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

Abstract

Provided in the present invention are a TSHR antagonist compound, a pharmaceutical composition, a preparation method therefor and the use thereof. The compound (I) has a good TSHR antagonistic effect, and is used for treating thyroid-associated disorders and / or diseases, such as hyperthyroidism, Graves' disease, Graves' ophthalmopathy, and thyroid eye disease, and for preparing drugs for such disorders or diseases.

Description

TSHR antagonist compounds, pharmaceutical compositions and methods of preparation and use thereof

[0001] The present application claims priority from the prior application filed with the China National Intellectual Property Office on May 13, 2024, with the patent application number 202410591301.X, and the name of "TSHR antagonist compounds, pharmaceutical compositions and methods of preparation and use thereof". The entire contents of the above-mentioned prior application are incorporated herein by reference. TECHNICAL FIELD

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

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

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

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

[0006] 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, the following group which is unsubstituted or optionally substituted by one, two or more R a1 OH, NH2, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=O)2R a2 or C(=O)R a3 ; each R a1 is the same or different, independently selected from oxo (=O), CN, halogen, OH, NH2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R a2 , R a3 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-, the following group which is unsubstituted or optionally substituted by one, two or more R 1-12 alkyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, halogenated 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 quinone heteroaryl; each R d They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0015] R2 is selected from H, CN, unsubstituted, or optionally replaced by one, two, or more Rs. e The following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C1-12 alkyl, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl; each R e are the same or different, independently of one another, selected from oxo (=0), CN, halogen, the following groups, which are unsubstituted or optionally substituted by one, two or more R e1 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 heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, S(=0)2R e2 or C(=0)R e3 ;

[0016] each R e1 are the same or different, independently of one another, selected from oxo (=0), CN, halogen, OH, NH2, 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 heterocyclyl, S(=0)2R e4 or C(=0)R e5 ; R e2 , R e3 , R e4 , R e5 are the same or different, independently of one another, selected from H, OH, NH2, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;

[0017] each R b are the same or different, independently of one another, selected from CN, halogen, oxo (=0), the following groups, which are unsubstituted or optionally substituted by one, two or more R b1 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 heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, S(=0)2R b2 or C(=0)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;

[0018] n is selected from 0, 1, 2, or 3;

[0019] Y1 is selected from -O-, -S-, unsubstituted, or optionally selected by one, two, or more elements selected from oxo (=O), OH, NH2, CN, halogen, C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-6 Substituents of cycloalkyl or 3-6 membered heterocyclic groups include the following groups: -NH-, C 1-12 Alkylene, -OC 1-12 Alkylene, -SC 1-12 Alkylene, -NH-C 1-12 Alkylene, -C 1-12 Alkylene -O-, -C 1-12 alkylene-S- or -C 1-12 alkylene-NH-;

[0020] R1 is selected from any of the following groups:

[0021] (i)-COR 11 ;R 11 Selected from one, two or more R c Replacement C 3-12 cycloalkyl; or R 11 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: OH, -NR 12 R 13 C 1-12 Alkoxy, halogenated C 3-12 cycloalkyl or 3-14 membered heterocyclic groups; R 12 R 13 Whether the two are the same or different, they are selected independently from H and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C1-12 alkoxy, haloC 1-12 alkoxy, C 3-12 cycloalkyl or 3-14 membered heterocyclyl; or R 12 , R 13 together with the N atom to which they are attached form a 3-14 membered N-containing heterocycle which is unsubstituted or optionally substituted by one, two or more R c ; provided that R 12 , R 13 are not simultaneously H, or not simultaneously C 1-12 alkyl, or when R 12 is selected from H, R 13 is not C 1-12 alkyl;

[0022] L1is absent or selected from C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, haloC 1-12 alkoxy, C 3-6 substituted by one, two or more substituents selected from oxo (=0), OH, NH2, CN, halogen, C 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;

[0023] (iii) -L2-COR 16 ; L2is selected from C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, haloC 1-12 alkoxy, C 3-6 substituted by one, two or more substituents selected from oxo (=0), OH, NH2, CN, halogen, C 1-12 alkylene; R 16 selected from unsubstituted or optionally substituted by one, two or more Rc substituted lower alkyl, OH, C 17 R 18 , C 1-12 lower alkyl, haloC 1-12 lower alkyl, C 1-12 lower alkoxy, C 3-12 cycloalkyl, 3-14 membered heterocyclyl; R 17 , R 18 are the same or different, independently of one another, selected from the group consisting of H, C 1-12 lower alkyl, haloC 1-12 lower alkyl, C 1-12 lower alkoxy, haloC 1-12 lower alkoxy, C 3-12 cycloalkyl or 3-14 membered heterocyclyl; or R 17 , R 18 form, together with the N atom to which they are attached, a 3-14 membered N- containing heterocyclic ring which is unsubstituted or optionally substituted by one, two or more R c substituted 3-14 membered N-containing heterocyclic ring;

[0024] Ring B is selected from C 3-14 carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic or 5-14 membered heteroaromatic ring;

[0025] each R c are the same or different, independently of one another, selected from the group consisting of oxo (=0), CN, halogen, the following radicals which are unsubstituted or optionally substituted by one, two or more R c1 OH, C 1-6 lower alkyl, haloC 1-6 lower alkyl, C 1-6 lower 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 form, together with the carbon atom to which they are attached, a ring system which is unsubstituted or optionally substituted by one, two or more R c1 substituted ring system: C 3-14 carbocyclic or 3-14 membered heterocyclic; or, two R c form, together with the carbon atoms to which they are attached, respectively, a ring system which is unsubstituted or optionally substituted by one, two or more R c1 substituted ring system: C 3-14 carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic or 5-14 membered heteroaromatic ring; or, two non-adjacent Rc together with the end groups to which they are attached, form unsubstituted or optionally substituted phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, or C c1 substituted C 1-3 alkylene; each R c1 are the same or different, independently of each other, selected from oxo (=0), OH, NH2, CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 3-6 cycloalkyl, or 3-6 membered heterocyclyl;

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

[0027] According to some embodiments, ring A is selected from a phenyl ring or a 5-6 membered heteroaryl ring.

[0028] 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.

[0029] According to some embodiments, ring A is a phenyl ring.

[0030] 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).

[0031] 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, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, or 3-6 membered heterocyclyl.

[0032] According to some embodiments, each R athe same or different, are independently from each other selected from F, CI, Br, cyclopropyl, -COCH3, -CºCCH3, or

[0033] According to some embodiments, each R a the same or different, are independently from each other selected from F, CI, Br, cyclopropyl, -COCH3, -CºCCH3, or

[0034] According to some embodiments, each R a the same or different, are independently from each other selected from F or CI.

[0035] According to some embodiments, m is 1.

[0036] According to some embodiments, m is 2.

[0037] According to some embodiments, is selected from

[0038] According to some embodiments, Y2is -O- or methylene.

[0039] According to some embodiments, Y2is -O-.

[0040] According to some embodiments, 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).

[0041] According to some embodiments, X1is CR X1 .

[0042] According to some embodiments, R X1 is selected from -CH3, -CI, or -F.

[0043] According to some embodiments, X1is CCI.

[0044] According to some embodiments, X1is CCH3.

[0045] According to some embodiments, X2is selected from CH or N.

[0046] According to some embodiments, X2is CH.

[0047] According to some embodiments, X3is selected from CH or N.

[0048] According to some embodiments, X3is CH.

[0049] 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.

[0050] According to some embodiments, R X1 is selected from -CH3, -F, -Cl, -Br, -CH2F, -CF2H, -CF3; R X2 is selected from -CH3, -F, -Cl, -Br; R X3 is selected from -CH3, -F, -Cl, -Br.

[0051] According to some embodiments, R2is 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.

[0052] According to some embodiments, R2is selected from H, no substitution or optionally one, two or more R e1 substituted following groups: C 1-4 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 1-4alkylene-3-6 membered heterocyclyl, phenyl ring, C 1-4 alkylene-phenyl ring, 5-6 membered heteroaryl, C 1-4 alkylene-5-6 membered heteroaryl.

[0053] According to some embodiments, R e1 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.

[0054] According to some embodiments, R2is selected from H, C 1-4 alkyl (such as methyl, ethyl, n-propyl, i-propyl, t-butyl), haloC 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), haloC 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy), C 3-6 cycloalkyl (such as cyclopropyl), haloC 3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0055] According to some embodiments, R2is selected from

[0056] According to some embodiments, R2is methyl.

[0057] According to some embodiments, n is 0.

[0058] 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 substituted -NH-, C 1-4 alkylene, -NH-C 1-4 alkylene or -C 1-4 alkylene-NH-.

[0059] According to some embodiments, Y1is -NH-.

[0060] According to some embodiments, R1is selected from any one of the following groups:

[0061] (i) -COR 11 ; R 11 selected from -NR12 R 13 Halogenated C 3-8 Cycloalkyl or unsubstituted or optionally with one, two or more R c Substituted 3-8 membered heterocyclic groups; R 12 R 13 They are the same or different, and are selected independently from H or C. 1-4 alkoxy; or R 12 R 13 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; condition: R 12 R 13 Not both H;

[0062] 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;

[0063] (iii)-L2-COR 16 L2 is selected from unsubstituted or optionally selected from one or two halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl substituents substituted C 1-4 Alkylene; R 16 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: H, OH, -NR 17 R 18 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups; R 17 R 18 Whether the two are the same or different, they are selected independently from H and C. 1-4 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; or R 17 R 18Together 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;

[0064] Ring B is selected from 5-6 membered heteroaromatic rings (e.g., pyrrole ring, pyrazole ring, imidazole ring, triazole ring, thiazole ring, thiadiazole ring, oxazole ring, dioxazole ring, furan ring, thiophene ring, pyridine ring, pyrimidine ring, piperidine ring, pyridazine ring, triazine ring).

[0065] According to some implementation schemes, R1 is selected from any of the following groups:

[0066] (i)-COR 11 ;R 11 Selected from -NR 12 R 13 Halogenated C 3-8 Cycloalkyl or unsubstituted or optionally with one, two or more R c Substituted 3-8 membered heterocyclic groups; R 12 R 13 They are the same or different, and are selected independently from H or C. 1-4 alkoxy; or R 12 R 13 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; condition: R 12 R 13 Not both H;

[0067] 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;

[0068] (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; R16 selected from the following groups, which are unsubstituted or optionally substituted by one, two or more R c H, OH, -NR 17 R 18 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; R 17 , R 18 are the same or different, independently of each other, selected from H, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; or R 17 , R 18 form, together with the N atom to which they are attached, a 3-8 membered N- containing heterocyclic ring which is unsubstituted or optionally substituted by one, two or more R c substituents.

[0069] According to some embodiments, each R c are the same or different, independently of each other, selected from oxo (=0), CN, halogen, OH, C 1-4 alkyl, 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, independently of each other, selected from H or C 1-4 alkyl.

[0070] According to some embodiments, each R c are the same or different, independently of each other, selected from oxo (=0), CN, halogen, OH, C 1-4 alkyl, 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, independently of each other, selected from H or C 1-4 alkyl; or, two R c form, together with the carbon atom to which they are attached, a C 3-6carbocyclic or 3-6 membered heterocyclic ring; or, two R c together with the carbon atom to which they are attached form a C 3-6 carbocyclic or 3-6 membered heterocyclic ring.

[0071] According to some embodiments, each R c are the same or different, independently of each other, selected from oxo (=0), 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 heterocyclyl; R c2 , R c3 are the same or different, independently of each other, selected from H or C 1-4 alkyl.

[0072] According to some embodiments, each R c are the same or different, independently of each other, selected from methyl, ethyl, isopropyl, F, CI, 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 attached form a cyclopropyl ring.

[0073] According to some embodiments, each R c are the same or different, independently of each other, selected from methyl, ethyl, isopropyl, F, CI, Br, CN, OH, CH2F, CHF2, CF3, OCH3, CONH2, CH2CH2OH, CH2CH2N(CH3)2,

[0074] According to some embodiments, each R c are the same or different, independently of each other, selected from oxo (=0), CN, halogen, OH, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0075] According to some embodiments, p is selected from 0 or 1.

[0076] According to some embodiments, R1is selected from any one of the following groups:

[0077] (i) -COR 11 ; R 11 is selected from -NR 12 ; R 13 , halocyclopropyl, halocyclobutyl or an azetidinyl ring, azetidinyl ring, azetidinyl ring, oxetanyl ring, morpholine ring optionally substituted with one or two R c ; R 12 is selected from H, R 13 is selected from methoxy; or R 12 , R 13 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.

[0078] (ii) L1is absent or selected from -CH2-, -CH(CH3)-; R 14 is 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;

[0079] (iii) -L2-COR 16 ; L2is selected from -CH2-, -CH(CH3)-; R 16 is selected from H, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2;

[0080] (iv) Ring B is selected from Preferably, Ring B is selected from Preferably, Ring B is selected from

[0081] According to some embodiments, R1is selected from any one of the following groups:

[0082] (i) -COR 11 ; R 11 is selected from -NR 12 ; R 13 , halocyclopropyl, halocyclobutyl or an unsubstituted or optionally substituted azetidinyl ring, azetidinyl ring, oxetanyl ring, morpholine ring; R c is selected from H, R 12 is selected from H, R 13 is selected from H, R 12 , R 13 together with the N atom to which they are attached form an unsubstituted or optionally substituted 3-6 membered N-containing heterocyclic ring; R c is selected from H, R c is selected from OH, F, Cl, Br, CN, CH3, CHF2, CH2F, OCH3.

[0083] (ii) L1is absent or selected from -CH2-, -CH(CH3)-; R 14 is 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;

[0084] (iii) -L2-COR 16 ; L2is selected from -CH2-, -CH(CH3)-; R 16 is selected from H, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2.

[0085] According to some embodiments, R1is selected from

[0086] According to some embodiments, R1is selected from

[0087] According to some embodiments, R1is selected from

[0088] According to some embodiments, R1is selected from

[0089] According to some embodiments, R1is selected from

[0090] According to some embodiments, the compound of Formula (I) has the structure shown below:

[0091] wherein,

[0092] ring A, X1, X2, X3, Y1, Y2, R1, R2, R a , R X1 , m have the definitions as described herein.

[0093] According to some embodiments, the compound of Formula (I) has the structure shown below:

[0094] wherein, Y2, R a , R1, R2, R X1 , m have the definitions as described herein.

[0095] According to some embodiments, the compound of Formula (I) has the structure shown below:

[0096] wherein, R1, R 14 , R X1 , R c , p have the definitions as described herein.

[0097] According to some embodiments, the compound of Formula (I) is selected from the following structures:

[0098] The present application also provides a method for preparing a compound represented by formula (II-4), comprising the following step A:

[0099] Step A:

[0100] wherein, ring A, X1, X2, X3, Y2, R1, R2, R a , m have the definitions described herein.

[0101] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0102] According to some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0103] According to some embodiments, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0104] The present application also provides 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 represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof. The present application also provides 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 the above-mentioned pharmaceutical composition.

[0105] According to some embodiments, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder.

[0106] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

[0107] According to some embodiments, the patient comprises a mammal, preferably a human.

[0108] The present application also provides at least one of the compounds represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or a pharmaceutical composition thereof, for use in treating or preventing a disease or disorder caused by TSHR abnormality.

[0109] According to some embodiments, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder.

[0110] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease.

[0111] The present application also provides use of at least one of the compounds of formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament.

[0112] According to some embodiments, the use can be use in the manufacture of a TSHR antagonist.

[0113] 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.

[0114] According to some embodiments, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease. Beneficial effects

[0115] 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 medicaments for treating or preventing such diseases and disorders.

[0116] Definitions and explanations of terms

[0117] Unless otherwise indicated, the definitions and explanations of terms recited in the present application specification and claims, including the definitions thereof 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 group 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.

[0118] The term "optional" (or "optionally", "option") in the general formula definition of the present application means the case of being substituted by zero, one or more substituents, for example "optionally substituted by one, two or more R" means that it can not be substituted by R (unsubstituted) or can be optionally substituted by one, two or more R.

[0119] "More" means three or more, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0120] Unless otherwise indicated, the numerical values in the presently disclosed embodiments and claims are to be rounded to the nearest whole or fractional integer as appropriate to the particular context. For example, the numerical range "1 to 12" is intended to state the range "1 to 12" inclusive of each integer value therein, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0121] The term "C 1-12 "alkyl" is understood to mean a straight or branched chain alkyl group having from 1 to 12 carbon atoms, "C 1-8 "alkyl" means a straight or branched chain alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 "alkyl" means a straight or branched chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-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.

