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

Abstract

The present invention discloses a penta-hexa-membered compound, its intermediate, preparation method, composition, and application. The present invention provides a compound represented by Formula III, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt. The compound of the present invention has good affinity for the FXR receptor and can induce the expression of FXR downstream target genes at the cellular level. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a penta-hexa-membered compound, an intermediate thereof, a preparation method, a composition and an application. Background Art

[0002] The farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-activated transcription factor (DJ Mangelsdorf, et al., Cell, 1995, 83(6), 841-850). There are four subtypes, which are widely distributed in tissues and organs such as the liver, intestines, and kidneys. FXR can be activated by endogenous ligands bile acids (Makishima M, et al. Identification of a Nuclear Receptor for Bile Acids. Science 1999, 284(5418), 1362-1365; Wang H, et al. Endogenous bile acids are ligands for the nuclear receptor FXR / BAR. Molecular cell 1999, 3(5), 543-53.), and is directly or indirectly involved in the transcriptional regulation of more than 40 downstream target genes. FXR is crucial for regulating metabolism and maintaining homeostasis of bile acids, lipids, and glucose in the body. Due to its multiple important roles in the body, FXR is considered an important target for the treatment of diseases such as hepatitis and liver fibrosis, diabetes, and obesity.

[0003] Reported FXR agonists can be divided into two main categories: steroidal, exemplified by Intercept's obeticholic acid (OCA); and nonsteroidal, often designed and synthesized based on earlier-developed compounds such as GW4604 (WO2000037077). Several FXR agonists, including OCA, EDP-305, cilofexor, tropifexor, WAY-450, and EYP001, have been or are currently in clinical development. Steroidal FXR agonists (such as OCA) have been associated with pruritus and effects on cholesterol metabolism (increasing serum total cholesterol and low-density lipoprotein cholesterol levels and decreasing high-density lipoprotein cholesterol). Nonsteroidal FXR agonists are believed to have the potential to mitigate and avoid drug-related side effects and are therefore a current development priority. Summary of the Invention

[0004] In order to solve the problems in the prior art, the present invention provides an FXR agonist, specifically a penta- and hexa-membered compound, an intermediate thereof, a preparation method, a composition and an application.

[0005] The present invention provides a compound as shown in Formula III, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0006]

[0007] W is CH or N;

[0008] Z is CH or N;

[0009] n is 1, 2, or 3;

[0010] L2 is unsubstituted or replaced by one or more L 2-1 Substituted -(CH2) q - or unsubstituted or replaced by one or more L 2-2 Substituted 1-10 membered heteroalkyl; q is 1, 2 or 3; the heteroatoms of the 1-10 membered heteroalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0011] 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 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;

[0012] Each L 2-1-1 、L 2-1-2 and L 2-1-3 are independently cyano, carboxyl or phenyl;

[0013] Each L 2-2 are independently C1-C6 alkyl;

[0014] Ring Cy is unsubstituted or substituted with one or more Cy -1 A substituted 5-10 membered heteroaromatic ring; the heteroatoms of the 5-10 membered heteroaromatic ring are selected from one or more of N and O, and the number of heteroatoms is 1, 2 or 3;

[0015] Each Cy -1 is independently C3-C9 cycloalkyl, unsubstituted or substituted with one or more Cy -1-1 substituted 6-10 membered aryl, halogen or C1-C6 alkyl;

[0016] Each Cy -1-1 are independently C3-C6 cycloalkyl, halogen, unsubstituted or substituted with one or more Cy -1-1-1Substituted C1-C6 alkyl or unsubstituted or with one or more Cy -1-1-2 Substituted C1-C6 alkoxy;

[0017] Each Cy -1-1-1 and Cy -1-1-2 are independently halogen;

[0018] X and Y are independently -N(R 4 )-, -O-, -S- or unsubstituted or replaced by one or two R 5 substituted -CH2-;

[0019] R 4 is hydrogen, C3-C6 cycloalkyl, C2-C6 alkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or unsubstituted or substituted by one or more R 4-1 Substituted C1-C6 alkyl; the heteroatoms of the 5-10 membered heteroaryl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0020] Each R 4-1 are independently carboxyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)-R 4-1-1 or a 6-10 membered aryl group;

[0021] R 4-1-1 -NR a R b 、-OR a , C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; 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; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0022] R a and R b are independently hydrogen, unsubstituted or replaced by one or more R a-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, unsubstituted or replaced by one or more R a-2 A substituted 6-10 membered aryl or 5-10 membered heteroaryl group; the heteroatoms of the 5-10 membered heteroaryl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0023] Each R a-1 are independently C1-C6 alkyl, C1-C6 alkoxy or 6-10 membered aryl;

[0024] Each R a-2are independently halogen, unsubstituted or substituted with one or more R a-1-1 Substituted C1-C6 alkyl or unsubstituted or with one or more R a-1-2 Substituted C1-C6 alkoxy;

[0025] Each R a-1-1 are independently halogen;

[0026] Each R a-1-2 are independently halogen;

[0027] 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;

[0028] Each R 3 are independently hydrogen, carboxyl, halogen, -C(=O)-NH2, -C(=O)-NH-R 3-3 , unsubstituted or replaced by one or more R 3-4 substituted 6-10 membered aryl, 5-10 membered heteroaryl, cyano, unsubstituted or replaced by one or more R 3-1 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-2 Substituted C1-C6 alkoxy; the heteroatoms of the 5-10 membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0029] Each R 3-1 and R 3-2 are independently halogen;

[0030] R 3-3 is unsubstituted or replaced by one or more R 3-3-1 Substituted C1-C6 alkyl;

[0031] Each R 3-3-1 are independently sulfonic acid or carboxyl;

[0032] Each R 3-4 are independently carboxyl, halogen or 5-6 membered heteroaryl; the heteroatom of the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1, 2, 3 or 4.

[0033] In a preferred embodiment, a five-membered and six-membered compound as shown in formula III 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 embodiment of the present invention (hereinafter referred to as "in a preferred embodiment"). In L2, the heteroatom of the 1-10 membered heteroalkyl group may be N, O or S; the number of heteroatoms of the 1-10 membered heteroalkyl group may be 1, 2 or 3; the 1-10 membered heteroalkyl group may be a 2-6 membered heteroalkyl group, and may also be

[0034] In a preferred embodiment, each L 2-1 In a preferred embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, a propyl group or an isopropyl group. 2-1 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.

[0035] In a preferred embodiment, each L 2-2 In the example, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, and also a methyl group.

[0036] In a preferred embodiment, each L 3-1 In the example, 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.

[0037] In a preferred embodiment, in the ring Cy, the 5-10 heteroaromatic rings may be 5-membered heteroaromatic rings, the heteroatoms of the 5-membered heteroaromatic rings may be O and / or N, and the number of heteroatoms may be 1 or 2, for example In a preferred embodiment, each Cy -1 In the embodiment, the C3-C9 cycloalkyl group may be a spirocyclic ring or a monocyclic ring; for example

[0038] In a preferred embodiment, each Cy -1 In a preferred embodiment, each Cy -1 In a preferred embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and methyl. -1 In the embodiment, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0039] In a preferred embodiment, each Cy -1-1 In the embodiment, the C3-C6 cycloalkyl group may be For example In a preferred embodiment, each Cy -1-1 In one preferred embodiment, each Cy -1-1 In a preferred embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and methyl. -1-1 In the embodiment, 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 a methoxy group.

[0040] In a preferred embodiment, each Cy -1-1-1 and Cy -1-1-2 In the embodiment of the present invention, the halogen can independently be fluorine, chlorine, bromine or iodine, for example fluorine.

[0041] In a preferred embodiment, R 4 In the embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and also such as methyl, ethyl or isopropyl. In a preferred embodiment, R 4 In a preferred embodiment, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group. 4 In the embodiment, the 5-10 membered heteroaryl group may be a 5-6 membered heteroaryl group, such as a furyl group, a thienyl group or a pyridyl group. 4 In the embodiment, the C3-C6 cycloalkyl group may be For example In a preferred embodiment, R 4 In the example, the C2-C6 alkenyl group may be vinyl, For example, vinyl. In a preferred embodiment, R 4 In the embodiment, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group.

[0042] In a preferred embodiment, each R 4-1 In a preferred embodiment, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; and another example is methoxy. 4-1 In a preferred embodiment, each R 5In the embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and also such as methyl, ethyl or isopropyl. In a preferred embodiment, each R 4-1 In the example, the C2-C6 alkenyl group may be vinyl, For example, vinyl.

[0043] In a preferred embodiment, R 4-1-1 In the embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and also such as methyl. 4-1-1 In the embodiment, the C3-C6 cycloalkyl group may be In a preferred embodiment, each R 4-1-1 wherein the heteroatom of the 3-6 membered heterocycloalkyl group is N; the number of heteroatoms of the 3-6 membered heterocycloalkyl group is preferably 1 or 2, and the 3-6 membered heterocycloalkyl group is preferably a 5-6 membered heterocycloalkyl group, for example In a preferred embodiment, R 4-1-1 In a preferred embodiment, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group. 4-1-1 In the 5-10 membered heteroaryl, the heteroatom is N and / or O, and the number of heteroatoms is 1 or 2, such as pyridyl.

[0044] In a preferred embodiment, R a and R b In the embodiment, the C1-C6 alkyl group may be independently a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and also such as methyl, ethyl, n-propyl or isopropyl. In a preferred embodiment, R a and R b In the embodiment, the C3-C6 cycloalkyl group can be independently For example In a preferred embodiment, R a and R b In a preferred embodiment, R a and R b wherein the heteroatoms of the 5-10 membered heteroaryl group are N and / or O, and the number of heteroatoms is 1 or 2, such as pyridyl or benzopyridyl, and also such as

[0045] In a preferred embodiment, R a-1In the embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and also such as methyl. a-1 In a preferred embodiment, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, and also such as methoxy. a-1 In the embodiment, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, for example, a phenyl group,

[0046] In a preferred embodiment, R a-2 In a preferred embodiment, R a-2 In the embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and also such as methyl. a-2 In the embodiment, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, and also such as methoxy.

[0047] In a preferred embodiment, each R 5 In the example, 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.

[0048] In a preferred embodiment, each R 5-1 In a preferred embodiment, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; and another example is methoxy. 5-1 In the embodiment, the 6-10 membered aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group.

[0049] In a preferred embodiment, each R 3 In one preferred embodiment, each R 3 In a preferred embodiment, each R 3 In a preferred embodiment, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group. 3In one preferred embodiment, each R 3 In the embodiment, 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 may be 1, 2 or 3.

[0050] In a preferred embodiment, each R 3-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0051] In a preferred embodiment, each R 3-2 In the above, the halogen may be fluorine, chlorine, bromine or iodine.

[0052] In a preferred embodiment, each R 3-3 In the example, 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.

[0053] In a preferred embodiment, each R 3-4 In one preferred embodiment, each R 3-4 In the embodiment, 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.

[0054] In a preferred embodiment, W is N.

[0055] In a preferred embodiment, Z is CH.

[0056] In a preferred embodiment, n is 2.

[0057] In a preferred embodiment, L2 is unsubstituted or replaced by one or more L 2-2 Substituted 2-6 membered heteroalkyl; q is 1, 2 or 3; the heteroatom of the 2-6 membered heteroalkyl is selected from one or more of N, O and S, and the number of heteroatoms is 1.

[0058] In a preferred embodiment, each L 2-2 are independently C1-C6 alkyl.

[0059] In a preferred embodiment, the ring Cy is unsubstituted or substituted with one or more Cy -1 a substituted 5-6 membered heteroaromatic ring; wherein the heteroatoms of the 5-6 membered heteroaromatic ring are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0060] In a preferred embodiment, each Cy -1 is independently C3-C9 cycloalkyl, unsubstituted or substituted with one or more Cy -1-1Substituted 6-10 membered aryl, halogen or C1-C6 alkyl.

[0061] In a preferred embodiment, each Cy -1-1 are independently unsubstituted or substituted with one or more Cy -1-1-2 Substituted C1-C6 alkoxy.

[0062] In a preferred embodiment, each Cy -1-1-2 are independently halogen.

[0063] In a preferred embodiment, X is -CH2-.

[0064] In a preferred embodiment, Y is -NR 4 -.

[0065] In a preferred embodiment, R 4 is hydrogen, C3-C6 cycloalkyl, C2-C6 alkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or unsubstituted or substituted by one or more R 4-1 substituted C1-C6 alkyl; 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.

[0066] In a preferred embodiment, each R 4-1 are independently carboxyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)-R 4 -1-1 or a 6-10 membered aryl group.

[0067] In a preferred embodiment, R 4-1-1 -NR a R b 、-OR a , C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; 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; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0068] In a preferred embodiment, R a and R b are independently hydrogen, unsubstituted or replaced by one or more R a-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, unsubstituted or replaced by one or more R a-2 a substituted 6-10 membered aryl group or a 5-10 membered heteroaryl group; the heteroatoms of the 5-10 membered heteroaryl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0069] In a preferred embodiment, each R a-1 are independently C1-C6 alkyl, C1-C6 alkoxy or 6-10 membered aryl.

[0070] In a preferred embodiment, each R a-2 are independently halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0071] In a preferred embodiment, each R 3 are independently hydrogen, carboxyl or halogen.

[0072] In a preferred embodiment, L2 is unsubstituted or replaced by one or more L 2-2 Substituted 2-6 membered heteroalkyl; q is 1, 2 or 3; the heteroatom of the 2-6 membered heteroalkyl is N, and the number of heteroatoms is 1.

[0073] In a preferred embodiment, the ring Cy is unsubstituted or substituted with one or more Cy -1 A substituted 5-6 membered heteroaromatic ring; the heteroatoms of the 5-6 membered heteroaromatic ring are selected from N and / or O, and the number of heteroatoms is 2.

[0074] In a preferred embodiment, each Cy -1 is independently C3-C6 cycloalkyl or unsubstituted or substituted by one or more Cy -1-1 Substituted 6-10 membered aryl.

[0075] In a preferred embodiment, R 4 is hydrogen or unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl.

[0076] In a preferred embodiment, R 4-1 -C(=O)-R 4-1-1 .

[0077] In a preferred embodiment, R 4-1-1 -NR a R b .

[0078] In a preferred embodiment, R a and R b are independently hydrogen or unsubstituted or replaced by one or more R a-1 Substituted C1-C6 alkyl.

[0079] In a preferred embodiment, each R a-1 are independently 6-10 membered aryl groups.

[0080] In a preferred embodiment, each R 3 are independently hydrogen, carboxyl or halogen.

