TSHR antagonist compound, pharmaceutical composition, and preparation method therefor and use thereof

Abstract

Provided in the present invention are a TSHR antagonist compound, a pharmaceutical composition, and a preparation method therefor and the use thereof. The compound has good TSHR antagonism, and is used in the treatment of thyroid-associated conditions and / or diseases, such as hyperthyroidism, Graves' disease, Graves' ophthalmopathy, and thyroid eye disease, and in the preparation of a drug for treating such conditions or diseases.

Description

TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same

[0001] The present application claims priority to the prior application of the Chinese Patent Application No. 202410756004.6, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on June 12, 2024, Chinese Patent Application No. 202410772832.9, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on June 14, 2024, Chinese Patent Application No. 202410840707.7, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on June 26, 2024, Chinese Patent Application No. 202411087297.X, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on August 8, 2024, Chinese Patent Application No. 202411353988.X, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on September 26, 2024, Chinese Patent Application No. 202411863901.3, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on December 17, 2024, Chinese Patent Application No. 202510167605.8, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on February 14, 2025, Chinese Patent Application No. 202510285836.9, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on March 11, 2025, Chinese Patent Application No. 202510479405.6, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on April 16, 2025, Chinese Patent Application No. 202510756393.7, entitled "TSHR antagonist compounds, pharmaceutical compositions, and methods of making and using the same", filed on June 6, 2025, to the Chinese Patent Office. The entire contents of the above-identified prior applications are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and particularly 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] wherein,

[0007] 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;

[0008] each R a is the same or different, independently selected from CN, halogen, non-substituted or optionally substituted with one, two or more R a1 substituted groups: OH, NH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=O)2R 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 is the same or different, independently selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0009] m is selected from 0, 1, 2, 3, 4 or 5;

[0010] Y2 is absent or selected from -O-, -S-, non-substituted or optionally substituted with one, two or more R 1-12 alkyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C3-6 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-;

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

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

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

[0014] R X1 R X2 R X3 They may be identical or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more R groups. d The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated 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;

[0015] 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 6-membered heterocyclyl, C 6-14 aryl, 5- to 10-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;

[0016] 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;

[0017] 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;

[0018] 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;

[0019] n is selected from 0, 1, 2 or 3;

[0020] 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-;

[0021] R1is selected from any one of the following groups:

[0022] (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;

[0023] (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 H, CN, -NH2, -NHC 1-12 alkyl, -N(C 1-12 alkyl)2, C 1-12 alkyl, haloC 1-12 alkyl, C 3-12 cycloalkyl, haloC 3-12 cycloalkyl or 3-14 membered heterocyclyl; X4is selected from O or NR 15 ; R 15 is selected from H, CN, C 1-12 alkyl, haloC 1-12 alkyl, C 3-12 cycloalkyl, haloC 3-12 cycloalkyl or 3-14 membered heterocyclyl;

[0024] (iii) -L2-COR 16 ; L2is selected from unsubstituted or optionally substituted C 1-12 alkylene; R 1-12 is selected from H, C 1-12 alkyl, haloC 1-12 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R 1-12 is selected from H, C 16 alkyl, haloC c alkyl, C 17 cycloalkyl, 3-14 membered heterocyclyl; R 18 , R 1-12 are the same or different, independently of each other, selected from H, C 1-12 alkyl, haloC 1-12 alkyl, C 3-12 cycloalkyl, 3-14 membered heterocyclyl; R 17 , R 18 are the same or different, independently of each other, selected from H, C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 cycloalkyl, 3-14 membered heterocyclyl; R 1-12 , R 3-12 together with the N atom to which they are attached form a 3-14 membered N- containing heterocyclic ring which is unsubstituted or optionally substituted by one, two or more R 17 ; R 18 is selected from H, C c alkyl, haloC

[0025] (iv) Ring B is selected from C 3-14 carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic or 5-14 membered heteroaromatic ring;

[0026] each R c identically or differently, independently of one another, selected from the group consisting of oxo (=0), 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 aromatic or 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, selected from the group consisting of oxo (=0), 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;

[0027] p is selected from 0, 1, 2, 3, 4 or 5.

[0028] The present application also provides a compound represented by formula (I-1), a racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof:

[0029] wherein,

[0030] ring A is selected from C 3-14 saturated or partially unsaturated carbocyclic, 3-14 membered heterocyclic, C 6-14an aromatic or 5- to 14-membered heteroaromatic ring;

[0031] each R a identically or differently, independently of one another, selected from CN, halogen, unsubstituted or optionally substituted with one, two or more substituents selected from oxo (=0), OH, NH2, CN, halogen, C a1 substituted with one, two or more substituents selected from 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- to 14-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, S(=0)2R a2 or C(=0)R a3 ; each R a1 identically or differently, independently of one another, selected from oxo (=0), 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- to 6-membered heterocyclyl; R a2 , R a3 identically or differently, independently of one another, selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0032] m is selected from 0, 1, 2, 3, 4 or 5;

[0033] Y2is absent or 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, halogenated C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl; -NH-, C 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-;

[0034] X1is selected from CR X1 or N;

[0035] X2is selected from CR X2 or N;

[0036] X3is selected from CR X3 or N;

[0037] R X1 , R X2 , R X3 are identical or different, independently of one another, selected from H, CN, halogen, unsubstituted or optionally substituted with one, two or more R d OH, NH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogen-C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl; or, R X1 and R X2 or R X2 and R X3 together with the carbon atom to which they are respectively attached form an unsubstituted or optionally substituted with one, two or more R d C3-14carbocyclic, 3-14 membered heterocyclic, C6-14aromatic or 5-14 membered heteroaromatic ring system; each R d are identical or different, independently of one another, selected from oxo (=0), CN, halogen, OH, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;

[0038] R2is selected from CN, C e alkyl, unsubstituted or optionally substituted with one, two or more R 1-12 OH, NH2, C e alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogen-C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R 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;

[0039] 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;

[0040] 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 C1-3 alkylene; R e2 , R e3 , R e4 , R e5 , R e6 are identical or different and independently of each other selected from H, OH, NH2, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0041] each R b are identical or different and independently of each other selected from CN, halogen, oxo (=0), unsubstituted or optionally substituted with one, two or more R b1 OH, NH2, C 1-12 alkyl, halo-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(=0)2R b2 or C(=0)R b3 ; each R b1 are identical or different and independently of each other selected from oxo (=0), CN, halogen, OH, NH2, C 1-6 alkyl, halo-C 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 identical or different and independently of each other selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0042] n is selected from 0, 1, 2 or 3;

[0043] 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, halo-C 1-12 alkyl, C 1-12 alkoxy, halo-C 1-12 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R 1-12 alkylene, -0-C 1-12 alkylene, -S-C 1-12alkylene, -NH-C 1-12 alkylene, -C 1-12 alkylene-O-, -C 1-12 alkylene-S-, or -C 1-12 alkylene-NH-;

[0044] R 11 , R 12 are the same or different, independently of each other, selected from H or C 1-12 alkyl.

[0045] According to some embodiments, ring A is selected from a phenyl ring or a 5-6 membered heteroaromatic ring.

[0046] According to some embodiments, ring A is selected from a phenyl ring, a pyrazole ring, a thiazole ring, an oxazole ring, a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, a piperidine ring, a pyridazine ring.

[0047] According to some embodiments, ring A is a phenyl ring, a thiophene ring (e.g. ) or a pyridine ring (e.g. ).

[0048] According to some embodiments, ring A is a phenyl ring or a thiophene ring (e.g. ).

[0049] According to some embodiments, ring A is a phenyl ring.

[0050] According to some embodiments, each R a are the same or different, independently of each other, selected from CN, F, Cl, Br, C 1-4 alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C 2-6 alkynyl (such as -CºCH, -CºCCH3), halogenated C 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy, ethoxy), halogenated C 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy), C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl (such as pyrazolyl).

[0051] According to some embodiments, each R a are the same or different, independently of each other, selected from CN, methyl, -CºCCH3, F, Cl, Br or cyclopropyl.

[0052] According to some embodiments, each R athe same or different, are independently of each other selected from the group consisting of methyl, -CºCCH3, F, CI, Br or cyclopropyl.

[0053] According to some embodiments, each R a the same or different, are independently of each other selected from the group consisting of F, CI, Br or cyclopropyl.

[0054] According to some embodiments, each R a the same or different, are independently of each other selected from the group consisting of F, CI or Br.

[0055] According to some embodiments, m is 1, 2, 3 or 4.

[0056] According to some embodiments, m is 1 or 2.

[0057] According to some embodiments, m is 2, 3 or 4.

[0058] 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 the group consisting of C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 alkyl, C 1-6 alkylene.

[0059] According to some embodiments, Y2is selected from the group consisting of -O-,

[0060] According to some embodiments, Y2is -O-.

[0061] 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.

[0062] 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 , X2is CR X2 , X3is N.

[0063] According to some implementation plans, 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 carbon 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 Alkyl group.

[0064] According to some implementation plans, 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.

[0065] According to some implementation schemes, 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).

[0066] According to some implementation schemes, 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 1-4alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), haloC 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy).

[0067] According to some embodiments, X1is CR X1 ; R X1 is selected from -CH3, -Cl or -F.

[0068] According to some embodiments, X2is selected from N, CH or CCl.

[0069] According to some embodiments, X2is CH.

[0070] According to some embodiments, X3is selected from N, CH or CCl.

[0071] According to some embodiments, X3is CH.

[0072] According to some embodiments, n is 0.

[0073] 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-.

[0074] According to some embodiments, Y1is -NH-.

[0075] According to some embodiments, R1is selected from any one of the following groups:

[0076] (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 11 , R 12 together with the N atom to which they are attached form a group unsubstituted or optionally substituted with one, two or more Rc Substituted 3-8 N-containing heterocycles;

[0077] (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;

[0078] (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;

[0079] (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).

[0080] According to some implementation schemes, each R c They are either identical or different, and are independently selected from oxo (=O), CN, halogen, OH, C. 1-4alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, hydroxyC 1-4 alkyl, C 1-4 alkyleneNR c2 R c3 , CONH2, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R c2 , R c3 are the same or different, each independently of the other, selected from H or C 1-4 alkyl.

[0081] According to some embodiments, each R c are the same or different, each independently of the other, selected from methyl, ethyl, isopropyl, F, Cl, Br, CN, OH, CH2F, CHF2, CF3, OCH3, CONH2, CH2CH2OH, CH2CH2N(CH3)2, or, two R c together with the carbon atom to which they are attached form a cyclopropyl ring; or, two R c together with the carbon atoms to which they are respectively attached form a cyclopropyl ring.

[0082] According to some embodiments, p is selected from 0 or 1.

[0083] According to some embodiments, R1is selected from any one of the following groups:

[0084] (i) -COR 13 ; R 13 is selected from -NR 11 R 12 , haloCyclopropyl, halocyclobutyl or an azetidinyl ring, azetidinyl ring, oxetanyl ring, morpholine ring, optionally unsubstituted or substituted by one or two R c ; R 11 is selected from H, R 12 is selected from methoxy; or R 11 , R 12 together with the N atom to which they are attached form a 3-6 membered N-containing heterocyclic ring, optionally unsubstituted or substituted by one or two R c ; R c is selected from OH, F, Cl, Br, CN, CH3, CHF2, CH2F, OCH3.

[0085] (ii) L1is absent or selected from -CH2-, -CH(CH3)-; R 14is selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, 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;

[0086] (iii) -L2-COR 16 ; L2is selected from -CH2-, -CH(CH3)-; R 16 is selected from H, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2;

[0087] (iv) Ring B is selected from Preferably, Ring B is selected from Preferably, Ring B is selected from

[0088] According to some embodiments, R1is selected from

[0089] According to some embodiments, R1is -COR 13 , -SO2R 14 , a 5-6 membered heterocyclic ring (e.g. ) or a 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 a 3-6 membered N-containing heterocyclic ring, which is unsubstituted or optionally substituted with C 1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl); R 14 is selected from -NH2or C 1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl).

[0090] According to some embodiments, R1is CONH2,

[0091] According to some embodiments, R 11 , R 12 are the same or different, each independently selected from H or C 1-6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, t-butyl).

[0092] According to some embodiments, R 11 , R 12 are each H.

[0093] According to some embodiments, R2is selected from the following groups, which are unsubstituted or optionally substituted with one, two, or more R e1 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 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, haloC 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 with R2, to form a 6-16 membered heterocyclic ring.

[0094] According to some embodiments, R e1 is selected from F, Cl, Br, CN, OH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl.

[0095] According to some embodiments, R2is selected from or R2is connected to any position on ring A to form together an 8-11 membered heterocyclic ring.

[0096] According to some embodiments, R2is selected from or R2is connected to any position on ring A to form together an 8-11 membered heterocyclic ring.

[0097] According to some embodiments, R2is

[0098] According to some embodiments, the compound of formula (I) has the following structure:

[0099] wherein,

[0100] X4is selected from CH or N;

[0101] X5is selected from CH2(CH2) t , O(CH2) t , S(CH2) t or NH(CH2) t wherein (CH2) t is connected 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;

[0102] t is selected from 0, 1, 2, 3, 4, 5, 6; preferably, t is 0 or 1 ;

[0103] p is selected from 0, 1, 2, 3, 4, 5, 6; preferably, p is selected from 2, 3 or 4;

[0104] q is selected from 0, 1, 2, 3, 4, 5, 6; preferably, q is 0;

[0105] each R e1 is the same or different, independently from each other, selected from preferably, R e1 is selected from F, CI, Br, CN, OH, C 1-4 alkyl, C 2-6 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 attached, respectively, form a group CH=CH, C 3-6 carbocyclic ring or 3-6 membered heterocyclic ring; or two non-adjacent Re1 together with the carbon atom to which they are attached form CH=CH; or, two non-adjacent R 1-3 alkylene;

[0106] preferably, two R e1 together with the carbon atom to which they are attached form CH=CH; or, two non-adjacent R e1 together with the carbon atom to which they are attached form CH=CH; or, two non-adjacent R

[0107] preferably, selected from wherein the “*” side is attached to N and the “#” side is attached to ring A;

[0108] ring A, X1, X2, X3, Y1, Y2, R1, R 11 , R 12 , R2, R a , R X1 , m have the definitions as described herein. According to some embodiments, the compound shown in formula (I) has the structure shown below:

[0109] wherein R aa , R ab are the same or different, each independently selected from H, F, Cl, or Br;

[0110] R ac is selected from H, F, Cl, Br, or cyclopropyl;

[0111] q is selected from 0, 1, 2, or 3; preferably, q is 0 or 1;

[0112] each R e1 is the same or different, each independently selected from C 1-4 alkyl (e.g., methyl); or, two R e1 together with the carbon atom to which they are attached form CH=CH;

[0113] X1, X2, X3, X4, X5, Y2, R a , R1, R 11 , R 12 , R2, R X1 , m, p have the definitions as described herein.

[0114] According to some embodiments, selected from

[0115] According to some embodiments, selected from

[0116] According to some embodiments, the compound of Formula (I) has the structure shown below:

[0117] wherein R 11 , R 12 , R2, R X1 have the definitions as described herein.

[0118] According to some embodiments, the compound of Formula (I) is selected from the following structures:

[0119] The present application also provides a method for preparing a compound of Formula (II-3), comprising the following step A:

[0120] Step A:

[0121] wherein ring A, X1, X2, X3, Y2, R 11 , R 12 , R2, R a , m have the definitions as described herein.

[0122] The present application also provides a method for preparing a compound of Formula (III-7), comprising the following step:

[0123] wherein,

[0124] R Z1 is selected from halogen (e.g., F, Cl, Br);

[0125] R Z2 selected from an amino protecting agent (e.g., Boc);

[0126] X4, Y2, R 11 , R 12 , R X1 , R a , m have the definitions described herein.

[0127] 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.

[0128] According to some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0129] According to some embodiments, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0130] 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.

