Quinoline compounds and uses thereof

Abstract

The present invention relates to a quinoline derivative (I) which can be used as an inhibitor of lactate dehydrogenase, a preparation method and use thereof, and also relates to a pharmaceutical composition comprising the quinoline derivative.

Description

[0001] Related Applications

[0002] The present invention claims priority to a prior application with application number 202210083662.4, filed with the State Intellectual Property Office of China on January 21, 2022, entitled “Fluoro-substituted quinoline compounds as inhibitors of lactate dehydrogenase and uses thereof”. The entire text of the prior application is incorporated into the present application by reference. Technical Field

[0003] The present invention relates to quinoline derivatives which can be used as inhibitors of lactate dehydrogenase, and preparation methods and uses thereof, and also relates to pharmaceutical compositions containing the quinoline derivatives. Background Art

[0004] Lactate dehydrogenase (LDH) is a tetramer that belongs to the 2-hydroxyacid oxidoreductase family. It can increase the rate of conversion of pyruvate to lactate and nicotinamide adenine dinucleotide (NAD)H to NAD+. It is usually used by cells for anaerobic respiration and is therefore one of the important rate-limiting enzymes in the glucose metabolism pathway. The two different subunits of lactate dehydrogenase are encoded by two independent genes, namely LDHA and LDHB. LDHA, also known as the M subunit, is mainly found in skeletal muscle; LDHB, also known as the H subunit, is mainly found in the heart. Since LDH is a tetramer, LDH can also be composed of five isoenzymes through M and H subunits: LDH-1 (4H, mainly found in the heart), LDH-2 (3H, 1M, mainly found in the reticuloendothelial system), LDH-3 (2H, 2M, mainly found in the lungs), LDH-4 (1H, 3M, mainly found in the kidneys) and LDH-5 (4M, mainly found in the liver and striated muscle).

[0005] One of the important characteristics of tumor cell energy metabolism is the Warburg effect, that is, under normal oxygen content, glucose metabolism gradually becomes dominated by glycolysis, in which glucose is converted into lactate and produces adenosine triphosphate (ATP). Therefore, the Warburg effect suggests that tumor cells switch from oxidative phosphorylation to glycolysis in the use of glucose, which not only enhances glycolysis, but also inhibits mitochondrial oxidative phosphorylation.

[0006] By inhibiting LDHA and inhibiting or regulating the expression of LDHB, it is expected to inhibit the energy metabolism, proliferation or invasion of tumor cells, and may reduce the drug resistance of tumor cells. Therefore, there is an urgent need in the art to obtain drugs targeting lactate dehydrogenase. Summary of the invention

[0007] In view of the deficiencies in the prior art and / or the needs in the art, the object of the present invention is to provide a compound or its derivatives that can be used as an inhibitor of lactate dehydrogenase and related pharmaceutical compositions. This object is achieved through the subject matter described in the following various aspects of this application.

[0008] In a first aspect, the present invention provides a compound of formula (I) or a physiologically / pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, a racemate, a nitrogen oxide, a solvate, an isotope-labeled substance, a prodrug or a metabolite thereof:

[0009]

[0010] in,

[0011] Cy1 represents unsubstituted or optionally substituted with one, two or more R a Substituted C 3-20 Cycloalkyl, 3-14 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl,

[0012] R a can be independently selected from the following groups: carboxyl, aminocarbonyl, C 1-12 Alkyl, halogen, nitro, cyano, hydroxyl, -CO-C 1-12 Alkoxy, C 1-12 Alkoxy, -OC 3-20 Cycloalkyl, -O-3-14 membered heterocyclic group, -OC 6-20 Aryl, hydroxyaminocarbonyl, 3-14 membered heterocyclic group, 5-20 membered heteroaryl, C 1-12 Alkylsulfonyl, C 1-12 Alkylsulfonylaminocarbonyl, where R a It may be optionally further substituted with oxo or with hydroxyl, halogen, C 3-20 Cycloalkyl or 3-14 membered heterocyclic group,

[0013] Cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted 3-20 membered heterocyclic group or C 6-20 Aryl or 5-20 membered heteroaryl,

[0014] R b can be independently selected from C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Haloalkoxy, halogen, aminocarbonyl, cyano, nitro, C 1-12 Alkoxycarbonyl and / or oxo.

[0015] R1 and R 2 can be independently selected from the following groups: hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Alkylamino, C 3-20 Cycloalkyl, C 3-20 Cycloalkyl C 1-12 Alkyl, C 1-12 Halogenated alkyl C 3-20 Cycloalkyl, C 3-20 Halogenated cycloalkyl, C 6-20 Aryl, 3-14 membered heterocyclic group, C 6-20 Aryl-C 1-12 Alkyl, C 1-12 Alkoxy C 1-12 Alkyl, cyano C 1-12 Alkyl; or, R 1 and R 2 Together with the nitrogen atom to which it is attached, it may form a 3- to 14-membered heterocyclic group optionally substituted by halogen or oxo, or a 5- to 20-membered heteroaryl group optionally substituted by halogen.

[0016] In some embodiments according to the present invention, Cy1 represents unsubstituted or optionally substituted with one, two or more R a Substituted C 3-12 Cycloalkyl or 3-14 membered heterocyclic group or C 6-14 Preferably, R a can be independently selected from carboxyl, aminocarbonyl, C 1-6 Alkyl, halogen, nitro, cyano, hydroxyl, -CO-C 1-12 Alkoxy, C 1-6 Alkoxy, -OC 3-12 Cycloalkyl, -OC 3-12 Heterocyclic group, -OC 6-14 Aryl, hydroxyaminocarbonyl, 3-14 membered heterocyclic group, 5-14 membered heteroaryl, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylaminocarbonyl, -SO3H or -SO3-C 1-6 Alkyl, where R a It may be optionally further substituted with oxo or with hydroxyl, halogen, C 3-12 The cycloalkyl or 3-14 membered heterocyclic group is substituted.

[0017] Preferably, Cy1 represents unsubstituted or optionally substituted with one, two or more R aSubstituted phenyl, naphthyl, pyridinyl, pyrimidinyl, thiazolyl, imidazolyl, furanyl, thienyl, pyrazolyl, pyrrolyl, thiadiazolyl, bicyclo[2.2.1]heptyl, cyclohexyl, chromanyl.

[0018] Preferably, R a can be independently selected from carboxyl, aminocarbonyl, C 1-6 Alkyl, halogen, nitro, cyano, hydroxyl, -CO-C 1-12 Alkoxy, C 1-6 Alkoxy, -OC 3-12 Cycloalkyl, -OC 3-12 Heterocyclic group, -OC 6-14 aryl, hydroxyaminocarbonyl, 5- or 6-membered heterocyclic group, 5- or 6-membered heteroaryl, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylaminocarbonyl, -SO3H or -SO3-C 1-6 Alkyl, where R a It may optionally be further substituted by oxo or by hydroxy, fluoro, chloro, bromo, oxetanyl or cyclobutyl.

[0019] More preferably, Cy1 represents unsubstituted or optionally substituted with one, two or more R a Substituted phenyl, pyridyl, thiazolyl, bicyclo[2.2.1]heptyl, cyclohexyl, chromanyl.

[0020] More preferably, R a are independently selected from the group consisting of carboxyl, difluorophenoxy, difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2H-tetrahydropyranyl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazolyl, morpholinyl, morpholinylmethyl, methylsulfonyl, methylsulfonylaminocarbonyl, 2-hydroxy-3,4-dioxocyclobutane, 1-hydroxy-2,2,2-trifluoroethyl, cyclobutyl, oxetanyl, oxetanylpiperidinyloxy, oxetanylpiperazinyl, cyclobutylpiperidinyloxy, hydroxydioxocyclobutyl and / or hydroxyisoxazolyl.

[0021] Still more preferably, Cy1 represents one, two or more R a Substituted phenyl, pyridin-2-yl, thiazol-2-yl, bicyclo[2.2.1]hept-1-yl, cyclohexyl or chromanyl.

[0022] Still more preferably, R aindependently selected from carboxyl, 3,5-difluorophenoxy, 4,4-difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2H-tetrahydropyran-4-yl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazol-5-yl, morpholin-4-yl, morpholin-4-ylmethyl, methylsulfonyl 1-(oxetane-3-yl)piperidin-4-yloxy, 4-(oxetane-3-yl)piperazin-1-yl, 1-cyclobutylpiperidin-4-yloxy, 2-hydroxy-3,4-dioxocyclobutyl and / or 3-hydroxyisoxazol-5-yl.

[0023] Most preferably, Cy1 has the following structure:

[0024]

[0025] In some embodiments according to the present invention, Cy1 can also be selected from the following structures:

[0026]

[0027]

[0028] In some embodiments according to the present invention, Cy1 is replaced by one or two R a Substitution; preferably, Cy1 is substituted with at least one carboxyl group.

[0029] In some embodiments according to the present invention, the compound of formula (I) has the structure of formula (IA), formula (IB), formula (IC) or formula (ID):

[0030]

[0031] Among them, R 1 , R 2 、Cy1、Cy2、R a , R b has the meanings defined in formula (I); h represents a number of 0, 1, 2 or 3, and i represents a number of 0, 1, 2 or 3.

[0032] In some embodiments according to the present invention, Cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted 3-14 membered heterocyclic group or C 6-14 Aryl or 5-14 membered heteroaryl.

[0033] Preferably, Cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy, phenylthio, phenylamino, pyrimidinyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridinyl, benzopyranyl, benzothiopyranyl, pyrazolopyrimidinyl, dihydrofuropyrimidinyl, furanopyrimidinyl, thiazolopyrimidinyl, imidazopyrimidinyl, dihydronaphthyridinyl or dihydrofuropyridinyl.

[0034] More preferably, Cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridinyl, benzopyranyl, pyrazolopyrimidinyl, dihydrofuropyrimidinyl, dihydropyridinyl, imidazopyrimidinyl, dihydronaphthyridinyl or dihydrofuropyridinyl.

[0035] Still more preferably, Cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridinyl, 4H-benzopyran-3-yl, 1H-pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydrofuro[3,2-c]pyrimidinyl, 1,2-dihydropyridinyl, imidazo[1,2-c]pyrimidinyl, 3,4-dihydro-1,5-naphthyridin-1(2H)-yl or 2,3-dihydrofuro[3,2-c]pyridin-7-yl.

[0036] Preferably, R b are independently selected from C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Haloalkyl, C 1-12 Haloalkoxy, halogen, aminocarbonyl, cyano, nitro, C 1-12 Alkoxycarbonyl and / or oxo.

[0037] More preferably, R b are independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, halogen, aminocarbonyl, cyano and / or oxo.

[0038] Still more preferably, R b are independently selected from the group consisting of methyl, ethyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, aminocarbonyl, cyano, oxo and / or 2,2-difluoroethoxy.

[0039] Most preferably, Cy2 has the following structure:

[0040]

[0041] In some embodiments according to the present invention, Cy2 can also be selected from the following structures:

[0042] In some embodiments according to the present invention, R 1 and R 2 can be independently selected from the following groups: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, C 1-6 Halogenated alkyl C 3-12 Cycloalkyl, C 3-12 Halogenated cycloalkyl, C 6-14 Aryl, 3-12 membered heterocyclic group, C 6-14 Aryl-C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl; or, R 1 and R 2 Together with the nitrogen atom to which it is attached, it may form a 3- to 12-membered heterocyclic group optionally substituted by halogen or oxo, or a 5- to 14-membered heteroaryl group optionally substituted by halogen.

[0043] Preferably, R 1 and R 2 can be independently selected from the following groups: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C 1-6 Halogenated alkyl C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, C 3-12 Halogenated cycloalkyl, C 6-14 Aryl, 3-12 membered heterocyclic group, C 6-14 Aryl-C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 Alkyl; or, R 1 and R 2 Together with the nitrogen atom to which it is attached, it may form a 3- to 8-membered heterocyclic group optionally substituted by halogen or oxo, or a 5- to 10-membered heteroaryl group optionally substituted by halogen.

[0044] More preferably, R 1and R 2 can be independently selected from the following groups: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, C 1-6 Halogenated alkyl C 3-12 Cycloalkyl, C 3-6 Halogenated cycloalkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or 5- or 6-membered heterocyclic group; or, R 1 and R 2 Together with the nitrogen atom to which it is attached, it may form a 3- to 6-membered heterocyclic group which may be optionally substituted by halogen or oxo.

[0045] Most preferably, R 1 and R 2 can be independently selected from the following groups: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C 1-6 Halogenated alkyl C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, 6-membered heterocyclic group or C 3-12 Halogenated cycloalkyl.

[0046] In some embodiments according to the present invention, R 1 and R 2 One of the groups represents hydrogen and the other represents hydrogen, cyclopropyl, 2,2,2-trifluoroethyl, methyl, propan-2-yl, tert-butyl, 1-trifluoromethyl-cyclopropyl-1-yl, 1-fluoro-cyclopropyl-1-yl, cyclobutyl, cyclopropylmethyl, cyanomethyl, tetrahydrofuran-3-yl, 2H-tetrahydropyran-4-yl, cyclohexyl, oxetan-3-yl or 2,2-difluorocyclopropyl-1-yl.

[0047] In some embodiments according to the present invention, there is also provided a compound of formula (IIA) or formula (IIB) or a physiologically / pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotope label, prodrug or metabolite thereof:

[0048]

[0049] Among them, R 1 , R 2 , Cy1, Cy2 and R aeach independently has a meaning as defined herein, X and Y are each independently selected from CH or N, m represents 0, 1, 2 or 3, and L represents -SO2- or -C(=O)-.

[0050] In some embodiments according to the present invention, there is also provided a compound of formula (IIC), (IID), (IIE) and (IIF) or a physiologically / pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotope label, prodrug or metabolite thereof:

[0051]

[0052] Among them, R 1 , R 2 , Cy1, Cy2 and R a Each independently has a meaning as defined herein, m represents 0, 1, 2 or 3, and L represents -SO2- or -C(=O)-.

[0053] In some embodiments according to the present invention, the compounds of Formula (I), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE) and (IIF) may be selected from the following compounds:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE), (IIF) as defined herein, or a salt or ester thereof, a stereoisomer or tautomer, a racemate, a nitrogen oxide, a solvate, an isotopically labeled prodrug or a metabolite thereof.

[0060] In some embodiments according to the present invention, the pharmaceutical composition according to the present invention may optionally further comprise at least one physiologically / pharmaceutically acceptable excipient.

[0061] In some embodiments according to the present invention, the pharmaceutical composition according to the present invention may also optionally include additional active ingredients. The additional active ingredients are, for example, anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; and cell cycle signal inhibitors.

[0062] In some embodiments according to the present invention, the pharmaceutical composition according to the present invention comprises a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF) or a salt or ester thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopically labeled, prodrugs or metabolites.

[0063] In some embodiments according to the present invention, the pharmaceutical composition according to the present invention is an inhibitor of lactate dehydrogenase.

[0064] In some embodiments according to the present invention, the pharmaceutical composition according to the present invention is used to prevent or treat a disease, condition, syndrome and / or disorder selected from the group consisting of, or to alleviate the symptoms of a disease, condition, syndrome and / or disorder selected from the group consisting of: autoimmune disease or cancer. Autoimmune diseases include, but are not limited to: systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, vitiligo, alopecia areata, etc. Examples of cancer include, but are not limited to, acute lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumors (gliomas), glioblastoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma and thyroid cancer, etc.

[0065] According to the present invention, the pharmaceutical composition according to the present invention can be prepared into a dosage form suitable for administration by methods known in the art.

[0066] In a third aspect, the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF) according to the present invention, or a salt or ester thereof, or a use of their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope-labeled, prodrugs or metabolites in the preparation of a medicament.

[0067] In some embodiments according to the present invention, the medicine may also optionally contain additional active ingredients. The additional active ingredients are, for example, anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; and cell cycle signal inhibitors.

[0068] In some embodiments of the present invention, the drug is an inhibitor of lactate dehydrogenase, and the purpose of the present invention is achieved by reducing the expression of LDHA and regulating the expression of LDHB.

[0069] In some embodiments according to the present invention, the drug is used to prevent or treat a disease, condition, syndrome and / or disorder selected from the group consisting of, or to alleviate the symptoms of a disease, condition, syndrome and / or disorder selected from the group consisting of: autoimmune disease or cancer. Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, vitiligo, alopecia areata, etc. Cancers include, but are not limited to: acute lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumor (glioma), glioblastoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma and thyroid cancer, etc.

[0070] According to the present invention, the drug can be further prepared into a dosage form suitable for administration by methods known in the art.

[0071] In a fourth aspect, the present invention provides a method for treating or preventing a disease, condition, syndrome and / or disorder of an autoimmune disease or cancer, the method comprising administering to an individual in need thereof a compound of Formula (A), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF) according to the present invention, or a salt or ester thereof, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopically labeled, prodrugs or metabolites.

[0072] In some embodiments according to the present invention, the diseases, conditions, syndromes and / or disorders of autoimmune diseases include: systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, vitiligo, alopecia areata, etc.

[0073] In some embodiments according to the present invention, the diseases, conditions, syndromes and / or disorders of cancer include: acute lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, etc., brain tumors (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcomas and thyroid cancer.

[0074] Those skilled in the art will understand that the features listed in various aspects and embodiments of the present invention may be freely combined as long as there is no conflict or incompatibility between them.

[0075] Beneficial Effects of the Invention

[0076] The invention provides a lactate dehydrogenase inhibitor with a quinoline structure, which has good biological activity and pharmacokinetic properties. DETAILED DESCRIPTION

[0077] The present invention is described in further detail below.

[0078] Unless otherwise specified, the following terms used in this document have the meanings explained below, and their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc. can be arbitrarily combined and coupled with each other; terms that are not explained in detail should have the same meanings as those generally understood by technicians in the relevant technical field; patents and non-patent literature cited in whole or in part or materials disclosed in other ways are all incorporated herein by reference.

[0079] For purposes of the present invention, the chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0080] the term

[0081] In this document, the terms “include”, “comprises” and / or “contains” are open expressions, that is, they include the contents specified in the present invention but do not exclude other contents.

[0082] In this document, when describing one, two or more, "more" should refer to a number greater than 2, for example, an integer greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0083] In this article, the term "optionally" means that the feature exists or does not exist, which means that the event described later can but does not necessarily occur, thus including two types of situations where the event occurs or does not occur. For example, "optionally a heterocyclic group substituted with an alkyl group" means that the alkyl group can but does not necessarily exist, thus including situations where the heterocyclic group is substituted with an alkyl group and a heterocyclic group is not substituted with an alkyl group.

[0084] In this document, the expressions “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B and / or C”, “X is A, B and / or C”, etc. all express the same meaning, that is, X can be any one, two or more of A, B and C.

[0085] In this article, the term "unsubstituted" means that one or some hydrogen atoms on the atom, residue, group or part used in conjunction with the term are not replaced by other atoms or atomic groups (i.e., substituents) other than hydrogen atoms, so that the atom, residue, group or part maintains its original structure. The term "(substituted)" means that one, two or more hydrogen atoms in the group, preferably up to 5 hydrogen atoms, more preferably 1-3 hydrogen atoms are each independently replaced by a corresponding number of substituents. When substituted by more than one substituent, these substituents are independent of each other, that is, the more than one substituent can be the same as each other, but the possibility of the same situation is not excluded. Unless specifically indicated, a substituent group can be substituted at any substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one, two or more substituents, then these substituents can be substituted independently at these positions. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions based on experiments or theories without excessive labor.

[0086] In this article, the phrase "each independently of one another" should be understood as each individual described is independent of one another and can be independently selected from the same or different options. For example, "each independently selected from one another" can mean that in different groups, the specific options expressed by the same symbol do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbol do not affect each other.

[0087] In this article, sometimes two or more groups with clear meanings are used together to describe a larger part, and the part described in this combined manner includes the structural combination formed by these two or more groups selected independently of each other. For example, "alkylaryl" means "alkyl" and "aryl" connected together, and the "alkyl" and the "aryl" each have the meanings described for them independently of each other, thereby jointly forming the combined group "alkylaryl".

[0088] In this article, sometimes a linker is described, which is in the middle part of the compound structure and is connected to the rest of the compound through at least two connection sites. The Markush variables listed for the linker should be understood to be the divalent group of the variable, i.e., the "subunit". For example, if a linker is defined in the compound structure and the Markush group definition for the linker lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents the alkylene group or arylene group of the linker, respectively.

[0089] In this article, the label “C x -C y When used in conjunction with a group, " indicates the upper and lower limits of the number of carbon atoms contained in the group. For example, "C1-C12 "Alkyl" refers to an alkyl group containing a minimum of one carbon atom and a maximum of twelve carbon atoms. Those skilled in the art will understand that such a number does not include the number of carbon atoms contained in the substituent to which these groups are attached when they are substituted.

[0090] The expression "XY member" when used in conjunction with a cyclic group indicates the upper and lower limits of the number of ring atoms contained in the cyclic group. For example, a "3-20 membered" heterocyclic group refers to a heterocyclic group containing a minimum of three ring atoms up to a maximum of twenty ring atoms. It will be understood by those skilled in the art that such a number does not include the number of carbon atoms contained in the substituents attached to these heterocyclic groups when they are additionally substituted.

[0091] As used herein, the term "oxo" refers to a group in which an oxo group is substituted (=O) with an oxy group formed on a carbon atom, a nitrogen atom or a sulfur atom of the group.

[0092] In this article, the term "halogen" means fluorine, chlorine, bromine and / or iodine. Accordingly, the term "halo" refers to fluoro, chloro, bromo and / or iodo. Within the scope of this article, when an atom, residue, group or part is halogenated, the atom in the halogenated position can be monosubstituted, disubstituted or polysubstituted by a halogen atom up to full substitution.

[0093] The term "alkyl" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.

[0094] The term "alkenyl" refers to a linear or branched monovalent unsaturated aliphatic hydrocarbon group containing one, two or more double bonds. It should be understood that where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated. Non-limiting examples of alkenyl include vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-4-enyl, (Z)-pent-2-enyl, (E)-pent-3-enyl, (Z)-pent-2-enyl, (E)-pent-2 ... E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl. 1-methylenyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl 1-ethylprop-1-enyl, 1-propylvinyl, and 1-isopropylvinyl.

[0095] The term "alkynyl" refers to a linear or branched monovalent unsaturated aliphatic hydrocarbon group containing one, two or more triple bonds. Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methyl In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0096] The term "alkylene" refers to a divalent group obtained by removing one hydrogen atom from an "alkyl". Similarly, "alkenylene" and "alkynylene" refer to divalent groups obtained by removing one hydrogen atom from an "alkenyl" and "alkynyl", respectively.

[0097] The term "alkoxy" refers to -O-alkyl, wherein alkyl is as defined herein. Non-limiting examples of alkoxy include, for example, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy may be unsubstituted or optionally substituted.

[0098] The term "carbocycle (base)" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, and the carbocycle can include 3 to 20 carbon atoms, preferably includes 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably includes 3 to 6 carbon atoms. The carbocycle can be monocyclic or polycyclic, and it can be a saturated cycloalkyl or can optionally include one, two or more double bonds and / or triple bonds on its ring, thus forming a so-called cycloalkenyl or cycloalkynyl. Saturated cyclic hydrocarbon groups or saturated carbocyclic groups are also referred to as "cycloalkyl". Carbocyclic groups or cyclic hydrocarbon groups, when having multiple rings, can form spirocyclic rings, condensed rings and bridged ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like; non-limiting examples of polycyclic carbocycles include decalinyl, bicyclo[2.2.1]heptyl, or isobornyl.

[0099] The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, preferably containing 3 to 20 ring atoms, one or more of which are heteroatoms or radicals selected from N, O, NH, S, S(O) or S(O)2, but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, 1-4 of which are heteroatoms (e.g., 1, 2, 3 and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6). The heterocyclic group can be connected to the rest of the molecule through any one of the carbon atoms or nitrogen atom (if present) or oxygen or sulfur atom (especially in the case of forming an onium salt). The heterocyclic group can include fused or bridged rings and / or spirocyclic rings. Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl, etc., preferably piperidinyl, pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups, and may also be benzo-fused heterocyclic groups such as dihydroisoquinolinyl. The heterocyclic group may be bicyclic, and non-limiting examples thereof include hexahydrocyclopenta [c] pyrrole -2 (1H) -yl, hexahydropyrrolo [1,2-a] pyrazine -2 (1H) -yl. The heterocyclic group may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, 4H-benzopyran-3-yl, 1H-pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydrofuro[3,2-c]pyrimidinyl, 1,2-dihydropyridinyl, 3,4-dihydro-1,5-naphthyridin-1(2H)-yl or 2,3-dihydrofuro[3,2-c]pyridin-7-yl.

