TSHR antagonist compound, pharmaceutical composition as well as preparation method and application of TSHR antagonist compound and pharmaceutical composition

Abstract

The invention provides a TSHR antagonist compound, a pharmaceutical composition as well as a preparation method and application of the TSHR antagonist compound. The compound has a good TSHR antagonism effect, is used for treating thyroid-related diseases and / or diseases, such as hyperthyroidism, Graves disease, Graves eye disease and thyroid eye disease, and is used for preparing medicaments for the diseases or diseases.

Description

[0001] The present application claims priority to the prior application of the same name, filed on June 12, 2024, with the China National Intellectual Property Office, with the patent application number 202410756004.6, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on June 14, 2024, with the China National Intellectual Property Office, with the patent application number 202410772832.9, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on June 26, 2024, with the China National Intellectual Property Office, with the patent application number 202410840707.7, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on August 8, 2024, with the China National Intellectual Property Office, with the patent application number 202411087297.X, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on September 26, 2024, with the China National Intellectual Property Office, with the patent application number 202411353988.X, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on December 17, 2024, with the China National Intellectual Property Office, with the patent application number 202411863901.3, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on February 14, 2025, with the China National Intellectual Property Office, with the patent application number 202510167605.8, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on March 11, 2025, with the China National Intellectual Property Office, with the patent application number 202510285836.9, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on April 16, 2025, with the China National Intellectual Property Office, with the patent application number 202510479405.6, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof", filed on June 6, 2025, with the China National Intellectual Property Office, with the patent application number 202510756393.7, entitled "TSHR Antagonist Compound, Pharmaceutical Composition and Preparation Method and Application Thereof". The above prior applications are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to a TSHR antagonist compound, a pharmaceutical composition, and a preparation method and application thereof. BACKGROUND

[0003] Approximately 40% of patients with hyperthyroidism suffer from Graves' disease, an autoimmune disease whose autoantibodies activate the thyrotropin receptor, mimicking its natural hormone ligand, thyrotropin (TSH). This pathological activation of the TSH receptor (TSHR) leads to uncontrolled production of thyroid hormones such as T3 and T4, causing hyperthyroidism. TSH and TSHR are important proteins for the control of thyroid function. TSHR is mainly expressed in thyroid follicular epithelial cells, but also in a variety of other cell types, such as retro-orbital fibroblasts, kidney cells, adipocytes and bone cells. TSH binds to its receptor and leads to stimulation of a second messenger pathway mainly involving cAMP. The inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) pathways are also activated at higher TSH concentrations. For decades, the clinically common treatment has included thyroid suppressive drugs that inhibit the secretion of thyroid hormones. These drugs act further downstream in the thyroid signaling cascade after TSHR activation. Since the thyroid secretes the thyroid hormones T3 and T4, thyroid suppressive drugs can inhibit their synthesis. Thus, the current main anti-thyroid treatment does not target the pathogenic molecular activation of the TSHR by autoantibodies, and therefore has an adverse reaction rate of at least 5% in patients. This requires frequent control of thyroid hormone levels and adjustment of the dose of thyroid suppressive agents. In contrast to these drugs that regulate thyroid hormone levels, another promising target is the TSHR itself. However, small allosteric antagonists that act directly on the TSHR are not yet on the market. In addition, about 25% of Graves' disease patients also develop ophthalmopathy, i.e. "Graves' ophthalmopathy", a related organ-specific autoimmune disease that affects the appearance and function of the eye. There is considerable evidence that the TSHR in retro-orbital fibroblasts and orbital adipocytes of the eye can contribute to this difficult-to-treat ophthalmopathy, with thyroid stimulating antibody titers often correlating with the severity of Graves' ophthalmopathy. Orbital fibroblasts are considered the main target cells of the autoimmune attack, and the TSHR is the main autoantigen of Graves' ophthalmopathy. Pathological activation of the TSHR leads to the production of extracellular matrix through the involvement of hyaluronan, fibrosis and swelling of the extraocular muscles, and adipogenesis of orbital fibroblasts (expansion of orbital fat). The increased volume of intraorbital tissue often causes double vision, compression of the optic nerve and exophthalmos. Thus, the TSHR is also a potential target for drug intervention in Graves' ophthalmology and thyroid eye disease.

[0004] Therefore, there is a need in the art to provide additional means for treating hyperthyroidism, in particular compounds that act as TSHR antagonists. SUMMARY

[0005] To improve the above technical problems, the present application provides a compound shown in formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof:

[0006]

[0007] wherein,

[0008] ring A is selected from C 3-14 saturated or partially unsaturated carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 aromatic ring or 5-14 membered heteroaromatic ring;

[0009] each R a is the same or different, independently selected from CN, halogen, the following group which is unsubstituted or optionally substituted by one, two or more R a1 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 a2 or C(=O)R a3 ; each R a1 is the same or different, independently selected from oxo (=O), CN, halogen, 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 or 3-6 membered heterocyclyl; R a2 , R a3 are the same or different, independently selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0010] m is selected from 0, 1, 2, 3, 4 or 5;

[0011] Y2 is absent or selected from -O-, -S-, the following group which is unsubstituted or optionally substituted by one, two or more R 1-12 alkyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, halogenated C1-12 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 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-;

[0012] X1 is selected from CR X1 Or N;

[0013] X2 is selected from CR X2 Or N;

[0014] X3 is selected from CR X3 Or N;

[0015] 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 heteroaryl; or, R X1 With R X2 Or R X2 With R X3 Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. d The following ring systems are substituted: C3-14 carbon rings, 3-14 membered heterocycles, C6-14 aromatic rings, or 5-14 membered heteroaromatic rings; 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;

[0016] R2is selected from the group consisting of CN, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, haloC1-6alkyl, C1-6alkoxy, C1-6alkylthio, cycloalkyl, 3- to 6-membered heterocyclyl, aryl, 5- to 10-membered heteroaryl, S(=O)2R e substituted C 1-12 alkyl, unsubstituted or optionally substituted by one, two or more R e substituted 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- to 14-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl; each R e is the same or different, independently of one another, selected from the group consisting of oxo (=O), CN, halogen, OH, NH2, C e1 substituted OH, NH2, C 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- to 6-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, S(=O)2R e2 or C(=O)R e3 ; when R2is C 1-12 alkyl, R e is not C 1-6 alkyl;

[0017] Alternatively, R2is connected to any position on ring A, together forming a 6- to 16-membered heterocyclic ring, unsubstituted or optionally substituted by one, two or more R e1 substituted 6- to 16-membered heterocyclic ring;

[0018] each R e1 is the same or different, independently of one another, selected from the group consisting of oxo (=O), 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- to 6-membered heterocyclyl, S(=O)2R e4 or C(=O)R e5 ; alternatively, two R e1 on the same carbon atom, together with the carbon atom to which they are attached, form a ring system, unsubstituted or optionally substituted by one, two or more R e6 substituted C 3-14carbocyclic or 3-14 membered heterocyclic ring; or, two R e1 together with the carbon atom to which they are attached form a non-substituted or optionally substituted C e6 substituted CH=CH, C 3-14 carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic or 5-14 membered heteroaromatic ring; or, two non-adjacent R e1 together form a non-substituted or optionally substituted C e6 substituted C 1-3 alkylene of R e2 , R e3 , R e4 , R e5 , R e6 are the same or different, independently of each other, selected from the group consisting of H, OH, NH2, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0019] each R b are the same or different, independently of each other, selected from the group consisting of CN, halogen, oxo (=0), non-substituted or optionally substituted R b1 substituted OH, NH2, C 1-12 alkyl, 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, S(=0)2R b2 or C(=0)R b3 ; each R b1 are the same or different, independently of each other, selected from the group consisting of 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; R b2 , R b3 are the same or different, independently of each other, selected from the group consisting of H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0020] n is selected from 0, 1, 2 or 3;

[0021] Y1is selected from -0-, -S-, unsubstituted or optionally substituted with one, two or more substituents selected from oxo (=0), OH, NH2, CN, halogen, C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, haloC 1-12 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R 1-12 alkylene, -0-C 1-12 alkylene, -S-C 1-12 alkylene, -NH-C 1-12 alkylene, -C 1-12 alkylene-0-, -C 1-12 alkylene-S- or -C 1-12 alkylene-NH-;

[0022] R1is selected from any one of the following groups:

[0023] (i) -COR 13 ; R 13 is selected from the following groups unsubstituted or optionally substituted with one, two or more R c substituents: -OH, -NR 11 R 12 , C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl or 3-14 membered heterocyclyl; R 11 , R 12 are the same or different, independently of each other, selected from H, C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, haloC 1-12 alkoxy, C 3-12 cycloalkyl or 3-14 membered heterocyclyl; or R 11 , R 12 form, together with the N atom to which they are attached, a 3-14 membered N- containing heterocyclic ring unsubstituted or optionally substituted with one, two or more R c substituents;

[0024] (ii) L1is absent or selected from the following groups unsubstituted or optionally substituted with one, two or more substituents selected from oxo (=0), OH, NH2, CN, halogen, C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, haloC 1-12 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R 1-12 alkylene; R14 Selected from H, CN, -NH2, -NHC 1-12 Alkyl, -N(C) 1-12 Alkyl)2, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3-12 cycloalkyl, halogenated C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; X4 is selected from O or NR. 15 ;R 15 Selected from H, CN, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3-12 cycloalkyl, halogenated C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups;

[0025] (iii)-L2-COR 16 L2 is selected from unsubstituted or optionally substituted by one, two or more elements selected from oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 C-substituents of cycloalkyl or 3-6 membered heterocyclic groups 1-12 Alkylene; R 16 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: H, OH, -NR 17 R 18 C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 cycloalkyl groups, 3-14 membered heterocyclic groups;

[0026] R 17 R 18 Whether the two are the same or different, they are selected independently from H and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; or R 17 R 18 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-14 N-containing heterocycles;

[0027] (iv) Ring B is selected from C 3-14 Carbon rings, 3-14 membered heterocycles, C6-14 an aromatic ring or a 5-14 membered heteroaromatic ring;

[0028] each R c identically or differently, independently of one another, are selected from the group consisting of oxo (=O), CN, halogen, unsubstituted or optionally substituted with one, two or more R c1 substituted with one, two or more R 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, NH2, S(O)2H, COH, hydroxyC 1-12 alkyl, aminoC 1-12 alkyl; or, two R c together with the carbon atom to which they are attached form an unsubstituted or optionally substituted with one, two or more R c1 substituted with one, two or more R 3-14 carbocyclic or 3-14 membered heterocyclic ring; or, two R c together with the carbon atoms to which they are respectively attached form an unsubstituted or optionally substituted with one, two or more R c1 substituted with one, two or more R 3-14 carbocyclic, 3-14 membered heterocyclic, C 6-14 an aromatic ring or a 5-14 membered heteroaromatic ring; or, two non-adjacent R c together form an unsubstituted or optionally substituted with one, two or more R c1 substituted C 1-3 alkylene; each R c1 identically or differently, independently of one another, are selected from the group consisting of oxo (=O), OH, NH2, CN, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl;

[0029] p is selected from 0, 1, 2, 3, 4 or 5.

[0030] The present application also provides a compound shown in formula (I-1), a racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof:

[0031]

[0032]

[0033] wherein,

[0034] Ring A is selected from C 3-14 saturated or partially unsaturated carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic or 5-14 membered heteroaromatic ring;

[0035] each R a are the same or different, independently of each other, selected from CN, halogen, unsubstituted or optionally substituted with one, two or more R a1 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 heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=O)2R a2 or C(=O)R a3 ; each R a1 are the same or different, independently of each other, selected from oxo (=O), CN, halogen, 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 or 3-6 membered heterocyclyl; R a2 , R a3 are the same or different, independently of each other, selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0036] m is selected from 0, 1, 2, 3, 4 or 5;

[0037] Y2is absent or selected from -O-, -S-, unsubstituted or optionally substituted with one, two or more substituents selected from oxo (=O), OH, NH2, CN, halogen, C 1-12 alkyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; -NH-, C 1-12 alkylene, -O-C 1-12 alkylene, -S-C 1-12 alkylene, -NH-C 1-12 alkylene, -C1-12 Alkylene -O-, -C 1-12 alkylene-S- or -C 1-12 alkylene-NH-;

[0038] X1 is selected from CR X1 Or N;

[0039] X2 is selected from CR X2 Or N;

[0040] X3 is selected from CR X3 Or N;

[0041] 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 heteroaryl; or, R X1 With R X2 Or R X2 With R X3 Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. d The following ring systems are substituted: C3-14 carbon rings, 3-14 membered heterocycles, C6-14 aromatic rings, or 5-14 membered heteroaromatic rings; 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;

[0042] R2 is selected from CN, and is determined by one, two or more R... e Replacement C 1-12 Alkyl, unsubstituted, or optionally with one, two, or more R e The following groups are substituted: C 2-12 alkenyl, C 2-12alkynyl, 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 e They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. e1 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 e2 Or C(=O)R e3 When R2 is C 1-12 When alkyl, R e Not C 1-6 alkyl;

[0043] Alternatively, R2 can be connected to any position on ring A to form a ring that is unsubstituted or arbitrarily bound by one, two or more Rs. e1 Replaced 6-16 membered heterocycles;

[0044] Each R e1 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 e4 Or C(=O)R e5 Or, two R atoms attached to the same carbon atom e1 Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. e6 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. e1 Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. e6 The following groups are substituted: CH=CH, C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14Aromatic rings or 5-14 heterocyclic aromatic rings; or, two non-adjacent R groups. e1 Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. e6 Replacement C 1-3 alkylene; R e2 R e3 R e4 R e5 R e6 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;

[0045] 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;

[0046] n is selected from 0, 1, 2, or 3;

[0047] Y1 is selected from -O-, -S-, unsubstituted, or optionally selected by one, two, or more elements selected from oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 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-;

[0048] R 11 R 12 They are the same or different, and are selected independently from H or C. 1-12 alkyl.

[0049] According to some implementation schemes, ring A is selected from benzene rings or 5-6 membered heteroaromatic rings.

[0050] According to some implementation schemes, ring A is selected from benzene ring, pyrazole ring, thiazole ring, oxazole ring, furan ring, thiophene ring, pyrrole ring, imidazole ring, pyridine ring, pyrimidine ring, piperidine ring, and pyridazine ring.

[0051] According to some implementation schemes, ring A is a benzene ring, a thiophene ring (e.g.) ) or pyridine ring (e.g. ).

[0052] According to some implementation schemes, ring A is a benzene ring or a thiophene ring (e.g. ).

[0053] According to some implementation schemes, ring A is a benzene ring.

[0054] According to some implementation schemes, 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).

[0055] According to some implementation schemes, each R a They may be the same or different, and are independently selected from CN, methyl, -C≡CCH3, F, Cl, Br or cyclopropyl.

[0056] each R is independently selected from the group consisting of H, F, Cl, Br, I, -OR a the same or different, are independently selected from the group consisting of methyl, -C≡CCH3, F, Cl, Br, or cyclopropyl.

[0057] each R is independently selected from the group consisting of H, F, Cl, Br, I, -OR a the same or different, are independently selected from the group consisting of F, Cl, Br, or cyclopropyl.

[0058] each R is independently selected from the group consisting of H, F, Cl, Br, I, -OR a the same or different, are independently selected from the group consisting of F, Cl, or Br.

[0059] According to some embodiments, m is 1, 2, 3, or 4.

[0060] According to some embodiments, m is 1 or 2.

[0061] According to some embodiments, m is 2, 3, or 4.

[0062] According to some embodiments, Y2is selected from the group consisting of -O-, or unsubstituted or optionally substituted with one, two, or more substituents selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl. 1-6 alkylene.

[0063] According to some embodiments, Y2is selected from the group consisting of -O-, or unsubstituted or optionally substituted with one, two, or more substituents selected from C

[0064] According to some embodiments, Y2is -O-.

[0065] According to some embodiments, X1is CR X1 , X2is CR X2 , X3is CR X3 ; or X1is N, X2is CR X2 , X3is CR X3 ; or X1is CR X1 , X2is N, X3is CR X3 ; or X1is CR X1 , X2is CR X2 , X3is N.

[0066] According to some embodiments, X1is CR X1 , X2is CR X2 , X3is CR X3 ; or X1is CR X1 , X2is N, X3is CR X3 ; or X1is CR X1, X2 is CR X2 , X3 is N.

[0067] According to some embodiments, R X1 , R X2 , R X3 are identical or different, independently of each other, selected from H, CN, OH, halogen (such as F, CI, Br), C 1-4 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl), halo-C 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), or halo-C 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy); or, R X1 together with the carbon atom to which they are attached, form a C4-6carbocyclic ring. X2 together with the carbon atom to which they are attached, form a C4-6carbocyclic ring. d are identical or different, independently of each other, selected from CN, OH, halogen, C d alkyl, halo-C 1-4 alkyl, C 1-4 alkoxy, or halo-C 1-4 alkoxy. 1-4 alkoxy.

[0068] According to some embodiments, R X1 is selected from H, -CH3, -F, -CI, -Br, -CH2F, -CF2H, -CF3; R X2 is selected from H, -CH3, -F, -CI, -Br; R X3 is selected from H, -CH3, -F, -CI, -Br; or, R X1 together with the carbon atom to which they are attached, form a C4-6carbocyclic ring. X2 together with the carbon atom to which they are attached, form a C4-6carbocyclic ring.

[0069] According to some embodiments, X1 is N or CR X1 ; R X1 is selected from H, CN, OH, halogen (such as F, CI, Br), C 1-4 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl), halo-C 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), or halo-C 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy).

[0070] According to some embodiments, X1 is CR X1 ; R X1 is selected from H, CN, OH, halogen (such as F, CI, Br), C1-4 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl), haloC 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), haloC 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy).

[0071] According to some embodiments, X1is CR X1 ; R X1 is selected from -CH3, -Cl or -F.

[0072] According to some embodiments, X2is selected from N, CH or CCl.

[0073] According to some embodiments, X2is CH.

[0074] According to some embodiments, X3is selected from N, CH or CCl.

[0075] According to some embodiments, X3is CH.

[0076] According to some embodiments, n is 0.

[0077] According to some embodiments, Y1is selected from unsubstituted or optionally substituted with one, two or more substituents selected from oxo (=0), OH, NH2, CN, halogen, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; -NH-, C 1-4 alkylene, -NH-C 1-4 alkylene or -C 1-4 alkylene-NH-.

[0078] According to some embodiments, Y1is -NH-.

[0079] According to some embodiments, R1is selected from any one of the following groups:

[0080] (i) -COR 13 ; R 13 is selected from -NR 11 R 12 , haloC 3-8 cycloalkyl or 3-8 membered heterocyclyl unsubstituted or optionally substituted with one, two or more R c ; R 11 , R 12 are the same or different, each independently of the other, selected from H or C 1-4 alkoxy; or R 11R 12 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-8 N-containing heterocycles;

[0081] (ii) L1 is absent or selected from unsubstituted or optionally selected from one or two halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl substituents substituted C 1-4 Alkylene; R 14 Selected from NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; X4 is selected from O or NR 15 ;R 15 Selected from H, CN, C 1-4 alkyl;

[0082] (iii)-L2-COR 16 L2 is selected from unsubstituted or optionally selected from one or two halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl substituents substituted C 1-4 Alkylene; R 16 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: H, OH, -NR 17 R 18 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups; R 17 R 18 Whether the two are the same or different, they are selected independently from H and C. 1-4 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; or R 17 R 18 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-8 N-containing heterocycles;

[0083] (iv) Ring B is selected from 5-6 membered heteroaromatic rings (e.g., pyrrole ring, pyrrole ring, pyrazole ring, imidazole ring, triazole ring, thiazole ring, thiadiazole ring, oxazole ring, dioxazole ring, furan ring, thiophene ring, pyridine ring, pyrimidine ring, piperidine ring, pyridazine ring, triazine ring).

[0084] According to some implementation schemes, each Rc They are either identical or different, and are independently selected from oxo (=O), CN, halogen, OH, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, C 1-4 Alkylene NR c2 R c3 CONH2, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R c2 R c3 They are the same or different, and are selected independently from H or C. 1-4 alkyl.

[0085] According to some implementation schemes, each R c They may be the same or different, and are independently selected from methyl, ethyl, isopropyl, F, Cl, Br, CN, OH, CH2F, CHF2, CF3, OCH3, CONH2, CH2CH2OH, CH2CH2N(CH3)2. Alternatively, two R atoms attached to the same carbon atom c Together with the carbon atom it is attached to, it forms a cyclopropyl ring; or, two R atoms attached to adjacent carbon atoms... c Together with the carbon atoms it is attached to, it forms a cyclopropyl ring.

[0086] According to some implementation schemes, p is selected from 0 or 1.

[0087] According to some implementation schemes, R1 is selected from any of the following groups:

[0088] (i)-COR 13 ;R 13 Selected from -NR 11 R 12 Halogenated cyclopropyl, halogenated cyclobutyl, or unsubstituted or optionally substituted with one or two R c Substituted azaheterocyclic butyl ring, azaheterocyclic pentyl ring, oxocyclic butyl ring, morpholine ring; R 11 Selected from H, R 12 Selected from methoxy; or R 11 R 12 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one or two R atoms. c Substituted 3-6 N-containing heterocycles; R c Selected from OH, F, Cl, Br, CN, CH3, CHF2, CH2F, OCH3.

[0089] (ii) L1is absent or selected from -CH2-, -CH(CH3)-; R 14 is selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, CH3, CH2CH3, CH2CH2CH3, CF3, CH2CF3, cyclopropyl; preferably, R 14 is selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, CH3, CH2CH3, CH2CH2CH3, CF3, CH2CF3, cyclopropyl; X4is selected from O or NR 15 ; R 15 is selected from H, CN, CH3;

[0090] (iii) -L2-COR 16 ; L2is selected from -CH2-, -CH(CH3)-; R 16 is selected from H, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2;

[0091] (iv) Ring B is selected from Preferably, Ring B is selected from Preferably, Ring B is selected from

[0092] According to some embodiments, R1is selected from

[0093]

[0094]

[0095] According to some embodiments, R1is -COR 13 , -SO2R 14 , 5-6 membered heterocyclic ring (e.g. ) or 5-6 membered heteroaromatic ring (e.g. ); R 13 is selected from -NR 11 R 12 ; R 11 , R 12 are the same or different, independently from each other, selected from H or C 1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl), or R 11 , R 12 together with the N atom to which they are attached form an unsubstituted or optionally substituted 5-6 membered heterocyclic ring (e.g. 1-6alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl) substituted 3-6 membered N-containing heterocycle; R 14 selected from -NH2or C 1-6 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl).

[0096] According to some embodiments, R1is CONH2,

[0097] According to some embodiments, R 11 , R 12 are identical or different, independently from each other, selected from H or C 1-6 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl).

[0098] According to some embodiments, R 11 , R 12 are both H.

[0099] According to some embodiments, R2is selected from the following groups, which are unsubstituted or optionally substituted by one, two or more R e1 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl). 2-6 alkenyl, C 2-6 alkynyl, halo-C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, C 1-4 alkylene-CN, C 1-4 alkylene-OH, C 1-4 alkylene-O-C 1-4 alkyl, C 1-4 alkylene-SO2-C 1-4 alkyl, C 1-4 alkylene-NHCO-C 1-4 alkyl, C 1-4 alkylene-CONH-C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkylene-C 3-6 cycloalkyl, halo-C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkylene-3-6 membered heterocyclyl, phenyl ring, C 1-4 alkylene-phenyl ring, 5-6 membered heteroaryl, C 1-4 alkylene-5-6 membered heteroaryl; or, R2is attached to any position on ring A, together forming a 6-16 membered heterocycle.

[0100] According to some embodiments, R e1 selected from F, Cl, Br, CN, OH, C 1-4 alkyl, C 2-6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl.

[0101] According to some embodiments, R2is selected from Alternatively, R2is attached to any position on ring A, together forming an 8-11 membered heterocyclic ring.

[0102] According to some embodiments, R2is selected from Alternatively, R2is attached to any position on ring A, together forming an 8-11 membered heterocyclic ring.

[0103] According to some embodiments, R2is

[0104] According to some embodiments, the compound of formula (I) has the structure as shown below:

[0105]

[0106]

[0107] wherein,

[0108] X4is selected from CH or N;

[0109] X5is selected from CH2(CH2) t , O(CH2) t , S(CH2) t or NH(CH2) t , wherein (CH2) t is attached to any position on ring A; preferably, X5is selected from CH2, O, OCH2, NHCH2; preferably, X5is selected from CH2, O, S or NH; preferably, X5is selected from CH2, O or CH2NH; preferably, X5is selected from CH2or O;

[0110] t is selected from 0, 1, 2, 3, 4, 5, 6; preferably, t is 0 or 1;

[0111] p is selected from 0, 1, 2, 3, 4, 5, 6; preferably, p is selected from 2, 3 or 4;

[0112] q is selected from 0, 1, 2, 3, 4, 5, 6; preferably, q is 0;

[0113] each R e1 is the same or different, each independently selected from preferably, R e1 is selected from F, Cl, Br, CN, OH, C 1-4 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; or, two R e1 together with the carbon atom to which they are respectively attached form a group CH=CH, C 3-6 carbocycle or 3-6 membered heterocycle; or, two non-adjacent R e1 together form C 1-3 alkylene;

[0114] preferably, two R e1 together with the carbon atom to which they are respectively attached form CH=CH; or, two non-adjacent R e1 together form methylene;

[0115] preferably, selected from wherein the “*” side is attached to N and the “#” side is attached to ring A;

[0116] ring A, X1, X2, X3, Y1, Y2, R1, R 11 , R 12 , R2, R a , R X1 , m have the definitions as described herein.

[0117] According to some embodiments, the compound of formula (I) has the structure shown below:

[0118]

[0119]

[0120]

[0121] wherein R aa , R ab are the same or different, each independently selected from H, F, Cl or Br;

[0122] R ac is selected from H, F, Cl, Br or cyclopropyl;

[0123] q is selected from 0, 1, 2 or 3; preferably, q is 0 or 1;

[0124] each R e1 is the same or different, each independently selected from C 1-4 alkyl (e.g. methyl); or, two R e1together with the carbon atom to which they are attached form CH=CH;

[0125] X1, X2, X3, X4, X5, Y2, R a , R1, R 11 , R 12 , R2, R X1 , m, p have the definitions as described herein.