[0081] In a preferred embodiment,

[0082] W is N; Z is CH; n is 2;

[0083] L2 is unsubstituted or replaced by one or more L 2-2 substituted 2-6 membered heteroalkyl; q is 1, 2 or 3; the heteroatom of the 2-6 membered heteroalkyl is selected from one or more of N, O and S, and the number of heteroatoms is 1; each L 2-2 are independently C1-C6 alkyl;

[0084] Ring Cy is unsubstituted or substituted with one or more Cy -1 substituted 5-6 membered heteroaromatic ring; the heteroatoms of the 5-6 membered heteroaromatic ring are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; each Cy -1 is independently C3-C9 cycloalkyl, unsubstituted or substituted with one or more Cy -1-1 substituted 6-10 membered aryl, halogen or C1-C6 alkyl; each Cy -1-1 are independently unsubstituted or substituted with one or more Cy -1-1-2 Substituted C1-C6 alkoxy; each Cy -1-1-2 are independently halogen;

[0085] X is -CH2-; Y is -NR 4 -;

[0086] R 4 is hydrogen, C3-C6 cycloalkyl, C2-C6 alkenyl, 6-10 membered aryl, 5-10 membered heteroaryl, or unsubstituted or substituted by one or more R 4-1 Substituted C1-C6 alkyl; the heteroatoms of the 5-10 membered heteroaryl group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0087] Each R 4-1 are independently carboxyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)-R 4-1-1 or 6-10 membered aryl; R 4 -1-1 -NR a R b 、-OR a , C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; 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; the heteroatoms of the 3-6 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0088] R a and R b are independently hydrogen, unsubstituted or replaced by one or more R a-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, unsubstituted or replaced by one or more R a-2 substituted 6-10 membered aryl or 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; each R a-1 are independently C1-C6 alkyl, C1-C6 alkoxy or 6-10 membered aryl; each R a-2 are independently halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0089] In a preferred embodiment,

[0090] L2 is unsubstituted or replaced by one or more L 2-2 substituted 2-6 membered heteroalkyl; q is 1, 2 or 3; the heteroatom of the 2-6 membered heteroalkyl is N, and the number of heteroatoms is 1; each L 2-2 are independently C1-C6 alkyl;

[0091] Ring Cy is unsubstituted or substituted with one or more Cy -1 Substituted 5-6 membered heteroaromatic ring; the heteroatom of the 5-6 membered heteroaromatic ring is selected from N and / or O, and the number of heteroatoms is 2; each Cy -1 is independently C3-C6 cycloalkyl or unsubstituted or substituted by one or more Cy -1-1 Substituted 6-10 membered aryl; each Cy -1-1 are independently unsubstituted or substituted with one or more Cy -1-1-2 Substituted C1-C6 alkoxy; each Cy -1-1-2 are independently halogen;

[0092] X is -CH2-; Y is -NR 4 -;

[0093] R 4 is hydrogen or unsubstituted or replaced by one R 4-1 Substituted C1-C6 alkyl; R 4-1 -C(=O)-R 4-1-1 ; R 4-1-1 -NR a R b ;

[0094] R a and R b are independently hydrogen or unsubstituted or replaced by one or more R a-1 Substituted C1-C6 alkyl; each R a-1 are independently 6-10 membered aryl groups;

[0095] Each R 3 are independently hydrogen, carboxyl or halogen.

[0096] In a preferred embodiment, the compound represented by formula III may be a compound represented by formula III-a or III-b:

[0097]

[0098] In a preferred embodiment, Y is

[0099] In a preferred embodiment, L2 is V1 is connected to the X terminal, and V2 is connected to the Y terminal.

[0100] In a preferred embodiment, each R 3 are independently carboxyl, methyl, methoxy, halogen,

[0101] In a preferred embodiment, the compound represented by formula III is any one of the following compounds:

[0102]

[0103]

[0104]

[0105]

[0106] The present invention also provides a compound as shown in formula IV or a salt thereof,

[0107]

[0108] Among them, Cy -1 、Cy -1-1-1 and L2 as described above.

[0109] In a preferred embodiment, the compound represented by formula IV is any one of the following compounds:

[0110]

[0111] The present invention also provides the following compounds

[0112] The present invention also provides a pharmaceutical composition comprising a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound as shown in Formula III, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0113] The present invention also provides a use of a substance Y in the preparation of an FXR agonist or a drug for treating and / or preventing FXR-related diseases, wherein the substance Y is a compound as shown in Formula III as described above, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0114] The present invention also provides a method for treating and / or preventing FXR-related diseases, comprising administering to a patient an effective amount of a substance Z, wherein the substance Z is a compound as shown in Formula III, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above.

[0115] In a preferred embodiment, the FXR-related disease may be fatty liver, non-alcoholic steatohepatitis, cholestatic liver disease, dyslipidemia or diabetes and its complications.

[0116] 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-.

[0117] The term "a group B which is unsubstituted or substituted by multiple groups A" means that one or more hydrogen atoms in group B are independently replaced by a group A or B is unsubstituted. When multiple groups A appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other. For example, "a C6-C8 substituted by 3 halogens" 10 "Aryl" refers to C6~C 10 The aryl group may be substituted by three halogens, the definitions of which are independent of each other and do not affect each other, including but not limited to: wait.

[0118] The term "plurality" refers to 2 or more, such as 2, 3, 4, 5.

[0119] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0120] 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.

[0121] 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.

[0122] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is monocyclic or polycyclic, and at least one ring is aromatic (conforming to Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl groups include, but are not limited to, imidazolyl.

[0123] The term "heteroaromatic ring" refers to a cyclic group having a specified number of ring atoms (e.g., 5-9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is monocyclic or polycyclic, and at least one ring is aromatic (conforming to Huckel's rule). The heteroaromatic ring is connected to other segments in the molecule through an aromatic ring or a non-aromatic ring.

[0124] 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.

[0125] " " means that the structural fragment is connected to other fragments in the molecule through this site. For example, It refers to the acetyl group.

[0126] 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. For example, 1-1 Substituted C6~C 10 Aryl refers to C6~C 10 The aromatic group will be 3 R 1-1 Replacement, 3 R 1-1 The definitions are independent of each other and do not affect each other.

[0127] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0128] 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 patient use) acid or base. When the 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 the 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, methanesulfonates, and the like. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Mse (P. Heinrich Stahl, 2002).

[0129] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances, other than the active ingredient, contained in pharmaceutical preparations. For details, see the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0130] 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 leads to a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

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

[0132] 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.

[0133] The term "alkylene" refers to a divalent group of a straight or branched saturated aliphatic hydrocarbon radical having a specified number of carbon atoms. The two valencies can be concentrated on the same atom, for example, methylene (-CH2-), ethylene ( ), the two valences can also be attached to two atoms respectively, such as 1,2-ethylene (-CH2CH2-).

[0134] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0135] The reagents and raw materials used in the present invention are commercially available.

[0136] The positive and progressive effects of the present invention are that the compounds of the present invention have good affinity for FXR receptors and can induce the expression of FXR downstream target genes at the cellular level. DETAILED DESCRIPTION

[0137] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0138] Example 1

[0139]

[0140] Synthesis of compound 1-B

[0141] Step 1: Compound 1-1

[0142] Intermediate A (500 mg, 1.0 eq.), N-Boc-ethanolamine (250 mg, 1.0 eq.), and 18-crown-6 (580 mg, 1.4 eq.) were dissolved in THF (20 mL). The mixture was cooled to 0°C in an ice-salt bath, and a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 2.2 mL, 1.4 eq.) was added dropwise over 35 minutes. The mixture was returned to room temperature and stirred for 1 hour. After the reaction, the solvent was evaporated and the mixture was diluted with ethyl acetate. The aqueous phase was washed with saturated brine and extracted twice with EA. The combined organic phases were evaporated and purified by silica gel column chromatography to yield 705 mg of the crude product as a pale yellow liquid with a purity of 83.8% and a yield of >100%. m / z: [M+1] + 443;

[0143] Step 2: Compound 1-2

[0144] Dissolve 418 mg of compound 1-1 (418 mg, 1.0 eq.) in 3 mL of homemade dioxane hydrochloride solution (4N, 3 mL, 12 eq.) and stir at room temperature for 10 min until the reaction is complete. Spin dry the solvent to obtain a yellow oil, which was used directly in the next step. m / z: [M+1] + 343;

[0145] Step 3: Compound 1-A

[0146] Compound 1-2 (323 mg, 1.0 eq.) was dissolved in N,N-dimethylacetamide (5 mL). Compound B (274 mg, 1.0 eq.) was added and stirred to dissolve. Diisopropylethylamine (468 μL, 3.0 eq.) was added and the reaction was heated at 65°C with stirring for 4 h. TLC was used to monitor the remaining starting material. Upon completion of the reaction, 30 mL of saturated ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography (PE:EA = 10:1) and recrystallized from ether / n-hexane to yield 97 mg of a yellow solid with a purity of 99.2%. Yield: 18.6%. m / z: [M+1] + 552;

[0147] 1 H NMR (400MHz, CDCl3): δ8.08(d,J=1.1Hz,1H),7.71(dd,J=11.2,1.2Hz,1H),7.56-7.49(m,2H),7.41-7.35(m,2H),5 .86(s,1H),4.42(s,2H),3.92(s,3H),3.60-3.56(m,4H),2.13-2.06(m,1H),1.24-1.20(m,2H),1.13-1.07(m,2H).

[0148] Step 4: Compound 1-B

[0149] Compound 1-A (50 mg, 1.0 eq.) was dissolved in a mixture of acetonitrile and water (10 V / 2 V). LiOH·H2O (10 mg, 3.0 eq.) was added and stirred at room temperature until completely dissolved. The reaction was heated and stirred at 45°C for 5 h until complete. The reaction was quenched with saturated ammonium chloride solution (5 ml). The mixture was extracted three times with EA (5 ml x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 35 mg of a white solid powder with a purity of 98% and a yield of 71.9%. m / z: [M+1] + 538;

[0150] 1 H NMR (400MHz, DMSO-d6): δ12.92(s,1H),8.67-8.61(m,1H),8.13(d,J=1.3Hz,1H),7.65-7.59(m,2H),7.5 8-7.50(m,2H),7.49-7.43(m,1H),4.35(s,2H),3.57-3.48(m,4H),2.35-2.30(m,1H),1.10-1.04(m,4H).

[0151] Example 2

[0152]

[0153] Synthesis of compound 2-B

[0154] Step 1: Compound 2-A

[0155] Compound 1-A (20 mg, 1.0 eq.) was dissolved in acetonitrile (1 mL), and cesium carbonate (35 mg, 3.0 eq.) was added. Iodomethane (9 μL, 4.0 eq.) was then added with stirring. The mixture was sealed and stirred at room temperature for 6 hours. After the reaction was complete, the mixture was quenched with 20 mL of saturated ammonium chloride solution. The organic phases were extracted with ethyl acetate, washed with pure water, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation and purified by column chromatography (PE:EA = 15:1) to obtain 19 mg of an off-white oil with a purity of 99.0% and a yield of 92.7%. m / z: [M+1] + 566;

[0156] 1 H NMR (400MHz, CDCl3): δ8.09(d,J=1.3Hz,1H),7.71(dd,J=11.4,1.4Hz,1H),7.54-7.44(m,2H),7.37-7.29(m,2H),4.39(s,2H) ,3.92(s,3H),3.77-3.69(m,2H),3.66(t,J=4.8Hz,2H),3.08(s,3H),2.11-2.03(m,1H),1.21-1.17(m,2H),1.07-1.02(m,2H).

[0157] Step 2: Compound 2-B

[0158] Compound 2-B was prepared by replacing compound 1-A with compound 2-A according to Example 1. m / z: [M+1] + 552;

[0159] 1 H NMR (400MHz, CDCl3): δ8.15 (s, 1H), 7.77 (d, J = 10.9Hz, 1H), 7.54-7.44 (m, 2H), 7.38-7.29 (m, 2H), 4.39 (s, 2H), 3.79 -3.70(m,2H),3.66(t,J=4.8Hz,2H),3.08(s,3H),2.08(td,J=8.4,4.2Hz,1H),1.23-1.17(m,2H),1.09-1.02(m,2H).

[0160] Example 3

[0161]

[0162] Synthesis of compound 3-B

[0163] Step 1: Compound 3-A

[0164] Compound 1-A (46 mg, 1.0 eq.) was dissolved in N,N-dimethylformamide (1 mL), and benzyl bromide (30 μL, 3.0 eq.) was added. After nitrogen purging, cesium carbonate (84 mg, 3.0 eq.) was added and stirred at room temperature for 1 hour. The mixture was quenched with 10 mL of pure water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed by rotary evaporation to yield 87 mg of the crude product. Purification by silica gel column chromatography (PE:EA = 10:1) afforded 44 mg of an oil with a purity of 97.2% and a yield of 82.2%. m / z: [M+1] + 642;

[0165] 1 H NMR (400MHz, CDCl3): δ8.07(d,J=1.3Hz,1H),7.72(dd,J=11.3,1.3Hz,1H),7.51(dd,J=7.6,1.6Hz,1H),7.48-7.43(m,1H),7.36-7.27(m,5 H),7.22-7.17(m,2H),4.65(s,2H),4.37(s,2H),3.92(s,3H),3.72-3.61(m,4H),2.10-2.03(m,1H),1.22-1.17(m,2H),1.07-1.01(m,2H).

[0166] Step 2: Compound 3-B

[0167] Compound 3-B was prepared by replacing compound 1-A with compound 3-A according to Example 1. m / z: [M+1] + 628;

[0168] 1 H NMR (400MHz, DMSO-d6): δ12.97(s,1H),8.21(d,J=1.3Hz,1H),7.63-7.55(m,3H),7.52-7.48(m,1H),7.44-7.39(m,1H),7. 35-7.22(m,5H),4.70(s,2H),4.35(s,2H),3.74-3.63(m,2H),3.63-3.58(m,2H),2.32-2.24(m,1H),1.03(d,J=6.7Hz,4H).

[0169] Example 4

[0170]

[0171] Synthesis of compound 4-B

[0172] Step 1: Compound 4-A

[0173] Compound 1-A (40 mg, 1.0 eq.) was dissolved in acetonitrile (1 mL), and 2-bromo-N-(pyrrolidin-1-yl)acetamide (30 μL, 3.0 eq.) was added. After nitrogen purging, potassium carbonate (23 mg, 2.0 eq.) was added and the mixture was stirred at room temperature overnight. After filtration, the solvent was removed by rotary evaporation to obtain 87 mg of the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 10:1) to obtain 50 mg of an off-white oil with a purity of 98.4% and a yield of 100%. m / z: [M+1] + 663;

[0174] 1 H NMR (400MHz, CDCl3): δ8.08 (d, J=1.3Hz, 1H), 7.71 (dd, J=11.3, 1.3Hz, 1H), 7. 55-7.45(m,2H),7.38-7.29(m,2H),4.41(s,2H),4.29(s,2H),3.94(s,3H),3.8 2-3.71(m,2H),3.69(t,J=4.9Hz,2H),3.48(t,J=6.8Hz,4H),2.14-2.09(m,1H ),2.06-2.00(m,2H),1.92-1.86(m,2H),1.24-1.20(m,2H),1.12-1.06(m,2H).

