TSHR antagonist compound, pharmaceutical composition, method for preparing same, and use thereof

Abstract

The present invention provides a TSHR antagonist compound of formula (I), a pharmaceutical composition, a method for preparing same, and use thereof. The compound has a good TSHR antagonistic effect and is used for treating thyroid-related disorders and / or diseases, such as hyperthyroidism, Graves' disease, Graves' ophthalmopathy, and thyroid-associated ophthalmopathy, and for preparing a medicament for such disorders or diseases.

Description

TSHR antagonist compounds, pharmaceutical compositions, their preparation methods and applications

[0001] This invention claims priority to the following patent applications filed with the China National Intellectual Property Administration (CNIPA) on November 15, 2024, with patent application number 202411638682.9 entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method Thereof and Application Thereof"; filed with the CNIPA on December 10, 2024, with patent application number 202411814177.5 entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method Thereof and Application Thereof"; and filed with the CNIPA on February 18, 2025, with patent application number 202510179434.0 entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method Thereof and Application Thereof". The entire contents of these earlier applications are incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to a TSHR antagonist compound, a pharmaceutical composition, its preparation method, and its application. Background Technology

[0003] Approximately 40% of patients with hyperthyroidism also have Graves' disease, an autoimmune disorder in which autoantibodies activate the thyroid-stimulating hormone receptor, mimicking its natural hormone ligand, thyroid-stimulating hormone (TSH). This pathological activation of the TSH receptor (TSHR) leads to the uncontrolled production of thyroid hormones such as T3 and T4, resulting in hyperthyroidism. TSHR is a crucial protein controlling thyroid function. TSHR is primarily expressed in thyroid follicular epithelial cells but is also expressed in a variety of other cell types, such as retro-orbital fibroblasts, kidney cells, adipocytes, and osteocytes. TSH binds to its receptor and leads to stimulation of the second messenger pathway, primarily involving cAMP. The inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) pathways are also activated at higher TSH concentrations. For decades, clinically common treatments have included thyroid-suppressing drugs that inhibit thyroid hormone secretion. These drugs act further downstream in the thyroid signaling cascade following TSHR activation. Because the thyroid gland secretes thyroid hormones T3 and T4, thyroid-suppressing drugs inhibit their synthesis. Therefore, current primary antithyroid treatments do not target the pathogenic molecular activation of TSHR by autoantibodies, resulting in an adverse reaction rate of at least 5% in patients. This necessitates frequent control of thyroid hormone levels and adjustment of thyroid inhibitor dosages. In contrast to these drugs that regulate thyroid hormone levels, another promising target is TSHR itself. However, small allosteric antagonists that act directly on TSHR are not yet commercially available. Furthermore, approximately 25% of Graves' disease patients also develop an eye condition, known as Graves' ophthalmopathy, an associated organ-specific autoimmune disease affecting the appearance and function of the eye. There is considerable evidence that TSHR in posterior orbital fibroblasts and orbital fat cells may contribute to this difficult-to-treat eye condition, and thyroid-stimulating antibody titers often correlate with the severity of Graves' ophthalmopathy. Orbital fibroblasts are considered the primary target cells for autoimmune attack, while TSHR is the primary autoantigen in Graves' ophthalmopathy. Pathological activation of TSHR leads to extracellular matrix production through its involvement in hyaluronic acid production, fibrosis and swelling of extraocular muscles, and adipogenesis by orbital fibroblasts (orbital fat expansion). Increased intraorbital tissue volume often causes diplopia, optic nerve compression, and proptosis. Therefore, TSHR is also a potential target for drug intervention in Graves' ophthalmopathy and thyroid ophthalmopathy.

[0004] Therefore, there is a need in the art to provide additional means of treating hyperthyroidism, particularly compounds that act as TSHR antagonists. Summary of the Invention

[0005] To address the aforementioned technical problems, the present invention provides a compound of formula (I), its racemic mixture, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound:

[0006] in,

[0007] R 11 R 12 R2 may be the same or different, and are independently selected from H and C. 1-12 Alkyl, C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups;

[0008] Each R b They may be identical or different, independently selected from CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R. b1 The following groups are substituted: OH, NH2, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2R b2 Or C(=O)R b3 ; Each R b1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R b2 R b3 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0009] n is selected from 0, 1, 2, or 3;

[0010] R3 is selected from H, CN, unsubstituted, or optionally replaced by one, two, or more R3s. c The following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R c They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally surrounded by one, two, or more R groups. c1 The following groups are substituted: OH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, S(=O)2R c2 Or C(=O)R c3 ; Each R c1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, S(=O)2R c4 Or C(=O)R c5 ;R c2 R c3 R c4 R c5 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0011] X1 is selected from CR X1 Or N;

[0012] X2 is selected from CR X2 Or N;

[0013] X3 is selected from CR X3 Or N;

[0014] R X1 R X2 R X3 They may be identical or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more R groups. d The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R d They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0015] Y1 is selected from -CR 61 R 62 -, -NR7-, or no substitution or optional use of one, two or more R d The following groups are substituted: C 2-12 Alkylene, -OC 1-12 Alkylene, -SC 1-12 Alkylene, -NH-C 1-12 Alkylene, -C 1-12 Alkylene -O-, -C 1-12 alkylene-S- or -C 1-12 alkylene-NH-;

[0016] R 61 Selected from H, CN, halogens, OH, NR 63 R 64 C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2R 65 Or C(=O)R 66 ;R 63 R 64 R 65 They are either the same or different, and are independently selected from H and C. 1-6 Alkyl or C 3-6 cycloalkyl; R 66 Selected from H, OH, NH2, C 1-6 Alkyl, C 1-6Alkoxy or C 3-6 cycloalkyl;

[0017] R 62 Selected from CN, halogen, OH, NR 67 R 68 C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2R 69 Or C(=O)R 610 ;R 67 R 68 R 69 They are either the same or different, and are independently selected from H and C. 1-6 Alkyl or C 3-6 cycloalkyl; R 610 Selected from H, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0018] Or, R 61 R 62 Together with the C atoms attached thereto, they form unsubstituted or optionally substituted by one, two or more R atoms. d Substitution of the following groups: olefinic bond (C=CH2), C 3-12 Carbon rings or 3-14 membered heterocyclic rings;

[0019] R7 is selected from H and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups;

[0020] Or, R 62 Alternatively, R7 can be connected to R3 or R5 to form a non-substituted or optionally substituted structure with one, two or more Rs. d The following ring systems are replaced: C 3-16 Carbon rings or 3-16 membered heterocyclic rings;

[0021] Each R d They may be identical or different, and are independently selected from CN, halogen, unsubstituted, or optionally composed of one, two, or more R. d1 The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2R d2 Or C(=O)R d3 Or, two R atoms attached to the same carbon atom d Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. d1 The following ring systems are replaced: C 3-14 A carbon ring or a 3-14 membered heterocycle; or, two R atoms attached to adjacent carbon atoms. d Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. d1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. d Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. d1 Replacement C 1-3 Alkylene; each R d1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R d2 R d3 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0022] R4 and R5 may be the same or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more Rs. a1 The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2Ra2 Or C(=O)R a3 ;

[0023] Each R a They may be identical or different, and are independently selected from CN, halogen, unsubstituted, or optionally composed of one, two, or more R. a1 The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2R a4 Or C(=O)R a5 Alternatively, two R atoms bonded to adjacent carbon atoms. a or R on adjacent carbon atoms a With R4, or R on adjacent carbon atoms a R5, together with the carbon atoms it is attached to, forms an unsubstituted or optionally substituted form with one, two or more R atoms. a1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings;

[0024] Each R a1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0025] R a2 R a3 R a4 R a5 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0026] m is selected from 0, 1, 2, 3, 4 or 5.

[0027] According to some implementation plans, R 11 R 12R2 may be the same or different, and are independently selected from H and C. 1-4 Alkyl or C 3-6 Cycloalkyl.

[0028] According to some implementation plans, R 11 R 12 R2 is H.

[0029] According to some implementation schemes, n is 0.

[0030] According to some implementation schemes, R3 is selected from H and C. 1-4 Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), halogenated C 1-4 Alkyl groups (such as trifluoromethyl, difluoromethyl, fluoroethyl), C 1-4 Alkoxy (such as methoxy), halogenated C 1-4 Alkyl groups (such as trifluoromethoxy and difluoromethoxy), C 3-6 Cycloalkyl (e.g., cyclopropyl), halogenated C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0031] According to some implementation schemes, R3 is methyl, ethyl, or fluoroethyl.

[0032] According to some implementation schemes, R3 is methyl.

[0033] According to some implementation schemes, X1 is CR X1 Or N.

[0034] According to some implementation plans, R X1 Selected from H, CN, OH, halogens (such as F, Cl, Br), C 1-4 Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), halogenated C 1-4 Alkyl groups (such as trifluoromethyl, difluoromethyl), C 1-4 Alkoxy (such as methoxy), halogenated C 1-4 Alkyl groups (such as trifluoromethoxy and difluoromethoxy).

[0035] According to some implementation schemes, X1 is N, CH, CF or CCl.

[0036] According to some implementation schemes, X1 is N, CH, or CF.

[0037] According to some implementation schemes, X2 is selected from CR. X2 Or N.

[0038] According to some implementation plans, R X2 Selected from H, CN, OH, halogens (such as F, Cl, Br), C 1-4 Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), halogenated C1-4 Alkyl groups (such as trifluoromethyl, difluoromethyl), C 1-4 Alkoxy (such as methoxy), halogenated C 1-4 Alkyl groups (such as trifluoromethoxy and difluoromethoxy).

[0039] According to some implementation schemes, X2 is selected from CH, CCH3, or N.

[0040] According to some implementation schemes, X2 is selected from CH or N.

[0041] According to some implementation schemes, X3 is selected from CR. X3 Or N.

[0042] According to some implementation plans, R X3 Selected from H, CN, OH, halogens (such as F, Cl, Br), C 1-4 Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), halogenated C 1-4 Alkyl groups (such as trifluoromethyl, difluoromethyl), C 1-4 Alkoxy (such as methoxy), halogenated C 1-4 Alkyl groups (such as trifluoromethoxy and difluoromethoxy).

[0043] According to some implementation schemes, X3 is selected from CH or N.

[0044] According to some implementation schemes, X1 is CR X1 X2 is CR X2 X3 is CR X3 ; or X1 is N, X2 is CR X2 X3 is CR X3 ; or X1 is CR X1 X2 is N, X3 is CR X3 ; or X1 is CR X1 X2 is CR X2 X3 is N.

[0045] According to some implementation schemes, X1 is CR X1 X2 is CR X2 X3 is CR X3 ; or X1 is N, X2 is CR X2 X3 is CR X3 ; or X1 is CR X1 X2 is CR X2 X3 is N.

[0046] According to some implementation plans, R X1 Selected from H, F, or Cl; R X2 Selected from H or CH3; R X3 For H.

[0047] According to some implementation plans, R X1 Selected from H or F; R X2 Selected from H or CH3; R X3 Selected from H or Cl.

[0048] According to some implementation plans, R X1 Selected from H or F; R X2 For H; R X3 For H.

[0049] According to some implementation schemes, Y1 is selected from -CR 61 R 62 -or -NR7-.

[0050] According to some implementation plans, R 61 Selected from H, C 1-6 Alkyl (e.g., methyl) or halogen (e.g., F, Cl, Br); R 62 Selected from halogens (e.g., F, Cl, Br), halogenated C 1-6 Alkyl groups (e.g., CF3, CHF2, CH2F, CH2CHF2, CH2CF3) or C 3-6 Cycloalkyl (e.g., cyclopropyl); or, R 61 R 62 Together with the C atoms it is attached to, it forms an unsubstituted or optionally substituted form with one or two R atoms. d Substitution with the following groups: olefinic bond (C=CH2) or C 3-6 Carbocyclic (e.g., cyclopropyl); or, R 62 Connected to R3 or R5, together they form a non-substituted or optionally substituted structure with one, two or more Rs. d The following ring systems are replaced: C 5-8 Carbon rings or 5-8 membered heterocyclic rings.

[0051] According to some implementation plans, R 61 Selected from H or C 1-6 Alkyl; R 62 Selected from halogens (e.g., F, Cl, Br), halogenated C 1-6 Alkyl groups (e.g., CF3, CHF2, CH2F, CH2CHF2, CH2CF3) or C 3-6 Cycloalkyl (e.g., cyclopropyl); or, R 61 R 62 Together with the C atoms it is attached to, it forms an unsubstituted or optionally substituted form with one or two R atoms. d Substitution with the following groups: olefinic bond (C=CH2) or C 3-6 Carbocyclic (e.g., cyclopropyl); or, R 62 Connected to R3 or R5, together they form a non-substituted or optionally substituted structure with one, two or more Rs. d The following ring systems are replaced: C5-8 Carbon rings or 5-8 membered heterocyclic rings.