[0131] According to some embodiments, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder.

[0132] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

[0133] According to some embodiments, the patient comprises a mammal, preferably a human.

[0134] 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.

[0135] According to some embodiments, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder.

[0136] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

[0137] 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.

[0138] According to some embodiments, the use can be use in the manufacture of a TSHR antagonist.

[0139] 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.

[0140] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease. Beneficial effects

[0141] 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.

[0142] Definitions and explanations of terms

[0143] Unless otherwise indicated, the definitions and explanations of terms recited in the present application specification and claims, including the definitions as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and integrated with each other arbitrarily. The definitions and compound structures after such combination and integration should be understood as within the scope recited in the present application specification and / or claims.

[0144] 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 be not substituted (unsubstituted) or can be optionally substituted by one, two or more R.

[0145] "More" means three or more, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0146] Unless otherwise indicated, the numerical ranges recited in the present specification and claims are meant to include each and every specific integer value within the range. For example, the numerical range "1-12" is meant to include each and every specific integer value, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0147] The term "C 1-12 "alkyl" is to be understood as meaning straight-chain and branched-chain alkyl groups having 1 to 12 carbon atoms. "C 1-8 "alkyl" means straight-chain and branched-chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. "C 1-6 "alkyl" means straight-chain and branched-chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Said alkyl groups are, 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, and the like or isomers thereof.

[0148] The term "C 2-12 "alkenyl" is to be understood as meaning straight-chain or branched-chain monovalent hydrocarbon radicals having 1 to 12 carbon atoms which contain one or more double bonds and have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. For example, 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. C 2-8 "alkenyl", for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. C 2-6 "alkenyl", for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. C 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.

[0149] 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.

[0150] 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 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. bridged, spiro) or tricyclic hydrocarbon ring 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 having 3 to 12 carbon atoms, preferably "C

[0151] 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 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] The term "halogen" denotes fluorine, chlorine, bromine and iodine.

[0156] 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.

[0157] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0158] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0159] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0160] 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 includes 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.

[0161] 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.

[0162] "Halo" means substituted with one or more halogens.

[0163] The term "haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0164] 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.

[0165] 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.

[0166] "Heteroalkyl" means an alkyl group, as defined above, in which one or more carbon atoms are replaced by atoms or groups selected from >O, >S, and >NH. Non-limiting examples of heteroalkyl groups include: hydroxymethyl, 1- and 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-, 2-, and 3-hydroxybutyl, and the like. A heteroalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, and heterocycloalkyloxy.

[0167] The term "alkyloxy" means -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkyloxy groups include: methoxy, ethoxy, propyloxy, butyloxy. An alkyloxy group can be optionally substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0168] 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. Those skilled in the art will appreciate that an 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.

[0169] 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 to be interpreted in the same manner, unless otherwise indicated.

[0170] In the chemical structure of the compounds of the present application, a bond indicates unspecified configuration, indicates absolute configuration, i.e., if stereoisomers exist in the chemical structure, a bond may be or both configurations. may exist.

[0171] 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 compounds of the present application does not exclude that said hydrogen(s) can be replaced by deuterium or tritium, or vice versa, insofar as such replacement results in a stable compound.

[0172] 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.

[0173] 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.

[0174] 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 polymers, can also be advantageously carried out. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0175] The corresponding stable isomers can be isolated according to known methods, for example by extraction, filtration or column chromatography.

[0176] 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.

[0177] 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

[0178] Figure 1: Serum TT4 concentration in rats after administration of different doses of compounds 294, 297, 328 and K1-70 12 h;

[0179] Figure 2: Serum TT4 concentration of rats after administration of different doses of compounds 294, 297, 328 and K1-70 for 24 h;

[0180] Figure 3: Serum TT4 concentration of rats after administration of different doses of compound 169 and K1-70 for 12 h;

[0181] Figure 4: Serum TT4 concentration of rats after administration of different doses of compound 169 and K1-70 for 24 h;

[0182] Figure 5: Serum TT4 concentration of rats after administration of different doses of compound 009 and 12 h;

[0183] Figure 6: Serum TT4 concentration of rats after administration of different doses of compound 009 for 24 h. DETAILED DESCRIPTION

[0184] 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.

[0185] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0186] 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).

[0187] The MS is measured by Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry instrument (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 Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

[0188] High performance liquid chromatography (HPLC) analysis used Agilent 1260 II HPLC, Waters Acquity UPLC H-Class high performance liquid chromatograph.

[0189] Chiral HPLC analysis determination used Waters Acquity UPCC high performance liquid chromatograph.

[0190] 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.

[0191] CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0192] Thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) was 0.15mm-0.2mm, and the specification of thin layer chromatography separation and purification product was 0.4mm-0.5mm.

[0193] Silica gel column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0194] Determination of average inhibition rate and IC 50 value of kinase used NovoStar microplate reader (Germany BMG company).

[0195] 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, Accela ChemBio Inc, Darui Chemicals and the like.

[0196] Unless otherwise specified in the examples, the reactions were carried out under argon or nitrogen atmosphere.

[0197] Argon or nitrogen atmosphere refers to that the reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1L.

[0198] Hydrogen atmosphere refers to that the reaction bottle is connected with a hydrogen balloon with a volume of about 1L.

[0199] The pressurized hydrogenation reaction used a Parr 3916EKX hydrogenation apparatus and a Qianlan QL-500 hydrogen generator or a HC2-SS hydrogenation apparatus.

[0200] The hydrogenation reaction was usually vacuumed, filled with hydrogen, and repeated 3 times.

[0201] The microwave reaction used a CEM Discover-S 908860 microwave reactor.

[0202] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0203] In the examples, unless otherwise specified, the reaction temperature is room temperature, which is 20-30°C.

[0204] In the examples, the monitoring of the reaction progress used thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent used in the column chromatography for purifying the compounds, and the developing agent used in the thin layer chromatography included: system A: dichloromethane / methanol system, system B: n-hexane / ethyl acetate system, the volume ratio of the solvents was adjusted according to the polarity of the compounds, and a small amount of triethylamine and acetic acid or other basic or acidic reagents could also be added for adjustment.

[0205] Preparation of intermediate (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3,4- dihydroquinolin-2(1H)-one (Int 1)

[0206] Preparation of first step 3-fluoro-4-methyl-2-nitroaniline (Int 1b)

[0207] 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-trioxatriborane (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 solution 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%).

[0208] MS m / z (ESI): 171.1 (M+1).

[0209] Preparation of second step 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (Int 1c)

[0210] To a solution of isopentylnitrite (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 h. To the reaction mixture was added compound Int lb (13 g, 0.076 mol) and stirring was continued for 0.5 h, followed by warming to 70 °C for 2 h. After completion of the reaction, 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 washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography using system B to obtain compound Int lc (10.1 g, yield: 56.5%).

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 7.64-7.58 (m, 1H), 7.53 (t, 1H), 2.32 (s, 3H).

[0212] Third step: Preparation of l-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2- nitrobenzene (Int Id)

[0213] Compound Int lc (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 and the reaction was stirred at 100 °C for 2 h. After completion of the reaction, the mixture was diluted with ethyl acetate (100 mL) and washed with water (200 mL x 5). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography using system B to obtain compound Int Id (10 g, yield: 65.0%).

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 7.64-7.58 (m, 1H), 7.53 (t, 1H), 2.32 (s, 3H).

[0215] Fourth step: Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2- chloro-5-fluorophenoxy)-4-methyl-2-nitrophenyl)propanoate (Int le)

[0216] To a reaction flask was added zinc dust (362 mg), purged with nitrogen, and a syringe was used to add N,N-dimethylformamide (4 mL) and stir at 40 °C for 15 min. The system was purged with nitrogen and 1,2-dibromoethane (26 mg, 0.14 mmol) and trimethylchlorosilane (15 mg, 0.14 mmol) were added. The reaction mixture was stirred at 40 °C for 15 min. The reaction mixture was purged with nitrogen and a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (912 mg, 4.26 mmol) in N,N-dimethylformamide (2 mL) was added. The reaction mixture was stirred at 40 °C for 30 min under nitrogen and cooled to room temperature to give a zinc reagent solution for later use. Another flask was prepared with a solution of compound Int Id (500 mg, 1.38 mmol) in N,N-dimethylformamide (6 mL). The reaction mixture was purged with nitrogen and Pd(dppf)Cl2(101 mg, 0.14 mmol), cuprous iodide (26 mg, 0.14 mmol), and the prepared zinc reagent solution (supernatant) were added. The resulting reaction mixture was stirred at 80 °C for 16 h under nitrogen. After the reaction was completed, the reaction mixture was filtered over celite and the filter cake was washed with ethyl acetate. The organic phase was washed with aqueous ammonium chloride twice and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography system B to give compound Int le (200 mg, yield: 29%).

[0217] MS m / z (ESI): 401.0 (M+1).

[0218] Fifth Step: Preparation of (R)-3-(2-amino-3-(2-chloro-5-fluorophenoxy)-4- methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester (Int If)

[0219] Compound Int le (200 mg, 0.4 mmol) was dissolved in a mixture of tetrahydrofuran / methanol / water (12 mL, V / V / V = 3:2:1), and zinc dust (135 mg, 2 mmol) and ammonium chloride (117 mg, 2 mmol) were added. The reaction was stirred at 70 °C for 1 h. After the reaction was completed, the reaction mixture was filtered over celite and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography system A gave compound Int If (100 mg, yield: 53%).

[0220] MS m / z (ESI): 338.1 (M+1).

[0221] Sixth Step: Preparation of (R)-3-(2-amino-3-(2-chloro-5-fluorophenoxy)-4- methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (Int Ig)

[0222] Compound Int 1f (800 mg, 1.8 mmol) was dissolved in a mixture solvent of tetrahydrofuran and water (15 mL, V / V = 2:1), 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 organic phase was combined and rotary evaporated to obtain the crude product Int 1g (700 mg, 90%). The product was directly used in the next step without purification.

[0223] MS m / z (ESI): 383 (M+1-56).

[0224] Seventh step, 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 1h)

[0225] Compound Int 1g (700 mg, 1.6 mmol) was dissolved in N,N-dimethylformamide (5 mL), HATU (738 mg, 1.9 mmol), N,N-diisopropylethylamine (412 mg, 4.8 mmol) was 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 solution of ammonium chloride, and rotary evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography system B to obtain compound Int 1h (650 mg, yield: 97%).

[0226] MS m / z (ESI): 365 (M+1-56).

[0227] Eighth step, preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (Int 1i)

[0228] Compound Int 1h (600 mg, 1.4 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (1.18 g, 8.5 mmol), iodomethane (1.2 g, 8.5 mmol) was 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 solution of ammonium chloride, and rotary evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography system B to obtain compound Int 1i (600 mg, yield: 89%).

[0229] MS m / z (ESI): 379 (M+1-56).

[0230] Ninth step, preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3,4- dihydroquinolin-2(1H)-one (Int 1)

[0231] Compound Int 1i (300 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL), 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 obtain compound Int 1 (230 mg).

[0232] MS m / z (ESI): 335 (M+1).

[0233] 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).

[0234] Preparation of intermediate (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-1- methyl-3,4-dihydroquinolin-2(lH)-one (Int 2)

[0235] Preparation of first step 4-chloro-3-fluoro-2-nitroaniline (Int 2b)

[0236] 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, the reaction was stirred at 25 °C under nitrogen protection for 12 hours. After the reaction was completed, the reaction was extracted with ethyl acetate, the organic phase was dried and concentrated, purified by column chromatography system B to obtain compound Int 2b (3.2 g, yield: 50%).

[0237] MS m / z (ESI): 191.0 (M+1).

[0238] Preparation of second step 1-bromo-4-chloro-3-fluoro-2-nitrobenzene (Int 2c)

[0239] To a solution of isopentylnitrite (1.8 g, 0.015 mol) in acetonitrile (50 mL) was added cuprous bromide (3.5 g, 0.01 mol) and the mixture was stirred at room temperature for 1 h. To the reaction mixture was added compound Int 2b (2.5 g, 0.01 mol) and stirring was continued for 0.5 h, followed by warming to 70 °C for 2 h. After completion of the reaction, 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 washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified on a normal phase silica gel column (petroleum ether 100%) to give compound Int 2c (2.5 g, yield: 71%).

[0240] MS m / z (ESI): 253.9 (M+1).

[0241] Third step: Preparation of l-bromo-4-chloro-3-(2-chloro-5-fluorophenoxy)-2- nitrobenzene (Int 2d)

[0242] 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 was stirred at 100 °C for 2 h. After completion of the reaction, the mixture was diluted with ethyl acetate (100 mL) and washed with water (200 mL x 5). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified on column chromatography system B to give compound Int 2d (3.0 g, yield: 71%).

[0243] MS m / z (ESI): 379.9 (M+1).

[0244] Fourth step: Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3- (2-chloro-5-fluorophenoxy)-2-nitrophenyl)propanoate (Int 2e)

[0245] To a flask was added zinc dust (3.0 g, 4 eq), purged with nitrogen, charged with a syringe 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 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, cooled to room temperature under nitrogen to give a zinc reagent compound stock solution. Prepare another flask 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 (stock solution) 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%).

[0246] MS m / z (ESI): 403.0 (M-100) +

[0247] Fifth step: Preparation of (R)-methyl 3-(2-amino-4-chloro-3-(2-chloro-5- fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (Int 2f)

[0248] 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 purified by flash column chromatography using system B to give compound Int 2f (400 mg, yield 95%).

[0249] MS m / z (ESI): 417.0 (M+1).

[0250] Sixth step: Preparation of tert-butyl (R)-(7-chloro-8-(2-chloro-5-fluorophenoxy)-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (Int 2g)

[0251] 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 solution was concentrated, purified by flash silica gel column chromatography system B to obtain compound Int 2g (300 mg, yield 81%).

[0252] MS m / z (ESI): 463.0 (M+23).

[0253] Seventh step: 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)

[0254] Compound Int 2g (300 mg, 0.68 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (282 mg, 2.0394 mmol) and iodomethane (116 mg, 0.81 mmol) were added. The reaction was stirred at 45 °C for 8 hours, 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 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%).

[0255] MS m / z (ESI): 477.0 (M+23) + .

[0256] Eighth step: preparation of (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-1- methyl-3,4-dihydroquinolin-2(1H)-one (Int 2)

[0257] 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 solution 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%).

[0258] MS m / z (ESI): 355.0 (M+1) + .

[0259] 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).

[0260] Preparation of intermediate (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l- methyl-3,4-dihydroquinolin-2(lH)-one (Int 3)

[0261] Preparation of intermediate (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l- methyl-3,4-dihydroquinolin-2(lH)-one (Int 3)

[0262] 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%).

[0263] MS m / z (ESI): 364.0 (M+l).

[0264] Preparation of intermediate (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l- methyl-3,4-dihydroquinolin-2(lH)-one (Int 3)

[0265] To a reaction flask was added zinc powder (3 g), replaced with nitrogen, N,N- dimethylformamide (8 mL) was added using a syringe, stirred at 40 °C for 15 min under nitrogen, 1,2-dibromoethane (26 mg, 0.48 mmol) and trimethylchlorosilane (45 mg, 0.48 mmol) were added to the system under nitrogen, the reaction mixture was stirred at 40 °C for 15 min, a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- iodopropionate (912 mg, 33.16 mmol) in N,N-dimethylformamide (2 mL) was added to the reaction mixture under nitrogen, stirred at 40 °C for 30 min under nitrogen, cooled to room temperature under nitrogen to obtain a zinc reagent solution for standby. Prepare another bottle to add a solution of compound Int 3b (4 g, 0.011 mol) in N,N-dimethylformamide (20 mL), add Pd(dppf)Cl2(1.6 g, 0.002 mol), cuprous iodide (380 mg, 0.002 mol) and the prepared zinc reagent solution (supernatant) to the reaction mixture under nitrogen at room temperature, the resulting reaction mixture was stirred at 80 °C for 16 h under nitrogen. After the reaction was completed, the reaction liquid was filtered with diatomite, the filter cake was washed with ethyl acetate, the organic phase was washed with aqueous ammonium chloride solution twice, and the organic phase was rotary evaporated to obtain a crude product, which was purified by silica gel column chromatography system B to obtain compound Int 3c (4 g, yield: 74%).