[0100] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0101] The term "aryl / aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated electron system, preferably a 6- to 14-membered or 6- to 10-membered ring, such as phenyl and naphthyl.

[0102] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.

[0103] In this article, the term "heteroaryl / heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan. Non-limiting examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or azinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, imidazo[1,2-c]pyrimidinyl, and / or phenoxazinyl, etc.

[0104] The heteroaryl / heteroaromatic ring may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one, two or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0105] Unless otherwise specified, heterocyclic groups, heteroaryls or heteroaromatic rings include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, forms substituted or bonded to other groups at one, two or more positions of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene; thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0106] Unless otherwise stated, the definitions of terms in this document also apply to expressions containing the term, e.g. 1-6 The definition of alkyl also applies to C 1-6 Alkyloxy (sometimes also called C 1-6 Alkoxy), -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, -SO-C 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, etc.

[0107] As used herein, "physiologically / pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0108] Physiologically / pharmaceutically acceptable salts include acid addition salts of compounds of the invention having nitrogen atoms in the chain or ring with sufficient basicity. In addition, basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc. As examples, physiologically / pharmaceutically acceptable salts include, but are not limited to, hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts, etc.

[0109] Since the compounds of the present invention may have multiple salt-forming sites, the physiologically / pharmaceutically acceptable salts include not only salts formed at one of the salt-forming sites of the compounds of the present invention, but also salts formed at 2, 3 or all of the salt-forming sites. To this end, in the physiologically / pharmaceutically acceptable salts, the molar ratio of the compound of formula (I), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF) to the radical ion (anion) of the acid or the cation of the base required for salt formation can vary within a large range, for example, it can be 4:1-1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0110] In this article, the term "nitrogen oxide" means that when a compound contains several nitrogen-containing functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. A special example of an N-oxide is an N-oxide of a tertiary amine or an N-oxide of a nitrogen-containing heterocyclic nitrogen atom. The corresponding nitrogen-containing compound can be treated with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, the nitrogen-containing compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

[0111] As used herein, the term "ester" refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl or carboxyl group. Such esters are, for example, physiologically / pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol or acid. The compounds of Formula (I), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF) of the present invention may contain a carboxyl group and may form in vivo hydrolyzable esters with appropriate groups, such groups including, but not limited to, alkyl, arylalkyl, etc.

[0112] Depending on the position and properties of the different substituents, the compounds of the present invention may also contain one or more asymmetric centers. Asymmetric carbon atoms may exist in (R) or (S) configurations, with only one asymmetric center resulting in a racemic mixture and multiple asymmetric centers resulting in a diastereomeric mixture. In some cases, asymmetry may also exist due to hindered rotation around a particular bond, such as the central bond connecting two substituted aromatic rings of a particular compound. Furthermore, the substituents may also exist in cis or trans isomeric forms.

[0113] The compounds of the present invention also include all possible stereoisomers thereof, in the form of a single stereoisomer or any mixture of any proportion of said stereoisomers (e.g., R-isomers or S-isomers, or E-isomers or Z-isomers). The separation of a single stereoisomer (e.g., a single enantiomer or a single diastereomer) of a compound of the present invention can be achieved by any suitable prior art method (e.g., chromatography, in particular, for example, chiral chromatography).

[0114] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0115] In the present invention, the compounds according to the present invention also include isotopically labeled compounds, which are the same as those shown in Formula (I), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF), but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually occurring in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, or physiologically / pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Isotopically labeled compounds according to the invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein. Certain isotopically labeled compounds of the invention, for example, have introduced a radioactive isotope (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2H) substitution may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) derived from greater metabolic stability and may therefore be preferred in certain circumstances. The compounds of the invention as claimed in the claims may be specifically limited to substitution with deuterium or tritium. In addition, the presence of hydrogen in a substituent, without the separate listing of the term deuterium or tritium, does not exclude deuterium or tritium, but may also contain deuterium or tritium.

[0116] As used herein, the term "prodrug" or "drug precursor" refers to a compound that is converted in vivo to a compound represented by the aforementioned formula (I), (IA), (IB), (IC), (ID), (IIA), (IIB), (IIC), (IID), (IIE) or (IIF) or a specific compound. Such conversion is affected by the prodrug being hydrolyzed in the blood or being converted to the parent structure by enzymes in the blood or tissues. The prodrug of the present invention may be an ester, and the esters that can be used as prodrugs in the present invention include phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl / carboxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent.

[0117] As used herein, the term "metabolite" refers to a product obtained by the metabolism of a specific compound or its salt in vivo. The metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.

[0118] Any abbreviations for protecting groups, amino acids and other compounds used in the present invention are based on their commonly used and recognized abbreviations, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11: 942-944), unless otherwise specified.

[0119] As used herein, the term "solvate" refers to an association formed by one or more solvent molecules and the compounds of the present invention. Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. Therefore, the term "hydrate" refers to an association formed by a solvent molecule that is water.

[0120] As used herein, the term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and then exert biological activity. The term "physiologically / pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, etc. The term "carrier" refers to a diluent, adjuvant, excipient, or matrix administered with the compound. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water and aqueous solutions saline solutions and aqueous glucose and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EWMartin.

[0121] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing down or preventing or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or deterioration of a disease or condition.

[0122] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition to be treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific compound selected, the dosage regimen relied on, whether to be administered in combination with other compounds, the time schedule of administration, the tissue to be administered, and the physical delivery system carried.

[0123] In some embodiments according to the present invention, pharmaceutical excipients can be excipients widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the active ingredient to be effectively absorbed after the subject receives the composition administration. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0124] Substances that can be used as physiologically / pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose. sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0125] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0126] The dosage form of the medicine of the present invention can be selected according to specific circumstances. Pharmaceutical dosage forms are often composed of medicine, excipients and container / sealing systems. One or more excipients (also known as inactive ingredients) can be added to the compound of the present invention to improve or promote the manufacture, stability, administration and safety of the medicine, and a method for obtaining a desired drug release curve can be provided. Therefore, the type of excipient added to the medicine can be determined depending on various factors, such as the physical and chemical properties of the medicine, route of administration and preparation steps. There are pharmaceutical excipients in this field and include those listed in various pharmacopoeias. (See US Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); the US Food and Drug Administration (www.fda.gov), Center for Drug Evaluation and Research (CEDR) publications, e.g., Inactive Ingredient Guide, 1996; Hand book of Pharmaceutical Additives, 2002, by Ash, Synapse Information Resources, Inc., Endicott NY; etc.).

[0127] The pharmaceutical compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecules into preparations for pharmaceutical use.

[0128] The appropriate formulation depends on the desired route of administration. Routes of administration include intravenous injection, transmucosal or nasal administration, oral administration, etc. For oral administration, the compound can be formulated into liquid or solid dosage forms and as immediate release or controlled release / slow release formulations. Suitable dosage forms for oral ingestion by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions, and emulsions.

[0129] Solid oral dosage forms can be obtained using excipients, including fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants and flavorings. These excipients can be synthetic or natural sources. Examples of the excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, mucilage of tragacanth, vegetable oils (hydrogenated) and waxes. Ethanol and water can be used as granulation aids. In some cases, tablets need to be coated with, for example, a taste masking film, a gastric acid resistant film or a delayed release film. Natural and synthetic polymers are often used to coat tablets in combination with colorants, sugars, and organic solvents or water to produce dragees. When capsules are preferred over tablets, drug powders, suspensions, or solutions thereof may be delivered in compatible hard or soft shell capsule forms.

[0130] The therapeutically effective dose can first be estimated using various methods well known in the art. The initial dose for animal studies can be based on the effective concentration established in the cell culture assay. The dosage range suitable for humans can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as a medicament for oral administration.

[0131] The correct formulation, administration route, dosage and dosing interval can be selected according to methods known in the art taking into account the particularities of the individual situation.

[0132] Example

[0133] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technical solutions implemented based on the content of the present invention are included in the scope that the present invention is intended to protect.

[0134] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art; the reagents, raw materials, instruments, equipment, etc. used in the following examples can all be obtained from commercial channels.

[0135] Reagents used

[0136] The starting materials and reagents in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0137] Instruments and equipment and measurement methods

[0138] NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic spectrometers. The measurement solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), etc. Tetramethylsilane (TMS) was used as the internal standard, and the chemical shift was measured in parts per million (ppm).

[0139] Liquid chromatography-mass spectrometry (LC-MS) was detected using an Agilent 1260 mass spectrometer, and HPLC was determined using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0140] The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

[0141] Abbreviation or abbreviation

[0142] Boc: tert-butyloxycarbonyl

[0143] Xantphos Pd G4: Methanesulfonate (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)

[0144] DIAD: diisopropyl azodicarboxylate

[0145] B2Pin2: Pinacol borate

[0146] AcOH: acetic acid

[0147] MeOH: Methanol

[0148] NaOH: Sodium hydroxide

[0149] DCM: dichloromethane

[0150] THF: Tetrahydrofuran

[0151] t-BuOH: tert-butyl alcohol

[0152] Et3N: triethylamine

[0153] H2O: water

[0154] PE: Petroleum ether

[0155] EA, EtOAc: ethyl acetate

[0156] KOAc: Potassium acetate

[0157] NMP: N-methylpyrrolidone

[0158] DIEA: N,N-diisopropylethylamine

[0159] Na2SO4: Sodium sulfate

[0160] HPLC: High Performance Liquid Chromatography

[0161] Pre-HPLC: Preparative High Performance Liquid Chromatography

[0162] Prep-TLC: Preparative Thin Layer Chromatography

[0163] rt: room temperature

[0164] Example 1: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (1)

[0165]

[0166] Step 1: Synthesis of methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (1-3)

[0167]

[0168] 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (20 mg, 0.05 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (19 mg, 0.07 mmol) were added to AcOH (5 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give compound 1-3 (10 mg, 32%).

[0169] MS (ESI, pos.ion) m / z: 682.2 [M+1] + .

[0170] Step 2: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (1)

[0171]

[0172] Methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (10 mg, 0.01 mmol) was dissolved in a mixture of MeOH (2 mL), THF (2 mL) and H2O (2 mL), and NaOH (2 mg, 0.04 mmol) was added, and stirred at 45°C for 2 hours. The mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran, and H2O (5 mL) was added. The pH was adjusted to about 5 with 1N HCl, and the crude product was filtered to obtain the title compound (2 mg, 18%).

[0173] MS (ESI, pos.ion) m / z: 668.2 [M+1] + .

[0174] 1 HNMR(DMSO-d6)δ:9.06(s,1H),8.64(s,1H),8.14(d,J=1.6Hz,1H),7.58(dd,J=13.7,1.4Hz,1H),7.37(s,1H),7.14-7.21(m,1H),6. 92(tt,J=9.3,2.1Hz,1H),6.79(t,J=2.0Hz,1H),6.65(dd,J=8.2,1.9Hz,2H),3.99(s,3H),3.97(s,3H),2.17-2.23(m,1H),0.38(br d,J=6.9Hz,2H),0.32-0.36(m,2H).

[0175] Example 2: Synthesis of 6-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-4-(3,5-difluorophenoxy)picolinic acid (2)

[0176]

[0177] Step 1: Synthesis of dimethyl 4-(3,5-difluorophenoxy)pyridine-2,6-dicarboxylate (2-3)

[0178]

[0179] Add dimethyl 4-chloropyridine-2,6-dicarboxylate (2.00 g, 8.73 mmol), 3,5-difluorophenol (1.36 g, 10.48 mmol) and cesium carbonate (5.69 g, 17.46 mmol) to DMF (20 mL). React at 70°C for 2 h. Add H2O (100 mL), extract with ethyl acetate (40 mL × 3), combine the organic phases and then wash with saturated NaCl solution (50 mL × 3), dry over anhydrous Na2SO4, and concentrate under reduced pressure to obtain a yellow solid (2.00 g, 80%).

[0180] MS (ESI, pos.ion) m / z: 324.1 [M+1] + .

[0181] Step 2: Synthesis of 4-(3,5-difluorophenoxy)-6-(methoxycarbonyl)picolinic acid (2-4)

[0182]

[0183] Add dimethyl 4-(3,5-difluorophenoxy)pyridine-2,6-dicarboxylate (1.70 g, 4.95 mmol) and NaOH (237 mg, 5.94 mmol) to a mixed solution of MeOH (16 ml) and THF (4 ml). React at room temperature for 5 h. Adjust the pH to 5-6 with 2N hydrochloric acid, and a white solid precipitates. Filter and concentrate to obtain a white solid (1.6 g, 90%).

[0184] MS (ESI, pos.ion) m / z: 310.1 [M+1] + .

[0185] Step 3: Synthesis of methyl 6-((tert-butoxycarbonyl)amino)-4-(3,5-difluorophenoxy)picolinate (2-5)

[0186]

[0187] 4-(3,5-difluorophenoxy)-6-(methoxycarbonyl)picolinic acid (1.6 g, 5.17 mmol) and Et3N (1.04 g, 10.34 mmol) were added to a mixed solution of t-BuOH (4 ml) and dioxane (20 ml), and DPPA (2.84 g, 10.34 mmol) was slowly added dropwise. The mixture was reacted at 80°C for 18 h. H2O (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and then washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography to obtain a yellow solid (220 mg, 5%).

[0188] MS (ESI, pos.ion) m / z: 381.2 [M+1] + .

[0189] Step 4: Synthesis of 6-amino-4-(3,5-difluorophenoxy)picolinic acid methyl ester (2-6)

[0190]

[0191] Methyl 6-((tert-butoxycarbonyl)amino)-4-(3,5-difluorophenoxy)picolinate (220 mg, 0.58 mmol) was added to HCl / dioxane (4N, 5 mL) and reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure, and H2O (10 mL) was added to the residue. The pH was adjusted to about 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and then washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the product as a white solid (150 mg, 90%).

[0192] MS (ESI, pos.ion) m / z: 281.1 [M+1] +

[0193] Step 5: Synthesis of methyl 6-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-4-(3,5-difluorophenoxy)picolinate (2-8)

[0194]

[0195] 6-Amino-4-(3,5-difluorophenoxy)picolinic acid methyl ester (25 mg, 0.089 mmol) and 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (30 mg, 0.068 mmol), cesium carbonate (42 mg, 0.13 mmol), Xantphos Pd G4 (6 mg, 0.006 mmol) were added to dioxane (4 ml), replaced with nitrogen three times, stirred at 110 ° C for 5 hours, stirred and cooled to room temperature, water (10 ml) and ethyl acetate (15 ml) were added, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by Prep-TLC plate to obtain a yellow solid (16 mg, 30%).

[0196] MS (ESI, pos.ion) m / z: 683.2 [M+1] + .

[0197] Step 6: Synthesis of 6-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-4-(3,5-difluorophenoxy)picolinic acid (2)

[0198]

[0199] Methyl 6-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-4-(3,5-difluorophenoxy)picolinate (16 mg, 0.02 mmol) was added to MeOH (2 ml) and then an aqueous NaOH solution (2N, 0.5 ml) was added dropwise. The mixture was stirred at room temperature for 1 h, and a 2N hydrochloric acid solution was added to adjust the pH to 5-6. The mixture was diluted with H2O (10 ml) and extracted with ethyl acetate (10 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The title compound (1.5 mg, 5%) was purified by Prep-HPLC.

[0200] MS (ESI, pos.ion) m / z: 669.2 [M+1] + .

[0201] 1 HNMR(DMSO-d6)δ:12.55-13.19(m,1H),9.15(br s,1H),9.05(br s,1H),8.66(brs,1H),8.34-8.46(m,1H),8.17(br d,J=1.0Hz,1H),7.59(br d,J=14.8Hz,1H),7.11-7.26(m,2H),7.06(br s,2H),6.83(br s,1H),4.03(br s,3H),3.99(br s,3H),2.23(br d,J=4.1Hz,1H),0.34(br s,4H).

[0202] Example 3: Synthesis of 2-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)thiazole-4-carboxylic acid (3)

[0203]

[0204] 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (30 mg, 0.07) and 2-aminothiazole-4-carboxylic acid (20 mg, 0.13 mmol) were added to NMP (2 ml), and finally DIEA (0.05 ml) was added. The mixture was reacted at 130°C in a microwave for 1 hour, and the pH was adjusted to 5-6 with 2N hydrochloric acid. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (10 ml×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure by filtration. Prep-HPLC purification gave the title compound (7 mg, 19%).

[0205] MS (ESI, pos.ion) m / z: 547.1 [M+1] + .

[0206] 1 HNMR(DMSO-d6)δ:8.53(s,1H),7.67(s,1H),7.16(s,1H),7.08-7.13(m,2H),3.98(s,3H),3.95-3.97(m,3H),0.78(br d,J=5.7Hz,2H),0.68-0.74(m,2H).

[0207] Example 4: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-((4,4-difluorocyclohexyl)oxy)benzoic acid (4)

[0208]

[0209] Step 1: Synthesis of methyl 3-((4,4-difluorocyclohexyl)oxy)-5-nitrobenzoate (4-2)

[0210]

[0211] Under nitrogen atmosphere, methyl 3-hydroxy-5-nitrobenzoate (650 mg, 3.30 mmol), 4,4-difluorocyclohexyl-1-ol (450 mg, 3.31 mmol) and PPh3 (1.04 g, 3.97 mmol) were added to anhydrous THF (20 mL), cooled to 0°C, DIAD (800 mg, 3.96 mmol) was added dropwise, and the mixture was reacted at 0°C for 1 h after the addition was complete, and then at room temperature for 16 h. After the reaction was completed, water (20 mL) and ethyl acetate (20 mL) were added, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (40 mL), and the organic phases were combined and then washed with saturated NaCl solution (60 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 10 / 1) to obtain a white solid (700 mg, 67%).

[0212] Step 2: Synthesis of methyl 3-amino-5-((4,4-difluorocyclohexyl)oxy)benzoate (4-3)

[0213]

[0214] Methyl 3-((4,4-difluorocyclohexyl)oxy)-5-nitrobenzoate (700 mg, 2.22 mmol) and Pd / C (70 mg) were added to MeOH (10 mL) and reacted at room temperature for 16 h under a hydrogen atmosphere. After the reaction was completed, the filter cake was filtered and rinsed with MeOH (20 mL), and concentrated under reduced pressure to obtain a crude product as a white solid (550 mg, 86%).

[0215] MS (ESI, pos.ion) m / z: 286.1 [M+1] +

[0216] Step 3: Synthesis of 3-amino-5-((4,4-difluorocyclohexyl)oxy)benzoic acid (4-4)

[0217]

[0218] Ethyl 7-bromo-4-chloro-5-fluoroquinoline-3-carboxylate (215 mg, 0.75 mmol) was added to MeOH (4 mL), and a solution of sodium hydroxide (40 mg, 3.00 mmol) in water (1 mL) was added dropwise at room temperature, and the mixture was reacted at 45°C for 1.5 h. After the reaction, hydrochloric acid (2N) was added dropwise to adjust the pH to about 6, and water (20 mL) and ethyl acetate (20 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (20 mL), and the organic phases were combined and then washed with a saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product as a white solid (200 mg, 98%).

[0219] MS (ESI, pos.ion) m / z: 272.1 [M+1] +

[0220] Step 4: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-((4,4-difluorocyclohexyl)oxy)benzoic acid (4)

[0221]

[0222] 3-Amino-5-((4,4-difluorocyclohexyl)oxy)benzoic acid (14 mg, 0.05 mmol) and 4-chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (20 mg, 0.05 mmol) were added to acetic acid (2 mL) and reacted at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to obtain the title compound (10 mg, 29%).

[0223] MS(ESI,pos.ion)m / z:674.2[M+1]+.

[0224] 1 H NMR(DMSO-d6)δ:9.04(s,1H),8.63(s,1H),8.50-8.57(m,1H),8.14(d,J=1.6Hz,1H),7.5 5(dd,J=13.4,1.4Hz,1H),7.11-7.16(m,1H),7.05(s,1H),6.75(t,J=2.0Hz,1H),4.50(br s,1H),3.99(s,3H),3.96(s,3H),2.21(td,J=6.5,3.8Hz,1H),1.65-1.97(m,8H),0.35-0.43(m,4H).

[0225] Example 5: Synthesis of (1r,4r)-4-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid (5)

[0226]

[0227] Step 1: Synthesis of methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (5-3)

[0228]

[0229] 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (10 mg, 0.02 mmol), methyl(1r,4r)-4-aminobicyclo[2.2.1]heptane-1-carboxylic acid ethyl ester (4 mg, 0.02 mmol) and DIEA (6 mg, 0.05 mmol) were added to NMP (2 mL). The mixture was heated in microwave at 130°C for 1 h, diluted with H2O (20 mL), extracted with EA (20 mL×3), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (DCM / MeOH (v / v)=30 / 1) to obtain a yellow solid (8 mg, 61%).

[0230] MS (ESI, pos.ion) m / z: 572.3 [M+1] + .

[0231] Step 2: Synthesis of (1r,4r)-4-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid (5)

[0232]

[0233] Methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (30 mg, 0.05 mmol) was dissolved in a mixture of MeOH (2 mL), THF (2 mL) and H2O (2 mL), and NaOH (6 mg, 0.16 mmol) was added, and stirred at 45°C for 2 hours. The mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran, and H2O (5 mL) was added. The pH was adjusted to 5 with 1N HCl, and the crude product was filtered and purified using Prep-HPLC to obtain the title compound (9 mg, 29%).

[0234] MS (ESI, pos.ion) m / z: 558.1 [M+1] + .

[0235] 1HNMR(DMSO-d6)δ:12.21(br s,1H),8.87(s,1H),8.67(s,1H),8.54(s,1H),8.00(s,1H),7.63(br d,J=13.3Hz,1H),6.95(br s,1H),4.02(s,3H),3.98(s,3H),2.27(br d,J=2.0Hz,1H),1.79-1.96(m,6H),1.65-1.74(m,2H),1.62(br d,J=12.0Hz,2H),0.49-0.59(m,2H),0.41(br s,2H).

[0236] Example 6: Synthesis of (1S,3R)-3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)cyclohexane-1-carboxylic acid (6)

[0237]

[0238] 4-Chloro-N-cyclopropyl-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (10 mg, 0.02 mmol), (1S,3R)-3-aminocyclohexane-1-carboxylic acid (3 mg, 0.02 mmol) and DIEA (6 mg, 0.05 mmol) were added to NMP (2 mL). The mixture was heated at 130°C for 1 h in a microwave oven, diluted with H2O (10 mL), extracted with EA (10 mL×3), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by HPLC to give the title compound (2 mg, 16%).

[0239] MS (ESI, pos.ion) m / z: 546.3 [M+1] + .

[0240] 1HNMR(DMSO-d6)δ:12.10(br s,1H),8.79(s,1H),8.65(s,1H),8.52(d,J=1.5Hz,1H),8.00(d,J=1.5Hz,1H),7.67(dd,J=14.1,1.4Hz,1H),6.58(br s,1H),4.02(s,3H),3.99(s,3H),2.24-2.35(m,2H),2.03(br d,J=11.5Hz,1H),1.92(br d,J=3.3Hz,1H),1.74-1.86(m,2H),1.43(br d,J=12.8Hz,1H),1.31(br t,J=10.5Hz,2H),1.13-1.27(m,2H),0.49-0.56(m,2H),0.34-0.46(m,2H).

[0241] Example 7: Synthesis of 3-((7-(2-carbamoyl-4-cyanophenyl)-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (7)

[0242]

[0243] Step 1: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborate-2-yl)isophthalonitrile (7-2)

[0244]

[0245] Under nitrogen protection, Pd(dppf)Cl2 (98 mg, 0.12 mmol) was added to a mixture of 4-bromoisophthalonitrile (500 mg, 2.42 mmol), B2Pin2 (675 mg, 2.66 mmol) and KOAc (713 mg, 7.26 mmol) in dioxane (15 mL). The mixture was stirred at 100 °C overnight. The reaction solution was cooled to room temperature, diluted with H2O (50 mL), and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain a white solid (150 mg, 24%).

