH to weak acidity, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride solution, the organic phases were separated and dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Column chromatography purification, the crude product was dissolved in DCM and wet loaded for silica gel column chromatography purification, the target product was eluted at PE:EA=15:1, and the eluent was rotary evaporated to obtain 344 mg of colorless oil, with a yield of 55%. LC-MS: [M+1] + =438, purity 99.22% (254nm).

[0308] Referring to Example 2, intermediate (15) was used instead of intermediate (6) to prepare compound (I-19). LC-MS: [M+1] + =560. 1 H NMR(400MHz, DMSO-d6)δ12.75(s,1H),8.24–8.17(m,1H),7.89(d,J=9.8Hz,1H),7.81–7.76(m,1H),7.73–7.67( m,1H),7.66–7.59(m,3H),6.45(dd,J=7.9,2.5Hz,1H),6.32(d,J=7.9Hz,1H),5.46–5.34(m,2H),5.21–5.08(m, 1H),5.02–4.92(m,1H),4.77–4.67(m,1H),4.61–4.52(m,1H),4.44–4.38(m,1H),4.33–4.25(m,1H),4.13–3.69 (m,3H),2.80–2.68(m,1H),2.54(d,J=5.1Hz,1H),2.31–2.23(m,1H),2.19(d,J=2.6Hz,3H),1.16–1.06(m,3H).

[0309] Example 19 Preparation of Compound (I-20)

[0310] Referring to Example 18, 1-amino-2-butanol was used instead of isopropanolamine to prepare compound (I-20). LC-MS: [M+1] + =574. 1H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.20(d,J=1.5Hz,1H),7.91(dd,J=10.0,1.5Hz,1H),7.78(dd,J=8.4,1.5Hz,1 H),7.73–7.69(m,1H),7.69–7.63(m,2H),7.61(dd,J=8.4,1.6Hz,1H),6.47–6.41(m,2H),5.44(d,J=3.7Hz,2H),5.0 4–4.96(m,1H),4.87–4.58(m,2H),4.47–4.41(m,1H),4.31–4.22(m,3H),4.16–4.01(m,2H),2.98–2.88(m,1H),2.66 –2.57(m,1H),2.32–2.24(m,1H),2.17(d,J=8.1Hz,3H),1.63–1.54(m,1H),1.43–1.34(m,1H),0.91(q,J=7.8Hz,3H).

[0311] Example 20 Preparation of Compound (I-21)

[0312] Referring to Example 18, 2-amino-2-propanol was used instead of isopropanolamine to prepare compound (I-21). LC-MS: [M+1] + =560. 1 H NMR (400MHz, DMSO-d6) δ12.73(s,1H),8.17(s,1H),7.91(d,J=10.0Hz,1H),7.78(d,J=8.4,1.5Hz,1H),7.7 1(dd,J=7.9,1.5Hz,1H),7.67–7.56(m,3H),6.45–6.37(m,2H),5.40(d,J=4.5Hz,2H),5.04–4.93(m,1H),4 .85–4.53(m,2H),4.44–4.37(m,1H),4.30–4.17(m,2H),4.10(dd,J=11.1,4.8Hz,1H),4.06–3.82(m,2H),3 .21–3.12(m,1H),2.63–2.53(m,1H),2.29–2.20(m,1H),2.14(d,J=6.5Hz,3H),1.02(t,J=6.7,5.0Hz,3H).

[0313] Example 21 Preparation of Compound (I-22)

[0314] Referring to Example 18, 2-amino-2-butanol was used instead of isopropanolamine to prepare compound (I-22). LC-MS: [M+1] + =574. 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.20(d,J=1.5Hz,1H),7.91(dd,J=10.0,1.5Hz,1H),7.78(dd,J=8.4,1.5Hz,1 H),7.73–7.69(m,1H),7.69–7.63(m,2H),7.61(dd,J=8.4,1.6Hz,1H),6.47–6.41(m,2H),5.44(d,J=3.7Hz,2H),5.0 4–4.96(m,1H),4.87–4.58(m,2H),4.47–4.41(m,1H),4.31–4.22(m,3H),4.16–4.01(m,2H),2.98–2.88(m,1H),2.66 –2.57(m,1H),2.32–2.24(m,1H),2.17(d,J=8.1Hz,3H),1.63–1.54(m,1H),1.43–1.34(m,1H),0.91(q,J=7.8Hz,3H).

[0315] Example 22 Preparation of Compound (I-24)

[0316] Referring to Example 18, 2-amino-1-phenylethanol was used instead of isopropanolamine to prepare compound (I-24). LC-MS: [M+1] + =622. 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.17(s,1H),7.89(d,J=10.0,1.5Hz,1H),7 .78(d,J=8.4,1.7Hz,1H),7.65–7.60(m,3H),7.46(t,J=7.6Hz,1H),7.26–7.21(m, 5H),6.46–6.40(m,2H),6.02–5.95(m,1H),5.29(d,J=2.5Hz,2H),4.93–4.82(m,1H ),4.63–3.79(m,8H),3.08–3.00(m,1H),2.82–2.75(m,1H),2.28(d,J=2.4Hz,3H).

[0317] Example 23 Preparation of Compound (I-26)

[0318] Referring to Example 18, 2-amino-3-phenylpropanol was used instead of isopropanolamine to prepare compound (I-26). LC-MS: [M+1] + =636. 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.11(s,1H),7.92(d,J=9.8Hz,1H),7. 78(d,J=8.4Hz,1H),7.70(d,J=8.1Hz,1H),7.67–7.55(m,3H),7.29–7.15(m, 4H),7.10(s,1H),6.49–6.29(m,2H),5.17(d,J=7.9Hz,2H),4.87(d,J=7.6Hz ,1H),4.52–3.95(m,9H),3.01–2.88(m,1H),2.70–2.60(m,1H),2.28(s,3H).

[0319] Example 24 Preparation of Compound (I-27)

[0320] Referring to Example 18, 1-amino-3-phenylpropane-2-ol was used instead of isopropanolamine to prepare compound (I-27). LC-MS: [M+1] + =636. 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.21(d,J=4.4Hz,1H),7.88(d,J=10.0Hz,1H),7.79(d,J=8.4Hz,1H) ,7.69–7.57(m,4H),7.17–7.04(m,5H),6.44(d,J=7.9Hz,1H),6.31(t,J=7.9,5.7Hz,1H),5.41(d,J=13.1Hz ,3H),5.04–4.91(m,1H),4.76–4.63(m,1H),4.58–4.49(m,1H),4.43–4.36(m,1H),4.29–4.20(m,1H),3.97– 3.88(m,1H),3.81(d,J=13.6Hz,1H),2.92–2.79(m,2H),2.74–2.66(m,1H),2.60–2.56(m,1H),2.17(s,3H).

[0321] Example 25 Preparation of Compound (I-28)

[0322] Compound (I-28) was prepared by using ethanolamine instead of isopropanolamine according to Example 18. LC-MS: [M+1] +=532. 1 H NMR(400MHz, DMSO-d6)δ8.20(s,1H),7.88(dd,J=10.0,1.4Hz,1H),7.80(dd,J=8.4,1.5Hz,1H),7.7 2–7.58(m,4H),6.45(d,J=7.8Hz,1H),6.39(d,J=7.9Hz,1H),5.41(s,2H),5.05(qd,J=7.2,2.8Hz,1 H),4.71(dd,J=15.4,7.3Hz,1H),4.57(dd,J=15.4,2.8Hz,1H),4.48–4.42(m,1H),4.35–4.28(m,1H ),4.25(t,J=5.7Hz,2H),4.09(dd,2H),2.92(t,J=5.7Hz,2H),2.70–2.61(m,1H),2.41–2.27(m,1H).

[0323] Example 26 Preparation of Compound (I-29)

[0324] Referring to Example 18, 2-phenylaminoethanol was used instead of isopropanolamine to prepare compound (I-29). LC-MS: [M+1] + =596.

[0325] 1 H-NMR: (400MHz, DMSO-d6) δ12.77(s,1H),8.14(d,J=1.6Hz,1H),7.81(dd,J=10.0,1.5Hz,1H),7.74( dd,J=8.4,1.6Hz,1H),7.70–7.53(m,4H),7.13(dd,J=8.7,7.2Hz,2H),6.84(d,J=8.2Hz,2H),6.63(t, J=7.2Hz,1H),6.44(d,J=7.8Hz,1H),6.36(d,J=7.8Hz,1H),5.76(s,1H),5.32(s,2H),4.96(s,2H),4. 51(t,J=5.1Hz,1H),4.46(t,J=6.0Hz,2H),3.87(t,J=6.0Hz,2H),3.65(t,J=5.0Hz,2H),3.19(s,3H).

[0326] Example 27 Preparation of Compound (I-31)

[0327] Step 1

[0328]

[0329] Take 2-aminoethane-1-thiol (1.98g, 1eq.) and dissolve it in 15mL water. Add di-tert-butyl dicarbonate (5.46g, 1.5eq.) in THF (15mL) dropwise at room temperature. After the addition is complete, stir and react at room temperature for 4h. Monitor the reaction by TLC. After iodine staining, the raw material reacts completely. DCM extraction, water washing, dry the organic layer with anhydrous sodium sulfate, and rotary evaporate to obtain 3.805g of oily product.

[0330]

[0331] Compound (16-a) (451 mg, 1.5 eq.) and intermediate (2) (500 mg, 1 eq.) were dissolved in 10 mL of acetonitrile, potassium carbonate (469 mg, 2 eq.) was added, and the mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC. The reaction of the raw materials was complete. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The mixture was purified by column chromatography and recrystallized from n-hexane / ether to obtain 718 mg of a white solid with a yield of 96.05%. LC-MS: [M+1] + =436, purity: 99.40% (254nm).