[0175] Step 2: Compound 4-B

[0176] Compound 4-B was prepared by replacing compound 1-A with compound 4-A according to Example 1. m / z: [M+1] + 671;

[0177] 1H NMR (400MHz, DMSO-d6): δ7.84(s,1H),7.63(d,J=11.5Hz,1H),7.53-7.49(m,1H),7.48-7.43(m,1H),7.36-7.30(m,2H),4.39(s,2H),4.31(s ,2H),3.75-3.65(m,4H),3.54-3.45(m,4H),2.12-2.08(m,1H),2.05- 2.01(m,2H),1.92-1.87(m,2H),1.22-1.18(m,2H),1.10-1.06(m,2H).

[0178] Example 5

[0179]

[0180] Synthesis of compound 5-B

[0181] Step 1: Compound 5-A

[0182] Referring to Example 4, 2-bromoacetophenone was used instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide to prepare compound 5-A. m / z: [M+1] + 670;

[0183] 1 H NMR (400MHz, CDCl3): δ8.09 (d, J = 1.2Hz, 1H), 7.96-7.89 (m, 2H), 7.74-7.6 4(m,2H),7.57-7.51(m,2H),7.51-7.47(m,1H),7.47-7.41(m,1H),7.35-7. 31(m,1H),7.30-7.25(m,1H),5.01(s,2H),4.38(s,2H),3.93(s,3H),3.68 (d,J=3.4Hz,5H),2.08-2.00(m,1H),1.20-1.15(m,2H),1.07-1.01(m,2H).

[0184] Step 2: Compound 5-B

[0185] Compound 4-B was prepared by replacing compound 1-A with compound 4-A according to Example 1. m / z: [M+1] + 656;

[0186] 1H NMR (400MHz, DMSO-d6): δ8.22(s,1H),8.00(d,J=7.2Hz,2H),7.73(t,J=7.4Hz,1H),7.59(t,J=7.9Hz,5H), 7.45(dd,J=17.5,7.5Hz,2H),5.17(s,2H),4.36(s,2H),3.63(s,4H),2.32-2.25(m,1H),1.03-1.01(m,4H).

[0187] Example 6

[0188]

[0189] Synthesis of compound 6-B

[0190] Step 1: Compound 6-A

[0191] Referring to Example 4, 2-bromophenylacetamide was used instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide to prepare compound 6-A. m / z: [M+1] + 685;

[0192] 1 H NMR (400MHz, DMSO-d6): δ10.17(s,1H),8.29(d,J=1.3Hz,1H),7.65(s,1H),7 .57(t,J=8.0Hz,4H),7.49(d,J=8.4Hz,1H),7.40(t,J=7.4Hz,1H),7.31(t,J= 7.9Hz,2H),7.06(t,J=7.3Hz,1H),4.44-4.32(m,4H),3.85(s,3H),3.80-3.5 6(m,4H),2.30(dt,J=13.5,6.8Hz,1H),1.24-1.22(m,2H),1.03-1.00(m,2H).

[0193] Step 2: Compound 6-B

[0194] Compound 6-B was prepared by replacing compound 1-A with compound 6-A according to Example 1. m / z: [M+1]+671;

[0195] 1H NMR (400MHz, CDCl3): δ9.26 (s, 1H), 8.16 (s, 1H), 7.82 (d, J = 11.1Hz, 1H), 7.56-7.35 (m, 4H), 7.33-7.26 (m, 4H) ,7.13-7.04(m,1H),4.47(s,2H),4.23(s,2H),3.78(s,4H),1.97(s,1H),1.13-1.04(m,2H),0.93-0.87(m,2H).

[0196] Example 7

[0197]

[0198] Synthesis of compound 7-B

[0199] Step 1: Compound 7-1

[0200] Compound 7-1 was prepared by using N-Boc-propanolamine instead of N-Boc-ethanolamine according to Example 1. m / z: [M+1] + 457;

[0201] Step 2: Compound 7-2

[0202] Compound 7-2 was prepared by replacing compound 1-1 with compound 7-1 according to Example 1. m / z: [M+1] + 357;

[0203] Step 3: Compound 7-A

[0204] Compound 7-A was prepared by replacing compound 1-2 with compound 7-2 according to Example 1. m / z: [M+1] + 566;

[0205] 1 H NMR (400MHz, CDCl3): δ8.09(d,J=1.3Hz,1H),7.71(dd,J=11.2,1.4Hz,1H),7.56(dd,J=7.5,1.7Hz,1H),7.52-7.46(m,1H),7.41-7.33(m,2H),6.05(s ,1H),4.39(s,2H),3.92(s,3H),3.49(t,J=5.6Hz,2H),3.43-3.37(m,2H),2 .16-2.09(m,1H),1.88-1.82(m,2H),1.26-1.22(m,2H),1.15-1.09(m,2H).

[0206] Step 4: Compound 7-B

[0207] Compound 7-B was prepared by replacing compound 1-A with compound 7-A according to Example 1. m / z: [M+1] + 552;

[0208] 1 H NMR (400MHz, DMSO-d6): δ8.57(t,J=4.4Hz,1H),8.13(d,J=1.0Hz,1H),7.66-7.61(m,2H),7.58-7.4 9(m,3H),4.31(s,2H),3.43-3.37(m,4H),2.37-2.29(m,1H),1.77-1.69(m,2H),1.15-1.04(m,4H).

[0209] Example 8

[0210]

[0211] Synthesis of compound 8-B

[0212] Step 1: Compound 8-A

[0213] Compound 8-A was prepared by using compound 7-A instead of compound 1-A according to Example 2. m / z: [M+1] + 580;

[0214] 1 H NMR (400MHz, CDCl3): δ8.07(d,J=1.2Hz,1H),7.70(dd,J=11.4,1.3Hz,1H),7.58-7.46(m,2H),7.40-7.34(m,2H),4.35(s,2H),3.92(s ,3H),3.57-3.45(m,2H),3.45-3.37(m,2H),3.13(s,3H),2.16-2.12(m,1H),1.90-1.84(m,2H),1.24-1.21(m,2H),1.12-1.08(m,2H).

[0215] Step 2: Compound 8-B

[0216] Compound 8-B was prepared by replacing compound 1-A with compound 8-A according to Example 1. m / z: [M+1] + 566;

[0217] 1H NMR (400MHz, CDCl3): δ8.13(d,J=1.3Hz,1H),7.76(dd,J=11.2,1.4Hz,1H),7.56(dd,J=7.8,1.7Hz,1H),7.53-7.47(m,1H),7.42-7.35(m,2H),4.36 (s,2H),3.55-3.46(m,2H),3.42(t,J=5.8Hz,2H),3.14(s,3H)2.16-2.11( m,1H),1.91-1.84(m,2H),1.25-1.21(m,2H),1.10(dt,J=7.4,4.4Hz,2H).

[0218] Example 9

[0219]

[0220] Synthesis of compound 9-B

[0221] Step 1: Compound 9-A

[0222] Compound 9-A was prepared by referring to Example 8 using bromoethane instead of iodomethane. m / z: [M+1] + 594;

[0223] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=1.2Hz,1H),7.68-7.58(m,3H),7.57-7.49(m,2H),4.34(s,2H),3.85(s,3H),3.5 4-3.45(m,2H),3.41-3.35(m,4H),2.38-2.30(m,1H),1.83-1.75(m,2H),1.16(t,J=6.8Hz,3H),1.13-1.06(m,4H).

[0224] Step 2: Compound 9-B

[0225] Compound 9-B was prepared by replacing compound 1-A with compound 9-A according to Example 1. m / z: [M+1] + 580;

[0226] 1H NMR (400MHz, CDCl3): δ8.14(d,J=1.2Hz,1H),7.71-7.61(m,2H),7.60-7.48(m,3H),4.34(s,2H),3.48(q,J=6 .8Hz,2H),3.42-3.35(m,4H),2.37-2.30(m,1H),1.84-1.75(m,1H),1.15(t,J=6.8Hz,3H),1.14-1.06(m,4H).

[0227] Example 10

[0228]

[0229] Synthesis of compound 10-B

[0230] Step 1: Compound 10-A

[0231] Compound 7-A (42 mg, 1 eq.) was dissolved in acetonitrile (2 mL). Cesium carbonate (49 mg, 2 eq.) and 2-bromopropane (45 mg, 5 eq.) were added to the reaction solution. The mixture was heated in a microwave oven at 120°C for 0.5 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. Column chromatography purification afforded 22 mg of a white solid with a purity of 99.0% and a yield of 49%. m / z: [M+1] + 608;

[0232] 1 H NMR (400MHz, CDCl3): δ8.09(d,J=1.4Hz,1H),7.71(dd,J=11.4,1.4Hz,1H),7.61(dd,J=7.6,1.6Hz,1H),7.53-7.49(m,1H),7.39(t,J=7.4Hz,2H),4.4 5-4.30(m,3H),3.93(s,3H),3.47(t,J=5.8Hz,2H),3.39-3.33(m,2H),2.16 -2.21(m,1H),1.96-1.90(m,2H),1.26(d,J=6.7Hz,8H),1.15-1.11(m,2H).

[0233] Step 2: Compound 10-B

[0234] Compound 10-B was prepared by replacing compound 1-A with compound 10-A according to Example 1. m / z: [M+1] + 594;

[0235] 1H NMR (400MHz, CDCl3): δ8.15(d,J=1.4Hz,1H),7.77(dd,J=11.2,1.4Hz,1H),7.61(dd,J=7.7,1.6Hz,1H),7.54-7.48(m,1H),7.39(t,J=7.4Hz, 2H),4.45-4.30(m,3H),3.48(t,J=5.6Hz,2H),3.36-3.39(m,2H),2.22 -2.16(m,1H),1.92-1.96(m,2H),1.28-1.26(m,8H),1.16-1.12(m,2H).

[0236] Example 11

[0237]

[0238] Synthesis of compound 11

[0239] Step 1: Compound 11-A

[0240] Compound 7-A (50 mg, 1 eq) was dissolved in acetonitrile (2 mL). Potassium carbonate (25 mg, 2 eq) and 1-bromopropane (43 mg, 4 eq) were added to the reaction solution. The mixture was heated in a microwave oven at 80°C for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain the crude product. Purification by column chromatography afforded 35 mg of a white solid with a purity of 94.5% and a yield of 65.0%. m / z: [M+1] + 608;

[0241] Step 2: Compound 11

[0242] Compound 11-A (35 mg, 1 eq.) was dissolved in tetrahydrofuran (1.4 mL), followed by dissolving LiOH·H2O (5 mg, 2 eq.) in water (350 μL). The organic and aqueous phases were mixed and reacted overnight at 40°C. The mixture was acidified with 0.1 M hydrochloric acid to a pH of approximately 6, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to yield 28 mg of the product with a purity of 95.6% and a yield of 74.77%. m / z: [M+1] + 594;

[0243] 1H NMR (400MHz, CDCl3): δ8.14(d,J=1.5Hz,1H),7.77(dd,J=11.2,1.6Hz,1H),7.59( dd,J=7.8,1.8Hz,1H),7.57-7.48(m,1H),7.43-7.35(m,2H),4.39(s,2H),3.51(s, 2H),3.47-3.37(m,4H),2.21-2.13(m,1H),1.96-1.87(m,2H),1.70(q,J=7.5Hz,2H ), 1.26 (dd, J = 5.1, 2.3Hz, 2H), 1.13 (dt, J = 8.5, 3.4Hz, 2H), 0.97 (t, J = 7.4Hz, 3H).

[0244] Example 12

[0245]

[0246] Synthesis of compound 12

[0247] Step 1: Compound 12-A

[0248] Compound 7-A (50 mg, 1 eq) was dissolved in acetonitrile (2 mL). Potassium carbonate (25 mg, 2 eq) and 1-bromobutane (48 mg, 4 eq) were added to the reaction solution. The mixture was heated in a microwave oven at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Purification by column chromatography afforded 42 mg of an oil with a purity of 95.7% and a yield of 72.7%. m / z: [M+1] + 622;

[0249] Step 2: Compound 12

[0250] Compound 12-B was prepared by referring to Example 11 and replacing compound 11-A with compound 12-A. m / z: [M+1] + 608;

[0251] 1H NMR (400MHz, CDCl3): δ8.14(d,J=1.5Hz,1H),7.77(dd,J=11.1,1.6Hz,1H),7.59(dd,J=7 .9,1.8Hz,1H),7.52(td,J=7.9,1.9Hz,1H),7.43-7.35(m,2H),4.39(s,2H),3.51(q,J=7 .0Hz,2H),3.49-3.41(m,4H),2.20-2.13(m,1H),1.97-1.86(m,2H),1.68-1.59(m,2H),1 .47-1.38(m,2H),1.27-1.21(m,2H),1.13(dt,J=8.5,3.4Hz,2H),0.98(t,J=7.3Hz,3H).

[0252] Example 13

[0253]

[0254] Synthesis of compound 13

[0255] Step 1: Compound 13-A

[0256] Compound A (100 mg, 1 eq.) was dissolved in acetonitrile (1 mL). Cs2CO3 (116 mg, 2 eq.) and 1-bromo-2-methylpropane (96 mg, 2.0 eq.) were then added to the reaction solution. The reaction was heated in a microwave oven at 80°C for 2 h, and the reaction was complete. Saturated ammonium chloride was added to the system for quenching, followed by extraction with ethyl acetate. The combined organic phases were washed with pure water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent removed by rotary evaporation to yield the crude product. Purification by silica gel column chromatography afforded 82 mg of a light yellow oil with a purity of 90% and a yield of 74.6%. m / z: [M+1] + 622;

[0257] Step 2: Compound 13

[0258] Compound 13 was prepared by referring to Example 11 and replacing compound 11-A with compound 13-A. m / z: [M+1] + 608;

[0259] 1H NMR (400MHz, DMSO-d6): δ8.18(d,J=1.6Hz,1H),7.65(q,J=1.7Hz,1H),7.63( q,J=1.8Hz,1H),7.58(dd,J=11.6,1.6Hz,1H),7.56-7.49(m,2H),4.34(s,2H) ,3.40(brs,2H),3.37(t,J=8.0Hz,2H),3.27(brs,2H),2.36-2.31(m,1H),2. 09-2.02(m,1H),1.83-1.76(m,2H),1.13-1.07(m,4H),0.88(d,J=6.6Hz,6H).