[0052] According to some implementation plans, R d Selected from halogens (e.g., F, Cl, Br), or two R atoms bonded to the same carbon atom. d Together with the carbon atoms it is attached to, they form C 3-6 Carbon rings or 3-6 membered heterocycles;

[0053] According to some implementation plans, R 61 For H, CH3 or F; R 62 Selected from F, Cl, Br, CF3, CHF2, CH2F, CH2CHF2, CH2CF3 or cyclopropyl; or, R 61 R 62 Together with the C atom it is attached to, it forms C=CF2 or cyclopropyl; or, R 62 Connected to R3, making The structure is as follows: Or, R 62 Connected to R5, making The structure is as follows:

[0054] According to some implementation plans, R 61 For H or CH3; R 62 Selected from F, Cl, Br, CF3, CHF2, CH2F, CH2CHF2, CH2CF3 or cyclopropyl; or, R 61 R 62 Together with the C atom it is attached to, it forms C=CF2 or cyclopropyl; or, R 62 Connected to R3, making The structure is as follows: Or, R 62 Connected to R5, making The structure is as follows:

[0055] According to some implementation plans, R 61 For H; R 62 Selected from F, Cl, Br, CF3, CHF2, CH2F, CH2CHF2, CH2CF3 or cyclopropyl; or, R 61 R 62 Together with the C atom it is attached to, it forms C=CF2 or cyclopropyl; or, R 62 Connected to R3, making The structure is as follows: Or, R 62 Connected to R5, making The structure is as follows:

[0056] According to some implementation schemes, R7 is selected from H and C. 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), halogenated C 1-6 Alkyl (e.g., CF3, CHF2, CH2F) or C 3-12 Cycloalkyl (e.g., cyclopropyl); or, R7 is linked to R3 or R5 to form a 5-8 member N-containing heterocycle.

[0057] According to some implementation schemes, R7 is selected from H, methyl, ethyl, cyclopropyl, CF3, CHF2, or CH2F; R7 is connected to R3, making... The structure is as follows: Alternatively, R7 and R5 can be connected, making The structure is as follows: R d4 Selected from F, Cl, or Br; or, two R atoms attached to the same carbon atom. d4 Together with the carbon atom it is attached to, it forms a cyclopropyl ring; q is selected from 0, 1, or 2. According to some embodiments, each R... a They are either the same or different, and are independently selected from CN, F, Cl, Br, and C. 1-4 Alkyl groups (such as methyl, ethyl, isopropyl, tert-butyl), C 2-6 Alkyne groups (such as -C≡CH, -C≡CCH3), halogenated C 1-4 Alkyl groups (such as trifluoromethyl, difluoromethyl), C 1-4 Alkoxy groups (such as methoxy and ethoxy groups), halogenated carbon groups 1-4 Alkyl groups (such as trifluoromethoxy and difluoromethoxy), C 3-6 Cycloalkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl (such as pyrazolyl).

[0058] According to some implementation schemes, R7 is selected from methyl, ethyl, cyclopropyl, CF3, CHF2, or CH2F; R7 is connected to R3, making... The structure is as follows: Alternatively, R7 and R5 can be connected, making The structure is as follows: R d4 Selected from F, Cl, or Br; or, two R atoms attached to the same carbon atom. d4Together with the carbon atom it is attached to, it forms a cyclopropyl ring; q is selected from 0, 1, or 2. According to some embodiments, each R... a They are either the same or different, and are independently selected from CN, F, Cl, Br, and C. 1-4 Alkyl groups (such as methyl, ethyl, isopropyl, tert-butyl), C 2-6 Alkyne groups (such as -C≡CH, -C≡CCH3), halogenated C 1-4 Alkyl groups (such as trifluoromethyl, difluoromethyl), C 1-4 Alkoxy groups (such as methoxy and ethoxy groups), halogenated carbon groups 1-4 Alkyl groups (such as trifluoromethoxy and difluoromethoxy), C 3-6 Cycloalkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl (such as pyrazolyl).

[0059] According to some implementation schemes, R7 is selected from methyl, ethyl, cyclopropyl, CF3, CHF2, or CH2F; R7 is connected to R3, making... The structure is as follows: Alternatively, R7 and R5 can be connected, making The structure is as follows: R d4 Selected from F, Cl, or Br; or, two R atoms attached to the same carbon atom. d4 Together with the carbon atom it is attached to, it forms a cyclopropyl ring; q is selected from 0, 1, or 2. According to some embodiments, each R... a They are either the same or different, and are independently selected from CN, F, Cl, Br, and C. 1-4 Alkyl groups (such as methyl, ethyl, isopropyl, tert-butyl), C 2-6 Alkyne groups (such as -C≡CH, -C≡CCH3), halogenated C 1-4 Alkyl groups (such as trifluoromethyl, difluoromethyl), C 1-4 Alkoxy groups (such as methoxy and ethoxy groups), halogenated carbon groups 1-4 Alkyl groups (such as trifluoromethoxy and difluoromethoxy), C 3-6 Cycloalkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl (such as pyrazolyl).

[0060] According to some implementation schemes, m is selected from 0, 1, 2 or 3.

[0061] According to some implementation schemes, m is selected from 0, 1 or 2.

[0062] According to some implementation schemes, m is 0.

[0063] According to some implementation schemes, m is 2.

[0064] According to some implementation schemes, R4 and R5 may be the same or different, and are independently selected from H or halogens (e.g., F, Cl, Br), halogenated C. 1-4 Alkyl (such as trifluoromethyl, difluoromethyl) or C 1-4 Alkyl groups (such as methoxy and ethoxy groups); or, R 62 Alternatively, R7 and R5 can be connected together to form a non-substituted or arbitrarily assigned one or two Rs. d The following ring systems are replaced: C 5-8 Carbon rings or 5-8 membered heterocycles; or, R on adjacent carbon atoms a With R4, or R on adjacent carbon atoms a R5, together with the carbon atoms it is attached to, forms the following ring system: C 4-6 Carbon rings, 4-6 membered heterocyclic rings, benzene rings, or 5-6 membered heteroaromatic rings.

[0065] According to some implementation schemes, R4 and R5 may be the same or different, and are independently selected from H or halogens (e.g., F, Cl, Br); or, R 62 Alternatively, R7 and R5 can be connected together to form a non-substituted or arbitrarily assigned one or two Rs. d The following ring systems are replaced: C 5-8 Carbon rings or 5-8 membered heterocycles; or, R on adjacent carbon atoms a With R4, or R on adjacent carbon atoms a R5, together with the carbon atoms it is attached to, forms the following ring system: C 4-6 Carbon rings, 4-6 membered heterocyclic rings, benzene rings, or 5-6 membered heteroaromatic rings.

[0066] According to some implementation schemes, each R a They may be the same or different, and are independently selected from CN, halogens (e.g., F, Cl, Br), C 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl (e.g., cyclopropyl) or 3-14 membered heterocyclic groups; or, R attached to an adjacent carbon atom. a With R4, or R on adjacent carbon atoms a R5, together with the carbon atoms it is attached to, forms an unsubstituted or optionally substituted form with one, two or more R atoms. a1 The following ring systems are replaced: C 3-6 Carbon rings, 3-6 membered heterocyclic rings, benzene rings, or 5-6 membered heteroaromatic rings.

[0067] According to some implementation plans Selected from

[0068] According to some implementation plans Selected from

[0069] According to some implementation schemes, R4 and R5 may be the same or different, and are independently selected from F, Cl, Br, CF3, or OCH3; m is selected from 0 or 1; each R a They may be the same or different, and are independently selected from CN, F, Cl, Br, methyl, ethyl, isopropyl, or cyclopropyl; or, R 62 Or R7 and R5 are connected, so that The structure is as follows:

[0070] Or, R on adjacent carbon atoms a R4, together with the carbon atoms it is attached to, forms a ring system, making The structure is as follows:

[0071] According to some implementation schemes, R4 and R5 may be the same or different, and are independently selected from F, Cl, and Br; m is selected from 0 or 1; each R a They may be the same or different, and are independently selected from CN, F, Cl, Br, methyl, ethyl, isopropyl, or cyclopropyl; or, R 62 Or R7 and R5 are connected, so that The structure is as follows:

[0072] Or, R on adjacent carbon atoms a R4, together with the carbon atoms it is attached to, forms a ring system, making The structure is as follows:

[0073] According to some implementation schemes, R4 and R5 may be the same or different, and are independently selected from F, Cl, and Br; or, R 62 Or R7 and R5 are connected, so that The structure is as follows: Or, R on adjacent carbon atoms a R4, together with the carbon atoms it is attached to, forms a ring system, making The structure is as follows:

[0074] According to some embodiments, the compound represented by formula (I) has the following structure:

[0075] Among them, X1, X2, X3, Y1, R 11 R 12 R2, R3, R4, R5, R a R b , m, and n have the definitions described in this article.

[0076] According to some embodiments, the compound represented by formula (I) has the following structure:

[0077] Among them, X1, X2, X3, Y1, R4, R5, R a , m has the definition as described in this article.

[0078] According to some embodiments, the compound shown in formula (I) is selected from the following structures:

[0079] The present invention also provides a method for preparing the compound shown in formula (I), comprising the following step A:

[0080] Step A:

[0081] Among them, X1, X2, X3, Y1, R 11 R 12 R2, R3, R4, R5, R a R b , m, and n have the definitions described in this article.

[0082] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of formula (I), a racemic mixture, a stereoisomer, a tautomer, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof.

[0083] According to some embodiments, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0084] According to some embodiments, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0085] The present invention also provides a method for treating or preventing diseases or symptoms caused by TSHR abnormalities, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the following: a compound of formula (I), its racemic mixture, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound.

[0086] The present invention also provides a method for treating or preventing diseases or conditions caused by TSHR abnormalities, comprising administering to a patient a preventive or therapeutically effective amount of the above-mentioned pharmaceutical composition.

[0087] According to some implementation schemes, the disease or condition caused by the TSHR abnormality is a thyroid-related disease or condition.

[0088] According to some implementation schemes, the thyroid-related diseases or conditions are hyperthyroidism, Graves' disease, Graves' eye disease, and thyroid eye disease.

[0089] According to some implementation schemes, the patients include mammals, preferably humans.

[0090] The present invention also provides at least one of the following: a compound of formula (I), a racemic mixture, a stereoisomer, a tautomer, a solvate, a polymorph, a pharmaceutically acceptable salt thereof, or a prodrug compound thereof, or a pharmaceutical composition thereof, for the treatment or prevention of diseases or conditions caused by TSHR abnormalities.

[0091] According to some implementation schemes, the disease or condition caused by the TSHR abnormality is a thyroid-related disease or condition.

[0092] According to some implementation schemes, the thyroid-related diseases or conditions are hyperthyroidism, Graves' disease, Graves' eye disease, and thyroid eye disease.

[0093] The present invention also provides the use of at least one of the compounds of formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof in the preparation of pharmaceuticals.

[0094] According to some implementations, the use may be in the preparation of a medicament for TSHR antagonists.

[0095] According to some implementation schemes, the use may be in the preparation of a medicine for the treatment or prevention of thyroid-related diseases or conditions.

[0096] According to some implementation schemes, the thyroid-related diseases or conditions are hyperthyroidism, Graves' disease, Graves' eye disease, and thyroid eye disease. Beneficial effects

[0097] The compounds provided by this invention have good TSHR antagonistic effects and can be used to treat or prevent symptoms and diseases related to thyroid, as well as to prepare drugs for treating or preventing such symptoms and diseases.

[0098] Terminology Definitions and Explanations

[0099] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0100] The term “optional” (or “optionally”, “optionally”) in the general formula definition of this application means the case of being substituted by zero or one or more substituents. For example, “optionally substituted by one, two or more R” means that it may not be substituted by R (no substitution) or may be substituted by one, two or more R.

[0101] "More than" means three or more, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0102] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-12" is equivalent to describing each integer value in the numerical range "1-12", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0103] Term "C" 1-12 "alkyl" should be understood to refer to straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0104] Term "C"2-12 "Alkenyl" should be understood as representing a monovalent hydrocarbon group with 1 to 12 carbon atoms, either linear or branched, containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. For example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C...). 2-8 Alkenyl), for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C64 ... 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3 Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0105] Term "C" 2-12 "Alkyne" should be understood as representing a monovalent hydrocarbon group with 1 to 12 carbon atoms, either directly linked or branched, containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C"). 2-8 "Alkyne group" has 2, 3, 4, 5 or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C")2-3 The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl -Alynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0106] Term "C" 3-12 "Cycloalkyl" should be understood to refer to saturated monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) hydrocarbon rings or tricyclic alkanes, having 3 to 12 carbon atoms, preferably "C". 3-10 "Cycloalkyl", more preferably "C" 3-8 cycloalkyl. The term "C" 3-12 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The C... 3-12 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0107] Term "C" 6-14"Aryl" should preferably be understood to represent a monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring), or tricyclic hydrocarbon ring having 6 to 14 carbon atoms and possessing monovalent aromaticity or partial aromaticity. It can be a monoaromatic ring or a polyaromatic ring fused together, preferably "C". 6-10 "Aromatic". The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0108] The term "5-14-membered heteroaryl" should be understood to include monocyclic, bicyclic (e.g., fused, bridged, spirocyclic), or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5-10-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzo[a]fused. "Hyperaryl" also refers to a group in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the root or point of the connection is on the heteroaryl ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indazinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinel, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-... -, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthidyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cenolinyl, 2-, 4-, 6- or 7-pteridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazole, 1-, 2-, 3-, 4-, 5-, 6- 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbaolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinel, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- Phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenthiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazin[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furano[3,2-b]-pyranolyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-azinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-azolel, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazolo[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furano[3,4-c]cenolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3] -c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thiopheneyl, 2-, 4-, 5-, 6- or 7-benzozolyl, 2-, 4-, 5-, 6- or 7-benzimidazinyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-4H-pyrrolo[1,2-b][2]benzozapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene, 2-, 4-, 5-, 6-, or 7-benzozozolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14-membered heteroaryl group is linked to other groups to form the compounds of the present invention, the carbon atom on the 5-14-membered heteroaryl ring may be linked to other groups, or the heteroatom on the 5-14-membered heteroaryl ring may be linked to other groups. When the 5-14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution sites; for example, hydrogen atoms bonded to carbon atoms on the heteroaryl ring can be substituted, or hydrogen atoms bonded to heteroatoms on the heteroaryl ring can be substituted.