[0332] Step 2

[0333]

[0334] The intermediate (16) (435 mg, 1 eq.) was dissolved in 40 mL DCM, TFA (7.2 g, 60 eq.) was added dropwise in an ice bath, and the reaction was stirred at room temperature for 2.5 h, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate was added to quench, and DCM was extracted twice, washed with saturated brine, dried over anhydrous sodium sulfate, and DCM was removed by rotary evaporation. The obtained product was directly transferred to the next step. 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=1.6Hz,1H),7.83(dd,J=8.5,1.6Hz,1H),7.68(d,J=8. 4Hz,1H),5.07(qd,J=7.1,2.8Hz,1H),4.72(dd,J=15.5,7.1Hz,1H),4.61(dd,J=15.5,2. 8Hz,1H),4.53–4.42(m,1H),4.32(dt,J=9.1,5.9Hz,1H),4.22–4.03(m,2H),3.88(s,3H) ,2.75–2.63(m,3H),2.58(ddd,J=7.7,6.1,2.1Hz,2H),2.38(ddt,J=9.0,6.9,2.0Hz,1H).

[0335] Step 3

[0336]

[0337] Take intermediate (3) (227 mg, 1 eq.) and intermediate (16) (290 mg, 1 eq.) and dissolve them in 30 mL of toluene, add cesium carbonate (564 mg, 4 eq.), repeatedly pump nitrogen 3 times, add Pd(dba)3 (80 mg, 0.1 eq.) and BINAP (108 mg, 0.2 eq.), repeatedly pump nitrogen 3 times, place at 110 ° C under nitrogen protection and stir to react overnight, and monitor the reaction raw materials by TLC. After the reaction is completed, filter with diatomaceous earth, and take the filtrate for rotary evaporation. Purify by column chromatography (PE: EA = 4: 1-2: 1) to obtain 156 mg of yellow solid. Yield: 29.85%. LC-MS: [M+1] + =562, purity: 93.61% (254nm).

[0338] Step 4

[0339]

[0340] Compound (30b) (80 mg, 1 eq.) was dissolved in methanol, POM (9 mg, 3 eq.) and 48 μL acetic acid were added, the temperature was raised to 50°C, the reaction was stirred for 2 h, and the reaction was monitored by TLC. Sodium cyanoborohydride (18 mg, 1.5 eq.) was added and the reaction was continued overnight, and the reaction was monitored by TLC. After the reaction was completed, the reaction was filtered, and the filtrate was evaporated to obtain a crude product. Column chromatography purification (PE:EA=2:1) ​​gave 62 mg of a yellow solid. Yield: 42.59%. LC-MS: [M+1] + =576, purity: 90.78% (254nm). 1H NMR (600MHz, DMSO-d6) δ8.26(s,1H),7.81(t,J=9.2Hz,2H),7.71–7.62(m,2H),7.57(t,J=7.5Hz,1H),7.43(td,J=7.9,2. 2Hz,1H),6.15(dd,J=8.1,2.1Hz,1H),6.05(dd,J=7.9,2.2Hz,1H),5.39(s,2H),5.05(t,J=7.6Hz,1H),4.69(dd,J=15.6, 7.3Hz,1H),4.62–4.55(m,1H),4.48–4.41(m,1H),4.30(dtd,J=8.6,6.2,2.1Hz,1H),4.21–4.09(m,2H),3.87(d,J=2.2Hz ,3H),3.56(q,J=6.4Hz,2H),2.90(d,J=2.2Hz,3H),2.67(d,J=7.6Hz,1H),2.65–2.57(m,2H),2.36(q,J=9.4,8.7Hz,1H).

[0341] Step 5

[0342]

[0343] Compound (30c) (53 mg, 1 eq.) was dissolved in 1 mL THF, and LiOH (15 mg, 3 eq.) aqueous solution (1 mL) was added. The mixture was heated to 40°C and stirred for 6 h. The reaction was monitored by TLC. After the reaction was completed, the pH value was adjusted to weak acidity, extracted with EA three times, washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain a crude product. Column chromatography separation and purification (DCM: MeOH = 50: 1-40: 1) gave 17 mg of a light yellow solid, with a yield of 32.33%. LC-MS: [M+1] + =576, purity: 97.66% (254nm). 1H NMR (400MHz, DMSO-d6) δ8.24(d,J=1.6Hz,1H),7.82(ddd,J=12.4,9.2,1.6Hz,2H),7.70–7.55(m,3H),7.44(t,J= 7.9Hz,1H),6.16(d,J=8.1Hz,1H),6.06(d,J=7.7Hz,1H),5.41(s,2H),5.06(qd,J=7.2,2.8Hz,1H),4.69(dd,J=1 5.6,7.1Hz,1H),4.57(dd,J=15.4,2.7Hz,1H),4.50–4.43(m,1H),4.32(dt,J=9.0,5.9Hz,1H),4.20–4.10(m,2H) ,3.56(td,J=7.0,2.1Hz,2H),2.91(s,3H),2.70(d,J=2.8Hz,1H),2.62(t,J=7.5Hz,2H),2.36(d,J=11.3Hz,1H).

[0344] Example 32 Preparation of Compound (I-38)

[0345] Step 1

[0346]

[0347] The intermediate (3) (800 mg, 1.0 eq.) and (R)-(1-amino-1-oxopropyl-2-yl)carbamic acid tert-butyl ester (573 mg, 1.0 eq.) were dissolved in dioxane (30 mL), cesium carbonate (1.98 g, 2.0 eq.) was added, and nitrogen was replaced by a water pump 3 times until there were no bubbles in the system, palladium acetate (69 mg, 0.1 eq.) and BINAP (758 mg, 0.4 eq.) were added, and nitrogen was replaced again 3 times until there were no bubbles in the system, and the system was placed in an oil bath at 100°C for reflux reaction for 15 h. TLC monitoring showed that the raw material reaction was complete. After the reaction was completed, the system was cooled and filtered on diatomaceous earth, the filter cake was washed with EA, and the filtrate was dried to obtain a crude product. Column chromatography purification: The crude product was dissolved in DCM and then wet loaded on a column for chromatography. The stationary phase was 100-200 mesh silica gel. The elution polarity was PE:EA=10:1. The product came down. The filtrate was concentrated and dried to obtain 1.05 g of off-white solid. The yield was 82%. LC-MS: [M+1] + =415, purity 98.22% (254nm).

[0348] Step 2

[0349]

[0350] Compound (38a) (0.72 g, 1.0 eq.) was dissolved in acetonitrile (10 mL), CH3I (545 μL, 5.0 eq.) and cesium carbonate (1.55 g, 3.0 eq.) were added, and placed in a microwave reactor for 6.5 h at 80°C. TLC monitoring showed that the reaction was complete. After the reaction was completed, the system was quenched with water, extracted with EA three times, washed once with saturated brine, dried over anhydrous NaSO4, and spin-dried to obtain a crude product. Column chromatography purification: The crude product was dissolved in DCM and wet-loaded on a column chromatography, and purified by column chromatography using a PE / EA system. After purification, 613 mg of the product was obtained as a light yellow solid with a yield of 82%. LC-MS: [M+1] + =429, purity 97.12% (254nm). 1 H NMR (400MHz, DMSO-d6) δ7.91–7.85(m,2H),7.71(d,J=3.8Hz,2H),7.12(d,J=7.6Hz,1H),6.99(d,J=7.7Hz,1H),6. 87(d,J=8.2Hz,1H),5.48(d,J=3.1Hz,2H),4.44(t,J=7.2Hz,1H),3.20(s,3H),1.33(s,9H),1.02(d,J=7.0Hz,3H).

[0351] Step 3

[0352]

[0353] Compound (38c) (490 mg, 1.0 eq.) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (2.62 mL, 30.0 eq.) was added. The reaction was allowed to react at room temperature for 1 h. TLC monitoring showed that the reaction was complete. After the reaction was completed, the system was adjusted to a weakly alkaline pH with a saturated NaHCO3 solution, and the reaction solution was washed once with pure water, washed with saturated brine, dried over anhydrous NaSO4, and the crude product was spin-dried to obtain a crude product, which was directly subjected to the next step of reaction.

[0354] Step 4

[0355]

[0356] Compound (38c) (2.0 eq.) was dissolved in acetonitrile (10 mL), potassium carbonate (0.16 g, 1.0 eq.) was added, and intermediate (2) (168 mg, 1.0 eq.) was dissolved in acetonitrile (5 mL), and slowly added to the reaction bottle using a syringe pump, and the addition was set to be completed over 20 h. After the addition was completed, TLC monitoring showed that the raw material remained, and there was almost no disubstituted by-product. After continuing the reaction for 21 h, LC-MS monitoring showed that there was still a small amount of raw material B remaining, and the post-treatment was directly carried out. After the system was quenched with water, the reaction solution was washed three times with EA, washed with saturated brine, dried over anhydrous NaSO4, and spin-dried to obtain a crude product. Column chromatography purification: The crude product was dissolved in DCM and then dry-loaded on a column for chromatography. The column chromatography was purified using a DCM / MeOH system. The stationary phase was 100-200 mesh silica gel. The polarity of the eluent was DCM:MeOH = 50:1. The product was removed. The eluent was dried by rotary evaporation to obtain 439 mg of a light yellow oily product. A small amount was taken for preparative plate purification, and the remainder was used for subsequent reactions. LC-MS: [M+1] + =587, purity 97.12% (254nm). 1 H NMR(400MHz,DMSO-d6)δ8.20(d,J=1.6Hz,1H),7.86(dd,J=10.0,1.5Hz,1H),7.79–7.55(m,5H),7 .07(d,J=7.7Hz,1H),6.79(d,J=8.2Hz,1H),5.42–5.25(m,2H),5.07–4.98(m,1H),4.69(dd,J=15 .3,7.3Hz,1H),4.58(dd,J=15.2,2.8Hz,1H),4.48–4.40(m,1H),4.35–4.25(m,1H),3.87(s,5H), 3.65(s,1H),3.19(d,J=5.3Hz,3H),2.70–2.61(m,1H),2.40–2.32(m,1H),1.03(d,J=6.7Hz,3H).