[0122] The term "C 2-12 "alkenyl" is understood to mean a straight or branched chain monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. For example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C 2-8 "alkenyl"), for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 "alkenyl"), having 2 or 3 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.

[0123] 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.

[0124] 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. bridged, spiro) or tricyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C

[0125] 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 is possible.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] The term "halogen" denotes fluorine, chlorine, bromine and iodine.

[0130] The term "nitrogen oxides" refers to compounds formed by the oxidation of nitrogen atoms in the structure of tertiary amines or nitrogen-containing (aromatic) heterocyclic compounds.

[0131] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0132] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0133] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0134] Unless otherwise stated, heterocyclic, hypocyclic, heteroaryl, or hypoaryl includes all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, it may include forms in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0135] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc.

[0136] "Halogenation" refers to the replacement of a substance by one or more halogens.

[0137] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0138] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0139] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, where alkyl is defined as described above. Non-limiting examples of alkylamino include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, etc.

[0140] "Heteroalkyl" means an alkyl group, as defined above, in which one or more carbon atoms are replaced by atoms of heteroatoms. Non-limiting examples of heteroalkyl groups include: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, dihydroxypropyl, and the like.

[0141] The term "alkyloxy" means -O-(alkyl), wherein alkyl is defined above. Non-limiting examples of alkyloxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkyloxy group can be optionally substituted or non-substituted, and when substituted, the substituent(s) are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0142] The terms "alkyleneoxy" and "oxyalkylene" mean -alkylene-O- or -O-alkylene-, 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 the alkyleneoxy or oxyalkylene group can be attached to the rest of the molecule in which it is contained in either direction, i.e., they can be used interchangeably.

[0143] Wavy line intersecting a chemical bond Used to indicate the position of attachment of a group to other atoms in a molecular 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. As 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 pyridine ring or to the carbon atom on the left side of the pyrazole ring. Similar expressions in this application are interpreted in the same manner unless otherwise stated.

[0144] In the chemical structures of the compounds described herein, a bond indicates unspecified configuration, indicates absolute configuration, i.e., if stereoisomers exist in the chemical structure, the bond may be or both configurations.

[0145] ​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, can be 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 as "and the like"), represents that not only the deuterium or tritium, but also hydrogen can be contained.

[0146] It will be appreciated by one of skill in the art that the compounds of Formula (I) can exist in various pharmaceutically acceptable salt forms. If these compounds have basic centers, they can form acid addition salts; if these compounds have acidic centers, they can form base addition salts; if these compounds contain both acidic and basic centers (for example, a carboxyl group and an amino group), they can also form inner salts.

[0147] The compounds of the present application can exist in the form of solvates (e.g., hydrates), wherein the compound of the present application contains as an element of the crystal lattice of said compound a polar solvent, in particular, for example, water, methanol or ethanol. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0148] Depending on its molecular structure, a compound of the application can be chiral and therefore various enantiomeric forms can exist. The compounds can thus exist in racemic or optically active forms. The compounds of the application encompass the isomers of each chiral carbon in the R or S configuration or mixtures thereof, racemates. The compounds of the application or intermediates thereto can be separated into the enantiomeric compounds by chemical or physical methods known to those of ordinary skill in the art, or used as such in the synthesis. 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 the R and S forms of tartaric acid, diacetyltartaric acid, binaphthyl-tartric acid, mandelic acid, malic acid, lactic acid, the appropriate N-protected amino acids, for example N-benzoyl-proline or N-benzenesulfonyl-proline, or the various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution with an optically active resolving agent, for example dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatizing agents, can also be advantageously performed. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0149] The corresponding stable isomers can be isolated according to known methods, for example by extraction, filtration or column chromatography.

[0150] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, goats, horses, or primates, most preferably humans.

[0151] 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 been experienced or displayed the pathology or symptomatology 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 symptomatology of the disease; (3) relieving the disease: for example, causing the regression of the pathology and / or symptomatology of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptomatology of the disease. DETAILED DESCRIPTION

[0152] 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 described and explained, 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 encompassed within the scope intended to be protected by the present application.

[0153] Unless otherwise indicated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0154] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in 10 -6 (ppm) units. NMR measurements are performed on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCI3), deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0155] MS measurements are performed on Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry (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)

[0156] High performance liquid chromatography (HPLC) analysis uses Agilent 1260 II HPLC, Waters Acquity UPLC H-Class high performance liquid chromatograph.

[0157] Chiral HPLC analysis measurement uses Waters Acquity UPC C high performance liquid chromatograph.

[0158] High performance liquid preparation uses 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.

[0159] CombiFlash rapid preparative instrument uses Combiflash Rf200 (TELEDYNE ISCO).

[0160] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of silica gel plate used in thin layer chromatography separation and purification product is 0.4mm-0.5mm.

[0161] Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0162] Determination of average inhibition rate of kinase and IC 50 value is measured by NovoStar microplate reader (Germany BMG company).

[0163] 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, Daejung Chemicals, etc.

[0164] Unless otherwise specified in the examples, the reactions can be carried out under argon atmosphere or nitrogen atmosphere.

[0165] Argon atmosphere or nitrogen atmosphere refers to connecting a 1L argon or nitrogen balloon to the reaction bottle.

[0166] Hydrogen atmosphere refers to connecting a 1L hydrogen balloon to the reaction bottle.

[0167] Pressurized hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

[0168] Hydrogenation reaction is usually vacuumed, filled with hydrogen, and repeated 3 times.

[0169] Microwave reaction uses CEM Discover-S 908860 type microwave reactor.

[0170] Unless otherwise specified in the examples, solution refers to aqueous solution.

[0171] Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20℃-30℃.

[0172] The monitoring of the reaction progress in the examples employs thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography used in the purification of the compounds and the developing agent system of the thin layer chromatography include: system A: dichloromethane / methanol system, system B: n-hexane / ethyl acetate system, the volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagent such as triethylamine and acetic acid can also be added for adjustment.

[0173] Preparation of intermediate (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3,4- dihydroquinolin-2(lH)-one (Int 1)

[0174] Preparation of first step 3-fluoro-4-methyl-2-nitroaniline (Int 1b)

[0175] 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 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%).

[0176] MS m / z (ESI): 171.1 (M+1).

[0177] Preparation of second step 1-bromo-3-fluoro-4-methyl-2-nitrobenzene (Int 1c)

[0178] Isopentyl nitrite (10.74 g, 0.092 mol) was dissolved in acetonitrile (250 mL), and cuprous bromide (13.15 g, 0.092 mol) was added, and the mixture was stirred at room temperature for 1 hour. Compound Int 1b (13 g, 0.076 mol) was added to the reaction system, and stirring was continued for 0.5 hours, and then the temperature was raised to 70°C and stirring was continued for 2 hours. After the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (50 mL) and filtered, the filtrate was diluted with water (100 mL) and further extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound Int 1c (10.1 g, yield: 56.5%).

[0179] 1H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.58 (m, 1H), 7.53 (t, 1H), 2.32 (s, 3H).

[0180] Step 3: Preparation of 1-bromo-3-(2-chloro-5-fluorophenoxy)-4-methyl-2-nitrobenzene (Int 1d)

[0181] Compound Int 1c (10.0 g, 0.043 mol) was dissolved in N,N dimethylformamide (100 mL), 2-chloro-5-fluorophenol (12.66 g, 0.086 mol) and potassium carbonate (11.94 g, 0.086 mol) were added 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), then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography system B to obtain compound Int 1d (10 g, yield: 65.0%).

[0182] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.58 (m, 1H), 7.53 (t, 1H), 2.32 (s, 3H).

[0183] Step 4: Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-(2-chloro-5- fluorophenoxy)-4-methyl-2-nitrophenyl)propanoate (Int 1e)

[0184] 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 under nitrogen. To the system was added 1,2-dibromoethane (26 mg, 0.14 mmol) and trimethylchlorosilane (15 mg, 0.14 mmol) under nitrogen, and the reaction mixture was stirred at 40 °C for 15 min. To the reaction mixture was added a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (912 mg, 4.26 mmol) in N,N-dimethylformamide (2 mL) under nitrogen, and stirred at 40 °C for 30 min under nitrogen. The reaction mixture was cooled to room temperature under nitrogen 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), and to the reaction mixture was added Pd(dppf)Cl2(101 mg, 0.14 mmol), cuprous iodide (26 mg, 0.14 mmol), and the prepared zinc reagent solution (supernatant) 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 solution was filtered through 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 column chromatography on silica gel using system B to give compound Int 1e (200 mg, yield: 29%).

[0185] MS m / z (ESI): 401.0 (M+1).

[0186] Fifth Step: Preparation of (R)-3-(2-amino-3-(2-chloro-5-fluorophenoxy)-4- methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester (Int 1f)

[0187] Compound Int 1e (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 solution was filtered using celite, and the filtrate was concentrated under reduced pressure. Purification by column chromatography on silica gel using system A gave compound Int 1f (100 mg, yield: 53%).

[0188] MS m / z (ESI): 338.1 (M+1).

[0189] Sixth Step: Preparation of (R)-3-(2-amino-3-(2-chloro-5-fluorophenoxy)-4- methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (Int 1g)

[0190] 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 compound Int 1g (700 mg, 90%). The product was directly used in the next step without purification.

[0191] MS m / z (ESI): 383 (M+1-56).

[0192] 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)

[0193] 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 ammonium chloride solution, and rotary evaporated to obtain the crude product, which was purified by silica gel column chromatography system B to obtain compound Int 1h (650 mg, yield: 97%).

[0194] MS m / z (ESI): 365 (M+1-56).

[0195] 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)

[0196] 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 ammonium chloride solution, and rotary evaporated to obtain the crude product, which was purified by silica gel column chromatography system B to obtain compound Int 1i (600 mg, yield: 89%).

[0197] MS m / z (ESI): 379 (M+1-56).

[0198] Ninth step, preparation of (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3,4- dihydroquinolin-2(1H)-one (Int 1)

[0199] 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).

[0200] MS m / z (ESI): 335 (M+1).

[0201] 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).

[0202] Preparation of intermediate (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-1- methyl-3,4-dihydroquinolin-2(lH)-one (Int 2)

[0203] Preparation of first step 4-chloro-3-fluoro-2-nitroaniline (Int 2b)

[0204] 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%).

[0205] MS m / z (ESI): 191.0 (M+1).

[0206] Preparation of second step 1-bromo-4-chloro-3-fluoro-2-nitrobenzene (Int 2c)

[0207] 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%).

[0208] MS m / z (ESI): 253.9 (M+1).

[0209] Third step: Preparation of l-bromo-4-chloro-3-(2-chloro-5-fluorophenoxy)-2- nitrobenzene (Int 2d)

[0210] 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%).

[0211] MS m / z (ESI): 379.9 (M+1).

[0212] Fourth step: Preparation of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3- (2-chloro-5-fluorophenoxy)-2-nitrophenyl)propanoate (Int 2e)

[0213] 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 stock solution of zinc reagent. A separate flask was charged with a solution of compound Int 2d (500 mg, 1.42 mmol) in N,N-dimethylformamide (10 mL), charged with Pd(dppf)Cl2(208 mg, 0.29 mmol), copper(I)iodide (54 mg, 0.29 mmol) and the stock solution of zinc reagent under nitrogen at room temperature. The resulting reaction mixture was stirred at 75 °C for 12 h under nitrogen. After the reaction was completed, 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 reduced pressure to give a crude product, which was purified by flash column chromatography on silica gel using system B to give compound Int 2e (450 mg, yield: 68%).

[0214] MS m / z (ESI): 403.0 (M-100) +

[0215] Fifth step: Preparation of (R)-methyl 3-(2-amino-4-chloro-3-(2-chloro-5- fluorophenoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (Int 2f)

[0216] 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 the reaction was completed, the reaction mixture was filtered over celite, the filtrate was concentrated under reduced pressure, and compound Int 2f (400 mg, yield 95%) was obtained by purification by flash column chromatography on silica gel using system B.

[0217] MS m / z (ESI): 417.0 (M+1).

[0218] Sixth step: Preparation of (R)-tert-butyl (7-chloro-8-(2-chloro-5-fluorophenoxy)- 2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (Int 2g)

[0219] 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%).

[0220] MS m / z (ESI): 463.0 (M+23).

[0221] 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)

[0222] 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%).

[0223] MS m / z (ESI): 477.0 (M+23) + .

[0224] Eighth step: preparation of (R)-3-amino-7-chloro-8-(2-chloro-5-fluorophenoxy)-1- methyl-3,4-dihydroquinolin-2(1H)-one (Int 2)

[0225] 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%).

[0226] MS m / z (ESI): 355.0 (M+1) + .

[0227] 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).

[0228] Preparation of intermediate (R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l- methyl-3,4-dihydroquinolin-2(lH)-one (Int 3)

[0229] Preparation of first step l-bromo-3-(2-chloro-5-fluorophenoxy)-4-fluoro-2- nitrobenzene (Int 3b)

[0230] 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%).

[0231] MS m / z (ESI): 364.0 (M+l).

[0232] Preparation of second step methyl (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-[3-(2- chloro-5-fluorophenoxy)-4-fluoro-2-nitrophenyl]propanoate (Int 3c)

[0233] To a reaction flask was added zinc dust (3 g), replaced with nitrogen, and N,N- dimethylformamide (8 mL) was added via syringe. The mixture was stirred at 40 °C for 15 min under nitrogen. To the mixture was added 1,2-dibromoethane (26 mg, 0.48 mmol) and trimethylchlorosilane (45 mg, 0.48 mmol) under nitrogen. The reaction mixture was stirred at 40 °C for 15 min. To the reaction mixture was added a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- iodopropionate (912 mg, 33.16 mmol) in N,N-dimethylformamide (2 mL) under nitrogen. The mixture was stirred at 40 °C for 30 min under nitrogen. The mixture was cooled to room temperature under nitrogen to give a zinc reagent solution for later use. Another flask was prepared with a solution of compound Int 3b (4 g, 0.011 mol) in N,N-dimethylformamide (20 mL). To the reaction mixture was added Pd(dppf)Cl2(1.6 g, 0.002 mol), cuprous iodide (380 mg, 0.002 mol), and the prepared zinc reagent solution (supernatant) under nitrogen at room temperature. 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. The crude product was purified by column chromatography on silica gel using system B to give compound Int 3c (4 g, yield: 74%).

[0234] MS m / z (ESI): 431.1 (M+1-56) + .

[0235] Step 3 Preparation of methyl (2R)-3-[2-amino-3-(2-chloro-5-fluorophenoxy)-4- fluorophenyl]-2-{[(tert-butoxy)carbonyl]amino}propanoate (Int 3d)

[0236] Compound Int 3c (3 g, 6.12 mmol) was dissolved in a mixture 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, the reaction mixture was filtered over celite. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using system B to give compound Int 3d (2.5 g, yield: 88%).

[0237] MS m / z (ESI): 457.1 (M+1).

[0238] Step 4 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)

[0239] 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 using a silica gel column chromatography system (petroleum ether: ethyl acetate = 2:1) to obtain compound Int 3e (1.6 g, yield: 85.4%).

[0240] MS m / z (ESI): 369.1 (M+1-56) + .

[0241] 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)

[0242] 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 with rotation to obtain a crude product, which was purified using a silica gel column chromatography system B to obtain compound Int 3f (1.35 g, yield: 89%).

[0243] MS m / z (ESI): 383.1 (M+1-56) + .

[0244] Preparation of (3R)-3-amino-8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-methyl-3,4-dihydroquinolin-2-one (Int 3)

[0245] 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 with rotation was performed to obtain compound Int 3 (300 mg, yield: 89%).

[0246] MS m / z (ESI): 339.1 (M+1).

[0247] 1H 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).

[0248] Example 1

[0249] (R)-1-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-3-methoxyurea (001)

[0250] Preparation of the first step 4-nitrophenylmethoxycarbamate (001b)

[0251] Compound 001a (100 mg, 1.20 mmol) was dissolved in ice water (3 mL), sodium bicarbonate (200 mg, 2.40 mol) and dichloromethane (5 mL) were added to the system. Compound p-nitrophenyl chloroformate (255 mg, 1.20 mmol) in dichloromethane (5 mL) was added to the reaction system at below 10 °C, the formation of white precipitate was observed, stirred for 30 minutes, filtered, the filter cake was washed with water three times, the filter cake was rotary dried to obtain compound 001b (80 mg, yield: 31%).