[0109] The term "carbocyclic ring" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic rings such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or bicyclic rings, including spirocyclic, fused, or bridged systems (such as bicyclic [11.1]pentane, bicyclic [2.2.1]heptane, bicyclic [3.2.1]octane, or bicyclic [5.2.0]nonane, tert-naphthalene, etc.), which may optionally be substituted with one or more (such as 1, 2, or 3) suitable substituents. The term "3-6 membered carbocyclic ring" refers to a carbocyclic ring containing 3, 4, 5, or 6 cyclic carbon atoms.

[0110] Unless otherwise defined, the term "3-14 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (such as a fused ring, bridged ring, or spirocyclic ring), or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2- states. For example, the "3-14 membered heterocyclic group" may be a 3-14 membered N-containing heterocyclic group (containing at least one N). Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the remainder of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the carbon atom on the 3-14-membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-14-membered heterocyclic ring can be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be attached to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinium, the nitrogen atom on the piperidinium ring and the carbon atom at its para position can be attached to other groups.

[0111] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0112] The term "nitrogen oxides" refers to compounds formed by the oxidation of nitrogen atoms in the structure of tertiary amines or nitrogen-containing (aromatic) heterocyclic compounds.

[0113] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0114] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0115] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0116] Unless otherwise stated, heterocyclic, hypocyclic, heteroaryl, or hypoaryl includes all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, it may include forms in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0117] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc.

[0118] "Halogenation" refers to the replacement of a substance by one or more halogens.

[0119] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0120] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0121] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, where alkyl is defined as described above. Non-limiting examples of alkylamino include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, etc.

[0122] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above. Non-limiting examples of hydroxyalkyl groups include: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, or dihydroxypropyl, etc.

[0123] The term "alkyloxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0124] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a straight-chain or branched saturated divalent hydrocarbon group. The definition of the number of carbon atoms in "alkylene" follows the definition of "alkyl" above. Those skilled in the art will understand that alkyleneoxy or oxyalkylene can be attached to the remainder of the molecule containing it in any orientation; that is, the two are used interchangeably.

[0125] Wavy lines intersecting chemical bonds Used to indicate the connection position of a group to other atoms in the molecular structure. For example... This indicates the 3-position connection with the pyridinium group. When the group connection position is not fixed, taking the pyridinium group as an example, it can be represented as follows: The method is shown to indicate that it can be connected to any connectable site on the pyridinyl group. For example... This indicates that it can be connected to any connectable position on the heteroaryl ring, for example, it can be connected to any of the four carbon atoms on the pyridine ring to the right of the heteroaryl group, or it can be connected to a carbon atom on the pyrazole ring to the left. Unless otherwise stated, similar expressions in this application are interpreted in the same way as above.

[0126] In the chemical structure of the compound described in this invention, the bond... This indicates that no configuration has been specified. Indicates absolute configuration, that is, if stereoisomers exist in the chemical structure, the bonds... It can be Or simultaneously include Two configurations.

[0127] In this invention, the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of H, C, N, O, S, F, and Cl, respectively such as 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention, their prodrugs, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those doped with radioactive isotopes (e.g.,... 3 H and 14 Compounds in (C) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2 H or D substitutions can provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements) and are therefore preferred in some cases. The presence of hydrogen in the substituents of this invention, without the separate mention of the terms deuterium or tritium, does not imply the exclusion of deuterium or tritium, but rather may also include deuterium or tritium.

[0128] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0129] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0130] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, and racemates. The compounds of the present invention or their intermediates can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in both R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0131] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0132] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0133] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Attached Figure Description

[0134] Figure 1: Serum TT4 concentrations in female rats 12 hours after a single administration of different doses of compounds 001A and K1-70;

[0135] Figure 2: Serum TT4 concentrations in female rats 24 hours after a single administration of different doses of compounds 001A and K1-70. Detailed Implementation

[0136] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0137] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0138] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0139] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0140] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent 1260II HPLC and a Waters Acquity UPLC H-Class HPLC system.

[0141] Chiral HPLC analysis was performed using a Waters Acquity UPCC high-performance liquid chromatograph.

[0142] High-performance liquid chromatography was performed using Waters MS-triggered Prep-LC with SQD2 detector, Waters MS triggered Prep-LC with Acquity QDA detector, Waters MS-triggered Prep-LC with QDA detector, and GILSON Prep LC with UV detector.

[0143] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0144] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0145] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0146] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0147] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0148] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0149] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0150] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0151] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0152] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0153] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0154] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0155] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0156] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: System A: dichloromethane / methanol system, System B: n-hexane / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0157] Example 1

[0158] Synthesis of Compound 001A and Compound 001B

[0159] Preparation of compound 001b in step one

[0160] Under nitrogen protection at 0°C, i-PrMgCl·LiCl (0.05 L, 1.3 M, 0.065 mol) was added to 15 mL of tetrahydrofuran containing 6.67 g (0.026 mol) of 1-chloro-4-fluoro-2-iodobenzene and stirred for 1 hour. Then, 3-bromo-2-nitrobenzaldehyde (compound 001a, 3 g, 0.013 mol) was added and the reaction was carried out at room temperature for 15 hours. After the reaction was completed, the reaction was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography system B to obtain compound 001b (1.6 g).

[0161] MS m / z(ESI): 358.9(M+1) + .

[0162] The second step involves the preparation of compound 001c.

[0163] Compound 001b (900 mg, 2.5 mmol) was dissolved in a mixture of methanol and water (15 mL, V / V = 3:1), and iron powder (698 mg, 12.5 mmol) and ammonium chloride (668 mg, 12.5 mmol) were added. The reaction was stirred at 70 °C for 1 hour. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 001c (480 mg, yield: 48%).

[0164] MS m / z(ESI): 329.9(M+1) + .

[0165] Step 3: Preparation of compound 001d

[0166] Compound 001c (600 mg, 1.82 mmol) was dissolved in dichloromethane (20 mL), and manganese dioxide (790 mg, 9.08 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 001d (500 mg). The product was used directly in the next reaction without purification.

[0167] MS m / z(ESI): 328.0(M+1) + .

[0168] Step 4: Preparation of compound 001e

[0169] Under ice bath conditions, NaH (73 mg, 60%, 3.05 mmol) was added to a DMF (10 mL) solution of compound 001d (500 mg, 1.52 mmol) and iodomethane (260 mg, 1.83 mmol), and the reaction was carried out at this temperature for 2 hours. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to give compound 001e (300 mg, yield: 40%).

[0170] MS m / z(ESI): 342.0(M+1) + .

[0171] Step 5: Preparation of compound 001f

[0172] A solution of compound 001e (300 mg, 0.876 mmol) in N,N-dimethylformamide (10 mL) was added to the reaction mixture under nitrogen protection at room temperature. Pd(dppf)Cl2 (128 mg, 0.18 mmol) and cuprous iodide (33 mg, 0.18 mmol) were then added. Finally, a solution of methyl(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-propionic acid iodide (691 mg, 1.75 mmol) in N,N-dimethylformamide was added under nitrogen protection. The reaction was stirred at 75 °C under nitrogen protection for 10 hours. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography system B to obtain compound 001f (200 mg, yield: 35%).

[0173] MS m / z(ESI): 465.1(M+1) + .

[0174] Step 6: Preparation of compound 001g

[0175] Compound 001f (100 mg, 0.22 mmol) was dissolved in THF (5 mL), and LiHMDS (0.3 mL, 1 M, 0.3 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel column chromatography system B to obtain compound 001g (70 mg, yield: 60%).

[0176] MS m / z(ESI): 377.0(M-56) + .

[0177] Step 7: Preparation of compound 001h

[0178] Compound 001 g (40 mg, 0.09 mmol) was dissolved in methanol (5 mL), and NaBH4 (7 mg, 0.19 mmol) was added. The mixture was stirred at 0 °C for 1 hour. After the reaction was completed, ammonium chloride was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography system B to obtain compound 001 h (30 mg, yield: 60%).

[0179] MS m / z(ESI): 379.1(M-56) + .

[0180] Step 8: Preparation of compound 001i

[0181] Compound 001h (30 mg, 0.07 mmol) was dissolved in dichloromethane (10 mL), and diethylaminosulfur trifluoride (23 mg, 0.14 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was diluted with dichloromethane (10 mL), washed with water (30 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to give compound 001i (30 mg, yield: 64%).

[0182] MS m / z(ESI): 381.0(M-56) + .

[0183] Step 9: Preparation of compound 001j

[0184] Compound 001i (30 mg, 0.07 mmol) was added to a solution of dioxane hydrochloride (5 mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the product was evaporated to dryness to obtain compound 001j (30 mg). The product was used directly in the next reaction without purification.

[0185] MS m / z(ESI): 337.1(M+1) + .

[0186] Step 10: Preparation of compounds 001A and 001B

[0187] Compound 001j (30 mg, 0.09 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of acetic acid (0.1 mL) and water (0.1 mL), and then potassium cyanate (11 mg, 0.13 mmol). The reaction was stirred at room temperature for 0.5 hours. After the reaction was complete as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weakly alkaline. The mixture was then concentrated and purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150×19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 55%-95%, flow rate: 20 mL / min) to obtain racemic compound 001 (12 mg, yield: 35%). Purification was performed using SFC chromatography (SFC150 column: Daicel CHIRALPAK IG_3, 3.0×150mm, 3μm; mobile phase 1: carbon dioxide; mobile phase 2: methanol (0.1% DEA, 7M methanol solution); 6-minute gradient, gradient ratio of carbon dioxide:methanol phase = 70 / 30, flow rate: 2mL / min) to obtain compound 001A (front peak, RT = 1.764min) and compound 001B (back peak, RT = 2.556min).

[0188] MS m / z(ESI): 380.0(M+1) + .

[0189] Compound 001A

[0190] 1 H NMR (400MHz, CD3OD) δ7.53(dd,1H),7.35(dd,1H),7.28(d,1H),7.18–7.00(m,3H),6.91(d,1H),4.26(dd,1H),3.60(s,3H),3.11(dd,1H),2.87(t,1H).

[0191] Compound 001B

[0192] 1H NMR(400MHz,CD3OD)δ7.57(dd,1H),7.22(d,1H),7.17-7.14(m,2H),7.06-7.0 1(m,2H),6.99(d,1H),4.32(dd,1H),3.31(s,3H),3.13(dd,1H),2.88(t,1H).

[0193] Example 2

[0194] Synthesis of Compound 010

[0195] Preparation of compound 010b in step one

[0196] Compound 010a (1.0 g, 4.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-chloro-5-fluoroaniline (0.79 g, 5.4 mmol) and cesium carbonate (4.4 g, 13.5 mmol) were added. The reaction was stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using system B to give compound 010b (600 mg, yield: 38%).

[0197] 1 H NMR (400MHz, CDCl3) δ7.41–7.34(m,4H), 6.99-6.96(m,1H), 6.73-6.80(m,1H).

[0198] The second step involves the preparation of compound 010c.

[0199] Compound 010b (200 mg, 0.58 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydroxide (27.78 mg, 0.69 mmol) was added at 0 °C. After stirring for 0.5 hours, iodomethane (98.6 mg, 0.69 mmol) was added, and the reaction was stirred at 25 °C for 1 hour. The reaction was quenched with ice water and then extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography separation system B to obtain compound 010c (150 mg, yield: 72%).

[0200] MS m / z(ESI): 359.0(M+1) + .

[0201] Preparation of compound 010d in step three

[0202] Compound 010c (100 mg, 0.28 mmol) was dissolved in a mixed solvent of methanol and water (6 mL, V / V = 5:1), and then ammonium chloride (74.38 mg, 1.39 mmol) and iron powder (77.66 mg, 1.39 mmol) were added. The reaction mixture was stirred at 75 °C for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography using system B to obtain compound 010d (90 mg, yield: 98%).

[0203] MS m / z(ESI): 329.0(M+1) + .