[0260] Example 14

[0261]

[0262] Synthesis of compound 14-B

[0263] Step 1: Compound 14-1

[0264] Compound 7-2 (120 mg, 1 eq.) and pivalaldehyde (52 mg, 2 eq.) were dissolved in methanol (2 mL) and stirred at room temperature for 8 hours. The reaction mixture was cooled to 0°C and sodium borohydride (51 mg, 4.0 eq.) was added in three batches. The mixture was returned to room temperature and allowed to react overnight. The reaction was quenched with 0.1 M dilute hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were washed with pure water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Purification by silica gel column chromatography yielded 65 mg of a colorless oil with a yield of 51% and a purity of 99.0%. m / z: [M+1] + 427;

[0265] Step 2: Compound 14-A

[0266] Compound 14-1 (65 mg, 1 eq.), compound B (31 mg, 1.1 eq.), and potassium iodide (5 mg, 0.2 eq.) were dissolved in acetonitrile (2 mL). Potassium carbonate (25 mg, 1.2 eq.) was added and the mixture was reacted at 85°C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography afforded 47 mg of a colorless oil with a yield of 37% and a purity of 99.0%. m / z: [M+1] + 636;

[0267] 1H NMR (600MHz, CDCl3): δ8.05(d,J=1.2Hz,1H),7.68(d,J=11.3Hz,1H),7.56(d,J=7.6Hz ,1H),7.49(t,J=7.2Hz,1H),7.36(t,J=7.6Hz,2H),4.35(d,J=6.8Hz,2H),3.91(s,3H), 3.56(d,J=6.9Hz,2H),3.38-3.43(m,2H),3.29(s,2H),2.16-2.12(m,1H),1.90(dd,J=1 4.3, 5.9Hz, 2H), 1.23 (dd, J=4.8, 2.2Hz, 2H), 1.10 (dd, J=8.3, 2.6Hz, 2H), 0.98 (s, 9H).

[0268] Step 3: Compound 14-B

[0269] Compound 14-B was prepared by using compound 14-A instead of compound 1-A according to Example 1. m / z: [M+1] + 622;

[0270] 1 H NMR (600MHz, CDCl3): δ8.12(s,1H),7.74(d,J=11.1Hz,1H),7.57(d,J=7.6Hz, 1H),7.49(t,J=7.2Hz,1H),7.37(t,J=7.6Hz,2H),4.36(d,J=6.7Hz,2H),3.54( d,J=45.1Hz,2H),3.41(dd,J=11.8,5.8Hz,2H),3.31(s,2H),2.16-2.13(m,1H ),1.93-1.88(m,2H),1.25-1.23(m,2H),1.12-1.09(m,2H),1.01-0.95(m,9H).

[0271] Example 15

[0272]

[0273] Synthesis of compound 15-B

[0274] Step 1: Compound 15-A

[0275] Compound 15-A was prepared by referring to Example 10 and replacing 2-bromopropane with bromocyclopentane. m / z: [M+1] + 634;

[0276] 1H NMR (400MHz, CDCl3): δ8.05(d,J=1.6Hz,1H),7.72-7.64(m,3H),7.60-7.52(m,2H),5.34-5.26(m,1H),4.36(s,2H),3.91(s, 3H),3.46(t,J=6.0Hz,2H),3.05(t,J=6.4Hz,2H),2.40-2.34(m,1H),2.20-1.58(m,8H),1.83-1.77(m,2H),1.18-1.10(m,4H)

[0277] Step 2: Compound 15-B

[0278] Compound 15-B was prepared by replacing compound 1-A with compound 15-A according to Example 1. m / z: [M+1] + 620;

[0279] 1 H NMR (400MHz, CDCl3) δ8.11 (d, J = 1.2Hz, 1H), 7.68-7.62 (m, 2H), 7.58-7.49 (m, 3H), 4.37 (s, 2H), 4.26 (s, 1H ),3.39(t,J=6.0Hz,2H),3.28(t,J=7.6Hz,2H),2.38-2.32(m,1H),1.94-1.52(m,10H),1.15-1.07(m,4H).

[0280] Example 16

[0281]

[0282] Synthesis of compound 16-B

[0283] Step 1: 16-A: Compound 7-A (55 mg, 1.0 eq.) was dissolved in N,N-dimethylformamide (2 mL). Cesium carbonate (99 mg, 3.0 eq.) and benzyl bromide (35 μL, 3.0 eq.) were added with ice-cooling and stirred for 1 hour until the reaction was complete. The mixture was quenched with 0.1 M dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Purification by silica gel column chromatography afforded 57 mg of a light yellow oil (89% yield), m / z: [M+1]. + 656;

[0284] 1H NMR (400MHz, CDCl3): δ8.08(d,J=1.1Hz,1H),7.73(dd,J=11.3,1.2Hz,1H),7 .56-7.49(m,1H),7.48-7.41(m,1H),7.38-7.32(m,4H),7.30-7.25(m,3H),4. 76(s,2H),4.35(s,2H),3.94(s,3H),3.54-3.44(m,2H),3.41(t,J=5.8Hz,2H) ,2.15-2.07(m,1H),1.93-1.83(m,2H),1.25-1.20(m,2H),1.11-1.05(m,2H).

[0285] Step 2: 16-B

[0286] Compound 16-B was prepared by replacing compound 1-A with compound 16-A according to Example 1. m / z: [M+1] + 642;

[0287] 1 H NMR (400MHz, CDCl3): δ8.12(s,1H),7.77(d,J=12.0Hz,1H),7.51(d,J=7.6H z,1H),7.45-7.40(m,1H),7.36-7.30(m,4H),7.28(d,J=7.5Hz,1H),7.26-7 .22(m,2H),4.74(s,2H),4.34(s,2H),3.46(s,2H),3.39(t,J=5.8Hz,2H),2 .12-2.07(m,1H),1.90-1.84(m,2H),1.22-1.19(m,2H),1.08-1.03(m,2H).

[0288] Example 17

[0289]

[0290] Preparation of compound 17

[0291] Step 1: Compound 17-A

[0292] Compound 17-A was prepared by referring to Example 11 and replacing 1-bromopropane with (1-bromoethyl)benzene. m / z: [M+1] + 670;

[0293] Step 2: Compound 17

[0294] Compound 17-B was prepared by referring to Example 11 and replacing compound 11-A with compound 17-A. m / z: [M+1] + 656;

[0295] 1 H NMR (400MHz, CDCl3): δ8.17(d,J=1.5Hz,1H),7.80(dd,J=11.1,1.5Hz,1H),7.54(dd ,J=7.6,1.8Hz,1H),7.45(td,J=7.9,1.8Hz,1H),7.35(s,5H),7.34(d,J=2.8Hz,1H) ,7.31(d,J=7.9Hz,1H),5.72(s,1H),4.32(s,2H),3.38-3.15(m,4H),2.16-2.06(m, 1H),1.87-1.72(m,2H),1.68(d,J=7.0Hz,3H),1.26-1.19(m,2H),1.11-1.03(m,2H).

[0296] Example 18

[0297]

[0298] Synthesis of compound 18

[0299] Step 1: Compound 18-A

[0300] Compound 16-A was prepared by referring to Example 4 using 3-bromopropene instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 606;

[0301] Step 2: Compound 18

[0302] Compound 18 was prepared by referring to Example 11 and replacing compound 11-A with compound 18-A. m / z: [M+1] + 592;

[0303] 1 H NMR (400MHz, DMSO-d6): δ12.87(s,1H),8.20(d,J=1.5Hz,1H),7.65-7.50(m,5H),5.88-5.80(m,1H),5.23-5.17(m,2H), 4.33(s,2H),4.11(s,2H),3.42(s,2H),3.38(d,J=5.9Hz,2H),2.35-2.31(m,1H),1.83-1.77(m,2H),1.12-1.06(m,4H).

[0304] Example 19

[0305]

[0306] Synthesis of compound 19-B

[0307] Step 1: Compound 19-A

[0308] Compound 19-A was prepared by referring to Example 4 using 2-bromoacetophenone instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 684;

[0309] 1 H NMR (400MHz, CDCl3): δ8.09(d,J=1.2Hz,1H),7.99(d,J=7.4Hz,2H),7.72-7.64(m,2H),7.58-7.52(m,3H),7.51-7.46(m,1H),7.40-7.32(m, 2H),5.09(s,2H),4.38(s,2H),3.93(s,3H),3.55-3.45(m,4H),2.16- 2.09(m,1H),1.96-1.88(m,2H),1.24-1.20(m,2H),1.12-1.06(m,2H).

[0310] Step 2: Compound 19-B

[0311] Compound 19-B was prepared by using compound 19-A instead of compound 1-A according to Example 1. m / z: [M+1] + 670;

[0312] 1 H NMR (400MHz, CDCl3): δ8.12(d,J=1.2Hz,1H),7.97(d,J=7.4Hz,2H),7.72(dd ,J=11.1,1.2Hz,1H),7.65(t,J=7.4Hz,1H),7.52(t,J=7.7Hz,3H),7.49-7.4 4(m,1H),7.34(t,J=7.6Hz,2H),5.08(s,2H),4.36(s,2H),3.53-3.43(m,4H) ,2.14-2.06(m,1H),1.94-1.87(m,2H),1.22-1.18(m,2H),1.10-1.04(m,2H).

[0313] Example 20

[0314]

[0315] Synthesis of compound 20-B

[0316] Step 1: Compound 20-A

[0317] Compound 20-A was prepared by using bromoacetone instead of iodomethane according to Example 2. m / z: [M+1] + 622;

[0318] 1 H NMR (400MHz, DMSO-d6): δ8.25(d,J=1.2Hz,1H),7.68-7.60(m,3H),7.57-7.50(m,2H),4.49(s,2H),4.32(s, 2H),3.85(s,3H),3.41-3.35(m,4H),2.36-2.31(m,1H),2.15(s,3H),1.80-1.72(m,2H),1.14-1.06(m,4H).

[0319] Step 2: Compound 20-B

[0320] Compound 20-B was prepared by using compound 20-A instead of compound 1-A according to Example 1. m / z: [M+1] + 608;

[0321] 1 H NMR (400MHz, DMSO-d6): δ12.98(s,1H),8.25(d,J=1.6Hz,1H),7.70-7.62(m,3H),7.63-7.55(m,2H),4.53(s ,2H),4.37(s,2H),3.46-3.40(m,4H),2.41-2.36(m,1H),2.20(s,3H),1.84-1.78(m,2H),1.18-1.11(m,4H).

[0322] Example 21

[0323]

[0324] Synthesis of compound 21

[0325] Compound 7-B (35 mg, 1 eq.) was dissolved in acetonitrile (2 mL), and methyl bromoacetate (14 mg, 1.5 eq.) was added and stirred to dissolve. Potassium carbonate (25 mg, 3 eq.) was added and the mixture was heated in a microwave at 60°C for 4 hours. After the reaction, the crude product was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 25 mg of a white solid with a purity of 99.9% and a yield of 67%. m / z: [M+1] + 624;

[0326] 1 H NMR (400MHz, DMSO-d6): δ8.63(s,1H),8.24(d,J=1.4Hz,1H),7.60-7.65(m,3H),7.56-7.51(m,2H),4.92(s,2H),4.32( s,2H),3.71(s,3H),3.70-3.64(m,2H),3.40(t,J=6.1Hz,2H),2.36-2.31(m,1H),1.77-1.72(m,2H),1.13-1.07(m,4H).

[0327] Example 22

[0328]

[0329] Synthesis of compound 22

[0330] Compound 22 was prepared by referring to Example 21 and replacing compound 7-B with compound 7-A. m / z: [M+1] + 637;

[0331] 1 H NMR (400MHz, CDCl3): δ8.10 (d, J=1.4Hz, 1H), 7.72 (dd, J=11.3, 1.5Hz, 1H), 7.5 8(dd,J=7.8,1.7Hz,1H),7.55-7.50(m,1H),7.42-7.38(m,2H),4.38(s,2H),4. 34(s,2H),3.94(s,3H),3.78(s,3H),3.50(t,J=7.1Hz,2H),3.45(t,J=5.7Hz,2 H),2.10-2.18(m,1H),1.93-1.86(m,2H),1.27-1.24(m,2H),1.16-1.10(m,2H).

[0332] Example 23

[0333]

[0334] Synthesis of compound 23

[0335] Step 1: Compound 23-A

[0336] Compound 23 was prepared by referring to Example 4 using tert-butyl bromoacetate instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 680;

[0337] Step 2: Compound 23

[0338] Compound 23-A (105 mg, 1.0 eq.) was placed in a reaction flask. A 4M solution of dioxane hydrochloride (6 mL) was added under a nitrogen balloon. The system was then placed in a 40°C oil bath and reacted for 2 h. The dioxane and excess hydrochloric acid were removed by rotary evaporation. m / z: [M+1] + 624;

[0339] 1 H NMR (400MHz, DMSO-d6): δ8.37-8.18(s,1H),7.74-7.46(m,5H),4.48-4.18(m,4H),3.8 6(s,3H),3.60-3.40(m,4H),2.39-2.29(s,1H),1.88-1.74(m,2H),1.16-1.05(m,4H).

[0340] Example 24

[0341]

[0342] Synthesis of compound 24

[0343] Compound 24 was prepared by replacing compound 1-A with compound 22 according to Example 1. m / z: [M+1] + 610; Example 25

[0344]

[0345] Synthesis of compound 25-B

[0346] Step 1: Compound 25-A

[0347] Compound 25-A was prepared by referring to Example 2 using 2-bromo-1-(pyrrolidin-1-yl)ethanone instead of iodomethane. m / z: [M+1] + 677;

[0348] 1H NMR (400MHz, CDCl3): δ8.07(d,J=1.1Hz,1H),7.70(d,J=11.3Hz,1H),7.61- 7.56(m,1H),7.55-7.49(m,1H),7.43-7.37(m,2H),4.37(s,2H),4.33(s,2H) ,3.94(s,3H),3.57(t,J=6.9Hz,4H),3.52-3.44(m,4H),2.19-2.13(m,1H), 2.07-2.02(m,2H),1.95-1.88(m,4H),1.26-1.23(m,2H),1.15-1.10(m,2H).

[0349] Step 2

[0350] Compound 25-B was prepared by replacing compound 1-A with compound 25-A according to Example 1. m / z: [M+1] + 663;

[0351] 1 H NMR (400MHz, CDCl3): δ7.86(s,1H),7.65-7.56(m,2H),7.56-7.50(m,1H),7.44-7.38(m,2H),4.38(s,2H),4.37(s,2H),3.62-3. 52(m,6H),3.47(t,J=5.7Hz,2H),2.19-2.14(m,1H),2.08-2.04(m,2H),1.97-1.88(m,4H),1.27-1.23(m,2H),1.16-1.11(m,2H).