[0126] According to some embodiments, selected from

[0127] According to some embodiments, selected from

[0128] According to some embodiments, the compound of formula (I) has the structure as shown below:

[0129]

[0130] wherein R 11 , R 12 , R2, R X1 have the definitions as described herein.

[0131] According to some embodiments, the compound of formula (I) is selected from the following structures:

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158] The present application also provides a preparation method of the compound shown in formula (II-3), comprising the following step A:

[0159] Step A:

[0160]

[0161] wherein, ring A, X1, X2, X3, Y2, R 11 , R 12 , R2, R a , m have the definitions described herein.

[0162] The present application also provides a preparation method of the compound shown in formula (III-7), comprising the following steps:

[0163]

[0164] wherein,

[0165] R Z1 is selected from halogen (e.g. F, Cl, Br);

[0166] R Z2selected from amino protecting agents (e.g., Boc);

[0167] X4, Y2, R 11 , R 12 , R X1 , R a , m has the definitions described herein.

[0168] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of Formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof.

[0169] According to some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0170] According to some embodiments, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0171] The present application also provides 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 of the compounds of Formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof. The present application also provides 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 the above pharmaceutical composition.

[0172] According to some embodiments, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder.

[0173] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

[0174] According to some embodiments, the patient comprises a mammal, preferably a human.

[0175] The present application also provides at least one of the compounds of Formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof, or a pharmaceutical composition thereof, for use in treating or preventing a disease or disorder caused by TSHR abnormality.

[0176] According to some embodiments, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder.

[0177] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

[0178] The present application also provides use of at least one of the compounds represented by Formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the manufacture of a medicament.

[0179] According to some embodiments, the use can be use in the manufacture of a TSHR antagonist.

[0180] According to some embodiments, the use can be use in the manufacture of a medicament for treating or preventing a thyroid-related disease or disorder.

[0181] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

[0182] Beneficial effects

[0183] The compounds provided by the present application have good TSHR antagonistic effect, and can be used for treating or preventing thyroid-related diseases and disorders, and for preparing a medicament for treating or preventing such diseases and disorders.

[0184] Definitions and explanations of terms

[0185] Unless otherwise indicated, the definitions of groups and terms recited in the specification and claims hereof, including definitions of examples, illustrative examples, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other in any manner. The group definitions and compound structures after such combination should be understood to be within the scope recited in the specification and / or claims.

[0186] The term "optional" (or "optionally", "option") in the general formula definition of the present application means the case of being substituted by zero, one or more substituents, for example "optionally substituted by one, two or more R" means that it can not be substituted (no substitution) or can be optionally substituted by one, two or more R.

[0187] "More" means three or more, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0188] Unless otherwise indicated, the numerical ranges recited in the specification and claims hereof are meant to include each and every specific integer value within the stated range. For example, a range of "1 to 12" is intended to include each and every specific integer value, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, within the stated range.

[0189] The 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.

[0190] 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 ... 2-3Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0191] 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") 2-3Alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0192] The term "C 3-12 Cycloalkyl" is to be understood as meaning a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon ring or a group of three or four rings which are fused or bridged or spiro together, having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 Cycloalkyl". The term "C 3-12 Cycloalkyl" is to be understood as meaning a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon ring or a group of three or four rings which are fused or bridged or spiro together, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C 3-12 Cycloalkyl" is to be understood as meaning a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon ring or a group of three or four rings which are fused or bridged or spiro together, having 3 to 12 carbon atoms, preferably "C

[0193] The term "C 6-14 Aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which can be a single aromatic ring or multiple aromatic rings which are fused or bridged together, preferably "C6-10 Aryl”. The term “C 6-14 Aryl” is understood to preferably mean a monovalent aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring (“C 6-14 Aryl”) having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms (“C6-aryl”), such as phenyl; or a ring having 9 carbon atoms (“C9-aryl”), such as indanyl or indenyl; or a ring having 10 carbon atoms (“C 10 Aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms (“C 13 Aryl”), such as fluorenyl; or a ring having 14 carbon atoms (“C 14 Aryl”), such as anthryl. When the C 6-20 Aryl” is substituted, it can be mono- or polysubstituted. Also, there is no restriction on the substitution site, for example ortho, para or meta substitution.

[0194] The term "5-14 membered heteroaryl" is to be understood as including a monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic aromatic ring system having 5 to 14 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, e.g. "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is to be understood as including a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and comprising 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, additionally in each case, can be benzo-fused. "Heteroaryl" also refers to groups in which the heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 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-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolizyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-oxazinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenoxazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 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-benzoisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-ortho-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 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]thiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 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-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazapinyl. 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]thiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14 membered heteroaryl is attached to other groups to form a compound of the invention, it can be attached to other groups through a carbon atom on the 5-14 membered heteroaryl ring or through a heteroatom on the 5-14 membered heteroaryl ring. When the 5-14 membered heteroaryl is substituted, it can be mono- or poly-substituted. Also, there is no limitation on the substitution site, for example, the hydrogen attached to a carbon atom on the heteroaryl ring can be substituted, or the hydrogen attached to a heteroatom on the heteroaryl ring can be substituted.

[0195] The term "carbocyclo" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, a cyclononane ring, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[l l.l]pentane ring, bicyclo[2.2.1]heptane ring, bicyclo[3.2.1]octane ring, or bicyclo[5.2.0]nonane ring, tetraline ring, and the like), which can be optionally substituted with 1 or more (such as 1, 2, or 3) suitable substituents. The term "3-6 membered carbocyclo" refers to a carbocyclo ring containing 3, 4, 5, or 6 ring-forming carbon atoms.

[0196] Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6- or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic (e.g., fused, bridged, spirocyclic) or 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, e.g., 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S can also be optionally oxidized into various oxidation states to form a nitro oxide, -S(O)- or -S(O)2- state. For example, the "3-14 membered heterocyclyl" can be a 3-14 membered N-containing heterocyclyl (containing at least one N). Preferably, the heterocyclyl can be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl can be attached to the rest of the molecule by any of the carbon atoms or the nitrogen atom (if present). The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl can include, but is not limited to: a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl can be benzo-fused. The heterocyclyl can be bicyclic, such as but not limited to a 5,5 membered ring such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6 membered bicyclic ring such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl can be partially unsaturated, i.e., it can contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[l,4]thiazinyl, or it can be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-14 membered heterocyclyl is attached to other groups to form a compound of the invention, it can be attached to the 3-14 membered heterocyclyl through a carbon atom or a heteroatom of the 3-14 membered heterocyclyl ring. For example, when the 3-14 membered heterocyclyl is selected from piperazinyl, it can be attached to other groups through a nitrogen atom of the piperazinyl. Or when the 3-14 membered heterocyclyl is selected from piperidinyl, it can be attached to other groups through a nitrogen atom and the carbon atom in para position of the piperidinyl ring.

[0197] The term "halogen" denotes fluorine, chlorine, bromine and iodine.

[0198] The term "nitroxide" refers to a compound formed by oxidation of a nitrogen atom in a tertiary amine or a nitrogen-containing (hetero)aromatic ring compound structure.

[0199] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0200] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0201] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0202] Unless otherwise indicated, a heterocyclyl, heterocyclyl ene, heteroaryl, or heteroarylene group includes all possible isomeric forms thereof, e.g., positional isomers. Thus, for some illustrative, non-limiting examples, forms that can be included are those substituted or bonded at one, two, or more positions in its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) including pyridin-2-yl, pyridin-2-yl ene, pyridin-3-yl, pyridin-3-yl ene, pyridin-4-yl, and pyridin-4-yl ene; thienyl or thienylene including thien-2-yl, thien-2-yl ene, thien-3-yl, and thien-3-yl ene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0203] The compounds of the present disclosure can exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomers" or "tautomeric forms" refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like.

[0204] "Halo" means substituted with one or more halogens.

[0205] The term "haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0206] The term "oxo" refers to an oxo substituent (=0) formed by oxidation of a carbon atom, a nitrogen atom, or a sulfur atom in a substituent.

[0207] The term "alkylamino" means -NH-(alkyl) or -N-(alkyl)2, wherein alkyl is as defined above. Non-limiting examples of alkylamino include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.

[0208] "Heteroalkyl" means an alkyl group, as defined above, in which one or more carbon atoms are replaced by one or more heteroatoms, as defined above. Non-limiting examples of heteroalkyl groups include: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, dihydroxypropyl, and the like.

[0209] The term "alkyloxy" means -O-(alkyl), wherein alkyl is defined above. Non-limiting examples of alkyloxy groups include: methoxy, ethoxy, propyloxy, butyloxy. The alkyloxy group can be optionally substituted or non-substituted, and when substituted, the substituent(s) are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0210] The terms "alkyleneoxy" and "oxyalkylene" mean -alkylene-O- or -O-alkylene-, respectively, wherein alkylene represents a straight-chained or branched saturated divalent hydrocarbon radical. The definition of the number of carbon atoms for "alkylene" applies to the definition of "alkyl" above. It will be understood by those skilled in the art that the alkyleneoxy or oxyalkylene group can be attached to the rest of the molecule in which it is contained in either direction, i.e., they can be used interchangeably.

[0211] Wavy line intersecting a chemical bond Used to indicate the position of attachment of a group to the rest of the molecule structure. For example, indicates attachment to the 3-position of the pyridyl group. When the position of attachment of a group is not fixed, as in the case of the pyridyl group, it can be shown in the manner which indicates that attachment can occur to any available position on the pyridyl group. For another example, which indicates that attachment can occur to any available position on the heteroaromatic ring, e.g., to any of the four carbon atoms on the right side of the pyridyl ring or to the carbon atom on the left side of the pyrazole ring. Similar expressions in this application are interpreted in the same manner, unless otherwise stated.

[0212] In the chemical structure of the compounds of the present application, the bond indicates unspecified configuration, or indicates absolute configuration, i.e., if stereoisomers exist in the chemical structure, the bond can be or or both and configurations.

[0213] In the present application, the compounds involved also include isotopically-labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes of atoms that can be incorporated into compounds of the application include isotopes of H, C, N, O, S, F, and CI, 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 application, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or of said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H, and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H or D, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances. The presence of hydrogen not individually listed (or, where appropriate, hydrogen or deuterium) in the substituents recited in the present application does not exclude that the hydrogen(s) can be replaced by deuterium or tritium, or vice versa, insofar as the respective molecule, salt, or solvate remains stable.

[0214] It will be appreciated by one skilled in the art that the compounds of Formula (I) can exist in various pharmaceutically acceptable salt forms. 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., carboxyl) and a basic center (e.g., amino), they can also form inner salts.

[0215] The compounds of the present application can exist in the form of solvates (e.g., hydrates), wherein the compound of the present application contains a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular, water, can be present in stoichiometric or non-stoichiometric amounts.

[0216] Depending on their molecular structure, the compounds according to the application can be chiral and thus can exist in various enantiomeric forms. The compounds can thus exist in racemic or optically active form. The compounds according to the application encompass the isomers in which the individual chiral carbons have the R or S configuration or mixtures thereof, the racemates. The compounds according to the application or intermediates thereof can be separated into the enantiomeric compounds by chemical or physical methods known to those skilled in the art or used in the synthesis in this form. In the case of racemic amines, the diastereomeric forms are prepared from the mixture by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids, such as, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids, for example N-benzoylproline or N-benzenesulfonylproline, or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution with the aid of optically active resolving agents, for example dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatizing ester polymeric reagents, can also be advantageously carried out. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0217] The corresponding stable isomers can be isolated according to known methods, for example by extraction, filtration or column chromatography.

[0218] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, most preferably humans.

[0219] The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or susceptible to the disease, but has not yet experienced or displayed pathogenesis or symptoms of the disease.(2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease (i.e., stopping the pathology and / or symptoms from advancing).(3) relieving the disease: for example, causing the regression of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease (i.e., reversing the pathology and / or symptoms). BRIEF DESCRIPTION OF DRAWINGS

[0220] Figure 1 : Serum TT4 concentration in rats 12 h after administration of different doses of compounds 294, 297, 328 and K1-70

[0221] Figure 2Serum TT4 concentration in rats 12 h after administration of different doses of compound 169 and K1-70

[0222] Figure 3 Serum TT4 concentration in rats 24 h after administration of different doses of compound 169 and K1-70

[0223] Figure 4 Serum TT4 concentration in rats 24 h after administration of different doses of compound 169 and K1-70

[0224] Figure 5 Serum TT4 concentration in rats 12 h after administration of different doses of compound 009

[0225] Figure 6 Serum TT4 concentration in rats 24 h after administration of different doses of compound 009 DETAILED DESCRIPTION

[0226] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of the present application.

[0227] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0228] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a Bruker AVANCE-400 nuclear magnetic instrument, and the measuring solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0229] MS determination Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), THERMO Ultimate3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

[0230] HPLC analysis High performance liquid chromatography (HPLC) analysis used Agilent 1260 II HPLC, Waters Acquity UPLC-Class high performance liquid chromatograph.

[0231] Chiral HPLC analysis determination used Waters Acquity UPC high performance liquid chromatograph.

[0232] High performance liquid preparation High performance liquid preparation used 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 preparative chromatograph.

[0233] CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0234] Thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the silica gel plate used in thin layer chromatography (TLC) adopted a specification of 0.15mm-0.2mm, and the specification adopted for thin layer chromatography separation and purification of products was 0.4mm-0.5mm.

[0235] Silica gel column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0236] Determination of average inhibition rate and IC 50 of kinase values used NovoStar enzyme marker (Germany B M G company).

[0237] The known starting materials of the present disclosure can be synthesized according to methods known in the art or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Daejung Chemicals, etc.

[0238] Unless otherwise specified in the examples, the reactions were carried out under an argon or nitrogen atmosphere.

[0239] An argon or nitrogen atmosphere means that a reaction flask is connected to an argon or nitrogen balloon of about 1 L in volume.

[0240] A hydrogen atmosphere means that a reaction flask is connected to a hydrogen balloon of about 1 L in volume.

[0241] A pressurized hydrogenation reaction uses a Parr 3916EKX-type hydrogenation apparatus and a Qinglan QL-500-type hydrogen generator or an HC2-SS-type hydrogenation apparatus.

[0242] A hydrogenation reaction is usually performed by repeating the operation of vacuuming and filling with hydrogen three times.

[0243] A microwave reaction uses a CEM Discover-S 908860-type microwave reactor.

[0244] Unless otherwise specified in the examples, a solution means an aqueous solution.

[0245] Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20℃ to 30℃.

[0246] The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), and the system of the developing agent used in the reaction, the eluent used in the column chromatography for purifying the compound, and the developing agent system of the thin layer chromatography include: system A: dichloromethane / methanol system, system B: n-hexane / ethyl acetate system, the volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of triethylamine and an alkaline or acidic reagent such as acetic acid can also be added for adjustment.

[0247] Preparation of intermediate (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3,4-dihydroquinolin-2(1H)-one (Int 1)

[0248]

[0249] Preparation of first step 3-fluoro-4-methyl-2-nitroaniline (Int 1b)

[0250] Compound Int 1a (25 g, 0.10 mol) was dissolved in dioxane (250 mL) and water (10 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborinane (37.5 mL, 3.5 mol, 50 wt%, 0.127 mol), cesium carbonate (70 g, 0.212 mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (7.72 g, 0.01 mol) were added, and the reaction was stirred at 90 °C under nitrogen protection for 16 hours. After the reaction was completed, it was concentrated and purified by silica gel column chromatography system B to obtain compound Int 1b (13.1 g, yield: 72.3%).

[0251] MS m / z (ESI): 171.1 (M+1).

[0252] Preparation of 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (Int 1c) in the second step

[0253] To a solution of isoamyl nitrite (10.74 g, 0.092 mol) in acetonitrile (250 mL) was added cuprous bromide (13.15 g, 0.092 mol), and the mixture was stirred at room temperature for 1 hour. Compound Int 1b (13 g, 0.076 mol) was added to the reaction system, and stirring was continued for 0.5 hours, followed by heating to 70 °C for 2 hours. After the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (50 mL) and filtered, the filtrate was diluted with water (100 mL) and further extracted with ethyl acetate (200 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound Int 1c (10.1 g, yield: 56.5%).

[0254] 1 H NMR (400 MHz, DMSO-d6) δ 7.64-7.58 (m, 1H), 7.53 (t, 1H), 2.32 (s, 3H).

[0255] Preparation of 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2-nitrobenzene (Int 1d) in the third step

[0256] Compound Int 1c (10.0 g, 0.043 mol) was dissolved in N,N dimethylformamide (100 mL), 2-chloro-5-fluorophenol (12.66 g, 0.086 mol) and potassium carbonate (11.94 g, 0.086 mol) were added, the reaction was stirred at 100 °C for 2 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL), washed with water (200 mL x 5), then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound Int 1d (10 g, yield: 65.0%).

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (d, 1H), 7.68 - 7.60 (m, 2H), 7.09 - 7.02 (m, 1H), 6.71 (dd, 1H), 2.07 (s, 3H).

[0258] Fourth step: Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5- fluorophenoxy)-4-methyl-2-nitrophenyl)propanoate (Int 1e)

[0259] Into a reaction flask was added zinc powder (362 mg), replaced with nitrogen, added N,N- dimethylformamide (4 mL) with a syringe, stirred at 40 °C for 15 minutes under nitrogen protection, added 1,2-dibromoethane (26 mg, 0.14 mmol) and trimethylchlorosilane (15 mg, 0.14 mmol) into the system under nitrogen protection, the reaction mixture was stirred at 40 °C for 15 minutes, a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (912 mg, 4.26 mmol) in N,N-dimethylformamide (2 mL) was added into the reaction mixture under nitrogen protection, stirred at 40 °C for 30 minutes under nitrogen protection, cooled to room temperature under nitrogen protection to obtain a zinc reagent solution for standby. Prepare another flask to add a solution of compound Int 1d (500 mg, 1.38 mmol) in N,N-dimethylformamide (6 mL), add Pd(dppf)Cl2 (101 mg, 0.14 mmol), cuprous iodide (26 mg, 0.14 mmol) and the prepared zinc reagent solution (supernatant) into the reaction mixture under nitrogen protection at room temperature, the resulting reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was filtered through celite, the filter cake was washed with ethyl acetate, the organic phase was washed with aqueous ammonium chloride solution twice, the organic phase was concentrated to obtain a crude product, which was purified by silica gel column chromatography system B to obtain compound Int 1e (200 mg, yield: 29%).

[0260] MS m / z (ESI): 401.0 (M+1).

[0261] Preparation of (R)-3-(2-amino-3-(2-chloro-5-fluorophenoxy)-4-methylphenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid methyl ester (Int If)

[0262] Compound Int 1e (200 mg, 0.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran / methanol / water (12 mL, V / V / V = 3:2:1), zinc powder (135 mg, 2 mmol), ammonium chloride (117 mg, 2 mmol) were added. The reaction was stirred at 70 °C for 1 hour. After the reaction was completed, the reaction solution was filtered using diatomite, and the filtrate was concentrated under reduced pressure. Purification was performed by column chromatography on silica gel using system A to obtain compound Int If (100 mg, yield: 53%).

[0263] MS m / z (ESI): 338.1 (M+1).

[0264] Preparation of (R)-3-(2-amino-3-(2-chloro-5-fluorophenoxy)-4-methylphenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid methyl ester (Int If)

[0265] Compound Int If (800 mg, 1.8 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (15 mL, V / V = 2:1), and lithium hydroxide (163 mg, 7.2 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the combined organic phase was concentrated under reduced pressure to obtain crude Int Ig (700 mg, 90%). The product was used directly in the next reaction without purification.

[0266] MS m / z (ESI): 383 (M+1-56).

[0267] Preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin- 3-yl)carbamic acid tert-butyl ester (Int Ih)

[0268] Compound Int Ig (700 mg, 1.6 mmol) was dissolved in N,N-dimethylformamide (5 mL), and HATU (738 mg, 1.9 mmol), N,N-diisopropylethylamine (412 mg, 4.8 mmol) were added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with ethyl acetate, and the organic phase was washed with an aqueous ammonium chloride solution. The crude product was obtained by concentration under reduced pressure, and purification was performed by column chromatography on silica gel using system B to obtain compound Int Ih (650 mg, yield: 97%).

[0269] MS m / z (ESI): 365 (M+1-56).

[0270] Eighth step: preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (Int 1i)

[0271] Compound Int 1h (600 mg, 1.4 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (1.18 g, 8.5 mmol) and iodomethane (1.2 g, 8.5 mmol) were added. The reaction was stirred at 40 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, diluted with ethyl acetate, and the organic phase was washed with an aqueous ammonium chloride solution, and dried under vacuum to obtain a crude product, which was purified by column chromatography on silica gel using system B to obtain compound Int 1i (600 mg, yield: 89%).

[0272] MS m / z (ESI): 379 (M+1-56).

[0273] Ninth step: preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl- 3,4-dihydroquinolin-2(lH)-one (Int 1)

[0274] Compound Int 1i (300 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL), and a hydrochloric acid dioxane solution (3 mL) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, compound Int 1 (230 mg) was obtained by drying under vacuum.

[0275] MS m / z (ESI): 335 (M+1).

[0276] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 2H), 7.65 (dd, 1H), 7.24 - 7.20 (m, 2H), 6.96 (d, 1H), 6.41 - 6.38 (m, 1H), 4.41 - 4.39 (m, 1H), 3.34 (s, 3H), 3.13 - 3.10 (m, 2H), 2.05 (s, 3H).

[0277] Eighth step: preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (Int 1i)

[0278]

[0279] First step: preparation of 4-chloro-3-fluoro-2-nitroaniline (Int 2b)

[0280] Compound Int 2a (5 g, 0.032 mol) was dissolved in N,N dimethylformamide (100 mL), N-chlorosuccinimide (4.27 g, 0.03 mol) was added, and the reaction solution was stirred at 25 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and the organic phase was dried and concentrated. Compound Int 2b (3.2 g, yield: 50%) was obtained after purification by column chromatography system B.

[0281] MS m / z (ESI): 191.0 (M+1).

[0282] Preparation of 1-bromo-4-chloro-3-fluoro-2-nitrobenzene (Int 2c) in the second step

[0283] Isopentyl nitrite (1.8 g, 0.015 mol) was added to a solution of cuprous bromide (3.5 g, 0.01 mol) in acetonitrile (50 mL), and the mixture was stirred at room temperature for 1 hour. Compound Int 2b (2.5 g, 0.01 mol) was added to the reaction system, and stirring was continued for 0.5 hours, followed by heating to 70 °C for 2 hours. After the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (50 mL), and filtered. The filtrate was diluted with water (100 mL) and further extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by normal phase silica gel column (petroleum ether 100%) to obtain compound Int 2c (2.5 g, yield: 71%).

[0284] MS m / z (ESI): 253.9 (M+1).

[0285] Preparation of 1-bromo-4-chloro-3-(2-chloro-5-fluorophenoxy)-2-nitrobenzene (Int 2d) in the third step

[0286] Compound Int 2c (2.5 g, 0.01 mol) was dissolved in N,N dimethylformamide (80 mL), 2-chloro-5-fluorophenol (1.4 g, 0.01 mol) and potassium carbonate (2.7 g, 0.02 mol) were added, and the reaction solution was stirred at 100 °C for 2 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL), washed with water (200 mL x 5), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography system B to obtain compound Int 2d (3.0 g, yield: 71%).

[0287] MS m / z (ESI): 379.9 (M+1).

[0288] Fourth step: Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- chloro-3-(2-chloro-5-fluorophenoxy)-2-nitrophenyl)propanoate (Int 2e)

[0289] To a flask was added zinc dust (3.0 g, 4 eq), purged with nitrogen, charged with N,N- dimethylformamide (8 mL), stirred at 40 °C for 15 min under nitrogen, charged with 1,2- dibromoethane (90 mg, 0.1 eq) and trimethylchlorosilane (50 mg, 0.1 eq) under nitrogen, stirred the reaction mixture at 40 °C for 15 min, charged with a solution of (S)-methyl 2-((tert- butoxycarbonyl)amino)-3-iodopropionate (7.1 g, 2 eq) in N,N-dimethylformamide (8 mL) under nitrogen, stirred at 40 °C for 30 min under nitrogen, cooled to room temperature under nitrogen to give the zinc reagent compound ready for use. Prepare another flask charged with a solution of compound Int 2d (500 mg, 1.42 mmol) in N,N-dimethylformamide (10 mL), charged with Pd(dppf)Cl2(208 mg, 0.29 mmol), copper(I) iodide (54 mg, 0.29 mmol) and zinc reagent solution (supernatant) under nitrogen at room temperature. Stir the resulting reaction mixture at 75 °C for 12 h under nitrogen. After completion of the reaction, the reaction mixture was filtered over celite, the filter cake was washed with ethyl acetate, the organic phase was washed with aqueous ammonium chloride solution twice and the organic phase was concentrated under vacuum to give the crude product which was purified by flash column chromatography using system B to give compound Int 2e (450 mg, yield: 68%).

[0290] MS m / z (ESI): 403.0 (M-100) +

[0291] Fifth step: Preparation of (R)-methyl 3-(2-amino-4-chloro-3-(2-chloro-5- fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (Int 2f)

[0292] Compound Int 2e (450 mg, 0.89 mmol) was dissolved in methanol (10 mL), water (2 mL), iron powder (250 mg, 4.47 mmol), ammonium chloride (240 mg, 4.47 mmol) were added. The reaction was stirred at 70 °C for 4 h, after completion of the reaction, the reaction mixture was filtered using celite, the filtrate was concentrated under reduced pressure and compound Int 2f (400 mg, yield 95%) was obtained by purification using flash column chromatography using system B.

[0293] MS m / z (ESI): 417.0 (M+1).

[0294] Step 6: Preparation of (R)-(7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (Int 2g)

[0295] Compound Int 2f (400 mg, 0.85 mmol) was dissolved in dichloromethane (10 mL), trimethylaluminum (182 mg, 2.53 mmol) was added. The reaction was stirred at 40 °C for 1 hour, after the reaction was completed, the reaction was concentrated, purified by flash silica gel column chromatography system B to obtain compound Int 2g (300 mg, yield 81%).

