A class of benzocycloheptane compounds and their applications

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labeled compound thereof. The structure of the compound of formula (I) is as follows: The compound has excellent inhibitory ability for selectively inhibiting estrogen receptor activity and anti-proliferative activity against human breast cancer cell line MCF-7 cell line of estrogen receptor wild type, Y537S and D538G mutants. The compound provided by the present invention can be used for preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to a benzocycloheptane compound, a preparation method thereof and an application. The present invention discloses its use as a post-estrogen failure regulator for preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders. Background Art

[0002] Among newly diagnosed female cancers, breast cancer has the highest incidence rate. And among all newly diagnosed breast cancers, about 75% of the patients belong to the estrogen receptor-positive (ER+) subgroup. Due to the important role of estrogen receptors in the tumors of these patients, the current main treatments are all targeted at this signaling pathway, including using aromatase inhibitors such as exemestane, letrozole, anastrozole to inhibit estrogen synthesis, and using estrogen receptor modulators (SERM) such as tamoxifen or degraders (SERD) such as fulvestrant to directly inhibit estrogen receptor function.

[0003] Drug resistance to these therapies is still a major problem in clinical practice. Current research has found many drug resistance mechanisms, including: activation of other kinases and related signaling pathways, especially HER2; dysregulation of cell cycle-related signaling pathways; abnormal expression of ER coactivators; and mutations in the ER protein itself. Hotspot mutations of ER have been found in about 30% of patients resistant to endocrine therapy. These mutations can lead to ligand-independent continuous activation of the receptor, resulting in drug resistance to existing therapies.

[0004] The prognosis of patients with ER hotspot mutations is significantly worse than that of wild-type ER. However, even after failure and drug resistance of multiple lines of standard therapies targeting estrogen receptors, these tumors still rely on the function of estrogen receptors. Therefore, it is still necessary to develop therapies for estrogen receptor-related signaling pathways based on new mechanisms of action.

[0005] In the process of developing small molecule targeted anti-tumor drugs, irreversible inhibitors are an important idea for solving drug resistance. A relatively classic example is the development of the EGFR receptor irreversible inhibitor afatinib (launched in 2013). The electrophilic active group acrylamide in its structure forms a covalent bond with the cysteine residue (sulfhydryl group) in the active site of the EGFR receptor, overcoming the drug resistance problem of the first-generation EGFR (gefitinib, erlotinib, etc.) receptor inhibitors, and at the same time showing good activity against non-drug-resistant EGFR receptors. The idea of irreversible inhibition also has hope for the drug development of drug-resistant ER+ patients. Summary of the Invention

[0006] Problems to be Solved by the Invention

[0007] To solve the above problems, the present invention provides a class of benzocycloheptane compounds capable of preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders.

[0008] Solutions for Solving the Problems

[0009] To solve the above technical problems, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, and the structure of the compound of formula (I) is:

[0010]

[0011] Wherein,

[0012] Each R 1 is independently selected from -H, D, -OH, -NH2, -COOH, -CH2NH2 and -CH2OH;

[0013] R 2 is selected from substituted or unsubstituted aryl, heterocyclic group and heteroaryl;

[0014] R 3 is selected from -(CH2) p CH=CHCONR 4 R 5 and -COCH=CR 6 R 7 wherein,

[0015] R 4 , R 5 , R 6 , R 7 are each independently selected from -H, D, alkyl, cycloalkyl and heterocyclic group;

[0016] Or R 4 and R 5 together with the connected nitrogen atom form a 3- to 7-membered heterocyclic group, or R 6 and R 7 together with the connected carbon atom form a C 3-6 cycloalkyl or a 3- to 7-membered heterocyclic group;

[0017] p is selected from 0, 1, 2 and 3;

[0018] Z is selected from O, S, CHR 11 and NH, and R 11 can be H, OH, D, NH2 and C 1-3 alkyl;

[0019] Y is selected from -R 8 NH-, -(CR 9 R 10) q NH- and 3- to 7-membered nitrogen-containing heterocyclic groups, wherein,

[0020] R 8 is a C 3-6 cycloalkyl group or a 3- to 7-membered heterocyclic group;

[0021] Each R 9 and R 10 are each independently selected from -H, a halogen atom, a substituted or unsubstituted C 1-6 alkyl group and a C 3-6 cycloalkyl group; or R 9 and R 10 together with the carbon atom to which they are attached form a substituted or unsubstituted C 3-6 cycloalkyl group or a 3- to 7-membered heterocyclic group; or R 9 or R 10 , together with the carbon atom of R 9 or R 10 and the carbon atom adjacent to said carbon atom form a C 3-6 cycloalkyl group;

[0022] q is selected from 1, 2, 3, 4 and 5;

[0023] is selected from a substituted or unsubstituted aryl group and a heteroaryl group;

[0024] m is selected from 1, 2, 3 and 4.

[0025] Preferably, R 2 is selected from a substituted or unsubstituted phenyl group, a 3- to 9-membered heterocyclic group and a 5- to 10-membered heteroaryl group, and the substitution is by one or more substituents selected from C 1-6 alkyl group, a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-6 cycloalkyl group, C 6-10 aryl group, a 5- to 10-membered heteroaryl group or a 3- to 7-membered heterocyclic group, and the above substituents are optionally substituted by 1 to 3 substituents selected from C 1-6 alkyl group, a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-6substituted by a cycloalkyl group. More preferably, the 3- to 9-membered heterocyclic group is selected from any one of aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactamyl, caprolactamyl, butyrolactonyl, valerolactonyl, caprolactonyl, 2,3-dihydro-1H-indolyl, and benzodioxolanyl;

[0026] The 5- to 10-membered heteroaryl group contains 1 to 3 heteroatoms each independently selected from N, NH, O, and S; preferably, the 5- to 10-membered heteroaryl ring is selected from any one of thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzopyrazole, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, or indolo[1,2-a]pyrazinyl.

[0027] Preferably, R 3 is selected from -(CH2) p CH=CHCONR 4 R 5 and -COCH=CR 6 R 7 , wherein,

[0028] R 4 , R 5 , R 6 , R 7 are each independently selected from -H, D, C 1-3 alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heterocyclic group;

[0029] Or R 4 and R 5 together with the connected nitrogen atom form a 5- to 6-membered heterocyclic group;

[0030] p is 1.

[0031] Preferably, Y is selected from -R 8 NH-, -(CR 9 R 10 ) q NH-, and 4- to 6-membered nitrogen-containing heterocyclic group, wherein,

[0032] R 8 is C 3-6 cycloalkyl or 4- to 6-membered heterocyclic group;

[0033] Each R9 and R 10 are each independently selected from -H, a halogen atom, a substituted or unsubstituted C 1-6 alkyl group and a C 3-6 cycloalkyl group; or R 9 and R 10 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group or a 3- to 7-membered heterocyclic group; or R 9 or R 10 , together with the carbon atom of R 9 or R 10 and the carbon atom adjacent to said carbon atom form a C 3-6 cycloalkyl group; the substituted C 1-6 alkyl group and the C 3-6 cycloalkyl group are substituted by a substituent selected from a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy group and C 1-6 alkylamino group;

[0034] q is selected from 1, 2 and 3, preferably 2.

[0035] Preferably, is selected from a substituted or unsubstituted C 6-10 aryl group and a 5- to 10-membered heteroaryl group, the substitution being by one or more substituents selected from C 1-6 alkyl group, a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-6 cycloalkyl group, C 6-10 aryl group, a 5- to 10-membered heteroaryl group or a 3- to 7-membered heterocyclic group, and the above substituents are optionally substituted by 1 to 3 substituents selected from C 1-6 alkyl group, a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-6 cycloalkyl group. More preferably, the above is selected from a substituted or unsubstituted phenyl group and a pyridyl group, the substitution being by one or more substituents selected from C 1-6 alkyl group, a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-6 cycloalkyl group, C 6-10 aryl group, a 5- to 10-membered heteroaryl group or a 3- to 7-membered heterocyclic group, and the above substituents are optionally substituted by 1 to 3 substituents selected from C 1-6An alkyl group, a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 an alkoxy group, C 1-6 an alkylamino group, C 3-6 substituted by a cycloalkyl group.

[0036] Preferably, the structure of the compound is as shown in Formula II:

[0037]

[0038] R 1 is independently selected from -H, -OH, and -NH2;

[0039] R 2 is selected from a substituted or unsubstituted phenyl group, C 5-10 a heteroaryl group; the substitution is by a substituent selected from a halogen, a cyano group, C 1-3 an alkoxy group, a halogen-substituted C 1-3 alkoxy group;

[0040] R 3 is selected from -CH2CH=CHCONR 4 R 5 , wherein,

[0041] R 4 , R 5 are each independently selected from -H and C 1-3 an alkyl group; or R 4 and R 5 together with the connected nitrogen atom form a pyrrolidinyl group or a piperidinyl group;

[0042] Z is selected from O, S, and NH;

[0043] Y is selected from -R 8 NH-, -(CR 9 R 10 ) q NH-, and a 3- to 7-membered nitrogen-containing heterocyclic group, wherein,

[0044] R 8 is a C 3-6 cycloalkyl group;

[0045] Each R 9 and R 10 is independently selected from -H, a halogen atom, C 1-3 an alkyl group; or R 9 and R 10 together with the connected carbon atom form a C 3-6 cycloalkyl group;

[0046] q is 2;

[0047] Selected from substituted or unsubstituted phenyl and pyridyl, wherein the substitution is by a substituent selected from -H, a halogen atom, and C 1-3 alkoxy.

[0048] The present invention also provides a compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope-labeled compound thereof, characterized in that the compound is selected from:

[0049]

[0050]

[0051]

[0052]

[0053] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope-labeled compound thereof as described above.

[0054] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope-labeled compound thereof as described above, or the pharmaceutical composition, for use in preventing and / or treating estrogen receptor-mediated or estrogen receptor-dependent diseases and disorders.

[0055] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope-labeled compound thereof as described above, or the pharmaceutical composition, for preventing and / or treating estrogen receptor-mediated or estrogen receptor-dependent diseases and disorders.

[0056] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope-labeled compound thereof as described above, or the pharmaceutical composition, in the preparation of a medicament for preventing and / or treating estrogen receptor-mediated or estrogen receptor-dependent diseases and disorders. Preferably, the disease is breast cancer.

[0057] The present invention also provides a method for preventing and / or treating estrogen receptor-mediated or estrogen receptor-dependent diseases and disorders, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope-labeled compound thereof as described above, or the pharmaceutical composition, to a patient in need thereof.

[0058] The present invention also provides a drug combination form, which comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound described above, or the pharmaceutical composition as described above, and at least one additional therapeutic agent.

[0059] Effects of the Invention

[0060] A class of benzocycloheptane compounds provided by the present invention have good inhibitory ability of selectively inhibiting estrogen receptor activity and anti-proliferative activity against human breast cancer cell line MCF-7 cell lines of estrogen receptor wild type, Y537S and D538G mutants. The compounds provided by the present invention can be used for preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders. Detailed Description of the Invention

[0061] To make the technical solutions and beneficial effects of the present invention more obvious and understandable, the following will be described in detail by way of specific examples.

[0062] First, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof. The structure of the compound of formula (I) is:

[0063]

[0064] Wherein,

[0065] Each R 1 independently selected from -H, D, -OH, -NH2, -COOH, -CH2NH2 and -CH2OH;

[0066] R 2 is selected from substituted or unsubstituted aryl, heterocyclic group and heteroaryl;

[0067] R 3 is selected from -(CH2) p CH=CHCONR 4 R 5 and -COCH=CR 6 R 7 wherein,

[0068] R 4 ,R 5 ,R 6 ,R 7 are each independently selected from -H, D, alkyl, cycloalkyl and heterocyclic group;

[0069] or R 4 and R 5 together with the connected nitrogen atom form a 3-7 membered heterocyclic group, or R6 and R 7 and the connected carbon atoms form C 3-6 cycloalkyl or 3- to 7-membered heterocyclic group;

[0070] p is selected from 0, 1, 2, and 3;

[0071] Z is selected from O, S, CHR 11 and NH, R 11 can be H, OH, D, NH2, and C 1-3 alkyl;

[0072] Y is selected from -R 8 NH-, -(CR 9 R 10 ) q NH- and 3- to 7-membered nitrogen-containing heterocyclic group, wherein,

[0073] R 8 is C 3-6 cycloalkyl or 3- to 7-membered heterocyclic group;

[0074] Each R 9 and R 10 are each independently selected from -H, halogen atom, substituted or unsubstituted C 1-6 alkyl and C 3-6 cycloalkyl; or R 9 and R 10 and the carbon atom connected thereto form a substituted or unsubstituted C 3-6 cycloalkyl or 3- to 7-membered heterocyclic group; or R 9 or R 10 and, together with the carbon atom of R 9 or R 10 and the carbon atom adjacent to said carbon atom form C 3-6 cycloalkyl;

[0075] q is selected from 1, 2, 3, 4, and 5;

[0076] is selected from substituted or unsubstituted aryl and heteroaryl;

[0077] m is selected from 1, 2, 3, and 4.