[0252] MS m / z (ESI): 213.0 (M+1).

[0253] Preparation of the second step (R)-1-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-3-methoxyurea (001)

[0254] Compound 001b (31 mg, 0.14 mmol) was dissolved in tetrahydrofuran (5 mL), Int 1 (25 mg, 0.07 mmol) and triethylamine (21 mg, 0.21 mmol) were added, after the reaction was stirred at 60 °C under nitrogen protection for 2 hours, after the reaction was completed, the reaction liquid was 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 SQD2 detector, chromatographic 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 001 (19 mg, yield: 63%).

[0255] MS m / z (ESI): 408.1 (M+1).

[0256] 1 H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.64 (dd, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 6.95-6.90 (m, 2H), 6.28 (d, 1H), 4.41-4.38 (m, 1H), 3.59 (s, 3H), 3.20 (s, 3H), 3.08-2.98 (m, 2H), 2.06 (s, 3H).

[0257] Example 2

[0258] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)azetidine-l-carboxamide (002)

[0259] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)azetidine-l-carboxamide (002)

[0260] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in dichloromethane (3 mL), triethylamine (19 mg, 0.18 mmol) was added to the system. At below 10 °C, compound bis(2,5-dioxopyrrolidin-l-yl) carbonate (16 mg, 0.06 mmol) was added to the reaction system, stirred for 10 minutes, azetidine hydrochloride (12 mg, 0.12 mmol) was added and stirred for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic 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 (5 mg, yield: 20%).

[0261] MS m / z (ESI): 418.1 (M+1).

[0262] 1H NMR (400 MHz, DMSO-d6) δ 7.64 (dd, 1H), 7.19 (d, 1H), 7.12 (d, 1H), 6.95 - 6.92 (m, 1H), 6.35 (d, 1H), 6.24 (s, 1H), 4.35 - 4.22 (m, 1H), 3.90 - 3.71 (m, 4H), 3.17 (s, 3H), 3.01 - 2.86 (m, 2H), 2.20 - 2.11 (m, 2H), 2.05 (s, 3H).

[0263] Example 3

[0264] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3-hydroxyazetidine-l-carboxamide (003)

[0265] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3-hydroxyazetidine-l-carboxamide (003)

[0266] Compound Int 1 (15 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), triethylamine (14 mg, 0.13 mmol) was added to the system. At below 10 °C, compound bis(2,5-dioxopyrrolidin-l-yl) carbonate (16 mg, 0.06 mmol) was added to the reaction system, stirred for 10 minutes, azetidin-3-ol (8 mg, 0.11 mmol) was added and stirred for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5 pm 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 50%-100%, flow rate: 20 mL / min) to obtain compound 003 (2.9 mg, yield: 15%).

[0267] MS m / z (ESI): 434.1 (M+l).

[0268] 1H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.15-7.12 (m, 2H), 6.83-6.76 (m, 1H), 6.07 (d, 1H), 4.58-4.51 (m, 1H), 4.37 (t, 1H), 4.24-4.16 (m, 2H), 3.79-3.75 (m, 2H), 3.30 (s, 3H), 3.00 (d, 2H), 2.12 (s, 3H).

[0269] Example 4

[0270] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)pyrrolidine-l-carboxamide

[0271] Preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)pyrrolidine-l-carboxamide

[0272] Compound Int 1 (20 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), triethylamine (26 mg, 0.25 mol) was added to the system. At below 10 °C, compound bis(2,5-dioxopyrrolidin-l-yl) carbonate (16 mg, 0.06 mmol) was added to the reaction system, stirred for 10 minutes, pyrrolidine (7 mg, 0.10 mmol) was added and stirred for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic 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 004 (1.68 mg, yield: 7.2%).

[0273] MS m / z (ESI): 432.2 (M+l).

[0274] 1H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.16-7.13 (m, 2H), 6.80-6.77 (m, 1H), 6.25 (d, 1H), 6.07 (d, 1H), 4.47-4.37 (m, 1H), 3.42-3.35 (m, 4H), 3.31 (s, 3H), 3.09-3.00 (m, 2H), 2.12 (s, 3H), 1.96-1.92 (m, 4H).

[0275] Example 5

[0276] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3-fluoroazetidine-l-carboxamide (005)

[0277] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3-fluoroazetidine-l-carboxamide (005)

[0278] Compound Int 1 (20 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), triethylamine (26 mg, 0.25 mol) was added to the system. At below 10 °C, compound bis(2,5-dioxopyrrolidin-l-yl) carbonate (16 mg, 0.06 mmol) was added to the reaction system, stirred for 10 minutes, 3-fluoroazetidine hydrochloride (7 mg, 0.05 mmol) was added and stirred for 20 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5u 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 005 (5 mg, yield: 20%).

[0279] MS m / z (ESI): 436.1 (M+l).

[0280] 1H NMR (400 MHz, DMSO-d6) δ 7.64 (dd, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 6.95-6.91 (m, 1H), 6.69 (d, 1H), 6.24 (d, 1H), 5.47-5.22 (m, 1H), 4.39-4.28 (m, 1H), 4.22-4.09 (m, 2H), 3.91-3.88 (m, 1H), 3.85-3.83 (m, 1H), 3.17 (s, 3H), 3.00-2.88 (m, 2H), 2.06 (s, 3H).

[0281] Example 6

[0282] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)morpholine-4-carboxamide (006)

[0283] Preparation of the first step (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)morpholine-4-carboxamide (006)

[0284] Compound Int 1 (20 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), triethylamine (26 mg, 0.25 mol) was added to the system. At below 10 °C, compound bis(2,5-dioxopyrrolidin-l-yl) carbonate (16 mg, 0.06 mmol) was added to the reaction system, stirred for 10 minutes, morpholine (5 mg, 0.05 mmol) was added and stirred for 20 minutes. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic 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 006 (7 mg, yield: 31%).

[0285] MS m / z (ESI): 448.1 (M+l).

[0286] 1H NMR (400 MHz, CD3OD) δ 7.53-7.49 (m, 1H), 7.16-7.13 (m, 2H), 6.81-6.77 (m, 1H), 6.08 (d, 1H), 4.46-4.41 (m, 1H), 3.67 (t, 4H), 3.42 (t, 4H), 3.31 (s, 3H), 3.04-3.00 (m, 2H), 2.12 (s, 3H).

[0287] Example 7

[0288] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3-cyanopyrrolidine-l-carboxamide (007)

[0289] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3-cyanopyrrolidine-l-carboxamide (007)

[0290] Compound Int 1 (13 mg, 0.0389 mmol) was dissolved in dichloromethane (3 mL), triethylamine (12 mg, 0.12 mmol) and N,N'-disuccinimidyl carbonate (29.89 mg, 0.12 mmol) were added, the reaction was stirred at room temperature for 0.5 h, then compound pyrrolidine-3-carbonitrile (3.19 mg, 0.039 mmol) was added and the reaction was stirred at room temperature for another 0.5 h, the reaction solution was concentrated under reduced pressure to give a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to give compound 007 (1.34 mg, yield: 7.8%).

[0291] MS m / z (ESI): 443.1 (M+1).

[0292] 1HNMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.17-7.13 (m, 2H), 6.83-6.75 (m, 1H), 6.08 (d, 1H), 4.38-4.35 (m, 1H), 4.29-4.25 (m, 2H), 4.15-4.12 (m, 2H), 3.68-3.64 (m, 1H), 3.32 (s, 3H), 3.07-2.97 (m, 2H), 2.12 (s, 3H).

[0293] Example 8

[0294] N-((R)-8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-2-methylazetidine-l-carboxamide (008)

[0295] First step preparation of N-((R)-8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-2-methylazetidine-l-carboxamide (008)

[0296] Compound Int 1 (13 mg, 0.0389 mmol) was dissolved in dichloromethane (3 mL), triethylamine (12 mg, 0.12 mmol) and N,N'-disuccinimidyl carbonate (30 mg, 0.12 mol) were added, after the reaction was stirred at room temperature for 0.5 hours, compound 2-methylazetidine (2.76 mg, 0.039 mmol) was added and the reaction was stirred at room temperature for another 0.5 hours, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic 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 008 (2.13 mg, yield: 12.70%).

[0297] MS m / z (ESI): 432.1 (M+1).

[0298] 1HNMR (400 MHz, DMSO-d6) δ 7.64 (dd, 1H), 7.20 (dd, 1H), 7.13 (d, 1H), 6.95-6.92 (m, 1H), 6.28-6.11 (m, 2H), 4.38-4.15 (m, 2H), 3.81-3.63 (m, 2H), 3.17 (s, 3H), 3.06-2.88 (m, 2H), 2.32-2.26 (m, 1H), 2.05 (s, 3H), 1.76-1.72 (m, 1H), 1.31 (s, 3H).

[0299] Example 9

[0300] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3-(difluoromethyl)azetidine-l-carboxamide (009)

[0301] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3-(difluoromethyl)azetidine-l-carboxamide (009)

[0302] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in dichloromethane (3 mL), triethylamine (14.3 mg, 0.135 mmol) and N,N'-disuccinimidyl carbonate (17.3 mg, 0.07 mmol) were added to the system, stirred at room temperature for 20 minutes. Compound 3-(difluoromethyl)azetidine (14.4 mg, 0.135 mmol) was added to the reaction system, stirred for 30 minutes, after the reaction was completed, the reaction liquid was 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 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 009 (6 mg, yield: 29%).

[0303] MS m / z (ESI): 468.1 (M+1).

[0304] 1H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.15 (d, 2H), 6.86 - 6.74 (m, 1H), 6.29 - 5.92 (m, 2H), 4.38 (dd, 1H), 4.10 (d, 2H), 4.00 - 3.91 (m, 2H), 3.31 (s, 3H), 3.16 - 3.05 (m, 1H), 3.02-2.99 (m, 2H), 2.12 (s, 3H).

[0305] Example 10

[0306] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3-(fluoromethyl)azetidine-l-carboxamide (010)

[0307] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3-(fluoromethyl)azetidine-l-carboxamide (010)

[0308] Compound Int 1 (15 mg, 0.0448 mmol) was dissolved in dichloromethane (3 mL), triethylamine (13.6 mg, 0.13 mmol) and N,N'-disuccinimidyl carbonate (34.4 mg, 0.13 mmol) were added, the reaction was stirred at room temperature for 0.5 h, then compound 3-(fluoromethyl)azetidine hydrochloride (4.8 mg, 0.054 mmol) was added and the reaction was stirred at room temperature for another 0.5 h, the reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to give compound 010 (4 mg, yield: 20%).

[0309] MS m / z (ESI): 450.1 (M+1).

[0310] 1H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.15 (q, 2H), 6.82-6.77 (m, 1H), 6.08-6.06 (m, 1H), 4.61 (d, 1H), 4.49 (d, 1H), 4.37-4.32 (m, 1H), 4.12-4.05 (m, 2H), 3.85-3.79 (m, 2H), 3.31 (s, 3H), 3.02-2.94 (m, 3H), 2.12 (s, 3H).

[0311] Example 11

[0312] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3-methoxyazetidine-l-carboxamide (011)

[0313] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3-methoxyazetidine-l-carboxamide (011)

[0314] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in dichloromethane (3 mL), triethylamine (14.3 mg, 0.135 mmol) and N,N'-disuccinimidyl carbonate (17.3 mg, 0.07 mmol) were added to the system, stirred at room temperature for 20 minutes. Compound 3-methoxyazetidine (11.7 mg, 0.135 mmol) was added to the reaction system, stirred for 30 minutes, after the reaction was completed, the reaction liquid was 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: WELCH Xtimate C18 21.2*250mm 10μm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 18 minute gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 30 mL / min) to obtain compound 011 (6 mg, yield: 30%).

[0315] MS m / z (ESI): 448.1 (M+1).

[0316] 1H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.15-7.13 (m, 2H), 6.79-6.75 (m, 1H), 6.07 (d, 1H), 4.43-4.30 (m, 1H), 4.23-4.20 (m, 1H), 4.20-4.11 (m, 2H), 3.88-3.78 (m, 2H), 3.30 (s, 3H), 3.29 (s, 3H), 3.01 (s, 2H), 2.12 (s, 3H).

[0317] Example 12

[0318] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)oxetane-3-carboxamide (013)

[0319] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)oxetane-3-carboxamide (013)

[0320] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (23 mg, 0.18 mmol), oxetane-3-carboxylic acid (6 mg, 0.06 mmol) and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.071 mmol) were added and the reaction was stirred at room temperature for 0.5 h. The crude reaction was purified directly by preparative high performance liquid chromatography (Waters, column: Xbridge 5 pm C18 150 x 21.2 mm; mobile phase 1 : water (with 0.05% ammonia water); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 5-100%, flow rate: 20 mL / min) to give compound 013 (8 mg, yield: 32%).

[0321] MS m / z (ESI): 419.1 (M+1).

[0322] 1 H NMR (400 MHz, CD3OD) δ 7.65-7.43 (m, 1H), 7.34-7.05 (m, 2H), 6.92-6.56 (m, 1H), 6.10 (d, 1H), 4.84-4.76 (m, 4H), 4.67-4.43 (m, 1H), 4.11-3.81 (m, 1H), 3.29 (s, 3H), 3.17-2.86 (m, 2H), 2.13 (s, 3H).

[0323] Example 13

[0324] (S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)oxetane-2-carboxamide (014)

[0325] First Step: Preparation of (S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl- 2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)oxetane-2-carboxamide (014)

[0326] Compound Int 1 (15 mg, 0.044 mmol) was dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (17 mg, 0.132 mmol) was added to the system. At 25 °C, (S)-oxetane-2-carboxylic acid (4.9 mg, 0.048 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (18.3 mg, 0.048 mmol) were added to the reaction system, and stirred at 25 °C for 60 min. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 16 min gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 014 (7 mg, yield: 38%).

[0327] MS m / z (ESI): 419.1 (M+l).

[0328] 1 H NMR (400 MHz, CD3OD) δ 7.54-7.50 (m, 1H), 7.18 (dd, 2H), 6.83-6.78 (m, 1H), 6.13 (d, 1H), 5.08-5.04 (m, 1H), 4.75-4.71 (m, 2H), 4.57-4.52 (m, 1H), 3.33 (s, 3H), 3.12-3.01 (m, 3H), 2.70-2.65 (m, 1H), 2.13 (s, 3H).

[0329] Example 14

[0330] (R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)oxetane-2-carboxamide (015)

[0331] First step: preparation of (R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl- 2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)oxetane-2-carboxamide (015)

[0332] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (17.4 mg, 0.13 mmol), compound (2R)-oxetane-2-carboxylic acid (5.1 mg, 0.05 mmol) and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.05 mmol) were added and the reaction was stirred at room temperature for 0.5 h. The crude reaction was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 pm C18 150 x 30 mm; mobile phase 1 : water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20-100%, flow rate: 25 mL / min) to give compound 015 (3 mg, yield: 17%).

[0333] MS m / z (ESI): 419.1 (M+1).

[0334] 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (d, 1H), 7.64 (dd, 1H), 7.24 (d, 1H), 7.15 (d, 1H), 6.95 (td, 1H), 6.31 (d, 1H), 4.98 - 4.95 (m, 1H), 4.66 - 4.49 (m, 3H), 3.20 (s, 3H), 3.11 (d, 2H), 2.98 - 2.90 (m, 1H), 2.49 - 2.47 (m, 1H), 2.05 (s, 3H).

[0335] Example 15

[0336] (1S,2R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-2-fluorocyclopropane-l-carboxamide (016)

[0337] Step 1 Preparation of (1S,2R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)-2-fluorocyclopropane-1-carboxamide (016)

[0338] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (17.4 mg, 0.13 mmol), (1S,2R)-2-fluorocyclopropane-1- carboxylic acid (5.2 mg, 0.05 mmol) and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.05 mmol) were added and the reaction was stirred at room temperature for 0.5 h. The crude reaction was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 pm C18 150 x 30 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20-100%, flow rate: 25 mL / min) to give compound 016 (3 mg, yield: 15.9%).

[0339] MS m / z (ESI): 421.1 (M+1).

[0340] 1 H NMR (400 MHz, DMSO-d6) d 8.63 (d, 1H), 7.64 (dd, 1H), 7.21 (d, 1H), 7.13 (d, 1H), 6.94 - 6.90 (m, 1H), 6.29 (d, 1H), 4.89 - 4.65 (m, 1H), 4.61 - 4.48 (m, 1H), 3.18 (s, 3H), 3.08 - 2.85 (m, 2H), 2.37 - 2.26 (m, 1H), 2.06 (s, 3H), 1.48 - 1.35 (m, 1H), 1.09 - 1.02 (m, 1H).