[0357] Step 5

[0358]

[0359] Compound (38d) (0.46 g, 1.0 eq.) was dissolved in acetonitrile (7.5 mL), CH3I (143 μL, 3.0 eq.) and potassium carbonate (0.24 g, 2.0 eq.) were added, and the mixture was allowed to react for 12 h at room temperature. TLC monitoring showed that the raw material remained. After the reaction was completed, the system was quenched with water, extracted three times with EA, washed once with saturated brine, dried over anhydrous NaSO4, and spin-dried to obtain a crude product. Column chromatography purification: The crude product was dissolved in DCM, and silica gel was added to mix the sample. The product was subjected to dry loading column chromatography and purified by column chromatography using a DCM / MeOH system. After purification, 160 mg of the product was obtained as a light yellow solid with a yield of 34%. LC-MS: [M+1] + =601, purity 95.16% (254nm).

[0360] Step 6

[0361]

[0362] Compound (38e) (124 mg, 1.0 eq.) was dissolved in tetrahydrofuran (4 mL), and a solution of LiOH·H2O (26 mg, 3.0 eq.) in water (1 mL) was added. The mixture was allowed to react at room temperature for 15.5 h. TLC monitoring showed that the raw material remained and by-products were generated. After the reaction, the system was adjusted to a weakly acidic pH with a dilute HCl solution, and the reaction solution was washed three times with EA, washed with saturated brine, dried over anhydrous NaSO4, and dried to obtain a crude product. Column chromatography purification: The crude product was purified by preparative plate, and developed twice with a developing solvent of DCM:MeOH=15:1. After purification, 44 mg of an off-white solid was obtained with a yield of 36%. LC-MS: [M+1] + =587, purity 99.15% (254nm). 1 HNMR(400MHz,DMSO-d6)δ8.18(d,J=1.6Hz,1H),7.87(dd,J=10.0,1.5Hz,1H),7.78(dd,J=8.4,1.5Hz, 1H),7.71–7.56(m,4H),7.03(t,J=9.0Hz,1H),6.72(dd,J=21.7,8.2Hz,1H),5.43–5.34(m,2H),5.02– 4.89(m,1H),4.71–4.57(m,1H),4.55–4.37(m,2H),4.33–4.23(m,1H),3.96(d,J=13.5Hz,1H),3.81–3 .72(m,2H),3.22(s,3H),2.71–2.57(m,1H),2.38–2.22(m,1H),2.17–2.07(m,3H),1.18–1.12(m,3H).

[0363] Example 33 Preparation of Compound (I-39)

[0364] Step 1

[0365]

[0366] Take tert-butyl (2-bromoethyl)carbamate (1.09 g, 1.2 eq.), NiBr2 (83 mg, 0.1 eq.), 4,7-diphenyl-1,10-phenanthroline (126 mg, 0.1 eq.), DMF (5 mL), replace with nitrogen, react at 40 ° C until the solution turns light green, then add intermediate (3) (1.0 g, 1.0 eq.), Mn (418 mg, 2 eq.), DMF (1 mL), replace with nitrogen, and react at 50 ° C for 16 h. After the reaction is completed, pass through a diatomaceous earth funnel, wash with DCM, wash the organic phase with saturated NH4Cl, water, and saturated brine, dry, and concentrate to obtain a crude product. Purify by column, PE:EA = 10:1-8:1, collect the product point and concentrate to obtain 371 mg of pure product, yield: 26%. LC-MS: [M+1] + =372 purity 91.92% (220nm).

[0367] Step 2

[0368]

[0369] Compound (39a) (589 mg, 1.0 eq.) was dissolved in 18 mL DCM (dichloromethane), 3.52 mL TFA (trifluoroacetic acid) (30 eq.) was added to the reaction system, and the mixture was reacted at room temperature under nitrogen protection. After 1 h, TLC monitoring showed that the reaction was complete, and 600 mg of crude oil was obtained by spin drying.

[0370] Step 3

[0371]

[0372] Take compound (39b) (600 mg, 2.0 eq.) and dissolve it in 10 mL MeCN (acetonitrile), add potassium carbonate (1.31 g, 12.0 eq.), measure the system pH = 8-9, slowly dropwise add the acetonitrile (4 mL) solution of intermediate (2) (233 mg, 0.5 eq.), and react at room temperature overnight. TLC confirms that the raw material reaction is complete. After the reaction is completed, add 10 mL of water to the system to dilute, adjust the pH to 7 with dilute hydrochloric acid, extract the aqueous phase 3 times with EA, combine the organic phases and wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and spin dry to obtain the crude product. Silica gel column chromatography, elution polarity DCM: MeOH = 80:1-60:1, collect the product spots, and concentrate under reduced pressure to obtain 185 mg, with a yield of 46%; LC-MS: [M+1] +=530. 1 H NMR(400MHz, DMSO-d6)δ8.23(d,J=0.9Hz,1H),7.88–7.81(m,1H),7.78(dd,J=8.4,1.5Hz,1H),7.72–7. 60(m,4H),6.87(d,J=7.2Hz,1H),6.72(d,J=8.2Hz,1H),5.35(s,2H),4.98(qd,J=7.4,2.7Hz,1H),4.66 (dd,J=15.3,7.3Hz,1H),4.48(ddd,J=21.3,15.3,5.3Hz,2H),4.28(dt,J=9.0,5.9Hz,1H),4.13–4.03( m,2H),3.90–3.82(m,3H),2.97–2.89(m,2H),2.86–2.77(m,2H),2.69–2.58(m,1H),2.37–2.27(m,1H).

[0373] Step 4

[0374]

[0375] Compound (39c) (142 mg, 1.0 eq.) was dissolved in a mixed solution (5 mL) of THF:H2O=4:1, and a solution of LiOH·H2O (33 mg, 3.0 eq.) in water (1 mL) was added. The mixture was reacted at room temperature for 16 h. TLC monitoring showed that the raw material was basically reacted. After the reaction, the system was adjusted to a weakly acidic pH with a dilute HCl solution, and the reaction solution was washed three times with EA, washed with saturated brine, dried over anhydrous NaSO4, and dried to obtain a crude product. The product was purified by column, DCM:MeOH=10:1-8:1, and the product was concentrated to obtain 90 mg of the product with a yield of 65%; LC-MS: [M+1] + =516. 1H NMR(400MHz, DMSO-d6)δ8.21(s,1H),7.84(d,J=9.8Hz,1H),7.81–7.75(m,1H),7.72–7.55(m,4H),6.8 8(d,J=7.2Hz,1H),6.72(d,J=8.2Hz,1H),5.38(s,2H),4.99(qd,J=7.5,3.0Hz,1H),4.66(dd,J=15.3,7 .2Hz,1H),4.48(ddd,J=21.3,14.6,5.0Hz,2H),4.34–4.20(m,1H),4.09(q,J=14.7Hz,2H),3.94(dd,J =13.7,6.6Hz,1H),2.94(t,J=6.7Hz,2H),2.82(t,J=6.7Hz,2H),2.69–2.57(m,1H),2.41–2.27(m,1H).

[0376] Example 34 Preparation of Compound (I-40)

[0377] Step 1

[0378]

[0379] Compound (39a) (302 mg, 1.0 eq.) was dissolved in anhydrous THF (4.6 mL), 60% NaH 164 mg (5 eq.) was added, and the mixture was stirred at room temperature for 30 min. 201 uL iodomethane (4 eq.) was added to the system and stirred at room temperature for 3 h. TLC monitored the reaction to be complete, the system was adjusted to pH ≈ 6 with dilute hydrochloric acid, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated brine, and dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure to obtain 0.40 g of a yellow oil. Column chromatography purification: The crude product was sanded and loaded dry. The product point was obtained when the eluent was PE:EA=16:1. The eluent was concentrated to obtain 177 mg of the product with a yield of 57%. LC-MS: [M+1] + =386, [M+23] + =408, purity 97.96% (254nm).

[0380] Referring to Example 2, compound (40a) was used instead of intermediate (6) to prepare compound (I-40). LC-MS: [M+1] + =530. 1H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.16(s,1H),7.84(d,J=9.8Hz,1H),7.73(d,J=8.4Hz ,1H),7.67–7.56(m,4H),6.87(d,J=7.2Hz,1H),6.71(d,J=8.2Hz,1H),5.21–5.12(m,2H),4 .87(d,J=5.7Hz,1H),4.45(ddd,J=21.4,14.6,7.4Hz,2H),4.34–4.21(m,2H),3.91(d,J=13 .4Hz,1H),3.79(d,J=13.4Hz,1H),2.85–2.71(m,4H),2.61–2.53(m,1H),2.26–2.15(m,4H).

[0381] Example 35 Preparation of Compound (I-41)

[0382] Step 1

[0383]

[0384] Take tert-butyl (3-bromopropyl)carbamate (1.09 g, 1.2 eq), NiBr2 (83 mg, 0.1 eq), 4,7-diphenyl-1,10-phenanthroline (126 mg, 0.1 eq), DMF: 5 ml, replace with nitrogen, react at 40 ° C until the solution turns light green, cool down, add intermediate (3) (1.0 g, 1.0 eq), Mn (418 mg, 2 eq), DMF: 1 mL, replace with nitrogen, and react at 50 ° C overnight. TLC monitoring reaction has a new point generated. Cool down, add DCM to dilute, pass through celite, wash with DCM, wash the organic phase with saturated NH4Cl, water, saturated brine, dry, and concentrate to obtain a crude product. Column chromatography purification: Column chromatography separation and purification (PE: EA = 10: 1) to obtain 0.65 g of white solid, yield: 44.2%. LC-MS: [M+H] + =386, purity: 95.00% (254nm).

[0385]

[0386] Compound (41b) (420 mg, 1.0 eq.) was dissolved in anhydrous THF (10 mL), and NaH (138 mg, 5.0 eq.) was added. After stirring at room temperature for 45 min, methyl iodide (618 mg, 4.0 eq.) was added to the system and reacted at room temperature for 3.5 h. TLC monitored the reaction to be complete, and the system was adjusted to a weakly acidic pH with dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate. After the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to obtain a crude product. Column chromatography purification: The crude product was dry-loaded on a column chromatography, and the stationary phase was 100-200 mesh silica gel. When the eluent polarity was PE:EA=10:1, the product came down. The eluent was rotary dried to obtain 379 mg of the product as a yellow-green oil, with a yield of 87%. LC-MS: [M+1] + =400, purity 95.01% (254nm). 1 H NMR (400MHz, DMSO-d6) δ7.88(d,J=10.0Hz,1H),7.70(d,J=4.0Hz,2H),7.64(t,J=7.7Hz,1H),6.88(d,J=7.3Hz,1H),6.73(d ,J=8.2Hz,1H),5.47(s,2H),3.13(t,J=7.2Hz,2H),2.73(s,3H),2.58(t,J=7.5Hz,2H),1.79(s,2H),1.35(d,J=26.6Hz,9H).