[0266] MS m / z (ESI): 431.1 (M+1-56) + .

[0267] Preparation of (2R)-3-[2-amino-3-(2-chloro-5-fluorophenoxy)-4-fluorophenyl]-2-{[(tert- butoxy)carbonyl]amino}propionic acid methyl ester (Int 3d)

[0268] 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), 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 diatomite, the filtrate was concentrated under reduced pressure, and purification by silica gel column chromatography system B to obtain compound Int 3d (2.5 g, yield: 88%).

[0269] MS m / z (ESI): 457.1 (M+1).

[0270] 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)

[0271] 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%).

[0272] MS m / z (ESI): 369.1 (M+1-56) + .

[0273] 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)

[0274] 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%).

[0275] MS m / z (ESI): 383.1 (M+1-56) + .

[0276] 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%).

[0277] MS m / z (ESI): 339.1 (M+1).

[0278] 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).

[0279] 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)

[0280] 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%).

[0281] MS m / z (ESI): 357.2 (M-56) + .

[0282] 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)

[0283] 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%).

[0284] MS m / z (ESI): 377.0 (M-56) + .

[0285] 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)

[0286] Compound Int 6d (synthesized based on similar method with 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 obtain the crude product. The crude product was purified by column chromatography in system B to obtain compound Int 6 (380 mg, yield: 68%).

[0287] MS m / z (ESI): 439.1 (M+23) + .

[0288] Example 1

[0289] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (001)

[0290] Preparation of the first step (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)

[0291] 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 obtain compound 001a (80 mg, yield: 69.5%).

[0292] MS m / z (ESI): 507.1 (M+23) + .

[0293] 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)

[0294] Compound 001a (80 mg, 0.16 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 001b (50 mg), the product was directly used in the next step reaction without purification.

[0295] MS m / z (ESI): 385.1 (M+1) + .

[0296] Preparation of (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (001), third step

[0297] 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 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 001 (15.0 mg, yield: 27%).

[0298] MS m / z (ESI): 428.1 (M+1) + .

[0299] 1 H 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).

[0300] Example 2

[0301] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-7-fluoro-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (002)

[0302] 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)

[0303] Compound Int 3e (50 mg, 0.12 mmol) was dissolved in N,N dimethylformamide (4 mL), 2,2-difluoroethyl trifluoromethanesulfonate (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%).

[0304] MS m / z (ESI): 489.1 (M+1) + .

[0305] 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)

[0306] Compound 002a (50 mg, 0.10 mmol) was dissolved in 4 M / L hydrochloric acid / dioxane (3 mL), 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 directly used in the next step without purification.

[0307] MS m / z (ESI): 389.1 (M+1) + .

[0308] Preparation of the third step (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-7- fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (002)

[0309] Compound 002b (40 mg, 0.10 mmol) was dissolved in tetrahydrofuran (3 mL), potassium cyanate (17 mg, 0.20 mmol) was added, water (6 mg, 0.31 mmol) was added, acetic acid (22 mg, 0.31 mmol) was added, the reaction was stirred at room temperature for 30 minutes, after the reaction was completed, neutralized to basic with sodium bicarbonate aqueous solution, rotary evaporation to get 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 pm 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 002 (15.5 mg, yield: 35.2%).

[0310] MS m / z (ESI): 432.1 (M+1) + .

[0311] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (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).

[0312] Example 3

[0313] (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)

[0314] Preparation of (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)

[0315] Compound Int 1h (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), then compound trifluoroethyl trifluoromethanesulfonate (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%).

[0316] MS m / z (ESI): 503.1 (M+1) + .

[0317] 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)

[0318] 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.

[0319] MS m / z (ESI): 403.1 (M+1) + .

[0320] 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)

[0321] 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 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 5μm C18 150x30mm; 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%).

[0322] MS m / z (ESI): 446.1 (M+1) + .

[0323] 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).

[0324] Example 4

[0325] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (007)

[0326] Preparation of first step (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)

[0327] 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 hour, then LC-MS was used to monitor the completion of the reaction, 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%).

[0328] MS m / z (ESI): 489.1 (M+23) + .

[0329] Preparation of second step (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-(2- fluoroethyl)-7-methyl-3,4-dihydroquinolin-2(1H)-one (007b)

[0330] 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%).

[0331] MS m / z (ESI): 367.1 (M+1) + .

[0332] 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

[0333] 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 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 007 (5.3 mg, yield: 50%).

[0334] MS m / z (ESI): 410.1 (M+1) + .

[0335] 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).

[0336] Example 5

[0337] (R)-1-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-(2-fluoroethyl)-2-oxo-1, 2, 3, 4- tetrahydroquinolin-3-yl) urea (008)

[0338] Preparation of (R)-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-(2-fluoroethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl) carbamic acid tert-butyl ester (008a)

[0339] 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 completion of the reaction the reaction 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%).

[0340] MS m / z (ESI): 493.1 (M+23) + .

[0341] Preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-(2- fluoroethyl)-3,4-dihydroquinolin-2(lH)-one (008b)

[0342] 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 reaction.

[0343] MS m / z (ESI): 371.0 (M+1) + .

[0344] Preparation of (R)-l-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-(2-fluoroethyl)-2- oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea (008)

[0345] 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, the reaction solution was neutralized to basic with sodium bicarbonate aqueous 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%).

[0346] MS m / z (ESI): 414.0 (M+1) + .

[0347] 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).

[0348] Example 6

[0349] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (009)

[0350] Preparation of tert-butyl (R)-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2- fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (009a)

[0351] 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, the reaction was stirred at 80°C for 2 hours, after the reaction was completed, the reaction solution 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 009a (40 mg, yield: 73%).

[0352] MS m / z (ESI): 509.0 (M+23) + .

[0353] Preparation of the second step (R)-3-amino-7-chloro-8-(2-chloro-5- fluorophenoxy)-1-(2-fluoroethyl)-3,4-dihydroquinolin-2(1H)-one (009b)

[0354] Compound 009a (40 mg, 0.082 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 solution was concentrated under reduced pressure to obtain the crude compound 009b (40 mg), which was used directly in the next step without purification.

[0355] MS m / z (ESI): 387.0 (M+1) + .

[0356] Preparation of the third step (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2- fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (009)

[0357] 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, sodium bicarbonate aqueous solution was added to neutralize to basic, and the crude product was obtained by rotary evaporation, 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 009 (5 mg, yield: 15%).

[0358] MS m / z (ESI): 430.0 (M+1) + .

[0359] 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).

[0360] Example 7

[0361] (R)-1-(1-allyl-8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)urea (010)

[0362] Preparation of the first step (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)

[0363] 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 continued to be 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 system B to obtain compound 010a (45 mg, yield: 83%).

[0364] MS m / z (ESI): 461.2 (M+1) + .

[0365] Preparation of the second step (R)-1-allyl-3-amino-8-(2-chloro-5-fluorophenoxy)-7-methyl-3,4- dihydroquinolin-2(1H)-one (010b)

[0366] Compound 010a (45 mg, 0.097 mmol) was dissolved in 4M hydrochloric acid / dioxane (3 mL), the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude compound 010b (40 mg), which was directly used in the next step without purification.

[0367] MS m / z (ESI): 361.1 (M+1) + .

[0368] Preparation of the third step (R)-1-(1-allyl-8-(2-chloro-5-fluorophenoxy)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (010)

[0369] 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) was added, acetic acid (22 mg, 0.33 mmol) was added, the reaction was stirred at room temperature for 30 minutes, after the reaction was completed, neutralized to basic with sodium bicarbonate aqueous solution, rotary evaporation 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 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%).

[0370] MS m / z (ESI): 404.1 (M+1) + .

[0371] 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).

[0372] Example 8

[0373] (R)-1-(13-Fluoro-1-methyl-6-oxo-5,6-dihydro-4H,8H-benzo[8,9][1,4]oxazolo[2,3,4- ij]quinolin-5-yl)urea (118)

[0374] Preparation of (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)

[0375] 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, the reaction was stirred at 50 °C for 16 h, LC-MS monitored 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 to give compound 118a (90 mg, yield: 68%).

[0376] MS m / z (ESI): 445.2 (M+23) + .

[0377] Preparation of (R)-(13-fluoro-l-methyl-6-oxo-5,6-dihydro-4H,8H- benzo[8,9][l,4]oxazocin[2,3,4-ij]quinolin-5-yl)carbamic acid tert-butyl ester (118b)

[0378] Compound 118a (90 mg, 0.20 mmol) was dissolved in 1,2- dichloroethane (90 mL), (l,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 h, LC-MS monitored the reaction was complete. Directly concentrated and purified by column chromatography to give compound 118b (30 mg, yield: 40%).

[0379] MS m / z (ESI): 445.2 (M+23) + .

[0380] Preparation of (R)-5-amino-l 3-fluoro-l-methyl-4,5-dihydro-6H,8H- benzo[8,9][l,4]oxazocin[2,3,4-ij]quinolin-6-one (118c)

[0381] 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 h, LC-MS monitored the reaction was complete, directly concentrated to give crude compound 118c (25 mg), the crude was used directly in the next step without purification.

[0382] MS m / z (ESI): 325.1 (M+1) + .

[0383] Step 4. 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)

[0384] 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, then potassium cyanate (15 mg, 0.14 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 10%-100%, flow rate: 20 mL / min) to obtain compound 118 (4 mg, yield: 15%).

[0385] MS m / z (ESI): 368.1 (M+1) + .

[0386] 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).

[0387] Example 9

[0388] (R)-1-(13-Fluoro-1-methyl-6-oxo-5,6,9,10-tetrahydro-4H,8H-benzo[8,9][1,4]oxazocino[2,3,4- ij]quinolin-5-yl)urea (088)

[0389] Step 1. Preparation of (R)-1-(13-fluoro-1-methyl-6-oxo-5,6,9,10-tetrahydro-4H,8H- benzo[8,9][1,4]oxazocino[2,3,4-ij]quinolin-5-yl)urea (088)

[0390] 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 under hydrogen atmosphere (15 psi) at room temperature for 3 hours, after the reaction was complete as monitored by LC-MS, 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%).

[0391] MS m / z (ESI): 370.1 (M+1) + .

[0392] 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).

[0393] Example 10

[0394] (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)

[0395] Preparation of (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)

[0396] 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 complete as monitored by LC-MS, the reaction was 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 using system B to give compound 121a (120 mg, yield: 88%).

[0397] MS m / z (ESI): 489.2 (M+23) + .

[0398] Step 2: Preparation of (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)

[0399] 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(ortho- isopropoxybenzylidene)ruthenium (120 mg, 0.2 mmol) was added, the solution was stirred at 80 °C under nitrogen for 16 hours, after the reaction was monitored by LC-MS, the solution was directly concentrated and purified by column chromatography with system B to give compound 121b (80 mg, yield: 71%).

[0400] MS m / z (ESI): 461.2 (M+23) + .

[0401] 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)

[0402] Compound 121b (80 mg, 0.18 mmol) was dissolved in 4M hydrochloric acid in 1,4- dioxane (5 mL), the solution was stirred at room temperature for 1 hour, after the reaction was monitored by LC-MS, the solution was directly concentrated to give crude compound 121c (60 mg), the crude was used in the next step without purification.

[0403] MS m / z (ESI): 339.1 (M+1) + .

[0404] 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)

[0405] Compound 121c (60 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of acetic acid (16 mg, 0.2 mmol) and water (7.2 mg, 0.4 mmol), and then potassium cyanate (30 mg, 0.28 mmol). The reaction was stirred at room temperature for 0.5 hours. After the reaction was complete as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weakly alkaline. The mixture was then concentrated and purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5 μm C18 100 × 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 25 mL / min) to obtain compound 121 (17 mg, yield: 24%).

[0406] MS m / z(ESI): 382.1(M+1) + .

[0407] 1 H NMR(400MHz,DMSO-d6)δ7.28–7.17(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).

[0408] Example 11

[0409] (R)-1-(11-fluoro-14-methyl-3-oxo-2,3,5,6,7,8-hexahydro-1H-benzo[9,10][1,4]oxazinedecane[2,3,4-ij]quinolin-2-yl)urea(094)

[0410] Preparation of step (R)-1-(11-fluoro-14-methyl-3-oxo-2,3,5,6,7,8-hexahydro-1H-benzo[9,10][1,4]oxazylidene[2,3,4-ij]quinolin-2-yl)urea (094)

[0411] Compound 121 (15 mg, 0.04 mmol) was dissolved in methanol (1 mL), palladium on carbon (10 mg) was added, the solution was stirred at room temperature under hydrogen atmosphere for 16 hours, after the reaction was monitored to be complete by LC-MS, 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 (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20 mL / min) to give compound 094 (9.3 mg, yield: 62%).

[0412] MS m / z (ESI): 384.2 (M+1) + .

[0413] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0414] Example 12

[0415] (R)-1-(12-Fluoro-15-methyl-3-oxo-2,3,6,7-tetrahydro-1H,5H- benzo[10,11] [1]oxa[4]azacyclotrideca-2,3,4-ij]quinolin-2-yl)urea (127)

[0416] 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)

[0417] Compound Int 4 (120 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (2 mL), 5-bromo-l-pentene (52 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, 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 127a (120 mg, yield: 86%).

[0418] MS m / z (ESI): 425.2 (M-56) + .

[0419] Preparation of (R)-(12-fluoro-15-methyl-3-oxo-2,3,5,6,7,8-hexahydro-lH- benzo[l l,12][l]oxa[4]azacyclotridecino[2,3,4-ij]quinolin-2-yl)carbamic acid tert-butyl ester (127b) - Second step

[0420] Compound 127a (80 mg, 0.17 mmol) was dissolved in 1,2-dichloroethane (80 mL), (l,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o- isopropoxybenzylidene)ruthenium (80 mg, 0.13 mmol) was added, the solution was stirred at 80 °C under nitrogen atmosphere for 16 hours, after the reaction was complete, it was concentrated under reduced pressure, and purified by column chromatography system B to obtain compound 127b (20 mg, yield: 22%).

[0421] MS m / z (ESI): 475.2 (M+23) + .

[0422] Preparation of (R)-2-amino-12-fluoro-15-methyl-l,2,5,6,7,8-hexahydro-3H- benzo[l l,12][l]oxa[4]azacyclotridecino[2,3,4-ij]quinolin-3-one (127c) - Third step

[0423] 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, the reaction was complete, then directly concentrated to obtain crude compound 127c (16 mg), which was used directly in the next step without purification.

[0424] MS m / z (ESI): 353.2 (M+1) + .

[0425] Step 4. Preparation of (R)-1-(12-fluoro-15-methyl-3-oxo-2,3,5,6,7,8- hexahydro-1H-benzo[11,12][1]oxaazacyclotrideca[2,3,4-ij]quinolin-2-yl)urea (127)

[0426] Compound 127c (16 mg, 0.04 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 under reduced pressure to obtain the crude product, which 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% 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%).

[0427] MS m / z (ESI): 396.1 (M+1) + .

[0428] 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).