[0204] Step 4: Preparation of compound 010e

[0205] Compound 010d (90 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 1,2,3,4,5-pentanylphenyl-1'-(di-tert-butylphospho)ferrocene (38.78 mg, 0.054 mmol) and tris(dibenzylacetone)palladium (49.49 mg, 0.054 mmol). Under nitrogen protection, a solution of methyl(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-propionic acid iodine (431 mg, 1.09 mmol) in N,N-dimethylformamide was added. The reaction was stirred at 80 °C under nitrogen protection for 12 hours. After monitoring for complete reaction, the reaction solution was filtered, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography separation system B to obtain compound 010e (90 mg, yield: 78%).

[0206] MS m / z(ESI): 364.1(M-56+1) + .

[0207] Step 5: Preparation of compound 010f

[0208] Compound 010e (90 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of cesium carbonate (209.47 mg, 0.64 mmol) and methyl iodoforme (60.86 mg, 0.43 mmol). The reaction was stirred at 40 °C for 1 hour, diluted with water, extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography separation system B to obtain compound 010f (60 mg, yield: 65%).

[0209] MS m / z(ESI): 378.1(M-56+1) + .

[0210] Step 6: Preparation of compound 010g

[0211] Compound 010f (60 mg, 0.14 mmol) was dissolved in 4 M hydrogen chloride / 1,4-dioxane (3 mL). The solution was stirred at room temperature for 1 hour. After the reaction was completed by LC-MS monitoring, the crude product compound 010g (40 mg, yield: 86%) was directly concentrated. The crude product was used directly in the next reaction without purification.

[0212] MS m / z(ESI): 334.1(M+1) + .

[0213] Step 7: Preparation of Compound 010

[0214] Compound 010 g (40 mg, 0.12 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), acetic acid (0.1 mL), and water (0.1 mL). Potassium cyanate (19.41 mg, 0.24 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weakly alkaline. The mixture was then concentrated and purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150×19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 35%-45%, flow rate: 20 mL / min) to obtain compound 010 (6.5 mg, yield: 15%).

[0215] MS m / z(ESI): 377.1(M+1) + .

[0216] 1 H NMR(400MHz,CD3OD)δ7.34-7.31(m,1H),7.05-6.99(m,3H),6.81–6.74(m,2H), 4.24(dd,1H),3.51(s,3H),3.11(s,3H),3.12-3.07(m,1H),2.88–2.81(m,1H).

[0217] Example 3

[0218] Synthesis of Compound 013

[0219] Following the synthetic route of Example 2, the starting material 2-chloro-5-fluoroaniline in the first step was replaced with 6-fluoroindoline. The final product was purified by high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150×19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 55%-95%, flow rate: 20 mL / min) to obtain compound 013 (4.5 mg, yield: 10%).

[0220] MS m / z(ESI): 355.1(M+1) + .

[0221] 1 HNMR(400MHz,DMSO-d6)δ7.71-7.40(m,1H),7.31(s,1H),7.16–7.10(m,1H),7.14-7.08(m,1H),7.05-6.61(m,1H),6.47-6.27(m,2H),5.70– 5.62(m,2H),4.27–4.33(m,1H),3.86–3.82(m,1H),3.17-3.07(m,3H), 2.91(s,1H),2.76–2.72(m,1H),2.52–2.50(m,1H),2.25–2.20(m,1H).

[0222] Example 4

[0223] Synthesis of Compound 032

[0224] Following the synthetic route of Example 1, the final product was purified by high-performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5μm C18 150×19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 3-minute gradient, gradient ratio: acetonitrile phase 55%-95%, flow rate: 20mL / min) to obtain compound 032A (first peak, 6mg, RT=1.925min) and compound 032B (last peak, 2mg, Rt=1.959min).

[0225] MS m / z(ESI): 398(M+1) + .

[0226] Compound 032A

[0227] 1 H NMR(400MHz,CD3OD)δ7.50-7.46(m,1H),7.45–7.33(m,2H),7.24–7.16(m,1H),7.12 –6.84(m,2H),4.30-4.27(m,1H),3.13-3.30(m,1H),3.09(s,3H),2.79-2.75(m,1H).

[0228] Compound 032B

[0229] 1 H NMR(400MHz,CD3OD)δ7.57-7.55(m,1H),7.40-7.26(m,2H),7.09-7.06(m,1H),6.81 -6.73(m,2H),4.29-4.26(m,1H),3.61(s,3H),3.08-3.06(m,1H),2.83-2.79(m,1H).

[0230] Example 5

[0231] Synthesis of Compound 004

[0232] Preparation of compound 004a in the first step

[0233] Compound 001d (500 mg, 1.52 mmol) was dissolved in tetrahydrofuran (10 mL), and cyclopropylmagnesium bromide (10 mL) was added under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, the organic phase was dried and concentrated, and purified by silica gel column chromatography system B to give compound 004a (400 mg, yield: 71%).

[0234] MS m / z(ESI): 352.0(M-18) + .

[0235] The second step involves the preparation of compound 004b.

[0236] Compound 004a (400 mg, 1.1 mmol) was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (5 mL) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, the organic phase was dried and concentrated, and purified by silica gel column chromatography system B to give compound 004b (250 mg, yield: 64%).

[0237] MS m / z(ESI): 354.0(M+1) + .

[0238] The third step involves the preparation of compound 004c.

[0239] Add zinc powder (3.0 g, 4 eq.) to the bottle, replace with nitrogen, add N,N-dimethylformamide (8 mL) using a syringe, stir at 40°C for 15 minutes under nitrogen protection, add 1,2-dibromoethane (90 mg, 0.1 eq.) and trimethylchlorosilane (50 mg, 0.1 eq.) to the system under nitrogen protection, stir the reaction mixture at 40°C for 15 minutes, add (S)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate methyl ester (7.1 g, 2 eq.) in N,N-dimethylformamide (8 mL) solution to the reaction mixture under nitrogen protection, stir at 40°C for 30 minutes under nitrogen protection, and cool to room temperature under nitrogen protection. In another bottle, a solution of compound 004b (250 mg, 0.7 mmol) in N,N-dimethylformamide (10 mL) was added. Under nitrogen protection at room temperature, palladium acetate (32 mg, 0.14 mmol), Xphos (67 mg, 0.14 mmol), and the previously prepared zinc reagent were added to the reaction mixture. The resulting reaction mixture was stirred at 75 °C for 10 hours under nitrogen protection. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the organic phase was washed twice with ammonium chloride aqueous solution. The organic phase was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography system B to obtain compound 004c (200 mg, yield: 63%).

[0240] MS m / z(ESI): 389.1(M-56) + .

[0241] Step 4: Preparation of compound 004d

[0242] Compound 004c (200 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (440 mg, 1.3 mmol) and methyl iodoforme (128 mg, 0.9 mmol) were added. The reaction was stirred at 50 °C for 0.5 h. After the reaction was completed, the reaction solution was filtered, diluted with ethyl acetate, and the organic phase was washed with ammonium chloride aqueous solution. The solution was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography system B to obtain compound 004d (90 mg, yield: 44%).

[0243] MS m / z (ESI): 403.1 (M-56) + .

[0244] Step 5: Preparation of compound 004e

[0245] Compound 004d (50 mg, 0.11 mmol) was dissolved in dioxane hydrochloride (5 mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to give compound 004e (30 mg, yield: 75%). The product was used directly in the next reaction without purification.

[0246] MS m / z(ESI): 359.1(M+1) + .

[0247] Step 6: Preparation of compounds 004A and 004B

[0248] Compound 004e (30 mg, 0.08 mmol) was dissolved in tetrahydrofuran (0.5 mL), potassium cyanate (10 mg, 0.12 mmol), water (2 mL), and acetic acid (2 mL) were added. The reaction was stirred at room temperature for 30 minutes. After the reaction was completed, sodium bicarbonate aqueous solution was added to neutralize to alkalinity, and the mixture was evaporated to dryness to obtain the crude product. The crude product was directly purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150×19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 16-minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 004A (first peak, 5.5 mg, RT = 5.34 min) and compound 004B (last peak, 5.6 mg, RT = 8.52 min).

[0249] Compound 004A:

[0250] MS m / z(ESI): 402.1(M+1) + .

[0251] 1 H NMR(400MHz,CD3OD)δ7.71(dd,1H),7.37-7.24(m,1H),7.19(dd,2H),6.94-6.80(m,2H),4.32(d,1H),3.94(dd,1H), 3.43(s,3H),3.01(dd,1H),2.74(t,1H),1.51-1.38(m,1H),0.94-0.83(m,1H),0.78-0.62(m,1H),0.60-0.45(m,2H).

[0252] Compound 004B:

[0253] MS m / z(ESI): 402.1(M+1) + .

[0254] 1 H NMR (400MHz, CD3OD) δ7.53-7.40(m,2H),7.27(d,1H),7.21-7.11(m,2H),7.09-6.96(m,1H),4.27(dd,1H),4.14( d,1H),3.27(s,3H),3.06(dd,1H),2.81(s,1H),1.21-1.08(m,1H),0.65(m,1H),0.48(d,2H),0.21-0.08(m,1H).

[0255] Example 6

[0256] Synthesis of Compound 040

[0257] Preparation of compound 040b in step one

[0258] A tetrahydrofuran solution (10 mL) of LDA (2 M, 0.0067 L, 0.013 mol) was added to a tetrahydrofuran solution of compound 040a (2 g, 0.012 mol). The mixture was stirred at -78 °C for 1 hour under nitrogen atmosphere. Then, a THF solution (10 mL) of N-phenylbis(trifluoromethanesulfonylimide) (4.79 g, 0.013 mmol) was added. The mixture was stirred at 25 °C for 11 hours. After the reaction was completed, the reaction was quenched with ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography system B to obtain compound 040b (3.0 g, yield: 75%).

[0259] 1 H NMR (400MHz, CD3OD) δ7.30-7.22(m,1H),7.08-6.93(m,2H),6.24-6.16(m,1H),2.84(t,2H),2.52(td,2H).

[0260] The second step involves the preparation of compound 040c.

[0261] Compound 004b (2 g, 0.0068 mmol), 2-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)aniline (2.15 g, 0.0082 mol), Pd(dppf)Cl 2(The reaction mixture was stirred at 100°C for 16 hours under nitrogen protection in a 50 mL mixed solvent of dioxane / water (0.25 g, 0.00034 mol) and potassium carbonate (1.88 g, 0.0136 mmol), with 0.25 g of dioxane and 0.0136 mmol of potassium carbonate. After the reaction was completed, the mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography system B to give compound 040c (1.5 g, yield: 74%).

[0262] MS m / z(ESI): 285.1(M+1) + .

[0263] Preparation of compound 040d in step three

[0264] At 70 °C, tert-butyl nitrite (0.93 g, 0.009 mol) was added to a 20 mL solution of compound 040c (1.5 g, 0.0053 mol) and CuBr2 (1.42 g, 0.0063 mol) in acetonitrile (20 mL), and the mixture was reacted at this temperature for 2 hours. After the reaction was completed, the mixture was cooled and quenched with water. The mixture was extracted with ethyl acetate, washed with saturated brine, concentrated, and purified by silica gel column chromatography system B to give compound 040d (750 mg, yield: 40%).

[0265] Step 4: Preparation of compound 040e

[0266] A methanol / water (20 / 5 mL) solution of compound 040d (750 mg, 2.15 mmol), Fe powder (601 mg, 10.77 mmol), and ammonium chloride (577 mg, 10.77 mmol) was stirred at 70 °C for 16 hours under nitrogen protection until the reaction was complete. The reaction solution was filtered and concentrated, and the crude product was separated and purified by column chromatography system B to obtain compound 040e (400 mg, yield: 58%).

[0267] MS m / z(ESI): 318.0(M+1) + .

[0268] Step 5: Preparation of compound 040f

[0269] Compound 040e (400 mg, 1.26 mmol) was dissolved in N,N-dimethylformamide (10 mL), and palladium acetate (57 mg, 0.25 mmol) and xphos (120 mg, 0.25 mmol) were added. Finally, under nitrogen protection, a solution of (S)-(2-((tert-butyloxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide (1487 mg, 3.77 mmol) in N,N-dimethylformamide was added. The reaction was stirred at 80 °C under nitrogen protection for 12 hours. The reaction was monitored by LC-MS until complete. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography system B to obtain compound 040f (80 mg, yield: 15%).

[0270] MS m / z (ESI): 353.1 (M-55) + .

[0271] Step 6: Preparation of compound 040g

[0272] Compound 040f (80 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (2 mL), and iodomethane (56 mg, 0.39 mmol) and cesium carbonate (128 mg, 0.39 mmol) were added. The reaction was stirred at 50 °C for 3 hours, and the reaction was monitored by LC-MS until complete. The reaction was quenched with water and then extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography separation system B to give compound 040g (50 mg, yield: 60%).

[0273] MS m / z (ESI): 367.1 (M-55) + .

[0274] Step 7: Preparation of compound 040h

[0275] Compound 040g (50mg, 0.12mmol) was dissolved in 4M hydrogen chloride / 1,4-dioxane (3mL). The solution was stirred at room temperature for 1 hour. After the reaction was completed by LC-MS monitoring, the crude product 040h (40mg) was directly concentrated. The product was used directly in the next reaction without purification.