[0078] In a preferred embodiment, R 2 is selected from substituted or unsubstituted phenyl, 3- to 9-membered heterocyclic group, and 5- to 10-membered heteroaryl, and the substitution is by a group selected from C 1-6 alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 6-10substituted by one or more substituents selected from aryl, 5- to 10-membered heteroaryl, or 3- to 7-membered heterocyclic group, and said substituents are optionally substituted by 1 to 3 substituents selected from C 1-6 alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl.

[0079] In a more preferred embodiment, the 3- to 9-membered heterocyclic group is selected from any one of aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactamyl, caprolactamyl, butyrolactonyl, valerolactonyl, caprolactonyl, 2,3-dihydro-1H-indolyl, and benzodioxolyl;

[0080] The 5- to 10-membered heteroaryl contains 1 to 3 heteroatoms selected from N, NH, O, and S; preferably, the 5- to 10-membered heteroaryl ring is selected from any one of thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzopyrazole, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, or indolo[1,2-a]pyrazinyl.

[0081] In a preferred embodiment, R 3 is selected from -(CH2) p CH=CHCONR 4 R 5 and -COCH=CR 6 R 7 , wherein,

[0082] R 4 , R 5 , R 6 , R 7 are each independently selected from -H, D, C 1-3 alkyl, C 3-6 cycloalkyl, and 5- to 6-membered heterocyclic group;

[0083] or R 4 and R 5 together with the connected nitrogen atom form a 5- to 6-membered heterocyclic group;

[0084] p is 1.

[0085] In a preferred embodiment, Y is selected from -R 8 NH-, -(CR 9 R 10 ) q NH- and a 4- to 6-membered nitrogen-containing heterocyclic group, wherein R 8 is a cycloalkyl or a 4- to 6-membered heterocyclic group; 3-6

[0086] Each R 9 and R 10 are each independently selected from -H, a halogen atom, a substituted or unsubstituted C 1-6 alkyl and a C 3-6 cycloalkyl; or R 9 and R 10 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3- to 7-membered heterocyclic group; or R 9 or R 10 , together with the carbon atom of R 9 or R 10 and the carbon atom adjacent to said carbon atom form a C 3-6 cycloalkyl; the substituted C 1-6 alkyl and the C 3-6 cycloalkyl are substituted by a substituent selected from a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy and C 1-6 alkylamino;

[0087] q is selected from 1, 2 and 3, preferably 2.

[0088] In a preferred embodiment, is selected from a substituted or unsubstituted C 6-10 aryl and a 5- to 10-membered heteroaryl, and the substitution is by one or more substituents selected from C 1-6 alkyl, a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl or a 3- to 7-membered heterocyclic group, and the above substituents are optionally substituted by 1 to 3 substituents selected from C 1-6 alkyl, a halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl.

[0089] In a more preferred embodiment, the above Selected from substituted or unsubstituted phenyl and pyridyl, wherein the substitution is by one or more substituents selected from C 1-6 alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-7 membered heterocyclic group, and the above substituents are optionally substituted by 1-3 substituents selected from C 1-6 alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl.

[0090] In a preferred embodiment, the structure of the compound is as shown in Formula II:

[0091]

[0092] R 1 independently selected from -H, -OH and -NH2;

[0093] R 2 selected from substituted or unsubstituted phenyl, C 5-10 heteroaryl; the substitution is by a substituent selected from halogen, cyano, C 1-3 alkoxy, halogen-substituted C 1-3 alkoxy.

[0094] R 3 selected from -CH2CH=CHCONR 4 R 5 , wherein,

[0095] R 4 , R 5 are each independently selected from -H and C 1-3 alkyl; or R 4 and R 5 together with the connected nitrogen atom form pyrrolidinyl or piperidinyl;

[0096] Z is selected from O, S and NH;

[0097] Y is selected from -R 8 NH-, -(CR 9 R 10 ) q NH- and 3-7 membered nitrogen-containing heterocyclic group, wherein,

[0098] R 8 is C 3-6 cycloalkyl;

[0099] Each R 9 and R 10 are each independently selected from -H, a halogen atom, C 1-3 alkyl; or R 9 and R 10 together with the carbon atom to which they are attached form C 3-6 cycloalkyl;

[0100] q is 2;

[0101] is selected from a substituted or unsubstituted phenyl and pyridyl group, and the substitution is by a substituent selected from -H, a halogen atom, and C 1-3 alkoxy.

[0102] The present invention also provides a compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, characterized in that the compound is selected from:

[0103]

[0104]

[0105]

[0106]

[0107] The present invention also provides a pharmaceutical composition comprising any one of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof.

[0108] The present invention also provides any one of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or the above-mentioned pharmaceutical composition, which is used for preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders.

[0109] The present invention also provides the use of any one of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or the above-mentioned pharmaceutical composition for preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders.

[0110] The present invention also provides the application of any one of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled compound thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders.

[0111] The present invention also provides a method for preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders, which comprises the following steps: administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labeled compound as described above, or the pharmaceutical composition as described above, to a patient in need thereof.

[0112] Finally, the present invention also provides a pharmaceutical combination form, which comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopically labeled compound as described above, or the pharmaceutical composition as described above, and at least one additional therapeutic agent.

[0113] For a clearer description of the content of the present invention, all terms involved are now defined as follows:

[0114] The term "halogen atom" refers to fluorine, chlorine, bromine or iodine, either alone or in combination, particularly fluorine, chlorine or bromine.

[0115] The term "C 1-6 alkyl" refers to a saturated straight-chain or branched-chain alkyl group containing 1-6 carbon atoms, either alone or in combination, including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3,-dimethyl-2-butyl, etc. Preferably, "C 1-6 alkyl" is any one of methyl, ethyl, n-propyl, isopropyl, tert-butyl. Similarly, the term "C 1-3 alkyl" refers to a saturated straight-chain or branched-chain alkyl group containing 1-3 carbon atoms, either alone or in combination, including methyl, ethyl, n-propyl, isopropyl, etc.

[0116] The term "C 1-6 alkoxy" refers to the group C 1-6 alkyl-O-, where "C 1-6"Alkyl" means as defined above, which includes (but is not limited to) methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), isopropoxy (-OCH(CH3)2), n-butoxy (-OCH2CH2CH2CH3), sec-butoxy (-OCH(CH3)CH2CH3), isobutoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), n-pentyloxy (-OCH2CH2CH2CH2CH3), neopentyloxy (-OCH2C(CH3)3), etc.

[0117] The term "C" 3-6 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cycloalkyl having 3 to 6 carbon atoms, either alone or in combination, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0118] The term "heterocyclic group" means a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group in which the carbon atoms in the ring are replaced by at least one heteroatom selected from sulfur, oxygen or nitrogen. The term "3-9 membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group containing 3-9, especially 3-7 carbon atoms and heteroatoms or heteroatom groups selected from N, NH, O, C(O), S(O) m (where m is 0, 1 or 2); the 3-9 membered heterocyclic group includes any one of aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactamyl, caprolactamyl, butyrolactonyl, valerolactonyl, caprolactonyl or 2,3-dihydro-1H-indolyl and benzodioxolyl, etc. The definition of the term "3-9 membered heterocyclic group" is similar to that of the term "3-9 membered heterocyclic group", and refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group containing 5-6 carbon atoms and heteroatoms or heteroatom groups

[0119] The term "aryl" means any stable 6-10 membered monocyclic or bicyclic aromatic group, including phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl or biphenyl, etc. The hydrogen atoms on the "aryl" are independently and optionally substituted by one or more substituents described in the present invention.

[0120] The term "heteroaryl" refers to an aromatic ring group formed by replacing at least one carbon atom on the ring with a heteroatom selected from sulfur, oxygen or nitrogen, and this aromatic ring group can be a 5-7 membered monocyclic or 7-12 membered bicyclic group. In the present invention, the number of heteroatoms in the heteroaryl is preferably 1, 2, 3 or 4. For example, the 5-10 membered heteroaromatic ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, benzopyrazole, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl or indolo[1,2-a]pyrazinyl, etc. The hydrogen atoms on the "heteroaryl" are independently and optionally substituted by one or more substituents described in the present invention.

[0121] The term "C 6-10 aryl" refers to an aryl group having 6-10 carbon atoms, where the aryl group is as defined above.

[0122] The term "5-10 membered heteroaryl" refers to a heteroaromatic ring having 5-10 carbon atoms and heteroatoms, where the heteroaromatic ring is as defined above.

[0123] The term "amino" alone or in combination refers to a primary amino group (-NH2), a secondary amino group (-NH-) or a tertiary amino

[0124] The term "C 1-6 alkylamino" alone or in combination refers to an amino group as defined above, where the hydrogen atom of the amino group is substituted by at least one C 1-6 alkyl group, where "C 1-6 alkyl" is as defined above. Accordingly, "C 1-6 alkylamino" includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl-3-pentylamino, 2,3-dimethyl-2-butylamino, 3,3-dimethyl-2-butylamino, etc. Particularly, "C1-C 10 alkylamino" is methylamino, ethylamino, isopropylamino, tert-butylamino, etc.

[0125] The term "isomer" encompasses all isomeric forms including enantiomers, diastereomers, tautomers, and geometric isomers (including cis-trans isomers). Accordingly, individual stereochemical isomers of the compounds contemplated in the present invention, or mixtures of their enantiomers, diastereomers, tautomers, or geometric isomers (or cis-trans isomers), are within the scope of the present invention.

[0126] The term "pharmaceutically acceptable salts" means that the compounds of the present invention exist in the form of their medicinal salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in the pharmaceutically salts described by S.M. Berge in J. Pharmaceutical Sciences (Vol. 66: pages 1-19, 1977). In the present invention, pharmaceutically acceptable non-toxic acid addition salts mean salts formed by the compounds in the present invention with organic or inorganic acids, and the organic or inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts mean salts formed by the compounds in the present invention with organic or inorganic bases, including, but not limited to, alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts or N + (C 1-6 (alkyl)4 salts, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia water, triethylamine, tetrabutylammonium hydroxide, etc.

[0127] The term "solvate" means an association formed by one or more solvent molecules with the compounds in the present invention. The solvents forming the solvate include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. "Pharmaceutically acceptable salts" can be synthesized by general chemical methods.

[0128] The term "ester" is used to denote organic esters, including mono-esters, di-esters, tri-esters, and more generally poly-esters.

[0129] The term "prodrug" means a chemical derivative of the compounds of the present invention, which derivative is converted in vivo by a chemical reaction into the compound represented by General Formula I.

[0130] The term "isotope derivative" means an isotope derivative obtained by replacing the hydrogen atoms in General Formula (I) with 1-6 deuterium atoms (D), or the carbon atoms in General Formula (I) with 1-3 carbon-14 atoms ( 14Isotope derivatives obtained by replacement with C).

[0131] The terms related to the present invention are defined above. Those skilled in the art can also understand the above terms in combination with the prior art. The following further describes based on the content of the present invention and the definitions of the terms.

[0132] The following examples can further describe the present invention. However, these examples should not be construed as limiting the scope of the present invention.

[0133] Example 1 Preparation of Compound 001

[0134]

[0135] The preparation route of Compound 001 is as follows:

[0136]

[0137]

[0138] To a solution of Compound 001-1 (15.0 g, 68.2 mmol, 1.0 eq.) in CH3CN (150 mL) was added Cs2CO3 (44.4 g, 136.3 mmol, 2.0 eq.) and Compound 001-2 (21.4 g, 95.4 mmol, 1.4 eq.) at once. The reaction mixture was reacted at 110 °C for 16 hours. After the reaction was completed, the reaction mixture was poured into 300 mL of water and extracted with ethyl acetate three times (450 mL). The organic phases were combined, dried over magnesium sulfate, concentrated, and purified by column chromatography to obtain Compound 001-3 as a yellow oil (21.8 g, 49.8 mmol, 73.1%). 1 1H NMR: (400 MHz, DMSO-d6) δ 7.60 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 3.98 (t, J = 5.8 Hz, 2H), 3.32 - 3.24 (m, 2H), 1.40 - 1.37 (m, 9H), 1.30 - 1.26 (m, 12H).

