N-Hydroxyquinoline carboxamide compounds and their uses

Abstract

The present invention relates to N-hydroxyquinolinecarboxamide derivatives (I), their preparation methods and uses. The present invention also additionally relates to pharmaceutical compositions containing the N-hydroxyquinolinecarboxamide derivatives.

Description

[0001] Priority Application

[0002] This application claims the priority of a prior application filed with the China National Intellectual Property Administration on January 21, 2022, with the patent application number 202210098470.0 and the invention title "N-hydroxyquinolinecarboxamide compounds as inhibitors of lactate dehydrogenase and their uses", the full text of which is incorporated herein by reference. Technical Field

[0003] The present invention relates to N-hydroxyquinolinecarboxamide derivatives that can be used as inhibitors of lactate dehydrogenase, and their preparation methods and uses. The present invention also additionally relates to pharmaceutical compositions containing the N-hydroxyquinolinecarboxamide derivatives. Background Art

[0004] Lactate dehydrogenase (LDH) is a tetrameric enzyme belonging to the 2-hydroxyacid oxidoreductase family, which can increase the rate of conversion of pyruvate to lactate and of nicotinamide adenine dinucleotide (NAD)H to NAD+, and is usually used by cells for anaerobic respiration, and thus is one of the important rate-limiting enzymes in the glycolysis pathway. The two different subunits of lactate dehydrogenase are encoded by two independent genes, namely LDHA and LDHB. LDHA is also called the M subunit and is mainly found in skeletal muscle; LDHB is also called the H subunit and is mainly found in the heart. Since LDH is a tetrameric enzyme, LDH can also form five isozymes through the 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 lung), LDH-4 (1H, 3M, mainly found in the kidney) and LDH-5 (4M, mainly found in the liver and striated muscle).

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

[0006] By inhibiting the activity of LDHA and regulating or inhibiting the activity 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, especially drugs with selectivity for the regulation of LDHA / LDHB. Summary of the Invention

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

[0008] In a first aspect, the present invention provides a compound of formula (I) or a physiologically / pharmaceutically acceptable salt or ester thereof, their stereoisomers or tautomers, racemates, N-oxides, solvates, isotope-labeled compounds, prodrugs or metabolites:

[0009]

[0010] wherein,

[0011] Cy1 represents an unsubstituted or optionally substituted by one, two or more R a substituted C 3-20 cycloalkyl, 3- to 14-membered heterocyclic group, C 6-20 aryl or 5- to 20-membered heteroaryl,

[0012] R a may each independently be selected from the group consisting of: carboxyl, aminocarbonyl, C 1-12 alkyl, halogen, nitro, cyano, hydroxyl, -CO-C 1-12 alkoxy, C 1-12 alkoxy, -O-C 3-20 cycloalkyl, -O-3- to 14-membered heterocyclic group, -O-C 6-20 aryl, hydroxyaminocarbonyl, 3- to 14-membered heterocyclic group, 5- to 20-membered heteroaryl or C 1-12 alkylsulfonyl, wherein R a may optionally be further substituted by oxo or by hydroxyl or halogen,

[0013] Cy2 represents an unsubstituted or optionally substituted by one, two or more R b substituted 3- to 20-membered heterocyclic group or C 6-20 aryl or 5- to 20-membered heteroaryl,

[0014] R b may each independently be 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] In some preferred embodiments according to the present invention, Cy1 represents an unsubstituted or optionally substituted by one, two or more R aSubstituted C 3-12 cycloalkyl or 3- to 14-membered heterocyclic group or C 6-14 aryl or 5- to 14-membered heteroaryl. Preferably, R a may each independently be selected from carboxyl, aminocarbonyl, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, -CO-C 1-12 alkoxy, C 1-6 alkoxy, -O-C 3-12 cycloalkyl, -O-3- to 14-membered heterocyclic group, -O-C 3-12 halocycloalkyl, -O-C 6-14 aryl, hydroxyaminocarbonyl, 3- to 14-membered heterocyclic group, 5- to 14-membered heteroaryl, C 1-6 alkylsulfonyl, -SO 3 H or -SO 3 -C 1-6 alkyl, where R a may optionally be further substituted by oxo or by hydroxy or halogen.

[0016] Preferably, Cy1 represents an unsubstituted or optionally substituted by one, two or more R a substituted phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, imidazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, thiadiazolyl, bicyclo[2.2.1]heptyl, cyclohexyl, chromanyl.

[0017] Preferably, R a may each independently be selected from carboxyl, aminocarbonyl, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, -CO-C 1-12 alkoxy, C 1-6 alkoxy, -O-C 3-12 cycloalkyl, -O-3- to 6-membered heterocyclic group, -O-C 3-12 halocycloalkyl, -O-C 6-14 aryl, hydroxyaminocarbonyl, 5- or 6-membered heterocyclic group, 5- or 6-membered heteroaryl, C 1-6 alkylsulfonyl, -SO 3 H or -SO 3 -C 1-6 alkyl, where R a may optionally be further substituted by oxo or by hydroxy, fluoro, chloro or bromo.

[0018] More preferably, Cy1 represents an unsubstituted or optionally substituted by one, two or more R a substituted phenyl, pyridyl, thiazolyl, bicyclo[2.2.1]heptyl, cyclohexyl, chromanyl.

[0019] More preferably, R aEach independently selected from carboxyl, difluorophenoxy, difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 2H-tetrahydropyranyl, 2H-tetrahydropyranyloxy, hydroxyaminocarbonyl, 1H-tetrazolyl, mesyl, 2-hydroxy-3,4-dioxocyclobutanyl, 1-hydroxy-2,2,2-trifluoroethyl and / or hydroxyisoxazolyl.

[0020] Still more preferably, Cy1 represents a phenyl, pyridin-2-yl, thiazol-2-yl, bicyclo[2.2.1]hept-1-yl, cyclohexyl or chromanyl substituted by one, two or more R a substituents.

[0021] Still more preferably, R a Each independently selected from carboxyl, 3,5-difluorophenoxy, 4,4-difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 2H-tetrahydropyran-4-yl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazol-5-yl, mesyl, 2-hydroxy-3,4-dioxocyclobutane-1-yl, 1-hydroxy-2,2,2-trifluoroethyl and / or 3-hydroxyisoxazol-5-yl.

[0022] Most preferably, Cy1 has the following structure:

[0023]

[0024]

[0025] In some preferred embodiments according to the present invention, Cy1 is substituted by one or two R a substituents; preferably, Cy1 is substituted by at least one carboxyl group.

[0026] In some preferred embodiments according to the present invention, Cy1 is a phenyl substituted by at least one carboxyl group, which may optionally be substituted by one, two or more R a substituents. Preferably, the compound of formula (I) has the structure of formula (I-1) below:

[0027]

[0028] wherein, Cy2 has the definition herein, R a each independently has the definition herein, and n represents 0, 1, 2, 3 or 4.

[0029] Preferably, R a is tetrahydro-2H-pyran-4-yl and n is 1.

[0030] In some preferred embodiments according to the present invention, Cy2 represents an unsubstituted or optionally substituted 3- to 14-membered heterocyclic group or C b aryl or 5- to 14-membered heteroaryl which is substituted by one, two or more R 6-14 groups.

[0031] Preferably, Cy2 represents an unsubstituted or optionally substituted phenyl, phenoxy, phenylthio, phenylamino, pyrimidinyl, pyridyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, benzopyran-2-yl, benzothiopyran-2-yl, pyrazolopyrimidinyl, dihydrofuranopyrimidinyl, furanopyrimidinyl, thiazolopyrimidinyl or imidazopyrimidinyl which is substituted by one, two or more R b groups.