[0429] Example 13

[0430] (R)-1-(12-Fluoro-15-methyl-3-oxo-2,3,6,7,8,9-hexahydro-1H,5H- benzo[10,11][1]oxaazacyclotridecan[2,3,4-ij]quinolin-2-yl)urea (100)

[0431] Step 1. Preparation of (R)-1-(12-fluoro-15-methyl-3-oxo-2,3,6,7,8,9- hexahydro-1H,5H-benzo[10,11][1]oxaazacyclotridecan[2,3,4-ij]quinolin-2-yl)urea (100)

[0432] Compound 127 (4.0 mg, 0.01 mmol) was dissolved in methanol (1 mL), 10% wet palladium on carbon (10 mg) was added, and the solution was stirred under a hydrogen atmosphere (15 psi) at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by high performance liquid chromatography, preparative (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 afford compound 100 (2.03 mg, yield: 50%).

[0433] MS m / z (ESI): 398.2 (M+1) + .

[0434] 1 H 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).

[0435] Example 14

[0436] (R)-1-(13-Fluoro-16-methyl-3-oxo-2,3,5,6,7,8-hexahydro-1H- benzo[11,12][1]oxa[4]azacyclododecine[2,3,4-ij]quinolin-2-yl)urea (136)

[0437] 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)

[0438] 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%).

[0439] MS m / z (ESI): 517.2 (M+23) + .

[0440] Preparation of (R)-(13-fluoro-16-methyl-3-oxo-2,3,5,6,7,8-hexahydro-1H- benzo[11,12][1]oxaazacyclododecine[2,3,4-ij]quinolin-2-yl)carbamic acid tert-butyl ester (136b)

[0441] 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 protection for 3 hours, after the reaction was completed, it was directly concentrated and purified by column chromatography in system B to obtain compound 136b (10 mg, yield: 15%).

[0442] MS m / z (ESI): 489.2 (M+23) + .

[0443] Preparation of (R)-2-amino-13-fluoro-16-methyl-1,2,5,6,7,8-hexahydro-3H- benzo[11,12][1]oxaazacyclododecine[2,3,4-ij]quinolin-3-one (136c)

[0444] Compound 136b (10.0 mg, 0.02 mmol) was dissolved in 4M 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 directly used in the next step without purification.

[0445] MS m / z (ESI): 367.2 (M+1) + .

[0446] Step 4. Preparation of (R)-1-(13-fluoro-16-methyl-3-oxo-2,3,5,6,7,8- hexahydro-1H-benzo[11,12][1]oxaazacyclododecine[2,3,4-ij]quinolin-2-yl)urea (136)

[0447] 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, and 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, 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 57%-100%, flow rate: 20 mL / min) to obtain compound 136 (1.16 mg, yield: 9%).

[0448] MS m / z (ESI): 410.1 (M+1) + .

[0449] 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).

[0450] Example 15

[0451] (R)-1-(13-fluoro-16-methyl-3-oxo-2,3,5,6,7,8,9,10-octahydro-1H- benzo[11,12][1]oxaazacyclododecine[2,3,4-ij]quinolin-2-yl)urea (106)

[0452] Step 1. Preparation of (R)-1-(13-fluoro-16-methyl-3-oxo-2,3,5,6,7,8,9,10- octahydro-1H-benzo[11,12][1]oxa[4]azacyclododecine[2,3,4-ij]quinolin-2-yl)urea (106)

[0453] Compound 136 (7.0 mg, 0.01 mmol) was dissolved in methanol (1 mL), 10% wet palladium on carbon (10 mg) was added, and the solution was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and 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 (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 106 (1.6 mg, yield: 22%).

[0454] MS m / z (ESI): 412.2 (M+1) + .

[0455] 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).

[0456] Example 16

[0457] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2-hydroxyethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (036)

[0458] Preparation of (R)-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-(2-chloro-5- fluorophenoxy)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (036a)

[0459] 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 and the reaction was stirred at 50 °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 using system B to afford compound 036a (130 mg, yield: 64 %).

[0460] MS m / z (ESI): 543.0 (M-56) + .

[0461] Preparation of (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-(2- hydroxyethyl)-3,4-dihydroquinolin-2(lH)-one (036b)

[0462] Compound 036a (130 mg, 0.22 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added dropwise to it. The reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to obtain crude compound 036b (100 mg) which was used as such in the next step without further purification.

[0463] MS m / z (ESI): 385.0 (M+1) + .

[0464] Preparation of (R)-l-(7-chloro-8-(2-chloro-5-fluorophenoxy)-l-(2- hydroxyethyl)-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)urea (036)

[0465] 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 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 036 (11.6 mg, yield: 10.5%).

[0466] MS m / z (ESI): 428.0 (M+1) + .

[0467] 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).

[0468] Example 17

[0469] (R)-1-(8-(2-chloro-5-fluorophenoxy)-7-(difluoromethyl)-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (169)

[0470] Preparation of the first step (4-amino-2-fluoro-3-nitrophenyl)methanol (169a)

[0471] Compound Int 1a (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 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%).

[0472] MS m / z (ESI): 187.1 (M+1) + .

[0473] Preparation of the second step (4-bromo-2-fluoro-3-nitrophenyl)methanol (169b)

[0474] Compound 169a (1.8 g, 9.6 mmol) was dissolved in acetonitrile (35 mL), cuprous bromide (2.6 g, 11.6 mmol), the reaction liquid was stirred at 25°C for 1 hour, isopentylnitrite (1.5 g, 211.6 mmol) was added, and the reaction liquid 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%).

[0475] MS m / z (ESI): 232.0 (M+1) + .

[0476] Preparation of the third step 4-bromo-2-fluoro-3-nitrobenzaldehyde (169c)

[0477] 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 liquid 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%).

[0478] MS m / z (ESI): 248.0 (M+1) + .

[0479] Preparation of the fourth step 1-bromo-4-(difluoromethyl)-3-fluoro-2-nitrobenzene (169d)

[0480] Compound 169c (400 mg, 1.6 mmol) was dissolved in dichloromethane (30 mL), diethylamine trifluoride (600 mg, 2.5 mmol) was added, and the reaction liquid 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%).

[0481] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.92 - 7.85 (m, 1H), 7.31 (t, 1H).

[0482] Preparation of 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-(difluoromethyl)-2- nitrobenzene (169e)

[0483] 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 was stirred at 80 °C for 4 h. After the reaction was completed, the mixture was diluted with ethyl acetate (80 mL), washed with water (80 mL x 3), and then dried over anhydrous sodium sulfate. After concentration, compound 169e (250 mg, yield: 68%) was obtained by purification on a silica gel column using system B.

[0484] MS m / z (ESI): 396.6 (M+1) + .

[0485] Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5- fluorophenoxy)-4-(difluoromethyl)-2-nitrophenyl)propanoate (169f)

[0486] Compound 169e (250 mg, 0.63 mmol) was dissolved in N,N-dimethylformamide (10 mL), and Pd(dppf)Cl2(95 mg, 0.13 mmol) and cuprous iodide (25 mg, 0.13 mmol) were added to the reaction mixture under nitrogen at room temperature. Then, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (600 mg, 1.9 mmol) in N,N-dimethylformamide was added under nitrogen. The reaction was stirred at 80 °C for 12 h. After the reaction was completed, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and purified by column chromatography using system B to obtain compound 169f (210 mg, yield: 64%).

[0487] MS m / z (ESI): 541.0 (M+23) + .

[0488] Preparation of (R)-methyl 3-(2-amino-3-(2-chloro-5-fluorophenoxy)-4- (difluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (169g)

[0489] Compound 169f (210 mg, 0.4 mmol) was dissolved in a mixed solvent of ethanol / water (15 mL, V / V = 3:1), 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 hours. After the reaction was completed, diatomite was used for filtration, and the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography system B to obtain compound 169g (100 mg, yield: 55%).

[0490] MS m / z (ESI): 511 (M+23) + .

[0491] Preparation of (R)-tert-butyl (8-(2-chloro-5-fluorophenoxy)-7- (difluoromethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (169h)

[0492] 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 hours. After the reaction was completed, diatomite was used for filtration, and the filtrate was concentrated under reduced pressure. Purification was performed by silica gel column chromatography system B to obtain compound 169h (85 mg, yield: 93%).

[0493] MS m / z (ESI): 479.0 (M+23) + .

[0494] Preparation of (R)-tert-butyl (8-(2-chloro-5-fluorophenoxy)-7- (difluoromethyl)-1-(2-fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (169i)

[0495] Compound 169h (85 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and bromofluoroethane (45 mg, 0.36 mmol) and potassium carbonate (125 mg, 0.9 mmol) were added. After the reaction was stirred at 50 °C for 3 hours, it was quenched with water and extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. Purification was performed by column chromatography to obtain compound 169i (80 mg, yield: 88%).

[0496] MS m / z (ESI): 525 (M+23) + .

[0497] Preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7- (difluoromethyl)-1-(2-fluoroethyl)-3,4-dihydroquinolin-2(1H)-one (169j)

[0498] To compound 169i (80 mg, 0.16 mmol) was added hydrochloric acid dioxane solution (3 mL), the reaction was stirred at room temperature for 1 hour, after the reaction was completed, rotary evaporation to obtain compound 169j (55 mg, yield: 86%).

[0499] MS m / z (ESI): 403 (M+1) + .

[0500] Tenth step preparation of (R)-1-(8-(2-chloro-5-fluorophenoxy)-7-(difluoromethyl)-1-(2-fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (169)

[0501] 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, and 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 monitoring, 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 150×19 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%).

[0502] MS m / z (ESI): 446.1 (M+1) + .

[0503] 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).

[0504] Example 18

[0505] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea (170)

[0506] First step: Preparation of tert-butyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate (170b)

[0507] Compound 170a (1.0 g, 3.5 mmol) was dissolved in tert-butanol (10 mL), di-tert-butyl dicarbonate (1.53 g, 7.0 mmol) was added followed by 4-dimethylamino pyridine (40 mg, 0.35 mmol) and the reaction was stirred at 50 °C for 12 h. The reaction was directly concentrated under reduced pressure to get crude which was purified by column chromatography using system B to get compound 170b (1 g, yield: 60 %).

[0508] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 - 7.80 (m, 2H), 1.58 (s, 9H).

[0509] Second step: Preparation of tert-butyl 6-bromo-2-(2-chloro-5-fluorophenoxy)-3- (trifluoromethyl)benzoate (170c)

[0510] 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 and the reaction was stirred at 100 °C for 12 h. The reaction was quenched with water and extracted with ethyl acetate and the organic phase was collected and dried over anhydrous sodium sulfate. The crude was purified by column chromatography to get compound 170c (1 g, yield: 66 %).

[0511] 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).

[0512] Third step: Preparation of 6-bromo-2-(2-chloro-5-fluorophenoxy)-3- (trifluoromethyl)benzoic acid (170d)

[0513] Compound 170c (1 g, 2.1 mmol) was dissolved in a mixture of dichloromethane and trifluoroacetic acid (12 mL, V / V = 5:1) and the reaction was stirred at 25 °C for 12 h. The reaction was directly concentrated under reduced pressure to get crude compound 170d (700 mg) which was used as such in the next step without purification.

[0514] Fourth step: Preparation of tert-butyl (6-bromo-2-(2-chloro-5-fluorophenoxy)-3- (trifluoromethyl)phenyl)carbamate (170e)

[0515] 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-diisopropyl ethylamine (654.7 mg, 5.1 mmol) were added, after the reaction was stirred at 100 °C under nitrogen protection for 3.5 hours, after the reaction was completed, the reaction was quenched with a small amount of water, concentrated and purified by column chromatography in system B to obtain compound 170e (500 mg, yield: 55%).

[0516] MS m / z (ESI): 427.9 (M+1-56) + .

[0517] Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5- fluorophenoxy)-2-((2-fluoroethyl)amino)-4-(trifluoromethyl)phenyl)propanoate (170h)

[0518] Compound 170e (230 mg, 0.47 mmol) was dissolved in N,N-dimethylformamide (5 mL), bromofluoroethane (120.3 mg, 0.95 mmol) was added, then sodium hydride (28.4 mg, 0.71 mmol) was added, after the reaction was stirred at 25 °C for 12 hours, after the reaction was completed, 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 in system B to obtain compound 170f (100 mg, yield: 40%).

[0519] MS m / z (ESI): 473.9 (M+1-56) + .

[0520] Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5- fluorophenoxy)-2-((2-fluoroethyl)amino)-4-(trifluoromethyl)phenyl)propanoate (170h)

[0521] Compound 170f (150 mg, 0.28 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (5 mL), the solution was stirred at room temperature for 1 hour, after the reaction was completed, the crude compound 170g (100 mg) was directly concentrated.

[0522] MS m / z (ESI): 429.9 (M+1) + .

[0523] Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5- fluorophenoxy)-2-((2-fluoroethyl)amino)-4-(trifluoromethyl)phenyl)propanoate (170h)

[0524] 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%).

[0525] MS m / z (ESI): 553.1 (M+1) + .

[0526] Preparation of (R)-tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5- fluorophenoxy)-2-((2-fluoroethyl)amino)-4-(trifluoromethyl)phenyl)propanoate (170i)

[0527] 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.

[0528] MS m / z (ESI): 539.1 (M+1) + .

[0529] 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)

[0530] 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%).

[0531] MS m / z (ESI): 543.2 (M+23) + .

[0532] Preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-7- (trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one (170k)

[0533] 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.

[0534] MS m / z (ESI): 421.0 (M+1) + .

[0535] 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)

[0536] 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%).

[0537] MS m / z (ESI): 464.0 (M+1) + .

[0538] 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).

[0539] Example 19

[0540] (R)-1-(1-allyl-8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)urea (011)

[0541] 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)

[0542] 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%).

[0543] MS m / z (ESI): 464.0 (M+1) + .

[0544] Preparation of the second step (R)-1-allyl-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-3,4- dihydroquinolin-2(1H)-one (011b)

[0545] 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 hours, after the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude compound 011b (70 mg), which was directly used in the next step reaction without purification.

[0546] MS m / z (ESI): 455.1 (M+1) + .

[0547] Preparation of (R)-1 -(1 -allyl-8-(2-chloro-5-fluorophenoxy)-7-fluoro-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea (011)

[0548] 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, rotary evaporation to get the crude product, the crude product was directly purified by high performance liquid chromatography (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 011 (28 mg, yield: 45%).

[0549] MS m / z (ESI): 408.1 (M+1) + .

[0550] 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).

[0551] Example 20

[0552] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (012)

[0553] 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)

[0554] 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%).

[0555] MS m / z (ESI): 425.0 (M-56) + .

[0556] Preparation of (R)-1-allyl-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-3,4- dihydroquinolin-2(lH)-one (012b) in the second step

[0557] 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 directly used in the next step reaction without purification.

[0558] MS m / z (ESI): 381.0 (M+1) + .

[0559] (R)-1-(1-allyl-7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea 012 in the third step

[0560] Compound 012d (170 mg, 0.45 mmol) was dissolved in tetrahydrofuran (5 mL), potassium cyanate (72 mg, 0.89 mmol) was added, and then two drops of water and two drops of acetic acid were added dropwise, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, saturated sodium bicarbonate was added to quench the reaction system to be alkaline. Concentrated under reduced pressure to obtain the crude product, the crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, chromatographic column: Xbridge 5 μm C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 10 minutes gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 25 mL / min) to obtain compound 012 (100 mg, yield: 47%).

[0561] MS m / z (ESI): 424.1 (M+1) + .

[0562] 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).

[0563] Example 21

[0564] (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)

[0565] First step: 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)

[0566] 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, 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 was purified by column chromatography in a separation system to obtain compound 055a (30 mg, yield: 79.9%).

[0567] MS m / z (ESI): 417.0 (M-55) + .

[0568] Second step: 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)

[0569] 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, LC-MS monitoring reaction was complete, the reaction was directly concentrated under reduced pressure to obtain the crude compound 055b (25 mg), the product was directly used in the next step without purification.

[0570] MS m / z (ESI): 373.0 (M-55) + .

[0571] 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)

[0572] 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 LC-MS monitoring reaction was complete, 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%).

[0573] MS m / z (ESI): 416.1 (M+1) + .

[0574] 1 H NMR (400 MHz, CDCl3) 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).