[0139]

[0140] Under nitrogen protection, SOCl2 (14.4 g, 121.2 mmol, 8.79 mL, 4.0 eq.) was added to a solution of 001-4 (5.0 g, 30.3 mmol, 1.0 eq.) in anhydrous tetrahydrofuran (100 mL) cooled to 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 12 h. The mixture was concentrated to give a brown oil, which was used directly in the subsequent reaction. The above brown oil was dissolved in 50 mL of anhydrous dichloromethane. Under nitrogen protection, dimethylamine hydrochloride (2.45 g, 30.0 mmol, 1.1 eq.) and a dichloromethane solution of triethylamine (8.27 g dissolved in 100 mL of dichloromethane, 3.0 eq.) were added in one portion. After the reaction was complete at room temperature, 100 mL of water was added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to give a brown oil, which was used directly in the next reaction.

[0141] 1 H NMR: (400 MHz, DMSO-d6) δ 6.93 - 6.77 (m, 1H), 6.55 - 6.37 (m, 1H), 4.16 - 3.95 (m, 2H), 3.04 - 2.93 (m, 6H). (ESI+) m / z 192.0 (M + H) + 。

[0142]

[0143] AlCl3 (75.7 g, 567.7 mmol, 31.0 mL, 2.4 eq.) was slowly added to a solution of compound 001-6 (45.0 g, 236.6 mmol, 1.0 eq.) in anhydrous toluene (500 mL). The reaction mixture was heated at 90 °C for 1 h. The reaction mixture was poured into 1500 mL of ice-water mixture. The suspension was stirred for 20 min, and the solid was filtered off. The filter cake was washed with 500 mL of water and concentrated under reduced pressure to give a yellow solid 001-7 (41.0 g, 232.7 mmol, 98.4%).

[0144] 1 H NMR: (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 6.70 (dd, J = 2.4, 8.4 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.65 - 2.57 (m, 2H), 1.80 - 1.71 (m, 2H), 1.71 - 1.62 (m, 2H).

[0145]

[0146] To a solution of compound 001-7 (41.0 g, 232.7 mmol, 1.0 eq.) in acetone (500 mL) was added potassium carbonate (32.2 g, 232.7 mmol, 1.0 eq.) and pivaloyl chloride (32.3 g, 267.6 mmol, 32.9 mL, 1.15 eq.) all at once, and the reaction was carried out at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, 500 mL of water and 500 mL of ethyl acetate were added thereto, the organic phase was washed with saturated brine, dried over magnesium sulfate, and the concentrated crude product was subjected to column chromatography to obtain the yellow solid compound 001-8 (52.0 g, 199.8 mmol, 85.9%).

[0147] 1 H NMR: (400 MHz, DMSO-d6) 7.68 - 7.75 (m, 1H), 7.27 - 6.88 (m, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H), 1.83 - 1.76 (m, 2H), 1.75 - 1.66 (m, 2H), 1.31 (s, 9H).

[0148]

[0149] At room temperature, trifluoromethanesulfonic anhydride (48.8 g, 172.9 mmol, 28.5 mL, 2.0 eq.) was added dropwise to a dichloromethane solution (500 mL) of compound 001-8 (22.5 g, 86.4 mmol, 1.0 eq.) and pyridine (10.3 g, 129.6 mmol, 10.5 mL, 1.5 eq.), and the reaction mixture was further reacted at room temperature for 2 h. 250 mL of water was slowly added dropwise to the reaction mixture, and the organic phase was separated. The organic phase was washed once with saturated brine and dried over magnesium sulfate. The concentrated crude product was subjected to column chromatography to obtain the white solid compound 001-9 (31.5 g, 80.3 mmol, 92.9%)

[0150] 1 H NMR: (400 MHz, DMSO-d6) δ 7.50 (d, J = 9.3 Hz, 1H), 7.13 (dd, J = 2.3, 4.5 Hz, 2H), 6.40 (t, J = 6.1 Hz, 1H), 2.85 - 2.62 (m, 2H), 2.33 - 2.17 (m, 2H), 2.08 - 1.86 (m, 2H), 1.31 (s, 9H).

[0151]

[0152] Compound 001-9 (13.0 g, 33.1 mmol, 1.0 eq.) and 001-3 (12.6 g, 34.8 mmol, 1.05 eq.) were dissolved in dioxane (130 mL) and water (25 mL), and Pd(dppf)Cl2 (1.21 g, 1.66 mmol, 0.05 eq.) and cesium carbonate (21.6 g, 66.3 mmol, 2.0 eq.) were added to this solution all at once. The reaction mixture was reacted at room temperature for one hour. Saturated brine (100 mL) and dichloromethane (100 mL) were slowly added to the reaction mixture, the organic phase was separated, and dried over magnesium sulfate. The concentrated crude product was purified by column chromatography to obtain the white solid product 001-10 (14.8 g, 30.9 mmol, 93.1%).

[0153] 1 1H NMR: (400 MHz, DMSO-d6) 7.13 (d, J = 8.8 Hz, 2H), 7.09 - 7.06 (m, 1H), 7.03 - 6.98 (m, 1H), 6.95 - 6.88 (m, 4H), 6.38 (t, J = 7.3 Hz, 1H), 3.96 (brt, J = 5.8 Hz, 2H), 3.31 - 3.26 (m, 2H), 2.62 - 2.56 (m, 2H), 2.17 - 2.08 (m, 2H), 1.88 (q, J = 7.4 Hz, 2H), 1.39 (s, 9H), 1.32 (s, 9H).

[0154]

[0155] At room temperature, tribromopyridinium salt (10.4 g, 32.4 mmol, 1.05 eq.) was added to a solution of compound 001-10 (14.8 g, 30.9 mmol, 1.0 eq.) in tetrahydrofuran (200 mL), and the reaction mixture was continued to react at room temperature for one hour. The reaction mixture was added to a saturated sodium bicarbonate (100 mL) solution, and the above mixture was extracted with dichloromethane (100 mL * 2). The organic phases were combined, washed with saturated brine, and dried over magnesium sulfate. The concentrated crude product was obtained by column chromatography to obtain the white solid product 001-11 (11.5 g, 20.6 mmol, 66.7%).

[0156] 11H NMR: (400 MHz, DMSO-d6) δ 7.14 (d, J = 8.8 Hz, 2H), 7.11 - 7.08 (m, 1H), 7.07 - 7.01 (m, 1H), 6.98 - 6.91 (m, 3H), 6.83 - 6.76 (m, 2H), 4.00 (br t, J = 5.8 Hz, 2H), 3.66 - 3.61 (m, 1H), 2.81 - 2.73 (m, 2H), 2.28 (br t, J = 6.9 Hz, 2H), 1.80 (td, J = 3.2, 6.7 Hz, 1H), 1.42 (s, 9H), 1.33 (s, 10H).

[0157]

[0158] Compound 001 - 11 (198.5 mg, 1.29 mmol, 1.2 eq.), (0.6 g, 1.07 mmol, 1.0 eq.), and Cs2CO3 (700.0 mg, 2.15 mmol, 2.0 eq.) were dissolved in dioxane (5 mL) and water (1 mL). The reaction mixture was degassed and protected with nitrogen. Pd(dppf)Cl2 (39.3 mg, 53.7 μmol, 0.05 eq.) was added to the above reaction mixture, and the reaction mixture was continued to react at 90 °C for one hour. The reaction mixture was diluted with H2O (100 mL) and extracted twice with ethyl acetate (100 mL * 2). The organic phase was washed with saturated brine, dried over magnesium sulfate, and the concentrated crude product was purified by column chromatography to obtain yellow oil 001 - 12 (750 mg, 1.02 mmol, 95.0%).

[0159] 1 1H NMR: (400 MHz, CDCl3) δ 6.96 - 6.85 (m, 2H), 6.80 - 6.69 (m, 6H), 6.57 - 6.44 (m, 2H), 4.97 - 4.78 (m, 1H), 3.85 (t, J = 5.0 Hz, 2H), 3.40 (d, J = 5.0 Hz, 2H), 2.73 (t, J = 6.9 Hz, 2H), 2.26 - 2.22 (m, 1H), 2.30 - 2.18 (m, 4H), 2.09 (q, J = 6.8 Hz, 2H), 1.37 (s, 9H), 1.29 (s, 9H).

[0160]

[0161] To a solution of compound 001-12 (500 mg, 850.8 μmol, 1.0 eq.) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.0 mL, 15.9 eq.). The reaction mixture was stirred at room temperature for 2 hours. After concentration, a yellow solid product 001-13 (500 mg, 831.1 μmol, 97.7%) was obtained and used directly in the next step without further purification.

[0162] (ESI+) m / z 488.2 (M+H) + 。

[0163]

[0164] To a solution of compound 001-13 (450 mg, 922.9 μmol, 1.0 eq.) in N,N-dimethylformamide (20 mL) was added compound 001-05 (141.8 mg, 738.3 μmol, 0.8 eq.), potassium iodide (153.2 mg, 922.9 μmol, 1.0 eq.) and potassium carbonate (255.1 mg, 1.85 mmol, 2.0 eq.) sequentially. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate three times (50 mL * 3). The combined organic layers were dried over magnesium sulfate, concentrated to give a crude product, and purified by column chromatography to afford a yellow oily compound 001-14 (76 mg, 124.4 μmol, 13.5%).

[0165] (ESI+) m / z 599.5 (M+H) + 。

[0166]

[0167] To a solution of compound 001-14 (76 mg, 126.9 μmol, 1.0 eq.) in methanol (1 mL) was added sodium hydroxide (10.2 mg, 253.9 μmol, 2.0 eq.). The reaction mixture was stirred for 1 hour. The pH of the reaction mixture was adjusted to 6 with 3 mol / L hydrochloric acid. The crude product was purified by preparative liquid chromatography to give a white solid compound 001 (43.74 mg, 62.6%). Preparative liquid chromatography conditions: column: Phenomenex Luna C18 100 * 30 mm * 3 μm; mobile phase: A water (0.225% formic acid), B acetonitrile, B%: 25% - 45%, 8 minutes.

[0168] 11H NMR: (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.91 - 6.80 (m, 2H), 6.73 (t, J = 9.3 Hz, 3H), 6.69 - 6.64 (m, 2H), 6.64 - 6.58 (m, 1H), 6.58 - 6.50 (m, 3H), 3.93 (t, J = 5.5 Hz, 2H), 3.27 - 3.18 (m, 2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.85 - 2.81 (m, 2H), 2.72 - 2.67 (m, 2H), 2.24 (s, 3H), 2.20 - 2.14 (m, 2H), 2.09 - 2.02 (m, 2H); (ESI+) m / z 515.3 (M + H) + 。

[0169] LCMS conditions: Mobile phase: 0.02% ammonia water (mobile phase A), acetonitrile (mobile phase B), mobile phase B increases from 10% to 80% in three minutes, maintain 80% of mobile phase B for 0.5 minutes, flow rate: 1.0 ml / min; Chromatographic column: Xbrige Shield RP-18, 5um, 2.1 * 50 mm; Detection wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C.

[0170] Preparation of Compound 002 in Example 2

[0171]

[0172] Refer to the synthetic route in Example 1 to synthesize the yellow solid compound 002.

[0173] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.07 - 8.81 (m, 2H), 7.57 (d, J = 2.1 Hz, 1H), 7.26 (dd, J = 2.1, 8.3 Hz, 1H), 7.20 - 7.13 (m, 1H), 6.86 - 6.73 (m, 6H), 6.63 - 6.53 (m, 3H), 4.13 (br t, J = 4.9 Hz, 2H), 3.83 (br d, J = 3.0 Hz, 2H), 3.05 (s, 4H), 2.89 (s, 4H), 2.82 - 2.72 (m, 2H), 2.23 - 2.14 (m, 2H), 2.13 - 2.04 (m, 2H); (ESI+) m / z 551.0 (M + H) + 。

[0174] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B). Mobile phase B is changed from 5% to 80% over 3 minutes and maintained at 80% for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0175] Preparation of Compound 003 in Example 3

[0176]

[0177] A white solid compound 003 was synthesized by referring to Example 1.