[0032] More preferably, Cy2 represents an unsubstituted or optionally substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridyl, benzopyran-2-yl, pyrazolopyrimidinyl, dihydrofuranopyrimidinyl, dihydropyridyl or imidazopyrimidinyl which is substituted by one, two or more R b groups.

[0033] Even more preferably, Cy2 represents an unsubstituted or optionally substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridyl, 4H-benzopyran-3-yl, 1H-pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydrofuro[3,2-c]pyrimidinyl, 1,2-dihydropyridyl, imidazo[1,2-c]pyrimidinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydrofuro[3,2-c]pyridinyl or 3,4-dihydro-1,5-naphthyridin-1(2H)-yl which is substituted by one, two or more R b groups.

[0034] 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.

[0035] 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.

[0036] Even more preferably, Rb independently selected from methyl, ethyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, chlorine, fluorine, aminocarbonyl, cyano, oxo and / or 2,2-difluoroethoxy.

[0037] Most preferably, Cy2 has the following structure:

[0038]

[0039] In some preferred embodiments according to the present invention, Cy2 is an unsubstituted 3- to 14-membered heterocyclic group, preferably 3,4-dihydro-1,5-naphthyridin-1(2H)-yl. Preferably, the compound of formula (I) has the structure of the following formula (I-2):

[0040]

[0041] wherein, Cy1 has the definition herein.

[0042] Preferably, R a is tetrahydro-2H-pyran-4-yl and n is 1.

[0043] In some preferred embodiments according to the present invention, the compound of formula (I) is selected from the following compounds:

[0044]

[0045]

[0046] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a salt or ester thereof, their stereoisomers or tautomers, racemates, N-oxides, solvates, isotopically labeled compounds, prodrugs or metabolites.

[0047] In some preferred embodiments according to the present invention, the pharmaceutical composition according to the present invention may also optionally comprise at least one physiologically / pharmaceutically acceptable excipient.

[0048] In some preferred embodiments according to the present invention, the pharmaceutical composition according to the present invention may also optionally comprise an additional active ingredient. The additional active ingredient is, for example, an anti-microtubule agent, a platinum coordination complex, an alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone and a hormone analogue, a signal transduction pathway inhibitor; a non-receptor tyrosine kinase angiogenesis inhibitor; an immunotherapeutic agent; a pro-apoptotic agent; and a cell cycle signal inhibitor.

[0049] In some preferred 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) or a salt or ester thereof, their stereoisomers or tautomers, racemates, N-oxides, solvates, isotopically labeled compounds, prodrugs or metabolites.

[0050] In some preferred embodiments according to the present invention, the pharmaceutical composition according to the present invention is an inhibitor of lactate dehydrogenase.

[0051] In some preferred embodiments according to the present invention, the pharmaceutical composition according to the present invention is used for preventing or treating diseases, disorders, syndromes and / or disorders selected from the following groups, or for alleviating the symptoms of diseases, disorders, syndromes and / or disorders selected from the following groups: autoimmune diseases or cancers. 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 cancers include, but are not limited to: acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin 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.

[0052] According to the present invention, the pharmaceutical composition according to the present invention can be formulated into a dosage form suitable for administration by methods known in the art.

[0053] In a third aspect, the present invention provides the use of a compound of formula (I) or a salt or ester thereof, their stereoisomers or tautomers, racemates, N-oxides, solvates, isotopically labeled compounds, prodrugs or metabolites according to the present invention in the preparation of a medicament.

[0054] In some preferred embodiments according to the present invention, the medicament may optionally further comprise an additional active ingredient. The additional active ingredient is, for example, an anti-microtubule agent, a platinum coordination complex, an alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone and a hormone analogue, a signal transduction pathway inhibitor; a non-receptor tyrosine kinase angiogenesis inhibitor; an immunotherapeutic agent; a pro-apoptotic agent; and a cell cycle signal inhibitor.

[0055] In some preferred embodiments according to the present invention, the drug is an inhibitor of lactate dehydrogenase, and the object of the present invention is achieved by inhibiting the activity of LDHA and regulating or inhibiting the activity of LDHB, especially by increasing the inhibitory selectivity for LDHA / LDHB.

[0056] In some preferred embodiments according to the present invention, the drug is used for preventing or treating diseases, disorders, syndromes and / or disorders selected from the following groups, or for relieving the symptoms of diseases, disorders, syndromes and / or disorders selected from the following groups: autoimmune diseases or cancers. 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 lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin 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.

[0057] According to the present invention, the drug can be further formulated into a dosage form suitable for administration by methods known in the art.

[0058] In a fourth aspect, the present invention provides a method for treating or preventing diseases, disorders, syndromes and / or disorders of autoimmune diseases or cancers, the method comprising administering to an individual in need a compound of formula (I) according to the present invention or a salt or ester thereof, their stereoisomers or tautomers, racemates, N-oxides, solvates, isotopically labeled compounds, prodrugs or metabolites.

[0059] In some preferred embodiments according to the present invention, the diseases, disorders, 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.

[0060] In some preferred embodiments according to the present invention, the diseases, disorders, syndromes and / or afflictions of cancer include: acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin lymphoma, breast cancer, pancreatic cancer, lung cancer, etc., 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.

[0061] Those skilled in the art can understand that the features listed in various aspects and embodiments according to the present invention can be freely combined as long as there is no conflict or incompatibility between them.

[0062] Advantages of the present invention

[0063] The present invention provides an inhibitor of lactate dehydrogenase having an N-hydroxyquinolinecarboxamide structure, which has good biological activity and pharmacokinetic properties. In particular, the compounds of the present invention have excellent selectivity for the regulation of LDHA / LDHB. Detailed implementation manners

[0064] The present invention will be further described in detail below.

[0065] Unless otherwise specified, the following terms used herein 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 combined and combined with each other arbitrarily; terms not explained in detail should have the same meaning as commonly understood by those skilled in the art; patents and non-patent documents cited in full or in part herein or other materials disclosed in other ways are incorporated herein by reference.

[0066] For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry can be referred to the descriptions 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.

[0067] Terms

[0068] In this text, the terms "comprising", "including" and / or "containing" are open-ended expressions, that is, they include the content specified in the present invention, but do not exclude other aspects.

[0069] In this text, when describing one / a kind, two / kinds or more than two / kinds, "more than two / kinds" shall refer to the case where the number is greater than 2, for example, it represents an integer case greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10 one / a kind(s).

[0070] In this text, the term "optional(ly)" means that the said feature exists or does not exist, which means that the subsequent described event can but does not necessarily occur, and thus includes two categories of cases where the event occurs or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may or may not exist, and thus includes the cases of a heterocyclic group substituted by an alkyl group and a heterocyclic group not substituted by an alkyl group.

[0071] In this text, expressions such as "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.

[0072] In this text, the term "unsubstituted" means that one or some hydrogen atoms on the atom, residue, group or moiety associated with this term are not substituted by other atoms or atomic groups (i.e., substituents) other than hydrogen atoms, so that the atom, residue, group or moiety retains its original structure. The term "(substituted)" means that one, two or more hydrogen atoms in the group, preferably at most 5 hydrogen atoms, more preferably 1 - 3 hydrogen atoms are each independently substituted by the 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 case of being the same is not excluded. Unless specifically indicated, a substituent group can be substituted at any substitutable position of the group to be substituted. When there is more than one position in the given structural formula that can be substituted by one, two or more substituents, then these substituents can be independently substituted at these positions. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine the possible or impossible substitutions without undue labor based on experiments or theories.