[0387] Referring to Example 2, compound (41a) was used instead of intermediate (6) to prepare compound (I-41). LC-MS: [M+1] + =544. 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.28–8.21(m,1H),7.91–7.85(m,1H),7.80(dd,J=8.4,1.5Hz,1H),7.73 –7.61(m,3H),7.52(t,J=7.7Hz,1H),6.78(d,J=7.2Hz,1H),6.66(d,J=8.2Hz,1H),5.43(s,2H),5.12–5.01(m, 1H),4.80(dd,J=15.2,7.4Hz,1H),4.64(dd,J=15.2,2.8Hz,1H),4.50–4.42(m,1H),4.35–4.26(m,1H),3.96–3 .90(m,1H),3.73(d,J=13.4Hz,1H),2.71–2.58(m,3H),2.42–2.31(m,3H),2.15(s,3H),1.81(t,J=7.2Hz,2H).

[0388] Example 36 Preparation of Compound (I-42)

[0389] Referring to Example 34, compound (I-42) was prepared by replacing (3-bromopropyl)carbamic acid tert-butyl ester with (2-bromobutyl)carbamic acid tert-butyl ester. LC-MS: [M+1] + =558. 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.12(d,J=1.5Hz,1H),7.82(dd,J=9.9,1.5Hz,1H),7.72(dd,J=8.4,1.6Hz,1H),7.65–7.56(m,3H) ,7.50(t,J=7.6Hz,1H),6.81(d,J=7.2Hz,1H),6.71(d,J=8.2Hz,1H),5.14(d,J=13.8Hz,1H),4.79(d,J=13.8Hz,1H),4.75–4.67(m,1H),4 .42–4.31(m,2H),4.26–4.19(m,1H),3.98–3.92(m,1H),3.87(d,J=13.3Hz,1H),3.64(d,J=13.3Hz,1H),2.80(dd,J=7.0,3.0Hz,2H),2.51 (d,J=2.4Hz,1H),2.50(d,J=2.1Hz,1H),2.40(d,J=6.9Hz,1H),2.15(s,4H),1.52–1.43(m,1H),1.40–1.34(m,1H),0.55(t,J=7.3Hz,3H).

[0390] Example 37 Preparation of Compound (I-43)

[0391] Referring to Example 34, compound (I-43) was prepared by replacing (3-bromopropyl)carbamic acid tert-butyl ester with (1-bromobutane-2-yl)carbamic acid tert-butyl ester. LC-MS: [M+1] + =558. 1H NMR (400MHz, DMSO-d6) δ12.65(s,1H),8.16(d,J=1.6Hz,1H),7.83(d,J=10.0Hz,1H),7.74(dd,J=8.3,1.5Hz,1 H),7.67–7.53(m,4H),6.88(d,J=7.2Hz,1H),6.72(d,J=8.2Hz,1H),5.35(d,J=13.6Hz,1H),5.18(d,J=13.6Hz, 1H),5.02–4.87(m,1H),4.53–4.32(m,3H),4.27–4.20(m,1H),4.00(d,J=13.4Hz,1H),3.94(d,J=13.5Hz,1H),2 .93–2.79(m,2H),2.68–2.52(m,2H),2.24–2.17(m,1H),2.14(s,3H),1.63–1.44(m,2H),0.79(t,J=7.3Hz,3H).

[0392] Example 38 Preparation of Compound (I-44)

[0393] Referring to Example 34, (S)-(1-hydroxy-3-phenylpropan-2-yl)carbamic acid tert-butyl ester was used instead of (3-bromopropyl)carbamic acid tert-butyl ester to prepare compound (I-44). LC-MS: [M+1] + =620. 1 H NMR (400MHz, DMSO-d6) δ12.67(s,1H),8.04(s,1H),7.79(d,J=9.8Hz,1H),7.72(d,J=8.5Hz,1H),7.66–7.56(m,2H),7. 50(d,J=4.2Hz,2H),7.31–7.05(m,5H),6.87(d,J=7.2Hz,1H),6.70(d,J=8.2Hz,1H),5.21(d,J=13.7Hz,1H),4.99(d,J= 13.7Hz,1H),4.74–4.63(m,1H),4.41–4.30(m,1H),4.20–4.11(m,1H),4.05–3.91(m,3H),3.72(dd,J=15.5,2.6Hz,1H), 3.37(d,J=9.0Hz,2H),3.00–2.83(m,2H),2.54(d,J=6.5Hz,1H),2.46(d,J=7.2Hz,1H),2.25(s,3H),2.03–1.95(m,1H).

[0394] Example 39 Preparation of Compound (I-45)

[0395] Referring to Example 34, (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamic acid tert-butyl ester was used instead of (3-bromopropyl)carbamic acid tert-butyl ester to prepare compound (I-44). LC-MS: [M+1] + =620. 1 H NMR (400MHz, DMSO-d6) δ12.67(s,1H),8.04(s,1H),7.79(d,J=9.8Hz,1H),7.72(d,J=8.5Hz,1H),7.67–7.56(m,2H),7.50(d,J =4.2Hz,2H),7.30–7.15(m,3H),7.12(d,J=7.3Hz,2H),6.87(d,J=7.2Hz,1H),6.70(d,J=8.2Hz,1H),5.21(d,J=13.7Hz,1H),4 .99(d,J=13.7Hz,1H),4.68(d,J=7.2Hz,1H),4.40–4.29(m,1H),4.21–4.11(m,1H),4.04–3.89(m,3H),3.72(dd,J=15.5,2.6H z,1H),3.37(d,J=8.9Hz,2H),2.99–2.84(m,2H),2.54(d,J=6.5Hz,1H),2.46(d,J=7.9Hz,1H),2.25(s,3H),2.02–1.93(m,1H).

[0396] Example 40 Preparation of Compound (I-46)

[0397] Step 1

[0398]

[0399] Take nitromethane (5.21g, 2.0eq) and dissolve it in 40mL THF / BuOH mixed solution, add t-BuOK (467mg, 0.1eq), and react at room temperature for 30min; put the system into an ice bath to cool down, use a constant pressure dropping funnel to slowly drop isobutyraldehyde (3.10g, 1.0eq) THF / BuOH solution (10mL), and slowly warm to room temperature to react for 3h after the drop is completed. TLC monitors the complete reaction of the raw materials, add 100mL EA to dilute the system, and add 150mL saturated NaCl to wash; the aqueous phase is extracted with EA twice, the organic phases are combined, and dried with anhydrous sodium sulfate, and the ethyl acetate is removed under reduced pressure to obtain 4.5g of oil, with a yield of 78.9%, and the next step is directly fed without purification.

[0400]

[0401] Dissolve 3-methyl-1-nitro-2-butanol (4.5 g) in EtOH (100 mL), add Pd / C (896 mg); replace the system with H2 several times, and react at room temperature overnight. TLC monitors the complete reaction of the raw material. Filter the system with diatomaceous earth, and concentrate the filtrate by rotary evaporation to obtain 4.2 g of oil. Yield: 120%. Proceed directly to the next step without purification.

[0402]

[0403] Dissolve 1-amino-3-methyl-2-butanol (4.1g, 1.0eq) in DCM (80mL); Dissolve di-tert-butyl dicarbonate (10.1g, 1.1eq) in DCM (20mL); Place the DCM solution of 1-amino-3-methyl-2-butanol in an ice bath, slowly add the DCM solution of di-tert-butyl dicarbonate using a constant pressure dropping funnel, and after the addition is complete (about 40min), warm to room temperature and react for 3h. TLC monitoring shows that the raw materials react completely. The system is first washed with saturated Na2CO3, the organic phase is washed with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 10.4g of crude product. Column chromatography purification: Take 5.8g of crude product, dissolve it in DCM, add silica gel to mix the sample, and perform column chromatography by dry loading, and column chromatography purification with PE / EA system to obtain 2.01g of product oil after purification, with a yield of 50%. 1 HNMR(600MHz,DMSO-d6)δ6.54(t,J=5.8Hz,1H),4.45(d,J=5.3Hz,1H),3.25–3.19(m,1H),3.06 –2.99(m,1H),2.84–2.71(m,1H),1.61–1.53(m,1H),1.37(s,9H),0.83(dd,J=14.7,6.8Hz,6H).

[0404]

[0405] Take the intermediate (3) (604 mg, 1.0 eq.) and dissolve it in toluene (18 mL). Add tert-butyl (2-hydroxy-3-methylbutyl)carbamate (1.16 g, 2.5 eq.) and Cs2CO3 (1.48 g, 2.0 eq.), and replace nitrogen three times; then add Pd(OAc)2 (78 mg, 0.15 eq.) and 2-(di-tert-butylphosphino)-1,1'-binaphthyl (275 mg, 0.3 eq.), replace nitrogen to ensure that the system is oxygen-free; heat to 78 °C and react overnight. TLC monitoring shows that new substances are generated. After the reaction is completed, the system is filtered with diatomaceous earth pads, washed with EA, and the filtrate is concentrated by rotary evaporation to obtain a crude product. Column chromatography purification: The crude product is sanded and loaded by dry method. The eluent starts to elute with PE:EA=60:1, and the product point is obtained when PE:EA=30:1. The eluate was concentrated to obtain 360 mg of the product, with a yield of 36.47%. LC-MS: [M+1] + =430, purity 98.07% (254nm).