[0178] 1 1H NMR: (400 MHz, DMSO - d6) δ 10.41 - 8.77 (m, 1H), 8.20 (s, 1H), 7.38 (dd, J = 2.5, 8.9 Hz, 1H), 7.17 (dd, J = 6.4, 8.4 Hz, 1H), 7.04 (dt, J = 2.6, 8.5 Hz, 1H), 6.78 - 6.59 (m, 6H), 6.58 - 6.49 (m, 3H), 3.92 (br t, J = 5.5 Hz, 2H), 3.36 (br d, J = 4.9 Hz, 2H), 3.02 (s, 3H), 2.90 - 2.73 (m, 7H), 2.24 - 2.15 (m, 2H), 2.09 (br s, 2H); 19 19F NMR: (400 MHz, DMSO - d6) δ - 114.18 (s, 1F); (ESI+) m / z 535.1 (M + H) + 。

[0179] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B). Mobile phase B is changed from 5% to 80% over 3 minutes and maintained at 80% for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0180] Preparation of Compound 004 in Example 4

[0181]

[0182] A white solid compound 004 was synthesized by referring to Example 1.

[0183] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.13 - 6.98 (m, 2H), 6.71 (s, 1H), 6.70 - 6.63 (m, 4H), 6.63 - 6.59 (m, 1H), 6.58 - 6.49 (m, 3H), 3.91 (t, J = 5.5 Hz, 2H), 3.30 (s, 1H), 3.01 (s, 3H), 2.86 (s, 3H), 2.80 (br t, J = 5.5 Hz, 2H), 2.77 - 2.66 (m, 3H), 2.14 (s, 5H), 2.07 (br dd, J = 5.6, 11.9 Hz, 2H); (ESI+) m / z 531.3 (M + H) + 。

[0184] LCMS conditions: Mobile phase: 0.02% ammonia water (mobile phase A), acetonitrile (mobile phase B), mobile phase B increases from 10% to 80% over six minutes, hold 80% of mobile phase B for one minute, flow rate: 1.0 ml / min; Column: Xbrige Shield RP-18, 5um, 2.1 * 50 mm; Detection wavelength: 220 nm and 254 nm; Column temperature: 45 °C.

[0185] Preparation of Compound 005 in Example 5

[0186]

[0187] Refer to Example 1 for synthesis to obtain the white solid compound 005.

[0188] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 6.98 - 6.91 (m, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.82 - 6.77 (m, 1H), 6.73 - 6.66 (m, 3H), 6.64 - 6.58 (m, 3H), 6.58 - 6.51 (m, 3H), 3.91 (br t, J = 5.4 Hz, 2H), 3.33 (br s, 2H), 3.01 (s, 3H), 2.86 (s, 3H), 2.85 - 2.81 (m, 2H), 2.81 - 2.72 (m, 1H), 2.72 - 2.66 (m, 1H), 2.49 - 2.40 (m, 1H), 2.19 (s, 3H), 2.15 (br d, J = 6.6 Hz, 1H), 2.12 (s, 3H), 2.09 - 1.98 (m, 3H); (ESI+) m / z 511.1 (M + H)+ .

[0189] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B). Mobile phase B changes from 5% to 80% over 3 minutes and maintains 80% mobile phase B for 0.5 minutes; Flow rate: 1 mL / min; Column: C18 2.1 * 30 mm, 3 μm; Detection wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; Mass spectrometry ion source: ESI.

[0190] Preparation of Compound 006 in Example 6

[0191]

[0192] A white solid compound 006 was synthesized by referring to Example 1.

[0193] 1 H NMR: (400 MHz, DMSO - d6) δ 9.38 (s, 1H), 6.98 - 6.91 (m, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.82 - 6.77 (m, 1H), 6.73 - 6.66 (m, 3H), 6.64 - 6.58 (m, 3H), 6.58 - 6.51 (m, 3H), 3.91 (brt, J = 5.6 Hz, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.01 (s, 3H), 2.86 (s, 3H), 2.76 - 2.65 (m, 4H), 2.09 - 2.07 (m, 2H), 2.06 - 2.04 (m, 4H), 1.29 (t, J = 7.2 Hz, 3H); (ESI+) m / z 561.1 (M + H) + .

[0194] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B). Mobile phase B changes from 5% to 80% over 3 minutes and maintains 80% mobile phase B for 0.5 minutes; Flow rate: 1 mL / min; Column: C18 2.1 * 30 mm, 3 μm; Detection wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; Mass spectrometry ion source: ESI.

[0195] Preparation of Compound 007 in Example 7

[0196]

[0197] A white solid compound 007 was synthesized by referring to Example 1.

[0198] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.85 - 9.68 (m, 1H), 7.24 - 7.15 (m, 3H), 7.06 - 7.00 (m, 2H), 6.74 - 6.65 (m, 7H), 6.55 - 6.50 (m, 1H), 3.95 - 3.91 (m, 2H), 3.06 - 2.97 (m, 4H), 2.90 - 2.79 (m, 6H), 2.69 - 2.52 (m, 5H); 19 19F NMR: (400 MHz, DMSO-d6) δ -82.23 (d, J = 3.5 Hz, 2F), -131.66 - 131.71 (s, 1F); (ESI+) m / z 567.1 (M + H) + 。

[0199] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B is from 5% - 80% over 3 minutes and maintained at 80% for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0200] Preparation of Compound 008 in Example 8

[0201]

[0202] Refer to Example 1 for synthesis to obtain white solid Compound 008.

[0203] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.82 - 9.65 (m, 1H), 7.07 - 6.98 (m, 2H), 6.92 - 6.86 (m, 1H), 6.74 - 6.59 (m, 8H), 6.56 - 6.49 (m, 1H), 3.96 - 3.83 (m, 4H), 3.05 - 2.98 (m, 3H), 2.88 - 2.79 (m, 5H), 2.70 - 2.54 (m, 3H), 2.49 - 2.31 (m, 4H), 1.23 - 1.18 (m, 3H); 19 19F NMR: (400 MHz, DMSO-d6) δ -137.38 (s, 1F); (ESI+) m / z 545.2 (M + H) + 。

[0204] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B ramps from 5% - 80% over 3 minutes and holds at 80% for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0205] Preparation of Compound 009 in Example 9

[0206]

[0207] A white solid compound 009 was synthesized with reference to Example 1.

[0208] 1 H NMR: (400 MHz, DMSO - d6) δ 8.19 (s, 1H), 6.97 - 6.89 (m, 2H), 6.89 - 6.82 (m, 1H), 6.79 - 6.74 (m, 2H), 6.71 (br d, J = 9.0 Hz, 3H), 6.66 - 6.59 (m, 1H), 6.58 - 6.42 (m, 3H), 4.03 (q, J = 7.0 Hz, 2H), 3.95 (br t, J = 5.5 Hz, 2H), 3.37 (br s, 2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.84 (br s, 2H), 2.67 (br d, J = 6.3 Hz, 2H), 2.23 (br t, J = 6.5 Hz, 2H), 2.09 - 1.99 (m, 2H), 1.31 (t, J = 6.8 Hz, 3H).; 19 F NMR: (400 MHz, DMSO - d6) δ - 135.44 (s, 1F); (ESI+) m / z 545.2 (M + H) + ;

[0209] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B ramps from 5% - 80% over 3 minutes and holds at 80% for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0210] Preparation of Compound 010 in Example 10

[0211]

[0212] The white solid compound 010 was synthesized with reference to Example 1.

[0213] 1 1H NMR: (400 MHz, DMSO-d6) δ 10.10 - 8.93 (m, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.18 (s, 1H), 7.88 - 7.82 (m, 1H), 7.74 (d, J = 8.1 Hz, 1H), 6.76 (br d, J = 13.4 Hz, 5H), 6.58 (s, 4H), 3.99 - 3.93 (m, 2H), 3.18 - 3.13 (m, 2H), 3.10 - 2.98 (m, 3H), 2.89 - 2.82 (m, 5H), 2.76 - 2.70 (m, 2H), 2.40 - 2.29 (m, 2H), 2.13 - 2.04 (m, 2H); 19 19F NMR: δ -66.11 (s, 1F); (ESI+) m / z 552.1 (M + H) + ;

[0214] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B was changed from 5% to 80% over 3 minutes and maintained at 80% for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0215] Preparation of Compound 011 in Example 11

[0216]

[0217] Under the condition of 0 °C, methanesulfonyl chloride (0.62 g, 5.41 mmol, 418.9 μL, 1.27 eq.) was slowly added to a dichloromethane solution (30 mL) of compound 011 - 1 (0.8 g, 4.27 mmol, 1.0 eq.) and triethylamine (864.7 mg, 8.55 mmol, 1.19 mL, 2.0 eq.). After addition, the reaction mixture was reacted at room temperature for 2 hours. The reaction was quenched with 100 mL of ice - water, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane (100 mL * 2). The combined organic phases were washed once with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was purified by column chromatography to give the white solid compound 011 - 2 (1.1 g, 3.32 mmol, 77.6%).

[0218] 1 1H NMR: (400 MHz, CDCl3) δ 4.77 - 4.70 (m, 2H), 3.84 (br s, 1H), 3.01 (s, 3H), 2.96 - 2.90 (m, 2H), 2.24 - 2.18 (m, 2H), 1.46 (s, 9H).

[0219]

[0220] Compound 011 - 2 (2.65 g, 9.99 mmol, 1.0 eq.) and compound 011 - 3 (2.20 g, 9.99 mmol, 1.0 eq.) were dissolved in N,N - dimethylformamide (80 mL). Potassium carbonate (2.76 g, 19.9 mmol, 2.0 eq.) was added thereto. The reaction mixture was reacted at 90 °C for 12 h. 300 mL of water was added to dilute the reaction mixture, and the mixture was extracted with ethyl acetate three times (20 mL * 3). The organic phases were combined, washed with saturated brine (100 mL * 2), dried over magnesium sulfate, and the concentrated crude product was subjected to column chromatography to obtain the yellow oily compound 011 - 4 (1.9 g, 4.88 mmol, 48.9%).

[0221] 1 1H NMR: (400 MHz, CDCl3) δ 7.71 - 7.62 (m, 2H), 6.80 - 6.65 (m, 2H), 4.80 - 4.57 (m, 1H), 4.38 - 4.14 (m, 1H), 2.88 (br s, 1H), 2.53 - 2.27 (m, 2H), 1.96 - 1.88 (m, 2H), 1.60 - 1.32 (m, 9H), 1.26 (s, 12H);.

[0222]

[0223] The white solid compound 011 was synthesized with reference to Example 1.

[0224] 11H NMR: (400 MHz, DMSO-d6) δ 9.79 - 9.17 (m, 1H), 8.17 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.24 (dd, J = 2.1, 8.3 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.76 - 6.69 (m, 3H), 6.67 - 6.47 (m, 6H), 4.72 - 4.67 (m, 1H), 4.30 - 4.25 (m, 1H), 3.40 - 3.26 (m, 2H), 3.01 (s, 3H), 2.86 (s, 3H), 2.72 - 2.64 (m, 2H), 2.25 - 2.01 (m, 8H).; LCMS: (ESI+) m / z 577.1 (M + H) + 。

[0225] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B from 5% - 80% over 3 minutes, hold 80% mobile phase B for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 um; detection wavelength: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0226] Preparation of Compound 012 in Example 12

[0227]

[0228] Refer to Example 1 for synthesis to obtain the white solid compound 012.

[0229] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.81 - 8.86 (m, 1H), 8.24 (s, 1H), 7.04 (dd, J = 6.3, 8.3 Hz, 1H), 6.95 (dd, J = 2.4, 10.4 Hz, 1H), 6.86 (dt, J = 2.8, 8.4 Hz, 1H), 6.74 - 6.59 (m, 5H), 6.58 - 6.47 (m, 3H), 3.91 (t, J = 5.6 Hz, 2H), 3.35 - 3.34 (m, 2H), 3.01 (s, 3H), 2.86 (s, 3H), 2.82 - 2.72 (m, 4H), 2.15 (s, 3H), 2.13 - 2.07 (m, 4H); LCMS: (ESI+) m / z 515.3 (M + H) + 。

[0230] LCMS conditions: Mobile phase: 0.02% ammonia water (Mobile phase A), acetonitrile (Mobile phase B). Mobile phase B changes from 10% to 80% over three minutes, and 80% of Mobile phase B is maintained for 0.5 minutes. Flow rate: 1.0 ml / min; Chromatographic column: Xbrige Shield RP-18, 5um, 2.1*50mm; Detection wavelength: UV 220nm and 254nm; Column temperature: 50°C.