[0352] Example 26

[0353]

[0354] Synthesis of compound 26-B

[0355] Step 1: Compound 26-A

[0356] Compound 26-A was prepared by referring to Example 4 using 2-bromo-N-methylacetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 637;

[0357] 1 H NMR (400MHz, DMSO-d6): δ8.27(d,J=1.6Hz,1H),8.05-7.99(m,1H),7.68-7.61(m,3H),7.56-7.50(m,2H),4.31(s,2H),4.15(s,2H),3 .86(s,3H),3.38(t,J=5.6Hz,2H),3.33-3.30(m,2H),2.61(d,J=4.8Hz,3H),2.35-2.30(m,1H),1.84-1.77(m,2H),1.13-1.06(m,4H).

[0358] Step 2: Compound 26-B

[0359] Compound 26-B was prepared by replacing compound 1-A with compound 26-A according to Example 1. m / z: [M+1] + 623;

[0360] 1 H NMR (400MHz, DMSO-d6): δ13.0(brs,1H),8.27(d,J=1.6Hz,1H),8.13-8.01(m,1H),7.74-7.63(m,3H),7.62-7.55(m,2H),4.37(s,2H), 4.20(s,2H),3.59-3.49(m,2H),3.44(t,J=6.0Hz,2H),2.67(d,J=4.4Hz,3H),2.42-2.35(m,1H),1.91-1.82(m,2H),1.20-1.12(m,4H).

[0361] Example 27

[0362]

[0363] Synthesis of compound 27-B

[0364] Step 1: Compound 27-A

[0365] Compound 27-A was prepared by referring to Example 2 using N,N-dimethyl-bromoacetamide instead of iodomethane. m / z: [M+1] + 651;

[0366] 1 H NMR (400MHz, DMSO-d6): δ8.24(d,J=1.2Hz,1H),7.68-7.60(m,3H),7.57-7.49(m,2H),4.46(s,2H),4.32(s,2H),3.85(s,3H), 3.39(t,J=6.0Hz,2H),3.33-3.30(m,2H),3.01(s,3H),2.85(s,3H),2.38-2.30(m,1H),1.85-1.77(m,2H),1.14-1.05(m,4H).

[0367] Step 2: Compound 27-B

[0368] The target compound 27-B was prepared by using compound 27-A instead of compound 1-A according to Example 1. m / z: [M+1] + 637;

[0369] 1H NMR (400MHz, DMSO-d6): δ13.05(brs,1H),8.25(s,1H),7.74-7.69(m,2H),7.67-7.56(m,3H),4.51(s,2H),4.39 (s,2H),3.47-3.43(m,4H),3.07(s,3H),2.91(s,3H),2.44-2.37(m,1H),1.91-1.83(m,2H),1.20-1.12(m,4H).

[0370] Example 28

[0371]

[0372] Synthesis of compound 28-B

[0373] Step 1: Compound 28-A

[0374] Compound 28-A was prepared by referring to Example 2 using N,N-diethyl-bromoacetamide instead of iodomethane. m / z: [M+1] + 679;

[0375] 1 H NMR (400MHz, DMSO-d6): δ8.25(d,J=1.6Hz,1H),7.68-7.60(m,3H),7.56-7.49(m,2H),4.43(s,2H),4.32(s,2H),3.85(s,1H),3.42-3 .35(m,4H),3.33-3.23(m,4H),2.37-2.31(m,1H),1.84-1.78(m,2H),1.19(t,J=7.2Hz,3H),1.13-1.06(m,4H),1.02(t,J=7.2Hz,3H).

[0376] Step 2: Compound 28-B

[0377] Compound 28-B was prepared by replacing compound 1-A with compound 28-A according to Example 1. m / z: [M+1] + 665;

[0378] 1H NMR (400MHz, DMSO-d6): δ8.07(s,1H),7.68-7.62(m,2H),7.57-7.50(m,3H),4.40(s,2H),4.32(s,2H),3.41-3.38(m,4H), 3.29-3.26(m,4H),2.37-2.32(m,1H),1.85-1.77(m,2H),1.19(t,J=7.2Hz,3H),1.14-1.06(m,4H),1.02(t,J=7.2Hz,3H).

[0379] Example 29

[0380]

[0381] Preparation of compound 29-B

[0382] Step 1: Compound 29-1

[0383] Compound 7-2 (107 mg, 1 eq.) was dissolved in acetonitrile (2 mL). 2-Bromo-N-cyclohexylacetamide (66 mg, 1 eq.) was added and stirred to dissolve. Potassium carbonate (83 mg, 2 eq.) was added and allowed to react at room temperature for 2 hours. The solvent was removed under reduced pressure and purified by silica gel column chromatography to obtain 15 mg of a colorless oil (10% yield). m / z: [M+1] + 496;

[0384] Step 2: Compound 29-A

[0385] Compound 29-1 (15 mg, 1 eq.) was dissolved in acetonitrile (1 mL), and compound B (13 mg, 1.5 eq.) was added and stirred to dissolve. Diisopropylethylamine (8 mg, 2 eq.) was added and microwave-heated at 80°C for 4 hours. After completion of the reaction, the crude product was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 13 mg of a colorless oil with a purity of 91% and a yield of 63%. m / z: [M+1] + 704;

[0386] 1H NMR (600MHz, CDCl3): δ8.01(d,J=1.2Hz,1H),7.66(dd,J=11.1,1.2Hz,1H),7.49(dd,J=7.9,1.6Hz ,1H),7.42(dd,J=11.8,4.0Hz,1H),7.32-7.29(m,2H),4.27(s,2H),4.06(s,2H),3.86(s,3H),3.7 0-3.65(m,1H),3.44(t,J=7.2Hz,2H),3.34(t,J=5.6Hz,2H),2.04(td,J=8.4,4.2Hz,1H),1.86-1. 82(m,2H),1.74(dd,J=12.4,3.6Hz,2H),1.29-1.21(m,4H),1.17-1.15(m,2H),1.09-1.00(m,6H).

[0387] Step 3: Compound 29-B

[0388] Compound 29-B was prepared by using compound 29-A instead of compound 1-A according to Example 1. m / z: [M+1] + 691;

[0389] 1 H NMR (400MHz, CDCl3): δ8.14 (d, J=1.4Hz, 1H), 7.79 (dd, J=11.0, 1.4Hz, 1H), 7.59 (dd, J=7. 8,1.7Hz,1H),7.55-7.50(m,1H),7.42-7.38(m,2H),4.37(s,2H),4.18(s,2H),3.81-3.75 (m,1H),3.54(t,J=7.2Hz,2H),3.44(t,J=5.6Hz,2H),2.16-2.11(m,1H),1.97-1.91(m,2H ),1.85(dd,J=12.4,3.7Hz,2H),1.67-1.61(m,2H),1.27-1.22(m,4H),1.19-1.09(m,6H).

[0390] Example 30

[0391]

[0392] Preparation of compound 30-B

[0393] Step 1: Compound 30-A

[0394] Compound 30-A was prepared by referring to Example 4 using 2-bromo-N-phenylacetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 699;

[0395] 1 H NMR (400MHz, CDCl3): 9.59 (s, 1H), 8.12 (s, 1H), 7.80 (d, J = 10.3Hz, 1H), 7.60-7.54 (m,1H),7.55-7.45(m,3H),7.41-7.35(m,2H),7.34-7.28(m,2H),7.11(t,J=7.5Hz, 1H),4.37(s,2H),4.34(s,2H),3.97(s,3H),3.53(t,J=7.1Hz,2H),3.44(t,J=5.4H z,2H),2.12-2.08(m,1H),2.00-1.94(m,2H),1.23-1.21(m,2H),1.11-1.09(m,2H).

[0396] Step 2: Compound 30-B

[0397] The target compound 30-B was prepared by using compound 30-A instead of compound 1-A according to Example 1. m / z: [M+1] + 685;

[0398] 1 H NMR (400MHz, CDCl3): δ9.53(s,1H),8.15(s,1H),7.83(d,J=11.2Hz,1H),7.55(d,J=7.5 Hz,1H),7.48(dd,J=12.3,7.5Hz,3H),7.37(d,J=7.7Hz,2H),7.31(dd,J=15.5,7.8Hz,2 H),7.09(t,J=7.5Hz,1H),4.35(s,2H),4.34(s,2H),3.53(t,J=7.2Hz,2H),3.42(t,J=5 .5Hz,2H),2.11-2.06(m,1H),1.99-1.92(m,2H),1.24-1.21(m,2H),1.11-1.05(m,2H).

[0399] Example 31

[0400]

[0401] Synthesis of compound 31

[0402] Step 1: Compound 31-A

[0403] Compound 31-A was prepared by referring to Example 4 using 2-bromo-N-methyl-N-acetanilide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 713;

[0404] Step 2: Compound 31

[0405] Compound 31 was prepared by referring to Example 11 and replacing compound 11-A with compound 31-A. m / z: [M+1] + 698;

[0406] 1 H NMR (400MHz, DMSO-d6): δ12.97(s,1H),8.20(d,J=1.5Hz,1H),7.68-7.44(m,10H),4.28(s,2H),4.06(s ,2H),3.44(s,2H),3.34(s,2H),3.19(s,3H),2.33-2.27(m,1H),1.80-1.72(m,2H),1.14-1.01(m,4H).

[0407] Example 32

[0408]

[0409] Synthesis of compound 32

[0410] Step 1: Compound 32-A

[0411] Compound 32-A was prepared by referring to Example 4 using 2-bromo-N-ethyl-N-acetanilide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 727;

[0412] Step 2: Compound 32

[0413] Compound 32 was prepared by referring to Example 11 and replacing compound 11-A with compound 32-A. m / z: [M+1] + 713;

[0414] 1H NMR (400MHz, DMSO-d6): δ8.25(d,J=1.5Hz,1H),7.70-7.63(m,3H),7.62-7.54(m,4H),7.54-7.46(m,3H),4.34(s,2H),4.04(s,2 H),3.72(q,J=8.0Hz,2H),3.48(s,2H),3.40(s,2H),2.39-2.33(m,1H),1.84-1.76(m,2H),1.16-1.11(m,4H),1.10-1.04(m,3H).

[0415] Example 33

[0416]

[0417] Synthesis of compound 33

[0418] Step 1: Compound 33-A

[0419] Compound 33-A was prepared by referring to Example 4 using N-benzyl-2-bromoacetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 713;

[0420] Step 2: Compound 33

[0421] Compound 33 was prepared by referring to Example 11 and replacing compound 11-A with compound 33-A. m / z: [M+1] + 699;

[0422] 1 H NMR (400MHz, DMSO-d6): δ13.00(s,1H),8.63(t,J=6.4Hz,1H),8.23(d,J=1.5Hz,1H),7.66-7.61(m,3H),7.56-7.51(m,2H),7.30-7.27(m,4H) ,7.25-7.21(m,1H),4.34-4.31(m,4H),4.25(s,2H),3.49(s,2H),3.41 -3.39(m,2H),2.36-2.31(m,1H),1.86-1.80(m,2H),1.12-1.07(m,4H).

[0423] Example 34

[0424]

[0425] Synthesis of compound 34

[0426] Step 1: Compound 34-A

[0427] Compound 34-A was prepared by referring to Example 4 using N-(1-naphthyl)-2-bromo-acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 749;

[0428] Step 2: Compound 34

[0429] Compound 34 was prepared by referring to Example 11 and substituting compound 34-A for compound 11-A. m / z: [M+1] + 735;

[0430] 1 H NMR (400MHz, DMSO-d6): δ12.91(s,1H),10.20(s,1H),8.25(d,J=1.5Hz,1H) ,8.18(d,J=8.0Hz,1H),7.94(d,J=8.0Hz,1H),7.79(d,J=8.2Hz,1H),7.67- 7.59(m,4H),7.57-7.47(m,5H),4.57(s,2H),4.34(s,2H),3.56(s,2H),3.4 4(t,J=5.9Hz,2H),2.37-2.29(m,1H),1.94-1.83(m,2H),1.12-1.04(m,4H).

[0431] Example 35

[0432]

[0433] Synthesis of compound 35

[0434] Step 1: Compound 35-A

[0435] Compound 35-A was prepared by referring to Example 4 using 2-bromo-N-(3-methoxyphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 729;

[0436] Step 2: Compound 35

[0437] Compound 35 was prepared by referring to Example 11 and replacing compound 11-A with compound 35-A. m / z: [M+1] + 715;

[0438] 1H NMR (400MHz, DMSO-d6): δ13.00(s,1H),10.22(s,1H),8.23(s,1H),7.67-7.56 (m,3H),7.52(q,J=7.3Hz,2H),7.31(s,1H),7.22(t,J=8.2Hz,1H),7.11(d,J=8 .1Hz,1H),6.65(d,J=8.0Hz,1H),4.40(s,2H),4.33(s,2H),3.72(s,3H),3.51 (s,2H),3.41(s,2H),2.35-2.31(m,1H),1.87-1.83(m,2H),1.13-1.06(m,4H).

[0439] Example 36

[0440]

[0441] Step 1: Compound 36-A

[0442] Compound 36-A was prepared by referring to Example 4 using 2-bromo-N-(4-methoxyphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 729;

[0443] Step 2: Compound 36

[0444] Compound 36 was prepared by referring to Example 11 and substituting compound 36-A for compound 11-A. m / z: [M+1] + 715;

[0445] 1 H NMR (400MHz, DMSO-d6): δ13.00(s,1H),10.08(s,1H),8.23(s,1H),7.67-7.46(m,7H),6.89(d,J=8.6Hz,2H),4.3 7(s,2H),4.33(s,2H),3.72(s,2H),3.51(m,2H),3.42(m,3H),2.33(s,1H),1.95-1.78(m,2H),1.13-1.06(m,4H).

[0446] Example 37

[0447]

[0448] Synthesis of compound 37

[0449] Step 1: Compound 37-A

[0450] Compound 37-A was prepared by referring to Example 4 using 2-bromo-N-(3-chlorophenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 733;

[0451] Step 2: Compound 37

[0452] Compound 37 was prepared by referring to Example 11 and replacing compound 11-A with compound 37-A. m / z: [M+1] + 719;

[0453] 1 H NMR (400MHz, DMSO-d6): δ13.04(s,1H),10.47(s,1H),8.22(s,1H),7.81(s,1H) ,7.70-7.62(m,2H),7.59-7.49(m,3H),7.47-7.43(d,J=8.2Hz,1H),7.38-7.33( t,J=8.1Hz,1H),7.13(d,J=7.7Hz,1H),4.43(s,2H),4.33(s,2H),3.51(s,2H), 3.41(t,J=5.9Hz,2H),2.37-2.30(m,1H),1.88-1.81(m,2H),1.12-1.07(m,4H).