[0341] Example 16

[0342] (1S,2S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)-2-fluorocyclopropane-1-carboxamide (017)

[0343] Step 1. Preparation of (1S,2S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7- dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-2-fluorocyclopropane-1- carboxamide (017)

[0344] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in N,N- dimethylformamide (3 mL), N,N-diisopropylethylamine (17.4 mg, 0.13 mmol), compound (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (5.1 mg, 0.05 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.05 mmol) were added and the reaction was stirred at room temperature for 0.5 h. The crude reaction was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 pm C18 150 x 30 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20-100%, flow rate: 25 mL / min) to give compound 017 (2.1 mg, yield: 11%).

[0345] MS m / z (ESI): 421.1 (M+1).

[0346] 1 H NMR (400 MHz, DMSO-d6) d 8.44 (d, 1H), 7.64-7.62 (m, 1H), 7.23-7.20 (m, 1H), 7.13 (d, 1H), 6.97-6.92 (m, 1H), 6.28 (s, 1H), 4.98-4.70 (m, 1H), 4.61-4.56 (m, 1H), 3.19 (s, 3H), 3.02-2.97 (m, 1H), 2.93-2.86 (m, 1H), 2.05 (s, 3H), 1.97-1.92 (m, 1H), 1.56-1.49 (m, 1H), 1.05-1.03 (m, 1H).

[0347] Example 17

[0348] (S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (018)

[0349] Step 1. Preparation of (S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (018)

[0350] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (17.4 mg, 0.13 mmol), compound (S)-2,2-difluorocyclopropane-1-carboxylic acid (6.0 mg, 0.05 mmol) and 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.05 mmol) were added and the reaction was stirred at room temperature for 0.5 h. The crude reaction mixture was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 pm C18 150 x 30 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20-100%, flow rate: 25 mL / min) to give compound 018 (8 mg, yield: 40.6%).

[0351] MS m / z (ESI): 439.0 (M+1).

[0352] 1 H NMR (400 MHz, CD3OD) δ 7.53-7.49 (m, 1H), 7.19-7.13 (m, 2H), 6.82-6.80 (m, 1H), 6.12 (d, 1H), 4.59-4.52 (m, 1H), 3.31 (s, 3H), 3.11-2.94 (m, 2H), 2.69-2.61 (m, 1H), 2.12 (s, 3H), 2.03-1.98 (m, 1H), 1.81-1.75 (m, 1H).

[0353] Example 18

[0354] (R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin- 3-yl)-2,2-difluorocyclopropane-1-carboxamide (019)

[0355] Step 1. Preparation of (R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-2,2-difluorocyclopropane-1-carboxamide (019)

[0356] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (24 mg, 0.18 mmol), compound (R)-2,2-difluorocyclopropane-l-carboxylic acid (11 mg, 0.09 mmol) and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) were added and the reaction was stirred at room temperature for 0.5 h. The crude reaction was purified directly 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; 15 min gradient, gradient ratio: acetonitrile phase 65-100%, flow rate: 20 mL / min) to give compound 019 (7 mg, yield: 27%).

[0357] MS m / z (ESI): 439.0 (M+1).

[0358] 1 H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.16-7.14 (m, 2H), 6.79-6.75 (m, 1H), 6.25-5.97 (m, 1H), 4.57-4.52 (m, 1H), 3.31 (s, 3H), 3.12-3.07 (m, 1H), 3.01-2.94 (m, 1H), 2.71-2.63 (m, 1H), 2.12 (s, 3H), 2.07-1.95 (m, 1H), 1.82-1.73 (m, 1H).

[0359] Example 19

[0360] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,3,4-tetrahydroquinolin-3- yl)-1-fluoropropan-1 -carboxamide (020)

[0361] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,3,4- tetrahydroquinolin-3-yl)-1-fluoropropan-1 -carboxamide (020)

[0362] Compound Int 1 (15 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (17 mg, 0.13 mmol) was added to the system. At 25 °C, 1-fluorocyclopropane carboxylic acid (5.0 mg, 0.05 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (18 mg, 0.05 mmol) were added to the reaction system, stirred at 25 °C for 60 min, after the reaction was completed, the reaction liquid was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 16 min gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 020 (4.6 mg, yield: 25%).

[0363] MS m / z (ESI): 421.1 (M+1).

[0364] 1 H NMR (400 MHz, CD3OD) δ 7.53-7.49 (m, 1H), 7.18 (dd, 2H), 6.82-6.77 (m, 1H), 6.12 (d, 1H), 4.60-4.55 (m, 1H), 3.32 (s, 3H), 3.14-3.09 (m, 2H), 2.12 (s, 3H), 1.38-1.36 (m, 1H), 1.34-1.31 (m, 3H).

[0365] Example 20

[0366] (1S,3S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-3-fluorocyclobutan-1-carboxamide (021)

[0367] Preparation of (1S,3S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-3-fluorocyclobutan-1-carboxamide (021)

[0368] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in N,N- dimethylformamide (3 mL), N,N-diisopropylethylamine (17 mg, 0.13 mmol), compound (1S,3S)-3-fluorocyclobutane-1 -carboxylic acid (5.1 mg, 0.05 mmol) and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.05 mmol) were added and the reaction was stirred at room temperature for 0.5 h. The crude reaction was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 pm C18 150 x 30 mm; mobile phase 1 : water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20-100%, flow rate: 25 mL / min) to give compound 021 (4 mg, yield: 20.6%).

[0369] MS m / z (ESI): 435.1 (M+1).

[0370] 1 H NMR (400 MHz, DMSO-d6) d 8.21 (d, 1H), 7.64 (dd, 1H), 7.21 (d, 1H), 7.13 (d, 1H), 6.95-6.92 (m, 1H), 6.29 (d, 1H), 4.96-4.92 (m, 1H), 4.59-4.46 (m, 1H), 3.17 (s, 3H), 3.03-2.82 (m, 2H), 2.71-2.53 (m, 2H), 2.44 (d, 1H), 2.32-2.17 (m, 2H), 2.05 (s, 3H).

[0371] Example 21

[0372] (1R,3R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-3-fluorocyclobutane-1-carboxamide (022)

[0373] First step Preparation of (1R,3R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7- dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-3-fluorocyclobutane-1-carboxamide (022)

[0374] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (17.4 mg, 0.135 mmol), compound 022a (5.8 mg, 0.05 mmol) and 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20 mg, 0.05 mmol) were added, the reaction was stirred at room temperature for 0.5 h. The crude reaction was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 30 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 65-100%, flow rate: 20 mL / min) to give compound 022 (6 mg, yield: 31%).

[0375] MS m / z (ESI): 435.1 (M+1).

[0376] 1 H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.16-7.14 (m, 2H), 6.86-6.74 (m, 1H), 6.09 (d, 1H), 5.33-5.08 (m, 1H), 4.51-4.49 (m, 1H), 3.31 (s, 3H), 3.23-3.10 (m, 1H), 3.10-2.92 (m, 2H), 2.67-2.52 (m, 2H), 2.52-2.37 (m, 2H), 2.12 (s, 3H).

[0377] Example 22

[0378] (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)-3,3-difluorocyclobutane-1-carboxamide (023)

[0379] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-3,3-difluorocyclobutane-1-carboxamide (023)

[0380] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (24 mg, 0.18 mmol), compound 023a (12 mg, 0.09 mmol) and 2-(7-azobenzo-triazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46 mg, 0.120 mmol) were added. The reaction was stirred at room temperature for 0.5 h. The crude reaction mixture was purified directly 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; 15 min gradient, gradient ratio: acetonitrile phase 75-100%, flow rate: 20 mL / min) to give compound 023 (6.43 mg, yield: 24%).

[0381] MS m / z (ESI): 453.1 (M+1).

[0382] 1 H NMR (400 MHz, DMSO-d6) d 8.37 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.17 (dd, J = 28.4, 7.6 Hz, 2H), 6.95 - 6.92 (m, 1H), 6.30 (d, J = 8.4 Hz, 1H), 4.66 - 4.48 (m, 1H), 3.18 (s, 3H), 3.08 - 2.86 (m, 3H), 2.76 - 2.65 (m, 4H), 2.05 (s, 3H).

[0383] Example 23

[0384] (R)-(N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)amino-sulfamide (024)

[0385] Preparation of tert-butyl chlorosulfonylcarbamate (024b)

[0386] Compound 024a (500 mg, 3.5 mmol) was dissolved in tetrahydrofuran (10 mL), a solution of compound tert-butanol (288.03 mg, 3.8 mmol) in tetrahydrofuran (3 mL) was added at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 2 h. The resulting tetrahydrofuran solution was compound 024b, which was used directly in the next step.

[0387] Step 2: Preparation of (R)-(N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)aminosulfonyl) tert-butyl carbamate (024c)

[0388] Compound Int 1 (25 mg, 0.075 mmol) was dissolved in tetrahydrofuran (3 mL), tetrahydrofuran solution of compound 024b (0.5 mL) was added, then triethylamine (22.6 mg, 0.23 mmol) was added. The reaction was stirred at room temperature for 0.5 hour. The reaction was directly concentrated under reduced pressure to give the crude product which was compound 024c (20 mg).

[0389] MS m / z (ESI): 536.0 (M+23).

[0390] Step 3: Preparation of (R)-(N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)amino-sulfonamide (024)

[0391] Compound 024c (20 mg, 0.039 mmol) was dissolved in 4M hydrochloric acid in dioxane (3 mL), the reaction was stirred at room temperature for 1 hour. The reaction was directly concentrated under reduced pressure. The crude product was 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; 16 min gradient, gradient ratio: acetonitrile phase 10% - 100%, flow rate: 20 mL / min) to give compound 024 (3 mg, yield: 18.5%).

[0392] MS m / z (ESI): 414.0 (M+1).

[0393] 1 H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.17 - 7.12 (m, 2H), 6.82 - 6.76 (m, 1H), 6.12 (d, 1H), 4.08 (dd, 1H), 3.33 (s, 3H), 3.25 - 3.22 (m, 1H), 2.99-2.93 (m, 1H), 2.12 (s, 3H).

[0394] Example 24

[0395] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)methanesulfonamide (025)

[0396] Preparation of first step (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2- oxo-l,2,3,4-tetrahydroquinolin-3-yl)methanesulfonamide (025)

[0397] Compound Int 1 (10 mg, 0.03 mmol) was dissolved in DCM (1 mL), triethylamine (6 mg, 0.06 mmol) was added to the system, the mixture was placed in 0 °C and stirred, methylsulfonyl chloride (5 mg, 0.04 mmol) was added dropwise to the reaction system, after the end of the dropwise addition, the mixture was placed at room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: Gemini 5 μm C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 60%-100%, flow rate: 25 mL / min) to obtain compound 025 (4.1 mg, yield: 30%).

[0398] MS m / z (ESI): 413.1 (M+1).

[0399] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.61 (m, 1H), 7.48 (d, 1H), 7.22 (d, 1H), 7.13 (d, 1H), 6.97 - 6.62 (m, 1H), 6.41 (s, 1H), 4.29 (s, 1H), 3.20 (s, 3H), 3.07 - 3.02 (m, 2H), 2.97 (s, 3H), 2.03 (s, 3H).

[0400] Example 25

[0401] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)ethanesulfonamide (026)

[0402] Preparation of first step (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2- oxo-l,2,3,4-tetrahydroquinolin-3-yl)ethanesulfonamide (026)

[0403] Compound Int 1 (20 mg, 0.060 mmol) was dissolved in dichloromethane (3 mL), triethylamine (19 mg, 0.180 mol) and N,N'-disuccinimidyl carbonate (23.1 mg, 0.091 mmol) were added to the system, stirred at room temperature for 20 minutes. Compound ethylsulfonyl chloride (23.1 mg, 0.180 mmol) was added to the reaction system, stirred for 30 minutes, after the reaction was completed, the reaction liquid was 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 SQD2 detector, chromatographic 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 026 (18 mg, yield: 71%).

[0404] MS m / z (ESI): 427.1 (M+1).

[0405] 1 H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.15 (dd, 2H), 6.80-6.75 (m, 1H), 6.17 (d, 1H), 4.17-4.12 (m, 1H), 3.30 (s, 3H), 3.19-3.03 (m, 4H), 2.11 (s, 3H), 1.34 (t, 3H).

[0406] Example 26

[0407] (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)- 2,2,2-trifluoroethanesulfonamide (027)

[0408] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-2,2,2-trifluoroethanesulfonamide (027)

[0409] Compound Int 1 (20 mg, 0.060 mmol) was dissolved in dichloromethane (3 mL), diisopropylethylamine (21 mg, 0.17 mol) and 2,2,2-trifluoroethane-1-sulfonyl chloride (12 mg, 0.07 mmol) were added to the system, the reaction was stirred at room temperature for 2 hours, after the reaction was completed, the reaction liquid was concentrated under reduced pressure to obtain a 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 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 75%-100%, flow rate: 20 mL / min) to obtain compound 027 (13.7 mg, yield: 51%).

[0410] MS m / z (ESI): 481.0 (M+1).

[0411] 1 H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.16-7.12 (m, 2H), 6.84-6.76 (m, 1H), 6.16 (d, 1H), 4.34-4.23 (m, 3H), 3.32 (s, 3H), 3.15-3.04 (m, 2H), 2.11 (s, 3H).

[0412] Example 27

[0413] (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)cyclopropylsulfamide (028)

[0414] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)cyclopropylsulfamide (028)

[0415] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in tetrahydrofuran (3 mL), triethylamine (19 mg, 0.18 mol) and cyclopropanesulfonyl chloride (13 mg, 0.09 mmol) were added to the system, the reaction was stirred at room temperature for 5 hours, after the reaction was completed, the reaction liquid was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, chromatographic column: Gemini 5 μm C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 65%-100%, flow rate: 25 mL / min) to obtain compound 028 (2 mg, yield: 7%).

[0416] MS m / z (ESI): 439.1 (M+1).

[0417] 1 H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.21-7.12 (m, 2H), 6.86-6.76 (m, 1H), 6.17-6.14 (m, 1H), 4.24-4.08 (m, 1H), 3.30 (d, 3H), 3.10 (d, 1H), 3.02 (s, 1H), 2.64 (s, 1H), 2.13 (s, 3H), 1.04-0.99 (m, 2H), 0.92-0.89 (m, 2H).

[0418] Example 28

[0419] (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)propane sulfonamide (029)

[0420] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)propane sulfonamide (029)

[0421] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in tetrahydrofuran (2 mL), triethylamine (18 mg, 0.18 mmol) was added, and propan-1-sulfonyl chloride (9 mg, 0.06 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated by evaporation to give a crude product, which was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xtimate 21.2 x 250 mm 10 pm C18; mobile phase 1 : water (with 0.1% ammonia water); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 10-100%, flow rate: 25 mL / min) to give compound 029 (1.91 mg, yield: 3.4%).

[0422] MS m / z (ESI): 441.1 (M+1).

[0423] 1 H NMR (400 MHz, CD3OD) δ 7.64 - 7.43 (m, 1H), 7.30 - 7.03 (m, 2H), 6.90 - 6.67 (m, 1H), 6.18 (d, 1H), 4.20 - 4.08 (m, 1H), 3.24 (s, 3H), 3.21 - 2.94 (m, 4H), 2.11 (s, 3H), 1.23 - 1.04 (m, 2H), 1.02 (t, 3H).

[0424] Example 29

[0425] (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)- 1,1,1-trifluoromethanesulfonamide (030)

[0426] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-1,1,1-trifluoromethanesulfonamide (030)

[0427] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in acetonitrile (3 mL), pyridine (10.5 mg, 0.13 mmol) and trifluoromethylsulfonyl chloride (8.3 mg, 0.05 mmol) were added and the reaction was stirred at 60 °C for 0.5 h. The crude reaction was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 pm C18 150 x 30 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20-100%, flow rate: 25 mL / min) to give compound 030 (2.1 mg, yield: 11%).

[0428] MS m / z (ESI): 467.0 (M+1).

[0429] 1 H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.17 (dd, 2H), 6.85-6.73 (m, 1H), 6.25-6.13 (m, 1H), 4.28-4.24 (m, 1H), 3.24 (s, 3H), 3.15-3.04 (m, 2H), 2.12 (s, 3H).