[0296] MS m / z (ESI): 463.0 (M+23).

[0297] Step 7: Preparation of (R)-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (Int 2h)

[0298] Compound Int 2g (300 mg, 0.68 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (282 mg, 2.0394 mmol), iodomethane (116 mg, 0.81 mmol) was added. The reaction was stirred at 45 °C for 8 hours, after the reaction was completed, the reaction was filtered, diluted with ethyl acetate, the organic phase was washed with aqueous ammonium chloride solution, and dried to obtain a crude product, which was purified by flash silica gel column chromatography system B to obtain compound Int 2h (300 mg, yield: 96%).

[0299] MS m / z (ESI): 477.0 (M+23) + .

[0300] Step 8: Preparation of (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3,4- dihydroquinolin-2(1H)-one (Int 2)

[0301] Compound Int 2h (300 mg, 0.66 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added. The reaction was stirred at room temperature for 1 hour, after the reaction was completed, the reaction was adjusted to pH = 8 with aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried and concentrated to obtain Int 2 (290 mg, yield: 98%).

[0302] MS m / z (ESI): 355.0 (M+1) + .

[0303] 1H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, 1H), 7.40 (dd, 2H), 7.04-6.95 (m, 1H), 6.49 (d, 1H), 4.00 (d, 1H), 3.21 (s, 3H), 3.06 (dd, 1H), 2.95 (t, 1H).

[0304] Preparation of intermediate (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l- methyl-3,4-dihydroquinolin-2(lH)-one (Int 3)

[0305]

[0306] Preparation of first step l-bromo-3-(2-chloro-5-fluorophenoxy)-4-fluoro-2- nitrobenzene (Int 3b)

[0307] Compound Int 3a (5.0 g, 0.018 mol) was dissolved in N,N dimethylformamide (50 mL), 2-chloro-5-fluorophenol (4.1 g, 0.028 mol) and potassium carbonate (5 g, 0.036 mol) were added, the reaction was stirred at 100 °C for 2 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3), then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound Int 3b (7 g, yield: 90%).

[0308] MS m / z (ESI): 364.0 (M+l).

[0309] Preparation of second step methyl (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-[3-(2- chloro-5-fluorophenoxy)-4-fluoro-2-nitrophenyl]propanoate (Int 3c)

[0310] To a reaction flask was added zinc dust (3 g), purged with nitrogen, and a needle tube was used to add N,N-dimethylformamide (8 mL) and stir at 40 °C for 15 min. To the system was added 1,2-dibromoethane (26 mg, 0.48 mmol) and trimethylchlorosilane (45 mg, 0.48 mmol) under nitrogen protection, and the reaction mixture was stirred at 40 °C for 15 min. To the reaction mixture was added a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (912 mg, 33.16 mmol) in N,N-dimethylformamide (2 mL) under nitrogen protection, and stirred at 40 °C for 30 min. The reaction mixture was cooled to room temperature under nitrogen protection to obtain a zinc reagent solution for later use. Another flask was prepared by adding a solution of compound Int 3b (4 g, 0.011 mol) in N,N-dimethylformamide (20 mL), and to the reaction mixture was added Pd(dppf)Cl2(1.6 g, 0.002 mol), cuprous iodide (380 mg, 0.002 mol), and the prepared zinc reagent solution (supernatant) under nitrogen protection at room temperature, and the resulting reaction mixture was stirred at 80 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was washed with an aqueous solution of ammonium chloride twice, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography system B to obtain compound Int 3c (4 g, yield: 74%).

[0311] MS m / z (ESI): 431.1 (M+1-56) + .

[0312] Preparation of (2R)-3-[2-amino-3-(2-chloro-5-fluorophenoxy)-4-fluorophenyl]-2-{[(tert-butoxy)carbonyl]amino}propionic acid methyl ester (Int 3d)

[0313] Compound Int 3c (3 g, 6.12 mmol) was dissolved in a mixed solvent of tetrahydrofuran / methanol / water (30 mL, V / V / V = 3:2:1), and iron powder (1.7 g, 30.6 mmol) and ammonium chloride (1.68 g, 30.6 mmol) were added. The reaction was stirred at 70 °C for 2 h. After the reaction was completed, filtration was performed using celite, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography system B gave compound Int 3d (2.5 g, yield: 88%).

[0314] MS m / z (ESI): 457.1 (M+1).

[0315] Preparation of tert-butyl N-[(3R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-3-yl]carbamate (Int 3e)

[0316] Compound Int 3d (2 g, 4.37 mmol) was dissolved in dichloromethane (20 mL), and trimethylaluminum (3.25 mL, 6.56 mmol) was added. The reaction was stirred at 40°C for 1.5 hours, and after the reaction was completed, filtration was performed using diatomite, and the filtrate was concentrated under reduced pressure, and purified by a silica gel column chromatography system (petroleum ether: ethyl acetate = 2:1) to obtain compound Int 3e (1.6 g, yield: 85.4%).

[0317] MS m / z (ESI): 369.1 (M+1-56) + .

[0318] Preparation of tert-butyl N-[(3R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-methyl-2-oxo-3,4-dihydroquinolin-3-yl]carbamate (Int 3f)

[0319] Compound Int 3e (1.6 g, 3.77 mmol) was dissolved in tetrahydrofuran (15 mL), and cesium carbonate (2.46 g, 7.5 mmol) and iodomethane (800 mg, 5.66 mmol) were added. The reaction was stirred at 40°C for 4 hours, and after the reaction was completed, the reaction solution was filtered, diluted with ethyl acetate, and the organic phase was washed with an aqueous ammonium chloride solution, and dried by rotation to obtain a crude product, which was purified by a silica gel column chromatography system B to obtain compound Int 3f (1.35 g, yield: 89%).

[0320] MS m / z (ESI): 383.1 (M+1-56) + .

[0321] Preparation of (3R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one (Int 3) Compound Int 3f (420 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), and a hydrochloric acid dioxane solution (3 mL) was added. The reaction was stirred at room temperature for 1 hour, and after the reaction was completed, drying by rotation was performed to obtain compound Int 3 (300 mg, yield: 89%).

[0322] MS m / z (ESI): 339.1 (M+1).

[0323] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 2H), 7.66 (dd, 1H), 7.39 (dd, 1H), 7.24 (dd, 1H), 7.02 (td, 1H), 6.81 (dd, 1H), 4.39 (dd, 1H), 3.26 (s, 3H), 3.22 (d, 1H), 3.12 (t, 1H).

[0324] Preparation of intermediate (R)-(8-(5-fluoro-2-vinylphenoxy)-7-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (Int 4)

[0325]

[0326] Compound Int 4d (synthesized based on similar method to compound Int 1h) (200 mg, 0.43 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (V / V = 10:1, 2.2 mL), potassium ethylene trifluoroborate (87 mg, 0.645 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (32 mg, 0.043 mmol) and potassium carbonate (178 mg, 1.38 mmol) were added, after the reaction was stirred at 100 °C for 16 hours under nitrogen protection, after the reaction was completed, the reaction liquid was spin dried. The crude product was purified by column chromatography system B to obtain compound Int 4 (120 mg, yield: 68%).

[0327] MS m / z (ESI): 357.2 (M-56) + .

[0328] Synthesis of intermediate (R)-(8-(5-fluoro-2-vinylphenoxy)-7-chloro-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (Int 5)

[0329]

[0330] Compound Int 5d (synthesized based on similar method to compound Int 2g) (250 mg, 0.51 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (V / V = 10:1, 2.2 mL), compound potassium ethylene trifluoroborate (60 mg, 0.64 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (75 mg, 0.10 mmol) and potassium carbonate (142 mg, 1.03 mmol) were added, after the reaction was stirred at 100 °C for 6 hours under nitrogen protection, after the reaction was completed, the reaction liquid was spin dried. The crude product was purified by column chromatography system B to obtain compound Int 5 (180 mg, yield: 80%).

[0331] MS m / z (ESI): 377.0 (M-56) + .

[0332] Synthesis of intermediate (R)-(8-(5-fluoro-2-vinylphenoxy)-7-fluoro-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (Int 6)

[0333]

[0334] Compound Int 6d (synthesized based on similar method to compound Int 3e) (500 mg, 1.07 mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (V / V = 10:1) (10 mL), compound potassium vinyltrifluoroborate (121 mg, 1.28 mmol) and potassium carbonate (441 mg, 3.20 mmol) were added, [1,1’-bis(diphenylphosphino)ferrocene]palladium dichloride (77 mg, 0.11 mmol), the reaction was stirred at 100 °C for 16 hours. The reaction was complete, the reaction solution was filtered and concentrated to get the crude product. The crude product was purified by column chromatography in system B to get compound Int 6 (380 mg, yield: 68%).

[0335] MS m / z (ESI): 439.1 (M+23) + .

[0336] Example 1

[0337] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (001)

[0338]

[0339] First step: preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-1-(2,2- difluoroethyl)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (001a)

[0340] Compound Int 1h (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), then compound 2,2-difluoroethyl trifluoromethanesulfonate (60.9 mg, 0.28 mmol) and cesium carbonate (231.7 mg, 0.71 mmol) were added, the reaction was stirred at 80 °C for 2 hours, after the reaction was completed, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography in system B to get compound 001a (80 mg, yield: 69.5%).

[0341] MS m / z (ESI): 507.1 (M+23)+ .

[0342] Preparation of the second step (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-(2,2- difluoroethyl)-7-methyl-3,4-dihydroquinolin-2(1H)-one (001b)

[0343] Compound 001a (80 mg, 0.16 mmol) was dissolved in 4 M hydrochloric acid / dioxane (3 mL), the reaction was stirred at room temperature for 0.5 h, after the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude compound 001b (50 mg), the product was directly used in the next step without purification.

[0344] MS m / z (ESI): 385.1 (M+1) + .

[0345] Preparation of the third step (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2,2- difluoroethyl)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (001)

[0346] Compound 001b (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (3 mL), water (0.1 mL) and acetic acid (0.1 mL), potassium cyanate (31.6 mg, 0.39 mmol) was added, the reaction was stirred at room temperature for 30 min, after the reaction was completed, saturated aqueous sodium bicarbonate solution was added to neutralize to basic, and the crude product was obtained by spin-drying, which was directly purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 μm C18 150 x 30 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25 mL / min) to obtain compound 001 (15.0 mg, yield: 27%).

[0347] MS m / z (ESI): 428.1 (M+1) + .

[0348] 1H NMR (400 MHz, DMSO-d6) δ 7.65 (dd, 1H), 7.25-7.18 (m, 2H), 6.99-6.94 (m, 1H), 6.42 (d, 1H), 6.33-6.29 (m, 1H), 6.28-5.99, (m, 1H), 5.82 (s, 2H), 4.58-4.47 (m, 1H), 4.44 - 4.37 (m, 1H), 4.26-4.15 (m, 1H), 3.14-3.09 (m, 1H), 2.80-2.73 (m, 1H), 2.04 (s, 3H).

[0349] Example 2

[0350] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-7-fluoro-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (002)

[0351]

[0352] Preparation of the first step (R)-(8-(2-chloro-5-fluorophenoxy)-1-(2,2- difluoroethyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (002a)

[0353] Compound Int 3e (50 mg, 0.12 mmol) was dissolved in N,N dimethylformamide (4 mL), 2,2-difluoroethyl triflate (50 mg, 0.235 mmol) and cesium carbonate (115 mg, 0.35 mmol) were added, the reaction was stirred at 80 °C for 2 hours, after the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (50 mL), filtered, the filtrate was diluted with water (100 mL) and further extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound 002a (50 mg, yield: 86.9%).

[0354] MS m / z (ESI): 489.1 (M+1) + .

[0355] Preparation of the second step (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-(2,2- difluoroethyl)-7-fluoro-3,4-dihydroquinolin-2(1H)-one (002b)

[0356] Compound 002a (50 mg, 0.10 mmol) was dissolved in 4 M / L hydrochloric acid / dioxane (3 mL), and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude compound 002b (40 mg), which was used directly in the next reaction without purification.

[0357] MSm / z(ESI): 389.1(M+1) + .

[0358] Step 3: Preparation of (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-3-yl)urea (002)

[0359] Compound 002b (40 mg, 0.10 mmol) was dissolved in tetrahydrofuran (3 mL), potassium cyanate (17 mg, 0.20 mmol), water (6 mg, 0.31 mmol), and acetic acid (22 mg, 0.31 mmol) 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 002 (15.5 mg, yield: 35.2%).

[0360] MSm / z(ESI): 432.1(M+1) + .

[0361] 1 H NMR(400MHz,DMSO-d6)δ7.65(dd,1H),7.34(dd,1H),7.22(dd,1H),7.02–7.00(m,1H),6.79(dd,1H),6.44(d,1H ),6.37–6.01(m,1H),5.82(s,2H),4.60–4.46(m,2H),4.24–4.20(m,1H),3.15–3.10(m,1H),2.77–2.74(m,1H).

[0362] Example 3

[0363] (R)-1-(8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea (004)

[0364]

[0365] Preparation of the first step (R)-(8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (004a)

[0366] Compound Int 1h (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), then compound trifluoroethyl triflate (64.9 mg, 0.28 mmol) and cesium carbonate (231.7 mg, 0.71 mmol) were added, the reaction was stirred at 80 °C for 2 hours, after the reaction was completed, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound 004a (70 mg, yield: 58%).

[0367] MS m / z (ESI): 503.1 (M+1) + .

[0368] Preparation of the second step (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-methyl-1-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-2(1H)-one (004b)

[0369] Compound 004a (70 mg, 0.14 mmol) was dissolved in 4M hydrochloric acid / dioxane (3 mL), the reaction was stirred at room temperature for 0.5 hours, after the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude compound 004b (50 mg), which was directly used in the next step reaction without purification.

[0370] MS m / z (ESI): 403.1 (M+1) + .

[0371] Preparation of the third step (R)-1-(8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea (004)

[0372] Compound 004b (30 mg, 0.08 mmol) was dissolved in tetrahydrofuran (3 mL), water (0.1 mL) and acetic acid (0.1 mL), potassium cyanate (19.4 mg, 0.24 mmol) was added, the reaction was stirred at room temperature for 30 minutes, after the reaction was completed, saturated aqueous sodium bicarbonate solution was added to neutralize to basic, spin dry to get the crude product, the crude product was directly purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 μm C18 150 x 30 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minutes gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25 mL / min) to obtain compound 004 (3.6 mg, yield: 10%).

[0373] MS m / z (ESI): 446.1 (M+1) + .

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 6.98-6.96 (m, 1H), 6.51 (d, 1H), 6.38 (dd, 1H), 5.80 (s, 2H), 5.15-5.09 (m, 1H), 4.61-4.48 (m, 2H), 3.17-3.12 (m, 1H), 2.75-2.68 (m, 1H), 2.04 (s, 3H).

[0375] Example 4

[0376] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (007)

[0377]

[0378] Preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (007a)

[0379] Compound Int 1h (30.0 mg, 0.07 mmol) was dissolved in N,N- dimethylformamide (3 mL), 1-bromo-2-fluoroethane (352.8 mg, 2.8 mmol) was added, then potassium carbonate (386.4 mg, 2.8 mmol) was added, the reaction was stirred at 50 °C for 1 h, LC-MS was used to monitor the reaction completion, then quenched with water, extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography system B to obtain compound 007a (15 mg, yield: 40%).

[0380] MS m / z (ESI): 489.1 (M+23) + .

[0381] Preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-(2- fluoroethyl)-7-methyl-3,4-dihydroquinolin-2(1H)-one (007b) in the second step

[0382] Compound 007a (15.0 mg, 0.03 mmol) was dissolved in hydrogen chloride in 1,4-dioxane (1 mL), the solution was stirred at room temperature for half an hour to obtain the crude compound 007b (10 mg, yield: 72%).

[0383] MS m / z (ESI): 367.1 (M+1) + .

[0384] Preparation of (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2- fluoroethyl)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (007) in the third step

[0385] Compound 007b (10.0 mg, 0.03 mmol) was dissolved in tetrahydrofuran (3 mL), acetic acid (40.0 mg, 0.66 mmol) and water (40.0 mg, 2.22 mmol) were added, then potassium cyanate (6 mg, 0.09 mmol) was added, the reaction was stirred at room temperature for 0.5 h, LC-MS was used to monitor the reaction completion, then sodium bicarbonate solution was added to adjust the pH to weak alkaline, then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20 mL / min) to obtain compound 007 (5.3 mg, yield: 50%).

[0386] MS m / z (ESI): 410.1 (M+1) + .

[0387] 1 H NMR (400 MHz, CD3OD) δ 7.53-7.50 (m, 1H), 7.22-7.17 (m, 2H), 6.83-6.78 (m, 1H), 6.10 (dd, 1H), 4.63-4.58 (m, 2H), 4.52-4.47 (m, 1H), 4.39-4.32 (m, 1H), 4.09-4.02 (m, 1H), 3.18-3.13 (m, 1H), 2.88-2.81 (m, 1H), 2.12 (s, 3H).

[0388] Example 5

[0389] (R)-1-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (008)

[0390]

[0391] Preparation of the first step tert-butyl (R)-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-1- (2-fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (008a)

[0392] Compound Int 3e (50 mg, 0.12 mmol) was dissolved in N,N dimethylformamide (4 mL), 1-bromo-2-fluoroethane (30 mg, 0.23 mmol) and cesium carbonate (115 mg, 0.35 mmol) were added, the reaction was stirred at 80 °C for 2 hours, after the reaction was completed, the reaction liquid was diluted with ethyl acetate and extracted. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound 008a (40 mg, yield: 73%).

[0393] MS m / z (ESI): 493.1 (M+23) + .

[0394] Preparation of the second step (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-1- (2-fluoroethyl)-3,4-dihydroquinolin-2(1H)-one (008b)

[0395] Compound 008a (40 mg, 0.085 mmol) was dissolved in dichloromethane (3 mL), then trifluoroacetic acid (1 mL) was added dropwise, the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to obtain crude compound 008b (30 mg), which was directly used in the next step.

[0396] MS m / z (ESI): 371.0 (M+1) + .

[0397] Step 3: Preparation of (R)-1-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-(2- fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (008)

[0398] Compound 008b (30 mg, 0.06 mmol) was dissolved in tetrahydrofuran (0.5 mL), potassium cyanate (17 mg, 0.20 mmol) was added, 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, it was neutralized to basic with aqueous sodium bicarbonate solution, and the crude product was obtained by rotary evaporation. 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 x 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 008 (5 mg, yield: 15%).

[0399] MS m / z (ESI): 414.0 (M+1) + .

[0400] 1 H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.28 (dd, 1H), 7.15-7.07 (m, 1H), 6.92-6.82 (m, 1H), 6.45 (dd, 1H), 4.57-4.39 (m, 4H), 4.25-4.07 (m, 1H), 3.18-3.12 (m, 1H), 2.87 (t, 1H).

[0401] Example 6

[0402] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (009)

[0403]

[0404] Preparation of first step (R)-(7-chloro-8-(2-chloro-5-fluorophenoxy)-l-(2- fluoroethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl) carbamate (009a)

[0405] Compound Int 2g (50 mg, 0.11 mmol) was dissolved in N,N dimethylformamide (5 mL), 1-bromo-2-fluoroethane (29 mg, 0.23 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added and the reaction was stirred at 80 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and extracted. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified on silica gel column chromatography system B to obtain compound 009a (40 mg, yield: 73%).

[0406] MS m / z (ESI): 509.0 (M+23) + .

[0407] Preparation of second step (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-l- (2-fluoroethyl)-3,4-dihydroquinolin-2(lH)-one (009b)

[0408] Compound 009a (40 mg, 0.082 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added dropwise to it and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain crude compound 009b (40 mg) which was used as such in the next step without purification.

[0409] MS m / z (ESI): 387.0 (M+1) + .

[0410] Preparation of third step (R)-l-(7-chloro-8-(2-chloro-5-fluorophenoxy)-l-(2- fluoroethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea (009)

[0411] Compound 009b (40 mg, 0.10 mmol) was dissolved in tetrahydrofuran (0.5 mL), potassium cyanate (25 mg, 0.30 mmol) was added, 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, neutralized to basic with aqueous sodium bicarbonate solution, rotary evaporation to get the crude product, the crude product was directly purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 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 009 (5 mg, yield: 15%).

[0412] MS m / z (ESI): 430.0 (M+1) + .

[0413] 1 H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.39 (d, 1H), 7.30 (d, 1H), 6.90-6.78 (m, 1H), 6.22-6.20 (m, 1H), 4.67-4.34 (m, 4H), 4.23-4.03 (m, 1H), 3.20 (dd, 1H), 2.88 (t, 1H).

[0414] Example 7

[0415] (R)-1-(1-allyl-8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)urea (010)

[0416]

[0417] Preparation of (R)-(1-allyl-8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (010a)

[0418] Compound Int 1h (50 mg, 0.119 mmol) was dissolved in N,N dimethylformamide (4 mL), allyl bromide (30 mg, 0.238 mmol) and potassium carbonate (50 mg, 0.353 mmol) were added, the reaction was stirred at 80 °C for 2 hours, after the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (50 mL), filtered, the filtrate was diluted with water (50 mL) and further extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound 010a (45 mg, yield: 83%).

[0419] MS m / z (ESI): 461.2 (M+1) + .

[0420] Preparation of (R)-1-allyl-3-amino-8-(2-chloro-5-fluorophenoxy)-7-methyl-3,4- dihydroquinolin-2(lH)-one (010b)

[0421] Compound 010a (45 mg, 0.097 mmol) was dissolved in 4 M hydrochloric acid / dioxane (3 mL), the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to obtain the crude compound 010b (40 mg), which was used directly in the next step without purification.

[0422] MS m / z (ESI): 361.1 (M+1) + .

[0423] Preparation of (R)-1-(l-allyl-8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)urea (010)

[0424] Compound 010b (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 mL), potassium cyanate (17 mg, 0.22 mmol) was added, water (6 mg, 0.33 mmol), acetic acid (22 mg, 0.33 mmol) were added, the reaction was stirred at room temperature for 30 minutes, after the reaction was completed, it was neutralized to basic with sodium bicarbonate aqueous solution, and dried to obtain a crude product, which was directly purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 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 010 (8.8 mg, yield: 20.1%).

[0425] MS m / z (ESI): 404.1 (M+1) + .

[0426] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (dd, 1H), 7.21 (d, 1H), 7.13 (d, 1H), 6.94 - 6.90 (m, 1H), 6.39 (d, 1H), 6.25 (dd, 1H), 5.81 (s, 2H), 5.62 - 5.58 (m, 1H), 5.07 (d, 1H), 4.95 (dd, 1H), 4.65 - 4.62 (m, 1H), 4.36 - 4.30 (m, 1H), 4.28 (dd, 1H), 3.13 - 3.10 (m, 1H), 2.76 (t, 1H), 2.00 (s, 3H).

[0427] Example 8

[0428] (R)-1-(13-Fluoro-1-methyl-6-oxo-5,6-dihydro-4H,8H-benzo[8,9][1,4]oxazocin[2,3,4- ij]quinolin-5-yl)urea (118)

[0429]

[0430] Preparation of first step (R)-(1-allyl-8-(5-fluoro-2-vinylphenoxy)-7-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (118a)

[0431] Compound Int 4 (120 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (2 mL), allyl bromide (42 mg, 0.35 mmol) and potassium carbonate (120 mg, 0.87 mmol) were added, after the reaction was stirred at 50 °C for 16 hours, LC-MS monitored the reaction was complete, quenched with water, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to give compound 118a (90 mg, yield: 68%).

[0432] MS m / z (ESI): 475.2 (M+23) + .

[0433] Preparation of second step (R)-(13-fluoro-1-methyl-6-oxo-5,6-dihydro-4H,8H- benzo[8,9][1,4]oxazocin[2,3,4-ij]quinolin-5-yl)carbamic acid tert-butyl ester (118b)

[0434] Compound 118a (90 mg, 0.20 mmol) was dissolved in 1,2-dichloroethane (90 mL), (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o- isopropoxybenzylidene) ruthenium (90 mg, 0.15 mmol) was added, the solution was stirred at 80 °C under nitrogen for 16 hours, LC-MS was used to monitor the reaction completion. The solution was directly concentrated and purified by column chromatography to give compound 118b (30 mg, yield: 40%).

[0435] MS m / z (ESI): 445.2 (M+23) + .

[0436] Preparation of (R)-5-amino-13-fluoro-1-methyl-4,5-dihydro-6H,8H- benzo[8,9][1,4]oxazocin[2,3,4-ij]quinolin-6-one (118c)

[0437] Compound 118b (30 mg, 0.07 mmol) was dissolved in 4 M hydrochloric acid / 1,4-dioxane (5 mL), the solution was stirred at room temperature for 1 hour, LC-MS was used to monitor the reaction completion, the solution was directly concentrated to give crude compound 118c (25 mg), the crude product was used in the next step without purification.

[0438] MS m / z (ESI): 325.1 (M+1) + .

[0439] Preparation of (R)-1-(13-fluoro-1-methyl-6-oxo-5,6-dihydro-1H,5H- benzo[8,9][1,4]oxazocin[2,3,4-ij]quinolin-5-yl)urea (118)

[0440] Compound 118c (25 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (8.2 mg, 0.1 mmol) and water (3.6 mg, 0.2 mmol) were added, potassium cyanate (15 mg, 0.14 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, LC-MS was used to monitor the reaction completion, sodium bicarbonate solution was added to adjust the pH to weak alkaline, the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minutes gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to give compound 118 (4 mg, yield: 15%).

[0441] MS m / z (ESI): 368.1 (M+1) + .

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 7.32 - 7.06 (m, 2H), 6.96 (m, 3H), 6.42 (d, 1H), 6.24 (d, 1H), 5.60 (s, 2H), 5.40 (s, 1H), 4.16 (s, 2H), 2.70 (t, 2H), 1.96 (s, 3H).