[0073] In this text, the phrase "each independently of the others" should be understood to mean that the described individuals are independent of each other and can be independently selected from the same or different options. For example, "each independently selected from" can either mean that among different groups, the specific options represented by the same symbol do not affect each other; or it can mean that within the same group, the specific options represented by the same symbol do not affect each other.

[0074] In this text, sometimes two or more groups with definite meanings are combined to describe a larger part, and the part described by this combination method includes the structural combinations formed by the independent selection of these two or more groups from each other. For example, "alkylaryl" means "alkyl" and "aryl" connected together, and the "alkyl" and the "aryl" each independently have the meanings described for them respectively, thus jointly forming the combined group "alkylaryl".

[0075] In this text, sometimes a linking group 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 linking sites. The Markush variables listed for the linking group should be understood as divalent groups of this variable, that is, "subgroups". For example, if a linking group is defined in the compound structure and the Markush group definition for this linking group lists "alkyl" or "aryl", then it should be understood that the "alkyl" or "aryl" respectively represents a linked alkylene group or arylene group.

[0076] In this text, the notation "C x -C y ", when combined with a group, represents the upper and lower limits of the number of carbon atoms contained in the group. For example, "C 1 -C 12 " alkyl refers to an alkyl group containing at least one carbon atom up to a maximum of twelve carbon atoms. Those skilled in the art can understand that such numbers do not include the number of carbon atoms contained in the substituents connected to these groups when they are additionally substituted.

[0077] The expression "X-Y membered" when combined with a cyclic group represents 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 at least three ring atoms up to a maximum of twenty ring atoms. Those skilled in the art can understand that such numbers do not include the number of carbon atoms contained in the substituents connected to these heterocyclic groups when they are additionally substituted.

[0078] In this text, the term "oxo" means that the carbon atom, nitrogen atom or sulfur atom in the group is substituted by an oxo group formed thereon (=O).

[0079] As used herein, the term "halogen" means fluorine, chlorine, bromine, and / or iodine. Accordingly, the term "halogenated" means fluorinated, chlorinated, brominated, and / or iodinated. Within the scope of this disclosure, when an atom, residue, group, or moiety is halogenated, the atom at the halogenated position can be mono-substituted, di-substituted, or poly-substituted with halogen atoms up to full substitution.

[0080] The term "alkyl" means a straight-chain or branched-chain monovalent saturated aliphatic hydrocarbon group. Non-limiting examples of alkyl 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 their various branched-chain isomers, etc.

[0081] The term "alkenyl" refers to a straight-chain or branched-chain monovalent unsaturated aliphatic hydrocarbon group containing one, two or more double bonds. It is to be understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated from each other 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-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, 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-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0082] The term "alkynyl" refers to a straight-chain or branched-chain 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-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0083] The term "alkylene" refers to a divalent group obtained by additionally removing one hydrogen atom from "alkyl". Similarly, "alkenylene" and "alkynylene" respectively refer to divalent groups obtained by additionally removing one hydrogen atom from "alkenyl" and "alkynyl".

[0084] The term "alkoxy" means -O-alkyl, where alkyl is defined as described herein. Non-limiting examples of alkoxy include, for example: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy can be unsubstituted or optionally substituted.

[0085] The term "carbocyclic (group)" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, which may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, and more preferably 3 to 6 carbon atoms. The carbocycle may be monocyclic or polycyclic, and it may be a saturated cycloalkyl group or may optionally contain one, two or more double bonds and / or triple bonds in its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl group. The saturated cyclic hydrocarbon group or the saturated carbocyclic group is also referred to as "cycloalkyl". When the carbocyclic group or the cyclic hydrocarbon group has multiple rings, these rings may form spiro, fused and bridged ring structures. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, etc.; non-limiting examples of polycyclic carbocycles include decahydronaphthyl, norbornyl or isobornyl.

[0086] The term "heterocyclic (group)" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which preferably contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from N, O, NH, S, S(O) or S(O) 2heteroatoms or atomic groups, but excluding the ring portion of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, among which 1 to 4 are heteroatoms (such as 1, 2, 3, and 4); more preferably, it contains 3 to 6 ring atoms (such as 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 atoms (if present) or oxygen or sulfur atoms (especially in the case of forming an onium salt) among the said carbon atoms. The heterocyclic group can include fused or bridged rings and / or spiro rings. Non-limiting examples of monocyclic heterocyclic groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolanyl, tetrahydropyranyl, pyrroline, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl, etc., preferably piperidyl, pyrrolidinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups, and can also be benzo-fused heterocyclic groups such as dihydroisoquinolinyl. The heterocyclic group can be bicyclic, and non-limiting examples thereof include hexahydrocyclopenta[c]pyrrol-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl. The heterocyclic group can also be partially unsaturated, that is, it can contain one or more double bonds, and non-limiting examples thereof 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, 2,3-dihydrofuro[3,2-c]pyrimidinyl, 1,2-dihydropyridinyl, imidazo[1,2-c]pyrimidinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydrofuro[3,2-c]pyridinyl, 3,4-dihydro-1,5-naphthyridin-1(2H)-yl or 2,3-dihydrofuro[3,2-c]pyridin-7-yl.

[0087] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.

[0088] The term "aryl / aromatic ring" refers to a fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated electron system, preferably a 6- to 14-membered or 6- to 10-membered ring, such as phenyl and naphthyl.

[0089] The aryl group can be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group, preferably phenyl.

[0090] As used herein, the term "heteroaryl / heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered), more preferably 5 membered or 6 membered. Non-limiting examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thieno-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and / or phenoxazinyl, etc.

[0091] The heteroaryl / heteroaromatic ring can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one, two or more groups independently selected from the following group: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0092] Unless otherwise specified, the heterocyclic group, heteroaryl group or heteroaromatic ring includes all its possible isomeric forms, such as its positional isomers. Thus, for some illustrative non-limiting examples, it can include forms substituted or bonded to other groups at one, two or more positions among its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12- positions, etc. (if present), including pyridin-2-yl, pyridin-2-ylidene, pyridin-3-yl, pyridin-3-ylidene, pyridin-4-yl and pyridin-4-ylidene; thienyl or thienylidene includes thien-2-yl, thien-2-ylidene, thien-3-yl and thien-3-ylidene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0093] Unless otherwise specified, the definitions of the terms in this text also apply to the expressions containing such terms, such as C 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.

[0094] In this text, "physiologically / pharmaceutically acceptable salts" refer to the salts of the compounds of the present invention, which are safe and effective when used in mammals and have the due biological activities.

[0095] Physiologically / pharmaceutically acceptable salts include acid addition salts of the compounds of the present invention having sufficient basicity with nitrogen atoms in the chain or ring. In addition, the 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 dipentyl 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, hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate, or meglumine salt, etc.

[0096] Since there may be multiple salt-forming sites in the compounds of the present invention, the physiologically / pharmaceutically acceptable salts include not only the salts formed at one salt-forming site of the compounds of the present invention, but also the salts formed at two, three, or all salt-forming sites. For this reason, in the physiologically / pharmaceutically acceptable salts, the molar ratio of the compound of formula (I) to the anionic or cationic moiety of the acid or base required for salt formation can vary within a relatively wide range, for example, it can be 4:1 - 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0097] In this text, 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 N-oxides. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The corresponding nitrogen-containing compounds can be treated with oxidants such as hydrogen peroxide or peracids (such as peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which, for example, in an inert solvent such as dichloromethane, the nitrogen-containing compound is reacted with m-chloroperoxybenzoic acid (MCPBA).