[0430] Example 30

[0431] (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)-3,3-difluorocyclobutane-1 -methylsulfonamide (031)

[0432] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-3,3-difluorocyclobutane-1 -methylsulfonamide (031)

[0433] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL), triethylamine (19 mg, 0.18 mmol) was added, compound methylsulfonamide chloro (15 mg, 0.12 mmol), the reaction was stirred at room temperature for 0.5 hours. The crude reaction was purified directly 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 minute gradient, gradient ratio: acetonitrile phase 63%-100%, flow rate: 20 mL / min) to give compound 031 (12 mg, yield: 48%).

[0434] MS m / z (ESI): 428.0 (M+1).

[0435] 1 H NMR (400 MHz, DMSO-d6) d 7.65 (dd, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 7.08 (d, 1H), 6.96 - 6.90 (m, 1H), 6.70 - 6.65 (m, 1H), 6.29 (s, 1H), 4.06 - 3.90 (m, 1H), 3.19 (s, 3H), 3.07 - 3.02 (m, 1H), 2.93 - 2.90 (m, 1H), 2.48 (s, 3H), 2.04 (s, 3H).

[0436] Example 31

[0437] (3R)-8-(2-Chloro-5-fluorophenoxy)-3-[(ethylsulfamoyl)amino]-1,7-dimethyl-3,4- dihydroquinolin-2-one (033)

[0438] First step Preparation of (3R)-8-(2-chloro-5-fluorophenoxy)-3-[(ethylsulfamoyl)amino]- 1,7-dimethyl-3,4-dihydroquinolin-2-one (033)

[0439] Compound Int 1 (13 mg, 0.0389 mmol) was dissolved in dichloromethane (3 mL), triethylamine (12 mg, 0.12 mmol) and ethylsulfamoyl chloride (11 mg, 0.08 mmol) were added. After the reaction was stirred at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1 : water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 033 (2.71 mg, yield: 16%).

[0440] MS m / z (ESI): 442.1 (M+1).

[0441] 1 H NMR (400 MHz, CD3OD) d 7.52 (dd, 1H), 7.16 (q, 2H), 6.89-6.64 (m, 1H), 6.11 (d, 1H), 3.98-3.95 (m, 1H), 3.30 (s, 3H), 3.19 (dd, 1H), 3.09-2.94 (m, 3H), 2.12 (s, 3H), 1.08 (t, 3H).

[0442] Example 32

[0443] (3R)-8-(2-Chloro-5-fluorophenoxy)-3-[(dimethylaminosulfonyl)amino]-1,7-dimethyl- 3,4-dihydroquinolin-2-one (032)

[0444] First Step Preparation of (3R)-8-(2-Chloro-5-fluorophenoxy)-3-[(dimethylaminosulfonyl)amino]-1,7-dimethyl-3,4-dihydroquinolin-2-one (032)

[0445] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in acetonitrile (3 mL), pyridine (24 mg, 0.30 mmol) and dimethylsulfamoyl chloride (9 mg, 0.06 mmol) were added. After the reaction was stirred at 65 °C for 16 hours, the reaction was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1 : water (with 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 10-100%, flow rate: 20 mL / min) to obtain compound 032 (7.86 mg, yield: 30%).

[0446] MS m / z (ESI): 442.1 (M+1).

[0447] 1 H NMR (400 MHz, CD3OD) d 7.62 - 7.43 (m, 1H), 7.25 - 7.07 (m, 2H), 6.89 - 6.72 (m, 1H), 6.31 - 6.08 (m, 1H), 4.18 - 3.92 (m, 1H), 3.28 (s, 3H), 3.22 - 3.06 (m, 1H), 3.05 - 2.90 (m, 1H), 2.76 (s, 6H), 2.13 (s, 3H).

[0448] Example 33

[0449] (R)-N-((R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-2-methylazetidin-l -carboxamide (044)

[0450] First step: preparation of (R)-N-((R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l- methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-2-methylazetidin-l -carboxamide (044)

[0451] Compound Int 2 (50 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL), triethylamine (43 mg, 0.42 mmol) and N,N'-disuccinimidyl carbonate (72 mg, 0.28 mmol) were added, after the reaction was stirred at room temperature for 0.5 hours, compound (R)-2-methylazetidine (20 mg, 0.28 mmol) was added and the reaction was stirred at room temperature for another 0.5 hours, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1 : water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 044 (10.12 mg, yield: 16%).

[0452] MS m / z (ESI): 452.1 (M+1).

[0453] 1 H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.34 (d, 1H), 7.26 (d, 1H), 6.89-6.78 (m, 1H), 6.19 (dd, 1H), 4.45-4.33 (m, 2H), 4.00-3.82 (m, 2H), 3.33 (s, 3H), 3.10-3.00 (m, 2H), 2.46-2.36 (m, 1H), 1.92-1.81 (m, 1H), 1.42 (t, 3H).

[0454] Example 34

[0455] (3R)-7-Chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3-[(methylsulfamoyl)amino]- 3,4-dihydroquinolin-2-one (045)

[0456] First step Preparation of (3R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3- [(methylsulfamoyl)amino]-3,4-dihydroquinolin-2-one (045)

[0457] Compound Int 2 (30 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL), triethylamine (25 mg, 0.25 mmol) and methanesulfonamide chloride (22 mg, 0.17 mmol) were added. After the reaction was stirred at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 045 (12 mg, yield: 32%).

[0458] MS m / z (ESI): 448.0 (M+1).

[0459] 1 H NMR (400 MHz, CD3OD) d 7.52 (dd, 1H), 7.35 (d, 1H), 7.28 (d, 1H), 6.90-6.77 (m, 1H), 6.24 (dd, 1H), 4.04-4.00 (m, 1H), 3.34 (s, 3H), 3.22-3.20 (m, 1H), 3.01-2.98 (m, 1H), 2.64 (s, 3H).

[0460] Example 35

[0461] (R)-N-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3,3-difluoroazetidine-l-carboxamide (046)

[0462] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3,3-difluoroazetidine-l-carboxamide (046)

[0463] Compound Int 3 (15.0 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL), triethylamine (13 mg, 0.13 mmol) was added, followed by N,N'-disuccinimidyl carbonate (15 mg, 0.06 mmol), the reaction was stirred at room temperature for 0.5 h, then compound 3,3-difluoroazetidine (5.6 mg, 0.06 mmol) was added, the reaction was stirred for another 20 min, after the reaction was complete by LC-MS, the mixture 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 046 (5.77 mg, yield: 28%).

[0464] MS m / z (ESI): 458.0 (M+1).

[0465] 1 H NMR (400 MHz, CD3OD) δ 7.54-7.50 (m, 1H), 7.27-7.23 (m, 1H), 7.10-7.05 (m, 1H), 6.87-6.83 (m, 1H), 6.46-6.43 (m, 1H), 4.47-4.40 (m, 1H), 4.36-4.27 (m, 4H), 3.34 (s, 3H), 3.06-3.03 (m, 2H).

[0466] Example 36

[0467] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3,3-difluoroazetidine-l-carboxamide (047)

[0468] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3,3-difluoroazetidine-l-carboxamide (047)

[0469] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in dichloromethane (3 mL), triethylamine (14.3 mg, 0.135 mol) and N,N'-disuccinimidyl carbonate (17.3 mg, 0.068 mmol) were added to the system, stirred at room temperature for 20 minutes. Compound 3,3-difluoroazetidine (12.6 mg, 0.135 mmol) was added to the reaction system, stirred for 30 minutes, after the reaction was completed, the reaction liquid was 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: Gemini 5 μm C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 62%-100%, flow rate: 25 mL / min) to obtain compound 047 (5 mg, yield: 25%).

[0470] MS m / z (ESI): 454.1 (M+1).

[0471] 1 H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.16 (q, 2H), 6.80 (td, 1H), 6.08 (d, J = 8.1 Hz, 1H), 4.44 - 4.25 (m, 5H), 3.30 - 3.29 (m, 3H), 3.06 - 2.97 (m, 2H), 2.12 (s, 3H).

[0472] Example 37

[0473] (R)-N-(7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)-3,3-difluoroazetidin-l-ylformamide (048)

[0474] First step: preparation of (R)-N-(7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-3,3-difluoroazetidin-l-ylformamide (048)

[0475] Compound Int 2 (30.0 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL), triethylamine (16 mg, 0.16 mmol) was added, followed by N,N'-disuccinimidyl carbonate (31 mg, 0.12 mmol), the reaction was stirred at room temperature for 0.5 hour, then compound 3,3-difluoroazetidine (11 mg, 0.12 mmol) was added, the reaction was continued to stir for 20 minutes, after LC-MS monitoring the reaction was complete, the mixture 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 minute gradient, gradient ratio: acetonitrile phase 57%-100%, flow rate: 20 mL / min) to give compound 048 (15.6 mg, yield: 39%).

[0476] MS m / z (ESI): 474.0 (M+1).

[0477] 1 H NMR (400 MHz, CD3OD) δ 7.54-7.50 (m, 1H), 7.35 (d, 1H), 7.27 (d, 1H), 6.86-6.81 (m, 1H), 6.22-6.19 (m, 1H), 4.47-4.42 (m, 1H), 4.36-4.29 (m, 4H), 3.37 (s, 3H), 3.07-3.04 (m, 2H).

[0478] Example 38

[0479] (R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)-2-methylazetidine-1-carboxamide (049)

[0480] First step: preparation of (R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-2-methylazetidine-1-carboxamide (049)

[0481] Compound Int 1 (30 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), triethylamine (27 mg, 0.27 mmol) and N,N'-disuccinimidyl carbonate (46 mg, 0.18 mmol) were added, after the reaction was stirred at room temperature for 0.5 hours, compound (R)-2-methylazetidine (13 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for another 0.5 hours, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 049 (17.29 mg, yield: 44.7%).

[0482] MS m / z (ESI): 432.1 (M+1).

[0483] 1 H NMR (400 MHz, DMSO-d6) d 7.64 (dd, 1H), 7.16 (dd, 2H), 7.01 - 6.88 (m, 1H), 6.26 - 6.11 (m, 2H), 4.38 - 4.14 (m, 2H), 3.84 - 3.61 (m, 2H), 3.17 (s, 3H), 3.07 - 2.87 (m, 2H), 2.34 - 2.22 (m, 1H), 2.05 (s, 3H), 1.80 - 1.69 (m, 1H), 1.30 (d, 3H).

[0484] Example 39

[0485] (S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)-2-methylazetidine-1-carboxamide (050)

[0486] First step: preparation of (S)-N-((R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)-2-methylazetidine-1-carboxamide (050)

[0487] Compound Int 1 (30 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), triethylamine (27.2 mg, 0.27 mmol) and N,N'-disuccinimidyl carbonate (45.91 mg, 0.18 mmol) were added, after the reaction was stirred at room temperature for 0.5 hours, compound (S)-2-methylazetidine (12.74 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for 0.5 hours, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 050 (17.22 mg, yield: 44.5%).

[0488] MS m / z (ESI): 432.1 (M+1).

[0489] 1 H NMR (400 MHz, DMSO-d6) d 7.64 (dd, 1H), 7.17 (dd, 2H), 7.00 - 6.88 (m, 1H), 6.29 - 6.12 (m, 2H), 4.32 (dd, 1H), 4.27 - 4.15 (m, 1H), 3.85 - 3.68 (m, 2H), 3.17 (s, 3H), 3.01 - 2.85 (m, 2H), 2.34 - 2.21 (m, 1H), 2.05 (s, 3H), 1.81 - 1.70 (m, 1H), 1.31 (d, 3H).

[0490] Example 40

[0491] (R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)-2-methylazetidine-l-carboxamide (051)

[0492] First step: preparation of (R)-N-((R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l- methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)-2-methylazetidine-l-carboxamide (051)

[0493] Compound Int 3 (25 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL), triethylamine (26 mg, 0.25 mol) was added to the system. At below 10 °C, compound bis(2,5-dioxopyrrolidin-1-yl) carbonate (32 mg, 0.14 mmol) was added to the reaction system, stirred for 10 minutes, (R)-2-methylazetidine (13 mg, 0.07 mmol) was added and stirred for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 16 minute gradient, gradient ratio: acetonitrile phase 10%-100%, flow rate: 20 mL / min) to obtain compound 051 (10.2 mg, yield: 31.25%).

[0494] MS m / z (ESI): 436.1 (M+1).

[0495] 1 HNMR (400 MHz, DMSO-d6) δ 7.65 (dd, 1H), 7.29 (dd, 1H), 7.20-7.13 (m, 1H), 7.01-6.68 (m, 1H), 6.73 (d, 1H), 6.24 (d, 1H), 4.48-4.35 (m, 1H), 4.29-4.18 (m, 1H), 3.79-3.71 (m, 1H), 3.70-3.65 (m, 1H), 3.21 (s, 3H), 3.04-2.91 (m, 2H), 2.32-2.22 (m, 1H), 1.76-1.72 (m, 1H), 1.31 (t, 3H).

[0496] Example 41

[0497] (3R)-8-(2-Chloro-5-fluorophenoxy)-7-fluoro-1-methyl-3-[(methylaminosulfonyl)amino]-3,4-dihydroquinolin-2-one (052)

[0498] First Step Preparation of (3R)-8-(2-Chloro-5-fluorophenoxy)-7-fluoro-1-methyl-3-[(methylaminosulfonyl)amino]-3,4-dihydroquinolin-2-one (052)

[0499] Compound Int 3 (25 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL), triethylamine (23 mg, 0.30 mmol) and methanesulfonamide chloride (29 mg, 0.06 mmol) were added. After the reaction was stirred at 25 degrees Celsius for 1.5 hours, the reaction was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography preparation (column: Xbridge 5 pm 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 052 (8.5 mg, yield: 26%).

[0500] MS m / z (ESI): 432.1 (M+1).

[0501] 1 HNMR (400 MHz, DMSO-d6) δ 7.65 (dd, 1H), 7.32 (dd, 1H), 7.19 - 7.15 (m, 2H), 7.02 (td, 1H), 6.77 (d, 1H), 6.68 - 6.65 (m, 1H), 4.08 - 4.02 (m, 1H), 3.23 (s, 3H), 3.11 - 3.08 (m, 1H), 2.94 - 2.90 (m, 1H), 2.51 (s, 3H).

[0502] Example 42

[0503] (R)-N-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)ethanesulfonamide (053)

[0504] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)ethanesulfonamide (053)

[0505] Compound Int 1 (15 mg, 0.045 mmol) was dissolved in DCM (3 mL), TEA (13 mg, 0.13 mmol) and ethylsulfonyl chloride (6.5 mg, 0.05 mmol) were added, the reaction was stirred at 25 °C for 2 hours. The crude reaction was purified directly by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with QDA detector, column: Xbridge 5 pm C18 150 x 30 mm; mobile phase 1: water (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20-100%, flow rate: 25 mL / min) to give compound 053 (2.1 mg, yield: 11%).

[0506] MS m / z (ESI): 431.0 (M+1).

[0507] 1 H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.25 (dd, 1H), 7.07 (dd, 1H), 6.87-6.83 m, 1H), 6.54-6.51 (m, 1H), 4.24-4.20 (m, 1H), 3.34 (s, 3H), 3.19-2.97 (m, 4H), 1.36 (t, 3H).

[0508] Example 43

[0509] (R)-N-(7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)ethanesulfonamide (054)

[0510] First step: preparation of (R)-N-(7-chloro-8-(2-chloro-5-fluorophenoxy)-l- methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)ethanesulfonamide (054)

[0511] Compound Int 2 (10 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL), triethylamine (19 mg, 0.18 mmol) was added, compound ethanesulfonyl chloride (15 mg, 0.12 mmol), the reaction was stirred at room temperature for 0.5 hours. The crude reaction was purified directly 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; 15 min gradient, gradient ratio: acetonitrile phase 63%-100%, flow rate: 20 mL / min) to give compound 054 (5.1 mg, yield: 42%).

[0512] MS m / z (ESI): 447.0 (M+1).

[0513] 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.62 (m, 2H), 7.39-7.34 (m, 2H), 6.98-6.95 (m, 1H), 6.66 (s, 1H), 4.33 (s, 1H), 3.21 (s, 3H), 3.13-2.93 (m, 4H), 1.21-1.19 (m, 3H).

[0514] Example 44

[0515] (R)-N-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)azetidin-l-ylformamide (055)

[0516] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)azetidin-l-ylformamide (055)

[0517] Compound Int 3 (15.0 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL), triethylamine (13 mg, 0.13 mmol) was added, followed by N,N'-disuccinimidyl carbonate (15 mg, 0.06 mmol), the reaction was stirred at room temperature for 0.5 hour, then compound azetidine (3.5 mg, 0.06 mmol) was added, the reaction was stirred for another 20 minutes, after the reaction was completed by LC-MS, 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 53%-100%, flow rate: 20 mL / min) to give compound 055 (5.90 mg, yield: 31%).