[0443] Example 9

[0444] (R)-1-(13-Fluoro-1-methyl-6-oxo-5,6,9,10-tetrahydro-4H,8H- benzo[8,9][1,4]oxazocin[2,3,4-ij]quinolin-5-yl)urea (088)

[0445]

[0446] First Step: Preparation of (R)-1-(13-Fluoro-1-methyl-6-oxo-5,6,9,10-tetrahydro- 4H,8H-benzo[8,9][1,4]oxazocin[2,3,4-ij]quinolin-5-yl)urea (088)

[0447] Compound 118 (4.0 mg, 0.01 mmol) was dissolved in methanol (1 mL), 10% wet palladium on carbon (10 mg) was added, the solution was stirred at room temperature under hydrogen atmosphere (15 psi) for 3 hours, after the reaction was complete by LC-MS monitoring, the mixture was filtered, the filtrate was concentrated and purified by column chromatography using system B to give compound 088 (2.03 mg, yield: 50%).

[0448] MS m / z (ESI): 370.1 (M+1) + .

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 7.21 (dd, 1H), 7.09 (d, 1H), 7.00 (d, 1H), 6.78 (td, 1H), 6.23 (d, 1H), 6.12 (d, 1H), 5.54 (s, 2H), 4.19 - 4.11 (m, 1H), 3.50 - 3.40 (m, 1H), 2.90 (dd, 1H), 2.70 - 2.58 (m, 2H), 2.38 (s, 2H), 2.02 (t, 3H), 1.51 - 1.44 (m, 2H).

[0450] Example 10

[0451] (R)-1-(11-Fluoro-14-methyl-3-oxo-2,3,5,6-tetrahydro-1H-benzo[9,10][1,4]oxazacyclodeca[2,3,4- ij]quinolin-2-yl)urea (121)

[0452]

[0453] Preparation of first step (R)-(1-(but-3-en-1-yl)-8-(5-fluoro-2-vinylphenoxy)-7-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (121a)

[0454] Compound Int 4 (120 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (2 mL), 4-bromo-1-butene (47 mg, 0.35 mmol) and potassium carbonate (120 mg, 0.87 mmol) were added, after the reaction was stirred at 50 °C for 16 hours, LC-MS monitoring reaction was complete, quenched with water, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography system B to obtain compound 121a (120 mg, yield: 88%).

[0455] MS m / z (ESI): 489.2 (M+23) + .

[0456] Preparation of second step (R)-(11-Fluoro-14-methyl-3-oxo-2,3,5,6-tetrahydro-1H- benzo[9,10][1,4]oxazacyclodeca[2,3,4-ij]quinolin-2-yl)carbamic acid tert-butyl ester (121b)

[0457] Compound 121a (120 mg, 0.26 mmol) was dissolved in 1,2-dichloroethane (120 mL), (1,3- bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxybenzylidene) ruthenium (120 mg, 0.2 mmol) was added, the solution was stirred at 80 °C under nitrogen protection for 16 hours, after LC-MS monitoring reaction was complete, direct concentration and purification by column chromatography separation system B to obtain compound 121b (80 mg, yield: 71%).

[0458] MS m / z (ESI): 461.2 (M+23) + .

[0459] Step 3. Preparation of (R)-2-amino-11-fluoro-14-methyl-1,2,5,6-tetrahydro-3H- benzo[9,10][1,4]oxazacyclodeca[2,3,4-ij]quinolin-3-one (121c)

[0460] Compound 121b (80 mg, 0.18 mmol) was dissolved in 4 Molar hydrochloric acid in 1,4-dioxane (5 mL) and the solution was stirred at room temperature for 1 hour. After the reaction was completed as monitored by LC-MS, the solution was directly concentrated to give crude compound 121c (60 mg). The crude compound was used in the next step without purification.

[0461] MS m / z (ESI): 339.1 (M+1) + .

[0462] Step 4. Preparation of (R)-1-(11-fluoro-14-methyl-3-oxo-2,3,5,6-tetrahydro-1H- benzo[9,10][1,4]oxazacyclodeca[2,3,4-ij]quinolin-2-yl)urea (121)

[0463] Compound 121c (60 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (16 mg, 0.2 mmol) and water (7.2 mg, 0.4 mmol) were added, and then potassium cyanate (30 mg, 0.28 mmol) was added. The reaction was stirred at room temperature for 0.5 hour. After the reaction was completed as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weakly basic, and then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5 μm C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 5% to 100%, flow rate: 25 mL / min) to give compound 121 (17 mg, yield: 24%).

[0464] MS m / z (ESI): 382.1 (M+1) + .

[0465] 1H NMR (400 MHz, DMSO-d6) δ 7.28 - 7.17 (m, 1H), 7.11 - 7.07 (m, 2H), 6.82 (td, 1H), 6.54 (d, 1H), 6.18 (d, 1H), 6.06 - 6.02 (m, 2H), 5.56 (s, 2H), 4.32 (s, 1H), 4.25 - 4.11 (m, 1H), 3.21 (s, 1H), 3.08 (d, 1H), 2.75 - 2.65 (m, 2H), 2.09 (s, 3H), 1.75 - 1.73 (m, 1H).

[0466] Example 11

[0467] (R)-1-(11-Fluoro-14-methyl-3-oxo-2,3,5,6,7,8-hexahydro-1H- benzo[9,10][1,4]oxazacyclodecino[2,3,4-ij]quinolin-2-yl)urea (094)

[0468]

[0469] First Step: Preparation of (R)-1-(11-Fluoro-14-methyl-3-oxo-2,3,5,6,7,8- hexahydro-1H-benzo[9,10][1,4]oxazacyclodecino[2,3,4-ij]quinolin-2-yl)urea (094)

[0470] Compound 121 (15 mg, 0.04 mmol) was dissolved in methanol (1 mL), palladium on carbon (10 mg) was added, and the solution was stirred at room temperature under hydrogen atmosphere for 16 hours. After the reaction was completed by LC-MS monitoring, the mixture was filtered, and the filtrate was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20 mL / min) to give compound 094 (9.3 mg, yield: 62%).

[0471] MS m / z (ESI): 384.2 (M+1) + .

[0472] 1H NMR (400 MHz, DMSO-d6) δ 7.24 (dd, 1H), 7.09 (q, 2H), 6.84 - 6.72 (m, 1H), 6.16 (d, 1H), 6.09 (dd, 1H), 5.55 (s, 2H), 4.11 (dt, 1H), 3.94 (dt, 1H), 3.65 (s, 1H), 3.17 (s, 2H), 3.01 - 2.95 (m, 1H), 2.72 (t, 2H), 2.21 (s, 1H), 2.17 (s, 3H), 1.69 (s, 1H), 1.53 (s, 1H).

[0473] Example 12

[0474] (R)-1-(12-Fluoro-15-methyl-3-oxo-2,3,6,7-tetrahydro-1H,5H- benzo[10,11][1]oxa[4]azacyclotridecine[2,3,4-ij]quinolin-2-yl)urea (127)

[0475]

[0476] First step: preparation of (R)-(8-(5-fluoro-2-vinylphenoxy)-1-(pent-4-en-1-yl)-7- methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (127a)

[0477] Compound Int 4 (120 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (2 mL), 5-bromo-1-pentene (52 mg, 0.35 mmol) and potassium carbonate (120 mg, 0.87 mmol) were added, after 16 hours of stirring at 50 °C the reaction was complete, it was quenched with water, extracted with ethyl acetate and the organic phase was collected, dried over anhydrous sodium sulfate. The crude was purified by column chromatography system B to obtain compound 127a (120 mg, yield: 86%).

[0478] MS m / z (ESI): 425.2 (M-56) + .

[0479] Second step: preparation of (R)-(12-fluoro-15-methyl-3-oxo-2,3,5,6,7,8- hexahydro-1H-benzo[11,12][1]oxa[4]azacyclotridecine[2,3,4-ij]quinolin-2-yl)carbamic acid tert-butyl ester (127b)

[0480] Compound 127a (80 mg, 0.17 mmol) was dissolved in 1,2-dichloroethane (80 mL), and (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxybenzyl)ruthenium (80 mg, 0.13 mmol) was added. The solution was stirred at 80 °C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the solution was concentrated under reduced pressure and purified by column chromatography system B to give compound 127b (20 mg, yield: 22%).

[0481] MSm / z(ESI): 475.2(M+23) + .

[0482] Step 3: Preparation of (R)-2-amino-12-fluoro-15-methyl-1,2,5,6,7,8-hexahydro-3H-benzo[11,12][1]oxo[4]azacyclic undecene[2,3,4-ij]quinoline-3-one (127c)

[0483] Compound 127b (20 mg, 0.04 mmol) was dissolved in 4 M hydrochloric acid / 1,4-dioxane (5 mL) solution. The solution was stirred at room temperature for 1 hour until the reaction was complete. The solution was then directly concentrated to obtain crude compound 127c (16 mg). The crude compound was used directly in the next reaction without purification.

[0484] MSm / z(ESI): 353.2(M+1) + .

[0485] Step 4: Preparation of (R)-1-(12-fluoro-15-methyl-3-oxo-2,3,5,6,7,8-hexahydro-1H-benzo[11,12][1]oxo[4]azacycloundecene[2,3,4-ij]quinolin-2-yl)urea (127)

[0486] Compound 127c (16 mg, 0.04 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of acetic acid (8.2 mg, 0.1 mmol) and water (3.6 mg, 0.2 mmol), and then potassium cyanate (6.6 mg, 0.08 mmol). The reaction was stirred at room temperature for 0.5 hours. After the reaction was complete, sodium bicarbonate solution was added to adjust the pH to weakly alkaline. The mixture was then concentrated under reduced pressure to obtain the crude product, which 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 10%-100%, flow rate: 20 mL / min) to obtain compound 127 (5 mg, yield: 28%).

[0487] MS m / z (ESI): 396.1 (M+1) + .

[0488] 1 H NMR (400 MHz, CD3OD) δ 7.13 - 7.08 (m, 3H), 6.72 (td, 1H), 6.46 (d, 1H), 5.97 - 5.85 (m, 2H), 4.33 (dd, 1H), 3.97 - 3.86 (m, 1H), 3.69 (t, 1H), 3.12 (dd, 1H), 2.81 (t, 1H), 2.43 - 2.21 (m, 2H), 2.04 (s, 3H), 1.95 - 1.79 (m, 2H).

[0489] Example 13

[0490] (R)-1-(12-Fluoro-15-methyl-3-oxo-2,3,6,7,8,9-hexahydro-1H,5H- benzo[10,11][1]oxaazacyloundecaphlo[2,3,4-ij]quinolin-2-yl)urea (100)

[0491]

[0492] Preparation of the first step (R)-1-(12-Fluoro-15-methyl-3-oxo-2,3,6,7,8,9- hexahydro-1H,5H-benzo[10,11][1]oxaazacyloundecaphlo[2,3,4-ij]quinolin-2-yl)urea (100)

[0493] Compound 127 (4.0 mg, 0.01 mmol) was dissolved in methanol (1 mL), 10% wet palladium on carbon (10 mg) was added, the solution was stirred under hydrogen atmosphere (15 psi) at room temperature for 3 hours, after the reaction was completed, the mixture was filtered, the filtrate was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20 mL / min) to give compound 100 (2.03 mg, yield: 50%).

[0494] MS m / z (ESI): 398.2 (M+1) + .

[0495] 1H NMR (400 MHz, DMSO-d6) δ 7.34 - 7.24 (m, 1H), 7.15-7.09 (m, 2H), 6.74 (s, 1H), 6.19 (d, 1H), 5.83 (s, 1H), 5.58 (s, 2H), 4.19-4.07 (m, 1H), 3.91-3.87 (m, 1H), 3.10-3.08 (m, 3H), 2.75 (t, 2H), 2.06 (d, 3H), 2.04-1.86 (m, 2H), 1.73-1.53 (m, 2H), 1.33-1.25 (m, 2H).

[0496] Example 14

[0497] (R)-1-(13-Fluoro-16-methyl-3-oxo-2,3,5,6,7,8-hexahydro-1H- benzo[11,12][1]oxaazacyclododecin[2,3,4-ij]quinolin-2-yl)urea (136)

[0498]

[0499] First step: Preparation of (R)-(8-(5-fluoro-2-vinylphenoxy)-1-(hex-5-en-1-yl)-7- methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (136a)

[0500] Compound Int 4 (40.0 mg, 0.097 mmol) was dissolved in N,N-dimethylformamide (2 mL), 6-bromo-1-hexene (47.3 mg, 0.29 mmol) and potassium carbonate (40.1 mg, 0.29 mmol) were added, after the reaction was stirred at room temperature for 16 hours, after the reaction was completed, quenched with water, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography in system B to obtain compound 136a (40.0 mg, yield: 75%).

[0501] MS m / z (ESI): 517.2 (M+23) + .

[0502] Second step: Preparation of (R)-(13-fluoro-16-methyl-3-oxo-2,3,5,6,7,8- hexahydro-1H-benzo[11,12][1]oxaazacyclododecin[2,3,4-ij]quinolin-2-yl)carbamic acid tert-butyl ester (136b)

[0503] Compound 136a (40.0 mg, 0.08 mmol) was dissolved in 1,2-dichloroethane (40 mL), (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o- isopropoxybenzylidene) ruthenium (50.5 mg, 0.08 mmol) was added, the solution was stirred at 80 °C under nitrogen atmosphere for 3 hours, after the reaction was completed, it was directly concentrated and purified by column chromatography with system B to obtain compound 136b (10 mg, yield: 15%).

[0504] MS m / z (ESI): 489.2 (M+23) + .

[0505] Preparation of (R)-2-amino-13-fluoro-16-methyl-1,2,5,6,7,8-hexahydro-3H- benzo[11,12][1]oxaazacylododecin[2,3,4-ij]quinolin-3-one (136c)

[0506] Compound 136b (10.0 mg, 0.02 mmol) was dissolved in 4 M hydrochloric acid / 1,4- dioxane (5 mL), the solution was stirred at room temperature for 1 hour, after the reaction was completed, it was directly concentrated to obtain crude compound 136c (9 mg). The crude product was used directly in the next step without purification.

[0507] MS m / z (ESI): 367.2 (M+1) + .

[0508] Preparation of (R)-1-(13-fluoro-16-methyl-3-oxo-2,3,5,6,7,8-hexahydro-1H- benzo[11,12][1]oxaazacylododecin[2,3,4-ij]quinolin-2-yl)urea (136)

[0509] Compound 136c (10.0 mg, 0.02 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (8.2 mg, 0.1 mmol) and water (3.6 mg, 0.2 mmol) were added, then potassium cyanate (6.6 mg, 0.08 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, after the reaction was completed, sodium bicarbonate solution was added to adjust the pH to weak alkaline, then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minutes gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20 mL / min) to obtain compound 136 (1.16 mg, yield: 9%).

[0510] MS m / z (ESI): 410.1 (M+1) + .

[0511] 1 H NMR (400 MHz, CD3OD) δ 7.17 - 7.01 (m, 2H), 7.05 - 7.01 (m, 1H), 6.80 - 6.75 (m, 1H), 6.61 - 6.59 (m, 1H), 6.15 - 6.00 (m, 1H), 5.90 - 5.75 (m, 1H), 4.80 - 4.79 (m, 1H), 4.36 - 4.19 (m, 1H), 4.15 - 3.79 (m, 1H), 3.19 - 3.14 (m, 1H), 2.93 - 2.82 (m, 1H), 2.10 - 1.97 (m, 5H), 1.90 - 1.79 (m, 2H), 1.62 - 1.43 (m, 2H).

[0512] Example 15

[0513] (R)-1-(13-Fluoro-16-methyl-3-oxo-2,3,5,6,7,8,9,10-octahydro-1H- benzo[11,12][1]oxa[4]azacyclododeca[2,3,4-ij]quinolin-2-yl)urea (106)

[0514]

[0515] Preparation of the first step (R)-1-(13-Fluoro-16-methyl-3-oxo-2,3,5,6,7,8,9,10- octahydro-1H-benzo[11,12][1]oxa[4]azacyclododeca[2,3,4-ij]quinolin-2-yl)urea (106)

[0516] Compound 136 (7.0 mg, 0.01 mmol) was dissolved in methanol (1 mL), 10% wet palladium on carbon (10 mg) was added, the solution was stirred under hydrogen atmosphere at room temperature for 3 hours, after the reaction was completed, the mixture was filtered, the filtrate was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20 mL / min) to obtain compound 106 (1.6 mg, yield: 22%).

[0517] MS m / z (ESI): 412.2 (M+1) + .

[0518] 1 H NMR (400 MHz, DMSO-d6) δ 7.31-7.27 (m, 1H), 7.12-7.11 (m, 1H), 7.08-7.06 (m, 1H), 6.79-6.77 (m, 1H), 6.22-6.21 (m, 1H), 5.87-5.85 (m, 1H), 5.59 (s, 2H), 4.27-4.22 (m, 1H), 3.81-3.75 (m, 1H), 3.52-3.44 (m, 1H), 2.79-2.73 (m, 1H), 2.14-2.11 (m, 1H), 1.99-1.90 (m, 6H), 1.62-1.50 (m, 3H), 1.33-1.25 (m, 2H), 1.16-1.15 (m, 2H).

[0519] Example 16

[0520] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2-hydroxyethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (036)

[0521]

[0522] Preparation of the first step tert-butyl (R)-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7- chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (036a)

[0523] Compound Int 2g (150 mg, 0.34 mmol) was dissolved in N,N dimethylformamide (5 mL), compound tert-butyl-(2-iodoethoxy)dimethylsilane (146 mg, 0.51 mmol) and potassium carbonate (94 mg, 0.68 mmol) were added, the reaction was stirred at 50 °C for 2 hours, after the reaction was completed, the reaction liquid was extracted with ethyl acetate after dilution. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound 036a (130 mg, yield: 64%).

[0524] MS m / z (ESI): 543.0 (M-56) + .

[0525] Preparation of the second step (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2- hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one (036b)

[0526] Compound 036a (130 mg, 0.22 mmol) was dissolved in dichloromethane (3 mL), then trifluoroacetic acid (1 mL) was added dropwise, the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to obtain crude compound 036b (100 mg), the product was used directly in the next step without purification.

[0527] MS m / z (ESI): 385.0 (M+1) + .

[0528] Preparation of (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2- hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (036)

[0529] Compound 036b (100 mg, 0.26 mmol) was dissolved in tetrahydrofuran (3 mL), potassium cyanate (42 mg, 0.52 mmol) was added, water (0.5 mL) and acetic acid (0.5 mL) were added, the reaction was stirred at room temperature for 30 minutes, after the reaction was completed, it was neutralized to basic with sodium bicarbonate aqueous solution, and then dried to obtain a crude product, which was directly purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 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 036 (11.6 mg, yield: 10.5%).

[0530] MS m / z (ESI): 428.0 (M+1) + .

[0531] 1H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.37 (d, 1H), 7.29 (d, 1H), 6.88-6.78 (m, 1H), 6.18 (dd, 1H), 4.47-4.32 (m, 2H), 3.97-3.87 (m, 1H), 3.74-3.65 (m, 1H), 3.61-3.53 (m, 1H), 3.18 (dd, 1H), 2.94 (t, 1H).

[0532] Example 17

[0533] (R)-1-(8-(2-chloro-5-fluorophenoxy)-7-(difluoromethyl)-1-(2-fluoroethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea (169)

[0534]

[0535] Preparation of the first step (4-amino-2-fluoro-3-nitrophenyl)methanol (169a)

[0536] Compound Int la (2.7 g, 11.6 mmol) was dissolved in 1,4-dioxane (30 mL), tri-n-butylmethoxytin (5.5 g, 17.2 mmol) and X-phos Pd G2 (1.8 g, 2.3 mmol) were added, and the reaction solution was stirred at 80°C for 16 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 169a (1.8 g, yield: 85%).

[0537] MS m / z (ESI): 187.1 (M+1) + .

[0538] Preparation of the second step (4-bromo-2-fluoro-3-nitrophenyl)methanol (169b)

[0539] Compound 169a (1.8 g, 9.6 mmol) was dissolved in acetonitrile (35 mL), cuprous bromide (2.6 g, 11.6 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour, and then isopropyl nitrite (1.5 g, 211.6 mmol) was added, and the reaction solution was stirred at 70°C for 4 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 169b (900 mg, yield: 38%).

[0540] MS m / z (ESI): 232.0 (M+1) + .

[0541] Preparation of the third step 4-bromo-2-fluoro-3-nitrobenzaldehyde (169c)

[0542] Compound 169b (900 mg, 3.6 mmol) was dissolved in ethyl acetate (30 mL), and manganese dioxide (3000 mg, 36 mmol) was added, and the reaction solution was stirred at 80°C for 16 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 169c (400 mg, yield: 49%).

[0543] MS m / z (ESI): 248.0 (M+1) + .

[0544] Fourth Step Preparation of 1-bromo-4-(difluoromethyl)-3-fluoro-2-nitrobenzene (169d)

[0545] Compound 169c (400 mg, 1.6 mmol) was dissolved in dichloromethane (30 mL), diethylamine sulfide trifluoride (600 mg, 2.5 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours. After the reaction was completed, the mixture was diluted with dichloromethane (80 mL), washed with water (80 mL x 3), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 169d (250 mg, yield: 57%).

[0546] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.92 - 7.85 (m, 1H), 7.31 (t, 1H).

[0547] Fifth Step Preparation of 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-(difluoromethyl)-2-nitrobenzene (169e)

[0548] Compound 169d (250 mg, 0.93 mmol) was dissolved in N,N-dimethylformamide (10 mL), 2-chloro-5-fluorophenol (108 mg, 0.74 mmol) was added, and the reaction solution was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (80 mL), washed with water (80 mL x 3), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 169e (250 mg, yield: 68%).

[0549] MS m / z (ESI): 396.6 (M+1) + .

[0550] Sixth Step Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5-fluorophenoxy)-4-(difluoromethyl)-2-nitrophenyl)propanoate (169f)

[0551] To a solution of compound 169e (250 mg, 0.63 mmol) in N,N-dimethylformamide (10 mL) was added Pd(dppf)Cl2(95 mg, 0.13 mmol), cuprous iodide (25 mg, 0.13 mmol) under nitrogen atmosphere at room temperature, and then a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- iodopropionate (600 mg, 1.9 mmol) in N,N-dimethylformamide was added under nitrogen atmosphere. The reaction was stirred at 80 °C for 12 h. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography system B to give compound 169f (210 mg, yield: 64%).

[0552] MS m / z (ESI): 541.0 (M+23) + .

[0553] Preparation of (R)-methyl 3-(2-amino-3-(2-chloro-5-fluorophenoxy)-4- (difluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (169g)

[0554] Compound 169f (210 mg, 0.4 mmol) was dissolved in a mixture solvent of ethanol / water (15 mL, V / V = 3:1), and iron powder (129 mg, 2.4 mmol), ammonium chloride (135 mg, 2.4 mmol) were added. The reaction was stirred at 25 °C for 2 h. After the reaction was completed, the reaction was filtered using celite, and the filtrate was concentrated under reduced pressure. The compound 169g (100 mg, yield: 55%) was obtained by purification using column chromatography system B.

[0555] MS m / z (ESI): 511 (M+23) + .

[0556] Preparation of (R)-tert-butyl (8-(2-chloro-5-fluorophenoxy)-7- (difluoromethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (169h)

[0557] Compound 169g (100 mg, 0.2 mmol) was dissolved in dichloromethane (6 mL), and trimethylaluminum (15 mg, 0.2 mmol) was added. The reaction was stirred at 25 °C for 1.5 h. After the reaction was completed, the reaction was filtered using celite, and the filtrate was concentrated under reduced pressure. The compound 169h (85 mg, yield: 93%) was obtained by purification using column chromatography system B.

[0558] MS m / z (ESI): 479.0 (M+23) + .

[0559] Preparation of (R)-tert-butyl (8-(2-chloro-5-fluorophenoxy)-7- (difluoromethyl)-l-(2-fluoroethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)carbamate (169i)

[0560] Compound 169h (85 mg, 0.18 mmol) was dissolved in N,N- dimethylformamide (5 mL), bromofluoroethane (45 mg, 0.36 mmol) and potassium carbonate (125 mg, 0.9 mmol) were added and the reaction was stirred at 50 °C for 3 h. After completion of the reaction, it was quenched with water and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. The crude was purified by column chromatography to get compound 169i (80 mg, yield: 88%).

[0561] MS m / z (ESI): 525 (M+23) + .

[0562] Preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7- (difluoromethyl)-l-(2-fluoroethyl)-3,4-dihydroquinolin-2(lH)-one (169j)

[0563] To compound 169i (80 mg, 0.16 mmol) was added hydrochloric acid in dioxane (3 mL) and the reaction was stirred at room temperature for 1 h. After completion of the reaction, it was evaporated to dryness to get compound 169j (55 mg, yield: 86%).

[0564] MS m / z (ESI): 403 (M+1) + .

[0565] Preparation of (R)-l-(8-(2-chloro-5-fluorophenoxy)-7- (difluoromethyl)-l-(2-fluoroethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)urea (169)

[0566] Compound 169j (30 mg, 0.06 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.1 mL) and water (0.1 mL) were added, then potassium cyanate (10 mg, 0.12 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, after the reaction was completed by LC-MS, sodium bicarbonate solution was added to adjust the pH to weak alkaline, then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 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 169 (2.1 mg, yield: 7.6%).

[0567] MS m / z (ESI): 446.1 (M+1) + .

[0568] 1 H NMR (400 MHz, CD3OD) δ 7.60-7.51 (m, 2H), 7.46 (d, 1H), 6.85-6.70 (m, 2H), 6.18 (dd, 1H), 4.62-4.34 (m, 4H), 4.11-3.91 (m, 1H), 3.28-3.23 (m, 1H), 2.92 (t, 1H).

[0569] Example 18

[0570] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-2-oxo-7- (trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea (170)

[0571]

[0572] Preparation of tert-butyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate (170b)

[0573] Compound 170a (1.0 g, 3.5 mmol) was dissolved in tert-butyl alcohol (10 mL), di-tert-butyl dicarbonate (1.53 g, 7.0 mmol) was added, then 4-dimethylaminopyridine (40 mg, 0.35 mmol) was added, the reaction was stirred at 50 °C for 12 hours. The reaction was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography system B to obtain compound 170b (1 g, yield: 60%).