[0098] In this text, the term "ester" means a hydrolyzable ester in vivo formed by a compound containing a hydroxyl group or a carboxyl group. Such esters are, for example, physiologically / pharmaceutically acceptable esters that hydrolyze in a human or animal body to produce the parent alcohol or acid. The compounds of formula (I) of the present invention contain a carboxyl group and can form hydrolyzable esters in vivo with appropriate groups, such groups including, but not limited to, alkyl, arylalkyl, and the like.

[0099] Depending on the position and nature of the different substituents, the compounds of the present invention may also contain one or more asymmetric centers. Asymmetric carbon atoms can exist in the (R) or (S) configuration. When there is only one asymmetric center, a racemic mixture is produced, and when there are multiple asymmetric centers, a mixture of diastereoisomers is obtained. In some cases, asymmetry may also exist due to hindered rotation around a specific bond, for example, when the central bond connects two substituted aromatic rings of a specific compound. Also, the substituents can exist in the form of cis or trans isomers.

[0100] The compounds of the present invention also include all possible stereoisomers thereof, which are in the form of a single stereoisomer or any mixture of the stereoisomers (such as R-isomers or S-isomers, or E-isomers or Z-isomers) in any proportion. The separation of the single stereoisomers (such as single enantiomers or single diastereoisomers) of the compounds of the present invention can be achieved by any suitable prior art method (such as chromatography, especially chiral chromatography, for example).

[0101] The term "tautomer" refers to functional group isomers resulting from the rapid movement of a particular atom within a molecule between two locations. The compounds of the present invention may exhibit tautomerism. Tautomers of a compound can exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are identical to those of a mixture of the compounds. The position of the 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.

[0102] 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), but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes which 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 present invention containing the above isotopes and / or other isotopes of other atoms, prodrugs thereof, or physiologically / pharmaceutically acceptable salts of said compounds or said prodrugs are within the scope of the present invention. Isotopically labeled compounds according to the present invention can generally be prepared by replacing a non-isotopically labeled reagent with an isotopically labeled reagent according to the methods described herein. Certain isotopically labeled compounds of the present invention, for example compounds incorporating a radioactive isotope (such as 3 H and 14 C) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2H) Substitution may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dose requirements) stemming from higher metabolic stability and may thus be preferred in certain situations. The compounds of the invention as claimed may be specifically defined in terms of substitution with deuterium or tritium. Moreover, hydrogen present in a substituent, where the terms deuterium or tritium are not separately specified, does not exclude deuterium or tritium but may equally well include deuterium or tritium.

[0103] As used herein, the term “prodrug” or “drug precursor” refers to a compound that is converted in vivo to a compound of formula (I) or a specific compound as described above. Such conversion is affected by hydrolysis of the prodrug in the blood or enzymatic conversion in the blood or tissues to the parent structure. The prodrugs of the invention may be esters, and in the present invention, esters that may serve as prodrugs include benzoates, aliphatic esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound in the present invention containing a hydroxyl / carboxyl group may be acylated to obtain a compound in the prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylating a hydroxyl group on the parent compound.

[0104] As used herein, the term “metabolite” refers to a product obtained by the metabolic action of a specific compound or its salt in vivo. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by methods such as those described in the present invention using assays. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds, including metabolites produced by bringing the compounds of the present invention into sufficient contact with a mammal for a period of time.

[0105] Unless otherwise indicated, any abbreviations used for protecting groups, amino acids, and other compounds in the present invention are in their commonly used and recognized abbreviations, or are referenced to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11: 942-944).

[0106] As used herein, the term “solvate” refers to an association formed between one or more solvent molecules and a compound 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. Accordingly, the term “hydrate” refers to an association in which the solvent molecule is water.

[0107] 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, along with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert biological activity. The term "physiologically / pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to a human and generally do not produce allergic or similar untoward reactions, such as gastrointestinal discomfort, dizziness, etc. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Aqueous solutions such as saline solutions and aqueous glucose and glycerol solutions are preferably used as carriers, especially for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0108] As used herein, the term "treating" any disease or disorder, in some embodiments, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing 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 perceptible to the patient. In other embodiments, "treating" refers to modulating the disease or disorder physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the physical parameters) or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of the disease or disorder.

[0109] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of the compound described herein 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 factors such as the intended application (in vitro or in vivo), or the subject and disease disorder being treated, such as the weight and age of the subject, the severity of the disease disorder, and the mode of administration, which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on factors such as the particular compound selected, the dosing regimen followed, whether co-administered with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system employed.

[0110] In some preferred embodiments according to the present invention, the pharmaceutical excipients may be excipients widely used in the field of drug production. The excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to enable the active ingredient to dissolve at a desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the administration of the composition. The pharmaceutical excipients may be inert fillers or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesives, glidants, wetting agents, gelling agents, absorption retardants, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0111] 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, buffering 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, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene-block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl 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 salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coating materials, sweeteners, flavoring agents and fragrances, preservatives and antioxidants.

[0112] The pharmaceutical composition of the present invention can be prepared by any method known to those skilled in the art according to the disclosed content. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

[0113] The dosage form of the drug of the present invention can be selected according to specific circumstances. A pharmaceutical dosage form often consists of a drug, excipients, and a container / sealing system. One or more excipients (also known as inactive ingredients) can be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration, and safety of the drug, and can provide a method for obtaining the desired drug release profile. Therefore, the type of excipient added to the drug can depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. There are pharmaceutical excipients in the art and include those listed in various pharmacopoeias. (See the U.S. Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British Pharmacopoeia (BP); publications of the Center for Drug Evaluation and Research (CEDR) of the U.S. Food and Drug Administration (www.fda.gov), such as the Inactive Ingredient Guide (1996); the Handbook of Pharmaceutical Additives written by Ash (2002), Synapse Information Resources, Inc., Endicott NY; etc.)

[0114] The pharmaceutical composition of the present invention may include one or more physiologically acceptable inactive ingredients, which facilitate the processing of the active molecule into a formulation for medical use.

[0115] 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 administered as immediate-release or controlled-release / sustained-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.

[0116] Solid oral dosage forms can be obtained using excipients, which include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adhesives, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavorants. These excipients can be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silica, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, 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, taste-masking films, anti-gastric acid films, or sustained-release films. Natural and synthetic polymers are often combined with colorants, sugars, and organic solvents or water for coating tablets, thus producing sugar-coated pills. When capsules are preferred over tablets, the drug powder, suspension, or solution can be delivered in the form of compatible hard or soft shell capsules.

[0117] A therapeutically effective dose can be initially estimated using various methods well-known in the art. The initial dose for animal studies can be based on the effective concentration established in cell culture assays. A suitable dose range 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 formulated as medicaments for oral administration.

[0118] The correct formulation, route of administration, dose, and dosing interval can be selected according to methods known in the art, taking into account the particularities of the individual condition.

[0119] Examples

[0120] The preparation method of the present invention will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only for illustrative explanation of the present invention and should not be construed as limiting the protection scope of the present invention. All technical solutions implemented based on the content of the present invention are covered within the scope of protection intended by the present invention.