[0246] Step 2: Synthesis of 2-(4-chloro-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-7-yl)-5-cyanobenzamide (7-4)

[0247]

[0248] 7-Bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (30 mg, 0.08 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborate-2-yl)isophthalonitrile (22 mg, 0.09 mmol), K2CO3 (33 mg, 0.24 mmol) and Pd(PPh3)4 (9 mg, 0.01 mmol) were added to a mixed solution of dioxane (4 mL) and H2O (1 mL). Stirred at 80 °C for 1 h under nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with H2O (10 mL), and extracted with EtOAc (10 mL×3). The combined organic phase was washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by Prep-TLC to obtain a yellow solid (15 mg, 43%).

[0249] MS (ESI, pos.ion) m / z: 445.1 [M+1] + .

[0250] Step 3: Synthesis of 3-((7-(2-carbamoyl-4-cyanophenyl)-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (7)

[0251]

[0252] 2-(4-chloro-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-7-yl)-5-cyanobenzamide (15 mg, 0.03 mmol) and 3-amino-5-(3,5-difluorophenoxy)benzoic acid (9 mg, 0.03 mmol) were added to AcOH (2 mL) and stirred at 50°C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Prep-HPLC to obtain the title compound (3 mg, 17%).

[0253] MS (ESI, pos.ion) m / z: 674.1 [M+1] + .

[0254] 1HNMR(DMSO-d6)δ:12.47-13.76(m,1H),9.10(s,1H),8.62(br s,1H),8.55(br s,1H),8.08(br s,1H),8.03-8.06(m,1H),8.02(s,1H),7.97(s,1H),7.70(d,J=8.0Hz,1H) ,7.65(s,1H),7.33-7.42(m,2H),7.18(s,1H),6.92-7.02(m,1H),6.80(br s,1H),6.67(dd,J=8.2,1.8Hz,2H),2.23(br d,J=3.4Hz,1H),0.34-0.44(m,4H).

[0255] Example 8: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-5-fluoro-7-(4-oxo-4H-benzopyran-3-yl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (8)

[0256]

[0257] Step 1: Synthesis of 7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (8-2)

[0258]

[0259] 7-Bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (3.00 g, 8.8 mmol), DMF (0.07 mL, 0.88 mmol) and POCl3 (6 mL, 66 mmol) were added to toluene (30 mL) and reacted at 100°C for 18 h. The reaction solution was concentrated under reduced pressure and washed with saturated NaHCO3. EtOAc (60 mL) was added for extraction, and the mixture was washed with H2O (30 mL × 2) and saturated NaCl solution (30 mL) in turn, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 20 / 1) to obtain a yellow oil (1.50 g, 4.2 mmol, 47%).

[0260] Step 2: Synthesis of 7-bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (8-4)

[0261]

[0262] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1.00 g, 2.9 mmol), TEA (1.2 mL, 8.8 mmol) and cyclopropylamine (0.41 mL, 5.8 mmol) were added to DCM (40 mL) at zero degrees and reacted at 18°C ​​for 1 hour. DCM (20 mL) was added for extraction, and the mixture was washed with H2O (10 mL × 2) and saturated NaCl solution (10 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 4 / 1) to give a white solid (120 mg, 0.33 mmol, 11%).

[0263] MS (ESI, pos.ion) m / z: 379.0 [M+1] +

[0264] Step 3: Synthesis of 4-chloro-N-cyclopropyl-5-fluoro-7-(4-oxo-4H-benzopyran-3-yl)quinoline-3-sulfonamide (8-6)

[0265]

[0266] Under N2 protection, 7-bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (80 mg, 0.21 mmol), K2CO3 (58 mg, 0.42 mmol), (4-oxo-4H-benzopyran-3-yl)boronic acid (80 mg, 0.42 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) were added to dioxane (5 mL) and H2O (1 mL) and reacted at 50°C for 2 h. EtOAc (20 mL) was added for extraction, and the mixture was washed with H2O (10 mL×2) and saturated NaCl solution (10 mL) in turn, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 2 / 1) to give a yellow solid (30 mg, 0.07 mmol, 32%).

[0267] MS (ESI, pos.ion) m / z: 445.0 [M+1] +

[0268] Step 4: Synthesis of 3-amino-5-(3,5-difluorophenoxy)benzoic acid (8-8)

[0269]

[0270] 3-Amino-5-(3,5-difluorophenoxy)benzoic acid methyl ester (1g, 3.6mmol) and LiOH.H2O (18mL, 18mmol) were added to MeOH (10mL) and H2O (2mL) and reacted at 25°C for 2h. The reaction solution was adjusted to pH=6 with 1N HCl solution, extracted with EtOAc (30mL), washed with H2O (50mL×2) and saturated NaCl solution (50mL) in turn, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v)=2 / 1) to obtain a white solid (120mg, 0.45mmol, 13%).

[0271] MS (ESI, pos.ion) m / z: 266.0 [M+1] +

[0272] Step 5: Synthesis of 4-chloro-N-cyclopropyl-5-fluoro-7-(4-oxo-4H-benzopyran-3-yl)quinoline-3-sulfonamide (8)

[0273]

[0274] 4-Chloro-N-cyclopropyl-5-fluoro-7-(4-oxo-4H-benzopyran-3-yl)quinoline-3-sulfonamide (70 mg, 0.16 mmol) and 3-amino-5-(3,5-difluorophenoxy)benzoic acid (83 mg, 0.31 mmol) were added to AcOH (5 mL) and reacted at 50° C. for 1 h. The mixture was concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography (0.01 mol / L NH4HCO3:MeCN (v / v) = 31%-100%) to obtain the title compound (20 mg, 0.03 mmol, 19%, HPLC: 96.0%).

[0275] MS (ESI, pos.ion) m / z: 674.1 [M+1] +

[0276] 1H NMR(400MHz,DMSO-d6)δ(ppm):9.08(s,1H),8.90(s,1H),8.60(s,1H),8.31(s,1H) ),8.21(dd,J=8.0,1.5Hz,1H),7.92–7.86(m,1H),7.77(d,J=8.3Hz,1H),7.64(d, J=13.6Hz,1H),7.59(t,J=7.5Hz,1H),7.34(s,1H),7.18(s,1H),6.98–6.90(m,1H ),6.78(s,1H),6.67(dd,J=8.4,2.1Hz,2H),2.27–2.19(m,1H),0.43–0.32(m,4H).

[0277] Example 9: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)benzoic acid (9)

[0278]

[0279] Step 1: Synthesis of 5-(((3-bromo-5-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9-2)

[0280]

[0281] 3-Bromo-5-fluoroaniline (2.00 g, 10.53 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.16 g, 11.58 mmol) were added to dioxane (20 mL). The mixture was reacted at room temperature for 2 h. PE (20 mL) was added and filtered to obtain a yellow solid (3.28 g, 90%).

[0282] MS (ESI, neg.ion) m / z: 343.8 [M-1] + .

[0283] Step 2: Synthesis of 7-bromo-5-fluoroquinolin-4-ol (9-3)

[0284]

[0285] Add 5-(((3-bromo-5-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.28 g, 9.53 mmol) to diphenyl ether (20 mL). React at 260°C for 30 min. Cool to room temperature, add PE (20 mL) and filter to obtain a gray solid (2.12 g, 92%).

[0286] MS (ESI, pos.ion) m / z: 243.8 [M+1] + .

[0287] Step 3: Synthesis of 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (9-4)

[0288]

[0289] 7-Bromo-5-fluoroquinolin-4-ol (1.00 g, 4.13 mmol) was added to ClSO3H (10 mL). The mixture was reacted at 100°C for 16 h. After cooling to room temperature, the mixture was added dropwise to ice water, and filtered and dried to obtain a gray solid (1.12 g, 80%).

[0290] MS (ESI, pos.ion) m / z: 341.7 [M+1] + .

[0291] Step 4: Synthesis of 7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (9-5)

[0292]

[0293] 7-Bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (50 mg, 0.15 mmol) was added to POCl3 (1 mL), DMF (0.1 mL) and PhMe (4 mL), and the mixture was reacted at 100°C for 5 h. The mixture was concentrated under reduced pressure to obtain a crude product as a yellow oily liquid (50 mg, crude product).

[0294] Step 5: Synthesis of 7-bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide (9-6)

[0295]

[0296] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (300 mg, 0.84 mmol) and TEA (254 mg, 2.51 mmol) were added to dry DCM (10 mL). Cyclopropylamine (48 mg, 0.84 mmol) was added at 0°C and stirred at 0°C for 1 hour. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give a yellow solid (120 mg, 38%).

[0297] MS (ESI, pos.ion) m / z: 381.0 [M+1] + .

[0298] Step 6: Synthesis of 4-chloro-N-(cyclopropylmethyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (9-7)

[0299]

[0300] 7-Bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide (120 mg, 0.32 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (58 mg, 0.32 mmol) and K2CO3 (109 mg, 0.79 mmol) were added to a mixture of dioxane (8 mL) and water (2 mL), the air in the reaction system was replaced with nitrogen, Pd(PPh3)4 (37 mg, 0.03 mmol) was added under nitrogen flow, and then replaced with nitrogen, and stirred at 80°C for 1 h. H2O (20 mL) was added for dilution, extracted with EA (20 mL*3), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain a yellow solid (44 mg, 32%).

[0301] MS (ESI, pos.ion) m / z: 439.1 [M+1] + .

[0302] Step 7: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)benzoic acid (9)

[0303]

[0304] 4-Chloro-N-(cyclopropylmethyl)-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-sulfonamide (40 mg, 0.09 mmol) and 3-aminobenzoic acid (13 mg, 0.09 mmol) were added to AcOH (5 mL). Stirred at room temperature overnight. Concentrated under reduced pressure, the crude product was purified by HPLC to obtain the title compound (8 mg, 17%).

[0305] MS (ESI, pos.ion) m / z: 540.1 [M+1] + .

[0306] 1HNMR(DMSO-d6)δ:9.04(s,1H),8.64(s,1H),8.52(s,1H),8.26(s,1H),8.13(d ,J=1.7Hz,1H),7.58(d,J=7.6Hz,1H),7.51(dd,J=13.5,1.8Hz,1H),7.45(t,J =1.9Hz,1H),7.29(t,J=7.8Hz,1H),7.04(dd,J=7.8,2.5Hz,1H),4.00(s,3H), 3.97(s,3H),2.21(dt,J=6.5,3.1Hz,1H),0.39(ddd,J=12.4,5.0,2.4Hz,4H).

[0307] Example 10: Synthesis of 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-(2,2,2-trifluoroethyl)sulfonylamino)quinolin-4-yl)benzoic acid (10)

[0308]

[0309] Step 1: Synthesis of 7-bromo-5-fluoro-4-hydroxy-N-(2,2,2-trifluoroethyl)quinoline-3-sulfonamide

[0310] Under ice bath, 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (3.20 g, 9.4 mmol) was dissolved in tetrahydrofuran (30.0 mL), and then trifluoroethylamine (3.66 mL, 26.4 mmol) and methylammonium chloride (3.91 mL, 28.2 mmol) were slowly added to the solution, and the reaction solution was stirred at 37°C for 2 hours. After the reaction of the raw materials was complete, 100-200 mesh silica gel (5.00 g) was added to the reaction solution, and the solvent was removed by reduced pressure distillation. The crude product was purified by medium pressure liquid separation (methanol: dichloromethane = 0%-8%) to obtain 7-bromo-5-fluoro-4-hydroxy-N-(2,2,2-trifluoroethyl)quinoline-3-sulfonamide (1.58 g, 42%).

[0311] MS(ESI,pos.ion)m / z:[M+H]=403.2

[0312] Step 2: Synthesis of 4,7-dichloro-5-fluoro-N-(2,2,2-trifluoroethyl)quinoline-3-sulfonamide

[0313] 7-Bromo-5-fluoro-4-hydroxy-N-(2,2,2-trifluoroethyl)quinoline-3-sulfonamide (1.58 g, 3.92 mmol) was added to phosphorus oxychloride (15.0 mL) in batches at 37°C, and the reaction solution was stirred at 100°C for 3 hours. After the reaction of the raw materials was complete, the phosphorus oxychloride in the solution was removed by concentration under reduced pressure, and the crude product was separated by medium pressure liquid phase separation (ethyl acetate: petroleum ether = 0%-60%) to obtain 4,7-dichloro-5-fluoro-N-(2,2,2-trifluoroethyl)quinoline-3-sulfonamide (260 mg, 18.5%).

[0314] MS(ESI,pos.ion)m / z:[M+H]=377.1

[0315] Step 3: Synthesis of 3-((7-chloro-5-fluoro-3-(N-(2,2,2-trifluoroethyl)carbamoyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0316] At 37°C, 4,7-dichloro-5-fluoro-N-(2,2,2-trifluoroethyl)quinoline-3-sulfonamide (100 mg, 0.26 mmol) was dissolved in acetic acid (3.00 mL), and 3-amino-5-[(3,5-difluorophenyl)oxy]benzoic acid (105 mg, 0.4 mmol) was added, and the reaction solution was stirred at room temperature for 18 hours. After the reaction of the raw materials was complete, the reaction solution was distilled under reduced pressure to remove the solvent to obtain a crude product 3-((7-chloro-5-fluoro-3-(N-(2,2,2-trifluoroethyl)carbamoyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (200 mg, 94%).

[0317] MS(ESI,pos.ion)m / z:[M+H]=605.9

[0318] Step 4: Synthesis of 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-(2,2,2-trifluoroethyl)amino)quinolin-4-yl)benzoic acid

[0319] At 37°C, 3-((7-chloro-5-fluoro-3-(N-(2,2,2-trifluoroethyl)carbamoyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (200 mg, 0.34 mmol) was dissolved in 1,4-dioxane (2.00 mL) and water (0.40 mL), and then 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (24.1 mg, 0.03 mmol) and potassium carbonate (228 mg, 1.65 mmol) were added. The solution was deoxygenated by blowing with a nitrogen balloon for 20 seconds, and heated to 100°C in a microwave reactor for 30 minutes. After the reaction of the raw materials was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to remove the solvent. The crude product was prepared by high pressure chromatography to obtain compound 10 (65.5 mg, 28%).

[0320] MS(ESI,pos.ion)m / z:[M+H]=709.6

[0321] 1 H NMR (400MHz, DMSO-d6) δ9.05(s,1H),8.64(s,1H),8.11(s,1H),7.56(d,J=13.7Hz,1H),7.38(s,1H),7.16(s,1H),6.91(t,J=9.3Hz,1H),6.64–6.63(m 3H),4.00(s,3H),3.98(s,3H)3.85–3.77(m,2H).

[0322] Example 11: Synthesis of 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)benzoic acid (11)

[0323]

[0324] Step 1: Synthesis of 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonamide

[0325] Under ice bath, 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (4.00 g, 11.75 mmol) was dissolved in tetrahydrofuran (80.0 mL), and then ammonia water (7.24 mL, 46.98 mmol) was slowly added to the solution, and the reaction solution was stirred at 37°C for 2 hours. After the reaction of the raw materials was complete, the reaction solution was directly concentrated to obtain a crude product, and silica gel was added to stir the sample. Normal phase column chromatography (MeOH: DCM = 0%-8%) was used to obtain compound 11-2 (1.05 g, 27.84%).

[0326] MS(ESI,pos.ion)m / z:[M+H]=320.8

[0327] Step 2: Synthesis of 7-bromo-4-chloro-5-fluoroquinoline-3-sulfonamide

[0328] At 37°C, 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonamide (500 mg, 1.56 mmol) was added to phosphorus oxychloride (10.0 mL) in batches, and the reaction solution was stirred at 100°C for 18 hours. After the reaction of the raw materials was complete, the phosphorus oxychloride in the solution was removed by concentration under reduced pressure, and the crude product was separated by medium pressure liquid phase (EA: PE = 0%-60%) to obtain a brown liquid (200 mg, 37.83%).

[0329] MS(ESI,pos.ion)m / z:[M+H]=338.9

[0330] Step 3: Synthesis of 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide

[0331] At 37°C, 7-bromo-4-chloro-5-fluoroquinoline-3-sulfonamide (50 mg, 0.15 mmol) was added to 1,4-dioxane (2.0 ml) and water (0.2 ml), potassium carbonate (61 mg, 0.44 mmol), 2,4-dimethoxypyrimidine-5-boric acid (32 mg, 0.18 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (22 mg, 0.03 mmol) were added, and the mixture was reacted at 100°C for 1 h. 5 ml of water was added to the reaction solution, and the product was extracted with ethyl acetate (3 ml*3), and the organic phase was washed with saturated brine, and compound 11-4 (50 mg, 42.58%) was obtained by medium pressure liquid separation (EA:PE=0%-60%).

[0332] MS(ESI,pos.ion)m / z:[M+H]=399.0

[0333] Step 4: Synthesis of 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)benzoic acid

[0334] At 37°C, 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (50 mg, 0.13 mmol) and 3-amino-5-(3,5-difluorophenoxy)benzoic acid (33 mg, 0.13 mmol) were added to acetic acid (2.0 ml) and reacted at 55°C for 16 hours. The reaction solution was directly concentrated and dissolved in 1 ml of methanol. The crude product was separated by medium pressure liquid phase separation (EA:PE = 0%-60%) to obtain compound 11 (2.00 mg, 67%).

[0335] MS(ESI,pos.ion)m / z:[M+H]=627.7

[0336] 1HNMR (400MHz, DMSO) δ; 9.13 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.14 (d, J = 7.6Hz, 1H), 7.92 (s, 1H), 7.60 (d, J = 13.6Hz, 1H), 7.57 (s ,1H),7.28(s,1H),7.14(t,J=9.3Hz,1H),6.96(s,1H),6.94(s,1H),6.91(s,1H),6.68(dd,J=8.4,2.0Hz,4H),4.00(d,J=8.8Hz,6H)

[0337] Example 12: Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-isopropylsulfonylamino)quinolin-4-yl)amino)benzoic acid (12)

[0338]

[0339] Step 1: Synthesis of 7-bromo-5-fluoro-4-hydroxy-N-isopropylquinoline-3-sulfonamide

[0340] Under ice bath, 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (5.00 g, 14.7 mmol) was dissolved in tetrahydrofuran (50.0 mL), and then triethylamine (10.2 mL, 73.4 mmol) and isopropylamine (5.0 mL, 58.3 mmol) were slowly added to the solution, and the reaction solution was stirred at 37°C for 2 hours. After the reaction of the raw materials was complete, 100-200 mesh silica gel (5.00 g) was added to the reaction solution, and the solvent was removed by reduced pressure distillation. The crude product was purified by medium pressure liquid separation (methanol: dichloromethane = 0%-8%) to obtain compound 12-2 (3.20 g, 60%).

[0341] MS(ESI,pos.ion)m / z:[M+H]=362.8

[0342] Step 2: Synthesis of 7-bromo-4-chloro-5-fluoro-N-isopropylquinoline-3-sulfonamide

[0343] At 37°C, 7-bromo-5-fluoro-4-hydroxy-N-isopropylquinoline-3-sulfonamide (1.50 g, 4.12 mmol) was added to phosphorus oxychloride (15.0 mL) in batches, and the reaction solution was stirred at 100°C for 18 hours. After the reaction of the raw materials was complete, the phosphorus oxychloride in the solution was removed by concentration under reduced pressure, and the crude product was separated by medium pressure liquid phase (EA: PE = 0% -60%) to obtain brown liquid 7-bromo-4-chloro-5-fluoro-N-isopropylquinoline-3-sulfonamide (220 mg, 13.9%).

[0344] MS(ESI,pos.ion)m / z:[M+H]=382.8

[0345] Step 3: Synthesis of 3-((7-bromo-5-fluoro-3-(N-isopropylaminosulfonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0346] At 37°C, 7-bromo-4-chloro-5-fluoro-N-isopropylquinoline-3-sulfonamide (220 mg, 0.58 mmol) was dissolved in acetic acid (2.00 mL), and 3-amino-5-[(3,5-difluorophenyl)oxy]benzoic acid (153 mg, 0.58 mmol) was added, and the reaction solution was stirred at room temperature for 18 hours. After the reaction of the raw materials was complete, the reaction solution was distilled under reduced pressure to remove the solvent to obtain a crude product of 3-((7-bromo-5-fluoro-3-(N-isopropylaminosulfonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (400 mg).

[0347] [MS(ESI,pos.ion)m / z:[M+H]=610.0

[0348] Step 4: Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-isopropylsulfonylamino)quinolin-4-yl)amino)benzoic acid

[0349] At 37°C, 3-((7-bromo-5-fluoro-3-(N-isopropylaminosulfonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (400 mg, 0.66 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (144 mg, 0.79 mmol) dissolved in 1,4-dioxane (2.00 mL) and water (0.40 mL) were added to a 5 mL microwave tube, followed by the addition of 1,1'-di(difluorophenoxy)benzoic acid. The solution was deoxygenated with a nitrogen balloon for 20 seconds, and heated to 100°C in a microwave reactor for 30 minutes. After the reaction of the raw materials was complete, the reaction solution was filtered through diatomaceous earth, and the solvent was removed from the filtrate by reduced pressure distillation. The crude product was prepared by high pressure chromatography to obtain the title compound 12 (40.0 mg, 9.12%).

[0350] MS(ESI,pos.ion)m / z:[M+H]=670.0

[0351] 1 HNMR(400MHz,DMSO)δ9.09(s,1H),8.65(s,1H),8.52(s,1H),8.22(d,J=7.5Hz,1H),8.14(s,1H),7.58(d,J=13.7Hz,1H),7.38(s,1H),7 .19(s,1H),6.93(t,J=9.3Hz,1H),6.73(s,1H),6.66(dd,J=8.3,2.0Hz,2H),4.00(d,J=8.8Hz,6H),2.52(s,1H),0.91(d,J=6.5Hz,6H).

[0352] Example 13: Synthesis of 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-methylaminosulfonyl)quinolin-4-yl)amino)benzoic acid (13)

[0353]

[0354] Step 1: Synthesis of 5-((3-bromo-5-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0355] At 37°C, 3-bromo-5-fluoroaniline (10.0 g, 52.6 mmol) was dissolved in 1,4-dioxane (50 mL), and then 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.0 g, 53.7 mmol) was added to the reaction solution in batches. The mixed solution was stirred at 37°C for 2 hours, and a large amount of solid was observed to precipitate in the reaction solution. After the raw materials reacted completely, petroleum ether (50 mL) was added to the reaction solution and stirred for 5 minutes. The reaction solution was then filtered, and the filter cake was rinsed twice with petroleum ether (20.0 mL). The solid was concentrated under reduced pressure to remove the residual solvent to obtain 5-((3-bromo-5-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (14.5 g, 80%).

[0356] MS(ESI,pos.ion)m / z:[M+H]=344.1

[0357] Step 2: Synthesis of 7-bromo-5-fluoroquinolin-4-ol

[0358] Diphenyl ether (20.0 mL) was placed in a 100 mL single-mouth bottle, and the solution was heated to 200 ° C. 5-((3-bromo-5-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.0 g, 14.5 mmol) was added to the solution in batches and stirred at 200 ° C for 30 minutes. After that, the reaction solution was cooled to room temperature, petroleum ether (20 mL) was added and stirred for 10 minutes, and filtered. The filter cake was washed twice with petroleum ether (10 mL), and the solid was concentrated under reduced pressure to remove the residual solvent to obtain 7-bromo-5-fluoroquinoline-4-ol (2.5 g, 71%).

[0359] MS(ESI,pos.ion)m / z:[M+H]=242.0

[0360] Step 3: Synthesis of 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride

[0361] 7-Bromo-5-fluoroquinolin-4-ol (2.5 g, 10.3 mmol) was added to chlorosulfonic acid (20 mL) in batches, and the solution was stirred at 100°C for 16 hours. After the reaction of the raw materials was complete, the reaction solution was slowly and gradually added dropwise to ice water, and a large amount of light yellow solid was observed to precipitate in the water. The solid was filtered out by suction and dissolved in acetonitrile (50.0 mL). The solvent and residual water were removed by reduced pressure distillation to obtain 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (4.6 g, 13.5 mmol, 98%).