[0518] MS m / z (ESI): 422.1 (M+1).

[0519] 1 H NMR (400 MHz, CD3OD) δ 7.53-7.50 (m, 1H), 7.26-7.22 (m, 1H), 7.09-7.04 (m, 1H), 6.88-6.83 (m, 1H), 6.45-6.41 (m, 1H), 4.43-4.38 (m, 1H), 4.07-3.97 (m, 4H), 3.33 (s, 3H), 3.04-3.01 (m, 2H), 2.33-2.25 (m, 2H).

[0520] Example 45

[0521] (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4-tetrahydroquinolin-3- yl)isopropyl-2-sulfonamide (056)

[0522] First step: preparation of (R)-N-(8-(2-chloro-5-fluorophenoxy)-l,7-dimethyl-2-oxo-l,2,3,4- tetrahydroquinolin-3-yl)isopropyl-2-sulfonamide (056)

[0523] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in dichloromethane (3 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (27 mg, 0.18 mmol) and propan-2-sulfonyl chloride (13 mg, 0.09 mmol) were added and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative high performance liquid chromatography (column: Xbridge 5 pm 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 67-100%, flow rate: 25 mL / min) to give compound 056 (5.8 mg, yield: 20%).

[0524] MS m / z (ESI): 441.1 (M+1).

[0525] 1 H NMR (400 MHz, CD3OD) δ 7.65 - 7.39 (m, 1H), 7.30 - 7.02 (m, 2H), 6.90 - 6.69 (m, 1H), 6.15 (d, 1H), 4.33 - 4.02 (m, 1H), 3.29 (s, 3H), 3.28 - 3.23 (m, 1H), 3.17 - 2.96 (m, 2H), 2.11 (s, 3H), 1.45 - 1.22 (m, 6H).

[0526] Example 46

[0527] (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3-(pyridazin-3-ylamino)- 3,4-dihydroquinolin-2(1H)-one (134)

[0528] First step: preparation of (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3- (pyridazin-3-ylamino)-3,4-dihydroquinolin-2(1H)-one (134)

[0529] Compound Int 2 (100 mg, 0.28 mmol) was dissolved in dioxane (5 mL), then compound 3-bromopyridazine (53.7 mg, 0.34 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium (23.65 mg, 0.028 mmol) and cesium carbonate (275.15 mg, 0.84 mmol) were added. The reaction was stirred at 90 °C under nitrogen protection for 12 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was directly purified by high performance liquid chromatography (Waters MS-triggered Prep-LC with QDA detector, column: Gemini5u C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 40%-100%, flow rate: 25 mL / min) to obtain compound 134 (8 mg, yield: 6.6%).

[0530] MS m / z (ESI): 433.0 (M+1) + .

[0531] 1 H NMR (400 MHz, CD3OD) δ 8.45-8.44 (m, 1H), 7.54-7.51 (m, 1H), 7.38-7.30 (m, 3H), 7.08-7.06 (m, 1H), 6.86-6.82 (m, 1H), 6.27-6.24 (m, 1H), 4.83-4.79 (m, 1H), 3.43-3.39 (m, 1H), 3.37 (s, 3H), 3.04-2.97 (m, 1H).

[0532] Example 47

[0533] (R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3-(pyridazin-3-ylamino)-3,4- dihydroquinolin-2(1H)-one (135)

[0534] First step: preparation of (R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3- (pyridazin-3-ylamino)-3,4-dihydroquinolin-2(1H)-one (135)

[0535] Compound Int 1 (20 mg, 0.060 mmol) was dissolved in dioxane (2 mL), cesium carbonate (58 mg, 0.180 mmol), 3-bromopyridazine (28 mg, 0.180 mmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (2-amino-1,1- biphenyl-2-yl)palladium(II) (5 mg, 0.006 mmol), 2-dicyclohexylphosphino-2',6'- dimethoxy-1,1'-biphenyl (3 mg, 0.006 mmol) were added and the reaction was stirred at 90 °C for 8 h. The crude reaction was purified directly 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; 15 min gradient, gradient ratio: acetonitrile phase 50-100%, flow rate: 20 mL / min) to give compound 135 (2.1 mg, yield: 9%).

[0536] MS m / z (ESI): 413.0 (M+1) + .

[0537] 1 H NMR (400 MHz, DMSO-d6) δ 8.61-8.59 (m, 2H), 7.96-7.43 (m, 3H), 7.23-7.21 (m, 2H), 6.98-6.97 (m, 1H), 6.27-6.26 (m, 1H), 4.77-4.75 (m, 1H), 3.26-3.02 (m, 5H), 2.06 (s, 3H).

[0538] Example 48

[0539] (R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-methyl-3-(pyridazin-3-ylamino)- 3,4-dihydroquinolin-2(1H)-one (136)

[0540] First step: preparation of (R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-1-methyl-3- (pyridazin-3-ylamino)-3,4-dihydroquinolin-2(1H)-one (136)

[0541] Compound Int 3 (20 mg, 0.060 mmol) was dissolved in dioxane (2 mL), cesium carbonate (58 mg, 0.180 mmol), 3-bromopyridazine (28 mg, 0.180 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.006 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg, 0.006 mmol) were added and the reaction was stirred at 90 °C for 8 h. The crude reaction was purified directly 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% trifluoroacetic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 50-100%, flow rate: 20 mL / min) to give compound 136 (1.54 mg, yield: 6%).

[0542] MS m / z (ESI): 417.0 (M+1) + .

[0543] 1 H NMR (400 MHz, CD3OD) δ 8.44-8.43 (m, 1H), 7.52-7.51 (m, 1H), 7.35-7.27 (m, 2H), 7.09-7.05 (m, 2H), 6.89-6.81 (m, 1H), 6.50-6.51 (m, 1H), 4.79-4.77 (m, 1H), 3.38-3.30 (m, 4H), 2.99-2.98 (m, 1H).

[0544] Example 49

[0545] (R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3-(pyrimidin-2-ylamino)-3,4- dihydroquinolin-2(1 H)-one (137)

[0546] First step: preparation of (R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3-(pyrimidin-2- ylamino)-3,4-dihydroquinolin-2(1 H)-one (137)

[0547] Compound Int 1 (20 mg, 0.06 mmol) was dissolved in 1.4-dioxane (1 mL), cesium carbonate (59 mg, 0.18 mmol), 2-iodopyrimidine (15 mg, 0.07 mmol) and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) dichloride (11 mg, 0.012 mmol) were added and the reaction was stirred at 80 °C under nitrogen atmosphere for 12 h. The crude reaction was purified directly 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; 15 min gradient, gradient ratio: acetonitrile phase 70-100%, flow rate: 20 mL / min) to give compound 137 (2.1 mg, yield: 8%).

[0548] MS m / z (ESI): 413.0 (M+1) + .

[0549] 1 H NMR (400 MHz, CD3OD) δ 8.31 (d, 2H), 7.52 (dd, 1H), 7.19 (d, 2H), 6.83-6.76 (m, 1H), 6.69 (t, 1H), 6.12 (d, 1H), 4.60 (dd, 1H), 3.34 (s, 3H), 3.30-3.29 (m, 1H), 2.99 (t, 1H), 2.14 (s, 3H).

[0550] Example 50

[0551] (R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-3-(pyridin-2-ylamino)-3,4- dihydroquinolin-2(lH)-one (138)

[0552] First step: preparation of (R)-8-(2-chloro-5-fluorophenoxy)-7-fluoro-l-methyl-3- (pyridin-2-ylamino)-3,4-dihydroquinolin-2(lH)-one (138)

[0553] Compound Int 3 (25 mg, 0.074 mmol) was dissolved in 1,4-dioxane (2 mL), added 2-iodopyridine (45.39 mg, 0.2214 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium (24.8 mg, 0.0.02952 mmol) and cesium carbonate (72.14 mg, 0.2214 mmol), stirred at 100 °C for 2 hours under N2condition. The crude reaction solution 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 (with 0.1% formic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 20% - 100%, flow rate: 25 mL / min) to give compound 138 (2.1 mg, yield: 7%).

[0554] MS m / z (ESI): 416.0 (M+1) + .

[0555] 1 H NMR (400 MHz, CD3OD) δ 7.93 (d, 1H), 7.57 - 7.39 (m, 2H), 7.28 (dd, 1H), 7.09 (dd, 1H), 6.90 - 6.81 (m, 1H), 6.69 (d, 1H), 6.64 - 6.56 (m, 1H), 6.49 - 6.46 (m, 1H), 4.64 (dd, 1H), 3.37 (s, 3H), 3.29 - 3.23 (m, 1H), 2.96 (t, 1H).

[0556] Example 51

[0557] (R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3-(oxazol-2-ylamino)-3,4- dihydroquinolin-2(1H)-one (139)

[0558] First step: preparation of (R)-8-(2-chloro-5-fluorophenoxy)-1,7-dimethyl-3-(oxazol-2- ylamino)-3,4-dihydroquinolin-2(1H)-one (139)

[0559] Compound Int 1 (20 mg, 0.060 mmol) was dissolved in dioxane (2 mL), cesium carbonate (58 mg, 0.180 mmol), 2-bromo-oxazole (26 mg, 0.180 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium(5 mg, 0.006 mmol) were added and the reaction was stirred at 80 °C for 16 h. The crude reaction mixture was purified directly 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; 15 min gradient, gradient ratio: acetonitrile phase 63-100%, flow rate: 20 mL / min) to give compound 139 (1.1 mg, yield: 5%).

[0560] MS m / z (ESI): 402.0 (M+1) + .

[0561] 1 H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.28-7.26 (m, 1H), 7.18-7.14 (m, 2H), 6.87-6.70 (m, 2H), 6.13 (d, 1H), 4.34-4.33 (m, 1H), 3.33 (s, 3H), 3.23-3.22 (m, 1H), 3.02-3.00 (m, 1H), 2.12 (s, 3H).

[0562] Example 52

[0563] (R)-3-((1,3,4-Thiadiazol-2-yl)amino)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1- methyl-3,4-dihydroquinolin-2(1H)-one (174)

[0564] First step: preparation of (R)-3-((1,3,4-thiadiazol-2-yl)amino)-7-chloro-8-(2-chloro-5- fluorophenoxy)-1-methyl-3,4-dihydroquinolin-2(1H)-one (174)

[0565] Compound Int 2 (20 mg, 0.06 mmol) was dissolved in dioxane (2 mL), cesium carbonate (58 mg, 0.18 mmol), 2-bromo-1,3,4-thiadiazole (28 mg, 0.18 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylmethylene]dichloropalladium (5 mg, 0.006 mmol) were added and the reaction was stirred at 80 °C for 16 h. The crude reaction was purified directly by high performance liquid chromatography (Waters MS-triggered Prep-LC with SQD2 detector, column: Gemini 5 μm C18 100 x 21.2 mm; mobile phase 1: water (with 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 15 min gradient, gradient ratio: acetonitrile phase 55-100%, flow rate: 25 mL / min) to give compound 174 (2.0 mg, yield: 8%).

[0566] MS m / z (ESI): 439.0 (M+1) + .

[0567] 1 H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 7.53-7.51 (m, 1H), 7.35-7.33 (m, 2H), 6.84-6.82 (m, 1H), 6.30-6.23 (m, 1H), 4.60-4.58 (m, 1H), 3.44-3.42 (m, 1H), 3.37 (s, 3H), 3.05-3.03 (m, 1H).

[0568] Example 53

[0569] (R)-8-(2-bromo-5-fluorophenoxy)-7-chloro-1-methyl-3-(pyridazin-3-ylamino)- 3,4-dihydroquinolin-2(1H)-one (180)

[0570] First step: preparation of (R)-8-(2-bromo-5-fluorophenoxy)-7-chloro-1-methyl-3- (pyridazin-3-ylamino)-3,4-dihydroquinolin-2(1H)-one (180)

[0571] Compound 180a (25 mg, 0.060 mmol) (synthesis method refer to the synthetic route of Int 2) was dissolved in 1,4 dioxane (3 mL), 3-bromopyridazine (15 mg, 0.091 mmol), cesium carbonate (61 mg, 0.19 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (5 mg, 0.006 mmol) were added, the reaction was stirred at 80 °C for 4 hours, after the reaction was completed by LC-MS monitoring, the reaction was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Gemini 5 μm C18 100 x 21.2 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 10 min gradient, gradient ratio: acetonitrile phase 5%-100%, flow rate: 25 mL / min) to obtain compound 180 (5 mg, yield: 9.1%).

[0572] MS m / z (ESI): 477.1 (M+1).

[0573] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, 1H), 8.26 - 7.91 (m, 1H), 7.88 - 7.72 (m, 1H), 7.61 - 7.49 (m, 1H), 7.49 - 7.29 (m, 3H), 7.07 - 6.85 (m, 1H), 6.44 (s, 1H), 5.00 - 4.74 (m, 1H), 3.26 (s, 3H), 3.17 - 2.93 (m, 2H).

[0574] Example 54

[0575] (R)-3-((1H-1,2,3-triazol-4-yl)amino)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1- methyl-3,4-dihydroquinolin-2(1H)-one (191)

[0576] First Step: Preparation of (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3- ((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-yl)amino)-3,4- dihydroquinolin-2(1H)-one (191a)

[0577] To a solution of 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,3-triazole (200 mg, 0.72 mmol) in tert-butanol (5 mL) was added Int 2 (255 mg, 0.72 mmol) and cesium carbonate (468 mg, 1.44 mmol), under nitrogen protection, 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-l,l'- biphenyl (2-amino-l,l'-biphenyl-2-yl)palladium(II) mesylate (61.5 mg, 0.072 mmol) was added, the mixture was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (10 mL), filtered, the filtrate was diluted with water (5 mL) and further extracted with ethyl acetate (10 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 give compound 191a (178 mg, yield: 45%).

[0578] MS m / z (ESI): 552.1 (M+1) + .

[0579] Preparation of (R)-3-((lH-l,2,3-triazol-4-yl)amino)-7-chloro-8-(2-chloro-5- fluorophenoxy)-l-methyl-3,4-dihydroquinolin-2(lH)-one (191)

[0580] Compound 191a (79 mg, 0.14 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, the reaction was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 pm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% formic acid); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 68%-100%, flow rate: 20 mL / min) to give compound 191 (2.0 mg, yield: 8.8%).

[0581] 1 H NMR (400 MHz, CD3OD) δ 7.52 (d, 1H), 7.37-7.28 (m, 2H), 7.16 (d, 1H), 6.82 (dd, 1H), 6.23 (dd, 1H), 4.22 (dd, 1H), 3.35 (s, 3H), 3.09-3.02 (m, 1H), 2.96-2.88 (m, 1H).

[0582] Example 55

[0583] (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((l-methyl-lH-l,2,3- triazol-4-yl)amino)-3,4-dihydroquinolin-2(lH)-one (192)

[0584] First step: preparation of (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((l- methyl-lH-l,2,3-triazol-4-yl)amino)-3,4-dihydroquinolin-2(lH)-one (192)

[0585] Compound Int 2 (30 mg, 0.08 mmol) was dissolved in 1,4 dioxane (3 mL), 4-bromo- 1-methyl-lH-l,2,3-triazole (21 mg, 0.13 mmol), cesium carbonate (83 mg, 0.25 mmol) and methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'- triisopropyl- 1, 1 '-biphenyl-2-yl)palladium(II) (7 mg, 0.008 mmol) were added and the reaction was stirred at 80 °C for 4 h. After the reaction was complete by LC-MS monitoring, the reaction was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Gemini 5 pm C18 100 x 21.2 mm; mobile phase 1: water (with 0.1% ammonia water); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 20-100%, flow rate: 25 mL / min) to give compound 192 (1 mg, yield: 3%).

[0586] MS m / z (ESI): 436.0 (M+1) + .

[0587] 1 H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.36 (d, 1H), 7.30 (d, 1H), 7.24 (s, 1H), 6.89-6.77 (m, 1H), 6.24 (dd, 1H), 4.16 (dd, 1H), 3.97 (s, 3H), 3.34-3.31 (m, 4H), 3.04-2.88 (m, 1H).