[0231] Preparation of Compound 013 in Example 13

[0232]

[0233] Referring to Example 1, a white solid compound 013 was synthesized.

[0234] 1 H NMR: (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.64 (s, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.81 - 6.70 (m, 5H), 6.56 (s, 4H), 3.95 (t, J = 5.5 Hz, 2H), 3.37 - 3.34 (m, 2H), 3.02 (s, 3H), 2.86 (s, 5H), 2.72 - 2.67 (m, 2H), 2.36 - 2.24 (m, 3H), 2.12 - 2.05 (m, 2H); 19 FNMR: δ -87.09 (s, 1F); LCMS: (ESI+) m / z 550.1 (M + H) + 。

[0235] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (Mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (Mobile phase B). Mobile phase B changes from 5% to 80% over 3 minutes, and 80% of Mobile phase B is maintained for 0.5 minutes; Flow rate: 1 mL / min; Column: C18 2.1*30mm, 3um; Detection wavelength: UV 220nm and 254nm; Column temperature: 50°C; Mass spectrometry ion source: ESI.

[0236] Preparation of Compound 014 in Example 14

[0237]

[0238] Referring to Example 11, a white solid compound 014 was synthesized.

[0239] 11H NMR: (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.76 - 6.69 (m, 3H), 6.62 (d, J = 8.8 Hz, 2H), 6.60 - 6.46 (m, 4H), 4.75 (t, J = 6.4 Hz, 1H), 3.20 (br d, J = 5.0 Hz, 2H), 3.00 (s, 3H), 2.86 (s, 3H), 2.80 - 2.62 (m, 4H), 2.56 (br d, J = 10.4 Hz, 1H), 2.41 (br d, J = 7.1 Hz, 1H), 2.22 (br s, 1H), 2.18 - 2.12 (m, 2H), 2.08 (br s, 2H), 1.71 (br dd, J = 5.5, 7.9 Hz, 1H).; (ESI+) m / z 577.2 (M+H) + 。

[0240] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B changes from 5% - 80% over 3 minutes and maintains 80% mobile phase B for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 um; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0241] Preparation of the compound 015 in Example 15

[0242]

[0243] Referring to Example 11, a white solid compound 015 was synthesized.

[0244] 11H NMR: (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.30 - 7.21 (m, 1H), 7.19 - 7.10 (m, 1H), 6.76 - 6.66 (m, 5H), 6.66 - 6.59 (m, 1H), 6.58 - 6.53 (m, 2H), 6.52 - 6.45 (m, 1H), 3.82 (s, 2H), 3.42 (br s, 2H), 2.99 - 2.95 (m, 3H), 2.84 (s, 3H), 2.80 - 2.70 (m, 2H), 2.22 - 2.12 (m, 2H), 2.12 - 1.98 (m, 2H), 0.66 - 0.57 (m, 2H), 0.57 - 0.47 (m, 2H); LCMS: (ESI+) m / z 577.0 (M+H) + 。

[0245] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B is increased from 5% to 80% over 3 minutes and maintained at 80% for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0246] Preparation of Compound 016 in Example 16

[0247]

[0248] Refer to Example 11 for synthesis to obtain the white solid compound 016.

[0249] 11H NMR: (400 MHz, DMSO-d6) δ 11.36 - 11.07 (m, 1H), 9.53 (br s, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.16 (d, J = 8.3 Hz, 1H), 6.96 - 6.84 (m, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 2.3 Hz, 1H), 6.67 - 6.61 (m, 2H), 6.60 - 6.55 (m, 1H), 6.52 - 6.43 (m, 1H), 6.52 - 6.42 (m, 1H), 5.12 - 4.76 (m, 1H), 4.62 (br s, 1H), 4.39 (br s, 1H), 4.24 - 3.87 (m, 4H), 3.06 (br s, 3H), 2.88 (s, 3H), 2.82 - 2.70 (m, 2H), 2.22 - 2.14 (m, 2H), 2.12 - 2.02 (m, 2H); LCMS: (ESI+) m / z 563.1 (M + H) + 。

[0250] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B from 5% - 80% over 3 minutes, hold 80% mobile phase B for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelength: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0251] Preparation of Compound 017 in Example 17

[0252]

[0253] Refer to Example 11 for synthesis to obtain the white solid compound 017.

[0254] 11H NMR: (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.21 - 7.15 (m, 1H), 6.82 - 6.71 (m, 6H), 6.67 - 6.61 (m, 2H), 6.59 - 6.49 (m, 2H), 4.10 (s, 2H), 3.93 (br d, J = 3.0 Hz, 2H), 3.57 - 3.47 (m, 2H), 3.35 - 3.24 (m, 2H), 2.84 - 2.71 (m, 2H), 2.22 - 2.14 (m, 2H), 2.13 - 2.03 (m, 2H), 1.87 (q, J = 6.5 Hz, 2H), 1.80 (q, J = 6.5 Hz, 2H), 1.28 - 1.19 (m, 2H), 1.00 - 0.91 (m, 2H).; LCMS: (ESI+) m / z 603.1 (M + H) + 。

[0255] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B is changed from 5% - 80% in 3 minutes and maintained at 80% for 0.5 minutes; flow rate: 1 mL / min; column: C18 2.1 * 30 mm, 3 μm; detection wavelengths: UV 220 nm and 254 nm; column temperature: 50 °C; mass spectrometry ion source: ESI.

[0256] Preparation of Compound 018 in Example 18

[0257]

[0258] Referring to Example 1, a white solid compound 018 was synthesized.

[0259] 11H NMR: (400 MHz, DMSO-d6) δ 9.72 - 9.44 (m, 1H), 9.35 (br s, 2H), 7.56 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 1.9, 8.3 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.86 - 6.70 (m, 5H), 6.69 - 6.61 (m, 2H), 6.60 - 6.52 (m, 2H), 4.18 (br t, J = 4.4 Hz, 2H), 3.82 (br s, 2H), 3.51 (br t, J = 6.8 Hz, 2H), 3.33 (br s, 2H), 3.28 (br s, 2H), 2.84 - 2.71 (m, 2H), 2.18 (br d, J = 6.4 Hz, 2H), 2.08 (br d, J = 5.0 Hz, 2H), 1.94 - 1.85 (m, 2H), 1.79 (td, J = 6.4, 13.3 Hz, 2H); LCMS: (ESI+) m / z 577.1 (M + H) + 。

[0260] Liquid chromatography - mass spectrometry (LC - MS) conditions: 0.037% trifluoroacetic acid aqueous solution (mobile phase A), 0.018% trifluoroacetic acid acetonitrile solution (mobile phase B), mobile phase B from 5% - 80% over 3 minutes, hold 80% mobile phase B for 0.5 minutes; Flow rate: 1 mL / min; Column: C18 2.1 * 30 mm, 3 um; Detection wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; Mass spectrometry ion source: ESI.

[0261] Preparation of Compound 030 in Example 19

[0262]

[0263] Refer to Example 1 for the synthesis of the white solid compound 030.

[0264] 11H NMR: (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.65 (s, 1H), 7.55 (dd, J = 3.4, 4.7 Hz, 2H), 7.19 (dd, J = 1.3, 8.6 Hz, 1H), 6.77 - 6.69 (m, 3H), 6.67 - 6.62 (m, 2H), 6.60 (s, 1H), 6.56 (d, J = 1.0 Hz, 2H), 6.53 - 6.47 (m, 1H), 3.89 (t, J = 5.5 Hz, 2H), 3.36 - 3.34 (m, 2H), 3.00 (s, 3H), 2.85 (s, 3H), 2.78 (br t, J = 5.0 Hz, 2H), 2.72 (brs, 2H), 2.32 (br d, J = 1.8 Hz, 2H), 2.14 - 1.99 (m, 3H); LCMS: (ESI+) m / z 524.6 (M + H) + 。

[0265] Preparation of Compound 031 in Example 20

[0266]

[0267] Referring to Example 1, a white solid compound 031 was synthesized.

[0268] 1 1H NMR: (400 MHz, DMSO-d6) δ 13.13 - 12.67 (m, 1H), 9.73 - 9.07 (m, 1H), 7.93 (s, 1H), 7.53 (s, 1H), 7.34 - 7.26 (m, 1H), 7.14 - 7.04 (m, 1H), 6.78 - 6.68 (m, 3H), 6.66 - 6.47 (m, 6H), 3.94 - 3.82 (m, 2H), 3.31 - 3.28 (m, 2H), 2.93 (s, 3H), 2.78 (br t, J = 5.3 Hz, 5H), 2.74 - 2.68 (m, 2H), 2.34 - 2.28 (m, 2H), 2.12 - 1.96 (m, 3H); LCMS: (ESI+) m / z 523.4 (M + H) + 。

[0269] Preparation of Compound 032 in Example 21

[0270]

[0271] Referring to Example 1, a white solid compound 032 was synthesized.

[0272] 11H NMR: (400 MHz, DMSO-d6) δ 9.63 - 9.17 (m, 1H), 7.46 - 7.40 (m, 1H), 7.40 - 7.37 (m, 1H), 7.12 - 7.07 (m, 1H), 6.77 - 6.69 (m, 3H), 6.67 - 6.58 (m, 3H), 6.57 - 6.48 (m, 3H), 3.93 - 3.85 (m, 2H), 3.32 - 3.28 (m, 2H), 3.05 - 2.97 (m, 3H), 2.88 - 2.83 (m, 3H), 2.81 - 2.75 (m, 2H), 2.74 - 2.69 (m, 2H), 2.57 - 2.54 (m, 3H), 2.33 - 2.26 (m, 2H), 1.99 (br s, 3H); LCMS: (ESI+) m / z 538.4 (M + H) + 。

[0273] Preparation of Compound 033 in Example 22

[0274]

[0275] Referring to Example 1, a white solid compound 033 was synthesized.

[0276] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.32 (d, J = 6.0 Hz, 2H), 7.09 (d, J = 6.0 Hz, 2H), 6.79 - 6.73 (m, 2H), 6.72 - 6.67 (m, 3H), 6.66 - 6.58 (m, 1H), 6.56 (s, 2H), 6.54 - 6.48 (m, 1H), 3.93 (t, J = 5.5 Hz, 2H), 3.01 (s, 3H), 2.85 (s, 3H), 2.81 (br t, J = 5.5 Hz, 2H), 2.67 (br t, J = 6.0 Hz, 2H), 2.53 - 2.52 (m, 2H), 2.27 (br t, J = 6.8 Hz, 2H), 2.04 (br t, J = 6.8 Hz, 2H); LCMS: (ESI+) m / z 484.3 (M + H) + 。

[0277] Preparation of Compound 034 in Example 23

[0278]

[0279] Referring to Example 1, a white solid compound 034 was synthesized.

[0280] 11H NMR: (400 MHz, DMSO-d6) δ 8.61 - 8.51 (m, 2H), 8.43 (d, J = 8.3 Hz, 1H), 7.88 (dd, J = 5.9, 8.1 Hz, 1H), 6.96 - 6.86 (m, 5H), 6.78 (d, J = 2.3 Hz, 1H), 6.69 (td, J = 6.8, 15.1 Hz, 1H), 6.66 - 6.62 (m, 1H), 6.62 - 6.57 (m, 1H), 4.32 - 4.19 (m, 2H), 3.94 (d, J = 6.6 Hz, 2H), 3.47 (t, J = 4.7 Hz, 2H), 3.16 (s, 3H), 3.01 (s, 3H), 2.82 (br t, J = 7.0 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 2.23 (br t, J = 6.9 Hz, 2H); LCMS: (ESI+) m / z 484.2 (M + H) + 。

[0281] Preparation of Compound 035 in Example 24

[0282]

[0283] Referring to Example 1, a white solid compound 035 was synthesized.