[0362] MS(ESI,pos.ion)m / z:[M+H]=340.5

[0363] Step 4: Synthesis of 7-bromo-5-fluoro-4-hydroxy-N-methylquinoline-3-sulfonamide

[0364] Under ice bath, 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (3.0 g, 8.8 mmol) was dissolved in tetrahydrofuran (15.0 mL), and then triethylamine (3.66 mL, 26.4 mmol) and methylammonium chloride (3.66 mL, 26.4 mmol) were slowly added to the solution, and the reaction solution was stirred at 37°C for 2 hours. After the reaction of the raw materials was complete, 100-200 mesh silica gel (5.0 g) was added to the reaction solution, and the solvent was removed by reduced pressure distillation. The crude product was purified by medium pressure liquid separation (methanol: dichloromethane = 10%) to obtain crude 7-bromo-5-fluoro-4-hydroxy-N-methylquinoline-3-sulfonamide (3.4 g, 98%).

[0365] MS(ESI,pos.ion)m / z:[M+H]=335.1

[0366] Step 5: Synthesis of 4,7-dichloro-5-fluoro-N-methylquinoline-3-sulfonamide

[0367] At 37°C, 7-bromo-5-fluoro-4-hydroxy-N-methylquinoline-3-sulfonamide (3.4 g, 10.1 mmol) was added to phosphorus oxychloride (25.0 mL) in batches, and the reaction solution was stirred at 100°C for 3 hours. After the reaction of the raw materials was complete, the phosphorus oxychloride in the solution was removed by vacuum concentration, and the crude product was separated by medium pressure liquid phase separation (ethyl acetate: petroleum ether = 0%-60%) to obtain 4,7-dichloro-5-fluoro-N-methylquinoline-3-sulfonamide (200 mg, 6.4%).

[0368] MS(ESI,pos.ion)m / z:[M+H]=309.4

[0369] Step 6: Synthesis of 3-((7-chloro-5-fluoro-3-(N-methylaminosulfonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0370] At 37°C, 4,7-dichloro-5-fluoro-N-methylquinoline-3-sulfonamide (100 mg, 0.32 mmol) was dissolved in acetic acid (2.00 mL), and 3-amino-5-[(3,5-difluorophenyl)oxy]benzoic acid (86 mg, 0.32 mmol) was added, and the reaction solution was stirred at room temperature for 18 hours. After the reaction of the raw materials was complete, the reaction solution was distilled under reduced pressure to remove the solvent, and the crude product was purified by thick preparative silica gel plate (dichloromethane: methanol = 10: 1) to obtain 3-((7-chloro-5-fluoro-3-(N-methylaminosulfonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (100 mg, 57%).

[0371] MS(ESI,pos.ion)m / z:[M+H]=573.9

[0372] Step 7: Synthesis of 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-methylaminosulfonyl)quinolin-4-yl)amino)benzoic acid

[0373] At 37°C, 3-((7-chloro-5-fluoro-3-(N-methylaminosulfonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (50 mg, 0.09 mmol) dissolved in 1,4-dioxane (1.00 mL) and water (0.20 mL) was added to a 5 mL microwave tube, followed by 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (13 mg, 0.02 mmol) and potassium carbonate (38 mg, 0.28 mmol). The solution was deoxygenated by blowing with a nitrogen balloon for 20 seconds, and heated to 100°C by a microwave reactor for 30 minutes. After the reaction of the raw materials was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to remove the solvent. The crude product was prepared by high pressure chromatography to obtain 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-methylaminosulfonyl)quinolin-4-yl)amino)benzoic acid (25 mg, 42.6%).

[0374] MS(ESI,pos.ion)m / z:[M+H]=641.6

[0375] 1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.63(s,1H),8.12(s,1H),7.55(s,1H),7.35(s,1H),7. 15(s,1H),6.90(t,J=9.3Hz,1H),6.72–6.61(m,3H),4.00(s,6H),3.99(s,3H),2.68(s,3H).

[0376] Example 14: Synthesis of 3-((3-(N-cyclobutylaminosulfonyl)-7-(2,4-dimethoxyphenyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (14)

[0377]

[0378] Step 1: Synthesis of 7-bromo-4-chloro-N-(cyclobutyl)-5-fluoroquinoline-3-sulfonamide

[0379] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (500 mg, 1.39 mmol) and TEA (423 mg, 4.18 mmol) were added to dry DCM (10 mL). Cyclobutylamine (89 mg, 1.25 mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 14-6 (33 mg, 6%).

[0380] MS (ESI, pos.ion) m / z: 392.9 [M+1] + .

[0381] Step 2: Synthesis of methyl 3-((3-(N-cyclobutylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0382] 7-Bromo-4-chloro-N-(cyclobutyl)-5-fluoroquinoline-3-sulfonamide (33 mg, 0.084 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (28 mg, 0.1 mmol) were added to AcOH (3 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 14-7 (42 mg, 79%).

[0383] MS (ESI, pos.ion) m / z: 636.2 [M+1] + .

[0384] Step 3: Synthesis of methyl 3-((3-(N-cyclobutylaminosulfonyl)-7-(2,4-dimethoxyphenyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0385] Methyl 3-((3-(N-cyclobutylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (42 mg, 0.066 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (18 mg, 0.099 mmol) and K2CO3 (32 mg, 0.226 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (7 mg, 0.006 mmol) was added under nitrogen flow, and then replaced with nitrogen, and stirred at 100°C for 1 h. H2O (5 mL) was added for dilution, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 14-8 (60 mg, crude product).

[0386] MS (ESI, pos.ion) m / z: 696.2 [M+1] + .

[0387] Step 4: Synthesis of 3-((3-(N-cyclobutylaminosulfonyl)-7-(2,4-dimethoxyphenyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0388] Methyl 3-((3-(N-cyclobutylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (60 mg, crude product) and lithium hydroxide (35.9 mg, 0.9 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 14 (9.5 mg).

[0389] MS (ESI, pos.ion) m / z: 682.1 [M+1] + .

[0390] 1H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),8.65(s,1H),8.61-8.51(m,2H),8.14(s,1H),7.59(br d,J=13.8Hz,1H),7.38(s,1H),7.19(s,1H),6.99-6.88(m,1H),6.72-6.62(m,3H),4.00(d,J=9.3Hz,6H),3.76-3.63(m,1H),1.83(br d,J=6.8Hz,2H),1.68(br t,J=9.8Hz,2H),1.51-1.34(m,2H).

[0391] Example 15: Synthesis of 3-((3-(N-cyclopropylmethylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (15)

[0392]

[0393] Step 1: Synthesis of 7-bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide

[0394] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g, 1.39 mmol) and TEA (846 mg, 8.36 mmol) were added to dry DCM (10 mL). Cyclopropylmethylamine (160 mg, 2.252 mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 15-6 (79 mg, 5%).

[0395] MS (ESI, pos.ion) m / z: 392.9 [M+1] + .

[0396] Step 2: Synthesis of methyl 3-((3-(N-cyclopropylmethylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0397] 7-Bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide (79 mg, 0.201 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (67 mg, 0.24 mmol) were added to AcOH (3 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 15-7 (51 mg, 40%).

[0398] MS (ESI, pos.ion) m / z: 636.0 [M+1] + .

[0399] Step 3: Synthesis of methyl 3-((3-(N-cyclopropylmethylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0400] Methyl 3-((3-(N-cyclopropylmethylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (51 mg, 0.08 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (22 mg, 0.12 mmol) and K2CO3 (32 mg, 0.226 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (9 mg, 0.008 mmol) was added under nitrogen flow, and then replaced with nitrogen, and stirred at 100°C for 1 h. H2O (5 mL) was added for dilution, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 15-8 (90 mg, crude product).

[0401] MS (ESI, pos.ion) m / z: 695.8 [M+1] + .

[0402] Step 4: Synthesis of 3-((3-(N-cyclopropylmethylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0403] Methyl 3-((3-(N-cyclopropylmethylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (90 mg, crude product) and lithium hydroxide (35.9 mg, 0.9 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 15 (10.5 mg, 51%).

[0404] MS (ESI, pos.ion) m / z: 682.1 [M+1] + .

[0405] 1H NMR(400MHz,DMSO-d6)δ:9.08(br s,1H),8.64(s,1H),8.53(br s,1H),8.30(br s,1H),8.13(br s,1H),7.57(br d,J=12.7Hz,1H),7.34(s,1H),7.16(s,1H),6.92(brt,J=9.4Hz,1H),6.77-6.56(m,3H),3.99(d,J=8.1Hz,6H),2.73(br d,J=6.8Hz,2H),0.71(br s,1H),0.33-0.17(m,2H),-0.04(br d,J=4.6Hz,2H).

[0406] Example 16: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxyphenyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (16)

[0407]

[0408] Step 1: Synthesis of methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxyphenyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0409] Methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (38 mg, 0.061 mmol), 2,4-dimethoxyphenylboronic acid (17 mg, 0.093 mmol) and K2CO3 (32 mg, 0.226 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (7 mg, 0.006 mmol) was added under a nitrogen flow, and then replaced with nitrogen, and stirred at 100°C for 1 h. H2O (5 mL) was added for dilution, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 16-8 (100 mg, crude product).

[0410] MS (ESI, pos.ion) m / z: 680.3 [M+1] + .

[0411] Step 2: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxyphenyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0412] Methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxyphenyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (100 mg, crude product) and lithium hydroxide (35.9 mg, 0.9 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 by adding an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 16 (3.6 mg).

[0413] MS (ESI, pos.ion) m / z: 666.1 [M+1] + .

[0414] 1HNMR (400MHz, DMSO-d6) δ: 9.05 (s, 1H), 8.58 (s, 1H), 8.49 (br s, 1H), 8.00 (s, 1H), 7.44 (br d, J = 8.7Hz, 2H), 7.35 (s, 1H), 7.16 (s, 1H), 6.93 (br t,J=9.2Hz,1H),6.79(s,1H),6.75-6.61(m,4H),3.83(d,J=9.3Hz,6H),2.21(br s,1H),0.48-0.29(m,4H).

[0415] Example 17: Synthesis of 3-(3-cyclopropylaminosulfonyl)-5-fluoro-7-phenylquinoline-4-amino)-5-(3,5-difluorophenoxy)benzoic acid (17)

[0416]

[0417] Step 1: Synthesis of 4-chloro-N-cyclopropyl-5-fluoro-7-phenylquinoline-3-sulfonamide

[0418] 7-Bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (50 mg, 0.132 mmol), tetrakistriphenylphosphine palladium (15 mg, 0.01 mmol), potassium carbonate (37 mg, 0.26 mmol) and phenylboronic acid (16 mg, 0.13 mmol) were dissolved in a mixed solution of dioxane / water (4:1, 2 mL) and stirred at 80°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added to extract the liquid. The organic phase was washed with a saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative silica gel plate (PE / EA=1 / 1) to obtain compound 17-2 (17 mg, 32%).

[0419] MS (ESI, pos.ion) m / z: 377.1 [M+1] + .

[0420] Step 2: Synthesis of 3-(3-cyclopropylaminosulfonyl)-5-fluoro-7-phenylquinolin-4-amino)-5-(3,5-difluorophenoxy)benzoic acid

[0421] 4-Chloro-N-cyclopropyl-5-fluoro-7-phenylquinoline-3-sulfonamide (10 mg, 0.02 mmol) and 3-amino-5-(3,5-difluorophenoxy)benzoic acid (12 mg, 0.04 mmol) were dissolved in acetic acid (2 mL) and stirred at 37°C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 3-(3-cyclopropylsulfonylamino)-5-fluoro-7-phenylquinoline-4-amino)-5-(3,5-difluorophenoxy)benzoic acid (6 mg, 22%).

[0422] MS (ESI, pos.ion) m / z: 606.1 [M+1] + .

[0423] 1 HNMR(DMSO-d6)δ:9.04(s,1H),8.53-8.66(m,1H),8.24(s,1H),8.17(s,1H),7.89(d,J=7.4Hz,2H),7.65(br d,J=13.6Hz,1H),7.51-7.59(m,2H),7.43-7.50(m,1H),7.35(s,1H),7.19(s,1H),6.86-6.96(m,1H),6.72(br s,1H),6.58-6.66(m,2H),2.19-2.26(m,1H),0.32-0.45(m,4H).

[0424] Example 18: Synthesis of 3-(7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (18)

[0425]

[0426] Step 1: Synthesis of 7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide

[0427] Under N2 protection, 7-bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (100 mg, 0.26 mmol), potassium carbonate (73 mg, 0.53 mmol), (2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)boric acid (75 mg, 0.26 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (19 mg, 0.03 mmol) were added to dioxane (10 mL) and water (2 mL) and reacted at 50°C for 1 hour. Ethyl acetate (10 mL) was added for extraction, and the mixture was washed with water (20 mL×2) and saturated sodium chloride solution (20 mL) in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give compound 18-2 (40 mg, 28%).

[0428] MS (ESI, pos.ion) m / z: 539.0 [M+1] +

[0429] Step 2: Synthesis of 3-(7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0430] 7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (40 mg, 0.074 mmol) and 3-amino-5-(3,5-difluorophenoxy)benzoic acid (39 mg, 0.15 mmol) were added to acetic acid (5 mL) and reacted at 18° C. for 18 hours. The mixture was concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography (0.01 mol / L formic acid: acetonitrile (v / v) = 0%-90%) to obtain compound 18 (1.6 mg, 2.8%).

[0431] MS (ESI, pos.ion) m / z: 768.1 [M+1] +

[0432] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.03 (s, 1H), 8.78 (s, 1H), 8.67 (s, 1H), 8.16 (s, 1H), 7.57 (d, J = 14.1Hz, 1H), 7.30 (s, 1H) ),7.15(s,1H),6.89(t,J=9.3Hz,1H),6.61(d,J=6.0Hz,5H),4.84–4.67(m,4H),2.21–2.20(m,1H),0.41–0.40(m,4H).

[0433] Example 19: Synthesis of 3-((3-(N-(tetrahydrofuran-3-yl)aminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (19)

[0434]

[0435]

[0436] Step 1: Synthesis of 7-bromo-4-chloro-5-fluoro-N-(tetrahydrofuran-3-yl)quinoline-3-sulfonamide

[0437] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g, 1.39 mmol) and TEA (846 mg, 8.36 mmol) were added to dry DCM (10 mL), and 3-aminotetrahydrofuran (194 mg, 2.23 mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 19-6 (52 mg, 4%).

[0438] MS (ESI, pos.ion) m / z: 408.8 [M+1] + .

[0439] Step 2: Synthesis of methyl 3-((3-(N-(tetrahydrofuran-3-yl)aminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0440] 7-Bromo-4-chloro-5-fluoro-N-(tetrahydrofuran-3-yl)quinoline-3-sulfonamide (52 mg, 0.127 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (42.7 mg, 0.153 mmol) were added to AcOH (3 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 19-7 (30 mg, 36%).

[0441] MS (ESI, pos.ion) m / z: 651.7 [M+1] + .

[0442] Step 3: Synthesis of methyl 3-((3-(N-(tetrahydrofuran-3-yl)aminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0443] Methyl 3-((3-(N-(tetrahydrofuran-3-yl)aminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (30 mg, 0.046 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (12.7 mg, 0.069 mmol) and K2CO3 (32 mg, 0.226 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL). The air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (5 mg, 0.004 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 1 h. H2O (5 mL) was added for dilution, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a brown oil (50 mg, crude product).

[0444] MS (ESI, pos.ion) m / z: 712.3 [M+1] + .

[0445] Step 4: Synthesis of 3-((3-(N-(tetrahydrofuran-3-yl)aminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0446] Methyl 3-((3-(N-(tetrahydrofuran-3-yl)aminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (50 mg, crude product) and lithium hydroxide (28.6 mg, 1.2 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 19 (1.88 mg).

[0447] MS (ESI, pos.ion) m / z: 698.1 [M+1] + .

[0448] 1H NMR (400MHz, DMSO-d6) δ: 9.09 (s, 1H), 8.64 (s, 1H), 8.60-8.45 (m, 2H), 8.14 (s, 1H), 7.58 (br d, J = 14.2Hz, 1H), 7.37 (s, 1H), 7.17 (s, 1H), 6.93 (br t,J=9.4Hz,1H),6.75(br s,1H),6.65(dd,J=2.0,8.4Hz,2H),3.99(d,J=7.9Hz,6H),3.81(br s,1H),3.62(q,J=7.5Hz,1H),3.57-3.48(m,2H),1.83(br dd,J=7.0,13.3Hz,1H),1.54(br s,1H).

[0449] Example 20: Synthesis of N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(methanesulfonamido)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (20)

[0450]

[0451]

[0452] Step 1: Synthesis of 1-bromo-3-(3,5-difluorophenoxy)-5-nitrobenzene

[0453] 3,5-Difluorophenylboronic acid (6.9 g, 43.70 mmol) and 3-bromo-5-nitrophenol (10.00 g, 45.88 mmol), Cu(OAc)2 (8.33 g, 45.88 mmol), DMAP (6.67 g, 54.62 mmol), 4A molecular sieve (6.9 g, 43.7 mmol) were added to dichloromethane (250 mL). The mixture was reacted at 30°C under oxygen for 16 h. The mixture was washed with H2O (100 mL*2) and saturated NaCl solution (200 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 20-2 (5.7 g, 39.52%).

[0454] 1 H NMR (400 MHz, deuterated chloroform) δ = 8.18 (t, J = 1.8 Hz, 1H), 7.80 (t, J = 2.1 Hz, 1H), 7.55-7.48 (m, 1H), 6.71 (tt, J = 2.3, 8.8 Hz, 1H), 6.65-6.54 (m, 2H)

[0455] Step 2: Synthesis of 1-(3,5-difluorophenoxy)-3-iodo-5-nitrobenzene

[0456] 1-Bromo-3-(3,5-difluorophenoxy)-5-nitrobenzene (2.0 g, 6.06 mmol), CuI (115.40 g, 605.91 mmol), NaI (2.72 g, 18.18 mmol), 1,10-phenanthroline (172.37 g, 1.21 mmol), Cs2CO3 (3.95 g, 12.12 mmol) were added to dioxane (50 mL). The mixture was reacted at 100°C for 16 h. After cooling to room temperature, PE (20 mL) was added and filtered to obtain compound 20-3 (1.5 g, 65.65%).

[0457] 1 H NMR (400 MHz, deuterated chloroform) δ = 8.36 (t, J = 1.7 Hz, 1H), 7.83 (t, J = 2.1 Hz, 1H), 7.70 (dd, J = 1.5, 2.2 Hz, 1H), 6.73-6.69 (m, 1H), 6.60-6.57 (m, 2H)

[0458] Step 3: Synthesis of 1-(3,5-difluorophenoxy)-3-(methylsulfonyl)-5-nitrobenzene

[0459] 1-(3,5-difluorophenoxy)-3-iodo-5-nitrobenzene (0.7 g, 1.86 mmol) and MeSO2 - Na + (379.02 mg, 3.71 mmol), L-proline (42.74 mg, 371.27 mmol), CuI (35.35 mg, 185.64 mmol), K2CO3 (51.31 mg, 371.27 mmol) were added to DMSO (20 mL). The reaction was carried out at 80°C for 16 h. EtOAc (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 4 / 1) to obtain compound 20-4 (120 mg, 19.63%).

[0460] Step 4: Synthesis of 1-(3,5-difluorophenoxy)-3-(methylsulfonyl)-5-aminobenzene

[0461] 1-(3,5-difluorophenoxy)-3-(methylsulfonyl)-5-nitrobenzene (100 mg, 303.70 mmol), Fe (84.80 mg, 1.52 mmol), NH4Cl (243.68 mg, 4.56 mmol), were added to EtOH (1 mL), THF (1 mL) and H2O (0.5 mL), and reacted at 90°C for 2 h. EtOAc (4 mL) was added for dilution, and the mixture was washed with H2O (2 mL*2) and saturated NaCl solution (10 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 20-5 (51 mg, 56.11%).

[0462] Step 5: Synthesis of 7-bromo-N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(methylsulfonyl)phenyl)amino)-5-fluoro-quinoline-3-sulfonamide

[0463] 7-Bromo-4-chloro-N-cyclopropyl-5-fluoro-quinoline-3-sulfonamide (65 mg, 171.22 mmol) and 1-(3,5-difluorophenoxy)-3-(methylsulfonyl)-5-aminobenzene (51.24 mg, 171.22 mmol) were added to dry AcOH (2 mL). The mixture was stirred at 80°C for 1 h. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 20-6 (52.7 mg, 47.91%).

[0464] MS (ESI, pos.ion) m / z: 643.6 [M+1] + .

[0465] Step 6: Synthesis of N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(methylsulfonyl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide

[0466] 7-Bromo-N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(methylsulfonyl)phenyl)amino)-5-fluoro-quinoline-3-sulfonamide (52.7 mg, 82.03 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (18.11 mg, 98.43 mmol) and K2CO3 (124.71 mg, 902.31 mmol) were added to a mixture of dioxane (5 mL) and water (1 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (9.48 mg, 8.20 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 80°C for 3 h. H2O (5 mL) was added to dilute, extracted with EA (5 mL*3), washed with saturated NaCl solution (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 20 (167 mg, crude product).

[0467] MS(ESI,pos.ion)m / z:702.69[M+1] + .

[0468] 1 H NMR (400MHz, DMSO-d6) δ = 9.10 (s, 1H), 8.76 (br s, 1H), 8.65 (s, 1H), 8.51 (brs, 1H), 8.17 (s, 1H), 7.62 (br d,J=13.6Hz,1H),7.37(s,1H),7.19(s,1H),6.97(br t,J=9.4Hz,1H),6.84-6.67(m,2H),6.84-6.66(m,1H),3.99(d,J=8.0Hz,6H),3.21(s,3H),2.23(br s,1H),0.36(br d,J=8.5Hz,4H)

[0469] Example 21: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)-N-hydroxybenzamide (21)

[0470]

[0471] Step 1: Synthesis of methyl 3-((7-bromo-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0472] 7-Bromo-4-chloro-N-cyclopropyl-5-fluoro-quinoline-3-sulfonamide (630 mg, 1.66 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (556 mg, 1.99 mmol) were added to acetic acid (5 mL). The mixture was reacted at 80°C for 1 h. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 21-2 (430 mg, 42%).

[0473] Step 2: Synthesis of 3-((7-bromo-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0474] Methyl 3-((7-bromo-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (100 mg, 160 mmol) and lithium hydroxide (18 mg, 480 mmol) were added to methanol (1 mL) and water (0.2 mL), and then added to methanol (2 mL). The mixture was reacted at 37°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 3-4 with an appropriate amount of 1M HCl. The mixture was extracted with EA (2 mL*3), concentrated under reduced pressure, cooled to room temperature, PE (20 mL) was added, and filtered to obtain compound 21-3 (80 mg, crude product).

[0475] Step 3: Synthesis of 3-((7-bromo-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)-N-((tetrahydrofuran-2H-pyran-2-yl)oxy)benzamide

[0476] 3-((7-bromo-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (80 mg, 131.5 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (15.4 mg, 131.5 mmol), 1-propylphosphoric acid cyclic anhydride (62.76 mg, 197.24 mmol), TEA (26.61 mg, 262.99 mmol) were added to dioxane (2 mL). The reaction was carried out at 50° C. for 16 h. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 21-4 (61 mg, 66%).

[0477] MS (ESI, pos.ion) m / z: 708.5 [M+1] + .

[0478] 1H NMR (400 MHz, deuterated chloroform) δ = 8.55 (t, J = 1.6 Hz, 1H), 8.10 (t, J = 2.1 Hz, 1H), 7.91 (dd, J = 1.5, 2.3 Hz, 1H), 6.78 (tt, J = 2.3, 8.8 Hz, 1H), 6.69-6.57 (m, 2H), 3.16 (s, 3H)

[0479] Step 4: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(difluorophenoxy)-N-((tetrahydrofuran-2H-pyran-2-yl)oxy)benzamide

[0480] 3-((7-Bromo-3-(N-cyclopropylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)-N-((tetrahydrofuran-2H-pyran-2-yl)oxy)benzamide (61 mg, 86.22 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (19 mg, 103.46 mmol) and K2CO3 (138.21 mg, 1 mmol) were added to a mixture of dioxane (5 mL) and water (1 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (9.96 mg, 8.62 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 5 h. H2O (5 mL) was added for dilution, extracted with EA (5 mL*3), washed with saturated NaCl solution (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a brown oil (126 mg, crude product).