[0588] Example 56

[0589] (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3-((5-methyl-1,3,4- oxadiazol-2-yl)amino)-3,4-dihydroquinolin-2(1H)-one (193)

[0590] Preparation of first step (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3-((5-methyl-1,3,4-oxadiazol-2-yl)amino)-3,4-dihydroquinolin-2(1H)-one (193)

[0591] Compound Int 2 (30 mg, 0.084 mmol) was dissolved in 1,4 dioxane (3 mL), added compound (15 mg, 0.13 mmol), cesium carbonate (83 mg, 0.25 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1- ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2- methylpyridine)palladium (7 mg, 0.0085 mmol), the reaction was stirred at 80 °C for 4 hours, after the reaction was monitored to be complete by LC-MS, the reaction was concentrated and purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Gemini 5 pm C18 100 x 21.2 mm; mobile phase 1: water (with 0.1% ammonia water); mobile phase 2: acetonitrile; 13 min gradient, gradient ratio: acetonitrile phase 20%-100%, flow rate: 25 mL / min) to give compound 193 (15 mg, yield: 37%).

[0592] MS m / z (ESI): 438.0 (M+1).

[0593] 1 H NMR (400 MHz, CD3OD) δ 7.58 - 7.46 (m, 1H), 7.42 - 7.34 (m, 1H), 7.32 - 7.25 (m, 1H), 6.90 - 6.78 (m, 1H), 6.33 - 6.15 (m, 1H), 4.50 - 4.25 (m, 1H), 3.36 (s, 3H), 3.06 - 2.87 (m, 2H), 2.38 (s, 3H).

[0594] Example 57

[0595] (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3-((-2-oxopyrrolidin-3-yl)amino)- 3,4-dihydroquinolin-2(1H)-one (208) (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-1-methyl-3-((-2-oxopyrrolidin-3-yl)amino)- 3,4-dihydroquinolin-2(1H)-one (208)

[0596] Preparation of tert-butyl 3-(((R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l- methyl-2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)amino)-2-oxopyrrolidine-l-carboxylate (208a)

[0597] Compound Int 2 (30 mg, 0.085 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (26 mg, 0.25 mmol), tert-butyl 3-bromo-2-oxopyrrolidine-l-carboxylate (60 mg, 0.34 mmol) and sodium iodide (2 mg, 0.0084 mmol) were added, and the reaction was stirred at 40 °C for 72 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 flash silica gel column system B to obtain compound 208a (22 mg, yield: 44%).

[0598] MS m / z (ESI): 438.0 (M+1) + .

[0599] Preparation of compound 208-1 and compound 208-2

[0600] Compound 208a (22 mg, 0.041 mmol) was dissolved in 4M hydrochloric acid in dioxane (5 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was directly purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.05% ammonia water); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 35%-95%, flow rate: 25 mL / min) to obtain compound 208-1 (retention time: 7.45 minutes, 1 mg, yield: 6%) and compound 208-2 (retention time: 9.22 minutes, 1 mg, yield: 6%).

[0601] Compound 208-1:

[0602] MS m / z (ESI): 438.0 (M+1) + .

[0603] 1H NMR (400 MHz, CD3OD) δ 7.66 - 7.46 (m, 1H), 7.45 - 7.23 (m, 2H), 6.96 - 6.78 (m, 1H), 6.38 - 6.18 (m, 1H), 4.25 - 4.07 (m, 1H), 3.53 - 3.45 (m, 1H), 3.46 - 3.41 (m, 2H), 3.39 (s, 3H), 3.18 - 3.02 (m, 1H), 2.67 - 2.48 (m, 1H), 2.25 - 2.11 (m, 1H), 2.12 - 1.95 (m, 1H).

[0604] Compound 208-2:

[0605] MS m / z (ESI): 438.0 (M+1) + .

[0606] 1 H NMR (400 MHz, CD3OD) δ 7.59 - 7.48 (m, 1H), 7.43 - 7.21 (m, 2H), 6.91 - 6.73 (m, 1H), 6.30 - 6.11 (m, 1H), 4.56 - 4.43 (m, 1H), 3.85 - 3.63 (m, 1H), 3.64 - 3.54 (m, 1H), 3.45 - 3.36 (m, 1H), 3.34 (s, 3H), 3.22 - 3.04 (m, 1H), 3.00 - 2.86 (m, 1H), 2.25 - 2.11 (m, 1H), 2.09 - 1.90 (m, 1H).

[0607] Example 58

[0608] (3R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-[(2-oxopiperazin-3-yl)amino]- 3,4-dihydroquinolin-2(lH)-one (209)

[0609] Compound 209 was obtained according to the synthetic route of Example 57.

[0610] MS m / z (ESI): 452.1 (M+1) + .

[0611] 1H NMR (400 MHz, DMSO-d6) δ 7.71 - 7.62 (m, 1H), 7.52 - 7.43 (m, 1H), 7.41 - 7.32 (m, 1H), 7.26 - 7.15 (m, 1H), 7.07 - 6.95 (m, 1H), 6.71 - 6.49 (m, 1H), 4.87 - 4.72 (m, 1H), 3.29 - 3.27 (m, 1H), 3.26 (s, 3H), 3.19 - 3.13 (m, 1H), 2.76 - 2.62 (m, 2H), 2.41 - 2.24 (m, 2H), 2.06 - 1.95 (m, 2H), 1.56 - 1.38 (m, 2H).

[0612] Example 59

[0613] (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((5-methyl-2-oxopyrrolidin-3- yl)amino)-3,4-dihydroquinolin-2(lH)-one (210)

[0614] Preparation of the first step 3-bromo-5-methyl-2-oxopyrrolidine-l-carboxylate benzyl ester (210b)

[0615] Compound 210a (1.1 g, 4.4 mmol) was dissolved in tetrahydrofuran (10 mL), lithium bis(trimethylsilyl)amide (4.4 mL, 8.8 mmol) was added slowly at -78 °C, the reaction was stirred at -78 °C for 1 hour. N-bromosuccinimide (940 mg, 5.3 mmol) was added, stirred at -78 °C for 3 hours. After the reaction was completed, ethyl acetate and water were added to extract, the organic phase was collected, dried, concentrated under reduced pressure, purified by flash silica gel column system B to give compound 210b (410 mg, 27.9%).

[0616] MS m / z (ESI): 647.0 (2M+23) + .

[0617] Preparation of the second step 3-(((R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl- 2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)amino)-5-methyl-2-oxopyrrolidine-l-carboxylate benzyl ester (210c)

[0618] Compound Int 2 (227 mg, 0.64 mmol) was dissolved in dichloromethane (10 mL), compound 210b (200 mg, 0.64 mmol) and silver carbonate (33 mg, 0.12 mmol) were added, the reaction was stirred at 40 °C for 16 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 system B to obtain compound 210c (90 mg, yield: 24%).

[0619] MS m / z (ESI): 586.0 (M+1) + .

[0620] Preparation of compound 210-1, compound 210-2, compound 210-3, compound 210-4

[0621] Compound 210c (90 mg, 0.153 mmol) was dissolved in dichloromethane (3 mL), triethylamine (200 mg, 0.64 mmol), triethylsilane (34 mg, 0.3 mmol) and palladium chloride (33 mg, 0.12 mmol) were added, the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, it was first filtered, concentrated, and then the crude product was directly purified by high performance liquid chromatography preparation (Waters MS-triggered Prep-LC with SQD2 detector, chromatographic column: Xbridge 5 μm C18 150 x 19 mm; mobile phase 1: water (containing 0.1% trifluoroacetic acid); mobile phase 2: acetonitrile; 13 minute gradient, gradient ratio: acetonitrile phase 35%-45%, flow rate: 20 mL / min) to obtain compound 210-1 (retention time 7.88 minutes, 8.5 mg, yield: 13%), compound 210-2 (retention time 9.87 minutes, 8 mg, yield: 12%), compound 210-3 (retention time 10.66 minutes, 9 mg, yield: 14%) and compound 210-4 (retention time 12.25 minutes, 7.5 mg, yield: 11%).

[0622] Compound 210-1: MS m / z (ESI): 452.0 (M+1) + .

[0623] 1H NMR (400 MHz, CD3OD) δ 7.55-7.52 (m, 1H), 7.38-7.35 (m, 2H), 6.88-6.83 (m, 1H), 6.34-6.31 (m, 1H), 4.59-4.46 (m, 2H), 3.89-3.86 (m, 1H), 3.49-3.44 (m, 1H), 3.40 (s, 3H), 3.23-3.16 (m, 1H), 2.36-2.31 (m, 2H), 1.29-1.27 (m, 3H).

[0624] Compound 210-2: MS m / z (ESI): 452.0 (M+1) + .

[0625] 1 H NMR (400 MHz, CD3OD) δ 7.55-7.52 (m, 1H), 7.38-7.35 (m, 2H), 6.88-6.83 (m, 1H), 6.34-6.31 (m, 1H), 4.59-4.46 (m, 2H), 3.89-3.86 (m, 1H), 3.49-3.44 (m, 1H), 3.40 (s, 3H), 3.23-3.16 (m, 1H), 2.36-2.31 (m, 2H), 1.29-1.27 (m, 3H).

[0626] Compound 210-3: MS m / z (ESI): 452.0 (M+1) + .

[0627] 1 H NMR (400 MHz, CD3OD) δ 7.55-7.52 (m, 1H), 7.38-7.35 (m, 2H), 6.88-6.83 (m, 1H), 6.34-6.31 (m, 1H), 4.59-4.46 (m, 2H), 3.89-3.86 (m, 1H), 3.49-3.44 (m, 1H), 3.40 (s, 3H), 3.23-3.16 (m, 1H), 2.36-2.31 (m, 2H), 1.29-1.27 (m, 3H).

[0628] Compound 210-4: 1H NMR (400 MHz, CD3OD) δ 7.54 - 7.5 (m, 1H), 7.35 - 7.27 (m, 2H), 6.89 - 6.80 (m, 1H), 6.24 - 6.22 (m, 1H), 3.73 - 3.62 (m, 3H), 3.32 (s, 3H), 3.18 - 3.15 (m, 1H), 2.92 - 2.85 (m, 1H), 2.67 - 2.63 (s, 1H), 1.49 - 1.41 (m, 1H), 1.25 - 1.23 (m, 3H).

[0629] Example 60

[0630] (3R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-[(4-methyl-2- oxopyrrolidin-3-yl)amino]-3,4-dihydroquinolin-2(lH)-one (211)

[0631] Using the same synthetic procedure as Example 59, the crude product was purified directly 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; 13 min gradient, gradient ratio: acetonitrile phase 40% - 50%, flow rate: 20 mL / min) to give compound 211-2 (retention time 8.1 min, 1.82 mg, yield: 9.1%).

[0632] Compound 211-2:

[0633] MS m / z (ESI): 452.1 (M+1) + .

[0634] 1 H NMR (400 MHz, CD3OD) δ 7.54 - 7.5 (m, 1H), 7.35 - 7.27 (m, 2H), 6.89 - 6.80 (m, 1H), 6.24 - 6.22 (m, 1H), 3.73 - 3.62 (m, 3H), 3.32 (s, 3H), 3.18 - 3.15 (m, 1H), 2.92 - 2.85 (m, 1H), 2.67 - 2.63 (s, 1H), 1.49 - 1.41 (m, 1H), 1.25 - 1.23 (m, 3H).

[0635] Example 61

[0636] (R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl-3-((lS,4S,5R)-3-oxo-2- azabicyclo[3.1.0]hexan-4-yl)amino)-3,4-dihydroquinolin-2(lH)-one (212)

[0637] First step: Preparation of 4-bromo-3-oxo-2-azabicyclo[3.1.0]hexane-2-carboxylic acid benzyl ester (212b)

[0638] Compound 212a (700 mg, 3.03 mmol) was dissolved in tetrahydrofuran (20 mL) and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (6.4 mL, 6.4 mmol) was added under nitrogen at -78°C and stirred at this temperature for 1 hour, then N-bromosuccinimide (565 mg, 3.18 mmol) was added. After 2 hours of stirring at -78°C, the reaction was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and the crude product was purified by column chromatography in system B to give compound 212b (450 mg, yield: 43%).

[0639] MS m / z (ESI): 310.0 (M+1) + .

[0640] Second step: Preparation of 4-(((R)-7-chloro-8-(2-chloro-5-fluorophenoxy)-l-methyl- 2-oxo-l,2,3,4-tetrahydroquinolin-3-yl)amino)-3-oxo-2-azabicyclo[3.1.0]hexane-2- carboxylic acid benzyl ester (212c)

[0641] Compound 212b (50 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (5 mL) and triethylamine (81 mg, 0.81 mmol), compound Int 2 (60 mg, 0.16 mmol) and sodium iodide (24 mg, 0.16 mmol) were added. The reaction was stirred at 60°C for 72 hours. After the reaction was completed, ethyl acetate and water were added and the organic phase was collected, dried and concentrated under reduced pressure. Purification by flash column chromatography in system B gave compound 212c (20 mg, yield: 21%).

[0642] MS m / z (ESI): 584.1 (M+1) + .

[0643] Third step: Preparation of compound 212-1, compound 212-2, compound 212-3, compound 212-4

[0644] Compound 212c (20 mg, 0.03 mmol) was dissolved in dichloromethane (5 mL), triethylsilane (40 mg, 0.34 mmol), triethylamine (35 mg, 0.34 mmol) and dichloropalladium (6 mg, 0.034 mmol) were added. The reaction was stirred at 25 degree Celsius for 10 minutes. After the reaction was completed, the reaction solution was filtered, and the organic phase was rotary evaporated to get the crude product. The crude product was purified by column chromatography with system A to get the crude product. The crude product was further 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; 13 minutes gradient, gradient ratio: acetonitrile phase 40%-95%, flow rate: 20 mL / min) to get compound 212-1 (retention time 4.83 minutes, 1.6 mg, yield: 4%), compound 212-2 (retention time 5.61 minutes, 1.4 mg, yield: 3.5%), compound 212-3 (retention time 6.93 minutes, 2.6 mg, yield: 7%) and compound 212-4 (retention time 8.97 minutes, 1.8 mg, yield: 4.5%).

[0645] Compound 212-1: MS m / z (ESI): 450.0 (M+1) + .

[0646] 1 H NMR (400 MHz, CD3OD) d 7.57-7.47 (m, 1H), 7.53-7.26 (m, 2H), 6.88-6.76 (m, 1H), 6.21 (dd, 1H), 3.98 (d, 1H), 3.79-3.76 (m, 1H), 3.33 (s, 3H), 3.27-3.25 (m, 1H), 3.07-2.86 (m, 2H), 1.84-1.82 (m, 1H), 0.57-0.51 (m, 2H).

[0647] Compound 212-2: MS m / z (ESI): 450.0 (M+1) + .

[0648] 1H NMR (400 MHz, CD3OD) δ 7.60-7.53 (m, 1H), 7.46-7.34 (m, 2H), 6.90-6.82 (m, 1H), 6.36 (dd, 1H), 4.73-4.72 (m, 1H), 3.53-3.45 (m, 1H), 3.34 (s, 3H), 3.22-3.20 (m, 1H), 3.05-3.03 (m, 1H), 2.07-2.00 (m, 1H), 1.73-1.55 (m, 1H), 1.02-0.87 (m, 2H).

[0649] Compound 212-3: 1 H NMR (400 MHz, CD3OD) δ 7.64-7.44 (m, 1H), 7.35-7.25 (m, 2H), 6.92-6.73 (m, 1H), 6.22 (t, 1H), 4.61 (d, 0.5H), 3.96 (d, 0.5H), 3.89-3.70 (m, 1H), 3.33 (s, 3H), 3.12-3.05 (m, 1H), 2.90-2.87 (m, 1H), 1.93-1.73 (m, 1H), 1.68-1.51 (m, 0.5H), 1.03-0.93 (m, 0.5H), 0.82-0.57 (m, 2H).

[0650] Compound 212-4: MS m / z (ESI): 450.0 (M+1) + .

[0651] 1 H NMR (400 MHz, CD3OD) δ 7.64-7.46 (m, 1H), 7.37–7.32 (m, 2H), 6.85 (s, 1H), 6.29 (t, 1H), 4.39 (s, 1H), 3.89-3.87 (m, 1H), 3.38 (s, 3H), 3.21-3.02 (m, 2H), 1.86-1.56 (m, 2H), 1.18-0.80 (m, 2H).

[0652] Biological evaluation

[0653] Test Example 1 TSHR inhibitory activity screening (cAMP) experiment

[0654] 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.