[0454] Example 38

[0455]

[0456] Synthesis of compound 38

[0457] Step 1: Compound 38-A

[0458] Compound 38-A was prepared by referring to Example 4 using 2-bromo-N-(4-chlorophenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 733;

[0459] Step 2: Compound 38

[0460] Compound 38 was prepared by referring to Example 11 and replacing compound 11-A with compound 38-A. m / z: [M+1] + 719;

[0461] 1H NMR (400MHz, DMSO-d6): δ10.42(s,1H),8.21(d,J=1.5Hz,1H),7.66-7.61(m,4H),7.58-7.48(m,3H),7.38(d,J=8.9Hz,2H ),4.42(s,2H),4.33(s,2H),3.51(s,2H),3.41(t,J=6.0Hz,2H),2.36-2.30(m,1H),1.89-1.81(m,2H),1.12-1.06(m,4H).

[0462] Example 39

[0463]

[0464] Step 1: Compound 39-A

[0465] Compound 39-A was prepared by referring to Example 4 using 2-bromo-N-(3-methylphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 733;

[0466] Step 2: Compound 39

[0467] Compound 39 was prepared by referring to Example 11 and substituting compound 39-A for compound 11-A. m / z: [M+1] + 719;

[0468] 1 H NMR (400MHz, DMSO-d6): δ12.90(s,1H),10.15(s,1H),8.26(s,1H),7.67-7.57( m,3H),7.55-7.48(m,2H),7.45(s,1H),7.35(d,J=7.9Hz,1H),7.19(t,J=7.8Hz, 1H),6.88(d,J=7.3Hz,1H),4.45(s,2H),4.33(s,2H),3.52(s,2H),3.41(t,J=6. 0Hz,2H),2.36-2.31(m,1H),2.27(s,3H),1.90-1.81(m,2H),1.13-1.05(m,4H).

[0469] Example 40

[0470]

[0471] Synthesis of compound 40

[0472] Step 1: Compound 40-A

[0473] Compound 40-A was prepared by referring to Example 4 using 2-bromo-N-(4-methylphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 713;

[0474] Step 2: Compound 40

[0475] Compound 40 was prepared by referring to Example 11 and using compound 40-A instead of compound 11-A. m / z: [M+1] + 699;

[0476] 1 H NMR (400MHz, DMSO-d6): δ12.98(s,1H),10.13(s,1H),8.23(d,J=1.6Hz,1H),7.66-7.57(m,3H),7.56-7.50(m,2H),7.47(d,J=8.4Hz,2H),7.12(d, J=8.2Hz,2H),4.42(s,2H),4.33(s,2H),3.52(s,2H),3.41(t,J=5.9Hz,2 H),2.36-2.30(m,1H),2.25(s,3H),1.90-1.81(m,2H),1.12-1.04(m,4H).

[0477] Example 41

[0478]

[0479] Synthesis of compound 41

[0480] Step 1: Compound 41-A

[0481] Compound 41-A was prepared by referring to Example 4 using 2-bromo-N-(2-methylphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 713;

[0482] Step 2: Compound 41

[0483] Compound 41 was prepared by referring to Example 11 and substituting compound 41-A for compound 11-A. m / z: [M+1] + 699;

[0484] 1H NMR (400MHz, DMSO-d6): δ13.06 (s, 1H), 9.59 (s, 1H), 8.23 (d, J = 1.6Hz, 1H), 7.67-7 .60(m,3H),7.56-7.50(m,2H),7.37(d,J=6.4Hz,1H),7.21(d,J=7.2Hz,1H),7.16(t ,J=7.6Hz,1H),7.11-7.07(m,1H),4.43(s,2H),4.33(s,2H),3.53(s,2H),3.42(t,J =5.9Hz,2H),2.36-2.31(m,1H),2.21(s,3H),1.89-1.82(m,2H),1.12-1.07(m,4H).

[0485] Example 42

[0486]

[0487] Synthesis of compound 42

[0488] Step 1: Compound 42-A

[0489] Compound 42-A was prepared by referring to Example 4 using 2-bromo-N-(2-chlorophenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 733;

[0490] Step 2: Compound 42

[0491] Compound 42 was prepared by referring to Example 11 and replacing compound 11-A with compound 42-A. m / z: [M+1] + 719;

[0492] 1 H NMR (600MHz, CDCl3): δ9.16 (s, 1H), 8.31 (d, J = 8.3Hz, 1H), 8.15 (d, J = 1.5Hz, 1H), 7.79 (d d,J=10.8,1.5Hz,1H),7.56(dd,J=7.5,1.8Hz,1H),7.48-7.44(m,1H),7.39-7.29(m,4H) ,7.04(td,J=7.7,1.5Hz,1H),4.45(s,2H),4.36(s,2H),3.52(t,J=7.4Hz,2H),3.41(t,J =5.6Hz,2H),2.11-2.08(m,1H),1.96-1.92(m,2H),1.23-1.21(m,2H),1.11-1.07(m,2H).

[0493] Example 43

[0494]

[0495] Synthesis of compound 43

[0496] Step 1: Compound 43-A

[0497] Compound 43-A was prepared by referring to Example 4 using 2-bromo-N-(2-methoxyphenyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 729;

[0498] Step 2: Compound 43

[0499] Compound 43 was prepared by referring to Example 11 and substituting compound 43-A for compound 11-A. m / z: [M+1] + 715;

[0500] 1 H NMR (600MHz, DMSO-d6): δ13.00(s,1H),9.47(s,1H),8.23(d,J=1.5Hz,1H),7. 98(d,J=8.0Hz,1H),7.66-7.58(m,3H),7.55-7.48(m,2H),7.11-7.03(m,2H),6 .90(t,J=7.5Hz,1H),4.49(s,2H),4.32(s,2H),3.82(s,3H),3.50(brs,2H),3 .40(t,J=6.0Hz,2H),2.36-2.30(m,1H),1.87-1.81(m,2H),1.13-1.04(m,4H).

[0501] Example 44

[0502]

[0503] Synthesis of compound 57-B

[0504] Step 1: Compound 57-A

[0505] Compound 57-A was prepared by referring to Example 4 using 2-bromo-N-propyl-N-acetanilide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 741;

[0506] 1H NMR (400MHz, DMSO-d6): δ8.25 (d, J=1.5Hz, 1H), 7.66-7.59 (m, 3H), 7.56-7.4 4(m,7H),4.28(s,2H),4.00(s,2H),3.86(s,3H),3.60(t,J=7.2Hz,2H),3.43 (s,2H),3.33(s,2H),2.31(td,J=8.0,3.9Hz,1H),1.76(d,J=7.0Hz,2H),1.4 2(q,J=7.2Hz,2H),1.07(ddt,J=10.8,5.1,2.7Hz,4H),0.82(t,J=7.3Hz,3H).

[0507] Step 2: Compound 57-B

[0508] Compound 57-B was prepared by referring to Example 11 and replacing compound 11-A with compound 57-A. m / z: [M+1] + 727;

[0509] 1 H NMR (400MHz, DMSO-d6): δ8.20(d,J=1.4Hz,1H),7.64-7.59(m,3H),7.56-7.42(m,7H),4.28(s,2H),4.07-3.94(m,2H),3.60(t,J=7. 2Hz,2H),3.52-3.32(m,4H),2.35-2.27(m,1H),1.80-1.72(m,2H),1.42(q,J=7.4Hz,2H),1.11-1.04(m,4H),0.82(t,J=7.4Hz,3H).

[0510] Example 45

[0511]

[0512] Synthesis of compound 58-B

[0513] Step 1: Compound 58-A

[0514] Compound 58-A was prepared by referring to Example 4 using 2-bromo-N-isopropyl-N-acetanilide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 741;

[0515] 1H NMR (400MHz, DMSO-d6): δ8.25(d,J=1.5Hz,1H),7.67-7.59(m,3H),7.57-7.46(m,5H),7.39(d,J=7.4Hz,2H),4.84-4.74(m,1H),4.27(s ,2H),3.86(s,3H),3.84(s,2H),3.52-3.33(m,4H),2.33-2.26(m,1H),1.80-1.65(m,2H),1.09(d,J=8.7Hz,4H),1.00(d,J=6.8Hz,6H).

[0516] Step 2: Compound 58-B

[0517] Compound 58-B was prepared by referring to Example 11 and replacing compound 11-A with compound 58-A. m / z: [M+1] + 727;

[0518] 1 H NMR (600MHz, DMSO-d6): δ12.96(s,1H),8.20(s,1H),7.64-7.58(m,3H),7.53(t,J= 7.5Hz,3H),7.49(t,J=7.2Hz,2H),7.40(d,J=7.5Hz,2H),4.83-4.76(m,1H),4.27( s,2H),3.84(s,2H),3.50-3.36(m,2H),3.32(d,J=6.0Hz,2H),2.33-2.26(m,1H),1 .73(t,J=6.8Hz,2H),1.11-1.07(m,2H),1.07-1.04(m,2H),1.00(d,J=6.8Hz,6H).

[0519] Example 46

[0520]

[0521] Synthesis of compound 59-B

[0522] Step 1: Compound 59-A

[0523] Compound 59-A was prepared by referring to Example 4 using 2-bromo-N-(methoxyethyl)-N-acetanilide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 757;

[0524] Step 2: Compound 59-B

[0525] Compound 59-B was prepared by referring to Example 11 and replacing compound 11-A with compound 59-A. m / z: [M+1] + 743;

[0526] Example 47

[0527]

[0528] Synthesis of compound 60-B

[0529] Step 1: Compound 60-A

[0530] Compound 60-A was prepared by referring to Example 4 using N-benzyl-2-bromo-N-ethylacetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 741;

[0531] 1 H NMR (400MHz, DMSO-d6): δ8.27(t,J=1.9Hz,1H),7.68-7.62(m,3H),7.57-7.48(m,2H),7.44-7.26(m,5H),4.61-4.53(m,4H),4.3 2(d,J=12.4Hz,2H),3.86(s,3H),3.55-3.37(m,4H),3.29-3.15(m,2H),2.37-2.30(m,1H),1.90-1.77(m,2H),1.12-0.94(m,7H).

[0532] Step 2: Compound 60-B

[0533] Compound 60-B was prepared by referring to Example 11 and replacing compound 11-A with compound 60-A. m / z: [M+1] + 727;

[0534] 1 H NMR (400MHz, DMSO-d6): δ12.95 (s, 1H), 8.22 (d, J = 1.8Hz, 1H), 7.67-7.60 ( m,3H),7.57-7.49(m,2H),7.43-7.39(m,1H),7.32-7.29(m,1H),7.28-7.2 3(m,3H),4.63-4.53(m,4H),4.32(d,J=12.3Hz,2H),3.50-3.36(m,4H),3. 30-3.14(m,2H),2.37-2.30(m,1H),1.87-1.77(m,2H),1.12-0.97(m,7H).

[0535] Example 48

[0536]

[0537] Synthesis of compound 61-B

[0538] Step 1: Compound 61-A

[0539] Compound 61-A was prepared by referring to Example 4 using 2-bromo-N-(1-phenylethyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 727;

[0540] 1 H NMR (400MHz, DMSO-d6): δ8.59(d,J=7.9Hz,1H),8.26(d,J=1.5Hz,1H),7.68-7.61(m,3H), 7.55-7.48(m,2H),7.34(d,J=7.2Hz,2H),7.28(t,J=7.5Hz,2H),7.20(t,J=7.2Hz,1H),4.9 3(t,J=7.3Hz,1H),4.31(s,2H),4.29-4.15(m,2H),3.86(s,3H),3.46(s,2H),3.38(t,J=5 .9Hz,2H),2.36-2.29(m,1H),1.85-1.77(m,2H),1.38(d,J=7.0Hz,3H),1.12-1.06(m,4H).

[0541] Step 2: Compound 61-B

[0542] Compound 61-B was prepared by referring to Example 11 and replacing compound 11-A with compound 61-B. m / z: [M+1] + 713;

[0543] 1H NMR (400MHz, DMSO-d6): δ12.92(s,1H),8.59(d,J=7.9Hz,1H),8.21(d,J=1.5Hz,1H),7.65 -7.60(m,3H),7.54-7.48(m,2H),7.35(d,J=7.1Hz,2H),7.29(t,J=7.4Hz,2H),7.23-7.18 (m,1H),4.93(t,J=7.3Hz,1H),4.31(s,2H),4.27-4.13(m,2H),3.46(s,2H),3.39(d,J=5. 9Hz,2H),2.36-2.29(m,1H),1.85-1.78(m,2H),1.38(d,J=7.0Hz,3H),1.12-1.06(m,4H).

[0544] Example 49

[0545]

[0546] Synthesis of compound 62-B

[0547] Step 1: Compound 62-A

[0548] Compound 62-A was prepared by referring to Example 4 using 2-bromo-N-(1-phenylpropyl)acetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 741;

[0549] 1 H NMR (400MHz, DMSO-d6): δ8.52(d,J=8.3Hz,1H),8.25(d,J=1.6Hz,1H),7.70-7.58(m,3 H),7.54-7.47(m,2H),7.34-7.26(m,4H),7.20(t,J=6.9Hz,1H),4.76-4.65(m,1H),4. 30(s,2H),4.24(s,2H),3.86(s,3H),3.46(s,2H),3.37(t,J=5.9Hz,2H),2.36-2.26(m ,1H),1.86-1.76(m,2H),1.75-1.66(m,2H),1.13-1.05(m,4H),0.87(t,J=7.2Hz,3H).

[0550] Step 2: Compound 62-B (BE048-133-P1)

[0551] Compound 62-B was prepared by referring to Example 11 and replacing compound 11-A with compound 62-A. m / z: [M+1] + 727;

[0552] 1 H NMR (400MHz, DMSO-d6): δ12.83(s,1H),8.52(d,J=8.4Hz,1H),8.21(d,J=1.5Hz,1H), 7.65-7.59(m,3H),7.54-7.47(m,2H),7.34-7.27(m,4H),7.23-7.18(m,1H),4.74-4.6 8(m,1H),4.30(s,2H),4.23(s,2H),3.46(s,2H),3.37(t,J=5.8Hz,2H),2.35-2.29(m ,1H),1.84-1.77(m,2H),1.74-1.66(m,2H),1.11-1.05(m,4H),0.87(t,J=7.3Hz,3H).

[0553] Example 50

[0554]

[0555] Synthesis of compound 64-B

[0556] Step 1: Compound 64-A (BE048-124-P1)

[0557] Compound 64-A was prepared by referring to Example 4 using N-benzyl-2-bromo-N-methylacetamide instead of 2-bromo-N-(pyrrolidin-1-yl)acetamide. m / z: [M+1] + 727;

[0558] Compound 64-A showed a mixture of isomers on NMR, with a ratio of a:b of approximately 2:1;

[0559] Isomer a 1 H NMR (400MHz, DMSO-d6): δ8.26(d,J=1.5Hz,1H),7.68-7.61(m,3H),7.57-7.49(m,2H),7.43-7.23(m,5H),4.63-4.50(m, 4H),4.33(s,2H),3.86(s,3H),3.52-3.35(m,4H),2.98(s,3H),2.38-2.29(m,1H),1.88-1.74(m,2H),1.13-1.05(m,4H).