[0481] MS (ESI, pos.ion) m / z: 767.7 [M+1] + .

[0482] Step 5: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)-N-hydroxybenzamide

[0483] 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(difluorophenoxy)-N-((tetrahydrofuran-2H-pyran-2-yl)oxy)benzamide (126 mg, crude) and TFA (770 mg, 6.75 mmol) were added to dry DCM (2 mL). The mixture was concentrated under reduced pressure and the crude product was purified by HPLC to give compound 21 (19.66 mg, 17.5%).

[0484] MS (ESI, pos.ion) m / z: 683.6 [M+1] + .

[0485] 1 H NMR (400MHz, DMSO-d6) δ = 11.49-10.98 (m, 1H), 9.05 (br s, 2H), 8.64 (s, 2H), 8.13 (s, 1H), 7.56 (br d,J=13.6Hz,1H),7.22(s,1H),7.10(s,1H),6.94(br t,J=9.3Hz,1H),6.75(s,1H),6.66(dd,J=2.1,8.4Hz,2H),4.00(s,3H),3.98(s,2H),3.99-3.97(m,1H),2.22(quin,J=5.1Hz,1H),0.37(br s,4H)

[0486] Example 22: Synthesis of 3-((3-(N-cyclobutylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (22)

[0487]

[0488]

[0489] Step 1: Synthesis of 7-bromo-4-chloro-N-(cyclobutyl)quinoline-3-sulfonamide

[0490] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (500 mg, 1.39 mmol) and TEA (423 mg, 4.18 mmol) were added to dry DCM (10 mL). Cyclobutylamine (89 mg, 1.25 mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 22-2 (33 mg, 6%).

[0491] MS (ESI, pos.ion) m / z: 392.9 [M+1] + .

[0492] 1H NMR (400 MHz deuterated chloroform) δ: 9.42-9.35 (m, 1H), 8.21 (t, J = 1.5 Hz, 1H), 7.54 (dd, J = 1.9, 11.4 Hz, 1H), 3.87 (sxt, J = 8.4 Hz, 1H), 2.14-2.02 (m, 2H), 1.95-1.77 (m, 2H), 1.69-1.57 (m, 2H).

[0493] Step 2: Synthesis of methyl 3-((3-(N-cyclobutylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0494] 7-Bromo-4-chloro-N-(cyclobutyl)quinoline-3-sulfonamide (33 mg, 0.084 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (28 mg, 0.1 mmol) were added to AcOH (3 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 22-3 (42 mg, 79%).

[0495] MS (ESI, pos.ion) m / z: 636.2 [M+1] + .

[0496] Step 3: Synthesis of methyl 3-((3-(N-cyclobutylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0497] Methyl 3-((3-(N-cyclobutylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (42 mg, 0.066 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (18 mg, 0.099 mmol) and K2CO3 (32 mg, 0.226 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (7 mg, 0.006 mmol) was added under nitrogen flow, and then replaced with nitrogen, and stirred at 100°C for 1 h. H2O (5 mL) was added for dilution, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 22-4 (60 mg, crude product).

[0498] MS (ESI, pos.ion) m / z: 696.2 [M+1] + .

[0499] Step 4: Synthesis of 3-((3-(N-cyclobutylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0500] Methyl 3-((3-(N-cyclobutylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (60 mg, crude product) and lithium hydroxide (35.9 mg, 0.9 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 by adding an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 22 (9.5 mg, 7%).

[0501] MS (ESI, pos.ion) m / z: 682.1 [M+1] + .

[0502] 1 H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),8.65(s,1H),8.61-8.51(m,2H),8.14(s,1H),7.59(br d,J=13.8Hz,1H),7.38(s,1H),7.19(s,1H),6.99-6.88(m,1H),6.72-6.62(m,3H),4.00(d,J=9.3Hz,6H),3.76-3.63(m,1H),1.83(br d,J=6.8Hz,2H),1.68(br t,J=9.8Hz,2H),1.51-1.34(m,2H).

[0503] Example 23: Synthesis of N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (23)

[0504]

[0505]

[0506] Step 1: Synthesis of methyl 3-(3,5-difluorophenoxy)-5-nitrobenzoate

[0507] 3-Methoxycarbonyl-5-nitrobenzeneboronic acid (5.00 g, 22.23 mmol) and 3,5-difluorophenol (3.04 g, 23.34 mmol), Cu(OAc) (4.24 g, 23.34 mmol), 4A MS (5.00 g, 22.23 mmol), DMAP (3.39 g, 27.78 mmol) were added to dichloromethane (200 mL), oxygen was replaced three times, and the mixture was reacted at 30°C for 16 h under oxygen conditions. The mixture was first filtered with diatomaceous earth, and the filtrate was quenched with an aqueous solution (100 mL), washed with EtOAc (100 mL*2) and saturated NaCl solution (100 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 23-2 (3.27 g, 47.58%).

[0508] MS (ESI, negative ion) m / z: 312.2 [M+1] + .

[0509] 1H NMR (400MHz, deuterated chloroform) δ=8.68-8.63 (m, 1H), 8.06 (t, J=2.2Hz, 1H), 8.01 (dd, J=1.3, 2.3Hz, 1H), 6.70 (dt, J=2.1, 4.4Hz, 1H), 6.62-6.56 (m, 2H), 3.99 (s, 3H)

[0510] Step 2: Synthesis of (3-(3,5-difluorophenoxy)-5-nitrobenzyl alcohol

[0511] Methyl 3-(3,5-difluorophenoxy)-5-nitrobenzoate (2.00 g, 6.47 mmol) was added to tetrahydrofuran (20 mL), and LiBH4 (281.79 mg, 12.94 mmol) was added at 0°C, and the mixture was reacted at 37°C for 2 h. Saturated NH4Cl solution (100 mL) was added to quench the mixture, and the mixture was washed with EtOAc (100 mL*2) and saturated NaCl solution (100 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 23-3 (570 mg, 31.34%).

[0512] MS (ESI, negative ion) m / z: 345.8 [M+1] + .

[0513] 1H NMR (400 MHz, deuterated chloroform) δ: 11.18 (br d, J = 13.4 Hz, 1H), 8.56 (d, J = 13.9 Hz, 1H), 7.23 (s, 1H), 7.15 (td, J = 1.8, 7.8 Hz, 1H), 6.94 (td, J = 2.0, 9.2 Hz, 1H), 1.76 (s, 6H).

[0514] Step 3: Synthesis of (3-(3,5-difluorophenoxy)-5-nitrobenzaldehyde

[0515] Add (3-(3,5-difluorophenoxy)-5-nitrobenzyl alcohol (570 mg, 2.03 mmol) and Dess-Martin (1.29 g, 3.04 mmol) to dichloromethane (10 mL). React at 30°C for 16 h. Add aqueous solution (10 mL) to quench, wash with EtOAc (10 mL*2) and saturated NaCl solution (10 mL) in sequence, dry over anhydrous Na2SO4, and concentrate under reduced pressure. The crude product is separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 23-4 (387 mg, 68.38%).

[0516] MS (ESI, neg.ion) m / z: 282.2 [M+1] + .

[0517] 1H NMR (400MHz, deuterated chloroform) δ=10.13-10.03(m,1H),8.51(s,1H),8.13(d,J=2.1Hz,1H),7.85(s,1H),6.73-6.71(m,1H),6.80-6.68(m,1H),4.04-3.93(m,1H)

[0518] Step 4: Synthesis of 1-(3-(3,5-difluorophenoxy)-5-nitrophenyl)-2,2,2-trifluoroethanol

[0519] (3-(3,5-difluorophenoxy)-5-nitrobenzaldehyde (387 mg, 1.39 mmol) and TMSCF3 (256.23 mg, 1.8 mmol), CsF (210.56 mg, 1.39 mmol), TBAF (36.24 mg, 138.61 mmol) were added to THF (3 mL). The mixture was reacted at 30°C for 2 h. The mixture was quenched by adding aqueous solution (10 mL), washed with EtOAc (10 mL*2) and saturated NaCl solution (10 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 23-5 (280 mg, 57.85%).

[0520] MS (ESI, pos.ion) m / z: 350.2 [M+1] + .

[0521] 1H NMR (400 MHz, deuterated chloroform) δ = 8.24-8.15 (m, 1H), 7.90 (br d, J = 1.9 Hz, 1H), 7.56 (s, 1H), 6.75-6.64 (m, 1H), 6.59 (br dd, J = 1.8, 7.6 Hz, 2H), 5.18 (br d, J = 2.6 Hz, 1H)

[0522] Step 5: Synthesis of 1-(3-(3,5-difluorophenoxy)-5-aminophenyl)-2,2,2-trifluoroethanol

[0523] 1-(3-(3,5-difluorophenoxy)-5-nitrophenyl)-2,2,2-trifluoroethanol (175 mg, 501.13 mmol) and Fe (139.93 mg, 2.51 mmol), NH4Cl (402.09 mg, 7.52 mmol) were added to EtOH (2 ml) and THF (2 ml), H2O (1 ml), and reacted at 90°C for 2 h. Aqueous solution (10 mL) was added to quench the mixture, and the mixture was washed with EtOAc (10 mL*2) and saturated NaCl solution (10 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 23-6 (120 mg, 75.01%).

[0524] MS (ESI, pos.ion) m / z: 350.2 [M+1] + .

[0525] 1H NMR (400 MHz, deuterated chloroform) δ = 8.24-8.15 (m, 1H), 7.90 (br d, J = 1.9 Hz, 1H), 7.56 (s, 1H), 6.75-6.64 (m, 1H), 6.59 (br dd, J = 1.8, 7.6 Hz, 2H), 5.18 (br d, J = 2.6 Hz, 1H)

[0526] Step 6: Synthesis of 7-bromo-N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(2,2,2-trifluoroether-1-hydroxyethyl)phenyl)amino)-5-fluoroquinoline-3-sulfonamide

[0527] 1-(3-(3,5-difluorophenoxy)-5-aminophenyl)-2,2,2-trifluoroethanol (72.32 mg, 226.54 mmol) and 7-bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide (86 mg, 226.54 mmol) were added to acetic acid (2 mL). Stirred at 80°C for 1 hour. Concentrated under reduced pressure, the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 23-7 (49 mg, 32.65%).

[0528] MS (ESI, pos.ion) m / z: 663.4 [M+1] + .

[0529] Step 7: Synthesis of N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide

[0530] 7-Bromo-N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(2,2,2-trifluoroether-1-hydroxyethyl)phenyl)amino)-5-fluoroquinoline-3-sulfonamide (49 mg, 73.97 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (16.33 mg, 88.77 mmol) and K2CO3 (112.46 mg, 813.71 mmol) were added to a mixture of dioxane (5 mL) and water (1 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (8.55 mg, 7.4 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 80°C for 16 h. H2O (5 mL) was added for dilution, extracted with EA (5 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 23 (15.81 mg).

[0531] MS (ESI, pos.ion) m / z: 722.6 [M+1] + .

[0532] 1H NMR (400MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.66-8.53 (m, 3H), 8.14-8.10 (m, 1H), 7.52 (br d,J=14.3Hz,1H),6.95-6.86(m,4H),6.72-6.60(m,3H),5.12(br t,J=6.8Hz,1H),3.99(d,J=6.0Hz,6H),2.17(br d,J=3.8Hz,1H),0.41-0.33(m,4H)

[0533] Example 24: Synthesis of N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(3-hydroxyisoxazol-5-yl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (24)

[0534]

[0535] Step 1: Synthesis of ethyl 3-(3-(3,5-difluorophenoxy)-5-nitrophenyl)propiolate

[0536] 1-(3,5-difluorophenoxy)-3-iodo-5-nitrobenzene (1.00 g, 2.65 mmol), ethyl propiolate (260.16 mg, 2.65 mmol), CuI (25.25 mg, 132.60 mmol), Pd(PPh3)2Cl2 (93.07 mg, 132.60 mmol), K2CO3 (733.05 mg, 5.30 mmol) were added to DCM (30 mL). The mixture was reacted at 37°C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 24-2 (760 mg, 82.6%).

[0537] 1 H NMR (400 MHz, deuterated chloroform) δ = 8.36 (t, J = 1.6 Hz, 1H), 8.24-8.15 (m, 2H), 7.94 (t, J = 2.2 Hz, 1H), 7.82 (td, J = 2.1, 7.8 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.51 (d, J = 1.4 Hz, 2H), 6.78-6.66 (m, 2H), 6.65-6.54 (m, 5H), 4.33 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H)

[0538] Step 2: Synthesis of ethyl 3-(3-(3,5-difluorophenoxy)-5-aminophenyl)propiolate

[0539] Add 3-(3-(3,5-difluorophenoxy)-5-nitrophenyl)propiolic acid ethyl ester (726 mg, 2.09 mmol), iron powder (583.75 mg, 10.45 mmol), ammonium chloride (1.68 g, 31.36 mmol) to a mixed solvent of ethanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL). React at 90 ° C for 16 hours. Cool to room temperature, dilute with water (3 mL), extract with EtOAc (3 mL*3), wash with saturated NaCl solution (3 mL), dry with anhydrous Na2SO4, and concentrate under reduced pressure. The crude product is separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain compound 24-3 (200 mg, 30.15%)

[0540] Step 3: Synthesis of ethyl 3-(3-((7-bromo-3-(N-cyclopropylsulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)phenyl)propiolate

[0541] 7-Bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide (100 mg, 263.41 mmol) and ethyl 3-(3-(3,5-difluorophenoxy)-5-aminophenyl)propiolate (83.58 mg, 263.41 mmol, 1 eq) were added to AcOH (4 mL). The mixture was stirred at 75°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 24-4 (62 mg, 35.64%).

[0542] MS (ESI, pos.ion) m / z: 661.4 [M+1] + .

[0543] Step 4: Synthesis of ethyl 3-(3-((3-(N-cyclopropylsulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)phenyl)propiolate

[0544] Ethyl 3-(3-((7-bromo-3-(N-cyclopropylsulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)phenyl)propiolate (62 mg, 93.87 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (25.90 mg, 140.81 mmol), and K2CO3 (142.72 mg, 1.03 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL). The air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (10.85 mg, 9.39 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 80°C for 1 h. Add H2O (3 mL) to dilute, extract with EA (3 mL*3), wash with saturated NaCl solution (3 mL), dry over anhydrous Na2SO4, and concentrate under reduced pressure to obtain compound 24-5 (123 mg, crude product).

[0545] MS (ESI, pos.ion) m / z: 720.6 [M+1] + .

[0546] Step 5: Synthesis of N-cyclopropyl-4-((3-(3,5-difluorophenoxy)-5-(3-hydroxyisoxazol-5-yl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide

[0547] NaOH (68.36 mg, 1.71 mmol) was added to H2O (0.5 mL) at 0°C. Hydroxylamine hydrochloride (35.63 mg, 512.72 mmol) was added slowly in batches. After 10 minutes, ethyl 3-(3-((3-(N-cyclopropylsulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)phenyl)propiolate (123 mg, crude product) was added to methanol (5 mL). The reaction was stirred at 30°C for 16 h. H2O (5 mL) was added for dilution, extracted with EA (5 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 24 (5.29 mg).

[0548] MS (ESI, pos.ion) m / z: 707.6 [M+1] + .

[0549] 1H NMR (400MHz, DMSO-d6) δ = 11.48 (s, 1H), 9.09-9.02 (m, 1H), 8.70-8.49 (m, 3H) ),8.19-8.08(m,1H),7.67-7.54(m,1H),7.37(s,1H),7.22(s,1H),6.91(br d,J=9.3Hz,2H),6.67-6.57(m,3H),4.02-3.97(m,6H),2.24(br s,1H),0.51-0.30(m,4H)

[0550] Example 25: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)-1H-tetrazolyl-5-ylbenzene (25)

[0551]

[0552] Step 1: Synthesis of 3-(3,5-difluorophenoxy)-5-nitrobenzonitrile

[0553] 3-Hydroxy-5-nitro-benzonitrile (1.00 g, 6.10 mmol), 3,5-difluorophenylboronic acid (0.92 g, 5.82 mmol), copper acetate (1.11 g, 6.10 mmol), DMAP (0.89 g, 7.30 mmol), 4A MS (6.9 g) were added to DCM (30 mL). The mixture was reacted at 37° C. for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 25-2 (0.26 g, 16%).

[0554] MS (ESI, neg.ion) m / z: 277.2 [M-1] + .

[0555] 1 H NMR (400 MHz, deuterated chloroform) δ: 8.32-8.25 (m, 1H), 8.06 (t, J = 2.1 Hz, 1H), 7.59 (dd, J = 1.3, 2.3 Hz, 1H), 6.78 (tt, J = 2.3, 8.8 Hz, 1H), 6.68-6.57 (m, 2H)

[0556] Step 2: Synthesis of 5-(3-(3,5-difluorophenoxy)-5-nitrophenyl)-1H-tetrazolyl

[0557] 3-(3,5-difluorophenoxy)-5-nitrobenzonitrile (150 mg, 0.54 mmol), ammonium chloride (145 mg, 2.71 mmol), and NaN3 (160 mg, 2.46 mmol) were added to DMF (5 mL). The mixture was reacted at 95°C for 16 h. After cooling to room temperature, the mixture was poured into H2O (20 mL) and diluted. The mixture was extracted with EtOAc (10 mL*3), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain compound 25-3 (270 mg, crude product).

[0558] MS (ESI, pos.ion) m / z: 319.9 [M+1] + .

[0559] Step 3: Synthesis of 3-(3,5-difluorophenoxy)-5-(1H-tetrazol-5-yl)aniline

[0560] 5-(3-(3,5-difluorophenoxy)-5-nitrophenyl)-1H-tetrazole (270 mg, crude), iron powder (236 mg, 4.21 mmol), ammonium chloride (678 mg, 12.8 mmol) were added to a mixed solvent of ethanol (1 mL), tetrahydrofuran (1 mL) and water (0.5 mL). The mixture was reacted at 90°C for 2 h. The mixture was cooled to room temperature, diluted with water (3 mL), extracted with EtOAc (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain compound 25-4 (390 mg, crude).

[0561] MS (ESI, pos.ion) m / z: 632.1 [M+1] + .

[0562] Step 4: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)-1H-tetrazol-5-ylbenzene

[0563] 7-Bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide (100 mg, 0.265 mmol) and 3-(1H-tetrazolyl-5-yl)-5-(3,5-difluorophenoxy)aniline (76 mg, 0.263 mmol) were added to AcOH (4 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 25-5 (79 mg, 47%).

[0564] MS (ESI, pos.ion) m / z: 633.1 [M+1] + .

[0565] Step 5: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)-1H-tetrazolyl-5-ylbenzene

[0566] 3-((3-(N-cyclopropylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)-1H-tetrazol-5-ylbenzene (79 mg, 0.125 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (34 mg, 0.187 mmol) and K2CO3 (130 mg, 0.94 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (14 mg, 0.01 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 5 h. H2O (3 mL) was added for dilution, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain Compound 25 (15.28 mg, 16.9%).

[0567] MS (ESI, pos.ion) m / z: 692.2 [M+1] + .

[0568] 1 H NMR (400MHz, DMSO-d6) δ: 9.03 (s, 1H), 8.63 (s, 1H), 8.11 (d, J = 1.5Hz, 1H), 7.60-7.18 (m, 6H), 6.94-6 .84(m,1H),6.66(dd,J=2.1,8.5Hz,2H),6.46(t,J=2.1Hz,1H),4.02-3.92(m,6H),0.47-0.29(m,4H).

[0569] Example 26: Synthesis of N-cyclopropyl-4-((3-((4,4-difluorocyclohexyl)oxy)-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-ylphenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (26)

[0570]

[0571] Step 1: Synthesis of methyl 3-(4,4-difluorocyclohexyloxy)-5-nitrobenzoate

[0572] Methyl 3-hydroxy-5-nitrobenzoate (1.00 g, 5.07 mmol), 4,4-difluorocyclohexanol (690.56 g, 5.07 mmol), triphenylphosphine (1.60 g, 6.09 mmol), DIAD (1.23 g, 6.09 mmol) were added to DCM (30 mL). The mixture was reacted at 37°C for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 10 / 1) to give a white solid (580 mg, 36.27%).

[0573] Step 2: Synthesis of 3-(4,4-difluorocyclohexyloxy)-5-nitrobenzoylhydrazide

[0574] Add methyl 3-(4,4-difluorocyclohexyloxy)-5-nitrobenzoate (580 mg, 1.84 mmol) and hydrazine hydrate (793 mg, 12.67 mmol) to EtOH (20 mL). React at 90°C for 5 h. Cool to room temperature, filter, and collect the solid to obtain the crude product compound 26-3 (580 mg, crude product).

[0575] 1 H NMR (400 MHz, deuterated chloroform) δ = 8.12 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.71 (s, 1H), 7.51 (br s, 1H), 4.68 (br s, 1H), 2.14-1.96 (m, 8H)

[0576] Step 3: Synthesis of 5-(3-((4,4-difluorocyclohexyloxy)-5-nitrobenzene)-1,3,4-oxadiazol-2(3H)-one

[0577] 3-(4,4-difluorocyclohexyloxy)-5-nitrobenzoic acid hydrazide (580 mg, 1.84 mmol), CDI (596.60 mg, 3.68 mmol), triethylamine (558.47 mg, 5.52 mmol) were added to tetrahydrofuran (5 mL) solvent. The reaction was carried out at 60°C for 16 h. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain compound 26-4 (480 mg, 76.45%).

[0578] 1 H NMR (400 MHz, deuterated chloroform) δ = 8.32 (t, J = 1.6 Hz, 1H), 7.88 (t, J = 2.1 Hz, 1H), 7.68 (dd, J = 1.4, 2.4 Hz, 1H), 4.68 (br d, J = 2.5 Hz, 1H), 2.15-1.96 (m, 8H)

[0579] Step 4: Synthesis of 5-(3-amino-5-(((4,4-difluorocyclohexyl)oxy))phenyl)-1,3,4-oxadiazol-2(3H)-one

[0580] 5-(3-((4,4-difluorocyclohexyloxy)-5-nitrobenzene)-1,3,4-oxadiazol-2(3H)-one (100 mg, 293.03 mmol) and tin dichloride dihydrate (264.48 mg, 1.17 mmol) were added to ethanol (2 mL) solvent. The mixture was reacted at 70°C for 1 h. The mixture was cooled to room temperature, diluted with water (3 mL), extracted with EtOAc (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (DCM / MeOH (v / v) = 10 / 1) to give compound 26-5 (120 mg, crude product).

[0581] MS (ESI, pos.ion) m / z: 312.2 [M+1] + .

[0582] 1 H NMR (400MHz, DMSO-d6) δ = 6.64 (s, 1H), 6.57 (s, 1H), 6.39 (t, J = 1.9Hz, 1H), 5.54 (br s, 1H), 4.50 (br d,J=3.0Hz,1H),4.08-3.99(m,1H),2.03-1.85(m,8H)

[0583] Step 5: Synthesis of 7-bromo-N-cyclopropyl-4-((3-((4,4-difluorocyclohexyl)oxy)-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-ylphenyl)amino)-5-fluoroquinoline-3-sulfonamide

[0584] 7-Bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide (70 mg, 184.39 mmol) and 5-(3-amino-5-(((4,4-difluorocyclohexyl)oxy)phenyl)-1,3,4-oxadiazol-2(3H)-one (57.4 mg, 184.39 mmol) were added to AcOH (2 mL). The mixture was stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 26-7 (55.5 mg, 45.99%).

[0585] MS (ESI, pos.ion) m / z: 655.4 [M+1] + .