[0284] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.14 - 9.02 (m, 2H), 7.06 - 7.00 (m, 1H), 6.97 - 6.92 (m, 1H), 6.89 - 6.82 (m, 1H), 6.78 - 6.68 (m, 6H), 6.66 - 6.59 (m, 1H), 6.56 (s, 2H), 4.17 - 4.09 (m, 2H), 3.86 - 3.77 (m, 2H), 3.41 - 3.36 (m, 2H), 3.31 - 3.26 (m, 3H), 2.80 - 2.67 (m, 2H), 2.19 - 2.11 (m, 5H), 2.10 - 2.01 (m, 2H), 1.14 - 1.08 (m, 3H), 1.06 - 0.99 (m, 3H); LCMS: (ESI+) m / z 543.5 (M + H) + 。

[0285] Preparation of Compound 036 in Example 25

[0286]

[0287] Referring to Example 1, a white solid compound 036 was synthesized.

[0288] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.10 (br s, 2H), 7.07 - 7.01 (m, 1H), 6.98 - 6.93 (m, 1H), 6.89 - 6.84 (m, 1H), 6.74 - 6.69 (m, 4H), 6.65 - 6.61 (m, 2H), 6.59 - 6.54 (m, 2H), 4.18 - 4.10 (m, 2H), 3.87 - 3.79 (m, 2H), 3.54 - 3.48 (m, 2H), 3.29 (br s, 3H), 2.70 (br s, 2H), 2.20 - 2.03 (m, 8H), 1.94 - 1.87 (m, 2H), 1.83 - 1.75 (m, 2H); LCMS: (ESI+) m / z 541.5 (M + H) + 。

[0289] Preparation of Compound 037 in Example 26

[0290]

[0291] Referring to Example 1, a white solid compound 037 was synthesized.

[0292] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.47 (br s, 1H), 7.37 (dd, J = 2.6, 8.9 Hz, 1H), 7.16 (dd, J = 6.4, 8.4 Hz, 1H), 7.09 - 6.97 (m, 1H), 6.74 (s, 1H), 6.71 (s, 2H), 6.67 (s, 2H), 6.65 - 6.61 (m, 1H), 6.55 (d, J = 1.0 Hz, 2H), 6.44 (d, J = 15.1 Hz, 1H), 3.90 (br t, J = 5.6 Hz, 2H), 3.33 (br d, J = 4.1 Hz, 2H), 3.31 - 3.27 (m, 2H), 2.84 - 2.78 (m, 2H), 2.78 - 2.68 (m, 2H), 2.52 (br s, 2H), 2.21 - 2.13 (m, 2H), 2.07 (br d, J = 2.9 Hz, 3H), 1.07 (br t, J = 7.0 Hz, 3H), 1.02 (br t, J = 7.0 Hz, 3H); LCMS: (ESI+) m / z 563.5 (M + H) + 。

[0293] Preparation of Compound 038 in Example 27

[0294]

[0295] The white solid compound 038 was synthesized with reference to Example 1.

[0296] 1 H NMR: (400 MHz, DMSO-d6) δ 9.58 - 9.49 (m, 1H), 7.73 - 7.64 (m, 1H), 7.35 - 7.25 (m, 1H), 7.16 - 7.06 (m, 1H), 6.79 - 6.71 (m, 5H), 6.67 - 6.60 (m, 1H), 6.59 - 6.50 (m, 3H), 4.00 - 3.91 (m, 2H), 3.05 - 2.98 (m, 3H), 2.92 - 2.78 (m, 6H), 2.71 - 2.65 (m, 3H), 2.32 - 2.24 (m, 2H), 2.15 - 2.00 (m, 3H); LCMS: (ESI+) m / z 526.5 (M + H) + 。

[0297] Preparation of Compound 039 in Example 28

[0298]

[0299] The white solid compound 039 was synthesized with reference to Example 1.

[0300] 1 H NMR: (400 MHz, DMSO-d6) δ 9.76 - 9.12 (m, 2H), 7.28 - 7.21 (m, 2H), 7.19 - 7.13 (m, 2H), 6.89 - 6.69 (m, 6H), 6.65 - 6.50 (m, 3H), 4.24 - 4.12 (m, 2H), 3.87 - 3.76 (m, 2H), 3.31 - 3.22 (m, 2H), 3.10 - 3.00 (m, 3H), 2.91 - 2.84 (m, 3H), 2.72 - 2.64 (m, 2H), 2.31 - 2.22 (m, 2H), 2.11 - 2.00 (m, 2H); LCMS: (ESI+) m / z 567.5 (M + H) + 。

[0301] Preparation of Compound 040 in Example 29

[0302]

[0303] Compound 040 was synthesized with reference to Example 1.

[0304] 11H NMR: (400 MHz, MeOH-d4) δ 7.65 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 2.4, 8.8 Hz, 1H), 7.05 (dd, J = 6.0, 8.4 Hz, 1H), 6.93 - 6.85 (m, 3H), 6.81 - 6.75 (m, 2H), 6.72 - 6.60 (m, 3H), 4.61 - 4.53 (m, 2H), 3.92 (dd, J = 0.8, 6.6 Hz, 2H), 3.52 - 3.44 (m, 2H), 3.15 (s, 3H), 3.01 (s, 3H), 2.92 - 2.75 (m, 2H), 2.32 - 2.17 (m, 7H); LCMS: (ESI+) m / z 516.4 (M + H) + 。

[0305] Preparation of Compound 041 in Example 30

[0306]

[0307] Compound 041 was synthesized by referring to Example 1.

[0308] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.70 - 9.10 (m, 1H), 7.07 (dd, J = 6.3, 8.3 Hz, 1H), 7.00 - 6.85 (m, 2H), 6.77 - 6.68 (m, 2H), 6.67 - 6.55 (m, 3H), 6.55 - 6.48 (m, 1H), 6.33 - 6.24 (m, 2H), 3.95 - 3.86 (m, 2H), 3.07 - 2.98 (m, 3H), 2.89 - 2.84 (m, 3H), 2.83 - 2.75 (m, 4H), 2.72 (br s, 2H), 2.58 - 2.57 (m, 3H), 2.20 - 2.15 (m, 1H), 2.15 - 2.13 (m, 3H), 2.12 - 1.91 (m, 3H); LCMS: (ESI+) m / z 545.5 (M + H) + 。

[0309] Preparation of Compound 042 in Example 31

[0310]

[0311] Compound 042 was synthesized by referring to Example 1.

[0312] 11H NMR: (400 MHz, DMSO-d6) δ 11.02 - 10.87 (m, 1H), 9.16 - 8.99 (m, 2H), 7.36 - 7.31 (m, 1H), 7.27 - 7.22 (m, 1H), 7.18 - 7.12 (m, 1H), 6.91 - 6.73 (m, 5H), 6.72 - 6.65 (m, 3H), 6.62 - 6.53 (m, 3H), 6.32 - 6.22 (m, 1H), 4.16 - 4.08 (m, 2H), 3.85 - 3.79 (m, 2H), 3.28 - 3.23 (m, 2H), 3.06 - 3.02 (m, 3H), 2.90 - 2.86 (m, 3H), 2.72 (br d, J = 6.3 Hz, 2H), 2.34 - 2.31 (m, 2H), 2.11 - 2.02 (m, 2H); LCMS: (ESI+) m / z 522.2 (M + H) + 。

[0313] Preparation of Compound 043 in Example 32

[0314]

[0315] Compound 043 was synthesized with reference to Example 1.

[0316] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.46 - 9.36 (m, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.22 - 7.15 (m, 1H), 6.77 - 6.61 (s, 8H), 6.56 - 6.50 (m, 3H), 3.98 - 3.90 (m, 2H), 3.48 - 3.42 (m, 2H), 3.04 - 2.99 (m, 3H), 2.88 - 2.80 (m, 5H), 2.69 - 2.64 (m, 2H), 2.23 - 2.16 (m, 2H), 2.08 - 2.01 (m, 2H); LCMS: (ESI+) m / z 524.5 (M + H) + 。

[0317] Preparation of Compound 044 in Example 33

[0318]

[0319] Compound 044 was synthesized with reference to Example 1.

[0320] 11H NMR: (400 MHz, DMSO-d6) δ 9.49 - 9.40 (m, 2H), 9.31 (d, J = 1.1 Hz, 1H), 8.51 - 8.46 (m, 1H), 8.34 - 8.27 (m, 1H), 7.97 - 7.90 (m, 2H), 7.86 - 7.82 (m, 1H), 7.30 - 7.20 (m, 1H), 6.81 - 6.75 (m, 2H), 6.73 - 6.70 (m, 1H), 6.67 - 6.62 (m, 2H), 6.59 - 6.56 (m, 2H), 6.55 - 6.46 (m, 1H), 3.98 (br s, 2H), 2.96 (s, 3H), 2.90 - 2.82 (m, 3H), 2.81 - 2.75 (m, 2H), 2.74 - 2.67 (m, 2H), 2.36 - 2.33 (m, 2H), 2.10 - 2.04 (m, 2H); LCMS: (ESI+) m / z 540.5 (M + H) + 。

[0321] Preparation of Compound 045 in Example 34

[0322]

[0323] Compound 045 was synthesized with reference to Example 1.

[0324] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.28 (br s, 2H), 7.73 (d, J = 7.0 Hz, 1H), 7.30 (d, J = 9.6 Hz, 1H), 6.86 - 6.72 (m, 6H), 6.64 - 6.52 (m, 3H), 4.17 (br t, J = 4.6 Hz, 2H), 3.81 (br d, J = 5.5 Hz, 2H), 3.28 (br s, 2H), 3.05 (s, 3H), 2.88 (s, 3H), 2.84 - 2.71 (m, 2H), 2.17 (br d, J = 6.3 Hz, 2H), 2.13 - 2.04 (m, 2H)); LCMS: (ESI+) m / z 569.4 (M + H) + 。

[0325] Preparation of Compound 046 in Example 35

[0326]

[0327] Compound 046 was synthesized with reference to Example 1.

[0328] 11H NMR: (400 MHz, DMSO-d6) δ 9.56 - 9.27 (m, 1H), 7.27 - 7.09 (m, 2H), 6.97 - 6.87 (m, 1H), 6.79 - 6.49 (m, 9H), 4.02 - 3.85 (m, 2H), 3.31 - 3.13 (m, 2H), 3.06 - 2.96 (m, 3H), 2.90 - 2.77 (m, 5H), 2.72 - 2.63 (m, 2H), 2.29 - 2.20 (m, 2H), 2.10 - 1.99 (m, 2H); LCMS: (ESI+) m / z 563.5 (M + H) + 。

[0329] Preparation of Compound 047 in Example 36

[0330]

[0331] Compound 047 was synthesized with reference to Example 1.

[0332] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.53 - 9.02 (m, 3H), 7.64 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 1.4 Hz, 1H), 6.89 - 6.75 (m, 5H), 6.71 - 6.68 (m, 1H), 6.62 - 6.50 (m, 3H), 4.20 - 4.13 (m, 2H), 3.84 - 3.79 (m, 3H), 3.77 (s, 2H), 3.34 - 3.27 (m, 2H), 3.06 - 3.03 (m, 3H), 2.88 - 2.85 (m, 3H), 2.67 - 2.63 (m, 2H), 2.26 - 2.18 (m, 2H), 2.07 - 1.98 (m, 5H); LCMS: (ESI+) m / z 528.5 (M + H) + 。

[0333] Preparation of Compound 048 in Example 37

[0334]

[0335] Compound 048 was synthesized with reference to Example 1.

[0336] 11H NMR: (400 MHz, DMSO-d6) δ 9.61 - 9.39 (m, 1H), 9.29 - 9.09 (m, 2H), 7.74 - 7.65 (m, 1H), 7.51 - 7.41 (m, 1H), 6.98 - 6.75 (m, 5H), 6.74 - 6.70 (m, 1H), 6.66 - 6.52 (m, 3H), 4.24 - 4.16 (m, 2H), 3.89 - 3.79 (m, 5H), 3.33 - 3.27 (m, 2H), 3.08 - 3.03 (m, 3H), 2.91 - 2.87 (m, 3H), 2.64 (br s, 2H), 2.29 - 2.21 (m, 2H), 2.13 - 2.05 (m, 2H); LCMS: (ESI+) m / z 532.3 (M + H) + 。

[0337] Preparation of Compound 049 in Example 38

[0338]

[0339] Compound 049 was synthesized with reference to Example 1.