[0575] Example 22

[0576] (R)-1-(8-(2-bromo-5-fluorophenoxy)-7-chloro-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (178)

[0577] Preparation of first step 1-bromo-3-(2-bromo-5-fluorophenoxy)-4-chloro-2- nitrobenzene (178a)

[0578] 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%).

[0579] MS m / z (ESI): 423.8 (M+1) + .

[0580] Preparation of second step (R)-3-(3-(2-bromo-5-fluorophenoxy)-4-chloro-2- nitrophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester (178b)

[0581] 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 iodide (II) (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 and the reaction was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction was monitored by LC-MS and upon completion the reaction mixture was evaporated. The crude was purified by column chromatography using system B to get compound 178b (150 mg, yield: 70%).

[0582] MS m / z (ESI): 569.0 (M+23) + .

[0583] Preparation of third step (R)-3-(2-amino-3-(2-bromo-5-fluorophenoxy)-4-chlorophenyl)- 2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester (178c)

[0584] 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, filtration was performed using celite, and the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography in system B to obtain compound 178c (100 mg, yield: 63%).

[0585] MS m / z (ESI): 460.9 (M+1-56) + .

[0586] Preparation of (R)-(8-(2-bromo-5-fluorophenoxy)-7-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)carbamic acid tert-butyl ester (178d)

[0587] Compound 178c (100 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and 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, methanol was added to quench the reaction, and the reaction was dried by evaporation, and the crude product was purified by column chromatography in system B to obtain compound 178d (90 mg, yield: 86%).

[0588] MS m / z (ESI): 429.0 (M+1-56) + .

[0589] Preparation of (R)-(8-(2-bromo-5-fluorophenoxy)-7-chloro-1-(2-fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)carbamic acid tert-butyl ester (178e)

[0590] 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, and the organic phase was washed with an aqueous ammonium chloride solution, and the crude product was dried by evaporation, and the crude product was purified by column chromatography in system B to obtain compound 178e (90 mg, yield: 82%).

[0591] MS m / z (ESI): 475.0 (M+1-56) + .

[0592] Step 6. Preparation of (R)-3-amino-8-(2-bromo-5-fluorophenoxy)-7-chloro-1-(2- fluoroethyl)-3,4-dihydroquinolin-2(1H)-one (178f)

[0593] 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.

[0594] MS m / z (ESI): 430.0 (M+1) + .

[0595] Step 7. Preparation of (R)-1-(8-(2-bromo-5-fluorophenoxy)-7-chloro-1-(2- fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (178)

[0596] 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 get 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 150×19 mm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min), purification to get compound 178 (4.36 mg, yield: 12%).

[0597] MS m / z (ESI): 474.0 (M+1) + .

[0598] 1 H NMR (400 MHz, CDCl3) 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).

[0599] Example 23

[0600] (R)-1-(8-(2-bromo-5-fluorophenoxy)-1-(2-fluoroethyl)-7-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (179)

[0601] Preparation of the first step (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)

[0602] 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%).

[0603] MS m / z (ESI): 511.1 (M+1) + .

[0604] 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)

[0605] 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.

[0606] MS m / z (ESI): 411.1 (M+1) + .

[0607] 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)

[0608] 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 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 179 (9.0 mg, yield: 18.3%).

[0609] MS m / z (ESI): 454.1 (M+1) + .

[0610] 1 HNMR (400 MHz, 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).

[0611] Example 24

[0612] (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1-(2,2-difluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea

[0613] 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)

[0614] 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%).

[0615] MS m / z (ESI): 527.0 (M+23).

[0616] Preparation of the second step (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1-(2,2- difluoroethyl)-7-chloro-3,4-dihydroquinolin-2(1H)-one (003b)

[0617] Compound 003a (330 mg, 0.65 mmol) was dissolved in dichloromethane (5 mL), 4M hydrochloric acid / dioxane (5 mL) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude compound 003b (265 mg, yield: 100%), which was directly used in the next step reaction.

[0618] MS m / z (ESI): 405.0 (M+1).

[0619] Preparation of the third step (R)-1-(7-chloro-8-(2-chloro-5-fluorophenoxy)-1- (cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (003)

[0620] 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, and 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, LC-MS was used to monitor the reaction, sodium bicarbonate solution was added to adjust the pH to weak alkaline, and 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%).

[0621] MS m / z (ESI): 448.0 (M+1).

[0622] 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).

[0623] Example 25

[0624] (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)

[0625] Preparation of first step (R)-(1-(but-3-en-1-yl)-7-chloro-8-(5-fluoro-2- vinylphenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (123a)

[0626] Compound Int 5 (180 mg, 0.42 mmol) was dissolved in N,N- dimethylformamide (5 mL), added compound 4-bromo-1-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%).

[0627] MS m / z (ESI): 487.1 (M+1) + .

[0628] Preparation of second step (R)-(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)carbamic acid tert-butyl ester (123b)

[0629] Compound 123a (180 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (180 mL), (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o- isopropoxybenzylidene) ruthenium (180 mg, 0.29 mmol) was added, and 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 system B to give compound 123b (150 mg, yield: 88%).

[0630] MS m / z (ESI): 403.1 (M-55) + .

[0631] Preparation of (R)-2-amino-14-chloro-11-fluoro-1,2,5,6-tetrahydro-3H- benzo[9,10][1,4]oxazacyclodeca[2,3,4-ij]quinolin-3-one (123c)

[0632] Compound 123b (80 mg, 0.17 mmol) was dissolved in 4 M hydrochloric acid / 1,4- dioxane (5 mL), and the solution was stirred at room temperature for 1 hour. After the reaction was completed, it was directly concentrated to give crude compound 123c (70 mg, ). The crude product was used directly in the next reaction without purification.

[0633] MS m / z (ESI): 359.1 (M+1) + .

[0634] 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]quinolin-2-yl)urea (123)

[0635] 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, and then potassium cyanate (19 mg, 0.23 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, and 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 give compound 123 (20 mg, yield: 26%).

[0636] MS m / z (ESI): 402.1 (M+1) + .

[0637] 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).

[0638] Example 26

[0639] (R)-1-(15-chloro-12-fluoro-3-oxo-2,3,6,9-tetrahydro-1H,5H- benzo[10,11][1]oxa[4]azacyclotetradeca[2,3,4-ij]quinoline-2-yl)urea (132)

[0640] Preparation of first step (R)-(8-(2-allyl-5-fluorophenoxy)-7-chloro-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (132a)

[0641] Compound Int 5d (400 mg, 0.83 mmol) was dissolved in toluene (5 mL), allyl tributyl tin (328 mg, 0.99 mmol) and dichlorobispalladium (88 mg, 0.12 mmol) were added and the reaction was stirred at 100 for 16 h. The reaction was monitored by LC-MS and was found to be complete. The reaction was evaporated to dryness and the crude was purified by column chromatography to get compound 132a (220 mg, yield: 60%).

[0642] MS m / z (ESI): 391.1 (M+1-56) + .

[0643] Preparation of second step (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)

[0644] 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 hours, the reaction was monitored by LC-MS, 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 give compound 132b (120 mg, yield: 80%).

[0645] MS m / z (ESI): 445.1 (M+1-56) + .

[0646] 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)

[0647] 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 in system B to give compound 132c (100 mg, yield: 80%).

[0648] MS m / z (ESI): 417.1 (M+1-56) + .

[0649] 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)

[0650] 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 give crude compound 132d (80 mg), which was used directly in the next step without purification.

[0651] MS m / z (ESI): 373.2 (M+1) + .

[0652] Step 5. 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)

[0653] Compound 132d (80 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (3 drops) and water (3 drops) were added, followed by potassium cyanate (23 mg, 0.29 mmol), the reaction was stirred at room temperature for 0.5 hour, after the reaction was complete, sodium bicarbonate solution was added to adjust the pH to weakly basic, the mixture was then 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; 13 minute gradient, gradient ratio: acetonitrile phase 45%-100%, flow rate: 20 mL / min) to give compound 132 (9.0 mg, yield: 11%).

[0654] MS m / z (ESI): 416.0 (M+1) + .

[0655] 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).

[0656] Example 27

[0657] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1-(2-fluoroethyl)-7-(fluoromethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (253)

[0658] 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 253 (4.5 mg, yield: 10.0%).

[0659] MS m / z (ESI): 428.1 (M+1) + .

[0660] 1 H NMR (400 MHz, DMSO-d6) d 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).

[0661] Example 28

[0662] (R)-1-(11,14-difluoro-3-oxo-2,3,5,6-tetrahydro-1H-benzo[9,10][1,4]oxazacyclodeca[2,3,4- ij]quinolin-2-yl)urea (122)

[0663] 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 122 (20 mg, yield: 31%).

[0664] MS m / z (ESI): 486.1 (M+1) + .

[0665] 1H NMR (400 MHz, DMSO-d6) δ 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).

[0666] Example 29

[0667] (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)

[0668] Preparation of the first step 5-chloro-4-(2-chloro-5-fluorophenoxy)-3-nitropyridin-2-amine (234b)

[0669] 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%).

[0670] MS m / z (ESI): 318.0 (M+1) + .

[0671] Preparation of the second step 2-bromo-5-chloro-4-(2-chloro-5-fluorophenoxy)-3-nitropyridine (234c)

[0672] Copper bromide (879 mg, 6.13 mmol) was dissolved in acetonitrile (30 mL), isoamyl nitrite (717 mg, 6.13 mmol) was added, the reaction was stirred at 25 °C for 1 hour, compound 234b (1.5 g, 4.72 mmol) was added, the reaction was stirred at 25 °C for 30 minutes, 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), then 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%).

[0673] MS m / z (ESI): 382.8 (M+1) + .

[0674] Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(5-chloro-4-(2-chloro-5- fluorophenoxy)-3-nitropyridin-2-yl)propanoate (234d)

[0675] Into a reaction flask was added zinc powder (3 g), replaced with nitrogen, and a needle tube was used to add N,N-dimethylformamide (8 mL), which was stirred at 40 °C for 15 minutes under nitrogen protection. Trimethylchlorosilane (55 mg, 0.51 mmol) and 1,2-dibromoethane (110 mg, 0.59 mmol) were added to the system under nitrogen protection, and the reaction mixture was stirred at 40 °C for 15 minutes. A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (7.1 g, 21.57 mmol) in N,N-dimethylformamide (8 mL) was added to the reaction mixture under nitrogen protection, and the mixture was stirred at 40 °C for 30 minutes under nitrogen protection. The mixture was cooled to room temperature under nitrogen protection to obtain a zinc reagent solution for standby use. Another flask was prepared to add a solution of compound 234c (200 mg, 0.52 mmol) in N,N-dimethylformamide (1 mL). 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) were added to the reaction mixture under nitrogen protection at room temperature. The resulting reaction mixture was stirred at 80 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction mixture was filtered through celite, and the filter cake was washed with ethyl acetate. The organic phase was washed twice with an aqueous solution of ammonium chloride, and the organic phase was concentrated to obtain a crude product, which was purified by silica gel column chromatography system B to obtain compound 234d (200 mg, yield: 76%).

[0676] MS m / z (ESI): 448.0 (M-55) + .

[0677] Step 4: Preparation of (R)-methyl 3-(3-amino-5-chloro-4-(2-chloro-5- fluorophenoxy)pyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (234e)

[0678] Compound 234d (200 mg, 0.40 mmol) was dissolved in a mixed solvent of ethanol and water (4 mL, V / V = 3:1), iron powder (67 mg, 1.19 mmol), ammonium chloride (64 mg, 1.19 mmol) were added. The reaction was stirred at 80 °C for 12 hours. After the reaction was completed, the reaction was filtered using diatomite, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography system B gave compound 234e (170 mg, yield: 90%).

[0679] MS m / z (ESI): 474.0 (M+1) + .

[0680] Step 5: 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)

[0681] Compound 234e (170 mg, 0.36 mmol) was dissolved in dichloromethane (2 mL), and trimethylaluminum (52 mg, 0.72 mmol) was added. The reaction was stirred at 25 °C for 1.5 hours. After the reaction was completed, the reaction was filtered using diatomite, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography system B gave compound 234f (120 mg, yield: 76%).

[0682] MS m / z (ESI): 386.0 (M-55) + .

[0683] Step 6: 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)

[0684] Compound 234f (120 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (112 mg, 0.81 mmol), and iodomethane (114 mg, 0.81 mmol) were added. The reaction was stirred at 40 °C for 4 hours. After the reaction was completed, the reaction was filtered, diluted with ethyl acetate, and the organic phase was washed with an aqueous ammonium chloride solution. The crude product was obtained by drying under reduced pressure and was purified by silica gel column chromatography system B to give compound 234g (90 mg, yield: 73%).

[0685] MS m / z (ESI): 400.0 (M-55) + .

[0686] Step 7. Preparation of (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-1- methyl-3,4-dihydro-1,5-naphthyridin-2(1 H)-one (234h)

[0687] 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 hour. After the reaction was completed, it was concentrated by rotary evaporation to give compound 234h (40 mg, yield: 87%).

[0688] MS m / z (ESI): 356.0 (M+1) + .

[0689] Step 8. 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)

[0690] Compound 234h (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.5 mL), H2O (0.5 mL), potassium cyanate (18 mg, 0.16 mmol) was added, and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was evaporated to give 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 give compound 234 (30 mg, yield: 67%).

[0691] MS m / z (ESI): 399.0 (M+1) + .

[0692] 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).

[0693] Example 30

[0694] (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)

[0695] Preparation of the first step (R)-(7-chloro-8-(5-fluoro-2- (hydroxymethyl)phenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamic acid tert-butyl ester (242a)

[0696] 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), compound tributylstannylmethanol (199 mg, 0.61 mmol), replaced with nitrogen, and the reaction was stirred at 80 °C for 16 hours. The reaction was reduced to room temperature, concentrated, and purified by silica gel column chromatography system A to obtain compound 242a (100 mg, yield 56%).

[0697] MS m / z (ESI): 381.1 (M-55) + .

[0698] Preparation of the second step (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)

[0699] 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 hours. 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 obtain compound 242b (70 mg, yield 66%).

[0700] MS m / z (ESI): 407.1 (M-55) + .

[0701] Step 3. Preparation of (R)-3-amino-7-chloro-l-(2-chloroethyl)-8-(5-fluoro-2- (hydroxymethyl)phenoxy)-3,4-dihydroquinolin-2(lH)-one (242c)

[0702] Compound 242b (70 mg, 0.65 mmol) was dissolved in dichloromethane (2 mL), 4 M hydrochloric acid / dioxane (2 mL) was added, the reaction was stirred at room temperature for 30 minutes, and the reaction solution was concentrated under reduced pressure to obtain crude compound 242c (60 mg, yield: 100%), which was directly used in the next step.

[0703] MS m / z (ESI): 363.1 (M+1) + .

[0704] Step 4. Preparation of (R)-l-(14-chloro-l l-fluoro-3-oxo-2,3,5,6-tetrahydro-lH,8H- benzo[9,10][l,7,4]dioxazocin[2,3,4-ij]quinolin-2-yl)urea (242)

[0705] 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 then potassium cyanate (16 mg, 0.2 mmol) was added, and 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 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 28%-95%, flow rate: 20 mL / min) to obtain compound 242 (3 mg, yield: 7.6%).

[0706] MS m / z (ESI): 406.0 (M+1) + .

[0707] 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).

[0708] Example 31

[0709] (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)

[0710] Referring to the synthetic route of Example 6, the final product was 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 (containing 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%).

[0711] MS m / z (ESI): 444.1 (M+1) + .

[0712] 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).

[0713] Example 32

[0714] Compound 268A, Compound 268B

[0715] First Step Preparation of compound 268b

[0716] 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).

[0717] MS m / z (ESI): 358.9 (M+1)+ .