[0586] Step 6: Synthesis of N-cyclopropyl-4-((3-((4,4-difluorocyclohexyl)oxy)-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-ylphenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide

[0587] 7-Bromo-N-cyclopropyl-4-((3-((4,4-difluorocyclohexyl)oxy)-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-ylphenyl)amino)-5-fluoroquinoline-3-sulfonamide (55.5 mg, 84.8 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (15.6 mg, 84.8 mmol) and K2CO3 (128.92 mg, 932.84 mmol) were added to dioxane (2 m L) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, Pd(PPh3)4 (9.80 mg, 8.48 mmol) was added under nitrogen flow, and then replaced with nitrogen, and stirred at 80°C for 1 h. H2O (3 mL) was added for dilution, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 26 (17.16 mg, 28.35%).

[0588] MS (ESI, pos.ion) m / z: 714.6 [M+1] + .

[0589] 1 H NMR (400MHz, DMSO-d6) δ = 12.84 (br s, 1H), 9.07 (s, 1H), 8.64 (s, 1H), 8.57 (brd, J = 7.8Hz, 2H), 8.17 (s, 1H), 7.56 (br d,J=13.6Hz,1H),7.05(s,1H),6.92(s,1H),6.78(s,1H),4.52(br s,1H),3.98(d,J=7.5Hz,6H),2.23(br s,1H),2.05-1.73(m,8H),0.43-0.38(m,4H),0.47-0.38(m,1H)

[0590] Example 27: Synthesis of N-cyclopropyl-4-((3-((4,4-difluorocyclohexyl)oxy)-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide (27)

[0591]

[0592] Step 1: Synthesis of 3-(4,4-difluorophenoxy)-5-nitrobenzonitrile

[0593] 3-Hydroxy-5-nitrobenzonitrile (1.00 g, 6.09 mmol), 4,4-difluorocyclohexanol (829.52 g, 6.09 mmol), triphenylphosphine (1.92 g, 7.31 mmol), DIAD (1.48 g, 7.31 mmol) were added to DCM (30 mL). The mixture was reacted at 37°C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 10 / 1) to give compound 27-2 (900 mg, 52.33%).

[0594] Step 2: Synthesis of (Z)-3-((4,4-difluorophenoxy)-N'-hydroxy-5-nitrobenzyl imine

[0595] 3-(4,4-difluorophenoxy)-5-nitrobenzonitrile (500 mg, 1.77 mmol) and 50% aqueous solution of hydroxylamine (1.17 g, 17.72 mmol) were added to EtOH (10 mL). The mixture was reacted at 90°C for 3 h. The mixture was cooled to room temperature, filtered, and the solid was collected to obtain the crude product compound 27-3 (600 mg, crude product).

[0596] 1 H NMR (400 MHz, deuterated chloroform) δ = 8.08 (t, J = 1.5 Hz, 1H), 7.79 (t, J = 2.1 Hz, 1H), 7.58-7.49 (m, 1H), 4.64 (br d, J = 2.8 Hz, 1H), 2.30-1.89 (m, 8H)

[0597] Step 3: Synthesis of 3-(3-((4,4-difluorophenoxy)-5-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one

[0598] (Z)-3-((4,4-difluorophenoxy)-N'-hydroxy-5-nitrobenzylamine (500 mg, 1.59 mmol), CDI (514.32 mg, 3.17 mmol), triethylamine (481.44 mg, 4.76 mmol) were added to tetrahydrofuran (5 mL) solvent. The mixture was reacted at 60°C for 16 h. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (DCM / MeOH (v / v) = 10 / 1) to give compound 27-4 (440 mg, 81.40%).

[0599] 1H NMR (400 MHz, deuterated chloroform) δ = 8.27 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 4.70 (br s, 1H), 2.19-1.95 (m, 8H)

[0600] Step 4: Synthesis of 3-(3-amino-5-((4,4-difluorophenoxy)nitrophenyl)-1,2,4-oxadiazol-5(4H)-one

[0601] 3-(3-((4,4-difluorophenoxy)-5-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one (100 mg, 293.03 mmol) and tin dichloride dihydrate (264.48 mg, 1.17 mmol) were added to ethanol (2 mL) solvent. The mixture was reacted at 70°C for 1 h. The mixture was cooled to room temperature, diluted with water (3 mL), extracted with EtOAc (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (DCM / MeOH (v / v) = 10 / 1) to give compound 27-5 (120 mg, crude product).

[0602] MS (ESI, pos.ion) m / z: 312.2 [M+1] + .

[0603] Step 5: Synthesis of 7-bromo-N-cyclopropyl-4-((3-((4,4-difluorophenoxy)-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-2-ylphenyl)amino)-5-fluoroquinoline-3-sulfonamide

[0604] 7-Bromo-4-chloro-N-(cyclopropylmethyl)quinoline-3-sulfonamide (70 mg, 184.39 mmol) and 5-(3-amino-5-((4,4-difluorophenoxy)phenyl)-1,2,4-oxadiazol-2(3H)-one (57.4 mg, 184.39 mmol) were added to AcOH (2 mL). The mixture was stirred at 75° C. for 1 hour. The mixture was concentrated under reduced pressure and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to give compound 27-7 (27.7 mg, 22.95%).

[0605] MS (ESI, pos.ion) m / z: 655.4 [M+1] + .

[0606] Step 6: Synthesis of N-cyclopropyl-4-((3-((4,4-difluorocyclohexyl)oxy)-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)amino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinoline-3-sulfonamide

[0607] 7-Bromo-N-cyclopropyl-4-((3-((4,4-difluorophenoxy)-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-2-ylphenyl)amino)-5-fluoroquinoline-3-sulfonamide (27.7 mg, 42.33 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (11.68 mg, 63.49 mmol) and K2CO3 (64.35 mg, 465.58 mmol) were added to dioxane (2 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, Pd(PPh3)4 (4.89 mg, 4.23 mmol) was added under nitrogen flow, and then replaced with nitrogen, and stirred at 80°C for 5 h. H2O (3 mL) was added for dilution, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 27 (1.30 mg, 4.31%).

[0608] MS (ESI, pos.ion) m / z: 714.6 [M+1] + .

[0609] 1 H NMR (400MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.63 (s, 2H), 8.28 (s, 1H), 8.15 (s, 1H), 7.56 (br d, J = 13.8Hz, 2H), 6.96 (br d,J=8.0Hz,2H),6.62(s,1H),4.52(br s,1H),3.98(d,J=7.5Hz,6H),2.24(br d,J=3.5Hz,1H),1.92-1.65(m,8H),0.43-0.39(m,4H)

[0610] Example 28: Synthesis of 3-((3-(N-cyclopropylsulfonylamino)-7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (28)

[0611]

[0612] Step 1: Synthesis of 2,3-dihydrofurano[3,2-c]pyridine

[0613] 4-Chlorofuran-[3,2-c]pyridine (4.00 g, 26.05 mmol) and wet palladium carbon (500 mg, 26.01 mmol) were added to a methanol solution (50 mL), replaced with nitrogen and hydrogen three times respectively, and the mixture was reacted at room temperature for 2 h under a hydrogen balloon (15 Psi). After the reaction was completed, the compound 28-2 (3 g, crude product) was obtained by filtration.

[0614] MS (ESI, pos.ion) m / z: 122.1 [M+1] + .

[0615] Step 2: Synthesis of 7-bromo-2,3-dihydrofuran[3,2]pyridine

[0616] 2,3-Dihydrofuran[3,2-c]pyridine (1.8 g, 14.86 mmol) and NBS (3.44 g, 19.32 mmol) were added to concentrated sulfuric acid (30 mL) in an ice-salt bath (0 ° C). The reaction was carried out at 25 ° C for 16 hours. After the reaction, the reaction solution was added dropwise to 150 mL of 2M sodium hydroxide solution in an ice-salt bath to adjust the pH of the reaction solution to 8-9. It was extracted with EA (50 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 3) to obtain compound 28-3 (1.3 g, 43.74%).

[0617] MS (ESI, negative ion) m / z: 201.9 [M+1] +

[0618] Step 3: Synthesis of (2,3-dihydrofuran[3,2-c]pyridin-7-yl)boronic acid

[0619] 7-Bromo-2,3-dihydrofuran[3,2]pyridine (500 mg, 2.5 mmol), bis(1S,2S,3R,5S)(+)-pinanediol diboron ester (1.16 g, 3.25 mmol), potassium acetate (490.62 mg, 5.00 mmol) and Pd(dppf)Cl2 (182.90 mg, 249.96 mmol) were added to anhydrous dioxane (8 mL) and replaced with nitrogen three times. The reaction solution was reacted at 100°C for 16 h. After the reaction was completed, the mixture was diluted with water (10 mL), extracted with EA (10 mL*3), washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 28-4 (120 mg, 29.10%).

[0620] MS (ESI, neg.ion) m / z: 165.8 [M+1]+ .

[0621] Step 4: Synthesis of methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,3-dihydrofuran[3,2-c]pyridin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0622] Methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-bromo-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (75 mg, 0.120 mmol), 2,3-dihydrofuran-pyridine borate (29.82 mg, 0.181 mmol) and K2CO3 (49.98 mg, 0.362 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(dppf)Cl2 (8.82 mg, 0.12 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 16 h. The reaction solution was concentrated in vacuo to remove part of the dioxane, diluted with H2O (5 mL), extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 28-5 (150 mg, crude product).

[0623] MS (ESI, pos.ion) m / z: 663.1 [M+1] + .

[0624] Step 5: Synthesis of 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,3-dihydrofuran[3,2-c]pyridin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0625] Methyl 3-((3-(N-cyclopropylaminosulfonyl)-7-(2,3-dihydrofuranpyridin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (150 mg, crude product) and lithium hydroxide (108.42 mg, 4.53 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 28 (3.58 mg).

[0626] MS (ESI, pos.ion) m / z: 649.1 [M+1] + .

[0627] 1H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),8.71(s,1H),8.49-8.64(m,2H),8.40(s,1H),8.34(s,1H),7.74(br d,J=13.30Hz,1H),7.37(s,1H),7.17(s,1H),6.86-6.95(m,1H),6.78(br s,1H),6.64(dd,J=2.13,8.41Hz,2H),4.79(t,J=8.91Hz,2H),3.50(br s, 2H), 2.22 (br d, J = 4.02Hz, 1H), 0.33-0.40 (m, 4H).

[0628] Example 29: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydro-2H-pyran-4-yl)sulfonylamino)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (29)

[0629]

[0630] Step 1: Synthesis of methyl 3-((7-bromo-3-(N-tetrahydro-2H-pyran-4-yl)-5-fluoroquinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0631] 7-Bromo-4-chloro-5-fluoro-N-(tetrahydro-2H-pyran-4-yl)quinoline-3-sulfonamide (275 mg, 649.07 mmol) and 3-amino-5-((tetrahydro-2H-pyran-4-ether)benzoic acid methyl ester (195.72 mg, 778.88 mmol) were added to AcOH (2 mL). The mixture was stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 2 / 1) to give compound 29-2 (260 mg, 62.74%).

[0632] MS (ESI, pos.ion) m / z: 639.5 [M+1] + .

[0633] Step 2: Synthesis of methyl 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(N-tetrahydro-2H-pyran-4-yl)sulfonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0634] Methyl 3-((7-bromo-3-(N-tetrahydro-2H-pyran-4-yl)-5-fluoroquinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (260 mg, 407.2 mmol), 2,3-dihydrofuran-pyridine borate (260 mg, 1.58 mmol) and K2CO3 (224.58 mg, 1.63 mmol) were added to a mixture of DMF (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(dppf)Cl2 (29.8 mg, 40.72 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 80°C for 1 h. The reaction solution was concentrated in vacuo to remove part of the dioxane, diluted with H2O (5 mL), extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 29-3 (300 mg, crude product).

[0635] MS (ESI, pos.ion) m / z: 679.7 [M+1] + .

[0636] Step 3: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydro-2H-pyran-4-yl)sulfonylamino)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0637] Methyl 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydro-2H-pyran-4-yl)sulfonylamino)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (150 mg, crude product) and lithium hydroxide (108.42 mg, 4.53 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 29 (7.28 mg).

[0638] MS (ESI, pos.ion) m / z: 665.7 [M+1] + .

[0639] 1H NMR (400MHz, DMSO-d6) δ = 9.10 (s, 1H), 8.71 (s, 1H), 8.49-8.33 (m, 4H), 8.16 (s, 1H), 7.72 (br d,J=13.8Hz,1H),7.12(s,1H),7.03(s,1H),6.72(s,1H),4.79(t,J=8.9Hz,2H),4.53-4.41(m,1H),3.80-3.69(m,2H),3.63(br d,J=11.5Hz,2H),3.06(br t,J=10.7Hz,2H),1.84(br d,J=11.3Hz,2H),1.55-1.45(m,4H),1.38-1.25(m,2H)

[0640] Example 30: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydro-2H-pyran-4-yl)sulfonylamino)quinolin-4-yl)amino)-N-(methylsulfonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzamide (30)

[0641]

[0642] Step 1: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydro-2H-pyran-4-yl)sulfonylamino)quinolin-4-yl)amino)-N-(methylsulfonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzamide

[0643] 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydro-2H-pyran-4-yl)sulfonylamino)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (80 mg, 120.36 mmol), methanesulfonamide (22.90 mg, 240.71 mmol), EDCI (46.14 mg, 240.71 mmol, 2 eq) and DMAP (14.70 mg, 120.36 mmol) were added to DCM (5 mL). Stir at 30°C for 2 hours. Concentrate under reduced pressure, add H2O (3 mL) to dilute, add an appropriate amount of 1M HCl to adjust the pH to 5-6, extract with EA (3 mL*3), concentrate under reduced pressure, and purify the crude product by HPLC to obtain compound 30 (25.5 mg).

[0644] MS (ESI, pos.ion) m / z: 742.8 [M+1] + .

[0645] 1 H NMR (400MHz, DMSO-d6) δ = 9.11 (s, 1H), 8.74 (s, 1H), 8.51-8.31 (m, 4H), 7.72 (d, J = 15.1Hz, 1H), 7.23 (s, 1H) ,7.11(s,1H),6.69(s,1H),4.81(t,J=8.9Hz,2H),4.50(td,J=4.3,8.4Hz,1H),3.81-3.71(m,2H),3.64(br d,J=11.5Hz,2H),3.41(br s,2H),3.33-3.21(m,6H),3.12-3.00(m,2H),1.86(br d,J=12.0Hz,2H),1.51(br t,J=12.3Hz,4H),1.38-1.25(m,2H).

[0646] Example 31: Synthesis of 3-((3-(N-cyclohexylsulfonylamino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (31)

[0647]

[0648] Step 1: Synthesis of 7-bromo-4-chloro-N-cyclohexylamino-fluoroquinoline-3-sulfonamide

[0649] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (2g, 5.57mmol) and TEA (2.82mg, 27.86mmol) were added to dry DCM (30mL). Cyclohexylamine (552.5mg, 5.57mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20mL) was added for dilution, and the mixture was washed with H2O (20mL*2) and saturated NaCl solution (20mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 31-2 (73mg, 3.11%).

[0650] MS (ESI, pos.ion) m / z: 421.0 [M+1] + .

[0651] Step 2: Synthesis of methyl (3-((7-bromo-3-N-cyclohexylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0652] 7-Bromo-4-chloro-N-(cyclohexylamino)fluoroquinoline-3-sulfonamide (73 mg, 0.173 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (48.34 mg, 0.173 mmol) were added to AcOH (3 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 31-3 (43.8 mg, 38%).

[0653] MS (ESI, pos.ion) m / z: 664.0 [M+1] + .

[0654] Step 3: Synthesis of methyl 3-((3-(N-cyclohexylsulfonylamino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0655] Methyl (3-((7-bromo-3-N-cyclohexylaminosulfonyl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (43.8 mg, 0.066 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (18.19 mg, 0.099 mmol) and K2CO3 (32 mg, 0.226 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL). The air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (7.62 mg, 0.006 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 1 h. H2O (5 mL) was added to dilute, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 31-4 (70 mg, crude product).

[0656] MS (ESI, pos.ion) m / z: 724.3 [M+1] + .

[0657] Step 4: Synthesis of 3-((3-(N-cyclohexylsulfonylamino)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid

[0658] Methyl 3-((3-(N-cyclohexylaminosulfonyl)-7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoroquinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (70 mg, crude product) and lithium hydroxide (35.9 mg, 0.9 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 31 (9.37 mg).

[0659] MS (ESI, pos.ion) m / z: 710.3 [M+1] + .

[0660] 1 H NMR (400MHz, DMSO-d6) δ: 9.09 (s, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.23 ​​(br d, J = 7.78Hz, 1H), 8.14 (s, 1H), 7.59 (br d,J=14.05Hz,1H),7.36(s,1H),7.18(s,1H),6.94(br t,J=9.41Hz,1H),6.73(s,1H),6.61-6.68(m,1H),6.61-6.68(m,1H),6.65(dd,J=2.01,8.28Hz, 2H),4.00(s,2H),3.99-4.03(m,1H),3.96-3.99(m,1H),3.96-3.99(m,1H),3.98(s,3H),3.01(br s,1H),1.33-1.57(m,1H),1.33-1.57(m,5H),0.93-1.12(m,5H).

[0661] Example 32: Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-(tetrahydropyran-4-yl)aminosulfonyl)quinolin-4-yl)amino)benzoic acid (32)

[0662]

[0663] Step 1: Synthesis of 7-bromo-4-chloro-5-fluoro-N-(tetrahydropyranyl)quinoline-3-sulfonamide

[0664] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (2g, 5.57mmol) and TEA (2.82g, 27.86mmol) were added to dry DCM (30mL). Epoxypentylamine (0.563g, 5.57mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20mL) was added for dilution, and the mixture was washed with H2O (20mL*2) and saturated NaCl solution (20mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 32-2 (590mg, 11.36%).

[0665] MS (ESI, pos.ion) m / z: 422.9 [M+1] + .

[0666] Step 2: Synthesis of methyl 3-((7-bromo-5-fluoro-3-(N-(tetrahydropyran-4-yl)aminosulfonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0667] 7-Bromo-4-chloro-5-fluoro-N-(tetrahydropyranyl)quinoline-3-sulfonamide (63 mg, 0.148 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (41.25 mg, 0.148 mmol) were added to AcOH (3 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 32-3 (38 mg, 39.35%).

[0668] MS (ESI, pos.ion) m / z: 666.1 [M+1] + .

[0669] Step 3: Synthesis of methyl 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-(tetrahydropyran-4-ylamino)sulfonyl)quinolin-4-yl)amino)benzoate

[0670] Methyl 3-((7-bromo-5-fluoro-3-(N-(tetrahydropyran-4-yl)aminosulfonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (38.1 mg, 0.057 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (15.77 mg, 0.086 mmol) and K2CO3 (86.91 mg, 0.628 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (6.61 mg, 0.0057 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 1 h. Add H2O (5 mL) to dilute, extract with EA (3 mL*3), wash with saturated NaCl solution (3 mL), dry over anhydrous Na2SO4, and concentrate under reduced pressure to obtain compound 32-4 (60 mg, crude product).

[0671] MS (ESI, pos.ion) m / z: 726.3 [M+1] + .

[0672] Step 4: Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-(tetrahydropyran-4-yl)aminosulfonyl)quinolin-4-yl)amino)benzoic acid

[0673] Methyl 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-(tetrahydropyran-4-yl)aminosulfonyl)quinolin-4-yl)amino)benzoate (60 mg, crude product) and lithium hydroxide (39.6 mg, 1.65 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 32 (7.51 mg).

[0674] MS (ESI, pos.ion) m / z: 712.2 [M+1] + .

[0675] 1H NMR (400MHz, DMSO-d6)δ:9.11(s,1H),8.64(s,1H),8.52(s,1H),8.38(br d,J=7.03Hz,1H),8.13(s,1H),7.58(br d,J=13.55Hz,1H),7.37(s,1H),7.17(s,1H),6.93(br t,J=9.41Hz,1H),6.77(s,1H),6.61-6.72(m,2H),4.00(s,3H),3.98(s,3H),3.62(br d,J=11.80Hz,2H),3.18-3.25(m,1H),3.02-3.14(m,2H),1.44-1.55(m,1H),1.48(br d,J=11.29Hz,2H),1.22-1.36(m,2H).

[0676] Example 33: Synthesis of 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-oxetan-3-yl)aminosulfonyl)quinolin-4-yl)amino)benzoic acid (33)

[0677]

[0678] Step 1: Synthesis of (7-bromo-4-chloro-5-fluoro-N-(oxetan-3-yl)quinoline-3-sulfonamide

[0679] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (2g, 5.57mmol) and TEA (2.82mg, 27.86mmol) were added to dry DCM (30mL). Oxetane-3-amine (407.21mg, 5.57mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20mL) was added for dilution, and the mixture was washed with H2O (20mL*2) and saturated NaCl solution (20mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 33-2 (150mg, 6.81%).

[0680] MS (ESI, pos.ion) m / z: 394.8 [M+1] + .

[0681] Step 2: Synthesis of methyl 3-((7-bromo-5-fluoro-3-(N-(oxetan-3-yl)sulfonylamino)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate

[0682] (7-Bromo-4-chloro-5-fluoro-N-(oxetan-3-yl)quinoline-3-sulfonamide (100 mg, 0.252 mmol) and methyl 3-amino-5-(3,5-difluorophenoxy)benzoate (70.58 mg, 0.252 mmol) were added to AcOH (3 mL). The mixture was stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 33-3 (92 mg, 57%).

[0683] MS (ESI, pos.ion) m / z: 637.9 [M+1] + .

[0684] Step 3: Synthesis of methyl 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-oxetan-3-yl)aminosulfonyl)quinolin-4-yl)amino)benzoate

[0685] Methyl 3-((7-bromo-5-fluoro-3-(N-(oxetane-3-yl)sulfonylamino)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoate (92.9 mg, 0.145 mmol), (2,4-dimethoxypyrimidin-5-yl)boric acid (40.15 mg, 0.218 mmol) and K2CO3 (226.7 mg, 1.65 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (16.82 mg, 0.0145 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 1 h. H2O (5 mL) was added to dilute, extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 33-4 (130 mg, crude product).

[0686] MS (ESI, pos.ion) m / z: 698.2 [M+1] + .

[0687] Step 4: Synthesis of 3-(3,5-difluorophenoxy)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-oxetan-3-yl)aminosulfonyl)quinolin-4-yl)amino)benzoic acid

[0688] Methyl 3-(3,5-difluorophenol)-5-(7-(2,4-dimethoxypyrimidin-5-yl)-5-fluoro-3-(N-oxetan-3-yl)aminosulfonyl)quinolin-4-yl)amino)benzoate (130 mg, crude product) and lithium hydroxide (89.26 mg, 3.73 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 33 (1.08 mg).

[0689] MS (ESI, pos.ion) m / z: 684.2 [M+1] + .

[0690] 1 H NMR (400MHz, DMSO-d6)δ:9.02(br s,1H),8.64(s,1H),8.53(br s,1H),8.08-8.22(m,1H),7.57(br d,J=14.56Hz,1H),7.33(br s,1H),7.16(br s,1H),6.87-6.99(m,1H),6.74(br s,1H),6.66(br d,J=7.78Hz,2H),4.45(br s,3H),4.26(br s, 2H), 4.00 (d, J = 3.01Hz, 3H), 3.98 (d, J = 3.01Hz, 3H).

[0691] Example 34: Synthesis of 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)-5-morpholinebenzoic acid (34)

[0692]

[0693] Step 1: Synthesis of 7-bromo-4-chloro-5-fluoro-N-(4-methoxyphenyl-methyl)quinoline-3-sulfonamide

[0694] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g, 2.79 mmol) and TEA (845.6 mg, 8.36 mmol) were added to dry DCM (20 mL). 4-Methoxyphenylmethylamine (800 mg, 0.305 mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 34-2 (100 mg, 7.8%).

[0695] MS (ESI, pos.ion) m / z: 460.7 [M+1] + .

[0696] Step 2: Synthesis of methyl 3-((7-bromo-5-fluoro-3-(N-4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-morpholinobenzoate

[0697] 7-Bromo-4-chloro-5-fluoro-N-(4-methoxyphenyl-methyl)quinoline-3-sulfonamide (100 mg, 0.217 mmol) and methyl 3-amino-5-morpholinobenzoate (61.67 mg, 0.261 mmol) were added to AcOH (4 mL). The mixture was stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain compound 34-3 (65 mg, 45.31%).