[0340] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.59 - 9.40 (m, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.16 (d, J = 1.3 Hz, 1H), 7.74 (s, 1H), 6.83 - 6.69 (m, 5H), 6.51 (s, 5H), 4.00 - 3.88 (m, 2H), 3.38 - 3.35 (m, 2H), 3.05 - 2.99 (m, 3H), 2.88 - 2.80 (m, 5H), 2.70 - 2.66 (m, 2H), 2.29 - 2.24 (m, 2H), 2.10 - 2.05 (m, 2H); LCMS: (ESI+) m / z 518.4 (M + H) + 。

[0341] Preparation of Compound 050 in Example 39

[0342]

[0343] Compound 050 was synthesized with reference to Example 1.

[0344] 11H NMR: (400 MHz, DMSO-d6) δ 9.52 (br s, 1H), 8.36 (d, J = 1.5 Hz, 1H), 8.24 (d, J = 4.6 Hz, 1H), 7.25 (dd, J = 5.2, 6.2 Hz, 1H), 6.77 - 6.72 (m, 3H), 6.71 - 6.66 (m, 2H), 6.60 (s, 1H), 6.58 (s, 2H), 6.54 - 6.48 (m, 1H), 3.92 (t, J = 5.6 Hz, 2H), 3.01 (s, 3H), 2.85 (s, 3H), 2.80 (t, J = 5.6 Hz, 2H), 2.70 (br t, J = 6.9 Hz, 2H), 2.52 (br s, 2H), 2.25 - 2.18 (m, 2H), 2.15 - 1.90 (m, 3H); LCMS: (ESI+) m / z 502.4 (M + H) + 。

[0345] Preparation of Compound 052 in Example 40

[0346]

[0347] Compound 052 was synthesized with reference to Example 1.

[0348] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.26 - 8.94 (m, 2H), 7.05 (dd, J = 6.3, 8.4 Hz, 1H), 6.98 (dd, J = 2.5, 10.1 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.84 - 6.77 (m, 2H), 6.75 - 6.68 (m, 2H), 6.64 - 6.54 (m, 3H), 4.24 (br d, J = 3.9 Hz, 2H), 3.88 (br d, J = 5.1 Hz, 2H), 3.04 (s, 3H), 2.88 (s, 3H), 2.83 - 2.69 (m, 2H), 2.52 - 2.52 (m, 2H), 2.17 (s, 3H), 2.14 (br s, 2H), 2.12 - 2.06 (m, 2H); LCMS: (ESI+) m / z 549.5 (M + H) + 。

[0349] Preparation of Compound 053 in Example 41

[0350]

[0351] Compound 053 was synthesized with reference to Example 1.

[0352] 1 H NMR: (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.23 - 8.89 (m, 2H), 7.06 (dd, J = 6.2, 8.4 Hz, 1H), 7.02 - 6.93 (m, 2H), 6.89 (dt, J = 2.8, 8.5 Hz, 1H), 6.81 (br d, J = 15.3 Hz, 1H), 6.74 (s, 1H), 6.62 - 6.54 (m, 5H), 4.23 (br s, 2H), 3.83 (br d, J = 5.5 Hz, 2H), 3.05 (s, 3H), 2.89 (s, 3H), 2.82 - 2.69 (m, 2H), 2.53 (br s, 2H), 2.18 (s, 3H), 2.14 (br d, J = 4.6 Hz, 2H), 2.13 - 2.07 (m, 2H); LCMS: (ESI+) m / z 533.4 (M + H) + 。

[0353] Preparation of Compound 054 in Example 42

[0354]

[0355] Compound 054 was synthesized with reference to Example 1.

[0356] 1 H NMR: (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.06 (br d, J = 1.3 Hz, 2H), 7.07 - 6.90 (m, 2H), 6.89 - 6.77 (m, 3H), 6.71 (s, 1H), 6.65 (dd, J = 2.3, 11.7 Hz, 1H), 6.62 - 6.55 (m, 2H), 6.54 (s, 2H), 4.15 (br d, J = 4.3 Hz, 2H), 3.81 (br d, J = 5.8 Hz, 2H), 3.28 (br s, 2H), 3.05 (s, 3H), 2.88 (s, 3H), 2.86 - 2.68 (m, 2H), 2.21 (br s, 3H), 2.19 - 2.09 (m, 4H); LCMS: (ESI+) m / z 533.3 (M + H) + 。

[0357] Preparation of Compound 055 in Example 43

[0358]

[0359] Compound 055 was synthesized with reference to Example 1.

[0360] 11H NMR: (400 MHz, DMSO-d6) δ 9.45 (br s, 3H), 7.05 - 6.82 (m, 3H), 6.82 - 6.67 (m, 3H), 6.66 - 6.57 (m, 1H), 6.57 - 6.42 (m, 2H), 6.41 - 6.21 (m, 2H), 4.17 (br t, J = 4.6 Hz, 2H), 3.80 (br d, J = 5.1 Hz, 2H), 3.56 - 3.43 (m, 3H), 3.25 (br s, 2H), 3.05 (s, 3H), 3.02 - 2.78 (m, 4H), 2.76 - 2.55 (m, 1H), 2.26 - 2.17 (m, 3H), 2.17 - 1.91 (m, 4H); LCMS: (ESI+) m / z 545.5 (M + H) + 。

[0361] Preparation of Compound 056 in Example 44

[0362]

[0363] Compound 056 was synthesized with reference to Example 1.

[0364] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.07 - 6.97 (m, 2H), 6.92 - 6.85 (m, 1H), 6.74 - 6.70 (m, 1H), 6.64 - 6.56 (m, 3H), 6.47 (s, 1H), 6.46 - 6.38 (m, 2H), 4.08 - 4.01 (m, 2H), 3.31 - 3.27 (m, 2H), 3.03 - 2.96 (m, 3H), 2.88 - 2.82 (m, 3H), 2.79 - 2.63 (m, 4H), 2.18 - 2.05 (m, 7H); LCMS: (ESI+) m / z 551.5 (M + H) + 。

[0365] Preparation of Compound 057 in Example 45

[0366]

[0367] Compound 057 was synthesized with reference to Example 1.

[0368] 11H NMR: (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.07 - 6.92 (m, 2H), 6.82 - 6.71 (m, 4H), 6.69 (d, J = 1.6 Hz, 1H), 6.67 - 6.58 (m, 1H), 6.58 - 6.48 (m, 3H), 4.05 (q, J = 7.0 Hz, 2H), 3.95 (t, J = 5.6 Hz, 2H), 3.01 (s, 3H), 2.85 (s, 3H), 2.82 (br t, J = 5.6 Hz, 2H), 2.70 - 2.64 (m, 2H), 2.52 (br d, J = 1.9 Hz, 2H), 2.27 - 2.20 (m, 2H), 2.10 - 2.01 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H); LCMS: (ESI+) m / z 579.4 (M + H) + 。

[0369] Preparation of Compound 059 in Example 46

[0370]

[0371] Compound 059 was synthesized with reference to Example 1.

[0372] 1 1H NMR: (400 MHz, DMSO-d6) δ 9.54 - 9.44 (m, 1H), 7.72 - 7.62 (m, 1H), 6.85 (br t, J = 7.6 Hz, 3H), 6.74 - 6.70 (m, 1H), 6.65 - 6.47 (m, 5H), 4.22 - 4.13 (m, 2H), 3.32 (br d, J = 5.0 Hz, 3H), 3.03 - 2.97 (m, 3H), 2.72 (br d, J = 5.8 Hz, 7H), 2.26 - 2.09 (m, 6H); LCMS: (ESI+) m / z 534.5 (M + H) + 。

[0373] Preparation of Compound 060 in Example 47

[0374]

[0375] Compound 060 was synthesized with reference to Example 1.

[0376] 11H NMR: (400 MHz, DMSO-d6) δ 9.52 - 9.39 (m, 1H), 7.78 - 7.67 (m, 1H), 7.28 - 7.00 (m, 1H), 6.79 (dt, J = 2.4, 8.5 Hz, 3H), 6.73 - 6.70 (m, 1H), 6.65 - 6.57 (m, 1H), 6.56 - 6.47 (m, 3H), 4.24 - 4.12 (m, 2H), 3.31 (br s, 3H), 2.95 (br s, 4H), 2.89 (br s, 3H), 2.81 - 2.74 (m, 2H), 2.68 - 2.57 (m, 1H), 2.35 - 2.24 (m, 3H), 2.21 - 2.06 (m, 4H); LCMS: (ESI+) m / z 550.4 (M + H) + 。

[0377] Preparation of Compound 062 in Example 48

[0378]

[0379] Compound 062 was synthesized with reference to Example 1.

[0380] 1 1H NMR: (400 MHz, DMSO-d6) δ 7.01 (dd, J = 6.1, 8.3 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.88 - 6.49 (m, 9H), 4.01 (br t, J = 4.8 Hz, 2H), 3.47 (d, J = 5.6 Hz, 2H), 3.29 - 3.14 (m, 1H), 3.12 (s, 3H), 3.06 - 2.94 (m, 5H), 2.78 - 2.57 (m, 1H), 2.42 - 2.10 (m, 7H); LCMS: (ESI+) m / z 549.2 (M + H) + 。

[0381] Preparation of Compound 063 in Example 49

[0382]

[0383] Compound 063 was synthesized with reference to Example 1.

[0384] 11H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.50 (s, 1H), 7.44–7.39 (m, 1H), 7.27 (d, J = 7.9 Hz, 1H), 6.75 (t, J = 1.4 Hz, 1H), 6.73–6.65 (m, 4H), 6.65–6.51 (m, 4H), 3.93 (t, J = 5.6 Hz, 2H), 3.03 (s, 3H), 2.88 (s, 3H), 2.82 (t, J = 5.5 Hz, 2H), 2.80–2.71 (m, 2H), 2.26 (s, 3H), 2.19 (t, J = 5.9 Hz, 2H), 2.11 (d, J = 6.7 Hz, 2H), 1.27 (s, 2H). LCMS: (ESI+) m / z 565.5 (M+H) + 。

[0385] Preparation of Compound 064 in Example 50

[0386]

[0387] Compound 064 was synthesized with reference to Example 1.

[0388] 1 1H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.95 (d, J = 5.3 Hz, 1H), 7.09 (d, J = 5.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 2H), 6.88–6.80 (m, 4H), 6.78 (d, J = 3.3 Hz, 2H), 6.67 (d, J = 8.3 Hz, 1H), 6.65–6.60 (m, 1H), 4.19 (t, J = 5.0 Hz, 2H), 3.74 (t, J = 2.3 Hz, 2H), 3.26 (t, J = 5.1 Hz, 2H), 3.18 (s, 3H), 3.04 (s, 3H), 2.79 (t, J = 7.1 Hz, 2H), 2.44 (t, J = 7.0 Hz, 2H), 2.20 (d, J = 8.0 Hz, 2H). LCMS: (ESI+) m / z 502.5 (M+H) + 。

[0389] Preparation of Compound 065 in Example 51

[0390]

[0391] Compound 065 was synthesized with reference to Example 1.

[0392] 11H NMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.31–8.15 (m, 2H), 7.17 (d, J = 5.1 Hz, 1H), 6.85–6.60 (m, 9H), 4.11 (t, J = 5.1 Hz, 2H), 3.65 (d, J = 5.5 Hz, 2H), 3.16 (d, J = 4.1 Hz, 5H), 3.03 (s, 3H), 2.86 (t, J = 7.1 Hz, 2H), 2.32 (d, J = 7.1 Hz, 2H), 2.19 (s, 5H). LCMS: (ESI+) m / z 498.6 (M+H) + 。

[0393] Preparation of Compound 066 in Example 52

[0394]

[0395] Compound 066 was synthesized with reference to Example 1.

[0396] 1 1H NMR (400 MHz, Methanol-d4) δ 7.41 (dd, J = 9.4, 2.8 Hz, 1H), 7.15 (dt, J = 19.5, 5.2 Hz, 2H), 6.95–6.47 (m, 9H), 4.03 (t, J = 5.0 Hz, 2H), 3.50 (d, J = 5.7 Hz, 2H), 3.14 (s, 3H), 3.01 (s, 3H), 2.98 (d, J = 5.5 Hz, 2H), 2.72 (d, J = 12.6 Hz, 2H), 2.36–2.12 (m, 4H). LCMS: (ESI+) m / z 569.5 (M+H) + 。

[0397] Preparation of Compound 067 in Example 53

[0398]

[0399] Compound 067 was synthesized with reference to Example 1.