[0574] 1H NMR (400 MHz, DMSO-d6) δ 7.88 - 7.80 (m, 2H), 1.58 (s, 9H).

[0575] Preparation of tert-butyl 6-bromo-2-(2-chloro-5-fluorophenoxy)-3- (trifluoromethyl)benzoate (170c) in the second step

[0576] Compound 170b (1 g, 2.9 mmol) was dissolved in dimethyl sulfoxide (10 mL), 2-chloro-5-fluorophenol (510 mg, 3.5 mmol) and potassium carbonate (1.2 g, 8.7 mmol) were added, after the reaction was stirred at 100 °C for 12 hours, quenched with water, extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to give compound 170c (1 g, yield: 66%).

[0577] 1 H NMR (400 MHz, CDCl3) δ 7.67 - 7.61 (m, 2H), 7.37 (d, 1H), 6.73 (d, 1H), 6.26 - 6.23 (m, 1H), 1.33 (s, 9H).

[0578] Preparation of 6-bromo-2-(2-chloro-5-fluorophenoxy)-3-(trifluoromethyl)benzoic acid (170d) in the third step

[0579] Compound 170c (1 g, 2.1 mmol) was dissolved in a mixed solvent of dichloromethane and trifluoroacetic acid (12 mL, V / V = 5:1), after the reaction was stirred at 25 °C for 12 hours, the reaction was monitored by TLC, the reaction was directly concentrated under reduced pressure to give the crude compound 170d (700 mg), which was used directly in the next step without purification.

[0580] Preparation of tert-butyl (6-bromo-2-(2-chloro-45-fluorophenoxy)-3- (trifluoromethyl)phenyl)carbamate (170e) in the fourth step

[0581] Compound 170d (700 mg, 1.7 mmol) was dissolved in toluene (6 mL) and tert-butyl alcohol (4 mL), diphenyl phosphorazide (929 mg, 3.4 mmol) and N,N- diisopropylethylamine (654.7 mg, 5.1 mmol) were added, after the reaction was stirred at 100 °C under nitrogen protection for 3.5 hours, the reaction was quenched with a small amount of water after completion, concentrated and purified by column chromatography in system B to give compound 170e (500 mg, yield: 55%).

[0582] MS m / z (ESI): 427.9 (M+1-56) + .

[0583] Step 5: Preparation of tert-butyl (6-bromo-2-(2-chloro-5-fluorophenoxy)-3- (trifluoromethyl)phenyl)(2-fluoroethyl)carbamate (170f)

[0584] Compound 170e (230 mg, 0.47 mmol) was dissolved in N,N-dimethylformamide (5 mL), bromofluoroethane (120.3 mg, 0.95 mmol) was added, followed by sodium hydride (28.4 mg, 0.71 mmol). The reaction was stirred at 25 °C for 12 h. After completion of the reaction, it was quenched with water and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. The crude was purified by column chromatography using system B to obtain compound 170f (100 mg, yield: 40%).

[0585] MS m / z (ESI): 473.9 (M+1-56) + .

[0586] Step 6: Preparation of 6-bromo-2-(2-chloro-5-fluorophenoxy)-N-(2- fluoroethyl)-3-(trifluoromethyl)aniline (170g)

[0587] Compound 170f (150 mg, 0.28 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (5 mL) and the solution was stirred at room temperature for 1 h. After completion of the reaction, it was directly concentrated to obtain crude compound 170g (100 mg), which was used as such in the next step without further purification.

[0588] MS m / z (ESI): 429.9 (M+1) + .

[0589] Step 7: Preparation of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-(2- chloro-5-fluorophenoxy)-2-((2-fluoroethyl)amino)-4-(trifluoromethyl)phenyl)propanoate (170h)

[0590] Compound 170g (100 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (5 mL), and copper(I) iodide (8.83 mg, 0.05 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (16.8 mg, 0.023 mmol) were added, and then a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (182.8 mg, 0.46 mmol) in N,N-dimethylformamide was added under nitrogen protection. After the reaction was stirred at 80°C for 12 hours under nitrogen protection, the reaction 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 to obtain compound 170h (80 mg, yield: 66%).

[0591] MS m / z (ESI): 553.1 (M+1) + .

[0592] Preparation of (R)-tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5- fluorophenoxy)-2-((2-fluoroethyl)amino)-4-(trifluoromethyl)phenyl)propanoate (170i)

[0593] Compound 170h (80 mg, 0.14 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (6 mL, V / V=1:1), and lithium hydroxide (10.4 mg, 0.43 mmol) was added. After the reaction was stirred at room temperature for 1 hour, the reaction solution was extracted with ethyl acetate, and the organic phase was collected and dried over anhydrous sodium sulfate. After concentration under reduced pressure, crude compound 170i (50 mg) was obtained, which was directly used in the next reaction.

[0594] MS m / z (ESI): 539.1 (M+1) + .

[0595] Preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-2-oxo-7- (trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (170j)

[0596] Compound 170i (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (5 mL), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42.3 mg, 0.11 mmol) and N,N-diisopropylethylamine (35.9 mg, 0.28 mmol) were added. The reaction was stirred at room temperature for 0.5 h. After completion of the reaction, it was extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate and the crude was purified by column chromatography to obtain compound 170j (20 mg, yield: 41%).

[0597] MS m / z (ESI): 543.2 (M+23) + .

[0598] Preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-7- (trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one (170k)

[0599] Compound 170j (20 mg, 0.04 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (3 mL) and the solution was stirred at room temperature for 1 h. After completion of the reaction, it was directly concentrated to obtain crude compound 170k (15 mg), which was used directly for the next step.

[0600] MS m / z (ESI): 421.0 (M+1) + .

[0601] Preparation of (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-2-oxo-7- (trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea (170)

[0602] Compound 170k (15 mg, 0.035 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.1 mL) and water (0.1 mL) were added, followed by potassium cyanate (5.8 mg, 0.071 mmol). The reaction was stirred at room temperature for 0.5 h. After completion of the reaction, as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weakly basic, and the mixture was concentrated and purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 55-95%, flow rate: 20 mL / min) to obtain compound 170 (2 mg, yield: 12%).

[0603] MS m / z (ESI): 464.0 (M+1) + .

[0604] 1 H NMR (400 MHz, CD3OD) δ 7.66 (d, 1H), 7.55 - 7.49 (m, 2H), 6.87 - 6.83 (m, 1H), 6.23-6.20 (m, 1H), 4.64 - 4.62 (m, 1H), 4.56 - 4.44 (m, 2H), 4.40-4.36 (m, 2H), 3.29-3.27 (m, 1H), 2.98-2.91 (m, 1H).

[0605] Example 19

[0606] (R)-1-(1-allyl-8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)urea (011)

[0607]

[0608] Preparation of the first step (R)-(1-allyl-8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (011a)

[0609] Compound Int 1h (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), then 3-bromoprop-1-ene (56.2 mg, 0.47 mmol) and potassium carbonate (100 mg, 0.71 mmol) were added, the reaction was stirred at 40 °C for 2 hours, after the reaction was completed, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound 011a (90 mg, yield: 82.5%).

[0610] MS m / z (ESI): 464.0 (M+1) + .

[0611] Preparation of the second step (R)-1-allyl-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-3,4- dihydroquinolin-2(1H)-one (011b)

[0612] Compound 011a (90 mg, 0.19 mmol) was dissolved in 4M hydrochloric acid / dioxane (3 mL), the reaction was stirred at room temperature for 0.5 hour, after the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude compound 011b (70 mg), the product was directly used in the next step reaction without purification.

[0613] MS m / z (ESI): 455.1 (M+1) + .

[0614] Preparation of (R)-1-(1-allyl-8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (011)

[0615] Compound 011b (70 mg, 0.09 mmol) was dissolved in tetrahydrofuran (3 mL), water (0.1 mL) and acetic acid (0.1 mL), potassium cyanate (15 mg, 0.18 mmol) was added, the reaction was stirred at room temperature for 30 minutes, after the reaction was completed, saturated aqueous sodium bicarbonate solution was added to neutralize to basic, spin dry to obtain the crude product, the crude product was directly purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 μm C18 150 x 30 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25 mL / min) to obtain compound 011 (28 mg, yield: 45%).

[0616] MS m / z (ESI): 408.1 (M+1) + .

[0617] 1 H NMR (400 MHz, DMSO-d6) 7.62 (dd, 1H), 7.31 (dd, 1H), 7.17 (dd, 1H), 6.99 (td, 1H), 6.70 (dd, 1H), 6.39 (d, 1H), 5.81 (s, 2H), 5.71 - 5.64 (m, 1H), 5.04 (dd, 1H), 4.95 (dd, 1H), 4.65 - 4.55 (m, 1H), 4.49 (dt, 1H), 4.37 (dd, 1H), 3.17 (dd, 1H), 2.79 (t, 1H).

[0618] Example 20

[0619] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)urea (012)

[0620]

[0621] Preparation of (R)-1 -(1 -allyl-7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (012a)

[0622] Compound Int 2g (200 mg, 0.470 mmol) was dissolved in N,N-dimethylformamide (10 mL), allyl bromide (123 mg, 1.01 mmol) and potassium carbonate (188 mg, 1.36 mmol) were added, the reaction was stirred at 25 °C for 16 hours, after the reaction was completed, water was added and extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by flash silica gel column system B to obtain compound 012a (250 mg, yield: 69%).

[0623] MS m / z (ESI): 425.0 (M-56) + .

[0624] Preparation of (R)-1 -allyl-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)- 3,4-dihydroquinolin-2(1 H)-one (012b) Compound 012a (250 mg, 0.51 mmol) was dissolved in 4 M hydrochloric acid / dioxane (5 mL), the reaction was stirred at room temperature for 2 hours, after the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude compound 012b (170 mg, yield: 76%), the product was used directly in the next step without purification.

[0625] MS m / z (ESI): 381.0 (M+1) + .

[0626] Third step (R)-1 -(1 -allyl-7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea 012

[0627] Compound 012d (170 mg, 0.45 mmol) was dissolved in tetrahydrofuran (5 mL), potassium cyanate (72 mg, 0.89 mmol) was added, followed by two drops of water and two drops of acetic acid. The reaction was stirred at room temperature for 0.5 hour. After the reaction was completed, saturated sodium bicarbonate was added to quench the reaction and make the reaction system basic. The crude product was obtained by concentration under reduced pressure, which was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 μm C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 10 minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 25 mL / min) to obtain compound 012 (100 mg, yield: 47%).

[0628] MS m / z (ESI): 424.1 (M+1) + .

[0629] 1 H NMR (400 MHz, CD3OD) δ 7.59 - 7.44 (m, 1H), 7.40 - 7.32 (m, 1H), 7.30 - 7.18 (m, 1H), 6.90 - 6.74 (m, 1H), 6.25 - 6.09 (m, 1H), 5.75 - 5.55 (m, 1H), 5.27 - 5.08 (m, 1H), 4.99 (d, 1H), 4.80 - 4.65 (m, 1H), 4.50 - 4.34 (m, 2H), 3.25 - 3.12 (m, 1H), 2.97 - 2.76 (m, 1H).

[0630] Example 21

[0631] (R)-1-(1-(But-2-yn-1-yl)-8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (055)

[0632]

[0633] Preparation of (R)-(1-(But-2-yn-1-yl)-8-(2-chloro-5-fluorophenoxy)-7-methyl-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (055a)

[0634] Compound Int 1h (30 mg, 0.071 mmol) was dissolved in N,N-dimethylformamide (5 mL), 1-bromobut-2-yne (11 mg, 0.078 mmol) and potassium carbonate (30 mg, 0.214 mmol) were added, after the reaction was stirred at 50 °C for 2 hours, quenched with water, 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 to obtain compound 055a (30 mg, yield: 79.9%).

[0635] MS m / z (ESI): 417.0 (M-55) + .

[0636] Preparation of (R)-3-amino-1-(but-2-yn-1-yl)-8-(2-chloro-5-fluorophenoxy)-7- methyl-3,4-dihydroquinolin-2(1H)-one (055b) in the second step

[0637] Compound 055a (30 mg, 0.063 mmol) was dissolved in 4M hydrochloric acid / 1,4- dioxane (3 mL), after the reaction was stirred at 25 °C for 2 hours, the reaction was monitored by LC-MS until completion, the reaction was directly concentrated under reduced pressure to obtain the crude compound 055b (25 mg), which was directly used in the next step without purification.

[0638] MS m / z (ESI): 373.0 (M-55) + .

[0639] Preparation of (R)-1-(1-(but-2-yn-1-yl)-8-(2-chloro-5-fluorophenoxy)-7-methyl-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (055) in the third step

[0640] Compound 055b (25 mg, 0.067 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.1 mL) and water (0.1 mL) were added, then potassium cyanate (8 mg, 0.10 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, after the reaction was monitored by LC-MS until completion, saturated sodium bicarbonate solution was added to adjust the pH to weak alkaline, then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 055 (8.37 mg, yield: 28.5%).

[0641] MS m / z (ESI): 416.1 (M+1) + .

[0642] 1 H NMR (400 MHz, CDC13) δ 7.30 (dd, 1H), 7.02 (dd, 2H), 6.59 (td, 1H), 6.34 (s, 1H), 5.91 (d, 1H), 4.85 (s, 2H), 4.62 - 4.46 (m, 2H), 4.36 (d, 1H), 3.37 (d, 1H), 2.72 (t, 1H), 2.02 (s, 3H), 1.43 (d, 3H).

[0643] Example 22

[0644] (R)-1-(8-(2-bromo-5-fluorophenoxy)-7-chloro-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (178)

[0645]

[0646] Preparation of first step 1-bromo-3-(2-bromo-5-fluorophenoxy)-4-chloro-2- nitrobenzene (178a)

[0647] Compound Int 2c (1000 mg, 3.93 mmol) was dissolved in N,N dimethylformamide (10 mL), 2-bromo-5-fluorophenol (826 mg, 4.32 mmol) and potassium carbonate (1358 mg, 9.83 mmol) were added and the reaction was stirred at 100 °C for 2 h. The reaction was monitored by TLC and upon completion the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (100 mL x 5) followed by saturated brine, dried over anhydrous sodium sulphate and the crude was purified by column chromatography using system B to get compound 178a (800 mg, yield: 43%).

[0648] MS m / z (ESI): 416.1 (M+1) + .

[0649] Preparation of second step (R)-3-(3-(2-bromo-5-fluorophenoxy)-4-chloro-2- nitrophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (178b)

[0650] Compound 178a (150 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (5 mL), (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc (II) iodide (278 mg, 0.71 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (26 mg, 0.03 mmol) and copper iodide (7 mg, 0.03 mmol) were added. After the reaction was stirred at 80 °C for 16 hours under nitrogen protection, the reaction was monitored to be completed by LC-MS, and the reaction solution was rotary evaporated. The crude product was purified by column chromatography in system B to obtain compound 178b (150 mg, yield: 70%).

[0651] MS m / z (ESI): 569.0 (M+23) + .

[0652] Preparation of (R)-methyl 3-(2-amino-3-(2-bromo-5-fluorophenoxy)-4- chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (178c)

[0653] Compound 178b (150 mg, 0.27 mmol) was dissolved in a mixed solvent of ethanol (4 mL) and water (2 mL), zinc powder (77 mg, 1.37 mmol) and ammonium chloride (74 mg, 0.37 mmol) were added. The reaction was stirred at 80 °C for 2 hours, after the reaction was completed, the filter was carried out using diatomite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography in system B to obtain compound 178c (100 mg, yield: 63%).

[0654] MS m / z (ESI): 460.9 (M+1-56) + .

[0655] Preparation of tert-butyl (R)-(8-(2-bromo-5-fluorophenoxy)-7-chloro-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamate (178d)

[0656] Compound 178c (100 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), 2M trimethylaluminum solution in toluene (0.1 mL, 0.19 mmol) was added. The reaction was stirred at room temperature for 1 hour, after the reaction was completed, the reaction solution was quenched by adding methanol, rotary evaporated, and the crude product was purified by column chromatography in system B to obtain compound 178d (90 mg, yield: 86%).

[0657] MS m / z (ESI): 429.0 (M+1-56) + .

[0658] Step 5: Preparation of (R)-(8-(2-bromo-5-fluorophenoxy)-7-chloro-l-(2- fluoroethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (178e)

[0659] Compound 178d (90 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (65 mg, 0.46 mmol) and 1-bromo-2-fluoroethane (36 mg, 0.28 mmol) were added. The reaction was stirred at 50 °C for 3 hours, after the reaction was completed, the reaction was filtered, diluted with ethyl acetate, the organic phase was washed with aqueous ammonium chloride solution, rotary evaporation to get the crude product, the crude product was purified by column chromatography in system B to get compound 178e (90 mg, yield: 82%).

[0660] MS m / z (ESI): 475.0 (M+1-56) + .

[0661] Step 6: Preparation of (R)-3-amino-8-(2-bromo-5-fluorophenoxy)-7-chloro-l-(2- fluoroethyl)-3,4-dihydroquinolin-2(lH)-one (178f)

[0662] Compound 178e (50 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL), 4M hydrochloric acid / dioxane solution (3 mL) was added. The reaction was stirred at room temperature for 1 hour, after the reaction was completed, rotary evaporation to get the crude compound 178f (40 mg), the product was used directly in the next step without purification.

[0663] MS m / z (ESI): 430.0 (M+1) + .

[0664] Step 7: Preparation of (R)-l-(8-(2-bromo-5-fluorophenoxy)-7-chloro-l-(2- fluoroethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea (178)

[0665] Compound 178f (30 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 mL), potassium cyanate (7 mg, 0.08 mmol) was added, water (0.1 mL) and acetic acid (0.1 mL) were added, the reaction was stirred at room temperature for 1 hour, after the reaction was completed, neutralized to basic with aqueous sodium bicarbonate solution, rotary evaporation to obtain the crude product, the crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min), purification to obtain compound 178 (4.36 mg, yield: 12%).

[0666] MS m / z (ESI): 474.0 (M+1) + .

[0667] 1 H NMR (400 MHz, CDC13) δ 7.50 (dd, 1H), 7.24 (d, 1H), 7.12 (d, 1H), 6.68 - 6.58 (m, 1H), 5.90 (dd, 1H), 5.81 (d, 1H), 4.60 (dd, 1H), 4.56 (s, 2H), 4.50 - 4.44 (m, 1H), 4.41 - 4.22 (m, 2H), 4.15 - 4.02 (m, 1H), 3.35 (dd, 1H), 2.77-2.69 (m, 1H).

[0668] Example 23

[0669] (R)-1-(8-(2-bromo-5-fluorophenoxy)-1-(2-fluoroethyl)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (179)

[0670]

[0671] Preparation of (R)-(8-(2-bromo-5-fluorophenoxy)-1-(2-fluoroethyl)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (179a)

[0672] Compound Int 4d (80 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (5 mL), then 1-bromo-2-fluoroethane (48.5 mg, 0.28 mmol) and cesium carbonate (185.8 mg, 0.57 mmol) were added, the reaction was stirred at 80 °C for 2 hours, after the reaction was completed, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound 179a (60 mg, yield: 62%).

[0673] MS m / z (ESI): 511.1 (M+1) + .

[0674] Preparation of the second step (R)-3-amino-8-(2-bromo-5-fluorophenoxy)-1-(2- fluoroethyl)-7-methyl-3,4-dihydroquinolin-2(1H)-one (179b)

[0675] Compound 179a (60 mg, 0.117 mmol) was dissolved in 4M hydrochloric acid / dioxane (3 mL), the reaction was stirred at room temperature for 0.5 hours, after the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude compound 179b (45 mg), which was directly used in the next step reaction without purification.

[0676] MS m / z (ESI): 411.1 (M+1) + .

[0677] Preparation of the third step (R)-1-(8-(2-bromo-5-fluorophenoxy)-1-(2- fluoroethyl)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (179)

[0678] Compound 179b (45 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 mL), water (0.1 mL) and acetic acid (0.1 mL), potassium cyanate (27.1 mg, 0.33 mmol) was added, the reaction was stirred at room temperature for 30 minutes, after the reaction was completed, saturated aqueous sodium bicarbonate solution was added to neutralize to basicity, and the crude product was obtained by rotary evaporation, which was directly purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 μm C18 150 x 30 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minutes gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25 mL / min) to obtain compound 179 (9.0 mg, yield: 18.3%).

[0679] MS m / z (ESI): 454.1 (M+1) + .

[0680] 1 HNMR (400MHz, DMSO-d6) δ 7.78 (dd, 1H), 7.24 (d, 1H), 7.17 (d, 1H), 6.91 (td, 1H), 6.41 (d, 1H), 6.25 (s, 1H), 5.80 (s, 2H), 4.67 - 4.28 (m, 4H), 3.94 (dd, 1H), 3.11 (dd, 1H), 2.73 - 2.65 (m, 1H), 2.03 (s, 3H).

[0681] Example 24

[0682] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (003)

[0683]

[0684] First step: preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-7- chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (003a)

[0685] Compound Int 2g (350 mg, 0.69 mmol) was dissolved in N,N dimethylformamide (6 mL), 2,2-difluoroethyl trifluoromethanesulfonate (887 mg, 4.14 mmol) and potassium carbonate (572 mg, 4.14 mmol) were added, the reaction was stirred at 70 °C for 24 hours, after the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (50 mL), filtered, the filtrate was diluted with water (100 mL) and further extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound 003a (330 mg, yield 82.5%).

[0686] MS m / z (ESI): 527.0 (M+23).

[0687] Second step: preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-(2,2- difluoroethyl)-7-chloro-3,4-dihydroquinolin-2(1H)-one (003b)

[0688] Compound 003a (330 mg, 0.65 mmol) was dissolved in dichloromethane (5 mL), 4M hydrochloric acid / dioxane (5 mL) was added, the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to obtain crude compound 003b (265 mg, yield: 100%), which was used directly in the next step.

[0689] MS m / z (ESI): 405.0 (M+1).

[0690] Step 3. Preparation of (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1- (cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (003)

[0691] Compound 003b (265 mg, 0.65 mmol) was dissolved in tetrahydrofuran (5 mL), acetic acid (0.1 mL) and water (0.1 mL) were added, then potassium cyanate (159 mg, 1.96 mmol) was added, the reaction was stirred at room temperature for 2 hours, after the reaction was completed by LC-MS, sodium bicarbonate solution was added to adjust the pH to weak alkaline, then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20 mL / min) to obtain compound 003 (8 mg, yield: 3%).

[0692] MS m / z (ESI): 448.0 (M+1).

[0693] 1 H NMR (400 MHz, CD3OD) δ 7.53-7.51 (m, 1H), 7.40-7.38 (m, 1H), 7.31-7.28 (m, 1H), 6.91-6.78 (m, 1H), 6.22-6.20 (m, 1H), 6.19-5.86 (m, 1H), 4.67-4.49 (m, 1H), 4.47-4.27 (m, 2H), 3.21-3.19 (m, 1H), 2.91-2.88 (m, 1H).

[0694] Example 25

[0695] (R)-1-(14-chloro-11-fluoro-3-oxo-2,3,5,6-tetrahydro-1H- benzo[9,10][1,4]oxazacyclodeca[2,3,4-ij]quinolin-2-yl)urea (123)

[0696]

[0697] First step: Preparation of (R)-(l-(but-3-en-l-yl)-7-chloro-8-(5-fluoro-2- vinylphenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (123a)

[0698] Compound Int 5 (180 mg, 0.42 mmol) was dissolved in N,N-dimethylformamide (5 mL), added compound 4-bromo-l-butene (84 mg, 0.62 mmol) and potassium carbonate (115 mg, 0.83 mmol), after the reaction was stirred at 50 °C for 16 hours, after the reaction was complete, quenched with water, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate. The crude was purified by column chromatography system B to obtain compound 123a (180 mg, yield: 77%).

[0699] MS m / z (ESI): 487.1 (M+1) + .

[0700] Second step: Preparation of (R)-(14-chloro-l l-fluoro-3-oxo-2,3,5,6-tetrahydro- IH- benzo[9,10][l,4]oxazacyclodeca[2,3,4-ij]quinolin-2-yl)carbamic acid tert-butyl ester (123b)

[0701] Compound 123a (180 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (180 mL), added (l,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o- isopropoxybenzylidene)ruthenium (180 mg, 0.29 mmol), the solution was stirred at 80 °C under nitrogen protection for 16 hours. After the reaction was complete, it was directly concentrated and purified by column chromatography system B to obtain compound 123b (150 mg, yield: 88%).

[0702] MS m / z (ESI): 403.1 (M-55) + .

[0703] Third step: Preparation of (R)-2-amino-14-chloro-l l-fluoro-l,2,5,6-tetrahydro-3H- benzo[9,10][l,4]oxazacyclodeca[2,3,4-ij]quinolin-3-one (123c)

[0704] Compound 123b (80 mg, 0.17 mmol) was dissolved in 4 M hydrochloric acid / 1,4-dioxane (5 mL), the solution was stirred at room temperature for 1 hour, after the reaction was completed, the crude product was directly concentrated to obtain compound 123c (70 mg, ). The crude product was directly used in the next step without purification.

[0705] MS m / z (ESI): 359.1 (M+1) + .

[0706] Preparation of (R)-1-(14-chloro-11-fluoro-3-oxo-2,3,5,6-tetrahydro-1H- benzo[9,10][1,4]oxazacyclodeca[2,3,4-ij]quinoline-2-yl)urea (123)

[0707] Compound 123c (70 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.5 mL) and water (0.5 mL) were added, then potassium cyanate (19 mg, 0.23 mmol) was added, the reaction was stirred at room temperature for 0.5 hour. After the reaction was completed, sodium bicarbonate solution was added to adjust the pH to weak alkaline, then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 123 (20 mg, yield: 26%).

[0708] MS m / z (ESI): 402.1 (M+1) + .

[0709] 1 H NMR (400 MHz, CD3OD) δ 7.34 (d, 1H), 7.27-7.14 (m, 2H), 6.84-6.74 (m, 1H), 6.55 (d, 1H), 6.18 (dd, 1H), 6.13-6.00 (m, 1H), 4.54-4.41 (m, 1H), 4.30 (dd, 1H), 3.29-3.21 (m, 1H), 3.16 (dd, 1H), 2.92-2.74 (m, 2H), 1.86-1.71 (m, 1H).