[0698] MS (ESI, pos.ion) m / z: 661.1 [M+1] + .

[0699] Step 3: Synthesis of methyl 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-morpholinobenzoate

[0700] Methyl 3-((7-bromo-5-fluoro-3-(N-4-methoxybenzyl)sulfonyl)quinolin-4-yl)amino)-5-morpholinobenzoate (65 mg, 0.091 mmol), 2,4-diethylpyrimidine borate (42.88 mg, 0.136 mmol) and K2CO3 (125.7 mg, 0.909 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (10.51 mg, 0.009 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 1 h. The reaction solution was concentrated in vacuo to remove part of the dioxane, diluted with H2O (5 mL), extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 34-4 (100 mg, crude product).

[0701] MS (ESI, pos.ion) m / z: 714.5 [M+1] + .

[0702] Step 4: Synthesis of 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-morpholinobenzoic acid

[0703] Methyl 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-morpholinylbenzoate (100 mg, crude) and lithium hydroxide (67.01 mg, 4.53 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3) and concentrated under reduced pressure to obtain compound 34-5 (140 mg, crude).

[0704] MS (ESI, pos.ion) m / z: 701.2 [M+1] + .

[0705] Step 5: Synthesis of 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)-5-morpholinebenzoic acid

[0706] 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-morpholinylbenzoic acid (140 mg, crude product) and trifluoroacetic acid (68.34 mg, 0.599 mmol) were added to anhydrous dichloromethane (2 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the crude product was directly purified by HPLC to obtain compound 34 (19.5 mg, 16.8%).

[0707] MS (ESI, pos.ion) m / z: 581.3 [M+1] + .

[0708] 1 H NMR (400MHz, DMSO-d6) δ: 7.39 (br d, J=12.55Hz, 1H), 7.14 (s, 1H), 6.83 (s, 1H), 6.72 (br s, 1H), 3.64-3.69 (m, 4H), 3.01 (br s, 4H), 2.93 (q, J = 7.53Hz, 2H), 2.68-2.75 (m, 2H), 1.32 (t, J = 7.53Hz, 3H), 1.09-1.15 (m, 3H).

[0709] Example 35: Synthesis of 3-((7-(2,3-dihydrofuran(3,2-c)pyridin-7-yl)-5-fluoro-3-sulfonylamino-4-quinolyl)amino)-5-(morpholinomethyl)benzoic acid (35)

[0710]

[0711]

[0712] Step 1: Synthesis of 7-bromo-4-chloro-N-(4-methoxyphenyl-methyl)quinoline-3-sulfonamide

[0713] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g, 2.79 mmol) and TEA (845.6 mg, 8.36 mmol) were added to dry DCM (20 mL). 4-Methoxyphenylmethylamine (800 mg, 0.305 mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 35-2 (100 mg, 7.8%).

[0714] MS (ESI, pos.ion) m / z: 460.7 [M+1] + .

[0715] Step 2: Synthesis of methyl 3-((7-bromo-5-fluoro-3-((4-methoxyphenyl)methylaminosulfonyl)-4-quinolinyl)amino)-5-(morpholinomethyl)benzoate

[0716] 7-Bromo-4-chloro-N-(4-methoxyphenyl-methyl)quinoline-3-sulfonamide (100 mg, 0.217 mmol) and methyl 3-amino-5-(morpholinylmethyl)benzoate (65.34 mg, 0.261 mmol) were added to AcOH (4 mL) and stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 35-3 (85 mg, 58.1%).

[0717] MS (ESI, pos.ion) m / z: 675.0 [M+1] + .

[0718] Step 3: Synthesis of methyl 3-((7-(2,3-dihydrofuran(3,2-c)pyridin-7-yl)-5-fluoro-3-(N-(4-methoxyphenyl)methylaminosulfonyl)-4-quinolinyl)amino)-5-(morpholinomethyl)benzoate

[0719] Methyl 3-((7-bromo-5-fluoro-3-((4-methoxyphenyl)methylaminosulfonyl)-4-quinolyl)amino)-5-(morpholinomethyl)benzoate (85 mg, 0.126 mmol), 2,3-dihydrofuran[3,2-c]pyridine-7-boronic acid (31.23 mg, 0.189 mmol) and K2CO3 (200 mg, 1.45 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL). The air in the reaction system was replaced with nitrogen. Pd(dppf)Cl2 (9.23 mg, 0.0126 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 1 h. The reaction solution was concentrated in vacuo to remove part of the dioxane, diluted with H2O (5 mL), extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 35-4 (200 mg, crude product).

[0720] MS (ESI, pos.ion) m / z: 714.1 [M+1] + .

[0721] Step 4: Synthesis of 3-((7-(2,3-dihydrofuran(3,2-c)pyridin-7-yl)-5-fluoro-3-(N-(4-methoxyphenyl)methylaminosulfonyl)-4-quinolinyl)amino)-5-(morpholinomethyl)benzoic acid

[0722] Methyl 3-((7-(2,3-dihydrofuran(3,2-c)pyridin-7-yl)-5-fluoro-3-(N-(4-methoxyphenyl)methylaminosulfonyl)-4-quinolyl)amino)-5-(morpholinomethyl)benzoate (200 mg, crude) and lithium hydroxide (65 mg, 2.51 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3) and concentrated under reduced pressure to obtain compound 35-5 (140 mg, crude).

[0723] MS (ESI, pos.ion) m / z: 699.8 [M+1] + .

[0724] Step 5: Synthesis of 3-((7-(2,3-dihydrofuran(3,2-c)pyridin-7-yl)-5-fluoro-3-sulfonylamino-4-quinolyl)amino)-5-(morpholinomethyl)benzoic acid

[0725] 3-((7-(2,3-dihydrofuran(3,2-c)pyridin-7-yl)-5-fluoro-3-(N-(4-methoxyphenyl)methylaminosulfonyl)-4-quinolyl)amino)-5-(morpholinomethyl)benzoic acid (140 mg, crude) and trifluoroacetic acid (68.34 mg, 0.599 mmol) were added to anhydrous dichloromethane (2 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the crude product was directly purified by HPLC to obtain compound 35 (7.37 mg, 4.45%).

[0726] MS (ESI, pos.ion) m / z: 580.1 [M+1] + .

[0727] 1H NMR (400MHz, METHANOL-d4) δ: 9.13 (s, 1H), 8.59 (s, 1H), 8.31 (d, J = 19.07Hz, 2H), 7.68 (s, 1H), 7.4 8-7.59(m,2H),7.07(s,1H),4.82-4.87(m,2H),3.53-3.63(m,6H),3.39(t,J=8.78Hz,2H),2.50(br s,4H).

[0728] Example 36: Synthesis of 3-(7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)-5-(1-(oxetane-3-yl)piperidin-4-yl)oxy)benzoic acid (36)

[0729]

[0730] Step 1: Synthesis of 7-bromo-4-chloro-5-fluoro-N-(4-methoxyphenyl-methyl)quinoline-3-sulfonamide

[0731] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g, 2.79 mmol) and TEA (845.6 mg, 8.36 mmol) were added to dry DCM (20 mL). 4-Methoxyphenylmethylamine (800 mg, 0.305 mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 36-2 (100 mg, 7.8%).

[0732] MS (ESI, pos.ion) m / z: 460.7 [M+1] + .

[0733] Step 2: Synthesis of methyl 3-((7-bromo-5-fluoro-3-(N-(4-methoxybenzyl)sulfonylamino)quinolin-4-yl)amino)-5-(1-(oxetane-3-yl)piperidin-4-yl)oxy)benzoate

[0734] 7-Bromo-4-chloro-5-fluoro-N-(4-methoxyphenyl-methyl)quinoline-3-sulfonamide (100 mg, 0.217 mmol) and methyl 3-amino-5-(1-(oxetane-3-yl)-piperidin-4-yl)oxybenzoate (79.97 mg, 0.261 mmol) were added to AcOH (4 mL). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 36-3 (100 mg, 63.01%).

[0735] MS (ESI, pos.ion) m / z: 731.2 [M+1] + .

[0736] Step 3: Synthesis of methyl 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-(1-(oxetan-3-yl)piperidin-4-yl)oxy)benzoate

[0737] Methyl 3-((7-bromo-5-fluoro-3-(N-(4-methoxybenzyl)sulfonylamino)quinolin-4-yl)amino)-5-(1-(oxetane-3-yl)piperidin-4-yl)oxy)benzoate (100 mg, 0.137 mmol), 2,4-diethylpyrimidine borate (64.6 mg, 0.205 mmol) and K2CO3 (18.74 mg, 0.137 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (15.84 mg, 0.014 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 1 h. The reaction solution was concentrated in vacuo to remove part of the dioxane, diluted with H2O (5 mL), extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 36-4 (180 mg, crude product).

[0738] MS (ESI, pos.ion) m / z: 785.3 [M+1] + .

[0739] Step 4: Synthesis of 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-(1-(oxetane-3-yl)piperidin-4-yl)oxy)benzoic acid

[0740] Methyl 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-(1-(oxetane-3-yl)piperidin-4-yl)oxy)benzoate (180 mg, crude product) and lithium hydroxide (54.9 mg, 2.29 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 36-5 (150 mg, crude product).

[0741] MS (ESI, pos.ion) m / z: 771.4 [M+1] + .

[0742] Step 5: Synthesis of 3-(7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)-5-(1-(oxetane-3-yl)piperidin-4-yl)oxy)benzoic acid

[0743] 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-(1-(oxetane-3-yl)piperidin-4-yl)oxy)benzoic acid (150 mg, crude) and trifluoroacetic acid (68.34 mg, 0.599 mmol) were added to anhydrous dichloromethane (2 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the crude product was directly purified by HPLC to obtain compound 36 (16.23 mg, 12.81%).

[0744] MS (ESI, pos.ion) m / z: 651.4 [M+1] + .

[0745] 1 H NMR(400MHz,DMSO-d6)δ:9.14(s,1H),8.63(s,1H),8.55(br s,1H),7.98(brs,1H),7.93(s,1H),7.43(br d,J=12.55Hz,1H),7.07(s,1H),6.99(s,1H),6.68(s,1H),4.48(t,J=6.53Hz,2H),4.36(t,J=6.15Hz,2H),4.30(br s,1H),2.93(q,J=7.53Hz,2H),2.73(q,J=7.36Hz,2H),2.54(br s,1H),2.41(br s,2H),1.94-2.05(m,2H),1.82(br s,2H),1.55(br d,J=8.28Hz,2H),1.32(t,J=7.53Hz,3H),1.13(t,J=7.53Hz,3H).

[0746] Example 37: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)-5-(4-(oxetane-3-yl)piperazin-1-yl)benzoic acid (37)

[0747]

[0748]

[0749] Step 1: Synthesis of 1-tert-butyloxycarbonyl-4-(3-(methoxycarbonyl)-5-nitro)piperazine

[0750] Methyl 3-bromo-5-nitrobenzoate (1.5 g, 5.77 mmol), N-BOC piperazine (1.29 g, 6.93 mmol), and Cs2CO3 (3.76 g, 11.54 mmol) were added to dry dioxane (20 mL). The air in the reaction system was replaced with nitrogen, and Ruphos Pd G3 (241 mg, 0.288 mmol) was added under nitrogen flow, and then replaced with nitrogen, and stirred at 100 ° C for 16 hours under nitrogen protection. Filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 37-2 (1.6 g, 75.9%).

[0751] MS(ESI,pos.ion)m / z:310.2[M-55] + .

[0752] Step 2: Synthesis of methyl 3-nitro-5-(piperazin-1-yl)benzoate

[0753] 1-tert-Butyloxycarbonyl-4-(3-(methoxycarbonyl)-5-nitrobenzene)piperazine (1.6 g, 4.38 mmol) and dioxane hydrochloride (4M, 20 mL) were added to MeOH (5 mL). The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain compound 37-3 (1.5 g, crude product).

[0754] MS (ESI, pos.ion) m / z: 266.0 [M+1] + .

[0755] Step 3: Synthesis of methyl 3-nitro-5-(4-(oxetane-3-yl)piperazin-1-yl)benzoate

[0756] Methyl 3-nitro-5-(piperazin-1-yl)benzoate (1.5 g, crude product), 3-oxetanone (815 mg, 11.32 mmol), triethylamine (1.14 g, 11.26 mmol) and sodium acetate borohydride (2.4 g, 11.32 mmol) were added to dichloromethane (15 mL) and stirred at 30°C for 16 hours. H2O (20 mL) was added for dilution, extracted with dichloromethane (15 mL*3), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain compound 37-4 (1.35 g).

[0757] MS (ESI, pos.ion) m / z: 322.2 [M+1] + .

[0758] Step 4: Synthesis of methyl 3-amino-5-(4-(oxetane-3-yl)piperazin-1-yl)benzoate

[0759] Methyl 3-nitro-5-(4-(oxetane-3-yl)piperazine-1-yl)benzoate (1.35 g, 4.21 mmol), iron powder (1.17 g, 2.09 mmol) and ammonium chloride (3.37 g, 63 mmol) were added to a mixed solution of ethanol (5 mL), tetrahydrofuran (5 mL) and water (2.5 mL) and stirred at 90°C for 2 hours. The mixture was filtered, and the filtrate was diluted with H2O (10 mL), extracted with EA (3 mL*3), and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 37-5 (1.0 g, 81.7%).

[0760] MS (ESI, pos.ion) m / z: 292.3 [M+1] + .

[0761] Step 5: Synthesis of methyl 3-((7-bromo-5-fluoro-3-(N-(4-methoxyphenyl)sulfonamido)quinolin-4-yl)amino)-5-(4-(oxetane-3-yl)piperazin-1-yl)benzoate

[0762] Methyl 3-amino-5-(4-(oxetane-3-yl)piperazine-1-yl)benzoate (91.3 mg, 0.31 mmol) and 7-bromo-4-chloro-5-fluoro-N-(4-methoxyphenyl)quinoline-3-sulfonamide (120 mg, 0.26 mmol) were added to AcOH (3 mL). The mixture was stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to give compound 37-6 (99 mg, 53%).

[0763] MS (ESI, pos.ion) m / z: 716.1 [M+2] + .

[0764] Step 6: Synthesis of methyl 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(4-methoxyphenyl)sulfonamido)quinolin-4-yl)amino)-5-(4-(oxetan-3-yl)piperazin-1-yl)benzoate

[0765] Methyl 3-((7-bromo-5-fluoro-3-(N-(4-methoxyphenyl)sulfonamide)quinolin-4-yl)amino)-5-(4-(oxetane-3-yl)piperazin-1-yl)benzoate (99 mg, 0.138 mmol), (2,3-dihydrofuran[3,2-c]pyridine)boric acid (68.5 mg, 0.415 mmol) and K2CO3 (38 mg, 0.276 mmol) were added to a mixture of DMF (4 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(dppf)Cl2 (10 mg, 0.014 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 80°C for 1 h. Add H2O (5 mL) to dilute, extract with EA (3 mL*3), wash with saturated NaCl solution (5 mL), dry over anhydrous Na2SO4, and concentrate under reduced pressure to obtain compound 37-7 (200 mg, crude product).

[0766] MS (ESI, pos.ion) m / z: 755.3 [M+1] + .

[0767] Step 7: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(4-methoxyphenyl)sulfonamido)quinolin-4-yl)amino)-5-(4-(oxetane-3-yl)piperazin-1-yl)benzoic acid

[0768] Methyl 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(4-methoxyphenyl)sulfonamide)quinolin-4-yl)amino)-5-(4-(oxetan-3-yl)piperazin-1-yl)benzoate (150 mg, crude) and lithium hydroxide (25.4 mg, 1.06 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 30°C for 1 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3) and concentrated under reduced pressure to obtain compound 37-8 (200 mg, crude).

[0769] MS (ESI, pos.ion) m / z: 741.3 [M+1] + .

[0770] Step 8: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)-5-(4-(oxetane-3-yl)piperazin-1-yl)benzoic acid

[0771] 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(4-methoxyphenyl)sulfonamide)quinolin-4-yl)amino)-5-(4-(oxetane-3-yl)piperazin-1-yl)benzoic acid (200 mg, crude product) and trifluoroacetic acid (0.5 mL, 27 mmol) were added to dichloromethane (5 mL). The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure and the crude product was purified by HPLC to obtain compound 37 (2.85 mg).

[0772] MS (ESI, pos.ion) m / z: 620.8 [M+1] + .

[0773] 1 H NMR(400MHz,DMSO-d6)δ:9.08(s,1H),8.71(s,1H),8.46(br s,1H),8.39(s,1H),8.32(s,1H),7.96(br s,1H),7.68(br d,J=13.3Hz,1H),7.14(s,1H),6.74(s,2H),4.79(t,J=8.9Hz,2H),4.53(t,J=6.7Hz,2H),4.43(t,J=6.0Hz,2H),3.11(br s,4H),2.33(br s,5H).

[0774] Example 38: Synthesis of 3-(1-cyclobutylpiperidin-4-yl)oxy)-5-(7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-aminosulfonylquinolin-4-yl)amino)benzoic acid (38)

[0775]

[0776] Step 1: Synthesis of 7-bromo-4-chloro-N-(4-methoxyphenyl-methyl)quinoline-3-sulfonamide

[0777] 7-Bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g, 2.79 mmol) and TEA (845.6 mg, 8.36 mmol) were added to dry DCM (20 mL). 4-Methoxyphenylmethylamine (800 mg, 0.305 mmol) was added at 0°C and stirred at 0°C for 2 hours. DCM (20 mL) was added for dilution, and the mixture was washed with H2O (20 mL*2) and saturated NaCl solution (20 mL) in sequence, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 38-2 (100 mg, 7.8%).

[0778] MS (ESI, pos.ion) m / z: 460.7 [M+1] + .

[0779] Step 2: Synthesis of methyl 3-((7-bromo-5-fluoro-3-((4-methoxyphenyl)methylaminosulfonyl)-4-quinolinyl)amino)-5-((1-cyclobutyl-4-piperidinyl)oxy)benzoate

[0780] 7-Bromo-4-chloro-5-fluoro-N-(4-methoxyphenyl-methyl)quinoline-3-sulfonamide (100 mg, 0.217 mmol) and methyl 3-amino-5-((1-(cyclobutyl)-4-piperidinyl)oxy)benzoate (79.97 mg, 0.261 mmol) were added to AcOH (4 mL). The mixture was stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 38-3 (150 mg, 92.01%).

[0781] MS (ESI, pos.ion) m / z: 729.3 [M+1] + .

[0782] Step 3: Synthesis of methyl 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-((4-methoxyphenyl)methylaminosulfonyl)-4-quinolinyl)amino)-5-((1-cyclobutyl-4-piperidinyl)oxy)benzoate

[0783] Methyl 3-((7-bromo-5-fluoro-3-((4-methoxyphenyl)methylaminosulfonyl)-4-quinolyl)amino)-5-((1-cyclobutyl-4-piperidinyl)oxy)benzoate (150 mg, 0.206 mmol), 2,4-diethylpyrimidine borate (97.17 mg, 0.309 mmol) and K2CO3 (28.49 mg, 0.206 mmol) were added to a mixture of dioxane (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(PPh3)4 (23.82 mg, 0.0206 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 100°C for 1 h. The reaction solution was concentrated in vacuo to remove part of the dioxane, diluted with H2O (5 mL), extracted with EA (3 mL*3), washed with saturated NaCl solution (3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 38-4 (150 mg, crude product).

[0784] MS (ESI, pos.ion) m / z: 784.3 [M+1] + .

[0785] Step 4: Synthesis of 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-((4-methoxyphenyl)methylaminosulfonyl)-4-quinolinyl)amino)-5-((1-cyclobutyl-4-piperidinyl)oxy)benzoic acid

[0786] Methyl 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-((4-methoxyphenyl)methylaminosulfonyl)-4-quinolyl)amino)-5-((1-cyclobutyl-4-piperidinyl)oxy)benzoate (150 mg, crude) and lithium hydroxide (60.2 mg, 2.52 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 30°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 38-5 (200 mg, crude).

[0787] MS (ESI, pos.ion) m / z: 768.8 [M+1] + .

[0788] Step 5: Synthesis of 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-(sulfonyl)-4-quinolinyl)amino)-5-((1-cyclobutyl-4-piperidinyl)oxy)benzoic acid

[0789] 3-((7-(2,4-diethylpyrimidin-5-yl)-5-fluoro-3-((4-methoxyphenyl)methylaminosulfonyl)-4-quinolyl)amino)-5-((1-cyclobutyl-4-piperidinyl)oxy)benzoic acid (200 mg, crude) and trifluoroacetic acid (68.34 mg, 0.599 mmol) were added to anhydrous dichloromethane (2 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the crude product was directly purified by HPLC to obtain compound 38 (6.95 mg, 4.12%).

[0790] MS (ESI, pos.ion) m / z: 629.2 [M+1] + .

[0791] 1H NMR(400MHz,DMSO-d6)δ:9.14(s,1H),8.63(s,1H),8.56(br s,1H),7.90-8.03(m,3H),7.43(br d,J=12.55Hz,1H),7.06(s,1H),7.01(s,1H),6.65(s,1H),4.24(br s,1H),2.93(q,J=7.61Hz,2H),2.74(q,J=7.53Hz,2H),1.90(br s,5H),1.65-1.83(m,5H),1.45-1.62(m,4H),1.32(t,J=7.53Hz,3H),1.14(t,J=7.40Hz,3H).

[0792] Example 39: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamide)quinolin-4-yl)amine)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (39)

[0793]

[0794] Step 1: Synthesis of methyl 3-((7-bromo-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamido)quinolin-4-yl)amine)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0795] 7-Bromo-4-chloro-5-fluoro-N-(tetrahydrofuran-3-yl)quinoline-3-sulfonamide (100 mg, 0.244 mmol) and methyl 3-amine-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (147 mg, 0.586 mmol) were added to acetic acid (3 mL). The mixture was stirred at 80° C. for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to give compound 39-2 (100 mg, 65.6%).

[0796] MS (ESI, pos.ion) m / z: 625.0 [M+1] + .

[0797] Step 2: Synthesis of methyl 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamido)quinolin-4-yl)amine)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0798] Methyl 3-((7-bromo-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamido)quinolin-4-yl)amine)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (100 mg, 0.16 mmol), (2,3-dihydrofuran[3,2-c]pyridin-7-yl)boric acid (102 mg, 0.62 mmol) and K2CO3 (88 mg, 0.64 mmol) were added to a mixture of DMF (3 mL) and water (0.5 mL), and the air in the reaction system was replaced with nitrogen. Pd(dppf)Cl2 (11.7 mg, 0.016 mmol) was added under a nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 80°C for 1 h. Add H2O (5 mL) to dilute, extract with EA (3 mL*3), wash with saturated NaCl solution (3 mL), dry over anhydrous Na2SO4, and concentrate under reduced pressure to obtain compound 39-3 (207 mg, crude product).

[0799] MS (ESI, pos.ion) m / z: 665.3 [M+1] + .

[0800] Step 3: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamido)quinolin-4-yl)amine)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0801] Methyl 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamide)quinolin-4-yl)amine)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (207 mg, crude product) and lithium hydroxide (7.46 mg, 0.31 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 50°C for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 39 (9.5 mg).

[0802] MS (ESI, pos.ion) m / z: 651.1 [M+1] + .

[0803] 1H NMR(400MHz,DMSO-d6)δ:9.08(br s,1H),8.71(s,1H),8.59(br s,1H),8.40(s,2H),8.35(br s,1H),7.71(br d,J=13.9Hz,1H),7.13(s,1H),7.05(s,1H),6.70(s,1H),4.80(t,J=8.9Hz,2H),4.46(td,J=4.3,8.4Hz,1H),3.86(br s,1H),3.77-3.70(m,2H),3.68-3.47(m,7H),2.02-1.75(m,4H),1.61-1.45(m,3H).