[0406]

[0407] Compound (46b) (0.28 g, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (8 mL), NaH (0.14 g, 5.0 eq.) was added, and the mixture was stirred at room temperature for 0.5 h. CH3I (400 μL, 6.0 eq.) was then added, and the mixture was stirred at room temperature for 15 h overnight. TLC monitored the complete reaction of the raw materials. After the reaction was completed, the system was adjusted to a neutral pH with ammonium chloride, extracted with EA three times, washed with saturated brine once, dried over anhydrous NaSO4, and spin-dried to obtain a crude product. Column chromatography purification: The crude product was dissolved in DCM and wet-loaded on a column chromatography, and column chromatography purification was performed using a PE / EA system. After purification, 257 mg of the product was obtained as a light yellow solid with a yield of 90%. LC-MS: [M+1] + =444, purity 95.21% (254nm). 1 H NMR(400MHz, DMSO-d6)δ7.92(d,J=10.0Hz,1H),7.72(d,J=7.9Hz,1H),7.68–7.55(m, 2H),6.47(d,J=7.6Hz,1H),6.36(d,J=8.8Hz,1H),5.51(d,J=14.0Hz,1H),5.40(d,J=1 3.9Hz,1H),5.10(d,J=32.4Hz,1H),3.47(dd,J=33.5,14.8Hz,1H),3.29–3.15(m,1H), 2.70(s,3H),1.86–1.75(m,1H),1.32(d,J=19.9Hz,9H),0.83(dd,J=14.4,7.0Hz,6H).

[0408] Referring to Example 2, compound (46a) was used instead of intermediate (6) to prepare compound (I-46). LC-MS: [M+1] + =588. 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),8.21(d,J=4.3Hz,1H),7.89(d,J=9.9Hz,1H),7.79(d,J=8.5Hz,1H),7.69–7.5 7(m,4H),6.46(d,J=7.8,1.8Hz,1H),6.33(t,J=7.9,5.8Hz,1H),5.45(d,J=6.5Hz,2H),5.10–5.01(m,1H),5.00–4.89 (m,1H),4.73–4.58(m,1H),4.52–4.37(m,2H),4.33–4.24(m,1H),3.92(dd,J=13.5,4.8Hz,1H),3.79(dd,J=13.4,6.1 Hz,1H),2.70–2.61(m,1H),2.61–2.56(m,1H),2.29–2.19(m,1H),2.13(s,3H),1.94–1.85(m,1H),0.80–0.69(m,6H).

[0409] Example 41 Preparation of Compound (I-47)

[0410] Referring to Example 39, 3-methylbutyraldehyde was used instead of isobutyraldehyde to prepare compound (I-47). LC-MS: [M+1] + =602. 1H NMR (400MHz, DMSO-d6) δ8.22(d,J=1.9Hz,1H),7.88(d,J=9.9,1.5Hz,1H),7.79(d,J=8.4,1.6Hz,1H),7.70–7.57(m,4H) ,6.47(dd,J=7.8,2.9Hz,1H),6.32(dd,J=7.8,2.6Hz,1H),5.51–5.39(m,2H),5.24(q,J=7.7Hz,1H),5.03–4.92(m,1H), 4.73–4.61(m,1H),4.55–4.39(m,2H),4.33–4.25(m,1H),3.92(dd,J=13.5,4.3Hz,1H),3.81(dd,J=13.5,11.0Hz,1H),2 .69–2.55(m,2H),2.31–2.21(m,1H),2.18(s,3H),1.53–1.35(m,3H),0.79(dd,J=6.6,4.6Hz,3H),0.72(d,J=6.4Hz,3H).

[0411] Example 42 Preparation of Compound (I-48)

[0412] Referring to Example 39, cyclopropanecarboxaldehyde was used instead of isobutylaldehyde to prepare compound (I-48). LC-MS: [M+1] + =586. 1 H NMR (400MHz, DMSO-d6) δ8.29–8.08(m,1H),7.89(d,J=10.0Hz,1H),7.79(d,J=8.5Hz,1H),7.70–7.55 (m,4H),6.50–6.38(m,1H),6.31(d,J=7.9Hz,1H),5.38(d,J=6.5Hz,2H),5.01–4.86(m,1H),4.65(t, J=9.1Hz,2H),4.55–4.37(m,2H),4.29(q,J=10.4,9.4Hz,1H),4.09–3.56(m,3H),2.89–2.78(m,1H), 2.65(d,J=11.1Hz,1H),2.28–2.19(m,1H),2.18–2.07(m,3H),1.02–0.76(m,2H),0.47–0.27(m,2H).

[0413] Example 43 Preparation of Compound (I-49)

[0414] Referring to Example 39, compound (I-49) was prepared by replacing isobutylaldehyde with pivalaldehyde. LC-MS: [M+1] + =602. 1 H NMR(400MHz, DMSO-d6)δ12.71(s,1H),8.17(dd,J=4.6,1.6Hz,1H),7.93–7.85(m,1H),7.79(dd,J=8.4,1.5Hz,1 H),7.68–7.53(m,4H),6.47(dd,J=7.9,2.1Hz,1H),6.29(dd,J=16.5,7.9Hz,1H),5.54–5.37(m,2H),5.15–5.07 (m,1H),4.91–4.84(m,1H),4.59–4.45(m,1H),4.43–4.35(m,1H),4.34–4.20(m,2H),3.90(t,J=13.7Hz,1H),3. 76(dd,J=13.5,2.3Hz,1H),2.74–2.59(m,2H),2.23–2.11(m,1H),2.07(d,J=14.7Hz,3H),0.76(d,J=3.6Hz,9H).

[0415] Example 44 Preparation of Compound (I-50)

[0416] Referring to Example 39, butyraldehyde was used instead of isobutyraldehyde to prepare compound (I-50). LC-MS: [M+1] + =588. 1HNMR (400MHz, DMSO-d6) δ12.56(s,1H),8.21(d,J=3.2,1.5Hz,1H),7.88(d,J=10.0Hz,1H),7.79(d,J=8.4Hz,1H),7.69–7.5 8(m,4H),6.46(dd,J=7.8,2.4Hz,1H),6.32(dd,J=7.9,2.8Hz,1H),5.51–5.37(m,2H),5.20–5.11(m,1H),5.03–4.92(m,1H), 4.74–4.63(m,1H),4.56–4.48(m,1H),4.46–4.39(m,1H),4.33–4.25(m,1H),3.93(d,J=13.4Hz,1H),3.87–3.77(m,1H),2.7 5–2.65(m,1H),2.61–2.52(m,2H),2.30–2.21(m,1H),2.17(s,3H),1.49–1.41(m,2H),1.17–1.08(m,2H),0.77–0.70(m,3H).

[0417] Example 45 Preparation of Compound (I-51)

[0418] Step 1

[0419]

[0420] Take phenylboronic acid (300mg, 1.0eq), 2-bromo-6-chloropyridine (473mg, 1.0eq) and dissolve in 10mL ethanol, sodium carbonate (521mg, 2.0eq) and tetrakis(triphenylphosphine)palladium (142mg, 0.5eq) in 5mL toluene, mix the solutions, and reflux at 90°C. TLC monitors the complete reaction of the raw materials. After the reaction is completed, the system is cooled, water is added to quench the reaction, EA is extracted, the organic phase is washed with saturated NaCl, dried over anhydrous sodium sulfate, and the organic phase is concentrated by rotary evaporation. Column chromatography purification: The crude product is dissolved in DCM and silica gel is added to mix the sample, and the dry-loading column chromatography is performed, and the column chromatography purification is performed with a PE / EA system to obtain 384mg of the product as a white solid, with a yield of 82%. LC-MS: [M+1] + =190, purity: 77.83% (254nm). 1 H NMR (400MHz, DMSO-d6) δ8.09–8.04(m,2H),8.03–7.90(m,2H),7.56–7.45(m,4H).

[0421]

[0422] Take tert-butyl (2-hydroxybutyl)carbamate (310 mg, 1.0 eq) and dissolve it in toluene (15 mL). Add 2-chloro-6-phenylpyridine (451 mg, 1.5 eq.) and Cs2CO3 (1.12 g, 2.0 eq.). Replace nitrogen three times. Then add Pd(OAc)2 (37 mg, 0.1 eq.),

[0423] 2-(Di-tert-butylphosphino)-1,1'-binaphthyl (255836-67-0) (98 mg, 0.15 eq.), replace nitrogen to ensure that the system is oxygen-free. Heat to 78°C and react overnight. TLC monitoring shows that new substances are generated and the raw materials react completely, so the reaction is stopped. The system is filtered with diatomaceous earth, rinsed with EA, and the filtrate is concentrated by rotary evaporation to obtain 700 mg of crude product. Column chromatography purification: The crude product is sanded and loaded by dry method. The product point is obtained when the eluent is PE:EA=50:1. Concentrate the eluent to obtain 382 mg of product, yield: 68.5%. LC-MS: [M+1] + =343, purity: 93.4% (254nm).

[0424]

[0425] Compound (51b) (353 mg, 1.0 eq.) was dissolved in anhydrous THF (8 mL), and NaH (217 mg, 5 eq.) was added. The mixture was stirred at room temperature for 30 min. 320 uL iodomethane (5 eq) was added to the system and stirred at room temperature for 15 h. TLC monitored the reaction to be complete, saturated NH4Cl was added to the system, the pH of the system was adjusted to be weakly acidic, and ethyl acetate was extracted 3 times. After the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 410 mg of a crude product. Column chromatography purification: The crude product was sanded and loaded by dry method. The product point was obtained when the eluent was PE:EA=80:1. The eluent was concentrated to obtain 290 mg of the product, with a yield of 79%. LC-MS: [M+1] + =357; purity: 99.3% (254nm). 1 H NMR (400MHz, DMSO-d6) δ8.11–8.01(m,2H),7.77(t,J=7.8Hz,1H),7.55–7.38(m,4H),6.79–6.66(m,1H),5.52(d, J=6.5Hz,1H),3.63–3.37(m,2H),2.81(s,3H),1.76–1.60(m,2H),1.32(d,J=18.5Hz,9H),0.96(t,J=7.4Hz,3H).