[0121] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods in the art; the reagents, raw materials, instruments, equipment, etc. used in the following examples can all be obtained commercially.

[0122] Reagents Used

[0123] The starting materials and reagents in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or in accordance with the literature reported in the art.

[0124] Instruments, Equipment and Measurement Methods

[0125] NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic resonance spectrometers. The solvents used for determination included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), etc. Tetramethylsilane (TMS) was used as the internal standard, and the chemical shift was measured in parts per million (ppm).

[0126] Liquid chromatography-mass spectrometry (LC-MS) was detected using an Agilent 1260 mass spectrometer. HPLC determination was performed using an Agilent 1100 high-pressure chromatograph (Microsorb 5 micron C18 100x 3.0 mm chromatographic column).

[0127] The thin-layer chromatography silica gel plate used was Qingdao GF254 silica gel plate. The thickness of TLC was 0.15 - 0.20 mm, and the thickness of preparative thin-layer chromatography was 0.4 mm - 0.5 mm. Column chromatography generally used Qingdao silica gel with 200 - 300 mesh as the carrier.

[0128] Abbreviations or Short Forms

[0129] Boc: tert-Butyloxycarbonyl

[0130] Xantphos Pd G 4 : Palladium(II) (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)(2'-methylamino-1,1'-biphenyl-2-yl) methanesulfonate

[0131] DIAD: Diisopropyl azodicarboxylate

[0132] B 2 Pin 2 : Bis(pinacolato)diboron

[0133] AcOH: Acetic acid

[0134] MeOH: Methanol

[0135] NaOH: Sodium hydroxide

[0136] DCM: Dichloromethane

[0137] THF: Tetrahydrofuran

[0138] t-BuOH: tert-Butanol

[0139] Et 3 N: Triethylamine

[0140] H 2 O: Water

[0141] PE: Petroleum ether

[0142] EA, EtOAc: Ethyl acetate

[0143] KOAc: Potassium acetate

[0144] NMP: N-Methylpyrrolidone

[0145] DIEA: N,N-Diisopropylethylamine

[0146] Na 2 SO 4 : Sodium sulfate

[0147] HPLC: High performance liquid chromatography

[0148] Pre-HPLC: Preparative high performance liquid chromatography

[0149] Prep-TLC: Preparative thin layer chromatography

[0150] rt: Room temperature

[0151] Example 1: Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(hydroxyaminocarbonyl)quinolin-4-yl)amino)benzoic acid (1)

[0152]

[0153] Step 1: Synthesis of ethyl 7-bromo-4-chloroquinoline-3-carboxylate (1-2)

[0154]

[0155] Ethyl 7-bromo-4-hydroxyquinoline-3-carboxylate (1.00 g, 3.38 mmol) was added to SOCl 2 (15 mL), and then the mixture was heated and stirred for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was added to saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (40 mL). The combined organic phases were then washed with saturated NaCl solution (60 mL), dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain a white solid (1.00 g, 84%).

[0156] MS (ESI, pos. ion) m / z: 314.1 [M+1] + .

[0157] Step 2: Synthesis of Ethyl 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxylate (1-4)

[0158]

[0159] Ethyl 7-bromo-4-chloroquinoline-3-carboxylate (1.00 g, 3.18 mmol), (2,4-dimethoxypyrimidin-5-yl)boronic acid (585 mg, 3.18 mmol) and K 2 CO 3 (1.32 g, 9.64 mmol) were added to a mixture of dioxane (20 mL) and water (5 mL). The air in the reaction system was replaced with nitrogen. Under a nitrogen stream, Pd(PPh 3 ) 4 (370 mg, 0.32 mmol) was added, and then the system was replaced with nitrogen again. The reaction was stirred at 80 °C for 1 h. Dilute with H 2 O (30 mL), extract with EA (30 mL × 3), wash with saturated NaCl solution (30 mL), and dry over anhydrous Na 2 SO 4 . Concentrate under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain a white solid (800 mg, 67%).

[0160] MS (ESI, pos. ion) m / z: 374.1 [M+1] + .

[0161] Step 3: Synthesis of 3-(3,5-Difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(ethoxycarbonyl)quinolin-4-yl)amino)benzoic acid (1-6)

[0162]

[0163] Ethyl 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxylate (150 mg, 0.40 mmol) and 3-amino-5-(3,5-difluorophenoxy)benzoic acid (106 mg, 0.40 mmol) were added to AcOH (5 mL). Stir at room temperature overnight. Concentrate under reduced pressure. The crude product was purified by trituration with EA (10 mL) to obtain a yellow solid (160 mg, 66%).

[0164] MS (ESI, pos. ion) m / z: 603.2 [M+1] + .

[0165] Step 4: Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(hydroxyaminocarbonyl)quinolin-4-yl)amino)benzoic acid (1)

[0166]

[0167] 3-(3,5-Difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(ethoxycarbonyl)quinolin-4-yl)amino)benzoic acid (65 mg, 0.11 mmol) and aqueous hydroxylamine solution (0.6 mL) were added to MeOH (2 mL), then LiOH (18 mg, 0.43 mmol) was added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, hydrochloric acid (2N) was added dropwise to adjust the pH to about 6, water (20 mL) and ethyl acetate (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were then washed with saturated NaCl solution (40 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to obtain a yellow solid (15.3 mg, 24%).

[0168] MS(ESI,pos.ion)m / z:590.1[M+1] + 。

[0169] 1 HNMR(DMSO-d 6 )δ:12.99-13.22(m,1H),11.32(br d,J=5.0Hz,1H),9.59(br s,1H),9.09-9.24(m,1H),8.77(s,1H),8.59(s,1H),8.18(s,1H),8.06(br d,J=8.6Hz,1H),7.72-7.80(m,1H),7.37(s,1H),7.09(s,1H),7.00(tt,J=9.3,2.3Hz,1H),6.80-6.89(m,3H),4.00(s,3H),3.99(s,3H).

[0170] Example 2: Synthesis of 3-((4,4-difluorocyclohexyl)oxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(hydroxyaminocarbonyl)quinolin-4-yl)amino)benzoic acid (2)

[0171]

[0172] Step 1: Synthesis of 3-((4,4-difluorocyclohexyl)oxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(ethoxycarbonyl)quinolin-4-yl)amino)benzoic acid (2-3)

[0173] Ethyl 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxylate (100 mg, 0.27 mmol) and 3-amino-5-((4,4-difluorocyclohexyl)oxy)benzoic acid (73 mg, 0.27 mmol) were added to CH 3 COOH (2 mL). The reaction was carried out at 50 °C for 3 h. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude product (162 mg, 99%).

[0174] MS (ESI, pos. ion) m / z: 609.2 [M+1] + .

[0175] Step 2: Synthesis of 3-((4,4-difluorocyclohexyl)oxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(hydroxyaminocarbonyl)quinolin-4-yl)amino)benzoic acid (2)

[0176] 3-((4,4-difluorocyclohexyl)oxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(ethoxycarbonyl)quinolin-4-yl)amino)benzoic acid (80 mg, 0.13 mmol) and aqueous hydroxylamine solution (0.6 mL) were added to MeOH (2 mL), then LiOH (22 mg, 0.52 mmol) was added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, hydrochloric acid (2 N) was added dropwise to adjust the pH to about 6, water (10 mL) and ethyl acetate (20 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were then washed with saturated NaCl solution (30 mL) and dried over anhydrous Na 2 SO 4 SO4. After concentration under reduced pressure, the crude product was separated by Pre-HPLC to obtain compound 2 (23.2 mg, 26%).