[0804] Example 40: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamide)quinolin-4-yl)amine)-N-(methylsulfonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzamide (40)

[0805]

[0806] Step 1: Synthesis of 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamido)quinolin-4-yl)amine)-N-(methylsulfonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzamide

[0807] 3-((7-(2,3-dihydrofuran[3,2-c]pyridin-7-yl)-5-fluoro-3-(N-(tetrahydrofuran-3-yl)sulfonamide)quinolin-4-yl)amine)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (300 mg, crude), EDCI (176.8 mg, 0.92 mmol), DMAP (56.3 mg, 0.46 mmol), triethylamine (93.3 mg, 0.92 mmol), methanesulfonamide (87.7 mg, 0.92 mmol) were added to dichloromethane (10 mL). The mixture was stirred at 30° C. for 2 hours. The mixture was concentrated under reduced pressure and the crude product was purified by HPLC to obtain compound 40 (12.2 mg).

[0808] MS (ESI, pos.ion) m / z: 728.3 [M+1] + .

[0809] 1H NMR (400MHz, DMSO-d6)δ:9.12-9.04(m,1H),8.72(s,1H),8.62(br d,J=7.0Hz,1H),8.46-8.38(m,2H),8.35(s,1H),7.70(br d,J=13.3Hz,1H),7.22(s,1H),7.13(s,1H),6.71-6.56(m,1H),4.80(br t,J=8.9Hz,2H),4.54-4.33(m,1H),3.88-3.65(m,7H),3.27-3.11(m,7H),1.95-1.78(m,3H),1.66-1.43(m,3H).

[0810] Example 41: Synthesis of 3-((7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-3-sulfonamido-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (41)

[0811]

[0812] Step 1: Synthesis of methyl 3-nitro-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0813] Methyl 3-hydroxy-5-nitrobenzoate (2.00 g, 10.14 mmol), 4-tetrahydropyranol (1.04 g, 10.14 mmol), PPh3 (3.19 g, 12.17 mmol), and DIAD (2.46 g, 12.17 mmol) were added to DCM (50 mL) and reacted at room temperature for 16 h. H2O (30 mL) was added for dilution, extracted with EA (30 mL*3), and washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1), and concentrated under reduced pressure to obtain compound 41-2 (3 g crude product).

[0814] Step 2: Synthesis of methyl 3-amino-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0815] Add 3-nitro-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid methyl ester (1g, 3.56mmol), iron powder (992.76mg, 17.78mmol), ammonium chloride (2.85g, 53.33mmol) to a mixed solvent of ethanol (10mL), tetrahydrofuran (10mL) and water (5mL). React at 90℃ for 16h. Cool to room temperature, dilute with water (30mL), extract with EtOAc (30mL*3), wash with saturated NaCl solution (30mL), dry with anhydrous Na2SO4, concentrate under reduced pressure, and separate the crude product by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain compound 41-3 (710mg, 79.47%)

[0816] 1 H NMR (400 MHz deuterated chloroform) δ = 7.02-6.95 (m, 2H), 6.45 (t, J = 2.3 Hz, 1H), 4.52 (tt, J = 3.8, 7.8 Hz, 1H), 4.14 (q, J = 7.3 Hz, 1H), 4.05-3.95 (m, 2H), 3.90 (s, 3H), 3.60 (ddd, J = 3.1, 8.3, 11.7 Hz, 2H), 2.09-2.02 (m, 2H), 1.79 (dtd, J = 3.9, 8.3, 12.8 Hz, 2H)

[0817] Step 3: Synthesis of 7-bromo-4-hydroxyquinoline-3-sulfonyl chloride

[0818] 4-Hydroxy-7-bromoquinoline (10 g, 44.63 mmol) was added to chlorosulfonic acid (100 mL), and the reaction solution was reacted at 100°C for 16 h. After the reaction was completed, the mixture was diluted with water (100 mL) and filtered to obtain a crude product, compound 41-5 (15 g crude product).

[0819] 1 H NMR (400MHz, DMSO-d6) δ = 8.92 (s, 1H), 8.26-8.09 (m, 2H), 7.78 (dd, J = 1.7, 8.8Hz, 1H), 7.89-7.72 (m, 1H)

[0820] Step 4: Synthesis of 7-bromo-4-chloroquinoline-3-sulfonyl chloride

[0821] 7-Bromo-4-hydroxyquinoline-3-sulfonyl chloride (10 g, 31.0 mmol) was added to phosphorus oxychloride (100 mL), and the reaction solution was reacted at 100°C for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 41-6 (14.77 g crude product).

[0822] 1H NMR (400 MHz deuterated chloroform) δ = 9.58 (s, 1H), 8.78-8.61 (m, 1H), 8.49 (d, J = 9.1 Hz, 1H), 8.21-8.01 (m, 1H)

[0823] Step 5: Synthesis of 7-bromo-4-chloro-N-(4-methoxybenzyl)quinoline-3-sulfonamide

[0824] 7-Bromo-4-chloroquinoline-3-sulfonyl chloride (2 g, 5.86 mmol), p-methoxybenzylamine (643.64 mg, 4.69 mmol), TEA (2.97 g, 29.3 mmol) were added to DCM (50 mL). The mixture was stirred at 0°C for 2 hours. The mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain compound 41-7 (620 mg, 23.95%).

[0825] MS (ESI, pos.ion) m / z: 442.7 [M+1] + .

[0826] 1 H NMR (400MHz, DMSO-d6) δ=9.06(s,1H),8.81(t,J=6.3Hz,1H),8.37(d,J=1.8Hz,1H),8.19(d,J=9.0Hz,1H),7.9 9(dd,J=2.0,9.0Hz,1H),6.98(d,J=8.8Hz,2H),6.44(d,J=8.8Hz,2H),4.11(d,J=6.5Hz,2H),3.43-3.39(m,3H)

[0827] Step 6: Synthesis of methyl 3-((7-bromo-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0828] 7-Bromo-4-chloro-N-(4-methoxybenzyl)quinoline-3-sulfonamide (300 mg, 679.15 mmol) and methyl 3-amino-5-((tetrahydro-2H-pyran-4-oxy)benzoate (204.79 mg, 814.98 mmol) were added to AcOH (2 mL). The mixture was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 4 / 1) to give compound 41-8 (100 mg, 22.43%).

[0829] MS (ESI, pos.ion) m / z: 657.5 [M+1] + .

[0830] Step 7: Synthesis of methyl 3-((7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0831] Methyl 3-((7-bromo-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (90 mg, 137.08 mmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (23.91 mg, 178.21 mmol) and Cs2CO3 (89.33 mg, 274.16 mmol) were added to dioxane (2 mL), and the air in the reaction system was replaced with nitrogen. RuPhos Pd G2 (10.65 mg, 13.71 mmol) was added under nitrogen flow, and then replaced with nitrogen. The reaction was stirred at 80°C for 1 h. Add H2O (3 mL) to dilute, extract with EA (3 mL*3), and wash with saturated NaCl solution (3 mL), dry over anhydrous Na2SO4, and the crude product is separated by column chromatography (PE / EtOAc (v / v) = 4 / 1), and concentrated under reduced pressure to give compound 41-9 (176 mg, crude product).

[0832] MS (ESI, pos.ion) m / z: 710.8 [M+1] + .

[0833] Step 8: Synthesis of 3-((7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0834] Methyl 3-((7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-3-(N-(4-methoxybenzyl)aminosulfonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (176 mg, crude product) and lithium hydroxide (130.64 mg, 5.45 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with H2O (3 mL), and the pH was adjusted to 5-6 with an appropriate amount of 1M HCl. The mixture was extracted with EA (3 mL*3), concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 41-10 (160 mg, crude product).

[0835] MS (ESI, pos.ion) m / z: 696.8 [M+1] + .

[0836] Step 9: Synthesis of 3-((7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-3-sulfonamido-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0837] 3-((7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-3-(N-(4-methoxybenzyl)sulfonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (160 mg, crude product) was added to DCM (3 mL) and TFA (0.5 mL) and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the crude product was purified by HPLC to give Compound 41 (1.17 mg, 0.88%).

[0838] MS(ESI,pos.ion)m / z:576.63[M+1] + .

[0839] 1 H NMR (400MHz, DMSO-d6) δ = 9.02 (s, 1H), 8.28 (s, 1H), 8.03 (d, J = 3.5Hz, 1H), 7.78 (br s,2H),7.60(s,1H),7.57(d,J=9.3Hz,1H),7.40-7.35(m,2H),7.11(s,1H) ,7.06-7.02(m,2H),6.72(s,1H),4.52(s,1H),3.80-3.74(m,4H),3.45(br s,2H),2.90(t,J=6.4Hz,2H),2.08-2.01(m,2H),1.90(br d,J=12.0Hz,2H),1.55(br s,2H),1.24(s,2H)

[0840] Example 42: Synthesis of 5-{[3-carbamoyl-7-(1,2,3,4-tetrahydropyridin-1-yl)quinolin-4-yl]amino}-3-(3,4,5,6-tetrahydro-2H-pyran-4-oxy)benzoic acid (42)

[0841]

[0842]

[0843] Step 1: Synthesis of ethyl 7-bromo-4-[(ethoxymethyl)oxy]quinoline-3-carboxylate

[0844] N,N-diisopropylethylamine (392 mg, 3.04 mmol) was added to ethyl 7-bromo-4-hydroxyquinoline-3-carboxylate (300 mg, 1.01 mmol) and [(chloromethyl)oxy]ethane (191 mg, 2.03 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 h. After the reaction, the reaction mixture was diluted with H2O (5 mL) and extracted with dichloromethane (10 mL×3). The organic layer was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 42-2 (335 mg, 93%).

[0845] MS (ESI, pos.ion) m / z: 354.0 [M+1] + .

[0846] Step 2: Synthesis of ethyl 4-[(ethoxymethyl)oxy]-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carboxylate

[0847] Under nitrogen atmosphere, Xphos Palladacycle Gen.4 (76 mg, 0.09 mmol) was added to ethyl 7-bromo-4-[(ethoxymethyl)oxy]quinoline-3-carboxylate (315 mg, 0.89 mmol), 1,2,3,4-tetrahydropyrido[3,2-b]pyridine (131 mg, 0.98 mmol), cesium carbonate (869 mg, 2.67 mmol) in 1,4-dioxane (6 mL), and the mixture was reacted overnight at 100°C. After the reaction was completed, the mixture was filtered, the filter cake was washed with dichloromethane (20 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA (v / v) = 2 / 1-1 / 10) to give compound 42-3 (263 mg, 72%).

[0848] MS (ESI, pos.ion) m / z: 408.6 [M+1] + .

[0849] Step 3: Synthesis of ethyl 4-hydroxy-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carboxylate

[0850] Ethyl 4-[(ethoxymethyl)oxy]-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carboxylate (263 mg, 0.65 mmol) was added to an ethanol solution of hydrochloric acid (5 mL, 10 mol / L) and stirred overnight at 60° C. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 42-4 (225 mg, 99%).

[0851] MS (ESI, pos.ion) m / z: 350.1 [M+1] + .

[0852] Step 4: Synthesis of 4-hydroxy-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carboxylic acid

[0853] 4-Hydroxy-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carboxylic acid ethyl ester (225 mg, 0.64 mmol) and potassium hydroxide (180 mg, 3.22 mmol) were added to water (4 mL) and refluxed overnight. After the reaction was completed, the pH was adjusted to neutral with 1 mol / L hydrochloric acid aqueous solution, filtered, the solid was washed with water (10 mL), and the filter cake was dried to obtain compound 42-5 (175 mg, 84%).

[0854] MS (ESI, pos.ion) m / z: 322.2 [M+1] + .

[0855] Step 5: Synthesis of 4-chloro-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carbonyl chloride

[0856] 4-Hydroxy-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carboxylic acid (175 mg, 0.54 mmol) was added to phosphorus oxychloride (3 mL) and reacted at 100° C. for 1 h. After the reaction, the reaction solution was concentrated to dryness to obtain compound 42-6 (195 mg, 99%).

[0857] Step 6: Synthesis of 4-chloro-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carboxamide

[0858] At 0°C, a solution of 4-chloro-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carbonyl chloride (195 mg, 0.54 mmol) in tetrahydrofuran (5 mL) was added dropwise to a mixed solution of ammonia in 1,4-dioxane (10 mL, 0.4 mol / L) and tetrahydrofuran (5 mL), and the mixture was kept at 0°C for 0.5 h. After the reaction was completed, water (10 mL) was added to dilute the mixture and the mixture was extracted with dichloromethane (20 mL×3). The organic layer was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 42-7 (120 mg, 65%). MS (ESI, pos.ion) m / z: 339.5 [M+1] + .

[0859] Step 7: Synthesis of 5-{[3-carbamoyl-7-(1,2,3,4-tetrahydropyridin[3,2-b]pyridin-1-yl)quinolin-4-yl]amino}-3-(3,4,5,6-tetrahydro-2H-pyran-4-oxy)benzoic acid

[0860] 4-Chloro-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinoline-3-carboxamide (50 mg, 0.15 mmol) and 5-amino-3-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid (35 mg, 0.15 mmol) were added to acetic acid (2 mL) and reacted at 50° C. for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by preparative chromatography (formic acid conditions) to obtain compound 42 (35 mg, 44%).

[0861] MS (ESI, pos.ion) m / z: 540.2 [M+1] + .

[0862] 1 HNMR(DMSO-d6)δ:12.93(br s,1H),10.37(s,1H),8.95(s,1H),8.21(br s,1H),7.98-8.02(m,1H),7.71(d,J=9.3Hz,1H),7.64(br s,1H),7.58(d,J=2.1Hz,1H),7.35(dd,J=9.3,2.1Hz,1H),7.32(dd,J=8.3,0.9 Hz,1H),7.09(s,1H),7.06(s,1H),7.02(dd,J=8.3,4.6Hz,1H),6.78-6.81(m,1 H),4.54(dt,J=8.4,4.3Hz,1H),3.75-3.83(m,4H),3.41-3.46(m,2H),2.91(t, J=6.5Hz,2H),2.06(quin,J=6.1Hz,2H),1.86-1.95(m,2H),1.47-1.61(m,2H).

[0863] Biological Examples

[0864] LDHA inhibitory activity test

[0865] 1. Prepare 200-fold dilutions of the test compound: Starting from 2 mM test compound concentration, perform 3-fold gradient dilutions with DMSO, including 10 concentration gradients, and prepare 2 replicate wells for each concentration.

[0866] 2. Prepare a 200-fold negative control (100% DMSO).

[0867] 3. Pipette 1 μL of the diluted test compound into 49 μL of 1x tween-20 buffer to obtain a 4x diluted test compound working solution.

[0868] 4. After sealing the plate, shake the experimental plate on an oscillator for 15 minutes.

[0869] 5. Add 5 μL of the 4-fold diluted compound working solution prepared in step 4 to a 384 experimental plate (784075, Greiner).

[0870] 6. Prepare a 4-fold diluted LDHA solution on ice and add 5 μL of the 4-fold diluted LDHA solution to the 384 assay plate.

[0871] 7. Seal the test plate and incubate it at room temperature in the dark for 15 minutes.

[0872] 8. Prepare 4-fold diluted substrate solution: β-NADH and sodium pyruvate dissolved in 1x tween-20 buffer.

[0873] 9. Add 5 μL of the 4-fold diluted substrate solution prepared in step 8 to the 384 assay plate.

[0874] 10. Centrifuge the 384 test plate at 1000 rpm for 1 minute and incubate in a 25°C incubator in the dark for 30 minutes.

[0875] 11. Prepare 4-fold diluted detection solution: dissolve diaphorase and resazurin in 1x tween-20 buffer.

[0876] 12. Add 5 μL of the 4-fold diluted detection solution prepared in step 11 to the 384 experimental plate.

[0877] 13. Centrifuge the 384 test plate at 1000 rpm for 1 minute and incubate in a 25°C incubator in the dark for 20 minutes.

[0878] 14. Use PHERAstar FSX to read EX540-EM590 data.

[0879] The compounds of the present invention have good LDHA inhibitory activity. The data obtained for the representative compounds of the present invention are shown in Table 1:

[0880] Table 1

[0881]

[0882]

[0883] (2) Liver microsome stability

[0884] Preheat a 5mM MgCl2 (pH 7.41) buffer solution. Prepare a 100μL acetonitrile solution of the test compound (0.1mM). Take 1.5μL of 500μM chloramphenicol standard additive solution and 18.75μL liver microsomes (20mg / mL) and add them to 479.75μL of the above MgCl2 buffer solution. Distribute the liver microsome solution to the experimental plate at different time points (0, 5, 15, 30, 45min) and pre-incubate at 37°C for 5 minutes. Add 150μL of the acetonitrile solution of the test compound to the above experimental plate. Prepare a (6mM, 5mg / mL) MgCl2 buffer solution of NADPH for use. Then, 15 μL of NADPH solution was added to the above experimental plate to start timing. After 5 minutes, 15 minutes, 30 minutes, and 45 minutes, the reaction of the corresponding experimental plate was quenched, and the plate was shaken for 10 minutes (600 rpm), centrifuged for 15 minutes (6000 rpm), and 80 μL of the supernatant was taken and 140 μL of pure water was added. The final solution was analyzed by LC / MS.

[0885] The compounds of the present invention have good liver microsome stability. The data obtained for the representative compounds of the present invention are as follows:

[0886] Table 2

[0887]

[0888] The structure of GSK808A is

[0889] (3) Selectivity

[0890] Selectivity mainly refers to the selectivity of the compound's inhibitory activity for LDHA relative to LDHB, that is, the selectivity is obtained by dividing the inhibitory activity of LDHB by the inhibitory activity of LDHA.

[0891] LDHA inhibitory activity test see priority text

[0892] The inhibitory activity of LDHB was tested as follows:

[0893] 1) Prepare 200-fold dilutions of the test compound: Starting from 2 mM concentration of the test compound, perform 3-fold gradient dilutions with DMSO, including 10 concentration gradients, and prepare 2 replicate wells for each concentration.

[0894] 2) Prepare a 200-fold negative control (100% DMSO).

[0895] 3) Pipette 1 μL of the diluted test compound into 49 μL of 1x tween-20 buffer to obtain a 4x diluted test compound working solution.

[0896] 4) After sealing the plate, shake the experimental plate on an oscillator for 15 minutes.

[0897] 5) Add 5 μL of the 4-fold diluted compound working solution prepared in step 4 to a 384 experimental plate (784075, Greiner).

[0898] 6) Prepare a 4-fold diluted LDHB solution on ice and add 5 μL of the 4-fold diluted LDHB solution to the 384 assay plate.

[0899] 7) Seal the test plate and incubate it at room temperature in the dark for 15 minutes.

[0900] 8) Prepare 4-fold diluted substrate solution: β-NADH and sodium pyruvate dissolved in 1x tween-20 buffer.

[0901] 9) Add 5 μL of the 4-fold diluted substrate solution prepared in step 8 to the 384 assay plate.

[0902] 10) Centrifuge the 384 test plate at 1000 rpm for 1 minute and incubate in a 25°C incubator in the dark for 30 minutes.

[0903] 11) Prepare 4-fold diluted detection solution: Dissolve diaphorase and resazurin in 1x tween-20 buffer.

[0904] 12) Add 5 μL of the 4-fold diluted detection solution prepared in step 11 to the 384 assay plate.

[0905] 13) Centrifuge the 384 test plate at 1000 rpm for 1 minute and incubate in a 25°C incubator in the dark for 20 minutes.

[0906] Reading EX540-EM590 data with PHERAstar FSX

[0907] The compounds of the present invention have good selectivity, and the selectivity of the exemplary compounds of the present invention is as follows:

[0908] Table 3

[0909]

[0910] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may freely combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0911] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, Cy1 represents unsubstituted or optionally substituted with one, two or more R a substituted phenyl, pyridyl, thiazolyl, or cyclohexyl, R a are independently selected from carboxyl, difluorophenoxy, difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazolyl, morpholinyl, morpholinylmethyl, methylsulfonyl, methylsulfonylaminocarbonyl, oxetanylpiperidinyloxy, oxetanylpiperazinyl, cyclobutylpiperidinyloxy, hydroxydioxocyclobutyl and / or hydroxyisoxazolyl; Cy2 represents unsubstituted or optionally substituted with one, two or more R b substituted phenyl, phenoxy, phenylthio, phenylamino, pyrimidinyl, pyridinyl, dihydropyridinyl, benzopyranyl, benzothiopyranyl, imidazopyrimidinyl, dihydronaphthyridinyl or dihydrofuropyridinyl; R b are independently selected from methyl, ethyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, aminocarbonyl, cyano and / or oxo; R 1 and R 2 Each independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, C 1-6 Halogenated alkyl C 3-12 Cycloalkyl, C 3-6 Halogenated cycloalkyl, cyano C 1-6 Alkyl or 5- or 6-membered heterocyclic group, wherein the heteroatom in the 5- or 6-membered heterocyclic group is oxygen.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Cy1 represents unsubstituted or optionally substituted with one, two or more R a Substituted phenyl, pyridyl, thiazolyl, cyclohexyl; R a are independently selected from carboxyl, 3,5-difluorophenoxy, 4,4-difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazol-5-yl, morpholin-4-yl, morpholin-4-ylmethyl, methylsulfonyl, methylsulfonylaminocarbonyl, 2-hydroxy-3,4-dioxocyclobutane-1-yl, 1-(oxetan-3-yl)piperidin-4-yloxy, 4-(oxetan-3-yl)piperazin-1-yl, 1-cyclobutylpiperidin-4-yloxy and / or 3-hydroxyisoxazol-5-yl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Cy1 indicates that one, two or more R a Substituted phenyl, pyridin-2-yl, thiazol-2-yl, or cyclohexyl.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridinyl, benzopyranyl, dihydropyridinyl, imidazopyrimidinyl, dihydronaphthyridinyl or dihydrofuropyridinyl.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridinyl, 4H-chromen-3-yl, 1,2-dihydropyridinyl or imidazo[1,2-c]pyrimidinyl, 3,4-dihydro-1,5-naphthyridin-1(2H)-yl or 2,3-dihydrofuro[3,2-c]pyridin-7-yl.

6. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Cy1 is selected from the following structures:

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Cy2 is selected from the following structures:

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 and R 2 One of the groups represents hydrogen and the other represents hydrogen, cyclopropyl, 2,2,2-trifluoroethyl, methyl, propan-2-yl, tert-butyl, 1-trifluoromethyl-cyclopropyl-1-yl, 1-fluoro-cyclopropyl-1-yl, cyclobutyl, cyanomethyl, tetrahydropyran-4-yl, tetrahydrofuran-3-yl, 2H-tetrahydropyran-4-yl, cyclohexyl, oxetan-3-yl or 2,2-difluorocyclopropyl-1-yl.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein The compound of formula (I) has the structure of formula (IA), formula (IB), formula (IC) or formula (ID): Among them, R 1 , R 2 、Cy1、Cy2、R a , R b has the meanings defined in formula (I); h represents a number of 0, 1, 2 or 3, and i represents a number of 0, 1, 2 or 3.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 9, wherein h represents 0, 1 or 2, and i represents 0, 1 or 2.

11. A compound of formula (IIA) or formula (IIB) or a pharmaceutically acceptable salt thereof: in, R 1 , R 2 Each independently has the meaning as defined in any one of claims 1 to 10 for the compound of formula (I), X and Y are each independently selected from N, m represents 0, 1, 2 or 3, L represents -SO2- or -C(=O)-; Cy1 represents unsubstituted or optionally substituted by one, two or more R a Substituted phenyl, R a are independently selected from carboxyl, 2H-tetrahydropyran-4-yloxy; Cy2 represents dihydronaphthyridinyl.

12. The compound of formula (IIA) or formula (IIB) or a pharmaceutically acceptable salt thereof according to claim 11, wherein: Cy1 represents the following structure: Alternatively, Cy2 represents the following structure:

13. A compound of formula (IIA) or formula (IIB) or a pharmaceutically acceptable salt thereof according to claim 11 or 12, wherein the compound has a structure of formula (IIC) or formula (IIF):

14. A compound or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the following compounds:

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof; the pharmaceutical composition optionally comprises at least one pharmaceutically acceptable excipient.

16. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is an inhibitor of lactate dehydrogenase.

17. Use of a compound according to claim 16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing, treating or alleviating a disease selected from the group consisting of an autoimmune disease or cancer, wherein the autoimmune disease is selected from systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, and / or, the cancer is selected from acute lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumor, glioblastoma, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma and thyroid cancer.

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