[0718] Preparation of compound 268c

[0719] 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) and ammonium chloride (668 mg, 12.5 mmol) were added. The reaction was stirred at 70 °C for 1 hour. After the reaction was completed, diatomite was used for filtration, and the filtrate was concentrated under reduced pressure to obtain compound 268c (480 mg, yield: 48%).

[0720] MS m / z (ESI): 329.9 (M+1) + .

[0721] Preparation of compound 268d

[0722] 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), which was directly used in the next reaction without purification.

[0723] MS m / z (ESI): 328.0 (M+1) + .

[0724] Preparation of compound 268e

[0725] 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%).

[0726] MS m / z (ESI): 342.0 (M+1) + .

[0727] Preparation of compound 268f

[0728] 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%).

[0729] MS m / z (ESI): 465.1 (M+1) + .

[0730] Sixth step Preparation of compound 268g

[0731] 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%).

[0732] MS m / z (ESI): 377.0 (M-56) + .

[0733] Seventh step Preparation of compound 268h

[0734] 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 slowly added dropwise over 5 min. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was slowly poured 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%).

[0735] MS m / z (ESI): 379.0 (M-56+1) + .

[0736] Eighth step Preparation of compound 268i

[0737] 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.

[0738] MS m / z (ESI): 317.0 (M+1) + .

[0739] Ninth step Preparation of compound 268j

[0740] 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%).

[0741] MS m / z (ESI): 361.0 (M-56+1) + .

[0742] Tenth step Preparation of compound 268k

[0743] 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%).

[0744] MS m / z (ESI): 363.0 (M-Boc+1) + .

[0745] Eleventh step Preparation of compound 268l

[0746] 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. The hydrogen was replaced and the reaction was stirred at 25 °C for 4 h. After the reaction was completed, the filter was used to filter using diatomite and the filtrate was concentrated under reduced pressure to obtain compound 268l (180 mg, yield: 90%).

[0747] MS m / z (ESI): 365.0 (M-Boc+1) + .

[0748] Twelfth Step Preparation of compound 268m

[0749] 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%).

[0750] MS m / z (ESI): 365.0 (M+1) + .

[0751] Thirteenth Step Preparation of compound 268, 268A, 268B

[0752] 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*250mm 10μm; mobile phase 1: water (containing 0.1% FA); mobile phase 2: acetonitrile; 10 min 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, 250mm x 30mm I.D., 10μm, mobile phase: CO2 / MeOH [0.2% NH3(7M MeOH solution)] = 50 / 50, flow rate: 80 g / min) was used to resolve 268A (front peak, 4 mg, RT = 1.372 min) and 268B (rear peak, 1 mg, RT = 2.106 min).

[0753] 268A:

[0754] MS m / z (ESI): 408.0 (M+1) + .

[0755] 1H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.41 (m, 1H), 7.36 - 7.32 (m, 1H), 7.18 - 7.14 (m, 1H), 7.12 - 7.01 (m, 3H), 6.43 (d, 1H), 5.80 (s, 2H), 4.74 - 4.54 (m, 2H), 4.48 - 4.30 (m, 2H), 3.99 - 3.90 (m, 1H), 3.81 - 3.68 (m, 1H), 2.91 - 2.86 (m, 1H), 2.67 - 2.61 (m, 1H), 1.68 (d, 3H).

[0756] 268B:

[0757] MS m / z (ESI): 408.0 (M+1) + .

[0758] 1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.44 (m, 1H), 7.38 - 7.35 (m, 1H), 7.22 - 7.16 (m, 2H), 7.12 - 7.07 (m, 2H), 6.45 (d, 1H), 5.82 (s, 2H), 4.75 - 4.58 (m, 2H), 4.50 - 4.35 (m, 2H), 4.02 - 3.93 (m, 1H), 3.84 - 3.69 (m, 1H), 2.94 - 2.89 (m, 1H), 2.69 - 2.65 (m, 1H), 1.71 (d, 3H).

[0759] Example 33

[0760] (R)-1-(2,2-difluoropropyl)-7-chloro-8-(2-chloro-5-fluorophenoxy)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl urea (280)

[0761] 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).

[0762] MS m / z (ESI): 462.1 (M+1) + .

[0763] 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).

[0764] Example 34

[0765] (R)-1-(7-chloro-8-(2-chloro-4,5-difluorophenoxy)-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (294)

[0766] First Step, Preparation of compound 294a

[0767] Compound Int 2c (150 mg, 0.59 mmol) was dissolved in N,N-dimethylformamide (5 mL), 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, 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 give the crude compound 294a (220 mg), which was used directly in the next step without purification.

[0768] MS m / z (ESI): 397.9 (M+1) + .

[0769] Second Step, Preparation of compound 294b

[0770] Compound 294a (220 mg, 0.55 mmol) was dissolved in methanol: tetrahydrofuran: water = 5:2:1 (8 mL), iron powder (308 mg, 5.5 mmol) and ammonium chloride (297 mg, 5.5 mmol) were added, the solution was stirred at 75 °C for 1 hour, after LC-MS monitoring showed that the reaction was complete, filtered, concentrated and purified by column chromatography with system B to give compound 294b (200 mg, yield: 98%).

[0771] MS m / z (ESI): 368.1 (M+1) + .

[0772] Third Step, Preparation of compound 294c

[0773] 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) iodide (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 give compound 294c (200 mg, yield: 80%).

[0774] MS m / z (ESI): 403.1 (M+1-56) + .

[0775] Fourth Step Preparation of compound 294d

[0776] 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 give compound 294d (160 mg, yield: 73%).

[0777] MS m / z (ESI): 449.1 (M+1-56) + .

[0778] Fifth Step Preparation of compound 294e

[0779] 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 give the crude compound 294e (125 mg), the product was used directly in the next step reaction without purification.

[0780] MS m / z (ESI): 405.1 (M+1) + .

[0781] Sixth Step Preparation of compound 294

[0782] 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, which 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%).

[0783] MS m / z (ESI): 448.1 (M+1) + .

[0784] 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).

[0785] Example 35

[0786] (R)-1-(8-(2-chloro-4,5-difluorophenoxy)-7-(difluoromethyl)-1-(2-fluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (300)

[0787] Using the synthetic route of Example 17, the final 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).

[0788] MS m / z (ESI): 464.0 (M+1) + .

[0789] 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).

[0790] Example 36

[0791] (R)-1-(7-chloro-8-(2,4-dichloro-5-fluorophenoxy)-1-(2-fluoroethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (297)

[0792] First Step Preparation of compound 297b

[0793] 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%).

[0794] 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65 (d, 1H), 6.96 (d, 1H).

[0795] Second Step Preparation of compound 297c

[0796] Compound 297b (0.85 g, 4.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 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 solution 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 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%). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65 (d, 1H), 6.96 (d, 1H).

[0795] Second Step Preparation of compound 297c

[0796] Compound 297b (0.85 g, 4.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 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 solution 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 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%). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65 (d, 1H), 6.96 (d, 1H).

[0795] Second Step Preparation of compound 297c

[0796] Compound 297b (0.85 g, 4.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 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 solution 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 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%). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65 (d, 1H), 6.96 (d, 1H).

[0795] Second Step Preparation of compound 297c

[0796] Compound 297b (0.85 g, 4.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 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 solution 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 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%). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65 (d, 1H), 6.96 (d, 1H).

[0795] Second Step Preparation of compound 297c

[0796] Compound 297b (0.85 g, 4.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 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 solution 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 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%). 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.65 (d, 1H), 6.96 (d, 1H).

[0795] Second Step Preparation of compound 297c

[0796] Compound 297b (0.85 g, 4.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 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 solution 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 the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column

[0797] 1 H NMR (400 MHz, CDC13) δ 7.60 (d, 1H), 7.52-7.49 (m, 2H), 6.51 (d, 1H).

[0798] Third Step Preparation of compound 297d

[0799] 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 reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography system B to obtain compound 297d (800 mg, yield: 86.2%).

[0800] MS m / z (ESI): 383.8 (M+1) + .

[0801] Fourth Step Preparation of compound 297e

[0802] 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. After the reaction was stirred at 80°C for 16 hours. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate, and 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%).

[0803] MS m / z (ESI): 418.9 (M+1-56) + .

[0804] Fifth Step Preparation of compound 297f

[0805] Compound 297g (80 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL) and potassium carbonate (69.7 mg, 0.50 mmol) was added. The reaction was stirred at 50 °C for 5 h. After the reaction was completed, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography on silica gel (eluent: 0% - 20% petroleum ether / ethyl acetate) to give compound 297f (50 mg, yield: 45.6%).

[0806] MS m / z (ESI): 421.0 (M+1-100) + .

[0807] Step 6 Preparation of compound 297g

[0808] Compound 297f (50 mg, 0.096 mmol) was dissolved in 4M hydrogen chloride / 1,4-dioxane (2 mL) and the solution was stirred at room temperature for 0.5 h. After the reaction was completed, it was directly concentrated to give crude 297g (20 mg). The crude was used directly in the next step without purification.

[0809] MS m / z (ESI): 421.0 (M+1) + .

[0810] Step 7 Preparation of compound 297

[0811] Compound 297g (20 mg, 0.047 mmol) was dissolved in tetrahydrofuran (2 mL), acetic acid (0.2 mL) and water (0.2 mL) were added, and then potassium cyanate (7.68 mg, 0.09 mmol) was added. The reaction was stirred at room temperature for 0.5 h. After the reaction was completed, sodium bicarbonate solution was added to adjust the pH to weak alkaline, and extracted with ethyl acetate. The organic phase was collected and concentrated to give a crude product. The crude product was purified by preparative high performance liquid chromatography (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 min gradient, gradient ratio: acetonitrile phase 49% - 100%, flow rate: 25 mL / min) to give compound 297 (1 mg, yield: 4.2%).

[0812] MS m / z (ESI): 464.0 (M+1) + .

[0813] 1H 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).

[0814] Example 37

[0815] (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)

[0816] First Step: Preparation of compound 328b

[0817] 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 using system B to obtain compound 328b (1.2 g, yield: 50.0%).

[0818] 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (dd, 1H), 7.92 (q, 2H), 7.32 (dd, 1H).

[0819] Second Step: Preparation of compound 328c

[0820] Compound 328b (1.2 g, 2.7 mmol) was dissolved in N,N-dimethylformamide (12 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (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 (II) iodide (5.4 mL, 5.4 mmol, N,N-dimethylformamide solution) was added under nitrogen protection, and the reaction was stirred at 80°C for 6 hours. After the reaction was completed, water was added to quench, and then ethyl acetate was added to extract, 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%).

[0821] MS m / z (ESI): 464.9 (M-100+1) + .

[0822] Step 3 Preparation of compound 328d

[0823] Compound 328c (1.0 g, 1.7 mmol) was dissolved in a mixture solvent of methanol / water (20 mL / 4 mL), 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, after the reaction was completed, the filter was carried out using diatomite, the filtrate was concentrated under reduced pressure to obtain the crude product, the crude product was purified by column chromatography system B to obtain compound 328d (800 mg, yield: 88%).

[0824] MS m / z (ESI): 535.1 (M+1) + .

[0825] Step 4 Preparation of compound 328e

[0826] Compound 328d (800 mg, 1.5 mmol) was dissolved in dichloromethane (20 mL), trimethylaluminum (1.15 mL, 2M, 2.3 mmol) was added, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, methanol was slowly added for dilution, and the crude product was obtained by rotary evaporation, which was purified by column chromatography system B to obtain compound 328e (550 mg, yield: 73%).

[0827] MS m / z (ESI): 503.1 (M+1) + .

[0828] Step 5 Preparation of compound 328f

[0829] 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, the reaction was stirred at 50 °C for 16 hours, LC-MS was used to monitor the completion of the reaction, water was used for quenching, and ethyl acetate was used for extraction, the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography separation system B to obtain compound 328f (200 mg, yield: 80%).

[0830] MS m / z (ESI): 501.7 (M+1-56) + .

[0831] Step 6 Preparation of compound 328g

[0832] 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-dimethylaminophenyl) palladium(II) (13 mg, 0.018 mmol) were added. The reaction was stirred at 90 °C for 3 hours and monitored by LC-MS. The reaction was concentrated and the crude product was purified by column chromatography using system B to give compound 328g (150 mg, yield: 82%).

[0833] MS m / z (ESI): 449.1 (M+1-56) + .

[0834] Seventh step: Preparation of compound 328h

[0835] 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 and the solution was stirred at 60 °C under nitrogen for 16 hours. The reaction was monitored by LC-MS and upon completion, the solution was concentrated and purified by column chromatography using system B to give compound 328h (20 mg, yield: 53%).

[0836] MS m / z (ESI): 421.0 (M+1-56) + .

[0837] Eighth step: Preparation of compound 328i

[0838] Compound 328h (20 mg, 0.042 mmol) was dissolved in 4M hydrochloric acid in 1,4-dioxane (2 mL) and the solution was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS and upon completion, the solution was concentrated to give crude 328i (20 mg) which was used directly in the next step.

[0839] MS m / z (ESI): 377.1 (M+1) + .

[0840] Ninth step: Preparation of compound 328

[0841] 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 the reaction was monitored by LC-MS to be completed, 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 get 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 get compound 328 (5 mg, yield: 25%).

[0842] MS m / z (ESI): 420.0 (M+1) + .

[0843] 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).

[0844] Using a similar synthetic route, the following compounds were synthesized, and the characterization data are shown in the following table:

[0845] Example 38

[0846] (R,Z)-1-(10,14-dichloro-11-fluoro-3-oxo-2,3,5,6-tetrahydro-1H- benzo[9,10][1,4]oxazocin-2-yl)urea (329)

[0847] Using a similar contractual route as in Example 37, the final product was purified by high performance liquid chromatography (Waters Prep-LC with 2489 Detector, column: Waters Xbridge C18 5μm 19*150mm; mobile phase 1: water (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 15-minute gradient, gradient ratio: acetonitrile phase 5%-95%, flow rate: 15mL / min) to obtain compound 329 (25mg, yield: 32%).

[0848] MS m / z(ESI): 436.1(M+1) + .

[0849] 1 H NMR(400MHz,CD3OD)δ7.34(dd,2H),7.27(d,1H),6.53(d,1H),6.37(d,1H),6.15(td,1 H),4.51(s,1H),4.35(dd,1H),3.27(dd,1H),3.20(dd,1H),2.90(t,2H),1.83(s,1H).

[0850] Example 39

[0851] (R,Z)-1-(10,11,14-trifluoro-3-oxo-2,3,5,6-tetrahydro-1H-benzo[9,10][1,4]oxacyclooctano[2,3,4-ij]quinoline-2-yl)urea(339)

[0852] Using a similar contractual route as in Example 37, the final 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-minute gradient, gradient ratio: acetonitrile phase 50%-100%, flow rate: 25mL / min) to obtain compound 339 (5mg, yield: 21%).

[0853] MS m / z(ESI): 404.1(M+1) + .

[0854] Example 40

[0855] (R)-1-(7-chloro-8-(2-chloro-4,5-difluorophenoxy)-1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-yl)urea(344)

[0856] First Step Preparation of compound 344a

[0857] Compound 294c (300 mg, 0.66 mmol) was dissolved in N,N-dimethylformamide (5 mL), 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, 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%).

[0858] MS m / z (ESI): 561.1 (M-56+1).

[0859] Second Step Preparation of compound 344b

[0860] Compound 344a (300 mg, 0.49 mmol) was dissolved in dichloromethane (6 mL), 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, the crude product was directly concentrated to obtain compound 344b (200 mg), which was directly used in the next step reaction.

[0861] MS m / z (ESI): 403.1 (M+1).

[0862] Third Step Preparation of compound 344

[0863] 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, and 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 as monitored by LC-MS, sodium bicarbonate solution was added to adjust the pH to weak alkaline, and ethyl acetate was added for extraction. The organic phase was collected, and 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 minutes gradient, gradient ratio: acetonitrile phase 40%-95%, flow rate: 15 mL / min) to obtain compound 344 (96 mg, yield: 43.4%).