[0426] Referring to Example 2, compound (I-51) was prepared by replacing intermediate (6) with compound (51a). LC-MS: [M+1] + =501. 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),8.22(d,J=1.9Hz,1H),8.12–8.00(m,2H),7.84–7.73(m,2H),7.63(dd,J=8.4,1.3Hz,1H), 7.52(dd,J=7.4,3.0Hz,1H),7.50–7.36(m,3H),6.72(d,J=8.2Hz,1H),5.56–5.42(m,1H),5.03–4.91(m,1H),4.80–4.65(m,1H),4 .62–4.50(m,1H),4.45–4.34(m,1H),4.33–4.21(m,1H),4.01(t,J=13.0Hz,1H),3.86(dd,J=13.3,2.5Hz,1H),2.85–2.75(m,1H) ,2.73–2.63(m,1H),2.62–2.52(m,1H),2.28(s,3H),2.26–2.14(m,1H),1.82–1.70(m,1H),1.69–1.59(m,1H),0.89–0.84(m,3H).

[0427] Example 46 Preparation of Compound (I-52)

[0428] Step 1

[0429]

[0430] Dissolve phenylacetylene (300 mg, 1.05 eq) and 2-bromo-6-chloropyridine (538 mg, 1.0 eq) in anhydrous THF (10 mL) and replace with nitrogen until there are no bubbles. Add Pd(PPh3)2 (39 mg, 0.02 eq), CuI (21 mg, 0.04 eq), triethylamine (311 mg, 1.1 eq), replace with nitrogen 3 times, and protect with nitrogen. React at room temperature for 2.5 h. TLC monitors the reaction to be complete, the system is poured into water to quench, the aqueous phase is extracted with EA, the organic phase is washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Column chromatography purification: The product point is obtained when column chromatography (PE / EA=150:1). Concentrate the eluent to obtain 400 mg of the product with a yield of 64%. LC-MS: [M+1] + =214, purity 98.79% (254nm). 1H NMR (400MHz, DMSO-d6) δ7.93 (t, J=7.8Hz, 1H), 7.68 (dd, J=7.6, 0.8Hz, 1H), 7.66–7.61 (m, 2H), 7.56 (dd, J=8.1, 0.8Hz, 1H), 7.52–7.45 (m, 3H).

[0431]

[0432] Take 2-chloro-6-phenylethynylpyridine (400mg, 1.0eq) and tert-butyl (2-hydroxybutyl)carbamate (531mg, 1.0eq) and dissolve them in 15mL toluene. After adding cesium carbonate (1.22g, 2.0eq), replace nitrogen. Add Pd(OAc)2 (63mg, 0.15eq) and ligand 255836-67-0 (149mg, 0.2eq) and react in an oil bath at 78°C. TLC monitoring reaction is basically complete. After the reaction is completed, the system is cooled, filtered with diatomaceous earth, the filter cake is washed with EA, and the filtrate is dried to obtain a crude product. Column chromatography purification: After the crude product is dissolved, add silica gel to mix the sample, and dry-load column chromatography is performed, and column chromatography purification is performed with a PE / EA system to obtain 358mg of the product. LC-MS: [M+1] + =367, purity 83.79% (220nm).

[0433]

[0434] Compound (52b) (350 mg, 1.0 eq) was dissolved in 15 mL of anhydrous THF, and NaH (115 mg, 5.0 eq) was added and reacted at room temperature. TLC monitored that the reaction was basically complete. After the reaction was completed, the system was quenched with a saturated ammonium chloride solution and extracted with EA. The solution was spin-dried to obtain a crude product. Column chromatography purification: After the crude product was dissolved, silica gel was added to mix the sample, and dry-loaded column chromatography was performed, and column chromatography purification was performed with a PE / EA system to obtain 314 mg of the product. The yield was 86%. LC-MS: [M+1] + =381, purity 88.13% (254nm).

[0435] Referring to Example 2, compound (I-52) was prepared by replacing intermediate (6) with compound (52a). LC-MS: [M+1] + =525. 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.24(s,1H),7.79(s,1H),7.73(td,J=7.8,4.2Hz,1H),7.64(d,J=8.4Hz,1H),7.55(d,J=6.9Hz,2H ),7.49–7.36(m,3H),7.31–7.16(m,1H),6.81(d,J=8.4Hz,1H),5.31(q,J=6.0,5.4Hz,1H),5.01(t,J=7.4Hz,1H),4.74(td,J=16.2,7.4H z,1H),4.63–4.52(m,1H),4.50–4.40(m,1H),4.39–4.28(m,1H),4.11(d,J=13.5Hz,1H),4.01(d,J=13.4Hz,0H),3.87(dd,J=25.9,13.5H z,1H),2.73(dd,J=13.0,6.4Hz,1H),2.69–2.55(m,2H),2.39–2.21(m,4H),1.81–1.68(m,1H),1.66–1.54(m,1H),0.85(d,J=4.5Hz,3H).

[0436] Example 47 Preparation of Compound (I-53)

[0437] Step 1

[0438]

[0439] Dissolve dibromopyridine (2.0 g, 2.0 eq.) in toluene (30 mL), add tert-butyl (2-hydroxybutyl)carbamate (800 mg, 1.0 eq.) and cesium carbonate (2.75 g, 2.0 eq.), and replace nitrogen. Then add palladium acetate (95 mg, 0.1 eq.) and ligand (255836-67-0) (253 mg, 0.15 eq.) and replace nitrogen again until there is no oxygen in the reaction bottle. Then react in an oil bath at 100 ° C for 16 h. TLC monitoring shows that a new spot is generated. After the reaction is completed, the system is filtered with diatomaceous earth pads and the crude product is obtained after spin drying. Column chromatography purification: The crude product was dissolved in DCM and then wet loaded on a column chromatography, the stationary phase was 100-200 mesh silica gel, the eluent polarity was PE:EA = 25:1, the product came down, the eluent was dried by rotary evaporation, the product was a light yellow oil 144 mg, the yield was 10%. LC-MS: [M+1] + =345, purity 87.07% (254nm).

[0440]

[0441] Dissolve tert-butyl (2-(6-bromopyridin-2-yl)oxy)butyl)carbamate (0.29g, 1.0eq.) in anhydrous tetrahydrofuran (6mL), add NaH (0.13g, 4.0eq.), stir at room temperature for 0.5h, then add iodomethane (0.60g, 5.0eq.), stir at room temperature for 14h. TLC monitors the complete reaction of the raw materials. After the reaction, the system is adjusted to a neutral pH with ammonium chloride, extracted with EA three times, washed with saturated brine once, dried with anhydrous NaSO4, and spin-dried to obtain a crude product. Column chromatography purification: The crude product is dissolved in DCM and wet-loaded on a column chromatography, the stationary phase is 100-200 mesh silica gel, the product is eluted when the eluent polarity is PE:EA=50:1, and the eluent is spin-dried to obtain 232mg of the product as a light yellow oil, with a yield of 77%. LC-MS: [M+1] + =359, purity 90.90% (254nm). 1 H NMR (400MHz, DMSO-d6) δ7.63(d,J=7.2Hz,1H),7.18(d,J=7.5Hz,1H),6.81(d,J=9.1Hz,1H),5.23(s,1H),3.4 6(d,J=14.5Hz,1H),2.79(d,J=10.8Hz,3H),1.69–1.55(m,2H),1.32(d,J=25.2Hz,9H),0.91(t,J=7.4Hz,3H).

[0442]

[0443] Tert-butyl (2-(6-bromopyridin-2-yl)oxy)butyl)(methyl)carbamate (200 mg, 1.0 eq.) was dissolved in DCM (10 mL), and TFA (1.28 mL, 30.0 eq.) was added and reacted at room temperature for 40 min. The reaction was complete after TLC monitoring. The system was spin-dried and then dissolved in DCM and spin-dried to obtain a crude secondary amine product, which was directly fed to the next step. The secondary amine raw material was dissolved in acetonitrile (10 mL), potassium carbonate (367 mg, 5.0 eq.) and intermediate (2) (131 mg, 0.8 eq.) were added and reacted at room temperature for 15 h. TLC monitoring showed that the benzyl chloride raw material reacted completely. After the reaction was completed, the system was filtered with diatomaceous earth pads, the filter cake was washed with EA, and the filtrate was spin-dried to obtain a crude product. Column chromatography purification: The crude product was dry-loaded on a column chromatography, and the stationary phase was 100-200 mesh silica gel. When the polarity of the eluent was DCM:MeOH=120:1, the product came down, and the eluent was dried by spin drying to obtain 203 mg of the product as a light yellow oil, with a yield of 88%. LC-MS: [M+1] + =517, purity 86.75% (254nm).

[0444] Step 2

[0445]

[0446] Compound (53a) (168 mg, 1.0 eq.) was dissolved in tetrahydrofuran (6 mL), and 1.5 mL of LiOH (23 mg, 3.0 eq.) aqueous solution was slowly added. The mixture was placed in an oil bath at 40°C for 17 h. TLC monitoring showed that a small amount of raw materials remained. 1.0 eq of lithium hydroxide was added and the temperature was raised to 50°C for 1.5 h. After the reaction was completed, dilute hydrochloric acid was slowly added to the system to adjust the pH to weak acid. The system changed from clear to turbid and then restored to clear. The aqueous phase was extracted 3 times with EA, and the organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. Column chromatography purification: The crude product was dry-loaded on a column chromatography, and the stationary phase was 100-200 mesh silica gel. When the eluent polarity was DCM:MeOH=30:1, the product came out. After the eluent was spin-dried, 149 mg of the product was obtained as a yellow viscous substance, with a yield of 91%. LC-MS: [M+1] + =503, purity 94.84% (254nm).