[0276] MS m / z(ESI): 323.1(M+1) + .

[0277] Step 8: Preparation of compound 040

[0278] Compound 040h (40 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of acetic acid (0.1 mL) and water (0.1 mL), and then potassium cyanate (15 mg, 0.19 mmol). The reaction was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weakly alkaline. The mixture was then concentrated and purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150×19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 45%-95%, flow rate: 20 mL / min) to obtain compound 040 (2.23 mg, yield: 5%).

[0279] MS m / z(ESI): 366.2(M+1) + .

[0280] 1 H NMR(400 MHz, CDCl3)δ7.28-6.69(m,6H),6.31-5.87(m,2H),4.50-4.26(m,1H),3. 43-3.40(m,1H),3.07-3.04(m,3H),2.86-2.75(m,3H),2.50-2.32(m,2H).

[0281] Example 7

[0282] Synthesis of Compound 009

[0283] Compound 040 (30 mg, 0.08 mmol) was dissolved in methanol (5 mL), and 10% palladium on carbon (15 mg) and Pd(OH)₂ (15 mg) were added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered. The crude product was concentrated and purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 × 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 45%-95%, flow rate: 20 mL / min) to give compound 009 (12 mg, yield: 37%).

[0284] MS m / z(ESI): 368.2(M+1) + .

[0285] 1 H NMR(400 MHz, CD3OD) δ7.19-7.02(m,3H),6.95-6.87(m,1H),6.78-6.70(m,2H),4.52-4. 18(m,2H),3.46(s,3H),3.18-3.01(m,1H),2.93-2.75(m,3H),2.42-1.58(m,H).

[0286] Example 8

[0287] Synthesis of Compound 008

[0288] Using a synthetic route similar to that in Example 6, the final product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA2 detector, column: Xbridge 5μm C18 150×19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 50%-95%, flow rate: 20mL / min) to obtain compound 008 (2.8mg, yield: 12%).

[0289] MS m / z(ESI): 354.1(M+1) + .

[0290] 1 H NMR(400MHz,CD3OD)δ7.28(dd,1H),7.14(t,1H),7.08(t,1H),6.92(dd,2H),6.78(d,1H),4.67(t,1H), 4.37–4.28(m,1H),3.46(d,3H),3.18–3.04(m,2H),2.94–2.86(m,2H),2.59–2.44(m,1H),1.93(dd,1H).

[0291] Example 9

[0292] Synthesis of Compound 011

[0293] Using a synthetic route similar to that in Example 2, the final product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5μm C18 150×19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 35%-45%, flow rate: 20mL / min) to obtain compound 011 (5.7mg, yield: 9%).

[0294] MS m / z(ESI): 391.1(M+1) + .

[0295] 1 H NMR(400MHz,CD3OD)δ7.38(dd,1H),7.17–6.87(m,3H),6.86–6.61(m,2H),4. 17(d,1H),3.71(d,2H),3.44(s,3H),3.11(dd,1H),2.82(t,1H),1.24(t,3H).

[0296] Example 10

[0297] Synthesis of Compound 014

[0298] Using a synthetic route similar to that in Example 2, the final product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5μm C18 150×19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 55%-95%, flow rate: 20mL / min) to obtain compound 014 (2.0mg, yield: 9.1%).

[0299] MS m / z(ESI): 369.1(M+1) + .

[0300] 1H NMR (400MHz, DMSO-d6) δ7.41–7.19(m,2H),7.15(d,1H),7.01(dd,1H),6.47–6.31(m,2H),6.15–6.09(m,1H),5.86–5.82( m,1H),5.50–5.46(m,1H),4.30–4.03(m,1H),3.98–3.50(m,1H),3.15–2.97(m,5H),2.79-2.67(m,3H),2.09–1.81(m,2H).

[0301] Example 11

[0302] Synthesis of Compound 016

[0303] Preparation of compound 016b in step one

[0304] Under nitrogen protection, compound 016a (400 mg, 1.43 mmol) was dissolved in N,N-dimethylformamide (5 mL). Under nitrogen protection at room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (104 mg, 0.14 mmol) and cuprous iodide (27 mg, 0.14 mmol) were added to the reaction mixture. Finally, under nitrogen protection, a solution of (S)-(2-((tert-butyloxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide (612 mg, 1.86 mmol) in N,N-dimethylformamide was added. The reaction was stirred at 80 °C under nitrogen protection for 16 hours. The reaction was monitored by LC-MS until complete. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography system A to obtain compound 016b (400 mg, yield: 69.6%).

[0305] MS m / z(ESI): 303(M+1-100) + .

[0306] The second step involves the preparation of compound 016c.

[0307] Compound 016b (400 mg, 1.07 mmol) was dissolved in a mixed solvent of tetrahydrofuran / methanol / water (12 mL / 6 mL / 3 mL), and zinc powder (349 mg, 5.35 mmol) and ammonium chloride (301 mg, 5.35 mmol) were added. The reaction was stirred at 70 °C for 1 hour. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 0-10%) to obtain compound 016c (300 mg, yield: 81.1%).

[0308] MS m / z(ESI): 317(M+1-56) + .

[0309] Preparation of compound 016d in step three

[0310] Compound 016c (300 mg, 0.81 mmol) was dissolved in dichloromethane (20 mL) and trimethylaluminum (0.6 mL, 2 M, 1.21 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was completed, methanol was slowly added to dilute the mixture, and the solution was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography system A to obtain compound 016d (200 mg, yield: 72.7%).

[0311] MS m / z(ESI): 285(M+1-56) + .

[0312] Step 4: Preparation of compound 016e

[0313] Compound 016d (200 mg, 0.58 mmol) was reacted with iodomethane (412 mg, 2.90 mmol) in a tetrahydrofuran (20 mL) solution, and cesium carbonate (377 mg, 1.16 mmol) was added. The reaction was carried out at 50 °C for 2 hours. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to give compound 016e (180 mg, yield: 86.9%).

[0314] MS m / z(ESI): 299(M+1-56) + .

[0315] Step 5: Preparation of compound 016f

[0316] Compound 016e (60 mg, 0.17 mmol) was dissolved in methanol (5 mL). Under nitrogen protection at room temperature, XphosPdG2 (13 mg, 0.017 mmol), X-Phos (16 mg, 0.034 mmol), diborane-1,1,2,2-tetraol (75 mg, 0.84 mmol), and potassium acetate (83 mg, 0.84 mmol) were added to the reaction mixture. The reaction was stirred at 80 °C under nitrogen protection for 16 hours. The reaction mixture was then evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography system A to obtain compound 016f (20 mg, yield: 29.4%).

[0317] MS m / z(ESI): 265(M+1-56) + .

[0318] Step 6: Preparation of compound 016g

[0319] Compound 016f (20 mg, 0.05 mmol) was dissolved in dioxane (5 mL) and water (1 mL). Under nitrogen protection at room temperature, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (6 mg, 0.007 mmol), 3-bromo-5-fluoro-1-benzothiophene (17 mg, 0.075 mmol), and potassium acetate (27 mg, 0.20 mmol) were added to the reaction mixture. The reaction was stirred at 90 °C under nitrogen protection for 4 hours. The reaction mixture was then evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography system A to obtain compound 016g (13 mg, yield: 61.4%).

[0320] MS m / z(ESI): 371(M+1-56) + .

[0321] Step 7: Preparation of compound 016h

[0322] Compound 016 g (13 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), and dioxane hydrochloride solution (3 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the product was evaporated to dryness to obtain crude compound 016 h (10 mg). The product was used directly in the next step without purification.

[0323] MS m / z(ESI): 327(M+1) + .

[0324] Step 8: Preparation of compound 016

[0325] Compound 016h (10 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of acetic acid (0.1 mL) and water (0.1 mL), and then potassium cyanate (10 mg, 0.125 mmol). The reaction was stirred at room temperature for 0.5 hours. After the reaction was complete as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weakly alkaline. The mixture was then concentrated and purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150×19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 30%-95%, flow rate: 20 mL / min) to obtain compound 016 (3 mg, yield: 26.5%).

[0326] 1H NMR(400MHz,CD3OD)δ7.97-7.95(m,1H),7.75-7.50(m,1H),7.49-7.36(m,2H),7.27 -7.20(m,3H),4.56-4.45(m,1H),3.48(m,3H),3.18-3.16(m,1H),2.90-2.80(m,1H).

[0327] Example 12

[0328] Synthesis of Compound 041

[0329] Preparation of compound 041a in step one

[0330] Compound 001 g (1 g, 2.39 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection at 0 °C. The reaction mixture was cooled to 0 °C. Methyllithium (1.6 M, 3 mL, 4.77 mmol) was slowly added dropwise over 5 minutes. The mixture was allowed to warm to room temperature and reacted for two hours. The reaction mixture was slowly poured into ice water. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (50 mL), and evaporated to dryness to give the crude product. The crude product was purified by rapid column chromatography system B to give compound 041a (300 mg, yield: 29%).

[0331] MS m / z(ESI): 379(M-56+1) + .

[0332] The second step involves the preparation of compound 041b.

[0333] Compound 041a (100 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL) under nitrogen protection at 0 °C. DAST reagent (370 mg, 2.30 mmol) was slowly added dropwise over 5 minutes. The mixture was allowed to warm to room temperature and reacted for two hours. The reaction mixture was slowly poured into a mixture of methanol and water. The aqueous phase was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saturated brine (20 mL), and evaporated to dryness to obtain the crude product. The crude product was purified by rapid column chromatography system B to give compound 041b (80 mg, yield: 80%).

[0334] MS m / z(ESI): 381(M-56+1) + .

[0335] Preparation of compound 041c in step three

[0336] Compound 041b (80 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (2 mL), and methyl iodide (226 mg, 0.55 mmol) and cesium carbonate (179 mg, 0.55 mmol) were added. The reaction was stirred at 50 °C for 2 hours. After the reaction was completed, water (10 mL) was added, and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (10 mL), and evaporated to dryness to obtain the crude product. The crude product was purified by rapid column chromatography system B to give compound 041c (60 mg, yield: 73%).

[0337] MS m / z(ESI): 351(M-100+1) + .

[0338] Step 4: Preparation of compound 041d

[0339] Compound 041c (60 mg, 0.13 mmol) was dissolved in dioxane hydrochloride solution (2 mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the solution was evaporated to dryness to give compound 041d (40 mg, yield: 85%).

[0340] MS m / z(ESI): 351(M+1) + .

[0341] Step 4: Preparation of compounds 041A and 041B

[0342] Compound 041d (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (1 mL), and acetic acid (2 drops), H2O (2 drops), and potassium cyanate (28 mg, 0.34 mmol) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated and concentrated to obtain the crude product. The crude product was directly purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2×250 mm 10 μm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 10-minute gradient, gradient ratio: acetonitrile phase 35%-65%, flow rate: 30 mL / min) to obtain the racemic compound 041. After purification by SFC (SFC 80, column: Daicel CHIRALCEL ID, 250mm×30mm I.D., 10μm, mobile phase: CO2 / MeOH [0.2% NH3 (7M Solution in MeOH)] = 50 / 50, flow rate: 80g / min), compound 041A (6mg, RT = 1.555min) and compound 041B (1mg, RT = 2.303min) were obtained.

[0343] Compound 041A:

[0344] MS m / z(ESI): 394(M+1) + .

[0345] 1 H NMR(400MHz,DMSO-d6)δ7.69-7.61(m,2H),7.39-7.33(m,2H),7.26-7.17(m,2H),6.27(d,1H),5 .81(s,2H),3.99-3.90(m,1H),2.97(s,3H),2.65-2.57(m,1H),2.14(d,3H),2.03-1.97(m,1H).

[0346] Compound 041B:

[0347] MS m / z(ESI): 394(M+1) + .

[0348] 1 H NMR(400MHz, DMSO-d6)δ7.54-7.51(m,1H),7.47–7.45(m,1H),7.42–7.40(m,1H),7.35-7.29(m,2H),7.26-7.21(m, 1H),6.33(d,1H),5.84(s,2H),4.17-4.06(m,1H),2.82(s,3H),2.63–2.55(m,1H),2.19(d,3H),2.04-1.95(m,1H).

[0349] Example 13

[0350] Synthesis of compounds 072A and 072B

[0351] Preparation of compound 072b in step one

[0352] Amyl nitrite (467 mg, 3.99 mmol) was dissolved in acetonitrile (10 mL), and cuprous iodide (1.18 g, 6.13 mmol) was added. After stirring at room temperature for 1 hour, compound 072a (500 mg, 3.07 mmol) was added. The reaction was stirred at 70 °C for 2 hours, and the reaction was monitored to be complete by LC-MS. The mixture was filtered, concentrated by rotary evaporation, and purified by column chromatography separation system B to give compound 072b (350 mg, yield: 42%).

[0353] 1H NMR (400MHz, DMSO-d6) δ8.12(dd,1H),7.89(dd,1H).

[0354] The second step involves the preparation of compound 072c.