[0864] MS m / z (ESI): 446.1 (M+1).

[0865] 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).

[0866] Using a similar synthetic route to Example 40, the following compounds were obtained

[0867] Example 41

[0868] (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)

[0869] First Step: Preparation of compound 343a

[0870] Compound INT 7 (synthesized using a similar synthetic route to 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 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. The crude product was obtained by rotary evaporation, and the crude product was purified by silica gel column chromatography system B to obtain compound 343a (90 mg, yield: 56%).

[0871] MS m / z (ESI): 466.0 (M-100) + .

[0872] Second Step: Preparation of compound 343b

[0873] Compound 343a (90 mg, 0.16 mmol) was dissolved in a dioxane solution (3 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (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 protection. 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. The crude product was obtained by rotary evaporation, and the crude product was purified by silica gel column chromatography system B to obtain compound 343b (80 mg, yield: 95%).

[0874] MS m / z (ESI): 470.1 (M-56+1) + .

[0875] Step 3 Preparation of compound 343c

[0876] Compound 343b (80 mg, 0.17 mmol) was dissolved in 4M hydrochloric acid / 1,4-dioxane (2 mL), the solution was stirred at room temperature for 1 hour, after the reaction was completed, the crude compound 343c (60 mg) was directly concentrated, the product was directly used in the next step without purification.

[0877] MS m / z (ESI): 370 (M+1) + .

[0878] Step 4 Preparation of compound 343

[0879] 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 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 150×19 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%).

[0880] MS m / z (ESI): 469.1 (M+1) + .

[0881] 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).

[0882] Biological evaluation

[0883] Test Example 1 TSHR inhibitory activity screening (cAMP) experiment

[0884] 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.

[0885] Experimental materials and reagents:

[0886] Experimental steps

[0887] 1. Compound preparation

[0888] (1) Compound samples were dissolved in DMSO to a storage concentration of 10 mM;

[0889] (2) Prepare sample dilution sequence on 384-well LDV plates, with a sample initial concentration of 2 mM (FAC = 10 μM), 3-fold gradient dilution, a total of 11 concentration points;

[0890] (i) Dilute the test sample with DMSO to obtain a 2 mM intermediate concentration, specifically: 2 μL of 10 mM sample mixed with 8 μL of DMSO.

[0891] (ii) Take a piece of LDV 384-well plate, and add the above prepared 2 mM test compound solution to A1-P1 wells, respectively; add 10 μL of DMSO to each well of A2-P11, respectively; then centrifuge at 1000 rpm for 30 seconds.

[0892] (iii) Use Bravo to perform continuous gradient dilution of the compound: take the first column of the LDV plate prepared in step b as the starting concentration column, take 5 μL to the next column each time, and mix well by blowing. After the dilution procedure is completed, centrifuge at 1000 rpm for 30 seconds.

[0893] (3) Use the Echo machine to transfer the sample dilution sequence to the experimental plate (Corning-3824), corresponding to 50 nL per well.

[0894] 2. cAMP experimental method

[0895] (1) Prepare the reagents required for the experiment

[0896] (i) Experimental buffer (1x Stimulation buffer): Dilute the 5x Stimulation buffer in the kit with ultrapure water at a ratio of 1:4 to room temperature,

[0897] and add IBMX to a final concentration of 500 μM before use. Prepare for use.

[0898] (ii) 2X Stimulation Buffer: 40 ng / mL FSH protein or 0.3 nM Anti-TSHR Antibody + 500 uM IBMX in assay buffer.

[0899] (iii) Detection Reagents: Lysis & detection buffer in kit was equilibrated to room temperature, cAMP-d2 and Anti-cAMP cryptate were diluted 1:20 respectively and ready for use.

[0900] (2) Preparation of cell suspension

[0901] (i) Human FSHR / TSHR cells on culture dishes were digested with 0.05% trypsin, and then the cells were eluted with culture medium and collected into 15 mL centrifuge tubes.

[0902] (ii) Centrifuged at 1000 rpm for 5 minutes, and then the supernatant was discarded.

[0903] (iii) The cells were resuspended with 1X Stimulation buffer, and then counted on Countess II FL Cell Counter. The cell density was adjusted to 1.0 X 10 6 / mL.

[0904] (3) cAMP HTRF assay

[0905] (i) The cell suspension was added to the assay plates containing compounds using Multidrop combi, 5 uL / well.

[0906] (ii) Centrifuged at 1000 rpm for 30 seconds, and then incubated at room temperature for 15 minutes.

[0907] (iii) 2X Stimulation Buffer was added to each well of the assay plate, 5 uL / well.

[0908] (iv) Centrifuged at 1000 rpm for 30 seconds, and then incubated at 37°C for 30 minutes.

[0909] (v) The diluted cAMP-d2 and Anti-cAMP cryptate detection reagents were added to each well of the assay plate in sequence, 5 uL / well.

[0910] 5 uL cAMP-d2 reagent was added first, and then 5 uL Cryptate reagent was added.

[0911] (vi) The assay plate was allowed to stand at room temperature for 60 minutes, and then read on Envision.

[0912] (4) Experimental data processing method

[0913] The experimental data was fitted to the percent activation and 11-point concentration data to the parametric non-linear logistic equation using XLFit to calculate the IC 50 values. Details are as follows:

[0914] (i) The inhibitory effect value of each well on the experimental plate was calculated according to the following formula:

[0915] % Effect = 100 x (value - ZPE) / (HPE - ZPE)

[0916] wherein % Effect is the inhibitory 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.

[0917] (ii) Then, according to the inhibitory effect values of the different concentration test points of the compound sample, the compound sample was fitted to the action curve using the XLFit four-parameter model, and the IC 50 value was calculated.

[0918] Experimental results:

[0919] IC 50 The test results of the experiment are shown in Table 1.

[0920] Table 1 Test results of the tested compounds

[0921] Conclusion: The compound of the present application has significant inhibitory activity on the release of cAMP of CHO-K1 / TSH cells.

[0922] Test Example Two: FSHR inhibitory activity (cAMP) experiment

[0923] 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.

[0924] The experimental method is the same as that of Test Example One.

[0925] Experimental results:

[0926] IC 50 The test results of the experiment are shown in Table 2.

[0927] Table 2 Test results of the tested compounds

[0928] Conclusion: The compound of the present application has no significant inhibition on the release of cAMP of CHO-K1 / FSH cells, and has good selectivity.

[0929] Test Example Three: LHCGR Inhibitory Activity (cAMP) Experiment

[0930] 1. Experimental Materials

[0931] cAMP Detection Kit (Revvity)

[0932] 384-well assay plate (Revvity)

[0933] Vi-cell counter (Beckman)

[0934] ECHO (Labcyte)

[0935] Envision (PerkinElmer)

[0936] 2. Experimental Steps

[0937] (1) Dilute the test compound by 3 times 10 points by Echo, and transfer 50 nL to the compound plate, double duplicate wells. Transfer 50 nL of the highest concentration point of the antagonist reference compound as the Low control, and transfer 50 nL of DMSO as the high signal control group High control. Transfer 50 nL of EC80 to the compound plate by Echo per well, with a final concentration of 0.08 nM.

[0938] 2) Resuspend the LHCGR cells with buffer to 0.1 x 10 6 / mL, add 10 μL of cell suspension to the compound plate, centrifuge at 1000 rpm for 1 minute. Incubate at room temperature for 60 minutes.

[0939] 4) cAMP standard curve preparation: Prepare 800 nM starting, 4-fold dilution of 10 points of cAMP standard, add to empty wells of the compound plate, 10 μL per well.

[0940] 5) Add 10 μL of detection reagent solution to the compound plate, centrifuge at 1000 rpm for 1 minute. Incubate at room temperature for 60 minutes in the dark.

[0941] 6) Place the reaction plate in the Enzyme Reader EnVision for reading. The final value is the ratio at 665 nm and 615 nm.

[0942] 7) Analyze the data:

[0943] a) Calculate the actual cAMP level (nM) of each sample well by the cAMP standard curve;

[0944] b) antagonist: Inhibition % = 100% x (1- (sample well cAMP value - low signal control group cAMP average value) / (high signal control group cAMP average value - low signal control group cAMP average value));

[0945] c) using GraphPad Prism 5 data analysis software, select Dose-response-Inhibition-log(inhibitor) vs.response-Variable slope mode for fitting analysis, to obtain the IC 50 value of each test sample.

[0946] Experimental results:

[0947] IC 50 The test results of the experiment are shown in Table 3.

[0948] Table 3 Test results of the test compounds

[0949] 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.

[0950] Test Example Four: Liver microsomal stability experiment

[0951] 1. Materials and reagents

[0952] The microsomes were stored in a-80℃ refrigerator, and the specific information is shown in the table below.

[0953] 2. Experimental design

[0954] 2.1 Preparation of compound working solution

[0955] The test substance and the control drug verapamil powder were prepared into high concentration stock solution with DMSO, and before use, they were diluted with acetonitrile: water = 1:1 to 100 μM working solution, and the final concentration of the test substance and verapamil was 1 μM.

[0956] 2.2 Preparation of phosphate buffered saline (100 mM, pH 7.4)

[0957] First, weigh 7.098 g of sodium hydrogen phosphate, add 500 mL of pure water and ultrasonic dissolve as solution A. Weigh 3.400 g of potassium dihydrogen phosphate, add 250 mL of pure water and ultrasonic dissolve as solution B. Add solution B to solution A until the pH is 7.4.

[0958] 2.3 Preparation of 10 mM NADPH

[0959] An appropriate amount of NADPH was weighed out before the experiment and dissolved in phosphate buffer to a concentration of 10 mM.

[0960] 2.4 Preparation of Incubation System

[0961] The incubation system was prepared according to the following table. The incubation system was preheated at 37°C for 10 minutes before use.

[0962] 2.5 Test Method

[0963] 1) Transfer 25 μL of NADPH or phosphate buffer to the above incubation system, add 2.5 μL of 100 μM test substance or verapamil. Double parallel preparation was performed for samples with NADPH; single parallel preparation was performed for samples without NADPH.

[0964] 2) At 0.5, 5, 15, 30 and 60 minutes, respectively, take 30 μL of the suspension. Add 150 μL of acetonitrile containing an internal standard to terminate the reaction, and vortex for 10 minutes.

[0965] 3) Then centrifuge at 3220 g for 30 minutes to precipitate the protein. Transfer 40 μL of supernatant to the injection plate, add 160 μL of pure water and mix well for UPLC-MS / MS analysis.

[0966] 3. Data Analysis

[0967] All data calculations were performed by Microsoft Excel software. The peak area was detected by extracting the ion spectrum. The in vitro half-life (T 1 / 2 ) of the parent drug was detected by linear fitting of the natural logarithm of the parent drug elimination percentage and time.

[0968] The in vitro half-life (T 1 / 2 ) was calculated by the slope:

[0969] in vitro t 1 / 2 = 0.693 / k

[0970] The in vitro clearance (unit: μL / min / mg) was calculated using the following formula:

[0971] in vitro CLint= kV / N

[0972] V = incubation volume per well (250 μL);

[0973] N = content of microsomes per well (0.125 mg).

[0974] Experimental Results:

[0975] The test results are shown in Table 4.

[0976] Table 4 Test results of test compounds

[0977] Conclusion: The compound of the present application has good in vitro metabolic stability.

[0978] Test Example Five: Pharmacokinetic test of C57 mice

[0979] The tool compounds, 294, 297, 329, were administered 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 in each group), and the 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 administration, and the average pharmacokinetic parameters in the plasma were as shown in Table 5 (wherein F = 1 / 2*AUC(PO: 2 mpk) / AUC(IV: 1 mpk)*100%):

[0980] Table 5 Pharmacokinetic test results of compounds in mice

[0981] Conclusion: The results show that the representative compounds of the present application have good absorption in mice and good pharmacokinetic properties.

[0982] Test Example Six: Pharmacokinetic test of beagle dogs

[0983] The tool compounds, 009, 169, 294, 297, 328, were administered 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 in each group), and the 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 administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after oral gavage administration. The average pharmacokinetic parameters in the plasma were as shown in Table 6 (wherein F = 1 / 4*AUC(PO: 2 mpk) / AUC(IV: 0.5 mpk)*100%):

[0984] Table 6 Pharmacokinetic test results of compounds in dogs

[0985] Conclusion: The results show that the representative compounds of the present application have good absorption in beagle dogs and good pharmacokinetic properties.

[0986] Test Example Seven: Rat hyperthyroidism PD efficacy model

[0987] 1. Materials and reagents

[0988] 2. Preparation of molding agent and test article

[0989] 2.1 M22 molding agent: Before each administration, take out and place at room temperature, melt and mix gently after overturning, and prepare the test article at the corresponding concentration with PBS. Store at 2-8°C, and take out and place at room temperature before use, and use within 4 hours.

[0990] 2.2 Solvent preparation

[0991] 3. Experimental content

[0992] (1) D-4 (four days before Day 0 (hereinafter referred to as DO)): evenly group the animals according to body weight.

[0993] (2) D-4: from D-4 to the end of the experiment, all animals are given a T3 aqueous solution of 3 pg / mL; the T3 aqueous solution needs to be prepared every day (T3 is first prepared into a 60 pg / 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 T3 aqueous solution of 3 pg / mL), and the water intake (weight) of the animals in each cage is recorded every day.

[0994] (3) DO: the animals in the administration group, the model group, and the positive control group are given the M22 molding agent diluted with PBS to a concentration of 150 pg / mL for molding according to the administration dose of 60 pg / kg, and the animals in the negative control group are given PBS of the corresponding volume (see Table 7).

[0995] Table 7: Animal grouping and molding

[0996] (4) DO: the animals in each group are respectively given the test compound (solvent: 5% (v / v) Soluto 1 HS15 + 5% TPGS + 90% (0.2% CMC-Na, viscosity 800-1200)), the positive control K1-70 (diluted with PBS to the corresponding volume), or the corresponding solvent treatment (Table 8).

[0997] Table 8: Animal administration

[0998] Note: The solvent in Table 8 is 5% (v / v) Soluto 1 HS15 + 5% TPGS + 90% (0.2% CMC-Na, viscosity 800-1200).

[0999] (5) DO-D1: the animals in each group are bled to prepare serum according to the following table (see Table 9).

[1000] Blood collection: 0.4 mL / time point of blood is collected from the jugular vein.

[1001] 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 the full-automatic biochemical analyzer cobas8000 c702 and the full-automatic electrochemical luminescence immunoassay analyzer cobas8000 e602) of Roche.

[1002] Table 9 animal sampling

[1003] The experimental results are shown in Figures 1-6.

[1004] Conclusion: The compounds of the present application can significantly reduce TT4.