[0560] Isomer b 1H NMR (400MHz, DMSO-d6): δ8.26(d,J=1.5Hz,1H),7.68-7.61(m,3H),7.57-7.49(m,2H),7.43-7.23(m,5H),4.63-4.50(m, 4H),4.31(s,2H),3.86(s,3H),3.52-3.35(m,4H),2.80(s,3H),2.38-2.29(m,1H),1.88-1.74(m,2H),1.13-1.05(m,4H).

[0561] Step 2: Compound 64-B

[0562] Compound 64-B was prepared by referring to Example 11 and replacing compound 11-A with compound 64-A. m / z: [M+1] + 713;

[0563] Compound 64-B was shown to be a mixture of isomers on NMR, with a ratio of a:b of approximately 2:1;

[0564] Isomer a 1 H NMR (400MHz, DMSO-d6): δ12.93(s,1H),8.22(d,J=1.5Hz,1H),7.66-7.60(m,3H),7.56-7.49(m,2H),7.42(d,J=4.3Hz,1H),7.32(dd,J=9.1,5.7Hz ,2H),7.28-7.22(m,2H),4.62-4.52(m,4H),4.33(s,2H),3.50-3.37(m,4 H),2.98(s,3H),2.37-2.30(m,1H),1.87-1.78(m,2H),1.12-1.06(m,4H).

[0565] Isomer b 1 H NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.66-7.60 (m, 3H), 7.56-7.49 (m, 2H), 7.42 (d, J = 4.3 Hz, 1H), 7.32 (dd, J = 9.1, 5.7 Hz, 2H), 7.28-7.22 (m, 2H), 4.62-4.52 (m, 4H), 4.31 (s, 2H), 3.50-3.37 (m, 4H), 2.80 (s, 3H), 2.37-2.30 (m, 1H), 1.87-1.78 (m, 2H), 1.12-1.06 (m, 4H). Example 51

[0566]

[0567] Synthesis of compound 44-B

[0568] Step 1: Compound 44-A

[0569] Compound 23 (70 mg, 1.0 eq.) was dissolved in dichloromethane (2.5 mL). 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (51 mg, 1.4 eq.) and diisopropylethylamine (30 μL, 1.5 eq.) were added under nitrogen at 0°C in an ice bath. After stirring for 30 minutes, 2-aminopyridine (13 mg, 1.2 eq.) was added and the mixture was allowed to react at room temperature for 16 hours. The reaction mixture was adjusted to weak acidity with 0.1 mol / L dilute hydrochloric acid, diluted with water, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography yielded 34 mg of a white solid with a purity of 95.0% and a yield of 43%. m / z: [M+1] + 700;

[0570] 1 H NMR (400MHz, DMSO-d6): δ10.79(s,1H),8.35(dd,J=5.3,1.9Hz,1H),8.27(d,J=1. 5Hz,1H),8.07-7.93(m,1H),7.83-7.73(m,1H),7.67-7.59(m,3H),7.55-7.48(m,2 H),7.12(dd,J=7.5,5.0Hz,1H),4.50(s,2H),4.33(s,2H),3.85(s,3H),3.50(s,2H ),3.40(t,J=5.9Hz,2H),2.37-2.30(m,1H),1.88-1.80(m,2H),1.12-1.04(m,4H).

[0571] Step 2: Compound 44-B

[0572] Compound 44-B was prepared by referring to Example 11 and replacing compound 11-A with compound 44-A. m / z: [M+1] + 686;

[0573] 1H NMR (400MHz, DMSO-d6): δ12.99(s,1H),10.78(s,1H),8.35(dd,J=5.0,1.8Hz,1H ),8.22(d,J=1.7Hz,1H),8.02(d,J=8.4Hz,1H),7.81-7.75(m,1H),7.65-7.60(m ,3H),7.54-7.50(m,2H),7.17-7.08(m,1H),4.50(s,2H),4.33(s,2H),3.50(s,2 H),3.41-3.39(m,2H),2.35-2.31(m,1H),1.86-1.81(m,2H),1.12-1.08(m,4H).

[0574] Example 52

[0575]

[0576] Synthesis of compound 45-B

[0577] Step 1: Compound 45-A

[0578] Compound 45-A was prepared by referring to Example 44 and using 3-aminopyridine instead of 2-aminopyridine. m / z: [M+1] + 700;

[0579] 1 H NMR (400MHz, DMSO-d6): δ10.47 (s, 1H), 8.74 (d, J = 2.5Hz, 1H), 8.28 (dd, J = 4. 5,1.5Hz,2H),8.07-7.97(m,1H),7.68-7.58(m,3H),7.55-7.45(m,2H),7.36( dd,J=8.3,4.7Hz,1H),4.46(s,2H),4.33(s,2H),3.85(s,3H),3.52(s,2H),3. 42(t,J=5.9Hz,2H),2.37-2.30(m,1H),1.91-1.81(m,2H),1.14-1.04(m,4H).

[0580] Step 2: Compound 45-B

[0581] Compound 45-B was prepared by referring to Example 11 and replacing compound 11-A with compound 45-A. m / z: [M+1] + 686;

[0582] 1H NMR (400MHz, CDCl3): δ10.37(s,1H),8.60(s,1H),8.32(dd,J=18.2,6.5Hz,2 H),8.10(s,1H),7.80(d,J=11.0Hz,1H),7.58-7.53(m,1H),7.50-7.45(m,1H ),7.39-7.32(m,3H),4.35(s,4H),3.53-3.48(m,2H),3.41(t,J=5.6Hz,2H), 2.12-2.06(m,1H),1.97-1.89(m,2H),1.23-1.18(m,2H),1.11-1.05(m,2H).

[0583] Example 53

[0584]

[0585] Synthesis of compound 46-B

[0586] Step 1: Compound 46-A

[0587] Compound 46-A was prepared by referring to Example 44 and using 4-aminopyridine instead of 2-aminopyridine. m / z: [M+1] + 700;

[0588] 1 H NMR (400MHz, DMSO-d6): δ10.63(s,1H),8.44(d,J=5.4Hz,2H),8.28(d,J=1.6Hz,1H),7.68-7.58(m,3H),7.59-7.47(m,4H),4.46 (s,2H),4.33(s,2H),3.85(s,3H),3.50(s,2H),3.41(t,J=5.9Hz,2H),2.37-2.29(m,1H),1.89-1.81(m,2H),1.13-1.04(m,4H).

[0589] Step 2: Compound 46-B

[0590] Compound 46-B was prepared by referring to Example 11 and replacing compound 11-A with compound 46-A. m / z: [M+1] + 686;

[0591] 1H NMR (400MHz, DMSO-d6): δ12.97(s,1H),10.68(s,1H),8.48-8.41(m,2H),8.23(d,J =1.6Hz,1H),7.64(dd,J=7.8,2.0Hz,2H),7.62-7.59(m,1H),7.58-7.56(m,2H),7. 54-7.52(m,1H),7.41-7.36(m,1H),4.46(s,2H),4.33(d,J=2.8Hz,2H),3.50(s,2H ),3.41(t,J=5.8Hz,2H),2.35-2.32(m,1H),1.86-1.82(m,2H),1.11-1.07(m,4H).

[0592] Example 54

[0593]

[0594] Synthesis of compound 47

[0595] Step 1: Compound 47-A

[0596] Compound 47-A was prepared by referring to Example 44 and replacing 2-aminopyridine with 3-aminoquinoline. m / z: [M+1] + 750;

[0597] 1 H NMR (400MHz, DMSO-d6): δ10.75(s,1H),8.93(d,J=2.6Hz,1H),8.71(d,J=2.5Hz,1H),8.29(d,J=1.6Hz,1H),8.00-7.87(m,2H),7.69-7.48( m,7H),4.53(s,2H),4.34(s,2H),3.85(s,3H),3.55(s,2H),3.44(t,J=5.9Hz,2H),2.38-2.30(m,1H),1.93-1.84(m,2H),1.14-1.04(m,4H).

[0598] Step 2: Compound 47-B

[0599] Compound 47-B was prepared by referring to Example 11 and replacing compound 11-A with compound 47-A. m / z: [M+1] + 736;

[0600] 1H NMR (400MHz, CDCl3): δ10.88(s,1H),8.91(s,1H),8.74(s,1H),8.26-8.09(m,2H),7.91( d,J=11.0Hz,1H),7.82(d,J=8.2Hz,1H),7.66(t,J=7.7Hz,1H),7.60-7.51(m,2H),7.49-7 .43(m,1H),7.39-7.31(m,2H),4.42(s,2H),4.36(s,2H),3.53(t,J=7.3Hz,2H),3.42(t,J =5.5Hz,2H),2.13-2.07(m,1H),2.00-1.92(m,2H),1.24-1.18(m,2H),1.12-1.04(m,2H).

[0601] Example 55

[0602]

[0603] Synthesis of compound 48

[0604] Step 1: Compound 48-1

[0605] Compound 48-1 was prepared by referring to Example 1 and replacing N-Boc-ethanolamine with tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate. m / z: [M+1] + 485;

[0606] Step 2: Compound 48-2

[0607] Compound 48-2 was prepared by replacing compound 1-1 with compound 48-1 according to Example 1. m / z: [M+1] + 385;

[0608] Step 3: Compound 48-A

[0609] Compound 48-A was prepared by using compound 48-2 instead of compound 1-2 according to Example 1. m / z: [M+1] + 594;

[0610] Step 4: Compound 48-B

[0611] Compound 48-B was prepared by referring to Example 11 and replacing compound 11-A with compound 48-A. m / z: [M+1] + 580;

[0612] 1H NMR (400MHz, DMSO-d6): δ12.88(brs,1H),8.37(s,1H),8.12(d,J=1.5Hz,1H),7.65-7.60(m,2H),7.57-7.46(m,3H),4 .35-4.29(m,4H),4.33(s,2H),3.22(d,J=5.5Hz,2H),3.10(s,2H),2.33-2.26(m,1H),1.10-1.04(m,4H),0.78(s,6H).

[0613] Example 56

[0614]

[0615] Synthesis of compound 49

[0616] Step 1: Compound 49-A

[0617] Compound 49-A was prepared by referring to Example 11 using bromoethane instead of 1-bromopropane. m / z: [M+1] + 622;

[0618] Step 2: Compound 49

[0619] Compound 49-B was prepared by referring to Example 11 and replacing compound 11-A with compound 49-A. m / z: [M+1] + 608;

[0620] 1 H NMR (400MHz, CDCl3): δ8.14(d,J=1.5Hz,1H),7.76(dd,J=11.1,1.5Hz,1H),7.62-7.56(m,1H),7.55-7.49(m,1H),7.43-7.35(m,2H),4.36(s,2H) ),3.61-3.53(m,2H),3.38(s,2H),3.12(s,2H),2.17-2.09(m,1H),1.25 (t,J=3.7Hz,2H),1.22(t,J=7.1Hz,3H),1.16-1.08(m,2H),0.90(s,6H).

[0621] Example 57

[0622]

[0623] Synthesis of compound 55-B

[0624] Step 1: Compound 55-A

[0625] Compound 55-A was prepared by referring to Example 11 using iodomethane instead of 1-bromopropane. m / z: [M+1] + 608;

[0626] 1 H NMR (400MHz, DMSO-d6): δ7.98(d,J=1.6Hz,1H),7.68-7.58(m,3H),7.55-7.45(m,2H),4.30(s,2H),3.84(s ,3H),3.54(d,J=3.3Hz,3H),3.12(s,2H),2.75(s,2H),2.33-2.26(m,1H),1.11-1.02(m,4H),0.78(s,6H).

[0627] Step 2: Compound 55-B

[0628] Compound 55-B was prepared by referring to Example 11 and replacing compound 11-A with compound 55-A. m / z: [M+1] + 594;

[0629] 1 H NMR (400MHz, CDCl3): δ8.11(s,1H),7.74(d,J=11.1Hz,1H),7.56(dd,J=7.8,1.8Hz,1H),7.52-7.47(m,1H),7.39-7.34(m,2H ),4.34(s,2H),3.38(s,2H),3.15(s,3H),3.10(s,2H),2.12-2.08(m,1H),1.24-1.21(m,2H),1.11-1.07(m,2H),0.88(s,6H).

[0630] Example 58

[0631]

[0632] Synthesis of compound 56-B

[0633] Step 1: Compound 56-A

[0634] Compound 56-A was prepared by referring to Example 11 using 2-bromo-N-ethyl-N-acetanilide instead of 1-bromopropane. m / z: [M+1] + 755;

[0635] Step 2: Compound 56-B

[0636] Compound 56-B was prepared by referring to Example 11 and replacing compound 11-A with compound 56-A. m / z: [M+1]+ 741;

[0637] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),8.18(d,J=1.5Hz,1H),7.65-7.57(m,3H),7.55-7.40(m,7H),4.28(s,2H),3.94(s ,2H),3.63(d,J=7.3Hz,2H),3.02(s,2H),2.24(d,J=13.2Hz,1H),1.10-1.03(m,4H),0.99(t,J=6.7Hz,3H),0.72(s,6H).

[0638] Example 59

[0639]

[0640] Synthesis of compound 63-B

[0641] Step 1: Compound 63-A

[0642] Compound 63-A was prepared by referring to Example 11 and replacing 1-bromopropane with N-benzyl-2-bromoacetamide. m / z: [M+1] + 622;

[0643] Step 2: Compound 63-B

[0644] Compound 63-B was prepared by referring to Example 11 and replacing compound 11-A with compound 63-A. m / z: [M+1] + 608;

[0645] 1 H NMR (400MHz, DMSO-d6): δ13.03(s,1H),8.66(t,J=6.0Hz,1H),7.96(d,J=1.6Hz,1H),7.66-7.47(m,5H),7.31-7.26(m,2H),7.22(d,J =6.9Hz,2H),4.78(s,2H),4.29(d,J=5.9Hz,2H),4.25(s,2H),3.07(s,2H),2.77(s,2H),2.26(s,1H),1.10-1.00(m,4H),0.74(s,6H).