[0355] Compound 072b (350 mg, 1.28 mmol) was dissolved in tetrahydrofuran (5 mL), and 1.3 M isopropyl magnesium chloride-lithium chloride (1.3 mL, 1.66 mmol) was added. After stirring at 0 °C for 1 hour, 3-bromo-2-nitrobenzaldehyde (293 mg, 1.28 mmol) was added. The reaction was stirred at room temperature for 16 hours, and the reaction was monitored to be complete by LC-MS. The solution was concentrated by rotary evaporation and purified by column chromatography to give compound 072c (400 mg, yield: 83%).

[0356] MS m / z(ESI): 330.1(M+1-18) + .

[0357] Preparation of compound 072d in step three

[0358] Compound 072c (400 mg, 1.06 mmol) was dissolved in methanol (10 mL), tetrahydrofuran (5 mL), and water (1 mL). Iron powder (594 mg, 10.6 mmol) and ammonium chloride (572 mg, 10.6 mmol) were added. The reaction was stirred at 75 °C for 6 hours. The reaction was monitored by LC-MS until complete. The solution was concentrated by rotary evaporation and purified by column chromatography to give compound 072d (350 mg, yield: 95%).

[0359] MS m / z(ESI): 330.1(M+1-18) + .

[0360] Step 4: Preparation of compound 072e

[0361] Compound 072d (350 mg, 1.01 mmol) was dissolved in dichloromethane (10 mL), and manganese dioxide (870 mg, 10.1 mmol) was added. The reaction was stirred at room temperature for 16 hours, and the reaction was monitored to be complete by LC-MS. The solution was concentrated by rotary evaporation and purified by column chromatography to give compound 072e (300 mg, yield: 86%).

[0362] MS m / z(ESI): 346.1(M+1) + .

[0363] Step 5: Preparation of compound 072f

[0364] Compound 072e (300 mg, 0.87 mmol) was dissolved in tetrahydrofuran (10 mL), and 1 M cyclopropylmagnesium bromide tetrahydrofuran solution (3 mL, 3.04 mmol) was added. The reaction was stirred at 70 °C for 6 hours, and the reaction was monitored to be complete by LC-MS. The solution was concentrated by rotary evaporation and purified by column chromatography to give compound 072f (260 mg, yield: 77%).

[0365] MS m / z(ESI): 370.1(M+1-18) + .

[0366] Step 6: Preparation of compound 072g

[0367] Compound 072f (260 mg, 0.67 mmol) was dissolved in trifluoroacetic acid (8 mL), and triethylsilane (4 mL) was added. The solution was stirred at 100 °C for 16 hours. After the reaction was complete as monitored by LC-MS, the solution was concentrated and purified by column chromatography to obtain compound 072g (100 mg, yield: 35%).

[0368] MS m / z(ESI): 372.1(M+1) + .

[0369] Step 7: Preparation of compound 072h

[0370] Compound 072 g (100 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (39 mg, 0.08 mmol), palladium acetate (10 mg, 0.04 mmol), and (S)-(2-((tert-butyloxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide (0.5 mL, 0.55 mmol) were added. The solution was stirred at 80 °C for 5 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the mixture was filtered, water (15 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The solution was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to obtain compound 072 h (30 mg, yield: 24%).

[0371] MS m / z(ESI): 407.1(M+1-56) + .

[0372] Step 8: Preparation of compound 072i

[0373] Compound 072h (30 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (64 mg, 0.2 mmol) and iodomethane (17 mg, 0.12 mmol) were added. The solution was stirred at 50 °C for 1 hour. After the reaction was monitored by LC-MS until complete, the solution was filtered, water (15 mL) was added, and the solution was extracted with ethyl acetate (10 mL × 3). The solution was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to obtain compound 072i (28 mg, yield: 91%).

[0374] MS m / z(ESI): 449.1(M+1-56) + .

[0375] Step 9: Preparation of compound 072j

[0376] Compound 072i (28 mg, 0.059 mmol) was dissolved in 5 mL of 4 mol / L hydrogen chloride / 1,4-dioxane solution. The solution was stirred at room temperature for 1 hour. After the reaction was completed by LC-MS monitoring, the crude compound 072j (23 mg) was directly concentrated. The crude product was used directly in the next step of the reaction without purification.

[0377] MS m / z(ESI): 377.1(M+1) + .

[0378] Step 10: Preparation of compounds 072A and 072B

[0379] Compound 072j (23 mg, 0.059 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of acetic acid (0.1 mL) and water (0.1 mL), and then potassium cyanate (10 mg, 0.12 mmol). The reaction was stirred at room temperature for 0.5 hours. After the reaction was complete as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weakly alkaline. The mixture was extracted with ethyl acetate, and the organic phase was collected and concentrated to obtain the crude product. The crude product was then prepared by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA2 detector, column: Xbridge 5 μm C18). The mobile phase was 150×19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 60%-100%, flow rate: 20 mL / min) to purify compound 072A (first peak, 1.7 mg, RT = 4.55 min) and compound 072B (last peak, 5 mg, RT = 7.32 min).

[0380] Compound 072A:

[0381] MS m / z(ESI): 420.1(M+1) + .

[0382] 1 H NMR(400MHz,CD3OD)δ7.66(dd,1H),7.47(dd,1H),7.18(dq,3H),4.27(dd,1H),4.11(d,1H),3.28(s,3 H),3.06(dd,1H),2.82(t,1H),1.68–1.53(m,1H),0.75–0.59(m,1H),0.59–0.37(m,2H),0.16(td,1H).

[0383] Compound 072B

[0384] MS m / z(ESI): 420.1(M+1) + .

[0385] 1 H NMR(400MHz,CD3OD)δ7.67(dd,1H),7.30(dd,1H),7.19(dd,2H),7.13(dd,1H),4.28(d,1H),3.97(dd,1H),3.43(s,3H),3 .01(dd,1H),2.75(t,1H),1.55–1.42(m,1H),0.94–0.84(m,1H),0.78–0.67(m,1H),0.63–0.52(m,1H),0.52–0.41(m,1H).

[0386] Example 14

[0387] Synthesis of Compound 075

[0388] Following a similar synthetic route as in Example 1, the final product was purified by high-performance liquid chromatography (Waters MS-triggered Prep-LC with QDA2 detector, column: Xbridge 5μm C18 150×19mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13-minute gradient, gradient ratio: acetonitrile phase 60%-100%, flow rate: 20mL / min) to obtain compound 075 (8mg).

[0389] MS m / z(ESI): 398.0(M+1) + .

[0390] 1H NMR(400MHz,CD3OD)δ7.41(d,1H),7.37-7.28(m,2H),7.26-7.20(m,1H),7.17(t, 1H),7.08(d,1H),4.27-4.20(m,1H),3.54(s,3H),3.13-3.08(m,1H),2.86(t,1H).

[0391] Using a similar synthetic route, the compounds in Table 1 below were synthesized, and the characterization data are shown in the following table:

[0392] Table 1

[0393] Biological evaluation

[0394] Test Example 1: TSHR Inhibitory Activity Screening (cAMP) Experiment

[0395] Experimental Objective: This experiment aims to test the inhibitory effect of the compound on the TSH receptor, based on IC50. 50 Size is used to evaluate the in vitro activity of compounds.

[0396] The experimental materials and reagents are shown in Table 2:

[0397] Table 2

[0398] Experimental steps

[0399] 1. Compound preparation

[0400] (1) The compound sample was dissolved in DMSO to a storage concentration of 10 mM;

[0401] (2) Sample dilution sequences were prepared on 384-well LDV plates. The initial concentration point of each sample was 2 mM (FAC = 10 μM), and the samples were serially diluted 3 times, for a total of 11 concentration points.

[0402] (i) Dilute the sample to be tested with DMSO to obtain an intermediate concentration of 2 mM, specifically by mixing 2 μL of 10 mM sample with 8 μL of DMSO.

[0403] (ii) Take an LDV 384-well plate and add the 2mM test compound solution prepared above to wells A1-P1 respectively; add 10μL DMSO to each well from A2 to P11 respectively; then centrifuge at 1000rpm for 30 seconds.

[0404] (iii) Perform serial dilutions of the compound using Bravo: Starting with column 1 of the LDV plate prepared in step b as the initial concentration column, pipette 5 μL into the next column each time and mix thoroughly by pipetting. After the dilution program is complete, centrifuge at 1000 rpm for 30 seconds.

[0405] (3) Use an Echo machine to transfer the sample dilution sequence to the experimental plate (Corning-3824), with 50 nL transferred per well.

[0406] 2. cAMP experimental method

[0407] (1) Prepare the reagents required for the experiment

[0408] (i) Experimental buffer (1×Stimulation buffer): Equilibrate the 5x Stimulation buffer from the kit to room temperature.

[0409] Dilute with ultrapure water at a ratio of 1:4, and add IBMX to a final concentration of 500μM before use.

[0410] (ii) 2X stimulator buffer: 40 ng / mL FSH protein or 0.3 nM Anti-TSHR Antibody + 500 uM IBMX dissolved in experimental buffer;

[0411] (iii) Detection reagents: Equilibrate the Lysis & detection buffer in the kit to room temperature, and then detect cAMP-d2 and Anti-cAMP separately.

[0412] Dilute the cryptate at a ratio of 1:20 and set aside.

[0413] (2) Prepare cell suspension

[0414] (i) Human FSHR / TSHR cells on culture dishes were digested with 0.05% trypsin, then washed with culture medium and collected into 15 mL centrifuge tubes.

[0415] (ii) Centrifuge at 1000 rpm for 5 minutes, then discard the supernatant.

[0416] (iii) Resuspend the cells in 1×Stimulation buffer, count them on a Countess II FL cell counter, and adjust the cell density to 1.0×10⁶ / mL.

[0417] (3) cAMP HTRF experiment

[0418] (i) Add the cell suspension to the experimental plate containing the compound using Multidrop combi, 5 μL / well.

[0419] (ii) Centrifuge at 1000 rpm for 30 seconds, then incubate at room temperature for 15 minutes.

[0420] (iii) Add 2X stimulant buffer to each well of the experimental plate, 5 μL per well.

[0421] (iv) Centrifuge at 1000 rpm for 30 seconds, then incubate at 37°C for 30 minutes.

[0422] (v) Add the diluted cAMP-d2 and Anti-cAMP cryptate detection reagents to each well of the experimental plate in sequence, 5 μL / well.

[0423] First add 5 μL of cAMP-d2 reagent, then add 5 μL of Cryptate reagent.

[0424] (vi) After the experimental plate has been left to stand at room temperature for 60 minutes, the readings are taken on the Envision.

[0425] (4) Experimental data processing methods

[0426] The IC50 of the compound was calculated using an XLFit fitting of percentage activation rate and 11-point concentration data to a parametric nonlinear logic formula. 50 Value. Details are as follows:

[0427] (i) Calculate the inhibition effect value of each well on the experimental plate according to the following formula:

[0428] %Effect=100×(value-ZPE) / (HPE-ZPE)

[0429] Wherein, %Effect is the inhibitory effect value of the corresponding experimental well, value is the signal value of the experimental well, ZPE is the mean signal value of the negative control experimental well, and HPE is the mean signal value of the positive control experimental well.

[0430] (ii) Subsequently, based on the inhibitory effect values ​​at different concentration test points of the compound sample, the XLFit four-parameter model was used to fit the interaction curve of the compound sample and the IC50 was calculated. 50 value.

[0431] Experimental results:

[0432] Detection of IC50 of TSHR antagonists using CHO-K1 / TSH cells 50 The test results are shown in Table 3.

[0433] Table 3 Test results of the tested compounds

[0434] Conclusion: The compound of this invention has significant inhibitory activity on the release of cAMP from CHO-K1 / TSH cells.

[0435] Test Example 2: FSHR Inhibitory Activity (cAMP) Experiment

[0436] Experimental Objective: This experiment aims to test the inhibitory effect of the compound on the FSH receptor, based on the IC50 value. 50 Size is used to evaluate the in vitro activity of compounds.

[0437] The experimental method is the same as that in Test Example 1.

[0438] Experimental results:

[0439] FSHR's IC 50 The test results are shown in Table 4.

[0440] Table 4. Test results of the tested compounds

[0441] Conclusion: The compounds of this invention do not significantly inhibit the release of cAMP from CHO-K1 / FSH cells and exhibit good selectivity.

[0442] Test Example 3: LHCGR Inhibitory Activity (cAMP) Experiment

[0443] 1. Experimental Materials

[0444] cAMP Detection Kit (Revvity)

[0445] 384-well assay plate (Revvity)

[0446] Vi-cell counter (Beckman)

[0447] ECHO (Labcyte)

[0448] Envision (PerkinElmer)

[0449] 2. Experimental Procedure

[0450] (1) The test compound was serially diluted 3-fold at 10 points using an Echo, and 50 nL was transferred to the compound plate in duplicate. 50 nL of the highest concentration antagonist reference compound was transferred as the Low control, and 50 nL of DMSO was transferred as the High control. 50 nL of EC80 was transferred to each well of the compound plate using an Echo, resulting in a final concentration of 0.08 nM.

[0451] 2) Resuspend LHCGR cells in buffer to 0.1 × 10⁻⁶. 6 Add 10 μL of cell suspension to the compound plate at / mL, and centrifuge at 1000 rpm for 1 minute. Incubate at room temperature for 60 minutes.