[0655] Experimental materials and reagents:

[0656] Experimental procedure

[0657] 1. Compound preparation

[0658] (1) Compound samples were dissolved in DMSO to a stock concentration of 10 mM;

[0659] (2) Sample dilution sequence was prepared on a 384-well LDV plate, with a starting concentration of 2 mM (FAC = 10 mM) and 3-fold serial dilution, for a total of 11 concentration points;

[0660] (i) The test sample was diluted with DMSO to an intermediate concentration of 2 mM, specifically: 2 pL of 10 mM sample was mixed with 8 pL of DMSO.

[0661] (ii) A 384-well LDV plate was taken, and the 2 mM test compound solution prepared above was added to A1-P1 wells, respectively; 10 pL of DMSO was added to each of A2-P11 wells, respectively; then 1000 rpm centrifugation was performed for 30 seconds.

[0662] (iii) The compound was serially diluted using Bravo: the first column of the LDV plate prepared in step b was used as the starting concentration column, 5 pL was taken each time to the next column, and mixed well by blowing. After the dilution procedure was completed, 1000 rpm centrifugation was performed for 30 seconds.

[0663] (3) The sample dilution sequence was transferred to the experimental plate (Corning-3824) using an Echo machine, corresponding to 50 nL per well.

[0664] 2. cAMP experimental method

[0665] (1) Preparation of reagents required for the experiment

[0666] (i) Experimental buffer (1x Stimulation buffer): the 5x Stimulation buffer in the kit was equilibrated to room temperature,

[0667] diluted with ultrapure water at a ratio of 1:4, and 500 pM of IBMX was added before use to a final concentration of 500 pM, ready for use.

[0668] (ii) 2X Stimulation buffer: 40 ng / mL FSH protein or 0.3 nM Anti-TSHR Antibody + 500 uM IBMX was dissolved in the experimental buffer;

[0669] (iii) Detection reagent: the Lysis & detection buffer in the kit was equilibrated to room temperature, and cAMP-d2 and Anti-cAMP

[0670] Cryptate was prepared at 1 :20 dilution and kept ready for use.

[0671] (2) Preparation of cell suspension

[0672] (i) The human FSHR / TSHR cells on the culture dish were digested with 0.05% trypsin, respectively, and then the cells were eluted with medium and collected into a 15 mL centrifuge tube.

[0673] (ii) Centrifuged at 1000 rpm for 5 minutes, and then the supernatant was discarded.

[0674] (iii) The cells were resuspended with 1x Stimulation buffer, counted on Countess II FL Cell Counter, and the cell density was adjusted to 1.0x106 / mL.

[0675] (3) cAMP HTRF assay

[0676] (i) The cell suspension was added to the experimental plate containing the compound by Multidrop combi, 5 μL / well.

[0677] (ii) Centrifuged at 1000 rpm for 30 seconds, and then incubated at room temperature for 15 minutes.

[0678] (iii) 2X Stimulation buffer was added to each well of the experimental plate, 5 μL / well.

[0679] (iv) Centrifuged at 1000 rpm for 30 seconds, and then incubated at 37°C for 30 minutes.

[0680] (v) The above diluted cAMP-d2 and Anti-cAMP cryptate detection reagents were sequentially added to each well of the experimental plate, 5 μL / well.

[0681] First, 5 μL of cAMP-d2 reagent was added, and then 5 μL of Cryptate reagent was added.

[0682] (vi) After the experimental plate was placed at room temperature for 60 minutes, it was read on Envision.

[0683] (4) Experimental data processing method

[0684] The experimental data were fitted to the percentage activation rate and 11-point concentration data to calculate the IC value of the compound using XLFit according to the parametric nonlinear logistic formula. 50 Detailed information is as follows:

[0685] (i) The inhibition effect value of each well on the experimental plate was calculated according to the following formula:

[0686] Effect = 100 x (value-ZPE) / (HPE-ZPE)

[0687] wherein, %Effect is the inhibition effect value of the corresponding experimental well, value is the signal value of the experimental well, ZPE is the signal mean value of the negative control experimental well, and HPE is the signal mean value of the positive control experimental well.

[0688] (ii) according to the inhibition effect value of the different concentration test points of the compound sample, the IC 50 value of the compound sample is calculated by using the XLFit four-parameter model to fit the action curve.

[0689] Experimental results:

[0690] The CHO-K1 / TSH cell is used to detect the IC 50 The test results of the experiment are shown in Table 1.

[0691] Table 1 Test results of the tested compounds

[0692] Conclusion: The compound of the present application has significant inhibitory activity on the release of cAMP of CHO-K1 / TSH cell.

[0693] The above has exemplarily described the embodiments of the technical scheme 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 the person 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 quinone heteroaryl; each R d They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; R2 is selected from H, CN, unsubstituted, or optionally replaced by one, two, or more Rs. e The following groups are substituted: C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl, halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R e They may be identical or different, and are independently selected from oxo (=O), CN, halogen, unsubstituted, or optionally substituted by one, two, or more R groups. e1 The following groups are substituted: OH, NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, S(=O)2R e2 Or C(=O)R e3 ; 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 ;R e2 R e3 R e4 R e5 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; Each R b They may be identical or different, independently selected from CN, halogen, oxo (=O), unsubstituted or optionally substituted by one, two or more R. b1 The following groups are substituted: OH, NH2, C 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, S(=O)2R b2 Or C(=O)R b3 ; Each R b1 They are selected independently of each other, either identical or different, from oxo (=O), CN, halogen, OH, NH2, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R b2 R b3 They are either the same or different, and are independently selected from H, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; n is selected from 0, 1, 2 or 3; 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-; R1is selected from any one of the following groups: (i)-COR 11 ;R 11 Selected from one, two or more R c Replacement C 3-12 cycloalkyl; or R 11 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: OH, -NR 12 R 13 C 1-12 Alkoxy, halogenated C 3-12 cycloalkyl or 3-14 membered heterocyclic groups; R 12 R 13 Whether the two are the same or different, they are selected independently from H and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; or R 12 R 13 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; condition: R 12 R 13 Not both H, or not both C 1-12 Alkyl, or when R 12 When selected from H, R 13 Not C 1-12 alkyl; (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, C 1-12 alkyl, haloC 1-12 alkyl, C 1-12 alkoxy, haloC 1-12 alkoxy, C 3-6 C substituted with one, two or more substituents selected from alkyl, cycloalkyl 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 Whether the two are the same or different, they are selected independently from H and C. 1-12 Alkyl, Halogenated C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-14 membered heterocyclic groups; or R 17 R 18 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-14 N-containing heterocycles; (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 are the same or different and 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 OH, C 1-6 alkyl, halogen-C 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(0)2H, COH, hydroxy-C 1-12 alkyl, amino-C 1-12 alkyl; or, two R c form, together with the carbon atom to which they are attached, an unsubstituted or optionally substituted with one, two or more R c1 substituted ring system C 3-14 carbocyclic or 3-14 membered heterocyclic ring; or, two R c form, together with the carbon atoms to which they are attached, respectively, an unsubstituted or optionally substituted with one, two or more R c1 substituted ring system C 3-14 carbocyclic, 3-14 membered heterocyclic, C 6-14 aromatic or 5-14 membered heteroaromatic ring; or, two non-adjacent R c attached as end groups, together form an unsubstituted or optionally substituted with one, two or more R c1 substituted C 1-3 alkylene; each R c1 are the same or different and independently of one another selected from the group consisting of oxo (=0), OH, NH2, CN, halogen, C 1-6 alkyl, halogen-C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; p is selected from 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that, 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; Preferably, each R a They are either the same or different, and are independently selected from CN, F, Cl, Br, and C. 1-4 Alkyl groups (such as methyl, ethyl, isopropyl, tert-butyl), C 2-6 Alkyne groups (such as -C≡CH, -C≡CCH3), halogenated C 1-4 Alkyl groups (such as trifluoromethyl, difluoromethyl), C 1-4 Alkoxy groups (such as methoxy and ethoxy groups), halogenated carbon groups 1-4 Alkyl groups (such as trifluoromethoxy and difluoromethoxy), C 3-6 Cycloalkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogenated C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, 5-6 membered heteroaryl groups (such as pyrazolyl); Preferably, each R a They are either the same or different, and are independently selected from CN, F, Cl, Br, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; Preferably, each R a are the same or different, independently of each other, selected from F, CI, Br, cyclopropyl, -COCH3, -CºCCH3, or Preferably, each R a are the same or different, independently of each other, selected from F, CI, cyclopropyl, -COCH3, -CºCCH3, or Preferably, each R a are the same or different, independently of each other, selected from F or Cl; Preferably, m is 1. Preferably, m is 2; Preferably, Y2is -O- or methylene; Preferably, Y2is -O-; Preferably, selected from the group consisting of 3. The compound of claim 1 or 2, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that, 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), halo-C 1-4 alkyl (such as trifluoromethyl, difluoromethyl), C 1-4 alkoxy (such as methoxy), halo-C 1-4 alkoxy (such as trifluoromethoxy, difluoromethoxy); Preferably, X1is CR X1 ; Preferably, R X1 is selected from -CH3, -Cl or -F; Preferably, X1is CCl; Preferably, X1is CCH3; Preferably, X2is selected from CH or N; Preferably, X2is CH; Preferably, X3is selected from CH or N; Preferably, X3is CH; 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; R is selected from -CH3, -F, -Cl, -Br, -CH2F, -CF2H, -CF3; R X1 R is selected from -CH3, -F, -Cl, -Br, -CH2F, -CF2H, -CF3; R X2 R is selected from -CH3, -F, -Cl, -Br; R X3 R is selected from -CH3, -F, -Cl, -Br; R2is 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; R2is selected from H, unsubstituted or optionally substituted with one, two or more R e1 substituted C 1-4 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; 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; R2is selected from H, C 1-4 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, t-butyl), halo-C 1-4 alkyl (e.g. trifluoromethyl, difluoromethyl), C 1-4 alkoxy (e.g. methoxy), halo-C 1-4 alkoxy (e.g. trifluoromethoxy, difluoromethoxy), C 3-6 cycloalkyl (e.g. cyclopropyl), halo-C 3-6 cycloalkyl or 3-6 membered heterocyclyl; Preferably, R2is selected from Preferably, n is 0.

4. The compound of any one of claims 1-3, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that, Y1is 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, 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-; Preferably, Y1is -NH-; Preferably, R1is selected from any one of the following groups: (i) -COR 11 ; R 11 is selected from -NR 12 ; R 13 halo-C 3-8 cycloalkyl or 3-8 membered heterocyclyl, unsubstituted or optionally substituted with one, two or more R c ; R 12 , R 13 are the same or different, each independently selected from H or C 1-4 alkoxy; or R 12 , R 13 together with the N atom to which they are attached form a 3-8 membered N-containing heterocycle, unsubstituted or optionally substituted with one, two or more R c ; provided that R 12 , R 13 are not simultaneously H; (ii) L1 is absent or selected from unsubstituted or optionally selected from one or two halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl substituents substituted C 1-4 Alkylene; R 14 Selected from NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; X4 is selected from O or NR 15 ;R 15 Selected from H, CN, C 1-4 alkyl; (iii)-L2-COR 16 L2 is selected from unsubstituted or optionally selected from one or two halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl substituents substituted C 1-4 Alkylene; R 16 Selected from unsubstituted or arbitrarily assigned to one, two or more R c The following groups are substituted: H, OH, -NR 17 R 18 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups; R 17 R 18 Whether the two are the same or different, they are selected independently from H and C. 1-4 Alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; or R 17 R 18 Together with the N atom it is attached to, it forms an unsubstituted or optionally substituted form with one, two or more R atoms. c Substituted 3-8 N-containing heterocycles; (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, R1is selected from any one of the following groups: (i) -COR 11 ; R 11 is selected from -NR 12 ; R 13 halo-C 3-8 cycloalkyl or 3-8 membered heterocyclyl, unsubstituted or optionally substituted with one, two or more R c ; R 12 , R 13 are the same or different, each independently selected from H or C 1-4 alkoxy; or R 12 , R 13 together with the N atom to which they are attached form a 3-8 membered N-containing heterocycle, unsubstituted or optionally substituted with one, two or more R c ; provided that R 12 , R 13 are not simultaneously H; (ii) L1 is absent or selected from unsubstituted or optionally selected from one or two halogens, C 1-4 Alkyl, Halogenated C 1-4 Alkyl substituents substituted C 1-4 Alkylene; R 14 Selected from NH2, -NHC 1-4 Alkyl, -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl or C 3-6 Cycloalkyl; X4 is selected from O or NR 15 ;R 15 Selected from H, CN, C 1-4 alkyl; (iii) -L2-COR 16 ; L2is selected from unsubstituted or optionally substituted C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkylene; R 16 is selected from the following groups, which are unsubstituted or optionally substituted by one, two or more R c groups: H, OH, -NR 17 R 18 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; R 17 , R 18 are the same or different, independently of each other, selected from H, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; or R 17 , R 18 form, together with the N atom to which they are attached, a 3-8 membered N-containing heterocyclic ring which is unsubstituted or optionally substituted by one, two or more R c groups; Preferably, each R c They are either identical or different, and are independently selected from oxo (=O), CN, halogen, OH, C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkyl, C 1-4 Alkylene NR c2 R c3 CONH2, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups; R c2 R c3 They are the same or different, and are selected independently from H or C. 1-4 alkyl; Preferably, each R c They 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; or, two R atoms attached to the same carbon atom. c Together with the carbon atoms it is attached to, they form C 3-6 Carbon rings or 3-6 membered heterocycles; or, two R atoms attached to adjacent carbon atoms. c Together with the carbon atoms they are attached to, they form C 3-6 Carbon rings or 3-6 membered heterocycles; 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, together with the carbon atom to which they are attached, a cyclopropyl ring; or, two R groups attached to adjacent carbon atoms c form, together with the carbon atoms to which they are attached, a cyclopropyl ring; 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, R is preferably selected, independently from each other, from oxo (=0), CN, halogen, OH, C c R is preferably selected, independently from each other, from oxo (=0), CN, halogen, OH, C 1-4 R is preferably selected, independently from each other, from oxo (=0), CN, halogen, OH, C 1-4 R is preferably selected, independently from each other, from oxo (=0), CN, halogen, OH, C 1-4 R is preferably selected, independently from each other, from oxo (=0), CN, halogen, OH, C 1-4 R is preferably selected, independently from each other, from oxo (=0), CN, halogen, OH, C 3-6 R is preferably selected, independently from each other, from oxo (=0), CN, halogen, OH, C Preferably, p is selected from 0 or 1; Preferably, R1is selected from any one of the following groups: (i) -COR 11 ; R 11 is selected from -NR 12 R 13 , halocyclopropyl, halocyclobutyl or an azetidinyl ring, azetidinyl ring, oxetanyl ring, morpholine ring optionally substituted with one or two R c ; R 12 is selected from H, R 13 is selected from methoxy; or R 12 , R 13 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 any one of the following groups: (i) -COR 11 ; R 11 is selected from -NR 12 ; R 13 , halocyclopropyl, halocyclobutyl or an azetidinyl ring, azetidinyl ring, oxetanyl ring, morpholine ring optionally substituted with one or two R c ; R 12 is selected from H, R 13 is selected from methoxy; or R 12 , R 13 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; Preferably, R1is selected from Preferably, R1is selected from Preferably, R1is selected from Preferably, R1is selected from Preferably, R1is selected from 5. The compound, racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to any one of claims 1-4, wherein, The compound of formula (I) has the structure shown below: wherein, Ring A, X1, X2, X3, Y1, Y2, R1, 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 Y2, R a , R1, R2, R X1 , m have the definitions given in any one of claims 1 to 4; Preferably, the compound of formula (I) has the structure shown below: wherein R1, R 14 , R X1 , R c , and p have the definitions described in any one of claims 1-4.

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

7. A method for preparing a compound of formula (II-4) as claimed in any one of claims 1-6, comprising the following step A: Step A: wherein Ring A, X1, X2, X3, Y2, R1, R2, R a , m have the definitions of any one of claims 1-4.

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

9. A method 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 compound of formula (I), racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof as claimed in any one of claims 1-6, or the pharmaceutical composition of claim 8; Preferably, the disease or disorder caused by TSHR abnormality is a thyroid-related disease or disorder. Preferably, the thyroid-related disease or disorder is hyperthyroidism, Graves' disease, Graves' ophthalmopathy, thyroid eye disease; and the patient is a mammal, preferably a human.

10. Use of at least one of the compound of formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or the pharmaceutical composition of claim 8 in the manufacture of a medicament. Preferably, the use can be in the manufacture of a TSHR antagonist. Preferably, the use can be 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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