[0710] Example 26

[0711] (R)-1-(15-chloro-12-fluoro-3-oxo-2,3,6,9-tetrahydro-1H,5H- benzo[10,11][1]oxa[4]azacyclotetradecine[2,3,4-ij]quinolin-2-yl)urea (132)

[0712]

[0713] Preparation of (R)-(8-(2-allyl-5-fluorophenoxy)-7-chloro-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (132a) in first step

[0714] Compound Int 5d (400 mg, 0.83 mmol) was dissolved in toluene (5 mL), allyl tributyl tin (328 mg, 0.99 mmol) and dichlorobis(triphenylphosphine)palladium (88 mg, 0.12 mmol) were added, the reaction was stirred at 100 for 16 h, the reaction was monitored by LC-MS, the reaction was complete. The reaction was evaporated to dryness, the crude was purified by column chromatography to get compound 132a (220 mg, yield: 60%).

[0715] MS m / z (ESI): 391.1 (M+1-56) + .

[0716] Preparation of (R)-(8-(2-allyl-5-fluorophenoxy)-1-(but-3-en-1-yl)-7-chloro-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (132b) in second step

[0717] Compound 132a (120 mg, 0.269 mmol) was dissolved in N,N- dimethylformamide (5 mL), compound 4-bromo-1-butene (40 mg, 0.295 mmol) and potassium carbonate (74 mg, 0.537 mmol) were added, the reaction was stirred at 50 °C for 16 h, the reaction was monitored by LC-MS, the reaction was complete, quenched with water, extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate. The crude was purified by column chromatography in system B to get compound 132b (120 mg, yield: 80%).

[0718] MS m / z (ESI): 445.1 (M+1-56) + .

[0719] Preparation of (R)-(15-chloro-12-fluoro-3-oxo-2,3,6,9-tetrahydro-1H,5H- benzo[10,11][1]oxa[4]azacyclotetradecine[2,3,4-ij]quinolin-2-yl)carbamic acid tert-butyl ester (132c) in third step

[0720] Compound 132b (120 mg, 0.24 mmol) was dissolved in 1,2-dichloroethane (120 mL), (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o- isopropoxybenzylidene) ruthenium (120 mg, 0.19 mmol) was added, the solution was stirred at 80 °C under nitrogen for 16 hours, after the reaction was completed, it was directly concentrated and purified by column chromatography with system B to obtain compound 132c (100 mg, yield: 80%).

[0721] MS m / z (ESI): 417.1 (M+1-56) + .

[0722] Preparation of (R)-2-amino-15-chloro-12-fluoro-1,2,6,9-tetrahydro-3H,5H- benzo[10,11][1]oxa[4]azacyclotetradecine[2,3,4-ij]quinolin-3-one (132d)

[0723] Compound 132c (100 mg, 0.21 mmol) was dissolved in 4 M hydrochloric acid / 1,4- dioxane (5 mL), the solution was stirred at room temperature for 1 hour, after the reaction was completed, it was directly concentrated to obtain crude compound 132d (80 mg), which was used directly in the next step without purification.

[0724] MS m / z (ESI): 373.2 (M+1) + .

[0725] Preparation of (R)-1-(15-chloro-12-fluoro-3-oxo-2,3,6,9-tetrahydro-1H,5H- benzo[10,11][1]oxa[4]azacyclotetradecine[2,3,4-ij]quinolin-2-yl)urea (132)

[0726] Compound 132d (80 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (3 drops) and water (3 drops) were added, then potassium cyanate (23 mg, 0.29 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, after the reaction was completed, sodium bicarbonate solution was added to adjust the pH to weak alkaline, then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 20 mL / min) to obtain compound 132 (9.0 mg, yield: 11%).

[0727] MS m / z (ESI): 416.0 (M+1) + .

[0728] 1 H NMR (400 MHz, CD3OD) δ 7.39 - 7.13 (m, 3H), 6.74 (t, 1H), 6.16 (d, 1H), 5.94 - 5.93 (m, 1H), 5.51 - 5.49 (m, 1H), 4.30 (d, 1H), 4.11 (d, 1H), 3.97 - 3.54 (m, 1H), 3.20 (dd, 1H), 3.00 - 2.91 (m, 3H), 2.78 - 2.77 (m, 1H), 2.63 - 2.49 (m, 1H).

[0729] Example 27

[0730] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-7-(fluoromethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (253)

[0731]

[0732] Referring to the synthetic route of Example 17, the final product was purified using high performance liquid chromatography preparative (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 55%-95%, flow rate: 20 mL / min) to give compound 253 (4.5 mg, yield: 10.0%).

[0733] MS m / z (ESI): 428.1 (M+1) + .

[0734] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (dd, 1H), 7.46 - 7.39 (m, 2H), 6.97 - 6.95 (m, 1H), 6.42 (d, 1H), 6.35 (dd, 1H), 5.81 (s, 2H), 5.36 - 5.32 (m, 1H), 5.24 - 5.20 (m, 1H), 4.62 - 4.31 (m, 4H), 3.95 - 3.79 (m, 1H), 3.18 (dd, 1H), 2.78-2.72 (m, 1H).

[0735] Example 28

[0736] (R)-1-(11,14-difluoro-3-oxo-2,3,5,6-tetrahydro-1H- benzo[9,10][1,4]oxazocin[2,3,4-ij]quinolin-2-yl)urea (122)

[0737]

[0738] Referring to the synthetic route of Example 25, the final product was purified using high performance liquid chromatography preparative (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1 : water (with 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 10-100%, flow rate: 20 mL / min) to give compound 122 (20 mg, yield: 31%).

[0739] MS m / z (ESI): 486.1 (M+1) + .

[0740] 1 H NMR (400 MHz, DMSO-d6) d 7.37 - 7.25 (m, 2H), 7.26 - 7.13 (m, 1H), 7.01 - 6.87 (m, 1H), 6.53 (d, 1H), 6.47 - 6.35 (m, 1H), 6.33 (d, 1H), 6.18 - 5.94 (m, 1H), 5.78 (s, 2H), 4.36 - 4.18 (m, 1H), 3.19 - 3.00 (m, 2H), 2.91 - 2.65 (m, 2H), 2.11 - 1.89 (m, 1H), 1.84 - 1.65 (m, 1H).

[0741] Example 29

[0742] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)urea (234)

[0743]

[0744] Preparation of the first step 5-chloro-4-(2-chloro-5-fluorophenoxy)-3- nitropyridin-2-amine (234b)

[0745] Compound 234a (2 g, 9.62 mmol) was dissolved in acetonitrile (30 mL), 2-chloro-5-fluorophenol (2.82 g, 19.23 mmol) and potassium carbonate (3.99 g, 28.86 mmol) were added, and the reaction solution was stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 234b (2.5 g, yield: 82%).

[0746] MS m / z (ESI): 318.0 (M+1) + .

[0747] Preparation of 2-bromo-5-chloro-4-(2-chloro-5-fluorophenoxy)-3-nitropyridine (234c) in the second step

[0748] Cuprous bromide (879 mg, 6.13 mmol) was dissolved in acetonitrile (30 mL), and isopropyl nitrite (717 mg, 6.13 mmol) was added, and the reaction solution was stirred at 25 °C for 1 hour, and then compound 234b (1.5 g, 4.72 mmol) was added, and the reaction solution was stirred at 25 °C for 30 minutes, and then stirred at 70 °C for 2 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 234c (420 mg, yield: 23%).

[0749] MS m / z (ESI): 382.8 (M+1) + .

[0750] Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(5-chloro-4-(2-chloro-5-fluorophenoxy)-3-nitropyridin-2-yl)propanoate (234d) in the third step

[0751] To a reaction flask was added zinc dust (3 g), purged with nitrogen, and a needle tube was used to add N,N-dimethylformamide (8 mL) and stir at 40 °C for 15 min. To the system was added trimethylchlorosilane (55 mg, 0.51 mmol) and 1,2-dibromoethane (110 mg, 0.59 mmol) under nitrogen protection, and the reaction mixture was stirred at 40 °C for 15 min. To the reaction mixture was added a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (7.1 g, 21.57 mmol) in N,N-dimethylformamide (8 mL) under nitrogen protection, and stirred at 40 °C for 30 min. The reaction mixture was cooled to room temperature under nitrogen protection to obtain a zinc reagent solution for standby. Another flask was prepared to add a solution of compound 234c (200 mg, 0.52 mmol) in N,N-dimethylformamide (1 mL), and to the reaction mixture was added Pd(dppf)Cl2(38 mg, 0.05 mmol), cuprous iodide (10 mg, 0.05 mmol), and the prepared zinc reagent solution (supernatant) (0.8 mL) under nitrogen protection at room temperature, and the resulting reaction mixture was stirred at 80 °C for 4 h. After the reaction was completed, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was washed with an aqueous solution of ammonium chloride twice, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography system B to obtain compound 234d (200 mg, yield: 76%).

[0752] MS m / z (ESI): 448.0 (M-55) + .

[0753] Preparation of (R)-methyl 3-(3-amino-5-chloro-4-(2-chloro-5-fluorophenoxy)pyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (234e)

[0754] Compound 234d (200 mg, 0.40 mmol) was dissolved in a mixed solvent of ethanol and water (4 mL, V / V = 3:1), and iron powder (67 mg, 1.19 mmol) and ammonium chloride (64 mg, 1.19 mmol) were added. The reaction was stirred at 80 °C for 12 h. After the reaction was completed, the reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography system B gave compound 234e (170 mg, yield: 90%).

[0755] MS m / z (ESI): 474.0 (M+1) + .

[0756] Preparation of (R)-tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)carbamate (234f)

[0757] Compound 234e (170 mg, 0.36 mmol) was dissolved in dichloromethane (2 mL), trimethylaluminum (52 mg, 0.72 mmol) was added. The reaction was stirred at 25 °C for 1.5 h, after the reaction was completed, filtration was performed using celite, the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography system B to obtain compound 234f (120 mg, yield: 76%).

[0758] MS m / z (ESI): 386.0 (M-55) + .

[0759] Preparation of (R)-tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)carbamate (234g)

[0760] Compound 234f (120 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (112 mg, 0.81 mmol), iodomethane (114 mg, 0.81 mmol) was added. The reaction was stirred at 40 °C for 4 h, after the reaction was completed, the reaction solution was filtered, diluted with ethyl acetate, the organic phase was washed with aqueous ammonium chloride solution, and dried under suction to obtain a crude product, which was purified by silica gel column chromatography system B to obtain compound 234g (90 mg, yield: 73%).

[0761] MS m / z (ESI): 400.0 (M-55) + .

[0762] Preparation of (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (234h)

[0763] Compound 234g (60 mg, 0.13 mmol) was dissolved in dichloromethane (1 mL), hydrochloric acid dioxane solution (2 mL) was added. The reaction was stirred at room temperature for 1 h, after the reaction was completed, dried under suction to obtain compound 234h (40 mg, yield: 87%).

[0764] MS m / z (ESI): 356.0 (M+1) + .

[0765] Preparation of (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)urea (234)

[0766] Compound 234h (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.5 mL), H20 (0.5 mL), potassium cyanate (18 mg, 0.16 mmol), and stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated by evaporation to obtain a crude product, which was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2 x 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 compound 234 (30 mg, yield: 67%).

[0767] MS m / z (ESI): 399.0 (M+1) + .

[0768] 1 H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 7.56 (dd, 1H), 6.91-6.88 (m, 1H), 6.57 (dd, 1H), 4.56 (dd, 1H), 3.39-3.35 (m, 1H), 3.32 (s, 3H), 3.21-3.15 (m, 1H).

[0769] Example 30

[0770] (R)-1-(14-chloro-11-fluoro-3-oxo-2,3,5,6-tetrahydro-1H,8H- benzo[9,10][1,7,4]dioxazocin[2,3,4-ij]quinolin-2-yl)urea (242)

[0771]

[0772] First Step: Preparation of (R)-(7-chloro-8-(5-fluoro-2- (hydroxymethyl)phenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (242a)

[0773] Compound Int 5d (200 mg, 0.41 mmol) was dissolved in dioxane (8 mL), added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (48.5 mg, 0.061 mmol), tributylstannylmethanol (199 mg, 0.61 mmol), and the reaction was stirred at 80 °C for 16 h. The reaction was reduced to room temperature, concentrated and purified by silica gel column chromatography system A to give compound 242a (100 mg, yield 56%).

[0774] MS m / z (ESI): 381.1 (M-55) + .

[0775] Preparation of (R)-(14-chloro-11-fluoro-3-oxo-2,3,5,6-tetrahydro-1H,8H- benzo[9,10][1,7,4]dioxazocin[2,3,4-ij]quinolin-2-yl)carbamic acid tert-butyl ester (242b)

[0776] Compound 242a (100 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (5 mL), added dibromoethane (65 mg, 0.35 mmol) and cesium carbonate (112 mg, 0.35 mmol), and the reaction was stirred at 50 °C for 24 h. After the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (50 mL), filtered, the filtrate was diluted with water (20 mL) and further extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system A to give compound 242b (70 mg, yield 66%).

[0777] MS m / z (ESI): 407.1 (M-55) + .

[0778] Preparation of (R)-3-amino-7-chloro-1-(2-chloroethyl)-8-(5-fluoro-2- (hydroxymethyl)phenoxy)-3,4-dihydroquinolin-2(1H)-one (242c)

[0779] Compound 242b (70 mg, 0.65 mmol) was dissolved in dichloromethane (2 mL), added 4M hydrochloric acid / dioxane (2 mL), and the reaction was stirred at room temperature for 30 min. The reaction was concentrated under reduced pressure to give crude compound 242c (60 mg, yield: 100%), which was used directly in the next step.

[0780] MS m / z (ESI): 363.1 (M+1) + .

[0781] Step 4. Preparation of (R)-1-(14-chloro-11-fluoro-3-oxo-2,3,5,6-tetrahydro- 1H,8H-benzo[9,10][1,7,4]dioxazocin[2,3,4-ij]quinolin-2-yl)urea (242)

[0782] Compound 242c (35 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.05 mL) and water (0.05 mL) were added, and potassium cyanate (16 mg, 0.2 mmol) was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, sodium bicarbonate solution was added to adjust the pH to weak alkaline, and the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1 : water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 28%-95%, flow rate: 20 mL / min) to obtain compound 242 (3 mg, yield: 7.6%).

[0783] MS m / z (ESI): 406.0 (M+1) + .

[0784] 1 H NMR (400 MHz, CD3OD) δ 7.58 - 7.43 (m, 1H), 7.30-7.26 (m, 2H), 6.80-6.78 (m, 1H), 6.01 (d, 1H), 4.77-4.75 (m, 2H), 4.35-4.29 (m, 2H), 3.94-3.93 (m, 1H), 3.69-3.67 (m, 1H), 3.55-3.48 (m, 1H), 3.17-3.15 (m, 1H), 2.93 (t, 1H).

[0785] Example 31

[0786] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-6-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea (255)

[0787]

[0788] The final product was purified by preparative high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1 : water (with 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 55-95%, flow rate: 20 mL / min) to give compound 255 (15.5 mg, yield: 19%).

[0789] MS m / z (ESI): 444.1 (M+1) + .

[0790] 1H NMR (400 MHz, DMSO-d6) d 7.65 (dd, 1H), 7.37 (s, 1H), 6.98 (td, 1H), 6.50 (dd, 1H), 6.41 (d, 1H), 5.80 (s, 2H), 4.49 - 4.37 (m, 3H), 4.01 - 3.89 (m, 1H), 3.12 (dd, 1H), 2.74 (t, 2H), 2.35 (s, 3H).

[0791] Example 32

[0792] Compound 268A, Compound 268B

[0793]

[0794] First Step Preparation of compound 268b

[0795] To 1-chloro-4-fluoro-2-iodobenzene (6.67 g, 0.026 mol) in tetrahydrofuran (15 mL) was added i-PrMgCl.LiCl (0.05 L, 1.3 M, 0.065 mol) at 0 °C under nitrogen protection and stirred for 1 hour, then 3-bromo-2-nitrobenzaldehyde (compound 268a, 3 g, 0.013 mol) was added and reacted at room temperature for 15 hours. After the reaction was completed, the reaction was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by silica gel column chromatography system B to give compound 268b (1.6 g).

[0796] MS m / z (ESI): 358.9 (M+1) + .

[0797] Second Step Preparation of compound 268c

[0798] Compound 268b (900 mg, 2.5 mmol) was dissolved in a mixed solvent of methanol and water (15 mL, V / V = 3:1), iron powder (698 mg, 12.5 mmol), ammonium chloride (668 mg, 12.5 mmol) were added. The reaction was stirred at 70 °C for 1 hour. After the reaction was completed, diatomite was used for filtration, and the filtrate was concentrated under reduced pressure to obtain compound 268c (480 mg, yield: 48%).

[0799] MS m / z (ESI): 329.9 (M+1) + .

[0800] Third Step Preparation of compound 268d

[0801] Compound 268c (600 mg, 1.82 mmol) was dissolved in dichloromethane (20 mL), and manganese dioxide (790 mg, 9.08 mmol) was added. The reaction was stirred at 25 °C for 1 hour. After the reaction was completed, diatomite was used for filtration, and the filtrate was concentrated to obtain compound 268d (500 mg). The product was used directly in the next reaction without purification.

[0802] MS m / z (ESI): 328.0 (M+1) + .

[0803] Fourth Step Preparation of compound 268e

[0804] NaH (73 mg, 60%, 3.05 mmol) was added to a solution of compound 268d (500 mg, 1.52 mmol) and iodomethane (260 mg, 1.83 mmol) in DMF (10 mL) under ice bath, and the reaction was carried out at this temperature for 2 hours. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 268e (300 mg, yield: 40%).

[0805] MS m / z (ESI): 342.0 (M+1) + .

[0806] Fifth Step Preparation of compound 268f

[0807] To a solution of compound 268e (300 mg, 0.876 mmol) in N,N- dimethylformamide (10 mL) under nitrogen at room temperature, Pd(dppf)Cl2(128 mg, 0.18 mmol), cuprous iodide (33 mg, 0.18 mmol) were added, and then a solution of methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3- propanoate iodide (691 mg, 1.75 mmol) in N,N-dimethylformamide was added under nitrogen. The reaction mixture was stirred at 75 °C for 10 h under nitrogen. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography system B to give compound 268f (200 mg, yield: 35%).

[0808] MS m / z (ESI): 465.1 (M+1) + .

[0809] Sixth step Preparation of compound 268g

[0810] Compound 268f (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 mixture was stirred at 0 °C for 1 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by column chromatography system B to give compound 268g (70 mg, yield: 60%).

[0811] MS m / z (ESI): 377.0 (M-56) + .

[0812] Seventh step Preparation of compound 268h

[0813] Compound 268g (1 g, 2.39 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen at 0 °C. The reaction mixture was cooled to 0 °C. Methyl lithium (1.6 M, 3 mL, 4.77 mmol) was added slowly dropwise over 5 min. The mixture was allowed to warm to room temperature and stirred for two hours. The reaction mixture was poured slowly into ice water and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL) and the organic phase was dried to give the crude product. The crude product was purified by flash column chromatography system B to give compound 268h (300 mg, yield: 29%).

[0814] MS m / z (ESI): 379.0 (M-56+1) + .

[0815] Eighth step Preparation of compound 268i

[0816] Compound 268h (300 mg, 0.69 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at 120 °C for 1 h. After concentration, the crude 268i (180 mg) was obtained. The product was used in the next step without purification.

[0817] MS m / z (ESI): 317.0 (M+1) + .

[0818] Ninth step Preparation of compound 268j

[0819] Compound 268i (180 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL), di-tert-butyl dicarbonate (248 mg, 1.14 mmol), triethylamine (173 mg, 1.71 mmol) were added. The reaction was stirred at 25 °C for half an hour. After the reaction was completed, it was concentrated under reduced pressure and purified by silica gel column chromatography system B to obtain compound 268j (220 mg, yield: 93%).

[0820] MS m / z (ESI): 361.0 (M-56+1) + .

[0821] Tenth step Preparation of compound 268k

[0822] Compound 268j (220 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 mL), 1-bromo-2-fluoroethane (201 mg, 1.58 mmol), cesium carbonate (514 mg, 1.58 mmol) were added. The reaction was stirred at 60 °C for 4 h. After the reaction was completed, the organic phase was dried by rotary evaporation to obtain the crude product, which was purified by flash chromatography system B to obtain compound 268k (200 mg, yield: 82%).

[0823] MS m / z (ESI): 363.0 (M-Boc+1) + .

[0824] Eleventh step Preparation of compound 268l

[0825] Compound 268k (200 mg, 0.43 mmol) was dissolved in methanol (5 mL), Pd / C (10%, 20 mg), 1,2-dichlorobenzene (0.5 mL) were added. Hydrogen was replaced and the reaction was stirred at 25 °C for 4 h. After the reaction was completed, the filter was concentrated under reduced pressure using diatomite to obtain compound 268l (180 mg, yield: 90%).

[0826] MS m / z (ESI): 365.0 (M-Boc+1) + .

[0827] Twelfth Step Preparation of compound 268m

[0828] Compound 2681 (180 mg, 0.39 mmol) was dissolved in a solution of hydrochloric acid in dioxane (2 mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated by rotary evaporation to give compound 268m (100 mg, yield: 71%).

[0829] MS m / z (ESI): 365.0 (M+1) + .

[0830] Thirteenth Step Preparation of compound 268, 268A, 268B

[0831] Compound 268m (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (2 drops), H20 (2 drops), potassium cyanate (67 mg, 0.81 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated by evaporation to give a crude product, which was 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 give compound 268 (6 mg). SFC (SFC 80, column: Daicel CHIRALCEL IG, 250 mm x 30 mm I.D., 10 μm, mobile phase: CO2 / MeOH [0.2% NH3(7M MeOH solution)] = 50 / 50, flow rate: 80 g / min) was used to separate 268A (front peak, 4 mg, RT = 1.372 min) and 268B (rear peak, 1 mg, RT = 2.106 min).

[0832] 268A:

[0833] MS m / z (ESI): 408.0 (M+1) + .

[0834] 1H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.41 (m, 1 H), 7.36 - 7.32 (m, 1 H), 7.18 - 7.14 (m, 1 H), 7.12 - 7.01 (m, 3 H), 6.43 (d, 1 H), 5.80 (s, 2 H), 4.74 - 4.54 (m, 2 H), 4.48 - 4.30 (m, 2 H), 3.99 - 3.90 (m, 1 H), 3.81 - 3.68 (m, 1 H), 2.91 - 2.86 (m, 1 H), 2.67 - 2.61 (m, 1 H), 1.68 (d, 3 H).

[0835] 268B:

[0836] MS m / z (ESI): 408.0 (M+1) + .

[0837] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.44 (m, 1 H), 7.38 - 7.35 (m, 1 H), 7.22 - 7.16 (m, 2 H), 7.12 - 7.07 (m, 2 H), 6.45 (d, 1 H), 5.82 (s, 2 H), 4.75 - 4.58 (m, 2 H), 4.50 - 4.35 (m, 2 H), 4.02 - 3.93 (m, 1 H), 3.84 - 3.69 (m, 1 H), 2.94 - 2.89 (m, 1 H), 2.69 - 2.65 (m, 1 H), 1.71 (d, 3 H).

[0838] Example 33

[0839] (R)-1-(2,2-difluoropropyl)-7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl urea (280)

[0840]

[0841] Using the same synthetic route as Example 6, the final product was purified by high performance liquid chromatography preparative (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10μm; mobile phase 1 : water (with 0.1% FA); mobile phase 2: acetonitrile; 10 min gradient, gradient ratio: acetonitrile phase 35%-65%, flow rate: 30 mL / min) to give compound 280 (52 mg).

[0842] MS m / z (ESI): 462.1 (M+1) + .

[0843] 1 H NMR (400 MHz, DMSO-d6) δ 7.71-7.63 (m, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.04-6.97 (m, 1H), 6.57-6.52 (m, 1H), 6.49 (d, 1H), 5.81 (s, 2H), 4.93-4.75 (m, 1H), 4.58-4.48 (m, 1H), 4.38-4.24 (m, 1H), 3.23-3.13 (m, 1H), 2.77 (t, 1H), 1.56 (t, 3H).

[0844] Example 34

[0845] (R)-1-(7-chloro-8-(2-chloro-4,5-difluorophenoxy)-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (294)

[0846]

[0847] Preparation of compound 294a in the first step

[0848] Compound Int 2c (150 mg, 0.59 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-chloro-4,5-difluorophenol (102 mg, 0.62 mmol) was added. After the reaction was stirred at 100 °C for 6 hours, TLC monitoring showed that the reaction was complete, and after cooling, water (15 mL) was added, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered and rotary evaporated to dryness to obtain the crude compound 294a (220 mg), which was used directly in the next step without purification.

[0849] MS m / z (ESI): 397.9 (M+1) + .

[0850] Preparation of compound 294b in the second step

[0851] Compound 294a (220 mg, 0.55 mmol) was dissolved in methanol: tetrahydrofuran: water = 5:2:1 (8 mL), and iron powder (308 mg, 5.5 mmol) and ammonium chloride (297 mg, 5.5 mmol) were added, and the solution was stirred at 75 °C for 1 hour. After LC-MS monitoring showed that the reaction was complete, it was filtered, concentrated and purified by column chromatography in system B to obtain compound 294b (200 mg, yield: 98%).

[0852] MS m / z (ESI): 368.1 (M+1) + .

[0853] Preparation of compound 294c in the third step

[0854] Compound 294b (200 mg, 0.54 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (78 mg, 0.16 mmol), palladium acetate (18 mg, 0.08 mmol) and (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc (II) (1 mL, 1.1 mmol) were added, the solution was stirred at 80 °C for 5 hours under nitrogen protection, after the reaction was completed by LC-MS monitoring, filtered, water (15 mL) was added, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography with system B to obtain compound 294c (200 mg, yield: 80%).

[0855] MS m / z (ESI): 403.1 (M+1-56) + .