[0452] 4) Preparation of cAMP standard curve: Prepare 800 nM starting material, 4-fold diluted cAMP standard for 10 points, and add 10 μL to each well of the compound plate.

[0453] 5) Add 10 μL of the detection reagent solution to the compound plate and centrifuge at 1000 rpm for 1 minute. Incubate at room temperature in the dark for 60 minutes.

[0454] 6) Place the reaction plate in an EnVision microplate reader and take the reading. The final value is the ratio of 665nm to 615nm.

[0455] 7) Analyze the data:

[0456] a) Calculate the actual cAMP level (nM) for each sample well using the cAMP standard curve;

[0457] b) Antagonist: Inhibition% = 100% × (1 - (cAMP value of sample wells - average cAMP value of low signal control group) / (average cAMP value of high signal control group - average cAMP value of low signal control group));

[0458] c) Using GraphPad Prism 5 data analysis software, the Dose-response-Inhibition-log(inhibitor) vs. response-variable slope mode was selected for fitting analysis to obtain the IC50 of each tested sample. 50 value.

[0459] Experimental results:

[0460] LHCGR IC 50 The test results are shown in Table 5.

[0461] Table 5. Test results of the tested compounds

[0462] Conclusion: The compound of this invention does not significantly inhibit the release of cAMP from CHO-K1 / LHCG cells and has good selectivity.

[0463] Test Example 4: Liver Microsomal Stability Experiment

[0464] 1. Materials and Reagents

[0465] Microparticles are stored in a -80°C freezer. See Table 6 below for details.

[0466] Table 6

[0467] 2. Experimental Design

[0468] 2.1 Preparation of the compound working solution

[0469] The test substance and the control drug verapamil powder were prepared into a high-concentration stock solution using DMSO. Before use, the stock solution was diluted to 100 μM with acetonitrile:water = 1:1. The final concentration of the test substance and verapamil was 1 μM.

[0470] 2.2 Preparation of phosphate buffer (100mM, pH 7.4)

[0471] First, weigh 7.098g of disodium hydrogen phosphate and dissolve it in 500mL of pure water by sonication, as solution A. Then, weigh 3.400g of potassium dihydrogen phosphate and dissolve it in 250mL of pure water by sonication, as solution B. Add solution B to solution A until the pH reaches 7.4.

[0472] 2.3 Preparation of 10mM NADPH

[0473] Before the experiment, weigh an appropriate amount of NADPH and prepare a 10mM working solution using phosphate solution.

[0474] 2.4 Preparation of the incubation system

[0475] The incubation system was prepared according to Table 7 below. Before use, the incubation system was preheated in a water bath at 37°C for 10 minutes.

[0476] Table 7

[0477] 2.5 Test Methods

[0478] 1) Transfer 25 μL of NADPH or phosphate buffer to the above incubation system, and add 2.5 μL of 100 μM test substance or verapamil. For NADPH-added samples, perform double-parallel preparation; for NADPH-negative samples, perform single-parallel preparation.

[0479] 2) Take 30 μL of the suspension at 0.5, 5, 15, 30 and 60 minutes respectively. Add 150 μL of acetonitrile containing the internal standard to terminate the reaction, and vortex for 10 minutes.

[0480] 3) Then, centrifuge at 3220g for 30 minutes to precipitate the protein. Transfer 40μL of supernatant to the sample plate, add 160μL of pure water and mix well for UPLC-MS / MS analysis.

[0481] 3. Data Analysis

[0482] All calculations were performed using Microsoft Excel. Peak areas were detected by extracting ion spectra. The in vitro half-life (T0) of the parent drug was determined by linearly fitting the natural logarithm of the elimination percentage of the parent drug to time. 1 / 2 ).

[0483] In vitro half-life (T 1 / 2 ) Calculated by slope:

[0484] in vitro t 1 / 2 =0.693 / k

[0485] In vitro clearance rate (unit: μL / min / mg) is calculated using the following formula:

[0486] in vitro CLint=kV / N

[0487] V = Incubation volume per well (250 μL);

[0488] N = the content of microparticles per pore (0.125 mg).

[0489] Experimental results:

[0490] The test results are shown in Table 8.

[0491] Table 8 Test results of the tested compounds

[0492] Conclusion: The compounds of this invention exhibit good in vitro metabolic stability.

[0493] Test Example 5: Pharmacokinetic Test of C57 Mice

[0494] The tool compound, compound 001A, and compound 004A were administered orally (2 mpk) and intravenously (1 mpk) to two female and two male C57BL / 6J mice in each group, using 5% DMSO + 5% Solutol + 90% Saline solvent. Blood samples were collected at eight time points: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The mean pharmacokinetic parameters in plasma are shown in Table 9 (where F = 1 / 2 * AUC(PO: 2 mpk) / AUC(IV: 1 mpk) * 100%).

[0495] Table 9 Results of pharmacokinetic assays of the compounds in mice.

[0496] Conclusion: The results show that the representative compound of this application is well absorbed in mice and has good pharmacokinetic properties.

[0497] Test Example 6: Pharmacokinetic Test in Beagle Dogs

[0498] The tool compound and compound 001A were administered orally (2 mpk) and intravenously (0.5 mpk) in 5% DMSO + 5% Solutol + 90% Saline solvent (two female and two male beagle dogs per group). Blood samples were collected at eight time points after intravenous administration: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h; and at eight time points after oral administration: 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h. The mean pharmacokinetic parameters in plasma are shown in Table 10 (where F = 1 / 4 * AUC(PO: 2 mpk) / AUC(IV: 0.5 mpk) * 100%).

[0499] Table 10 Results of canine pharmacokinetic tests of the compounds.

[0500] Conclusion: The results show that the representative compound of this application is well absorbed in beagle dogs and has good pharmacokinetic properties.

[0501] Test Example 7: Rat Hyperthyroidism PD Efficacy Model

[0502] 1. Materials and reagents are shown in Table 11.

[0503] Table 11

[0504] 2. Preparation of modeling agents and test materials

[0505] 2.1 M22 modeling agent: Before each administration, remove and allow to room temperature to thaw. Gently invert and mix well. Prepare the corresponding concentration of the test sample with PBS and mix well. Store at 2–8°C. Remove and allow to room temperature before use. Use within 4 hours.

[0506] 2.2 The solvent configuration is shown in Table 12

[0507] Table 12

[0508] 3. Experiment Content

[0509] (1) D-4 (the first four days of Day 0 (hereinafter referred to as D0)) The animals were divided into equal groups according to their body weight.

[0510] (2) D-4: From D-4 until the end of the experiment, all animals were given a 3 μg / mL T3 aqueous solution. The T3 aqueous solution needed to be prepared daily (T3 was first prepared into a 60 μg / mL stock solution with water, and the stock solution was stored in a 4℃ refrigerator. The animal drinking water was diluted 20 times to obtain a 3 μg / mL T3 aqueous solution). The water intake (weight) of each cage animal was recorded daily.

[0511] (3) D0: Animals in the drug administration group, positive control group and model group were given M22 modeling agent diluted with PBS to a concentration of 150 μg / mL at a drug administration dose of 60 μg / kg. Animals in the negative control group were given the corresponding volume of PBS (see Table 13).

[0512] Table 13 Animal grouping and modeling

[0513] (4) D0: Each group of animals was given the test compound (solvent: 5% (v / v) Soluto1 HS15 + 5% TPGS + 90% (0.2% CMC-Na, viscosity 800-1200)), positive control K1-70 (PBS diluted to the corresponding volume) or the corresponding solvent (Table 14).

[0514] Table 14 Animal Dosing

[0515] Note: The solvent in Table 8 is 5% (v / v) Solutol HS15 + 5% TPGS + 90% (0.2% CMC-Na, viscosity 800-1200).

[0516] (5) D0-D1: Blood samples were collected from each group of animals according to the table below to prepare serum (see Table 15).

[0517] Blood collection: 0.4 mL of blood was collected from the jugular vein at each time point.

[0518] Blood sample processing and testing: Whole blood was collected and placed in serum separation gel tubes. After standing at room temperature for half an hour, the supernatant was collected by centrifugation at 2000 rcf at room temperature for 10 minutes. The serum samples were directly tested for TT4 levels in the serum samples of each group of animals using the Roche cobas8000 fully automated biochemical and immunoassay system (consisting of the cobas8000 c702 fully automated biochemical analyzer and the cobas8000 e602 fully automated electrochemiluminescence immunoassay analyzer).

[0519] Table 15 Animal Sampling

[0520] The experimental results are shown in Figures 1 and 2.

[0521] Conclusion: All compounds of the present invention can significantly reduce TT4.

[0522] Unless otherwise specified, the structures of the tool compounds described in this invention are as follows:

[0523] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. The compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: wherein R 11 , R 12 , R2are the same or different, independently of one another, selected from H, C 1-12 alkyl, C 3-12 cycloalkyl or 3-14 membered heterocyclyl; Each R b They may be identical or different, independently selected from CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R. b1 The following groups are substituted: OH, NH2, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2R b2 Or C(=O)R b3 ; Each R b1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R b2 R b3 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; n is selected from 0, 1, 2 or 3; R3is selected from H, CN, unsubstituted or optionally substituted with one, two or more R c the following groups, which are unsubstituted or optionally substituted with one, two or more R 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, haloC 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl; each R c are the same or different and independently of each other selected from oxo (=0), CN, halogen, unsubstituted or optionally substituted with one, two or more R c1 the following groups, which are unsubstituted or optionally substituted with one, two or more R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, S(=0)2R c2 or C(=0)R c3 ; each R c1 are the same or different and independently of each other selected from oxo (=0), CN, halogen, OH, NH2, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, S(=0)2R c4 or C(=0)R c5 ; R c2 , R c3 , R c4 , R c5 are the same or different and independently of each other selected from H, OH, NH2, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; X1is selected from CR X1 or N; X2is selected from CR X2 or N; X3is selected from CR X3 or N; R X1 R X2 R X3 They may be identical or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more R groups. d The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R d They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; Y1is selected from -CR 61 R 62 -; -NR7-; or unsubstituted or optionally substituted by one, two or more R d ; C 2-12 alkylene; -O-C 1-12 alkylene; -S-C 1-12 alkylene; -NH-C 1-12 alkylene; -C 1-12 alkylene-O-; -C 1-12 alkylene-S-; or -C 1-12 alkylene-NH-; R 61 H, CN, halogen, OH, NR 63 R 64 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogen-C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=O)2R 65 or C(=O)R 66 ; R 63 , R 64 , R 65 are identical or different and independently of each other selected from H, C 1-6 alkyl or C 3-6 cycloalkyl; R 66 is selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; R 62 selected from CN, halogen, OH, NR 67 R 68 , C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=O)2R 69 or C(=O)R 610 ; R 67 , R 68 , R 69 are identical or different and independently from each other selected from H, C 1-6 alkyl or C 3-6 cycloalkyl; R 610 is selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; Or, R 61 R 62 Together with the C atoms attached thereto, they form unsubstituted or optionally substituted by one, two or more R atoms. d Substitution of the following groups: olefinic bond (C=CH2), C 3-12 Carbon rings or 3-14 membered heterocyclic rings; R7is selected from H, C 1-12 alkyl, haloC 1-12 alkyl, C 3-12 cycloalkyl or 3-14 membered heterocyclyl; or R 62 or R7is attached to R3or R5together to form an optionally substituted C d substituted C 3-16 carbon ring or 3-16 membered heterocyclic ring; Each R d They may be identical or different, and are independently selected from CN, halogen, unsubstituted, or optionally composed of one, two, or more R. d1 The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2R d2 Or C(=O)R d3 Or, two R atoms attached to the same carbon atom d Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. d1 The following ring systems are replaced: C 3-14 A carbon ring or a 3-14 membered heterocycle; or, two R atoms attached to adjacent carbon atoms. d Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. d1 The following ring systems are replaced: C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. d Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. d1 Replacement C 1-3 Alkylene; each R d1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R d2 R d3 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; R4, R5are the same or different, independently of one another selected from the group consisting of H, CN, halogen, unsubstituted or optionally with one, two or more R a1 substituted OH, NH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogen-C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, S(=O)2R a2 or C(=O)R a3 ; each R a is independently selected from the group consisting of CN, halogen, unsubstituted or optionally substituted with one, two or more R a1 substituted groups OH, NH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=O)2R a4 or C(=O)R a5 ; or, two R a , or R a on adjacent carbon atoms, together with R4, or R a on adjacent carbon atoms, form an unsubstituted or optionally substituted with one, two or more R a1 ring system C 3-14 carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic or 5-14 membered heteroaromatic ring; Each R a1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; R a2 , R a3 , R a4 , R a5 are identical or different and independently of each other selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; m is selected from 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof, wherein R 11 , R 12 , R2are the same or different, independently of one another, selected from H, C 1-4 alkyl or C 3-6 cycloalkyl; Preferably, R 11 , R 12 , R2 is H; preferably, n is 0; R3 is selected from H, C 1-4 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl), halo-C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl, fluoroethyl), C 1-4 alkoxy (e.g. methoxy), halo-C 1-4 alkoxy (e.g. trifluoromethoxy, difluoromethoxy), C 3-6 cycloalkyl (e.g. cyclopropyl), halo-C 3-6 cycloalkyl or 3-6 membered heterocyclyl; preferably, R3 is methyl, ethyl or fluoroethyl; preferably, R3 is methyl; Preferably, X1is CR X1 or N; R is preferably selected from H, CN, OH, halogen (e.g. F, CI, Br), C X1 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl), halo-C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl), C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl), C 1-4 alkoxy (e.g. methoxy), halo-C 1-4 alkoxy (e.g. trifluoromethoxy, difluoromethoxy); preferably, X1 is N, CH, CF or CCI; preferably, X1 is N, CH or CF; Preferably, X2is selected from CR X2 or N; R is preferably selected from H, CN, OH, halogen (e.g. F, CI, Br), C X2 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl), halo-C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl), C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl), C 1-4 alkoxy (e.g. methoxy), halo-C 1-4 alkoxy (e.g. trifluoromethoxy, difluoromethoxy); preferably, X2 is selected from CH, CCH3 or N; preferably, X2 is selected from CH or N; Preferably, X3is selected from CR X3 or N; R is preferably selected from H, OH, CN, halogen (e.g. F, Cl, Br), C X3 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl), halo-C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl), C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl), C 1-4 alkoxy (e.g. methoxy), halo-C 1-4 alkoxy (e.g. trifluoromethoxy, difluoromethoxy); preferably, X3 is selected from CH or N; Preferably, X1is CR X1 , X2is CR X2 , X3is CR X3 ; or X1is N, X2is CR X2 , X3is CR X3 ; or X1is CR X1 , X2is CR X2 , X3is N; Preferably, R X1 is selected from H, F or Cl; R X2 is selected from H or CH3; R X3 is H; Preferably, R X1 is selected from H or F; R X2 is selected from H or CH3; R X3 is selected from H or Cl; Preferably, R X1 is selected from H or F; R X2 is H; R X3 is H.