[0177] MS (ESI, pos. ion) m / z: 596.2 [M+1] + .

[0178] 1 1H NMR (DMSO-d 6)δ: 12.68 - 13.04 (m, 1H), 11.26 - 11.56 (m, 1H), 9.64 (br s, 1H), 9.08 - 9.25 (m, 1H), 8.82 (s, 1H), 8.59 (s, 1H), 8.18 (d, J = 1.4 Hz, 1H), 7.94 (br d, J = 8.9 Hz, 1H), 7.70 (br d, J = 8.4 Hz, 1H), 7.10 (br s, 2H), 6.79 (s, 1H), 4.56 (br d, J = 2.4 Hz, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.74 - 2.07 (m, 8H).

[0179] Example 3: Synthesis of 3 - ((7 - (2,4 - bis(2,2 - difluoroethoxy)pyrimidin - 5 - yl) - 3 - (hydroxyaminocarbonyl)quinolin - 4 - yl)amino) - 5 - (3,5 - difluorophenoxy)benzoic acid (3)

[0180]

[0181] Step 1: Synthesis of 3 - ((7 - bromo - 3 - (ethoxycarbonyl)quinolin - 4 - yl)amino) - 5 - (3,5 - difluorophenoxy)benzoic acid (3 - 5)

[0182]

[0183] To a solution of ethyl 7 - bromo - 4 - chloroquinoline - 3 - carboxylate (295 mg, 0.94 mmol) in DMSO (5 mL) was added K 2 CO 3 (250 mg, 1.81 mmol) and 5 - amino - 3 - [(3,5 - difluorophenyl)oxy]benzoic acid (250 mg, 0.94 mmol), and the reaction was stirred at 100 °C for 3 hours. LCMS showed that the starting materials were consumed and the product was formed. H 2 O (20 mL) was added and a suspension was formed. The mixture was filtered and the filter cake was washed with H 2 O (10 mL), and then dried to obtain a white solid (320 mg, 0.59 mmol, 62%).

[0184] MS (ESI, pos. ion) m / z: 543.0 [M + 1] + .

[0185] Step 2: Synthesis of 3 - ((7 - (2,4 - bis(2,2 - difluoroethoxy)pyrimidin - 5 - yl) - 3 - (ethoxycarbonyl)quinolin - 4 - yl)amino) - 5 - (3,5 - difluorophenoxy)benzoic acid (3 - 7)

[0186]

[0187] Under a nitrogen atmosphere, to a solution of 3-{[7-bromo-3-(ethoxycarbonyl)quinolin-4-yl]amino}-5-[(3,5-difluorophenyl)oxy]benzoic acid (270 mg, 0.50 mmol) in 1,4-dioxane (8 mL) and H 2 O (2 mL) was added K 2 CO 3 (206 mg, 1.49 mmol), (2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)boronic acid (170 mg, 0.60 mmol), and Pd(dppf)Cl 2 (36 mg, 0.05 mmol), and the reaction was stirred at 80 °C for 2 h. LCMS showed that the starting material was consumed and the product was formed. HCOOH (2 mL) was added to the mixture, and then it was concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH (v / v) = 10 / 1) to give a yellow solid (200 mg, 0.28 mmol, 57%).

[0188] MS (ESI, pos. ion) m / z: 703.3 [M+1] + .

[0189] Step 3: Synthesis of 3-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxyaminocarbonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (3)

[0190]

[0191] To a solution of 3-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(ethoxycarbonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (140 mg, 0.20 mmol) in MeOH (5 mL) and H 2 O (2 mL) were added LiOH (47 mg, 1.96 mmol) and an aqueous solution of 50% NH 2 OH (0.5 mL), and the reaction was stirred at 25 °C for 1 h. LCMS showed that the starting material was consumed and the product was formed. The pH was adjusted to 3 with 2M HCl(aq) and concentrated to obtain the crude product. The crude product was purified by pre-HPLC (eluent: CH 3 CN and H 2 O, containing 0.025% NH 4 HCO 3 ) to give the title compound 3 (8 mg, 0.01 mmol, 5%).

[0192] MS(ESI,pos.ion)m / z:690.0[M+1] + 。

[0193] 1 H NMR(400MHz,CD 3 OD)δ8.72(s,1H),8.59(s,1H),8.26 - 8.06(m,2H),7.77(d,J=8.0Hz,1H),7.58(s,1H),7.37(s,1H),6.92(s,1H),6.79 - 6.59(m,3H),6.48 - 6.08(m,2H),4.83 - 4.63(m,4H).

[0194] Example 4: Synthesis of 3-(3,5-difluorophenoxy)-5-((3-(hydroxycarbamoyl)-7-(4-oxo-4H-chromen-3-yl)quinolin-4-yl)amino)benzoic acid (4)

[0195]

[0196] Step 1: Synthesis of 7-bromo-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide

[0197] O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (42 mg, 0.36 mmol) was added to dry THF (5 mL), and the mixture was stirred at 0 °C for 5 min. Then, a solution of 7-bromo-4-chloroquinoline-3-carbonyl chloride (110 mg, 0.36 mmol) and TEA (0.5 mL) in THF (5 mL) was slowly added to the solution, and the mixture was stirred at 0 °C for an additional 0.5 h. After the reaction was completed, it was diluted with H 2 O (20 mL), and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated aqueous NaCl solution (20 mL), and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain the title compound 4-2 (104 mg, 75%).

[0198] MS(ESI,pos.ion)m / z:386.9[M+1] + 。

[0199] Step 2: Synthesis of 4-chloro-7-(4-oxo-4H-chromen-3-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide

[0200] 7-Bromo-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide (100 mg, 0.26 mmol), (4-oxo-4H-chromen-3-yl)boronic acid (49 mg, 0.26 mmol), K 2 CO 3 (90 mg, 0.65 mmol) and Pd(PPh 3 ) 4 (30 mg, 0.03 mmol) were successively added to a mixture of dioxane (4 mL) and H 2 O (1 mL). The mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with H 2 O (20 mL), and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with saturated aqueous NaCl solution (20 mL), dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and the crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to give the title compound 4-3 (82 mg, 70%).

[0201] MS (ESI, pos. ion) m / z: 451.0 [M+1] + .

[0202] Step 3: Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(4-oxo-4H-chromen-3-yl)-3-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)benzoic acid

[0203] 4-Chloro-7-(4-oxo-4H-chromen-3-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide (40 mg, 0.09 mmol) and 3-amino-5-(3,5-difluorophenoxy)benzoic acid (24 mg, 0.09 mmol) were added to AcOH (2 mL), and the mixture was stirred at 45 °C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give the title compound 4-4 (42 mg, 90%).

[0204] MS (ESI, pos. ion) m / z: 680.2 [M+1] + .

[0205] Step 4: Synthesis of 3-(3,5-difluorophenoxy)-5-((3-(hydroxycarbamoyl)-7-(4-oxo-4H-chromen-3-yl)quinolin-4-yl)amino)benzoic acid

[0206] 3-(3,5-Difluorophenoxy)-5-((3-(hydroxycarbamoyl)-7-(4-oxo-4H-chromen-3-yl)quinolin-4-yl)amino)benzoic acid (42 mg, 0.06 mmol) was added to DCM (5 mL), and then TFA (1.5 mL) was added dropwise. The mixture was stirred at 40 °C for 4 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by Prep-HPLC to obtain Compound 4 (8 mg, 22%).