[0447] Step 3

[0448]

[0449] Compound (53b) (120 mg, 1.0 eq) was dissolved in 3 mL K2CO3 (66 mg, 2.0 eq) was added to NMP; 2R, 4S-4-(3-chlorophenyl)-1,3,2-dioxaphosphine 2-oxide (118 mg, 1.5 eq) was dissolved in 3 mL NMP and placed in a constant pressure low liquid funnel, catalyst Pd(dppf)Cl2.DCM (19 mg, 0.1 eq) was added to the system, and nitrogen was replaced several times until the system was in an oxygen-free state; the system was placed in a 65°C oil bath and kept warm for 10 min, the constant pressure dropping funnel was quickly opened and the NMP solution of 2R, 4S-4-(3-chlorophenyl)-1,3,2-dioxaphosphine 2-oxide was dropped, and the reaction was carried out in an oil bath at 65°C; after the reaction was completed, DCM was added to dilute, filtered, and K2CO3 was removed; the organic phase was washed with water 4 times, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 430 mg of a crude product. Column chromatography purification: The crude product was dissolved in DCM and then silica gel was added to mix the sample. The product was purified by wet loading column chromatography using a DCM / MeOH system to obtain 150 mg of solid product. 70 mg was taken and purified by preparative plate to obtain 21 mg of white solid, with a yield of 27%. LC-MS: [M+1] + =656, purity: 95.5% (220nm). 1H NMR(600MHz,DMSO-d6)δ12.74(s,1H),8.23(dd,J=3.5,1.6Hz,1H),7.91–7.83(m,1H),7.82–7.74(m,1H),7.69–7.53(m,2H),7.4 9–7.31(m,4H),7.02–6.95(m,1H),5.85(d,J=11.3Hz,1H),5.38–5.25(m,1H),5.02–4.89(m,1H),4.74–4.62(m,2H),4.58–4.39(m ,3H),4.34–4.25(m,1H),3.96(dd,J=26.8,13.6Hz,1H),3.82(dd,J=13.5,7.8Hz,1H),2.80–2.69(m,1H),2.64(d,J=13.1Hz,1H) ,2.59–2.52(m,1H),2.49–2.42(m,1H),2.37–2.30(m,1H),2.28–2.18(m,3H),2.13(s,1H),1.72–1.53(m,2H),0.86–0.71(m,3H).

[0450] Activity test results

[0451] Activity test results (The activity test methods and results described below are provided by the commissioned test company Kanglong Chemical Co., Ltd.)

[0452] By using HEK293 cells with high expression of GLP-1 receptor, namely Flpin-293-GLP-1R (source: Humanembryonic kidney (Graham et al., 1977); supplier: Thermo Fisher Scientific; catalog number: CRL-1573), the activation activity of the new compound on the GLP-1 receptor was verified by detecting the changes in cAMP content. The cAMP detection kit (LANCEΜltra cAMP Detection Kit, Perkin Elmer, TRF0263) was used for detection. For detailed test principles, please refer to Μltra cAMP Kit-Perkin Elmer instructions.

[0453] Preparation of compounds: DMSO was used as solvent, the starting concentration of the test compound was 10 μM, and the starting concentration of the control compound was 0.1 nM, and they were diluted 4-fold, and 10 data points were taken for each.

[0454] Prepare cell suspension: resuspend the digested cells in 1*HBSS experimental buffer and seed them into 284 cell culture plates at a seeding density of 20,000 cells / 15 μl / well.

[0455] Determination of cAMP: After diluting the compound with experimental buffer, add 5 μl of compound to each well and incubate at 37 degrees for 30 minutes. Add 10 μl of diluted Eμ-cAMP tracer and Μlight-anti-cAMP to the experimental wells respectively, centrifuge quickly, incubate at 25 degrees for 1 hour, and collect data using Envision.

[0456] Data Analysis: (1) Calculate %Activity using the following formula:

[0457] %Activity=(Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )×100.

[0458] Cmpd is the compound, Ave_PC is the positive control, and Ave_VC is the negative control.

[0459] (2) Calculate compound EC50 using GraphPad nonlinear fitting formula

[0460] Y=Bottom+(Top-Bottom) / (1+10^((LogEC50-X)*HillSlope))

[0461] X: log value of compound concentration; Y: Activity%

[0462] The biologically active test structures of the compounds are listed in Table 1 below.

[0463] Among them, A=≤0.015μM, B=≤0.15μM, C=≤1μM, D=>1μM

[0464] Table 1 EC values ​​of compounds in HEK293T cells 50 value

[0465]

[0466]

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that: ； W is CH or N; Z is CH or N; n is 1, 2 or 3; R 1 is unsubstituted or substituted with one or more R 1-1 Substituted 6-10 membered aryl; Each R 1-1 are independently halogen, cyano, carboxyl, unsubstituted or substituted with one or more R 1-1-1 Substituted C1-C6 alkyl or unsubstituted or with one or more R 1-1-2 Substituted C1-C6 alkoxy; Each R 1-1-1 and R 1-1-2 are independently halogen; L1 is -(CH2) p -; p is 1, 2 or 3; L2 is unsubstituted or replaced by one or more L 2-1 Substituted -(CH2) q -; q is 1, 2 or 3; Each L 2-1 are independently unsubstituted or substituted with one or more L 2-1-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more L 2-1-2 substituted 6-10 membered aryl, unsubstituted or substituted with one or more L 2-1-3 substituted 5-10 membered heteroaryl or unsubstituted or substituted with one or more L 2-1-4 A substituted 3-6 membered cycloalkyl group; the heteroatom of the 5-10 membered heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each L 2-1-1 , L 2-1-2 , L 2-1-3 and L 2-1-4 are independently cyano, carboxyl or phenyl; L3 does not exist, , , , , or unsubstituted or replaced by one or more L 3 -1 Replaced ; m is 1, 2 or 3; T is absent, O, NH or S; Each L 3-1 are independently C1-C6 alkyl; The ring Cy is unsubstituted or substituted with one or more Cy -1 substituted 6-10 membered heteroaromatic ring; the heteroatom of the 6-10 membered heteroaromatic ring is selected from one or more of N and O, and the number of heteroatoms is 1, 2 or 3; each Cy -1 are independently halogen or C1-C6 alkyl; X and Y are independently -N(R 4 )-, -O-, -S- or unsubstituted or substituted by one or two R 5 Substituted -CH2-; R 4 is hydrogen, 6-10 membered aryl or 5-10 membered heteroaryl or is unsubstituted or substituted by one or more R 4-1 Substituted C1-C6 alkyl; each R 4-1 are independently carboxyl, C1-C6 alkoxy or 6-10 membered aryl; the heteroatoms of the 5-10 membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 5 are independently unsubstituted or substituted with one or more R 5-1 Substituted C1-C6 alkyl; each R 5-1 are independently C1-C6 alkoxy or 6-10 membered aryl; R 2 is hydrogen, unsubstituted or replaced by one or more R 2-1 Substituted C1-C6 alkyl or unsubstituted or with one or more R 2-2 Substituted C1-C6 alkoxy; Each R 2-1 and R 2-2 are independently halogen, C1-C6 alkoxy, 3-6 membered heterocycloalkyl or unsubstituted or substituted by one or more R 2 -1-1 substituted 5-10 membered heteroaryl; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5-10 membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 2-1-1 are independently C1-C6 alkyl; Each R 3 are independently carboxyl or -C(=O)-NH2; Each R 3-1 and R 3-2 are independently halogen.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Each L 2-1 are independently unsubstituted or substituted with one or more L 2-1-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more L 2-1-2 Substituted 6-10 membered aryl or unsubstituted or substituted by one or more L 2-1-3 Substituted 5-10 membered heteroaryl; the heteroatom of the 5-10 membered heteroaryl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Each L 2-1 are independently unsubstituted or substituted with one or more L 2-1-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more L 2-1-2 Substituted phenyl, unsubstituted or replaced by one or more L 2-1-3 substituted 5-6 membered heteroaryl or unsubstituted or substituted by one or more L 2-1-4 The heteroatom of the 5-6 membered heteroaryl is N, O or S, and the number of the heteroatom is 1.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: L3 does not exist, , or unsubstituted or replaced by one or more L 3-1 Replaced ; m is 1, 2 or 3; T is absent, O, NH or S.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: L3 does not exist, , , or unsubstituted or replaced by one or more L 3-1 Replaced ; m is 1, 2 or 3; T is absent, O or NH.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 4 is hydrogen, phenyl or unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl; each R 4-1 are independently carboxyl, C1-C6 alkoxy or phenyl.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 4 is hydrogen, phenyl, unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl; R 4-1 It is a C1-C6 alkoxy group or a carboxyl group.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 4 It is phenyl or C1-C6 alkyl which is unsubstituted or substituted by carboxyl.

9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Each R 5 are independently C1-C6 alkyl.

10. 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 or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) R 1 wherein the 6-10 membered aryl group is a phenyl group or a naphthyl group; (2) Each R 1-1 wherein the halogen is fluorine, chlorine, bromine or iodine; (3) Each R 1-1 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (4) Each R 1-1 wherein the C1-C6 alkoxy group is a C1-C4 alkoxy group; (5) Each R 1-1-1 wherein the halogen is fluorine, chlorine, bromine or iodine; (6) Each R 1-1-2 wherein the halogen is fluorine, chlorine, bromine or iodine; (7) Each L 2-1 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (8) Each L 2-1 wherein the 6-10 membered aryl group is phenyl or naphthalene; (9) Each L 2-1 In the above, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group; (10) Each L 2-1 wherein the 3-6 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (11) Each L 3-1 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (12) In the ring Cy, the 6-10 heteroaromatic rings are or a benzo 5-membered heterocyclic ring, Z1, Z2 and Z3 are independently N or CH, the heteroatom of the 5-membered heterocyclic ring is O, and the number of heteroatoms is 1 or 2; (13) Each Cy -1 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (14) Each Cy -1 wherein the halogen is fluorine, chlorine, bromine or iodine; (15) R 4 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (16) R 4 wherein the 6-10 membered aryl group is a phenyl group or a naphthyl group; (17) R 4 In the above, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group; (18) Each R 4-1 wherein the C1-C6 alkoxy group is a C1-C4 alkoxy group; (19) Each R 4-1 wherein the 6-10 membered aryl group is a phenyl group or a naphthyl group; (20) Each R 5 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (21) Each R 5-1 wherein the C1-C6 alkoxy group is a C1-C4 alkoxy group; (22) Each R 5-1 wherein the 6-10 membered aryl group is a phenyl group or a naphthyl group; (23) R 2 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (24) R 2 wherein the C1-C6 alkoxy group is a C1-C4 alkoxy group; (25) Each R 2-1 wherein the halogen is fluorine, chlorine, bromine or iodine; (26) Each R 2-1 wherein the C1-C6 alkoxy group is a C1-C4 alkoxy group; (27) Each R 2-1 wherein the heteroatom of the 3-6 membered heterocycloalkyl is N, S or O, and the number of heteroatoms is 1; (28) Each R 2-1 wherein the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, the heteroatom of the 5-10 membered heteroaryl group is N, and the number of heteroatoms of the 5-10 membered heteroaryl group is 1, 2 or 3; (29) Each R 2-2 wherein the halogen is fluorine, chlorine, bromine or iodine; (30) Each R 2-2 wherein the C1-C6 alkoxy group is a C1-C4 alkoxy group; (31) Each R 2-2 wherein the heteroatom of the 3-6 membered heterocycloalkyl is N, S or O, and the number of heteroatoms is 1; (32) Each R 2-2 wherein the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group, the heteroatom of the 5-10 membered heteroaryl group is N, and the number of heteroatoms of the 5-10 membered heteroaryl group is 1, 2 or 3; (33) Each R 2-1-1 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (34) Each R 3 wherein the halogen is fluorine, chlorine, bromine or iodine; (35) Each R 3 wherein the C1-C6 alkoxy group is a C1-C4 alkoxy group; (36) Each R 3 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; (37) Each R 3-1 wherein the halogen is fluorine, chlorine, bromine or iodine; (38) Each R 3-2 wherein the halogen is fluorine, chlorine, bromine or iodine; (39) R 4 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and (40) each R 5 In the above, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