[0856] Preparation of compound 294d in the fourth step

[0857] Compound 294c (200 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (2 mL), cesium carbonate (430 mg, 1.32 mmol) and 1-bromo-2-fluoroethane (83 mg, 0.66 mmol) were added, the solution was stirred at 50 °C for 1 hour, after the reaction was completed by LC-MS monitoring, filtered, water (15 mL) was added, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography with system B to obtain compound 294d (160 mg, yield: 73%).

[0858] MS m / z (ESI): 449.1 (M+1-56) + .

[0859] Preparation of compound 294e in the fifth step

[0860] Compound 294d (160 mg, 0.32 mmol) was dissolved in 4 mol / L hydrogen chloride / 1,4-dioxane solution (5 mL), the solution was stirred at room temperature for 1 hour, after the reaction was completed by LC-MS monitoring, directly concentrated to obtain the crude compound 294e (125 mg), the product was used directly in the next step reaction without purification.

[0861] MS m / z (ESI): 405.1 (M+1) + .

[0862] Preparation of compound 294 in the sixth step

[0863] Compound 294e (125 mg, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.2 mL) and water (0.2 mL) were added, then potassium cyanate (50 mg, 0.62 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, after LC-MS monitoring reaction was completed, sodium bicarbonate solution was added to adjust the pH to weak alkaline, extracted with ethyl acetate, the organic phase was collected and concentrated to obtain the crude product, the crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 60%-100%, flow rate: 20 mL / min) to obtain compound 294 (52 mg, yield: 38%).

[0864] MS m / z (ESI): 448.1 (M+1) + .

[0865] 1 H NMR (400 MHz, CD3OD) δ 7.57 (dd, 1H), 7.38 (d, 1H), 7.29 (d, 1H), 6.47 (dd, 1H), 4.57-4.50 (m, 2H), 4.47-4.36 (m, 2H), 4.16-4.05 (m, 1H), 3.19 (dd, 1H), 2.85 (d, 1H).

[0866] Example 35

[0867] (R)-1-(8-(2-chloro-4,5-difluorophenoxy)-7-(difluoromethyl)-1-(2-fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (300)

[0868]

[0869] Using the synthetic route of Example 17, the end product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2 x 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 compound 300 (20 mg).

[0870] MS m / z (ESI): 464.0 (M+1)+ .

[0871] 1 H NMR (400 MHz, CD3OD) δ 7.63-7.51 (m, 2H), 7.46 (d, 1H), 6.84 (t, 1H), 6.47-6.36 (m, 1H), 4.61-4.34 (m, 4H), 4.03-3.89 (m, 1H), 3.29-3.23 (m, 1H), 2.92 (t, 1H).

[0872] Example 36

[0873] (R)-1-(7-chloro-8-(2,4-dichloro-5-fluorophenoxy)-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (297)

[0874]

[0875] Preparation of compound 297b in the first step

[0876] Compound 297a (2 g, 8.2 mmol) was dissolved in N,N-dimethylformamide (20 mL) and water (0.7 ml), and [2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2',4',6'- triisopropylbiphenyl]palladium(II)(2'-amino-2-biphenyl) (70 mg, 0.08 mmol) was added, and the reaction solution was stirred at 85°C under nitrogen protection for 12 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL x 3), and the aqueous phase was collected and adjusted to weakly acidic pH with 4 mol / L dilute hydrochloric acid, and extracted again with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 297b (0.2 g, yield: 12%).

[0877] 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65 (d, 1H), 6.96 (d, 1H).

[0878] Preparation of compound 297c in the second step

[0879] Compound 297b (0.85 g, 4.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), 1-bromo-4-chloro-3-fluoro-2-nitrobenzene (1 g, 3.9 mmol) and potassium carbonate (1.62 g, 11.7 mmol) were added, and the reaction was stirred at 100 °C for 12 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL x 3), and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography system B to obtain compound 297c (900 mg, yield: 48.7%).

[0880] 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, 1H), 7.52-7.49 (m, 2H), 6.51 (d, 1H).

[0881] Preparation of compound 297d in the third step

[0882] Compound 297c (900 mg, 2.17 mmol) was dissolved in a mixed solvent of methanol / water (V / V = 5:1, 12 mL), iron powder (605 mg, 10.8 mmol) and ammonium chloride (579 mg, 10.8 mmol) were added. The reaction was stirred at 75 °C for 5 hours, after the reaction was completed, the filter was performed using diatomite, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography system B to obtain compound 297d (800 mg, yield: 86.2%).

[0883] MS m / z (ESI): 383.8 (M+1) + .

[0884] Preparation of compound 297e in the fourth step

[0885] Compound 297d (500 mg, 1.29 mmol) was dissolved in N,N-dimethylformamide (5 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (185 mg, 0.39 mmol) and palladium acetate (58.77 mg, 0.26 mmol) were added to the reaction mixture, and finally (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc iodide (II) (2.5 mL, 2.59 mmol, N,N-dimethylformamide solution) was added under nitrogen protection, and the reaction was stirred at 80 °C for 16 hours. After the reaction was completed, it was quenched with water, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, and the crude product was separated and purified by column chromatography system B to obtain compound 297e (500 mg, yield: 72.9%).

[0886] MS m / z (ESI): 418.9 (M+1-56)+ .

[0887] Preparation of compound 297f in the fifth step

[0888] Compound 297g (80 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (69.7 mg, 0.50 mmol) was added, and the reaction was stirred at 50 °C for 5 hours. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography on silica gel (eluent: 0% to 20% petroleum ether / ethyl acetate) gave compound 297f (50 mg, yield: 45.6%).

[0889] MS m / z (ESI): 421.0 (M+1-100) + .

[0890] Preparation of compound 297g in the sixth step

[0891] Compound 297f (50 mg, 0.096 mmol) was dissolved in 4 mol / L hydrogen chloride / 1,4-dioxane (2 mL), and the solution was stirred at room temperature for 0.5 hours. After the reaction was completed as monitored by LC-MS, the crude product 297g (20 mg) was directly concentrated. The crude product was used directly in the next step without purification.

[0892] MS m / z (ESI): 421.0 (M+1) + .

[0893] Preparation of compound 297 in the seventh step

[0894] Compound 297g (20 mg, 0.047 mmol) was dissolved in tetrahydrofuran (2 mL), and acetic acid (0.2 mL) and water (0.2 mL) were added. Then, potassium cyanate (7.68 mg, 0.09 mmol) was added, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weak alkalinity, and ethyl acetate was added for extraction. The organic phase was collected, and the mixture was concentrated to give the crude product. Purification by high-performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: WELCH Xtimate C18 21.2*250mm 10μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 49% to 100%, flow rate: 25 mL / min) gave compound 297 (1 mg, yield: 4.2%).

[0895] MS m / z (ESI): 464.0 (M+1) + .

[0896] 1 H NMR (400 MHz, CD3OD) δ 7.71 (d, 1H), 7.39 (d, 1H), 7.31 (d, 1H), 6.44 (d, 1H), 4.62 - 4.39 (m, 4H), 4.16 - 4.05 (m, 1H), 3.13-3.18 (m, 1H), 2.92-2.85 (m, 1H).

[0897] Example 37

[0898] (R,Z)-1-(14-chloro-10,11-difluoro-3-oxo-2,3,5,6-tetrahydro-1H- benzo[9,10][1,4]oxazocin-2-yl)urea (328)

[0899]

[0900] Preparation of compound 328b in the first step

[0901] Compound Int 2c (1.4 g, 5.5 mmol) was dissolved in N,N-dimethylformamide (20 mL), 2-bromo-4,5-difluorophenol (1.36 g, 6.6 mmol) was slowly added at room temperature, and the reaction was stirred at 100 °C for 4 hours. After the reaction was completed, ethyl acetate and water were added to extract, the organic phase was collected, dried, concentrated under reduced pressure, and purified by column chromatography on silica gel with system B to obtain compound 328b (1.2 g, yield: 50.0%).

[0902] 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (dd, 1H), 7.92 (q, 2H), 7.32 (dd, 1H).

[0903] Preparation of compound 328c in the second step

[0904] Compound 328b (1.2 g, 2.7 mmol) was dissolved in N,N-dimethylformamide (12 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (160 mg, 0.54 mmol) and cuprous iodide (102 mg, 0.54 mmol) were added to the reaction mixture, and finally (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(ll) iodide (5.4 mL, 5.4 mmol, N,N-dimethylformamide solution) was added under nitrogen protection. After the reaction was stirred at 80°C for 6 hours. After the reaction was completed, it was quenched with water, extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography using system B to obtain compound 328c (1.0 g, yield: 68.9%).

[0905] MS m / z (ESI): 464.9 (M-100+1) + .

[0906] Preparation of compound 328d in the third step

[0907] Compound 328c (1.0 g, 1.7 mmol) was dissolved in a mixed solvent of methanol / water (20 mL / 4 mL), and zinc powder (571 mg, 10.2 mmol) and ammonium chloride (550 mg, 10.2 mmol) were added. The reaction was stirred at 75°C for 2 hours, and after the reaction was completed, it was filtered using diatomite, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography using system B to obtain compound 328d (800 mg, yield: 88%).

[0908] MS m / z (ESI): 535.1 (M+1) + .

[0909] Preparation of compound 328e in the fourth step

[0910] Compound 328d (800 mg, 1.5 mmol) was dissolved in dichloromethane (20 mL), and trimethylaluminum (1.15 mL, 2M, 2.3 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was diluted with methanol and dried by rotary evaporation to obtain a crude product, which was purified by column chromatography using system B to obtain compound 328e (550 mg, yield: 73%).

[0911] MS m / z (ESI): 503.1 (M+1) + .

[0912] Preparation of compound 328f in the fifth step

[0913] Compound 328e (200 mg, 0.397 mmol) was dissolved in N,N-dimethylformamide (5 mL), compound 4-bromo-1-butene (80 mg, 0.595 mmol) and cesium carbonate (259 mg, 0.794 mmol) were added, after the reaction was stirred at 50 °C for 16 hours, LC-MS monitoring reaction was complete, quenched with water, extracted with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography in system B to obtain compound 328f (200 mg, yield: 80%).

[0914] MS m / z (ESI): 501.7 (M+1-56) + .

[0915] Preparation of compound 328g in the sixth step

[0916] Compound 328f (200 mg, 0.359 mmol) was dissolved in dioxane (10 mL) and water (1 mL), vinylboronic acid pinacol ester (58 mg, 0.38 mmol), potassium carbonate (99 mg, 0.717 mmol) and dichlorobis-(4-dimethylamino phenyl) palladium (II) (13 mg, 0.018 mmol) were added, after the reaction was stirred at 90 °C for 3 hours, LC-MS monitoring reaction was complete. The reaction was rotary dried, the crude product was purified by column chromatography in system B to obtain compound 328g (150 mg, yield: 82%).

[0917] MS m / z (ESI): 449.1 (M+1-56) + .

[0918] Preparation of compound 328h in the seventh step

[0919] Compound 328g (40 mg, 0.079 mmol) was dissolved in 1,2-dichloroethane (40 mL), Grubbs second-generation catalyst (40 mg, 0.047 mmol) was added, the solution was stirred at 60 °C under nitrogen protection for 16 hours, after LC-MS monitoring reaction was complete, it was directly concentrated and purified by column chromatography in system B to obtain compound 328h (20 mg, yield: 53%).

[0920] MS m / z (ESI): 421.0 (M+1-56) + .

[0921] Preparation of compound 328i in the eighth step

[0922] Compound 328h (20 mg, 0.042 mmol) was dissolved in 4M hydrochloric acid / 1,4-dioxane (2 mL), the solution was stirred at room temperature for 1 hour, after LC-MS monitoring the reaction was complete, the solution was directly concentrated to give crude 328i (20 mg), which was used directly in the next step.

[0923] MS m / z (ESI): 377.1 (M+1) + .

[0924] Preparation of compound 328

[0925] Compound 328i (20 mg, 0.042 mmol) was dissolved in tetrahydrofuran (3 mL), acetic acid (0.1 mL) and water (0.1 mL) were added, then potassium cyanate (6 mg, 0.063 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, after LC-MS monitoring the reaction was complete, sodium bicarbonate solution was added to adjust the pH to weak alkaline, ethyl acetate was extracted, the organic phase was collected, the mixture was concentrated to give crude product, which was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: XBridge Prep C18 19*150mm 5μm; mobile phase 1: water (containing 0.1% ammonium bicarbonate); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 40%-95%, flow rate: 15 mL / min) to give compound 328 (5 mg, yield: 25%).

[0926] MS m / z (ESI): 420.0 (M+1) + .

[0927] 1 H NMR (400 MHz, DMSO-d6) δ 7.52-7.12 (m, 3H), 6.51-6.32 (m, 3H), 6.16-6.08 (m, 1H), 5.79 (s, 2H), 4.50-4.16 (m, 2H), 3.10-3.07 (m, 2H), 2.93-2.63 (m, 2H), 1.80-1.60 (m, 1H).

[0928] Using similar synthetic routes, the following compounds were synthesized, and the characterization data are shown in the following table:

[0929]

[0930]

[0931]

[0932] Example 38

[0933] (R,Z)-l-(10,14-dichloro-l l-fluoro-3-oxo-2,3,5,6-tetrahydro-lH- benzo[9,10][l,4]oxazocin-2-yl)urea (329)

[0934]

[0935] The end product was purified by preparative high performance liquid chromatography (Waters Prep-LC with 2489 Detector, column: Waters Xbridge C18 5 μm 19*150 mm; mobile phase 1 : water (with 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 5%-95%, flow rate: 15 mL / min) using a similar protocol to Example 37 to give compound 329 (25 mg, yield: 32%).

[0936] MS m / z (ESI): 436.1 (M+1) + .

[0937] 1 H NMR (400 MHz, CD3OD) δ 7.34 (dd, 2H), 7.27 (d, 1H), 6.53 (d, 1H), 6.37 (d, 1H), 6.15 (td, 1H), 4.51 (s, 1H), 4.35 (dd, 1H), 3.27 (dd, 1H), 3.20 (dd, 1H), 2.90 (t, 2H), 1.83 (s, 1H).

[0938] Example 39

[0939] (R,Z)-l-(10,11,14-trifluoro-3-oxo-2,3,5,6-tetrahydro-lH- benzo[9,10][l,4]oxazocin-2-yl)urea (339)

[0940]

[0941] The end product was purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: WELCH ultimate C18 21.2*250mm 10μm; mobile phase 1: water (containing 0.1% ammonium bicarbonate); mobile phase 2: acetonitrile; 15 minutes gradient, gradient ratio: acetonitrile phase 50%-100%, flow rate: 25 mL / min) to obtain compound 339 (5 mg, yield: 21%) in a similar contract route as Example 37.

[0942] MS m / z (ESI): 404.1 (M+1) + .

[0943] Example 40

[0944] (R)-1-(7-chloro-8-(2-chloro-4,5-difluorophenoxy)-1-(2-hydroxyethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (344)

[0945]

[0946] First Step Preparation of compound 344a

[0947] Compound 294c (300 mg, 0.66 mmol) was dissolved in N,N-dimethylformamide (5 mL), and compound tert-butyl-(2-iodoethoxy)dimethylsilane (243 mg, 0.85 mmol) was added at room temperature. The reaction was stirred at 50°C for 2 hours. After the reaction was completed, ethyl acetate and water were added for extraction, and the organic phase was collected, dried, concentrated under reduced pressure, and purified by flash silica gel column chromatography in system B to obtain compound 344a (300 mg, yield: 74.4%).

[0948] MS m / z (ESI): 561.1 (M-56+1).

[0949] Second Step Preparation of compound 344b

[0950] Compound 344a (300 mg, 0.49 mmol) was dissolved in dichloromethane (6 mL), and a solution of trifluoroacetic acid (2 mL) was added and stirred at room temperature for 1 hour. After the reaction was completed as monitored by LC-MS, it was directly concentrated to obtain a crude product, which was compound 344b (200 mg). The crude product was directly used in the next step reaction.

[0951] MS m / z (ESI): 403.1 (M+1).

[0952] Third Step Preparation of compound 344

[0953] Compound 344b (200 mg, 0.49 mmol) was dissolved in tetrahydrofuran (1.5 mL), acetic acid (0.5 mL) and water (0.5 mL) were added, then potassium cyanate (80 mg, 0.99 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, after the reaction was completed by LC-MS monitoring, sodium bicarbonate solution was added to adjust the pH to weak alkaline, ethyl acetate was extracted, the organic phase was collected, the mixture was concentrated to obtain the crude product, the crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: XBridge Prep C18 19*150mm 5μm; mobile phase 1: water (containing 0.1% ammonium bicarbonate); mobile phase 2: acetonitrile; 15 minute gradient, gradient ratio: acetonitrile phase 40%-95%, flow rate: 15 mL / min) to obtain compound 344 (96 mg, yield: 43.4%).

[0954] MS m / z (ESI): 446.1 (M+1).

[0955] 1 H NMR (400 MHz, CD3OD) δ 7.56 (dd, 1H), 7.36 (d, 1H), 7.28 (dd, 1H), 6.43 (dd, 1H), 4.43-4.33 (m, 2H), 3.90 (dt, 1H), 3.69 (dt, 1H), 3.59-3.53 (m, 1H), 3.17 (dd, 1H), 2.99-2.85 (m, 1H).

[0956] Using a similar synthetic route to Example 40, the following compounds were obtained

[0957]

[0958] Example 41

[0959] (R)-1-(7-chloro-8-(2-chloro-5-fluoro-4-(prop-1-yn-1-yl)phenoxy)-1-(2- fluoroethyl)-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)urea (343)

[0960]

[0961] First Step Preparation of Compound 343a

[0962] Compound INT 7 (synthesized using a similar synthetic route as for intermediate 234f in example 29) (150 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (3 mL), cesium carbonate (229 mg, 0.7 mmol) and 1-iodo-2-fluoroethane (97 mg, 0.56 mmol) were added. The reaction was stirred at 40 °C for 2 hours. After completion of the reaction, the reaction mixture was filtered, diluted with ethyl acetate and the organic phase was washed with aqueous ammonium chloride solution. The crude was obtained after drying and purified by silica gel column chromatography system B to yield compound 343a (90 mg, yield: 56%).

[0963] MS m / z (ESI): 466.0 (M-100) + .

[0964] Second step: Preparation of compound 343b

[0965] Compound 343a (90 mg, 0.16 mmol) was dissolved in dioxane (3 mL), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (23 mg, 0.032 mmol) and tributylstannylpropyne (55 mg, 0.48 mmol) were added to the reaction mixture. The reaction was stirred at 90 °C for 12 hours under nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, diluted with ethyl acetate and the organic phase was washed with aqueous ammonium chloride solution. The crude was obtained after drying and purified by silica gel column chromatography system B to yield compound 343b (80 mg, yield: 95%).

[0966] MS m / z (ESI): 470.1 (M-56+1) + .

[0967] Third step: Preparation of compound 343c

[0968] Compound 343b (80 mg, 0.17 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (2 mL) and the solution was stirred at room temperature for 1 hour. After completion of the reaction, the crude compound 343c (60 mg) was obtained directly by concentration. The product was used directly in the next reaction without purification.

[0969] MS m / z (ESI): 370 (M+1) + .

[0970] Fourth step: Preparation of compound 343

[0971] Compound 343c (60 mg, 0.16 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.1 mL) and water (0.1 mL) were added, then potassium cyanate (25.6 mg, 0.32 mmol) was added, the reaction was stirred at room temperature for 0.5 hours, after the reaction was monitored by LC-MS to be completed, sodium bicarbonate solution was added to adjust the pH to weak alkaline, then the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 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 343 (17 mg, yield: 23%).

[0972] MS m / z (ESI): 469.1 (M+1) + .

[0973] 1 H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 7.58 (d, 1H), 6.63 (d, 1H), 4.69-4.38 (m, 4H), 4.22-3.99 (m, 1H), 3.37 (dd, 1H), 3.22-3.06 (m, 1H), 2.05 (s, 3H).

[0974] Biological evaluation

[0975] Test Example 1 TSHR inhibitory activity screening (cAMP) experiment

[0976] Purpose of the experiment: This experiment is to test the inhibitory effect of the compound on TSH receptor, according to IC 50 Size evaluation of in vitro activity of the compound.

[0977] Experimental materials and reagents:

[0978]

[0979]

[0980] Experimental procedure

[0981] 1. Compound preparation

[0982] (1) Compound sample was dissolved in DMSO to a storage concentration of 10 mM;

[0983] (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.

[0984] (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.

[0985] (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.

[0986] (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.

[0987] (3) Use an Echo machine to transfer the sample dilution sequence to the experimental plate (Corning-3824), with 50 nL transferred per well.

[0988] 2. cAMP experimental method

[0989] (1) Prepare the reagents required for the experiment

[0990] (i) Experimental buffer (1×Stimulation buffer): Equilibrate the 5x Stimulation buffer from the kit to room temperature.

[0991] Dilute with ultrapure water at a ratio of 1:4, and add IBMX to a final concentration of 500μM before use.

[0992] (ii) 2X stimulator buffer: 40 ng / mL FSH protein or 0.3 nM Anti-TSHR Antibody + 500 uM IBMX dissolved in experimental buffer;

[0993] (iii) Detection reagents: Equilibrate the Lysis & detection buffer in the kit to room temperature, and dilute cAMP-d2 and Anti-cAMP cryptate at a ratio of 1:20 for later use.

[0994] (2) Prepare cell suspension

[0995] (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.

[0996] (ii) Centrifuge at 1000 rpm for 5 minutes, then discard the supernatant.

[0997] (iii) Resuspend the cells with 1x Stimulation buffer, count on Countess II FL Cell Counter, adjust the cell density to 1.0 x 10 6 / mL.

[0998] (3) cAMP HTRF assay

[0999] (i) Add the cell suspension to the assay plate containing the compounds using Multidrop combi, 5 μL / well.

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

[1001] (iii) Add 2X Stimulation Buffer to each well of the assay plate, 5 μL / well.

[1002] (iv) Centrifuge at 1000 rpm for 30 seconds, then incubate at 37 °C for 30 minutes.

[1003] (v) Add the above diluted cAMP-d2 and Anti-cAMP cryptate detection reagents to each well of the assay plate in sequence, 5 μL / well.

[1004] First add 5 μL cAMP-d2 reagent, then add 5 μL Cryptate reagent.

[1005] (vi) After the assay plate is incubated at room temperature for 60 minutes, read on Envision.

[1006] (4) Experimental data processing method

[1007] The experimental data is fitted to the percentage activation rate and 11-point concentration data to the parameter nonlinear logistic formula using XLFit to calculate the IC 50 value of the compound. Details are as follows:

[1008] (i) Calculate the inhibition effect value of each well on the assay plate according to the following formula:

[1009] % Effect = 100 x (value-ZPE) / (HPE-ZPE)

[1010] Wherein, % Effect is the inhibition effect value of the corresponding experimental well, value is the signal value of the experimental well, ZPE is the signal average of the negative control experimental well, and HPE is the signal average of the positive control experimental well.

[1011] (ii) After the inhibition effect value of different concentration test points of the compound sample, the XLFit four-parameter model is used to fit the action curve of the compound sample, and the IC 50 value is calculated.

[1012] Experimental results:

[1013] The IC 50 of TSHR antagonists is detected by CHO-K1 / TSH cells.

[1014] Table 1 Test results of test compounds

[1015]

[1016]

[1017] Conclusion: The compound of the present application has significant inhibitory activity on the release of cAMP of CHO-K1 / TSH cells.

[1018] Experimental purpose: This experiment is to test the inhibitory effect of the compound on the FSH receptor, and to evaluate the in vitro activity of the compound according to the IC 50 size.

[1019] The experimental method is the same as that of test example one.

[1020] Experimental results:

[1021] The IC 50 of FSHR is detected by CHO-K1 / FSH cells.

[1022] Table 2 Test results of test compounds

[1023] Compound IC 50 (nM) Compound 003 13299 Compound 007 6055 Compound 009 10135 Compound 010 2752 Compound 012 2507 Compound 036 10586 Compound 121 13077 Compound 123 16270 Compound 127 27005 Compound 132 26552 Compound 169 3332 Compound 255 16477 Compound 268A 10816 Compound 294 12689 Compound 300 2945 Compound 297 11506 Compound 328 19405 Compound 329 6811 Compound 343 2952 Compound 364 3400 Tool Compound 1879

[1024] Conclusion: The compound of the present application has no significant inhibitory activity on the release of cAMP of CHO-K1 / FSH cells, and has good selectivity.

[1025] Test example three: LHCGR inhibitory activity (cAMP) experiment

[1026] 1. Experimental materials

[1027] cAMP Detection Kit (Revvity)

[1028] 384-well assay plate (Revvity)

[1029] Vi-cell counter (Beckman)

[1030] ECHO (Labcyte)

[1031] Envision (PerkinElmer)

[1032] 2. Experimental procedure (1) Dilute the test compound by 3-fold 10-point gradient by Echo, and transfer 50 nL to compound plate, double duplicate wells. Transfer 50 nL highest concentration point of antagonist reference compound as Low control, transfer 50 nL DMSO as High control. Transfer 50 nL EC80 to compound plate by Echo per well, final concentration is 0.08 nM.

[1033] 2) Resuspend LHCGR cells with buffer to 0.1 x 10 6 / mL, add 10 pL cell suspension to compound plate, centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 60 min.

[1034] 4) cAMP standard curve preparation: prepare 800 nM starting, 4-fold dilution of 10 points of cAMP standard, add to empty wells of compound plate, 10 pL per well.

[1035] 5) Add 10 pL detection reagent solution to compound plate, centrifuge at 1000 rpm for 1 min. Incubate at room temperature for 60 min in the dark.

[1036] 6) Place the reaction plate into the Enzyme Labeling Instrument EnVision for reading. The final value is the ratio at 665 nm and 615 nm.

[1037] 7) Analyze data:

[1038] a) Calculate the actual cAMP level (nM) of each sample well by the cAMP standard curve;

[1039] b) Antagonist: Inhibition % = 100% x (1- (sample well cAMP value - low signal control group cAMP average) / (high signal control group cAMP average - low signal control group cAMP average));

[1040] c) Use GraphPad Prism 5 data analysis software, select Dose-response-Inhibition—log(inhibitor) vs. response--Variable slope mode for fitting analysis, and obtain the IC 50 value of each test sample.