[1005] Unless otherwise specified, the tool compound structures described in the present application are as follows:

[1006] 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 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: wherein, Ring A is selected from C 3-14 saturated or partially unsaturated carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic ring or 5-14 membered heteroaromatic ring; 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 -0-, -S-, unsubstituted or optionally substituted with one, two or more radicals 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; -NH-, C 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-; X1is selected from CR X1 or N; X2is selected from CR X2 or N; X3is selected from CR X3 or N; R X1 R X2 R X3 They may be identical or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more R groups. d The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl, 5-14 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; R2is selected from CN, one, two or more, independently from each other, selected from OH, NH2, C e substituted C 1-12 alkyl, unsubstituted or optionally substituted with one, two or more R e substituted C 2-12 alkenyl, C 2-12 alkynyl, halo 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; each R e is the same or different, independently from each other, selected from oxo (=0), CN, halogen, unsubstituted or optionally substituted with one, two or more R e1 substituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, S(=0)2R e2 or C(=0)R e3 ; when R2is C 1-12 alkyl, R e is not C 1-6 alkyl; Alternatively, R2is attached to any position on ring A to collectively form a substituted or unsubstituted 5-20 membered heteroaryl e1 substituted 6-16 membered heterocycle; each R e1 are the same or different, independently of one another, selected from oxo (=0), CN, halogen, OH, NH2, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, S(=0)2R e4 or C(=0)R e5 ; alternatively, two R e1 on the same carbon atom, together with the carbon atom to which they are attached, form an optionally substituted ring system: C e6 carbocyclic or 3-14 membered heterocyclic; alternatively, two R 3-14 on adjacent carbon atoms, together with the carbon atoms to which they are respectively attached, form an optionally substituted group: CH=CH, C e1 carbocyclic, 3-14 membered heterocyclic, C e6 aromatic or 5-14 membered heteroaromatic; alternatively, two non-adjacent R 3-14 are attached to the same carbon atom, together form an optionally substituted alkylene group; R 6-14 , R e1 , R e6 , R 1-3 , R e2 , R e3 , R e4 , R e5 , R e6 are the same or different, independently of one another, selected from H, OH, NH2, C 1-6 alkyl, haloC 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; Y1is selected from -O-, -S-, unsubstituted or optionally substituted with one, two or more radicals 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; -NH-, C 1-12 alkylene, -O-C 1-12 alkylene, -S-C 1-12 alkylene, -NH-C 1-12 alkylene, -C 1-12 alkylene-O-, -C 1-12 alkylene-S- or -C 1-12 alkylene-NH-; R1is selected from any one of the following groups: (i) -COR 13 ; R 13 is selected from the following groups, which are unsubstituted or optionally substituted by one, two or more R c ; -NR 11 R 12 , C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl or 3- to 14-membered heterocyclyl; R 11 , R 12 are identical or different and independently of each other selected from H, C 1-12 alkyl, halogen-C 1-12 alkyl, C 1-12 alkoxy, halogen-C 1-12 alkoxy, C 3-12 cycloalkyl or 3- to 14-membered heterocyclyl; or R 11 , R 12 form, together with the N atom to which they are attached, a 3- to 14-membered N-containing heterocyclic ring which is unsubstituted or optionally substituted by one, two or more R c ; (ii) L1is absent or selected from the group consisting of no substitution or optionally substituted with one, two or more substituents selected from oxo (=0), OH, NH2, CN, halogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, 3-6 membered heterocyclyl, aryl, heteroaryl, haloC3-6cycloalkyl, halo3-6 membered heterocyclyl, haloaryl, and haloheteroaryl; 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, haloC 1-12 alkoxy, C 3-6 C1-6alkyl substituted with one substituent selected from C3-6cycloalkyl or 3-6 membered heterocyclyl; X4is selected from O or NR 1-12 alkylene; R 14 selected from H, CN, -NH2, -NHC 1-12 alkyl, -N(C 1-12 alkyl)2, C 1-12 alkyl, haloC 1-12 alkyl, C 3-12 cycloalkyl, haloC 3-12 cycloalkyl or 3-14 membered heterocyclyl; X4is selected from O or NR 15 ; R 15 selected from H, CN, C 1-12 alkyl, haloC 1-12 alkyl, C 3-12 cycloalkyl, haloC 3-12 cycloalkyl or 3-14 membered heterocyclyl; (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 carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic or 5-14 membered heteroaromatic ring; each R c independently of one another, are selected from oxo (=0), CN, halogen, unsubstituted or optionally substituted by one, two or more R c1 substituted by 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- to 6-membered heterocyclyl, C 6-14 aryl, 5- to 14-membered heteroaryl, NH2, S(0)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 by one, two or more R c1 substituted by one, two or more R 3-14 substituted by one, two or more R c together with the carbon atoms to which they are attached, respectively, form an unsubstituted or optionally substituted by one, two or more R c1 substituted by one, two or more R 3-14 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aromatic or 5- to 14-membered heteroaromatic ring; or, two non-adjacent R c together form an unsubstituted or optionally substituted by one, two or more R c1 substituted by one, two or more R 1-3 alkylene; each R c1 independently of one another, are selected from oxo (=0), OH, NH2, CN, halogen, unsubstituted or optionally substituted by one, two or more R 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl; p is selected from 0, 1, 2, 3, 4 or 5.

2. A compound represented by formula (I-1), racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof: wherein, Ring A is selected from C 3-14 saturated or partially unsaturated carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic ring or 5-14 membered heteroaromatic ring; each R a are the same or different and independently of each other selected from CN, halogen, non- substituted or optionally substituted with one, two or more R a1 substituted groups OH, NH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogen-C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=O)2R a2 or C(=O)R a3 ; each R a1 are the same or different and independently of each other selected from oxo (=O), CN, halogen, OH, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen-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 and independently of each other selected from H, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; m is selected from 0, 1, 2, 3, 4 or 5; Y2 is absent or selected from -0-, -S-, unsubstituted or optionally substituted with one, two or more radicals 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; and wherein the substituents of the cycloalkyl or 3-6 membered heterocyclyl are selected from the group consisting of: -NH-, C 1-12 alkylene, -0-C 1-12 alkylene, -S-C 1-12 alkylene, -NH-C 1-12 alkylene, -C 1-12 alkylene-O-, -C 1-12 alkylene-S- or -C 1-12 alkylene-NH-; X1is selected from CR X1 or N; X2is selected from CR X2 or N; X3is selected from CR X3 or N; R X1 R X2 R X3 They may be identical or different, and are independently selected from H, CN, halogens, unsubstituted, or optionally substituted by one, two, or more R groups. d The following groups are substituted: OH, NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 aryl, 5-14 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; R2is selected from CN, one, two or more, independently from each other, selected from OH, NH2, C e substituted C 1-12 alkyl, unsubstituted or optionally substituted with one, two or more R e substituted C 2-12 alkenyl, C 2-12 alkynyl, halo 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; each R e is the same or different, independently from each other, selected from oxo (=0), CN, halogen, unsubstituted or optionally substituted with one, two or more R e1 substituted OH, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, S(=0)2R e2 or C(=0)R e3 ; when R2is C 1-12 alkyl, R e is 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 are the same or different, independently of one another, selected from the group consisting of oxo (=0), CN, halogen, OH, NH2, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, S(=0)2R e4 or C(=0)R e5 ; alternatively, two R e1 together with the carbon atom to which they are attached form an optionally substituted ring system selected from the group consisting of C e6 carbocyclic or 3-14 membered heterocyclic; alternatively, two R 3-14 together with the carbon atoms to which they are attached, respectively, form an optionally substituted group selected from the group consisting of CH=CH, C e1 carbocyclic, 3-14 membered heterocyclic, C e6 aromatic or 5-14 membered heteroaromatic; alternatively, two non-adjacent R 3-14 are attached to the same carbon atom, together form an optionally substituted C 6-14 alkylene; R e1 , R e6 , R 1-3 , R e2 , R e3 , R e4 , R e5 , R e6 are the same or different, independently of one another, selected from the group consisting of H, OH, NH2, C 1-6 alkyl, halo-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; Y1is selected from -0-, -S-, unsubstituted or optionally substituted with one, two or more radicals 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; -NH-, C 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-; R 11 , R 12 are identical or different and independently of each other selected from H or C 1-12 alkyl.

3. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to claim 1 or 2, wherein, ring A is selected from a phenyl ring or a 5-6 membered heteroaromatic ring; Preferably, ring A is selected from a phenyl ring, a pyrazole ring, a thiazole ring, an oxazole ring, a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, a piperidine ring, a pyridazine ring; Preferably, ring A is a phenyl ring, a thiophene ring (e.g. ) or a pyridine ring (e.g. )； Preferably, ring A is a phenyl ring or a thiophene ring (e.g. )； Preferably, ring A is a phenyl 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 are identical or different, independently of one another selected from CN, methyl, -C≡CCH3, F, CI, Br or cyclopropyl a are identical or different, independently of one another selected from methyl, -C≡CCH3, F, CI, Br or cyclopropyl; Preferably, each R a are the same or different, independently of each other, selected from F, CI, Br or cyclopropyl; Preferably, each R a are the same or different, independently of each other, 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, Y2is selected from -O- or unsubstituted or optionally substituted by one, two or more substituents selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 C1-6alkyl substituted by one substituent selected from C3-6cycloalkyl or 3-6 membered heterocyclyl; 1-6 alkylene; Preferably, Y2is selected from -O-, Preferably, Y2is -O-.

4. [Corrected according to Rule 26 23.06.2025] The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-3, wherein, 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; Preferably, X1is 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), halogenated C 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), halogenated C 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy); Preferably, X1is CR X1 , X2is CR X2 , X3is CR X3 ; or X1is CR X1 , X2is N, X3is CR X3 ; or X1is CR X1 , X2is CR X2 , X3is 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 carbon 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; R is selected from H, -CH3, -F, -Cl, -Br, -CH2F, -CF2H, -CF3; R X1 R is selected from H, -CH3, -F, -Cl, -Br, -CH2F, -CF2H, -CF3; R X2 R is selected from H, -CH3, -F, -Cl, -Br; R X3 R is selected from H, -CH3, -F, -Cl, -Br; or, R X1 R is selected from H, -CH3, -F, -Cl, -Br; R X2 together with the carbon atom to which they are attached form a C4-6carbocyclic ring; Preferably, X1is 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), halogenated C 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), halogenated C 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy); Preferably, X1is 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), halogenated C 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), halogenated C 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy); Preferably, X1is CR X1 ; R X1 is selected from -CH3, -Cl or -F; Preferably, X2is selected from N, CH or CCl; Preferably, X2is CH; Preferably, X3is selected from N, CH or CCl; Preferably, X3is CH; Preferably, n is 0.

5. [Corrected according to Rule 26 23.06.2025] The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to claim 1, wherein, 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, Y1is -NH-; Preferably, R1is selected from any one of the following groups: (i) -COR 13 ; R 13 is selected from -NR 11 ; R 12 haloC 3-8 cycloalkyl or 3-8 membered heterocyclyl which is unsubstituted or optionally substituted by one, two or more R c ; R 11 , R 12 are the same or different, independently of each other, selected from H or C 1-4 alkoxy; or R 11 , R 12 form, together with the N atom to which they are attached, a 3-8 membered N-containing heterocycle which is unsubstituted or optionally substituted by one, two or more R c ; (ii) L1is absent or selected from the group consisting of unsubstituted or optionally substituted with one or two substituents selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C3-C6cycloalkyl, C3-C6halocycloalkyl, C2-C4alkenyl, C2-C4haloalkenyl, C2-C4alkynyl, C2-C4haloalkynyl, phenyl, heteroaryl, heterocycloalkyl, halogen, CN, OH, oxo, and NH2; 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkyl; R 14 selected from NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, C 1-4 alkyl, haloC 1-4 alkyl or C 3-6 cycloalkyl; X4is 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 a 5-6 membered heteroaromatic ring (e.g. a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, a thiazole ring, a thiadiazole ring, an oxazole ring, a dioxazole ring, a furan ring, a thiophene ring, a pyridine ring, a pyrimidine ring, a piperidine ring, a pyridazine ring, a 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 are the same or different, independently of each other, selected from the group consisting of methyl, ethyl, isopropyl, F, CI, Br, CN, OH, CH2F, CHF2, CF3, OCH3, CONH2, CH2CH2OH, CH2CH2N(CH3)2, or, two R groups attached to the same carbon atom c form a cyclopropyl ring together with the carbon atom to which they are attached; or, two R groups attached to adjacent carbon atoms c form a cyclopropyl ring together with the carbon atoms to which they are attached, respectively; Preferably, p is selected from 0 or 1; Preferably, R1is selected from any one of the following groups: (i) -COR 13 ; R 13 is selected from -NR 11 ; R 12 halocyclopropyl, halocyclobutyl or an azetidinyl ring, azetidinyl ring, oxetanyl ring, morpholine ring optionally substituted with one or two R c ; R 11 is selected from H, R 12 is selected from methoxy; or R 11 ; R 12 together with the N atom to which they are attached form a 3-6 membered N-containing heterocyclic ring optionally substituted with one or two R c ; R c is selected from OH, F, Cl, Br, CN, CH3, CHF2, CH2F, OCH3; (ii) L1is absent or selected from -CH2-, -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; X4is selected from O or NR 15 ; R 15 selected from H, CN, CH3; (iii) -L2-COR 16 ; L2is selected from -CH2-, -CH(CH3)-; R 16 is 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, R1is selected from Preferably, R1is -COR 13 , -SO2R 14 , 5-6 membered heterocycle (e.g. ) or a 5-6 membered heteroaromatic ring (e.g. ); R 13 is selected from -NH2or C 11 R 12 ; R 11 , R 12 are identical or different and independently of 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 form together with the N atom to which they are attached an unsubstituted or optionally C 1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl) substituted 3-6 membered N-containing heterocycle; R 14 is selected from -NH2or C 1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl); Preferably, R1 is CONH2, 6. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to claim 2, wherein, R 11 , R 12 are identical or different and independently of each other selected from H or C 1-6 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl); Preferably, R 11 , R 12 are each H.

7. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-6, wherein, R2is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R e1 substituted C 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 with R1, to form a 6-16 membered heterocyclic ring; 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, R2is selected from or R2is connected to any position on ring A, together forming an 8-11 membered heterocyclic ring; Preferably, R2is selected from or R2is connected to any position on ring A, together forming an 8-11 membered heterocyclic ring; Preferably, R2 is 8. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-7, wherein, The compound of formula (I) has the structure shown below: wherein, X4is selected from CH or N; X5is selected from CH2(CH2) t , O(CH2) t , S(CH2) t or NH(CH2) t wherein (CH2) t is attached to ring A at any position; 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; 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 are the same or different, independently of each other, selected from F, Cl, Br, CN, OH, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; or, two R e1 together with the carbon atoms to which they are attached, respectively, form a group CH=CH, C 3-6 carbocyclic or 3-6 membered heterocyclic ring; or, two non-adjacent R e1 are attached as end groups, together form an alkylene group C 1-3 of C preferably, two R groups attached to adjacent carbon atoms e1 together with the carbon atom to which they are attached form CH=CH; or, two non-adjacent R e1 together form methylene; Preferably, selected from the group consisting of wherein, the side of "*" is connected to N, and the side of "#" 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 of formula (I) has the structure shown below: wherein R aa , R ab are the same or different, independently of one another, selected from H, F, Cl or Br; R ac selected from H, F, CI, Br, or cyclopropyl; q is selected from 0, 1, 2 or 3; preferably, q is 0 or 1; wherein, the side of "*" is connected to N, and the side of "#" is connected to ring A; 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, p have the definitions described in any one of claims 1 to 4; Preferably, selected from the group consisting of Preferably, selected from the group consisting of Preferably, the compound of formula (I) has the structure shown below: wherein R 11 , R 12 , R2, R X1 have the definitions given in any of claims 1 to 4.

9. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-8, wherein, The compound of formula (I) is selected from the following structures:

10. A process for preparing a compound of formula (II-3) comprising the following step A: Step A: wherein A, X1, X2, X3, Y2, R 11 , R 12 , R2, R a , m have the definitions given in any one of claims 1 to 8.

11. A process for the preparation of a compound of formula (III-7) comprising the steps of: wherein, R Z1 selected from halogen (e.g., F, CI, Br); R Z2 selected from an amino protecting agent (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 compounds of formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof according to any one of claims 1-9. Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition further comprises one or more additional therapeutic agents.

13. A method for 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 prodrugs thereof according to any one of claims 1-9, or the pharmaceutical composition of claim 12. Preferably, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder. Preferably, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease; and the patient is a mammal, preferably a human.

14. Use of at least one of the compounds of formula (I), racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof according to any one of claims 1-9, or the pharmaceutical composition of claim 8, in the manufacture of a medicament. Preferably, the use is in the manufacture of a TSHR antagonist. Preferably, the use is in the manufacture of a medicament for treating or preventing a thyroid-related disease or disorder. Preferably, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

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