11. 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 or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) R 1 wherein the 6-10 membered aryl group is a phenyl group; (2) Each R 1-1 wherein the halogen is fluorine or chlorine; (3) Each R 1-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (4) Each R 1-1 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (5) Each R 1-1-1 wherein the halogen is fluorine, chlorine, bromine or iodine; (6) Each R 1-1-2 wherein the halogen is fluorine, chlorine, bromine or iodine; (7) Each L 2-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, isobutyl or tert-butyl; (8) Each L 2-1 wherein the 6-10 membered aryl group is a phenyl group; (9) Each L 2-1 wherein the 5-10 membered heteroaryl is furyl, thienyl or pyridyl; (10) Each L 2-1 wherein the 3-6 membered cycloalkyl group is a cyclopropyl group; (11) Each L 3-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (12) In the ring Cy, the 6-10 heteroaromatic rings are or a benzo 5-membered heterocyclic ring, Z1, Z2 and Z3 are independently N or CH, the heteroatom of the 5-membered heterocyclic ring is O, and the number of heteroatoms is 1 or 2; the benzo 5-membered heterocyclic ring is ; is a pyridine ring or a pyrazine ring; (13) Each Cy -1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (14) Each Cy -1 wherein the halogen is fluorine; (15) R 4 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (16) R 4 wherein the 6-10 membered aryl group is a phenyl group; (17) R 4 wherein the 5-10 membered heteroaryl is furyl, thienyl or pyridyl; (18) Each R 4-1 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (19) Each R 4-1 wherein the 6-10 membered aryl group is a phenyl group; (20) Each R 5 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (21) Each R 5-1 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (22) Each R 5-1 wherein the 6-10 membered aryl group is a phenyl group; (23) R 2 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (24) R 2 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (25) Each R 2-1 wherein the halogen is fluorine or chlorine; (26) Each R 2-1 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (27) Each R 2-1 wherein the 3-6 membered heterocycloalkyl is oxetane; (28) Each R 2-1 wherein the 5-10 membered heteroaryl group is imidazolyl; (29) Each R 2-2 wherein the halogen is fluorine or chlorine; (30) Each R 2-2 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (31) Each R 2-2 wherein the heteroatom of the 3-6 membered heterocycloalkyl is N, S or O, and the number of heteroatoms is 1; (32) Each R 2-2 wherein the 5-10 membered heteroaryl group is imidazolyl; (33) Each R 2-1-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (34) Each R 3 wherein the halogen is fluorine, chlorine, bromine or iodine; (35) Each R 3 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (36) Each R 3 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (37) Each R 3-1 wherein the halogen is fluorine, chlorine, bromine or iodine; (38) Each R 3-2 wherein the halogen is fluorine, chlorine, bromine or iodine; (39) R 4 In which the C1-C6 alkyl group is a methyl group; and (40) each R 5 In the above, the C1-C6 alkyl group is an ethyl group.

12. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The compound as shown in Formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) W is N; (2) Z is CH; (3) n is 1; (4) R 1 is unsubstituted or substituted with one or more R 1-1 Substituted phenyl; (5) Each R 1-1 are independently halogen or cyano; (6) p is 1 or 2; (7) q is 2 or 3; (8) m is 1; (9) T is O or NH; (10) Ring Cy is unsubstituted or replaced by a Cy -1 Substituted: pyridine ring, pyrazine ring or benzo 5-membered heterocyclic ring; the heteroatom of the 5-membered heterocyclic ring is O, and the number of heteroatoms is 1 or 2; (11) Each Cy -1 are independently halogen; (12) Each L 2-1 are independently unsubstituted or substituted with one or more L 2-1-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more L 2-1-2 Substituted phenyl or unsubstituted or with one or more L 2-1-3 A substituted 5-6 membered heteroaryl group; the heteroatom of the 5-6 membered heteroaryl group is N, O or S, and the number of heteroatoms is 1; (13) L3 is absent, unsubstituted or replaced by one or more L 3-1 Replaced ; m is 1, 2 or 3; T is absent, O or NH; (14) Each R 4-1 are independently carboxyl, C1-C6 alkoxy or phenyl; (15) Each R 5 are independently unsubstituted C1-C6 alkyl; (16) R 2 is unsubstituted or substituted with one or more R 2-1 Substituted C1-C6 alkyl; (17) Each R 2-1 is independently C1-C6 alkoxy, 3-6 membered heterocycloalkyl or unsubstituted or substituted with one or more R 2-1-1 substituted 5-6 membered heteroaryl; the heteroatom of the 3-6 membered heterocycloalkyl is N, S or O, and the number of heteroatoms is 1; the heteroatom of the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; (18) Each R 3 are independently carboxyl; (19) R 1 is phenyl or is replaced by one or two R 1-1 Substituted phenyl; (20) X is -N(R 4 )-, -O- or -S-, R 4 is hydrogen or unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl; each R 4-1 are independently carboxyl, C1-C6 alkoxy or phenyl; and (21)Y is -N(R 4 )-, -O- or -S-, R 4 It is hydrogen, unsubstituted C1-C6 alkyl, -CH2COOH or phenyl.

13. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: for ; Or X is -O-, Y is -N(R 4 )-or-O-, R 4 is hydrogen or unsubstituted C1-C6 alkyl, L2 is unsubstituted or replaced by one or more L 2-1 Substituted -(CH2) q -; q is 2; each L 2-1 are independently methyl, ethyl or isopropyl.

14. 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 or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) R 1 for , , , , or ; (2) L3 does not exist, , , or ; (3) Ring Cy is , , , or ; (4) X is , , , , , , , , or ; (5) Y is , , , , , , , , , , or ; (6) L1 is -CH2-; (7) L2 is -CH(Bn)-, -CH2-, -CH(CH2CH3)-, , , , , , , -CH2-CH2-, -CH(CH3)-CH2-, -CH(CH2CH3)-CH2-, -C(CH3)2-CH2-, -CH(Ph)-CH2- or -CH(Bn)-CH2-; and (8) R 2 for , , or .

15. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, characterized in that: The compound as shown in Formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (2) L3 does not exist, , , or , r and R 1 connected, s is connected to the ring Cy; (7) L2 is -CH2-, c-CH(CH2CH3)-d, , , , , , , , , , , , , -CH2-CH2-, c-CH(CH3)-CH2-d, d-CH(CH3)-CH2-c, c-CH(CH2CH3)-CH2-d, d-CH(CH2CH3)-CH2-c, cC(CH3)2-CH2-d, dC(CH3)2-CH2-c, c-CH(Ph)-CH2-d, d-CH(Ph)-CH2-c, c-CH(Bn)-CH2-d or d-CH(Bn)-CH2-c, wherein c is connected to X and d is connected to Y.

16. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, characterized in that: for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

17. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, characterized in that: for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , where the a-end is connected to Cy and the b-end is connected to L1.

18. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, characterized in that: for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

19. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, characterized in that: for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , where the a-end is connected to Cy and the b-end is connected to L1.

20. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, characterized in that: for , , , , , , , , , , , , or .

21. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

22. A pharmaceutical composition comprising substance Z and pharmaceutical excipients, characterized in that: The substance Z is a compound as shown in formula I according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

23. Use of a substance Y in the preparation of a cAMP agonist or a drug for treating and / or preventing a cAMP-related disease, characterized in that: The substance Y is a compound as shown in formula I according to any one of claims 1 to 21, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22.

24. The use according to claim 23, wherein the cAMP-related disease is diabetes or a related disease caused by diabetic complications.

25. The use according to claim 24, wherein the diabetes is type 2 diabetes, gestational diabetes, hyperglycemia, insulin resistance or malnutrition-related diabetes.

26. The use according to claim 24, wherein the related diseases caused by diabetic complications are diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hyperinsulinemia, NAFLD, cardiovascular disease, endothelial dysfunction, poor vascular compliance, traumatic brain injury, intermittent claudication, postprandial lipemia, stroke, peripheral vascular disease, vascular restenosis, inflammatory bowel disease, Alzheimer's disease, schizophrenia, hypertension or impaired cognitive function.

27. The use according to claim 26, wherein the cardiovascular disease is atherosclerosis, coronary artery disease, congestive heart failure, angina pectoris or myocardial infarction.

28. The use according to claim 26, wherein the stroke is hemorrhagic stroke or ischemic stroke; and the hypertension is pulmonary hypertension.

29. The use according to claim 26, wherein the vascular restenosis is restenosis after angioplasty; and the inflammatory bowel disease is ulcerative colitis.

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