[0207] MS(ESI,pos.ion)m / z:596.2[M+1] + 。

[0208] 1 HNMR(DMSO-d 6 )δ:12.90-13.30(m,1H),11.32(s,1H),9.60(br s,1H),9.14(s,1H),8.82(s,1H),8.77(s,1H),8.32(d,J=1.0Hz,1H),8.21(dd,J=8.0,1.5Hz,1H),8.10(br d,J=8.8Hz,1H),7.85-7.92(m,1H),7.82(br d,J=8.4Hz,1H),7.76(d,J=8.4Hz,1H),7.52-7.61(m,1H),7.36(s,1H),7.09(s,1H),6.95-7.04(m,1H),6.88(br s,1H),6.85(dd,J=8.4,2.1Hz,2H).

[0209] Example 5: Synthesis of 5-((7-(2,4-Bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-2-((4,4-difluorocyclohexyl)oxy)benzoic acid (5)

[0210]

[0211]

[0212] Step 1: Synthesis of 5-Bromo-2,4-bis(2,2-difluoroethoxy)pyrimidine

[0213] At 37 °C, sodium (1.82 g, 78.99 mmol) was added to a solution of 5-bromo-2,4-dichloropyrimidine (9.00 g, 39.49 mmol) in 2,2-difluoroethanol (24.00 g, 292.50 mmol), and the reaction was carried out at 25 °C for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to obtain the title compound 5-3 (11.3 g, 90%).

[0214] MS(ESI,pos.ion)m / z:319.0[M+1] + 。

[0215] Step 2: Synthesis of (2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)boronic acid

[0216] 5-Bromo-2,4-bis(2,2-difluoroethoxy)pyrimidine (4.00 g, 12.54 mmol), bis(pinacolato)diboron (4.78 g, 18.81 mmol), potassium acetate (3.69 g, 37.61 mmol) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.92 g, 1.25 mmol) were added to a toluene (50 mL) solution, and the reaction was carried out under nitrogen protection at 100 °C for 5 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to obtain the title compound 5-4 (2.8 g, 79%).

[0217] MS(ESI,pos.ion)m / z:284.5[M+1] + 。

[0218] Step 3: Synthesis of methyl 2-((4,4-difluorocyclohexyl)oxy)-5-nitrobenzoate

[0219] At 37 °C, diisopropyl azodicarboxylate (3.85 g, 19.02 mmol) was added to a solution of methyl 2-hydroxy-5-nitrobenzoate (2.50 g, 12.68 mmol), 4,4-difluorocyclohexan-1-ol (1.73 g, 12.68 mmol) and triphenylphosphine (4.99 g, 19.02 mmol) in tetrahydrofuran (15 mL), and the reaction was carried out under nitrogen protection at 25 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography twice (dichloromethane / methanol (v / v) = 10 / 1) to obtain the title compound 5-7 (3.9 g, 98%).

[0220] Step 4: Synthesis of methyl 5-amino-2-((4,4-difluorocyclohexyl)oxy)benzoate

[0221] At 37 °C, iron powder (3.45 g, 61.85 mmol) was added to a solution of methyl 2-((4,4-difluorocyclohexyl)oxy)-5-nitrobenzoate (3.90 g, 12.37 mmol) and ammonium chloride (6.62 g, 123.70 mmol) in water (4 mL) and ethanol (20 mL), and the reaction was carried out at 90 °C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain Compound 5-8 (6.00 g, crude product).

[0222] MS(ESI,pos.ion)m / z:286.3[M+1] + 。

[0223] Step 5: Synthesis of 5-amino-2-((4,4-difluorocyclohexyl)oxy)benzoic acid

[0224] At 37 °C, sodium hydroxide (0.87 g, 21.73 mmol) was added to a solution of 5-amino-2-((4,4-difluorocyclohexyl)oxy)benzoic acid (3.10 g, 10.87 mmol) in water (11 mL) and methanol (6 mL), and the reaction was carried out at 25 °C for 18 hours. The reaction mixture was adjusted to pH 5 - 6 with dilute hydrochloric acid (4 mL, 4 equiv), and a solid precipitated. The crude product was obtained as a brown filter cake by filtration and dried to obtain Compound 5-9 (1.40 g, 48%).

[0225] MS(ESI,pos.ion)m / z:271.9[M+1] + 。

[0226] Step 6: Synthesis of ethyl 7-bromo-4-chloroquinoline-3-carboxylate

[0227] At 37 °C, ethyl 7-bromo-4-hydroxyquinoline-3-carboxylate (20 mg, 0.17 mmol) was added to phosphorus oxychloride (1 mL), and the reaction was carried out at 100 °C for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain Compound 5-11 (10.80 g, 95%).

[0228] MS(ESI,pos.ion)m / z:313.7[M+1] + 。

[0229] Step 7: Synthesis of 7-bromo-4-chloroquinoline-3-carboxylic acid

[0230] At 37 °C, lithium hydroxide (10.40 g, 247.97 mmol) was added to a solution of ethyl 7-bromo-4-chloroquinoline-3-carboxylate (7.80 g, 24.80 mmol) in water (25 mL) and tetrahydrofuran (30 mL). The reaction was carried out at 25 °C for 18 hours. The reaction solution was adjusted to pH 5 - 6 with dilute hydrochloric acid (50 mL), and a solid precipitated. The crude product filter cake was obtained by filtration and dried to give compound 5-12 (6.30 g, 89%).

[0231] MS(ESI,pos.ion)m / z:285.7[M+1] + 。

[0232] Step 8: Synthesis of 7-bromo-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide

[0233] 7-Bromo-4-chloroquinoline-3-carboxylic acid (2.85 g, 9.95 mmol) was added to a solution of thionyl chloride (30 mL). The reaction was carried out at 80 °C for 30 minutes, and the reaction solution was concentrated under reduced pressure to obtain the intermediate acyl chloride. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (1.17 g, 9.95 mmol) was added to a solution of the intermediate acyl chloride in tetrahydrofuran (25 mL). The reaction was carried out at 0 °C for 1 hour, and the reaction solution was concentrated under reduced pressure. The crude product was separated by column chromatography (petroleum ether / ethyl acetate (volume / volume) = 1 / 1) to give the title compound 5-14 (2.00 g, 52%).

[0234] MS(ESI,pos.ion)m / z:384.6[M+1] + 。

[0235] Step 9: Synthesis of 7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide

[0236] 7-Bromo-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide (1.89 g, 4.90 mmol), 2,4-bis(2,2-difluoroethoxy)pyrimidine-5-boronic acid (1.39 g, 4.90 mmol), potassium carbonate (2.03 g, 14.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.570 g, 0.490 mmol) were added to 1,4-dioxane (16 mL) and water (2 mL). Under nitrogen protection, the reaction was carried out at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography twice (petroleum ether / ethyl acetate (volume / volume) = 1 / 1) to give the title compound 5-15 (1.46 g, 55%).

[0237] MS(ESI,pos.ion)m / z:544.8[M+1] + 。

[0238] Step 10: Synthesis of 5-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)-2-((4,4-difluorocyclohexyl)oxy)benzoic acid

[0239] 5-Amino-2-((4,4-difluorocyclohexyl)oxy)benzoic acid (40 mg, 0.15 mmol) was added to a solution of 7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide (80 mg, 0.15 mmol) in acetic acid (5 mL), and the reaction was carried out at 25 °C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain compound 5-16 (150 mg, 67%).