[1041] Experimental results:

[1042] IC of LHCGR 50 The test results of the experiment are shown in Table 3.

[1043] Table 3 Test results of the test compound

[1044] Compound IC 50 (nM) Compound 009 7460 Compound 132 9991 Compound 294 9008 Compound 297 1799 Compound 343 4118

[1045] Conclusion: The compound of the present application has no significant inhibition on the release of cAMP of CHO-K1 / LHCG cells, and has good selectivity.

[1046] Test Example Four: Liver microsomal stability experiment

[1047] 1. Materials and reagents

[1048] The microsomes were stored in a -80°C refrigerator, and the specific information is shown in the table below.

[1049] Species Strain Gender Supplier Human N / A Pool BD Gentest Monkey Cynomolgus Male BD Gentest Dog Beagle Male BD Gentest Rat Sprague Dawley Male BD Gentest Mouse ICR / CD-1 Male BD Gentest

[1050] 2. Experimental design

[1051] 2.1 Preparation of compound working solution

[1052] The test substance and the control drug verapamil powder were prepared into high concentration stock solutions with DMSO, and before use, they were diluted with acetonitrile: water = 1:1 to a working solution of 100 μM, and the final concentration of the test substance and verapamil was 1 μM.

[1053] 2.2 Preparation of phosphate buffer (100 mM, pH 7.4)

[1054] First, weigh 7.098 g of disodium hydrogen phosphate and add 500 mL of pure water to dissolve by ultrasonic, as solution A. Weigh 3.400 g of potassium dihydrogen phosphate and add 250 mL of pure water to dissolve by ultrasonic, as solution B. Add solution B to solution A until the pH is 7.4.

[1055] 2.3 Preparation of 10 mM NADPH

[1056] Before the experiment, weigh an appropriate amount of NADPH and prepare a working solution with a concentration of 10 mM with phosphate solution.

[1057] 2.4 Preparation of incubation system

[1058] The incubation system was prepared according to the table below, and the incubation system was preheated at 37°C for 10 minutes before use.

[1059] Component Stock Concentration Volume Final Concentration in System Microsomes 20 mg / mL 6.25 μL 0.5 mg / mL Phosphate Buffered Salts 100 mM 216.25 μL 100 mM

[1060] 2.5 Test method

[1061] 1) Transfer 25 μL NADPH or phosphate buffered saline to the incubation system above, add 2.5 μL 100 μM test article or verapamil. Prepare samples in duplicate for NADPH addition; prepare samples in single for NADPH negative.

[1062] 2) At 0.5, 5, 15, 30 and 60 minutes, respectively, take 30 μL of the suspension. Add 150 μL acetonitrile containing internal standard to terminate the reaction, vortex for 10 minutes.

[1063] 3) Then centrifuge at 3220 g for 30 minutes to precipitate the protein. Transfer 40 μL supernatant to the injection plate, add 160 μL pure water to mix, for UPLC-MS / MS analysis.

[1064] 3. Data analysis

[1065] All data calculation is performed by Microsoft Excel software. The peak area is detected by extracting the ion spectrum. The in vitro half-life (T 1 / 2 ) of the parent drug is detected by linear fitting of the natural logarithm of the parent drug elimination percentage versus time.

[1066] The in vitro half-life (T 1 / 2 ) is calculated by the slope:

[1067] in vitro t 1 / 2 = 0.693 / k

[1068] The in vitro clearance (unit: μL / min / mg) is calculated by the following formula:

[1069] in vitro CLint = kV / N

[1070] V = incubation volume per well (250 μL);

[1071] N = content of microsomes per well (0.125 mg).

[1072] Experimental results:

[1073] The test results are shown in Table 4.

[1074] Table 4 Test results of test compounds

[1075]

[1076] Conclusion: The compound of the present application has good in vitro metabolic stability.

[1077] Test Example Five: Pharmacokinetic test of C57 mice

[1078] Tool compounds, 294, 297, 329 were dosed by single oral gavage (2 mpk) and intravenous injection (1 mpk) in 5% DMSO + 5% Solutol + 90% Saline vehicle (two female and two male C57BL / 6J mice per group), and blood sampling time points were 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after dosing. The average pharmacokinetic parameters in plasma are shown in Table 5 (where F = 1 / 2*AUC(PO: 2 mpk) / AUC(IV: 1 mpk)*100%):

[1079] Table 5. Compound pharmacokinetic test results in mice

[1080]

[1081] Conclusion: The results show that the representative compounds of the present application have good absorption and good pharmacokinetic properties in mice.

[1082] Test Example Six: Pharmacokinetic test in beagle dogs

[1083] Tool compounds, 009, 169, 294, 297, 328 were dosed by single oral gavage (2 mpk) and intravenous injection (0.5 mpk) in 5% DMSO + 5% Solutol + 90% Saline vehicle (two female and two male beagle dogs per group), and blood sampling time points were 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after intravenous injection, and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after oral gavage. The average pharmacokinetic parameters in plasma are shown in Table 6 (where F = 1 / 4*AUC(PO: 2 mpk) / AUC(IV: 0.5 mpk)*100%):

[1084] Table 6. Compound pharmacokinetic test results in dogs

[1085]

[1086] Conclusion: The results show that the representative compounds of the present application have good absorption and good pharmacokinetic properties in beagle dogs.

[1087] Test Example Seven: Rat hyperthyroidism PD efficacy model

[1088] 1. Materials and reagents

[1089]

[1090] 2. Preparation of modeling agents and test substances

[1091] 2.1 M22 modeling agent: Before each administration, take out and place at room temperature, melt and mix gently, prepare the corresponding concentration of test product with PBS, mix well. Store at 2-8°C, take out and place at room temperature before use, use within 4 hours.

[1092] 2.2 Solvent preparation

[1093]

[1094] 3. Experimental content

[1095] (1) D-4 (the four days before Day 0 (hereinafter referred to as DO)) According to the body weight, the animals were evenly grouped.

[1096] (2) D-4: From D-4 to the end of the experiment, all animals were given 3 μg / mL T3 aqueous solution; T3 aqueous solution needs to be prepared every day (T3 is first prepared into a 60 μg / mL stock solution with water, and the stock solution is stored in a 4°C refrigerator; the drinking water of the animals is diluted 20 times to obtain a 3 μg / mL T3 aqueous solution), and the water intake (weight) of the animals in each cage is recorded every day.

[1097] (3) D0: The animals in the administration group, the model group and the positive control group were given M22 modeling agent diluted with PBS to a concentration of 150 μg / mL at a dose of 60 μg / kg for modeling, and the animals in the negative control group were given PBS of the corresponding volume (see Table 7).

[1098] Table 7 Animal grouping and modeling

[1099]

[1100] (4) D0: The animals in each group were respectively given test compounds (solvent: 5% (v / v) Soluto 1 HS15 + 5% TPGS + 90% (0.2% CMC-Na, viscosity 800-1200)), positive control K1-70 (diluted with PBS to the corresponding volume) or corresponding solvent treatment (Table 8).

[1101] Table 8 Animal administration

[1102]

[1103] Note: The solvent in Table 8 is 5% (v / v) Soluto 1 HS15 + 5% TPGS + 90% (0.2% CMC-Na, viscosity 800-1200).

[1104] (5) D0-D1: The animals in each group were bled to prepare serum according to the following table (see Table 9).

[1105] Blood collection: 0.4 mL of blood was collected from the jugular vein per time point.

[1106] Blood sample processing and detection: collect whole blood into serum separation gel coagulation tube, place at room temperature for half an hour, then centrifuge at 2000rcf, room temperature, for 10 minutes to obtain supernatant. The serum samples are directly detected for the level of TT4 in the serum samples of each group of animals by using the full-automatic electrochemical luminescence immunoassay analyzer cobas8000 e602 in the full-automatic biochemical immunoassay system cobas8000 (consisting of full-automatic biochemical analyzer cobas8000 c702 and full-automatic electrochemical luminescence immunoassay analyzer cobas8000 e602) of Roche.

[1107] Table 9 animal sampling

[1108]

[1109] The experimental results are shown in Table 9. Figure 1 - Figure 6

[1110] Conclusion: The compounds of the present application can significantly reduce TT4.

[1111] Unless otherwise specified, the tool compound structures described in the present application are as follows:

[1112]

[1113] The above has exemplarily described the embodiments of the technical solutions of the present application. It should be understood that the protection scope of the present application is not limited to the above-mentioned embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.​

Claims

1. The compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: in, Ring A is selected from C 3-14 Saturated or partially unsaturated carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; 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 a2 Or C(=O)R a3 ; 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 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; m is selected from 0, 1, 2, 3, 4 or 5; Y2 is absent or selected from -O-, -S-, unsubstituted, or optionally selected by one, two, or more elements from oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 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-; X1 is selected from CR X1 Or N; X2 is selected from CR X2 Or N; X3 is 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 heteroaryl; or, R X1 With R X2 Or R X2 With R X3 Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. d The following ring systems are substituted: C3-14 carbon rings, 3-14 membered heterocycles, C6-14 aromatic rings, or 5-14 membered heteroaromatic rings; 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; R2 is selected from CN, and is determined by one, two or more Rs. e Replacement C 1-12 Alkyl, unsubstituted, or optionally with one, two, or more R e The following groups are substituted: 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 e They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. e1 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 e2 Or C(=O)R e3 When R2 is C 1-12 When alkyl, R e Not C 1-6 alkyl; Alternatively, R2 can be connected to any position on ring A to form a ring that is unsubstituted or arbitrarily bound by one, two or more Rs. e1 Replaced 6-16 membered heterocycles; Each R e1 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 e4 Or C(=O)R e5 Or, two R atoms attached to the same carbon atom e1 Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. e6 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. e1 Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. e6 The following groups are substituted: CH=CH, 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. e1 Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. e6 Replacement C 1-3 alkylene; R e2 R e3 R e4 R e5 R e6 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; 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; Y1 is selected from -O-, -S-, unsubstituted, or optionally selected by one, two, or more elements selected from oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 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-; R1 is selected from any of the following groups: (i)-COR 13 ;R 13 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: -OH, -NR 11 R 12 C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 cycloalkyl or 3-14 membered heterocyclic groups; R 11 R 12 They are either the same or different, and are independently selected from H and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; or R 11 R 12 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-14 N-containing heterocycles; (ii) L1 is absent or selected from unsubstituted or optionally selected by one, two or more of the following: oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 C-substituents of cycloalkyl or 3-6 membered heterocyclic groups 1-12 Alkylene; R 14 Selected from H, CN, -NH2, -NHC 1-12 Alkyl, -N(C) 1-12 Alkyl)2, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3-12 cycloalkyl, halogenated C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; X4 is selected from O or NR. 15 ;R 15 Selected from H, CN, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 3-12 cycloalkyl, halogenated C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; (iii)-L2-COR 16 L2 is selected from unsubstituted or optionally substituted by one, two or more elements selected from oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 C-substituents of cycloalkyl or 3-6 membered heterocyclic groups 1-12 Alkylene; R 16 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: H, OH, -NR 17 R 18 C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups; R 17 R 18 They are either the same or different, and are independently selected from H and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; or R 17 R 18 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-14 N-containing heterocycles; (iv) Ring B is selected from C 3-14 Carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; Each R c They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. c1 The following groups are substituted: OH, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-14 Aryl, 5-14 heteroaryl, NH2, S(O)2H, COH, hydroxyl C 1-12 Alkyl, amino C 1-12 Alkyl; or, two R atoms attached to the same carbon atom. c Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c1 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. c Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. c1 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. c Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. c1 Replacement C 1-3 Alkylene; each R c1 They are either identical or different, and are independently selected from oxo (=O), OH, NH2, CN, halogens, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; p is selected from 0, 1, 2, 3, 4 or 5.

2. The compound represented by formula (I-1), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: in, Ring A is selected from C 3-14 Saturated or partially unsaturated carbon rings, 3-14 membered heterocycles, C 6-14 Aromatic rings or 5-14 heterocyclic aromatic rings; 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 a2 Or C(=O)R a3 ; 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 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; m is selected from 0, 1, 2, 3, 4 or 5; Y2 is absent or selected from -O-, -S-, unsubstituted, or optionally selected by one, two, or more elements from oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 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-; X1 is selected from CR X1 Or N; X2 is selected from CR X2 Or N; X3 is 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 heteroaryl; or, R X1 With R X2 Or R X2 With R X3 Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. d The following ring systems are substituted: C3-14 carbon rings, 3-14 membered heterocycles, C6-14 aromatic rings, or 5-14 membered heteroaromatic rings; 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; R2 is selected from CN, and is determined by one, two or more Rs. e Replacement C 1-12 Alkyl, unsubstituted, or optionally with one, two, or more R e The following groups are substituted: 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 e They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. e1 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 e2 Or C(=O)R e3 When R2 is C 1-12 When alkyl, R e Not C 1-6 alkyl; Alternatively, R2 can be connected to any position on ring A to form a ring that is unsubstituted or arbitrarily bound by one, two or more Rs. e1 Replaced 6-16 membered heterocycles; Each R e1 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 e4 Or C(=O)R e5 Or, two R atoms attached to the same carbon atom e1 Together with the carbon atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. e6 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. e1 Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. e6 The following groups are substituted: CH=CH, 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. e1 Connected by their end groups, they together form unsubstituted or optionally substituted by one, two or more R groups. e6 Replacement C 1-3 alkylene; R e2 R e3 R e4 R e5 R e6 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; 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; Y1 is selected from -O-, -S-, unsubstituted, or optionally selected by one, two, or more elements selected from oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 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-; R 11 R 12 They are the same or different, and are selected independently from H or C. 1-12 alkyl.

3. The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, Ring A is selected from a benzene ring or a 5-6 membered heteroaromatic ring; Preferably, ring A is selected from benzene ring, pyrazole ring, thiazole ring, oxazole ring, furan ring, thiophene ring, pyrrole ring, imidazole ring, pyridine ring, pyrimidine ring, piperidine ring, and pyridazine ring; Preferably, ring A is a benzene ring or a thiophene ring (e.g. ) or pyridine ring (e.g. ); Preferably, ring A is a benzene ring or a thiophene ring (e.g. ); Preferably, ring A is a benzene ring; Preferably, 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 groups, 5-6 membered heteroaryl groups (such as pyrazolyl); Preferably, each R a They may be the same or different, and are independently selected from CN, methyl, -C≡CCH3, F, Cl, Br, or cyclopropyl. Preferably, each R a They may be the same or different, and are independently selected from methyl, -C≡CCH3, F, Cl, Br or cyclopropyl; Preferably, each R a They may be the same or different, and are independently selected from F, Cl, Br or cyclopropyl; Preferably, each R a They are either the same or different, and are independently selected from F, Cl, or Br; Preferably, m is 1, 2, 3, 4 or 5; Preferably, m is 1 or 2; Preferably, m is 2, 3, or 4; Preferably, Y2 is selected from -O- or unsubstituted or optionally substituted with one, two or more C-. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 C-substituents of cycloalkyl or 3-6 membered heterocyclic groups 1-6 Alkylene; Preferably, Y2 is selected from -O-, Preferably, Y2 is -O-.

4. The compound according to any one of claims 1-3, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, 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; Preferably, X1 is CR X1 ;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); Preferably, X1 is CR X1 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; Preferably, R X1 R X2 R X3 They are selected independently from H, CN, OH, halogens (such as F, Cl, Br), and C, whether they are the same or different. 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 Alkyl groups (such as methoxy groups) or halogenated C groups 1-4 Alkyl groups (such as trifluoromethoxy, difluoromethoxy); or, R X1 With R X2 Together with the carbon atoms respectively attached thereto, they form unsubstituted or optionally substituted with one, two or more R atoms. d The following ring systems are substituted: C4-6 carbon rings or 4-6 membered heterocycles; each R d They are either the same or different, and are independently selected from CN, OH, halogens, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 Alkoxy; Preferably, R X1 Selected from H, -CH3, -F, -Cl, -Br, -CH2F, -CF2H, -CF3; R X2 Selected from H, -CH3, -F, -Cl, -Br; R X3 Selected from H, -CH3, -F, -Cl, -Br; or, R X1 With R X2 Together with the carbon atoms they are attached to, they form a C4-6 carbon ring; Preferably, X1 is N or CR X1 ;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); Preferably, X1 is CR X1 ;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); Preferably, X1 is CR X1 ;R X1 Selected from -CH3, -Cl, or -F; Preferably, X2 is selected from N, CH or CCl; Preferably, X2 is CH; Preferably, X3 is selected from N, CH or CCl; Preferably, X3 is CH; Preferably, n is 0.

5. The compound according to claim 1, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, Preferably, Y1 is selected from unsubstituted or optionally substituted by one, two or more of the following: oxo (=O), OH, NH2, CN, halogen, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-4 Alkylene, -NH-C 1-4 alkylene or -C 1-4 alkylene-NH-; Preferably, Y1 is -NH-; Preferably, R1 is selected from any one of the following groups: (i)-COR 13 ;R 13 Selected from -NR 11 R 12 Halogenated C 3-8 Cycloalkyl or unsubstituted or optionally with one, two or more R c Substituted 3-8 membered heterocyclic groups; R 11 R 12 They are the same or different, and are selected independently from H or C. 1-4 alkoxy; or R 11 R 12 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-8 N-containing heterocycles; (ii) L1 is absent or selected from unsubstituted or optionally selected from one or two halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl substituents substituted C 1-4 Alkylene; R 14 Selected from NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; X4 is selected from O or NR 15 ;R 15 Selected from H, CN, C 1-4 alkyl; (iii)-L2-COR 16 L2 is selected from unsubstituted or optionally selected from one or two halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl substituents substituted C 1-4 Alkylene; R 16 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: H, OH, -NR 17 R 18 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups; R 17 R 18 They are either the same or different, and are independently selected from H and C. 1-4 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; or R 17 R 18 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-8 N-containing heterocycles; (iv) Ring B is selected from 5-6 membered heteroaromatic rings (e.g., pyrrole ring, pyrazole ring, imidazole ring, triazole ring, thiazole ring, thiadiazole ring, oxazole ring, dioxazole ring, furan ring, thiophene ring, pyridine ring, pyrimidine ring, piperidine ring, pyridazine ring, triazine ring); Preferably, each R c They are either identical or different, and are independently selected from oxo (=O), CN, halogen, OH, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, C 1-4 Alkylene NR c2 R c3 CONH2, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R c2 R c3 They are the same or different, and are selected independently from H or C. 1-4 alkyl; Preferably, each R c They may be the same or different, and are independently selected from methyl, ethyl, isopropyl, F, Cl, Br, CN, OH, CH2F, CHF2, CF3, OCH3, CONH2, CH2CH2OH, CH2CH2N(CH3)2. Alternatively, two R atoms attached to the same carbon atom c Together with the carbon atom it is attached to, it forms a cyclopropyl ring; or, two R atoms attached to adjacent carbon atoms... c Together with the carbon atoms it is attached to, it forms a cyclopropyl ring; Preferably, p is selected from 0 or 1; Preferably, R1 is selected from any one of the following groups: (i)-COR 13 ;R 13 Selected from -NR 11 R 12 Halogenated cyclopropyl, halogenated cyclobutyl, or unsubstituted or optionally substituted with one or two R c Substituted azaheterocyclic butyl ring, azaheterocyclic pentyl ring, oxocyclic butyl ring, morpholine ring; R 11 Selected from H, R 12 Selected from methoxy; or R 11 R 12 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one or two R atoms. c Substituted 3-6 N-containing heterocycles; R c Selected from OH, F, Cl, Br, CN, CH3, CHF2, CH2F, OCH3. (ii) L1 is absent or selected from -CH2- or -CH(CH3)-; R 14 Selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CF3, CH2CF3, cyclopropyl; preferably, R 14 Selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, CH3, CH2CH3, CH2CH2CH3, CF3, CH2CF3, cyclopropyl; X4 selected from O or NR 15 ;R 15 Selected from H, CN, and CH3; (iii)-L2-COR 16 L2 is selected from -CH2- and -CH(CH3)-; R 16 Selected from H, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2; (iv) Ring B is selected from Preferably, ring B is selected from Preferably, ring B is selected from Preferably, R1 is selected from Preferably, R1 is -COR 13 -SO2R 14 5-6 membered heterocyclic rings (e.g.) ) or 5-6 quinary aromatic rings (e.g. ); R 13 Selected from -NR 11 R 12 ;R 11 R 12 They are the same or different, and are selected independently from H or C. 1-6 Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), or R 11 R 12 Together with the N atom it is attached to, they form unsubstituted or optionally C-substituted forms. 1-6 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, tert-butyl) substituted 3-6 membered nitrogen-containing heterocycles; R 14 Selected from -NH2 or C 1-6 Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl); Preferably, R1 is CONH2, 6. The compound according to claim 2, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, R 11 R 12 They are the same or different, and are selected independently from H or C. 1-6 Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl); Preferably, R 11 R 12 All are H.

7. The compound according to any one of claims 1-6, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, R2 is selected from unsubstituted or optionally by one, two or more R... e1 The following groups are substituted: C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Alkylene-CN, C 1-4 alkylene-OH, C 1-4 Alkylene-OC 1-4 Alkyl, C 1-4 Alkylene-SO2-C 1-4 Alkyl, C 1-4 Alkylene-NHCO-C 1-4 Alkyl, C 1-4 Alkylene-CONH-C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkylene-C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-4 Alkylene-3-6-membered heterocyclic groups, benzene rings, C 1-4 alkylene ring, 5-6 membered heteroaryl, C 1-4 Alkylene-5-6-membered heteroaryl; or, R2 is attached to any position on ring A to form a 6-16-membered heterocycle; Preferably, R e1 Selected from F, Cl, Br, CN, OH, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl groups, 3-6 membered heterocyclic groups; Preferably, R2 is selected from Alternatively, R2 can be connected to any position on ring A to form an 8-11 member heterocyclic ring; Preferably, R2 is selected from Alternatively, R2 can be connected to any position on ring A to form an 8-11 member heterocyclic ring; Preferably, R2 is 8. The compound according to any one of claims 1-7, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, The compound shown in formula (I) has the following structure: in, X4 is selected from CH or N; X5 is selected from CH2(CH2). t O(CH2) t S(CH2) t Or NH(CH2) t , of which (CH2) t It is connected to any position of ring A; preferably, X5 is selected from CH2, O, OCH2, NHCH2; preferably, X5 is selected from CH2, O, S or NH; preferably, X5 is selected from CH2, O or CH2NH; preferably, X5 is selected from CH2 or O; t is selected from 0, 1, 2, 3, 4, 5, 6; preferably, t is 0 or 1; p is selected from 0, 1, 2, 3, 4, 5, 6; preferably, p is selected from 2, 3 or 4; q is selected from 0, 1, 2, 3, 4, 5, 6; preferably, q is 0; Each R e1 They are either the same or different, and are independently selected from F, Cl, Br, CN, OH, and C. 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups; or, two R groups attached to adjacent carbon atoms. e1 Together with the carbon atoms they are attached to, they form the following groups: CH=CH, C 3-6 Carbon rings or 3-6 membered heterocycles; or, two non-adjacent Rs. e1 Connected by their end groups, they together form C 1-3 Alkylene; Preferably, the two R atoms connected to adjacent carbon atoms e1 Together with the carbon atoms they are attached to, they form CH=CH; or, two non-adjacent R atoms... e1 They are connected by their terminal groups to form a methylene group; Preferably, Selected from The "*" side is connected to N, and the "#" side is connected to ring A; Ring A, X1, X2, X3, Y1, Y2, R1, R 11 R 12 R2, R a R X1 m has the definition of any one of claims 1-4; Preferably, the compound represented by formula (I) has the following structure: Among them, R aa R ab They may be the same or different, and are independently selected from H, F, Cl, or Br; R ac Selected from H, F, Cl, Br or cyclopropyl; q is selected from 0, 1, 2 or 3; preferably, q is 0 or 1; Each R e1 Same or different, selected independently from C 1-4 Alkyl groups (e.g., methyl); or, two R atoms attached to adjacent carbon atoms. e1 Together with the carbon atoms they are attached to, they form CH=CH; X1, X2, X3, X4, X5, Y2, R a R1, R 11 R 12 R2, R X1 m and p have the definitions of any one of claims 1-4; Preferably, Selected from Preferably, Selected from Preferably, the compound represented by formula (I) has the following structure: Among them, R 11 R 12 R2, R X1 It has the definition of any one of claims 1-4.

9. The compound according to any one of claims 1-8, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, The compound shown in formula (I) is selected from the following structures:

10. A method for preparing the compound shown in formula (II-3), comprising the following step A: Step A: in, Ring A, X1, X2, X3, Y2, R 11 R 12 R2, R a m has the definition of any one of claims 1-8.

11. A method for preparing the compound shown in formula (III-7), comprising the following steps: in, R Z1 Selected from halogens (e.g., F, Cl, Br); R Z2 Selected from amino protecting agents (e.g., Boc); X4, Y2, R 11 R 12 R X1 R a m has the definition of any one of claims 1-5.

12. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the following: a compound of formula (I) according to any one of claims 1-9, a racemic mixture, a stereoisomer, a tautomer, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof; Preferably, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients; Preferably, the pharmaceutical composition further contains one or more additional therapeutic agents.

13. A method of treating or preventing a disease or condition caused by TSHR abnormality, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the following: a compound of formula (I) as claimed in any one of claims 1-9, 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 as claimed in claim 12. Preferably, the disease or condition caused by the abnormal TSHR is a thyroid-related disease or condition; Preferably, the thyroid-related disease or condition is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, or thyroid eye disease; the patient includes mammals, preferably humans.

14. The use of at least one of the compounds of formula (I) according to any one of claims 1-9, their racemic mixtures, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds, or the use of the pharmaceutical composition according to claim 8 in the preparation of a medicament; Preferably, the use may be in the preparation of a medicament for TSHR antagonists; Preferably, the use may be in the preparation of a medicament for the treatment or prevention of thyroid-related diseases or conditions; Preferably, the thyroid-related disease or condition is hyperthyroidism, Graves' disease, Graves' eye disease, or thyroid eye disease.

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