3. The compound of claim 1 or 2, racemate, stereoisomer, tautomer, solvate, polymorph or pharmaceutically acceptable salt or prodrug thereof, wherein Y1is selected from -CR 61 R 62 - or -NR7-; Preferably, R 61 Selected from H, C 1-6 Alkyl (e.g., methyl) or halogen (e.g., F, Cl, Br); R 62 Selected from halogens (e.g., F, Cl, Br), halogenated C 1-6 Alkyl groups (e.g., CF3, CHF2, CH2F, CH2CHF2, CH2CF3) or C 3-6 Cycloalkyl (e.g., cyclopropyl); or, R 61 R 62 Together with the C atoms it is attached to, it forms an unsubstituted or optionally substituted form with one or two R atoms. d Substitution with the following groups: olefinic bond (C=CH2) or C 3-6 Carbocyclic (e.g., cyclopropyl); or, R 62 Connected to R3 or R5, together they form a non-substituted or optionally substituted structure with one, two or more Rs. d The following ring systems are replaced: C 5-8 Carbon rings or 5-8 membered heterocycles; Preferably, R 61 Selected from H or C 1-6 Alkyl; R 62 Selected from halogens (e.g., F, Cl, Br), halogenated C 1-6 Alkyl groups (e.g., CF3, CHF2, CH2F, CH2CHF2, CH2CF3) or C 3-6 Cycloalkyl (e.g., cyclopropyl); or, R 61 R 62 Together with the C atoms it is attached to, it forms an unsubstituted or optionally substituted form with one or two R atoms. d Substitution with the following groups: olefinic bond (C=CH2) or C 3-6 Carbocyclic (e.g., cyclopropyl); or, R 62 Connected to R3 or R5, together they form a non-substituted or optionally substituted structure with one, two or more Rs. d The following ring systems are replaced: C 5-8 Carbon rings or 5-8 membered heterocycles; R is preferably selected from hydrogen, halogen (e.g. F, CI, Br), or, two R d selected from halogen (e.g. F, CI, Br), or, two R d together with the carbon atom to which they are attached form a C 3-6 carbocycle or 3-6 membered heterocycle; Preferably, R 61 is H, CH3or F; R 62 is selected from F, Cl, Br, CF3, CHF2, CH2F, CH2CHF2, CH2CF3or cyclopropyl; or, R 61 , R 62 together with the C atom to which they are attached form C=CF2or cyclopropyl; or, R 62 is connected to R3, such that The structure of the compound of formula (I) is as follows: or R 62 with R5, so that The structure of the compound of formula (I) is as follows: Preferably, R 61 is H or CH3; R 62 is selected from F, Cl, Br, CF3, CHF2, CH2F, CH2CHF2, CH2CF3, or cyclopropyl; or, R 61 , R 62 together with the C atom to which they are attached form C=CF2 or cyclopropyl; or, R 62 is connected to R3, such that The structure of the compound of formula (I) is as follows: or R 62 with R5, making The structure of the compound of formula (I) is as follows: R is preferably H; R 61 is H; R 62 is selected from F, Cl, Br, CF3, CHF2, CH2F, CH2CHF2, CH2CF3, or cyclopropyl; or R 61 , R 62 together with the C atom to which they are attached form C=CF2 or cyclopropyl; or R 62 is connected to R3, such that The structure of the compound of formula (I) is as follows: or R 62 with R5, so that The structure of the compound of formula (I) is as follows: R7is selected from H, C 1-6 alkyl (e.g., methyl, ethyl, isopropyl), haloC 1-6 alkyl (e.g., CF3, CHF2, CH2F) or C 3-12 cycloalkyl (e.g., cyclopropyl); or, R7is linked with R3or R5together to form: a 5-8 membered N-containing heterocyclic ring; Preferably, R7is selected from H, methyl, ethyl, cyclopropyl, CF3, CHF2or CH2F; R7is attached to R3such that The structure of the compound of formula (I) is as follows: or R7 is attached to R5, such that The structure of the compound of formula (I) is as follows: R d4 selected from F, CI or Br; or, two R d4 form, together with the carbon atom to which they are attached, a cyclopropyl ring; q is selected from 0, 1 or 2. According to some embodiments, each R a are the same or different, independently of one another, selected from CN, F, CI, Br, C 1-4 alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 2-6 alkynyl (such as -CºCH, -CºCCH3), haloC 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy, ethoxy), haloC 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy), C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), haloC 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl (such as pyrazolyl); Preferably, R7is selected from methyl, ethyl, cyclopropyl, CF3, CHF2or CH2F; R7is attached to R3such that The structure of the compound of formula (I) is as follows: or R7 is attached to R5, such that The structure of the compound of formula (I) is as follows: R d4 selected from F, CI or Br; or, two R d4 form, together with the carbon atom to which they are attached, a cyclopropyl ring; q is selected from 0, 1 or 2. According to some embodiments, each R a are the same or different, independently of one another, selected from CN, F, CI, Br, C 1-4 alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 2-6 alkynyl (such as -CºCH, -CºCCH3), haloC 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy, ethoxy), haloC 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy), C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), haloC 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl (such as pyrazolyl); Preferably, R7is selected from methyl, ethyl, cyclopropyl, CF3, CHF2or CH2F; R7is attached to R3such that The structure of the compound of formula (I) is as follows: or R7 is attached to R5, such that The structure of the compound of formula (I) is as follows: R d4 is selected from F, CI or Br; or, two R d4 form, together with the carbon atom to which they are attached, a cyclopropyl ring; q is selected from 0, 1 or 2. According to some embodiments, each R a are the same or different, independently of one another, selected from CN, F, CI, Br, C 1-4 alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 2-6 alkynyl (such as -CºCH, -CºCCH3), haloC 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy, ethoxy), haloC 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy), C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), haloC 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl (such as pyrazolyl); preferably, m is selected from 0, 1, 2 or 3; preferably, m is selected from 0, 1 or 2; preferably, m is 0; preferably, m is 2.

4. The compound of any one of claims 1-3, racemate, stereoisomer, tautomer, solvate, polymorph pharmaceutically acceptable salt or prodrug thereof, wherein R4, R5are the same or different, independently of one another selected from H or halogen (e.g. F, Cl, Br), halogenated C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl) or C 1-4 alkoxy (e.g. methoxy, ethoxy); or, R 62 or R7is attached to R5, together forming an optionally substituted ring system selected from C d alkyl (e.g. trifluoromethyl, difluoromethyl) or C 5-8 carbocyclic or 5-8 membered heterocyclic; or, R a and R4, or R a and R5together with the carbon atom to which they are respectively attached form a ring system selected from C 4-6 carbocyclic, 4-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl; Preferably, R4, R5are the same or different, independently of one another selected from H or halogen (e.g. F, CI, Br); or, R 61 or R7is attached to R5, together forming the following ring system: C d substituted by one or two R 5-8 carbocyclic or 5-8 membered heterocyclic; or, R a and R4, or R a and R5, together with the carbon atom to which they are respectively attached, form the following ring system: C 4-6 carbocyclic, 4-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl; Preferably, each R a are the same or different and are independently selected from CN, halogen (e.g. F, CI, Br), C 1-6 alkyl (e.g. methyl, ethyl, isopropyl), haloC 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl (e.g. cyclopropyl) or 3-14 membered heterocyclyl; or, R a and R4, or R a together with the carbon atom to which they are respectively attached, form an unsubstituted or optionally substituted ring system: C a1 substituted with one, two or more R 3-6 carbocyclic, 3-6 membered heterocyclic, phenyl or 5-6 membered heteroaryl ring; Preferably, selected from the group consisting of Preferably, selected from the group consisting of Preferably, R4, R5are the same or different, independently of one another, selected from F, Cl, Br, CF3or OCH3; m is selected from 0 or 1 ; each R a are the same or different, independently of one another, selected from CN, F, Cl, Br, methyl, ethyl, isopropyl or cyclopropyl; or, R 62 or R7is connected with R5, making The structure of the compound of formula (I) is as follows: or R on adjacent carbon atoms together with the carbon atom to which they are respectively attached form a ring system, such that the compound of formula (I) is: a or R on adjacent carbon atoms together with the carbon atom to which they are respectively attached form a ring system, such that the compound of formula (I) is: The structure of the compound of formula (I) is as follows: Preferably, R4, R5are the same or different, independently of one another selected from F, Cl, Br; m is selected from 0 or 1 ; each R a the same or different, independently of one another selected from CN, F, Cl, Br, methyl, ethyl, isopropyl or cyclopropyl; or, R 62 or R7is connected with R5, making The structure of the compound of formula (I) is as follows: or R on adjacent carbon atoms together with the carbon atom to which they are respectively attached form a ring system, such that the compound of formula (I) is: a or R on adjacent carbon atoms together with the carbon atom to which they are respectively attached form a ring system, such that the compound of formula (I) is: The structure of the compound of formula (I) is as follows: Preferably, R4, R5are the same or different, independently of one another selected from the group consisting of F, CI, Br; or, R 62 or R7is connected with R5, making The structure of the compound of formula (I) is as follows: or R on adjacent carbon atoms together with the carbon atom to which they are respectively attached form a ring system, such that the compound of formula (I) is: a or R on adjacent carbon atoms together with the carbon atom to which they are respectively attached form a ring system, such that the compound of formula (I) is: The structure of the compound of formula (I) is as follows:

5. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-4, wherein, The compound of formula (I) has the structure shown below: wherein X1, X2, X3, Y1, R 11 , R 12 2, R3, R4, R5, R a , R b 2, m, n have the definitions described in any one of claims 1 to 4; Preferably, the compound of formula (I) has the structure shown below: wherein X1, X2, X3, Y1, R4, R5, R a , m have the definitions of any one of claims 1-4.

6. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-5, wherein, The compound of formula (I) is selected from the following structures:

7. A process for the preparation of a compound of formula (II-4) as defined in any one of claims 1 to 6, comprising the following step A: Step A: wherein X1, X2, X3, Y1, R 11 , R 12 , R2, R3, R4, R5, R a , R b , m, n have the definitions described in any one of claims 1 to 4.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), racemate, stereoisomer, tautomer, solvate, polymorph, or pharmaceutically acceptable salt or prodrug thereof of any one of claims 1-6; preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients; preferably, the pharmaceutical composition further comprises one or more additional therapeutic agents.

9. A method of treating or preventing a disease or disorder caused by TSHR abnormality, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one compound of formula (I), racemate, stereo isomer, tautomer, solvate, polymorph, or pharmaceutically acceptable salt, or prodrug thereof of any one of claims 1-6, or a pharmaceutical composition of claim 8; preferably, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder; preferably, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease; and the patient is a mammal, preferably a human.

10. Use of at least one compound of formula (I), racemate, stereoisomer, tautom er, solvate, polymorph, or pharmaceutically acceptable salt, or prodrug thereof, of any one of claims 1-6, or a pharmaceutical composition of claim 8, in the manufacture of a medicament; preferably, the use is in the manufacture of a TSHR antagonist; preferably, the use is in the manufacture of a medicament for treating or preventing a thyroid-related disease or disorder; preferably, the thyroid-related disease or disorder is hyperthyro idism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

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