[0400] 11H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.73 (d, J = 10.6 Hz, 1H), 7.39–7.01 (m, 3H), 6.97 (dd, J = 8.5, 1.9 Hz, 1H), 6.72 (d, J = 2.2 Hz, 1H), 6.65–6.55 (m, 4H), 6.51 (d, J = 15.2 Hz, 1H), 4.23 (t, J = 5.7 Hz, 2H), 3.40 - 3.30 (m, 3H), 3.01 (s, 3H), 2.85 (s, 3H), 2.81 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 7.0 Hz, 2H), 2.30 (t, J = 7.0 Hz, 2H), 2.17–2.08 (m, 2H). LCMS: (ESI+) m / z 586.5 (M+H) + 。

[0401] Preparation of Compound 068 in Example 54

[0402]

[0403] Compound 068 was synthesized with reference to Example 1.

[0404] 1 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.68 (d, J = 10.7 Hz, 1H), 7.51 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.64–6.53 (m, 4H), 6.50 (d, J = 15.2 Hz, 1H), 4.18 (t, J = 5.7 Hz, 2H), 3.31 (s, 2H), 3.30 (s, 2H), 3.00 (s, 3H), 2.85 (s, 3H), 2.78 (t, J = 5.7 Hz, 2H), 2.30 (s, 3H), 2.22 (t, J = 5.6 Hz, 2H), 2.14 (t, J = 6.3 Hz, 2H). LCMS: (ESI+) m / z 584.5 (M+H) + 。

[0405] Preparation of Compound 069 in Example 55

[0406]

[0407] Compound 069 was synthesized with reference to Example 1.

[0408] 11H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.72 (d, J = 10.6 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.91 (dd, J = 8.3, 1.7 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 6.62–6.55 (m, 4H), 6.54–6.48 (m, 1H), 4.22 (t, J = 5.7 Hz, 2H), 3.28 (s, 2H), 3.01 (s, 3H), 2.85 (s, 3H), 2.80 (t, J = 5.7 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.33–2.26 (m, 2H), 2.12 (t, J = 7.0 Hz, 2H). LCMS: (ESI+) m / z 582.5 (M+H) + 。

[0409] Preparation of Compound 070 in Example 56

[0410]

[0411] Compound 070 was synthesized with reference to Example 1.

[0412] 1 1H NMR (400 MHz, DMSO-d6) 8.23 (s, 1H), 7.68 (d, J = 10.6 Hz, 1H), 7.59 (dd, J = 9.3, 2.7 Hz, 1H), 7.40 (td, J = 8.3, 2.7 Hz, 1H), 7.34 (d, J = 6.8 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.65–6.48 (m, 5H), 4.19 (t, J = 5.8 Hz, 2H), 3.32 (d, J = 1.5 Hz, 3H), 3.00 (s, 3H), 2.85 (s, 3H), 2.79 (t, J = 5.7 Hz, 2H), 2.70 (dt, J = 12.0, 5.0 Hz, 1H), 2.30–2.11 (m, 4H). LCMS: (ESI+) m / z 588.5 (M+H) + 。

[0413] Preparation of Compound 071 in Example 57

[0414]

[0415] Compound 071 was synthesized with reference to Example 1.

[0416] 11H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.25 (s, 1H), 7.87 (dd, J = 8.1, 2.1 Hz, 1H), 7.81–7.72 (m, 2H), 6.75 (d, J = 2.3 Hz, 1H), 6.66–6.57 (m, 4H), 6.51 (dt, J = 15.1, 1.5 Hz, 1H), 4.22 (t, J = 5.7 Hz, 2H), 3.25 - 3.10 (m, 2H), 3.01 (s, 3H), 2.85 (s, 3H), 2.81 (t, J = 5.8 Hz, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.37 (t, J = 7.0 Hz, 2H), 2.15 (t, J = 7.0 Hz, 2H). LCMS: (ESI+) m / z 571.4 (M + H) + 。

[0417] Preparation of Compound 072 in Example 58

[0418]

[0419] Compound 072 was synthesized with reference to Example 1.

[0420] 1 1H NMR (400 MHz, Methanol-d4) δ 7.41 (d, J = 2.0 Hz, 1H), 7.13–7.03 (m, 1H), 6.93 (dd, J = 11.6, 2.1 Hz, 2H), 6.87–6.74 (m, 3H), 6.74–6.61 (m, 3H), 4.47 (t, J = 5.4 Hz, 2H), 3.66–3.55 (m, 2H), 3.14 (d, J = 13.8 Hz, 5H), 3.03 (s, 3H), 2.93–2.77 (m, 2H), 2.37–2.27 (m, 5H), 2.22 (t, J = 6.8 Hz, 2H). LCMS: (ESI+) m / z 534.5 (M + H) + 。

[0421] Preparation of Compound 073 in Example 59

[0422]

[0423] Compound 073 was synthesized with reference to Example 1.

[0424] 11H NMR (400 MHz, Methanol-d4) δ 7.48 (d, J = 1.8 Hz, 1H), 7.01 (m, 2H), 6.99 (s, 1H), 6.97 (m, 1H), 6.73 (m, 1H), 6.66 (s, 1H), 6.64 (m, 1H), 6.58 (m, 1H), 6.35 (m, 1H), 3.69 (m, 3H), 3.68–3.63 (m, 2H), 3.59 (s, 3H), 3.52 (m, 1H), 3.16 (m, 3H), 3.09 (m, 2H), 3.03 m, 3H), 2.46–2.35 (m, 2H), 2.22 (m, 2H). LCMS: (ESI+) m / z 594.2 (M+H) + 。

[0425] Biological Activity Evaluation

[0426] The inhibitory ability of the compounds of the present invention to selectively inhibit estrogen receptor activity and the anti-proliferative activity against the human breast cancer cell line MCF-7 cell line of estrogen receptor wild type, Y537S and D538G mutants can be demonstrated by the tests in the following experiments described herein.

[0427] This experiment is based on the principle of nuclear receptor (NR) agonist-dependent co-activator peptide recruitment reaction: Tb is labeled on NR through antigen-antibody reaction. The binding of Agonist to NR leads to a conformational change, which in turn leads to an increase in the affinity between NR and the co-activator peptide. When the co-activator peptide (FITC) and NR (Tb) approach each other, a FRET signal is generated. Based on the above reaction, the inhibitory activity of the compounds in this application against ERα protein is evaluated.

[0428] Add 5 μL of the test compound and 10 nM of ERα protein (5 μL) to a 384-well plate respectively. Starting from 10 μM of the compound, it is diluted 5-fold, with 9 concentration points and three replicates, and control wells and blank wells are set. No compound is added to the control wells, and no protein is added to the blank wells. The final concentration of DMSO is 1%. After reacting at room temperature for 15 min, add 1 test Tb antibody and 500 nM polypeptide, 5 μL each. After mixing the system, react at room temperature for 24 h and read the TR-FRET value. Excitation at 334 nm, emission at 492 nm; excitation at 334 nm, emission at 520 nm; delay 200 μs, integration 100 μs. Then calculate the inhibition rate at each concentration, IC 50 Obtained by fitting with GraphPad Prism 7.0 software.

[0429] Table 1 Inhibitory activity of test compounds against ERα protein (IC 50 )

[0430]

[0431]

[0432] In the above list, the activity less than *** is expressed as <10 nM; ** is expressed as >10 nM and <100 nM; * is expressed as >100 nM.

[0433] The CCK8 method was used to evaluate the anti-proliferative activity of the test compounds against the stably transfected monoclonal cell lines of human breast cancer cell line MCF-7-ERα (WT, Y537S, D538G) point mutations. The above-mentioned cells with normal growth were digested with trypsin cell digestive solution, centrifuged, counted, and seeded into 96-well plates at a cell density of 5000 cells / well, 100 μL per well. The next day after cell seeding, drugs were administered, and different concentration gradients of the compounds were added to each well. Three replicates were set for each concentration point, and a corresponding DMSO negative control group was also set. After 72 h of drug treatment, CCK8 solution was added to each well. After incubation at 37 °C for a period of time (the OD450 of the Vehicle group reached above 1.0), the absorption at 450 nm of the microplate reader was read, the inhibition rate was calculated, and the IC50 value was obtained by fitting with GraphPad Prism 7.0 software.

[0434] Table 2 Proliferation inhibition activity of the test compounds against MCF-7-ERα / WT cell line (IC 50 )

[0435]

[0436]

[0437] In the above list, ND indicates not tested; the activity less than *** is expressed as <10 nM; ** is expressed as >10 nM and <100 nM; * is expressed as >100 nM.

[0438] It should be understood that the above embodiments are all exemplary and do not cover all possible implementation manners included in the claims. Without departing from the scope of the present disclosure, various deformations and changes can be made based on the above embodiments. Similarly, any combination of the technical features of the above embodiments can be made to form additional embodiments of the present invention that may not be clearly described. Therefore, the above embodiments only represent several implementation manners of the present invention and do not limit the protection scope of the present invention patent.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, the structure of the compound of formula (I) being: Wherein, Each R 1 is independently selected from -H, D, -OH, -NH2, -COOH, -CH2NH2, and -CH2OH; R 2 Selected from substituted or unsubstituted phenyl, 3- to 9-membered heterocyclic groups, and 5- to 10-membered heteroaryl groups, wherein the substitution is by one or more substituents selected from C 1-6 alkyl groups, halogen atoms, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C 1-6 alkoxy groups, C 1-6 alkylamino groups, and the above substituents are optionally substituted by 1 to 3 substituents selected from C 1-6 alkyl groups, halogen atoms, -NH2, -CN, -COOH, -CHO, -OH, -NO2; The 3- to 9-membered heterocyclic group is selected from any one of 2,3-dihydro-1H-indolyl and benzodioxolyl; The 5- to 10-membered heteroaryl group is selected from any one of thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzopyrazole, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl or indolo[1,2-a]pyrazinyl; R 3 selected from -(CH2) p CH=CHCONR 4 R 5 , wherein, R 4 , R 5 are each independently selected from -H and C 1-3 alkyl; or R 4 together with R 5 and the attached nitrogen atom form a pyrrolidinyl or piperidinyl group; p is selected from 1 and 2; Z is selected from O and S; Y is selected from -(CR 9 R 10 ) q NH-, wherein, Each R 9 and R 10 are each independently selected from -H, a halogen atom, C 1-3 alkyl; q is selected from 1, 2, 3, 4 and 5; Selected from substituted or unsubstituted phenyl and pyridyl, where the substitution is by a substituent selected from halogen atoms and C 1-3 alkoxy; m is selected from 1, 2, 3 and 4.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein The 5- to 10-membered heteroaryl group is selected from any one of pyridyl, indolyl, benzothiazolyl, benzopyrazole, benzoxazolyl and benzisoxazolyl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 Selected from -(CH2) p CH=CHCONR 4 R 5 , wherein, R 4 , R 5 are independently selected from -H, C 1-3 Alkyl; or R 4 With R 5 and the attached nitrogen atom forms a pyrrolidinyl or piperidinyl group; p is 1.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is selected from -(CR 9 R 10 ) q NH-, wherein, Each R 9 and R 10 are each independently selected from -H, a halogen atom, C 1-3 alkyl; q is selected from 1, 2 and 3.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein q is 2.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The structure of the compound is as shown in formula II: Wherein, R 1 independently selected from -H, -OH and -NH2; R 2 selected from substituted or unsubstituted phenyl, 5- to 10-membered heteroaryl; said substitution is by a substituent selected from halogen, cyano, C 1-3 alkoxy, halogen-substituted C 1-3 alkoxy; The 5- to 10-membered heteroaryl group is selected from any one of thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzopyrazole, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl or indolo[1,2-a]pyrazinyl; R 3 selected from -CH2CH=CHCONR 4 R 5 , wherein, R 4 , R 5 are each independently selected from -H and C 1-3 alkyl; or R 4 together with R 5 and the attached nitrogen atom form a pyrrolidinyl or piperidinyl group; Z is selected from O and S; Y is selected from -(CR 9 R 10 ) q NH-, wherein, Each R 9 and R 10 are each independently selected from -H, a halogen atom, C 1-3 alkyl; q is 2; Selected from substituted or unsubstituted phenyl and pyridyl, wherein the substitution is by a substituent selected from halogen atoms and C 1-3 alkoxy groups.

7. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from:

8. A pharmaceutical composition comprising the compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof.

9. Use of the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the manufacture of a medicament for preventing and / or treating estrogen receptor-mediated or -dependent diseases and disorders.

10. A combined form of medicament comprising the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, and at least one additional therapeutic agent.

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