[0646] Example 60

[0647]

[0648] Preparation of compound 50-B

[0649] Step 1: Compound 50-1

[0650] tert-Butyl 2-(methylamino)ethylcarbamate (522 mg, 2 eq.) and compound B (433 mg, 1 eq.) were dissolved in tetrahydrofuran (5 mL). Triethylamine (150 mg, 3 eq.) was added and stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined organic phases were washed with purified water and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and slurried with diethyl ether to obtain 525 mg of a white solid product with a purity of 99% and a yield of 91%. m / z: [M+1] + 384;

[0651] Step 2: Compound 50-2

[0652] Compound 50-1 (334 mg, 1 eq.) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (4 mL, 40 eq.) was added. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure to obtain 170 mg of a light yellow oil with a purity of 98.0% and a yield of 69%. m / z: [M+1] + 284;

[0653] Step 3: Compound 50-A

[0654] Compound A (48 mg, 1 eq.) and compound 50-2 (82 mg, 2 eq.) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (98 mg, 2 eq.) was added. The mixture was allowed to react overnight at room temperature. The mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude product. Purification by silica gel column chromatography afforded 24 mg of a white solid with a purity of 96% and a yield of 28%. m / z: [M+1] + 565;

[0655] 1 H NMR (400MHz, CDCl3): δ8.10(d,J=1.4Hz,1H),7.73(dd,J=11.4,1.4Hz,1H),7.53(dd,J=7.5,1.6Hz,1H),7.50-7.45(m,1H),7.35(dd,J=7.9,3.2 Hz,2H),3.94(s,3H),3.70-3.64(m,4H),3.14(s,3H),2.88(t,J=6.1Hz, 2H),2.15(td,J=8.4,4.2Hz,1H),1.16-1.20(m,2H),1.04-1.00(m,2H).

[0656] Step 4: Compound 50-B

[0657] Compound 50-B was prepared by using compound 50-A instead of compound 1-A according to Example 1. m / z: [M+1] + 565;

[0658] 1 H NMR (600MHz, DMSO-d6): δ8.20(s,1H),7.67(dd,J=7.6,1.4Hz,1H),7.62-7.57(m,2H),7.47(dd,J=19.5,7.9H z,2H),3.59-3.53(m,4H),3.07(s,3H),2.74(t,J=6.0Hz,2H),2.34-2.30(m,1H),1.00(dd,J=9.3,5.9Hz,4H).

[0659] Example 61

[0660]

[0661] Synthesis of compound 51-B

[0662] Step 1: Compound 51-1

[0663] Compound 51-1 was prepared by referring to Example 50 and replacing tert-butyl 2-(methylamino)ethylcarbamate with tert-butyl methyl(2-(methylamino)ethyl)carbamate. m / z: [M+1] + 398;

[0664] Step 2: Compound 51-2

[0665] Compound 51-2 was prepared by referring to Example 50 and replacing compound 50-1 with compound 51-1. m / z: [M+1] + 298;

[0666] Step 3: Compound 51-A

[0667] Compound 51-A was prepared by referring to Example 50 and replacing compound 50-2 with compound 51-2. m / z: [M+1] + 579;

[0668] 1H NMR (400MHz, CDCl3): δ7.60-7.46(m,4H),7.41-7.34(m,2H),4.00(s,2H),3.88(s,3H),3.43-3.36 (m,2H),3.36-3.27(m,2H),2.62(s,6H),2.18-2.10(m,1H),1.19-1.14(m,2H),1.02-1.07(m,2H).

[0669] Step 4: Compound 51-B

[0670] Compound 51-B was prepared by using compound 51-A instead of compound 50-A according to Example 1. m / z: [M+1] + 565;

[0671] 1 H NMR (400MHz, CDCl3): δ7.63(s,1H),7.58-7.53(m,2H),7.53-7.48(m,1H),7.40-7.36(m,2H),4.01(s,2H),3 .42-3.39(m,2H),3.38-3.33(m,2H),2.64(s,6H),2.18-2.13(m,1H),1.20-1.16(m,2H),1.09-1.04(m,2H).

[0672] Example 62

[0673]

[0674] Synthesis of compound 52

[0675] Step 1: Compound 52-1

[0676] Referring to Example 50, compound 52-1 was prepared by replacing tert-butyl 2-(methylamino)propylcarbamate with tert-butyl 2-(methylamino)ethylcarbamate. m / z: [M+1] + 398;

[0677] Step 2: Compound 52-2

[0678] Compound 52-2 was prepared by referring to Example 50 and replacing compound 50-1 with compound 52-1. m / z: [M+1] + 298;

[0679] Step 3: Compound 52-A

[0680] Compound 52-A was prepared by referring to Example 50 and replacing compound 50-2 with compound 52-2. m / z: [M+1]+ 579;

[0681] Step 4: Compound 51-B

[0682] Compound 52-B was prepared by using compound 52-A instead of compound 50-A according to Example 1. m / z: [M+1] + 565;

[0683] 1 H NMR (600MHz, DMSO-d6): δ8.2(s,1H),7.72-7.68(m,1H),7.65-7.61(m,1H),7.59(d,J=11.5Hz,1H),7.51(dd,J=13.8,6.7H z,2H),3.61(s,2H),3.51(s,2H),3.28-3.20(s,2H),3.09(s,3H),2.41-2.36(m,1H),1.76-1.67(m,2H),1.10-1.05(m,4H).

[0684] Example 63

[0685]

[0686] Synthesis of compound 53-B

[0687] Step 1: Compound 53-A

[0688] Compound 52-A (38 mg, 1 eq.) and iodomethane (9 mg, 1 eq.) were dissolved in acetonitrile (2 mL). Potassium carbonate (9 mg, 1 eq.) was added and allowed to react overnight. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography to yield 20 mg of a colorless oil with a purity of 99% and a yield of 50%. m / z: [M+1] + 592;

[0689] 1H NMR (400MHz, CDCl3): δ8.10(d,J=1.5Hz,1H),7.72(dd,J=11.3,1.5Hz,1H),7.59(d d,J=7.6,1.6Hz,1H),7.50-7.46(m,1H),7.36(dd,J=11.6,4.2Hz,2H),3.93(s,3H), 3.36(s,2H),3.34-3.28(m,2H),3.13(s,3H),2.31(t,J=6.5Hz,2H),2.21-2.16(m,1 H),2.09(s,3H),1.75-1.71(m,2H),1.23(dd,J=5.0,2.4Hz,2H),1.12-1.08(m,2H).

[0690] Step 2: Compound 53-B

[0691] Compound 53-B was prepared by using compound 53-A instead of compound 1-A according to Example 1. m / z: [M+1] + 579;

[0692] 1 H NMR (400MHz, CDCl3): δ7.90(s,1H),7.66(dd,J=11.4,1.2Hz,1H),7.58(dd,J=7.5,1.6Hz,1H),7.50(dd,J=8.5,1.6Hz,1H),7.42-7.38(m,2H),3.68 (s,2H),3.39(s,2H),3.15(s,3H),2.54(s,2H),2.17(s,3H),2.10-1.95( m,1H),1.91-1.84(m,2H),1.26(dd,J=4.9,2.3Hz,2H),1.15-1.10(m,2H).

[0693] Example 64

[0694]

[0695] Synthesis of compound 54-B

[0696] Step 1: Compound 54-1

[0697] Compound 48-1 was prepared by referring to Example 1 using 4-(N-tert-butyloxycarbonylamino)-1-butanol instead of N-Boc-ethanolamine. m / z: [M+1] + 471;

[0698] Step 2: Compound 54-2

[0699] Compound 54-2 was prepared by replacing compound 1-1 with compound 54-1 according to Example 1. m / z: [M+1] + 371;

[0700] Step 3: Compound 54-3

[0701] Compound 54-3 was prepared by using compound 54-2 instead of compound 1-2 according to Example 1. m / z: [M+1] + 580;

[0702] Step 4: Compound 54-A

[0703] Compound 54-A was prepared by using compound 54-3 instead of compound 1-A according to Example 2. m / z: [M+1] + 594;

[0704] 1 H NMR (400MHz, DMSO-d6): δ8.26(d,J=1.6Hz,1H),7.64-7.56(m,3H),7.51-7.43(m,2H),4.30(s,2H),3.85(s,3H),3.48( brs,2H),3.32-3.29(m,2H),3.12(s,3H),2.33-2.26(m,1H),1.54-1.46(m,2H),1.44-1.37(m,2H),1.11-1.03(m,4H).

[0705] Compound 54-B was prepared by referring to Example 11 and replacing compound 11-A with compound 54-A. m / z: [M+1] + 580;

[0706] 1 H NMR (400MHz, DMSO-d6): δ8.16(d,J=1.2Hz,1H),7.63-7.55(m,3H),7.53-7.44(m,2H),4.30(s,2H),3.49-3.45(m,2 H),3.33(t,J=6.0Hz,2H),3.11(s,3H),2.34-2.26(m,1H),1.53-1.46(m,2H),1.45-1.38(m,4H),1.12-1.04(m,4H).

[0707] Compound Receptor Affinity Assay Method: Labeled human FXR (GST-FXR) (Cat. No. PV4834) protein (Invitrogen) and biotinylated SRC-1 peptide (Biotin-Src-1) (Cat. No. PV4586) were incubated with test compounds in HTRF assay buffer to achieve a dose response. After a 1-hour incubation in the dark, the plate was read on an Envision 2105 plate reader (Perkin Elmer). Each compound was tested in triplicate, and the mean values are displayed. Data were processed using GraphPad Prism 8.0 to calculate the EC50 value of receptor affinity.

[0708] The EC50 values reported in the FXR receptor affinity assay are as follows: A represents <100 nM, B represents 100 nM-500 nM, C represents 500 nM-1 μM, and D represents 1 μM-10 μM.

[0709] Table 1. FXR receptor affinity determination results

[0710] Compound number FXR affinity (EC50) Compound number FXR affinity (EC50) 1-B D 24 D 2-B C 25-B D 5-B C 28-B D 7-B B 30-B B 8-B B 32 B 9-B A 33 A 10-B B 48 A 11 B 54-B B 12 B 55-B A 14-B D 56-B B 15-B C 57-B A 16-B B 58-B A 18 B 60-B B 19-B B 61-B B 20-B D 64-B B 21 B

[0711] Compound cell-level activity assay

[0712] The restriction endonucleases, KOD PLUS high-fidelity DNA polymerase (Pfu DNA polymerase), LA-Taq DNA polymerase, T4 DNA polymerase, T4 DNA ligase, dNTPs, and T4 DNA ligase used in this example were purchased from TaKaRa. Other conventional reagents were imported or domestically produced analytical grade.

[0713] TEBuffer: 10mM Tris·HCl, 1mM EDTA (pH8.0);

[0714] Ampicillin: Prepare a 100 mg / mL stock solution with sterile water and store at -20°C.

[0715] The sequence from 500 bp upstream to 100 bp downstream of BSEP gene with GenBank accession number AC008177 was amplified by PCR and ligated into pGL3-Basic expression vector with double restriction enzyme sites KpnI and HindIII to construct recombinant plasmid pGL3-Basic-BSEP.

[0716] The FXR (NR1H4) sequence with GenBank accession number NM_001206977.1 was amplified by PCR and ligated into the pLVCS2.0 expression vector via the double restriction enzyme sites BamHI and SmaI to construct the recombinant plasmid pLV-FXR.

[0717] The RXRa sequence with GenBank accession number NM_002957 was amplified by PCR and ligated into the pLV CS2.0 expression vector via the double restriction enzyme sites XbaI and MluI to construct the recombinant plasmid pLV-RXRa.

[0718] The recombinant plasmid was transformed into competent Escherichia coli (E. coli) cells, spread on LB medium containing 30 μg / mL ampicillin, cultured at 37° C. overnight, harvested, and verified by colony PCR.

[0719] Plasmid construction and sequencing verification were performed by Wuhan Jinkairui Bioengineering Co., Ltd.

[0720] The gene amplification system is shown in Table 2 below:

[0721] Table 2

[0722]

[0723] The PCR amplification reaction conditions are shown in Table 3 below:

[0724] Table 3

[0725]

[0726] The vector and target fragment enzyme digestion system is as follows in Table 4:

[0727] Table 4

[0728]

[0729] Experimental method: Lipofectamin 2000 reagent and plasmids: 10ng pLV-hRXR, 10.4ng pLV-hFXR, 10.4ng pGL3-pBSEP-Luc and 40ng pRL-TK were transfected into 5*10 cells per well of a 96-well plate. 5 293T cells were cultured. After 24 hours, the medium was replaced and various compounds were added at specified concentrations. After 24 hours, the cells were lysed and substrate was added. Firefly luciferase and Renilla luciferase activities were measured using a microplate reader. The ratio of the two values represents the transcriptional activity of the compound. Data were processed using GraphPad 8.0, and dose-response curves were generated and EC50 values were calculated. The results are shown in Table 5.

[0730] The EC50 values reported in the dual-luciferase reporter gene assay for FXR cell activity are as follows: A represents <200 nM, B represents 200 nM-500 nM, C represents 500 nM-1 μM, and D represents 1 μM-10 μM.

[0731] Table 5. FXR cell level activity results

[0732] Compound number FXR cell activity (EC50) Compound number FXR cell activity (EC50) 1-B D 18 C 2-B C 19-B D 3-B D 20-B D 7-B C 28-B D 8-B A 30-B D 9-B A 31 B 11 A 32 A 12 A 33 B 13 D 48 A 16-B C 49 B 15-B B 54-B D 17 C

Claims

1. A compound represented by the formula: ； L2 is 、 、 or ; X is unsubstituted -CH2-; Y is -N(R 4 )-; R 4 For hydrogen, 、 、 、 , unsubstituted C1-C6 alkyl or one R 4-1 Substituted C1-C6 alkyl; R 4-1 Carboxyl, 6-membered aromatic group, -C(=O)-R 4-1-1 ; in, R 4-1-1 Methyl, , phenyl; or, R 4-1-1 -NR a R b ; the R a and R b One of them is hydrogen, and the other is unsubstituted or replaced by an R a-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, , pyridyl, unsubstituted 6-membered or 10-membered aryl or an R a-2 substituted 6-membered aryl groups; or, R 4-1-1 -NR a R b , the R a and R b One of them is an unsubstituted C1-C6 alkyl group, and the other is a 6-membered aryl group, a C1-C6 alkyl group that is unsubstituted or substituted with a 6-membered aryl group; or, R 4-1-1 -NR a R b , the R a and R b One of them is an ethyl group substituted with a methoxy group, and the other is an unsubstituted six-membered aryl group; or, R 4-1-1 For-OR a , the R a is methyl; R a-1 is a C1-C6 alkyl group, a methoxy group or a 6-membered aryl group; R a-2 is chlorine, methyl or methoxy.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound satisfies one or more of the following conditions: (1) Y is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or ; L2 is 、 、 or , V1 is connected to the X end, and V2 is connected to the Y end.

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

4. A pharmaceutical composition, characterized in that The invention comprises a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. Use of a substance Y in the preparation of an FXR agonist or a medicament for treating and / or preventing FXR-related diseases, wherein the substance Y is a compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4; The FXR-related diseases are non-alcoholic steatohepatitis and cholestatic liver disease.

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