[0240] MS(ESI,pos.ion)m / z:779.8[M+1] + 。

[0241] Step 11: Synthesis of 5-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-2-((4,4-difluorocyclohexyl)oxy)benzoic acid

[0242] Trifluoroacetic acid (219 mg, 01.92 mmol) was added to a solution of 5-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)-2-((4,4-difluorocyclohexyl)oxy)benzoic acid (150 mg, 0.19 mmol) in tetrahydrofuran (2 mL), and the reaction was carried out at 60 °C for 18 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography (mobile phase: A was 0.01 mol / l aqueous formic acid solution, B was acetonitrile; flow rate: 30 ml / min wavelength: 220 nm and 254 nm) to obtain the title compound 5 (16.6 mg, 13%).

[0243] MS(ESI,pos.ion)m / z:695.8[M+1] + 。

[0244] HPLC: 90.80%

[0245] 11H NMR (400 MHz, DMSO) δ (ppm): 12.70 (s, 1H), 11.33 (s, 1H), 9.10 (s, 1H), 8.74 (d, J = 2.6 Hz, 2H), 8.17 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.17 (t, J = 13.4 Hz, 2H), 6.64–6.28 (m, 2H), 4.88–4.63 (m, 6H), 2.02–1.68 (m, 8H).

[0246] Example 6: Synthesis of 3-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)methyl)oxy)benzoic acid (6)

[0247]

[0248] Step 1: Synthesis of methyl 3-hydroxy-5-nitrobenzoate

[0249] At 37 °C, sulfuric acid (3.85 g, 19.02 mmol) was added to a solution of 3-hydroxy-5-nitrobenzoic acid (2.50 g, 12.68 mmol) in methanol (15 mL), and the reaction was carried out at 60 °C for 5 h. The reaction solution was concentrated under reduced pressure. The crude product was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 15 / 1) to obtain the title compound 6-2 (3.80 g, 71%).

[0250] MS (ESI, pos. ion) m / z: 196.0 [M-1] - .

[0251] Step 2: Synthesis of methyl 3-nitro-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0252] At 37 °C, diisopropyl azodicarboxylate (1076 mg, 5.33 mmol) was added to a solution of methyl 3-hydroxy-5-nitrobenzoate (700 mg, 3.55 mmol), tetrahydro-2H-pyran-4-ol (362 mg, 3.55 mmol) and triphenylphosphine (1396 mg, 5.33 mmol) in tetrahydrofuran (10 mL), and the reaction was carried out at 25 °C for 1 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography twice (petroleum ether / ethyl acetate (v / v) = 15 / 1) to obtain the title compound 6-4 (950 mg, 95%).

[0253] Step 3: Synthesis of methyl 3-amino-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0254] At 37 °C, iron powder (0.97 g, 17.30 mmol) was added to a solution of methyl 3-nitro-5-(tetrahydro-2H-pyran-4-yloxy)benzoate (0.97 g, 3.46 mmol) and ammonium chloride (1.85 g, 34.59 mmol) in water (2 mL) and ethanol (10 mL), and the reaction was carried out at 80 °C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-5 (0.87 g, crude product).

[0255] MS (ESI, pos. ion) m / z: 251.9 [M+1] + 。

[0256] Step 4: Synthesis of 3-amino-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid

[0257] At 37 °C, sodium hydroxide (143 mg, 3.58 mmol) was added to a solution of methyl 3-amino-5-(tetrahydro-2H-pyran-4-yloxy)benzoate (450 g, 1.79 mmol) in water (2 mL), tetrahydrofuran (3 mL) and methanol (1 mL), and the reaction was carried out at 25 °C for 18 hours. The reaction mixture was adjusted to pH 3-2 with dilute hydrochloric acid (10 mL, 0.1 eq), and a solid precipitated. The crude product was obtained as a brown filter cake by filtration and dried to obtain compound 6-6 (400 mg, 94%).

[0258] MS (ESI, pos. ion) m / z: 236.1 [M-1] - 。

[0259] Step 5: Synthesis of 3-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-ylmethyl)oxy)benzoic acid

[0260] 3-Amino-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (44 mg, 0.18 mmol) was added to a solution of 7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide (100 mg, 0.18 mmol) in acetic acid (2 mL), and the reaction was carried out at 50 °C for 18 hours. The reaction mixture was concentrated under reduced pressure. The crude product was separated by prep-HPLC (mobile phase: A was 0.225% aqueous formic acid, B was acetonitrile; flow rate: 30 ml / min, wavelength: 220 nm and 254 nm) to obtain the title compound 6 (30 mg, 11%).

[0261] MS (ESI, pos. ion) m / z: 662.0 [M+1]+ .

[0262] HPLC: 99.22%

[0263] 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm): 12.93 (s, 1H), 11.41 (s, 1H), 9.59 (s, 1H), 9.17 (s, 1H), 8.82 (s, 1H), 8.73 (s, 1H), 8.24 (s, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.08 (s, 2H), 6.79 (s, 1H), 6.34 - 6.31 (m, 2H), 4.78 - 4.71 (m, 4H), 4.55 - 4.53 (m, 1H), 3.82 - 3.80 (m, 2H), 3.46 - 3.43 (m, 2H), 1.93 - 1.91 (m, 2H), 1.56 - 1.54 (m, 2H).

[0264] Example 7: Synthesis of 5 - ((7 - (2,4 - bis(2,2 - difluoroethoxy)pyrimidin - 5 - yl) - 3 - (hydroxycarbamoyl)quinolin - 4 - yl)amino) - 2 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)benzoic acid (7)

[0265]

[0266] Step 1: Synthesis of 7 - {2,4 - bis[(2,2 - difluoroethyl)oxy]pyrimidin - 5 - yl} - 4 - chloro - N - (3,4,5,6 - tetrahydro - 2H - pyran - 2 - yloxy)quinoline - 3 - carboxamide

[0267] Under a nitrogen atmosphere, to a mixed solution of 7 - bromo - 4 - chloro - N - (3,4,5,6 - tetrahydro - 2H - pyran - 2 - yloxy)quinoline - 3 - carboxamide (230 mg, 0.60 mmol), 2,4 - bis[(2,2 - difluoroethyl)oxy] - 5 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)pyrimidine (230 mg, 0.63 mmol), potassium carbonate (206 mg, 1.49 mmol), H 2 O (1 mL) in 1,4 - dioxane (4 mL) was added tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol), and the reaction was carried out at 80 °C for 1.5 hours. After the reaction was completed, water (5 mL) was added for dilution and the mixture was extracted and separated with ethyl acetate (10 mL × 3). The organic layer was washed with saturated brine (5 mL), and anhydrous Na 2 SO 4Dry, filter, and concentrate under reduced pressure. The residue was triturated (PE / EA (v / v) = 10 / 1, 10 mL) to give the title compound 7-2 (140 mg, 43%).

[0268] MS (ESI, pos. ion) m / z: 545.1 [M+1] + 。

[0269] Step 2: Synthesis of 5-[(7-{2,4-bis[(2,2-difluoroethyl)oxy]pyrimidin-5-yl}-3-{[(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)amino]carbonyl}quinolin-4-yl)amino]-2-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid

[0270] 7-{2,4-Bis[(2,2-difluoroethyl)oxy]pyrimidin-5-yl}-4-chloro-N-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)quinoline-3-carboxamide (75 mg, 0.14 mmol) and 5-amino-2-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid (33 mg, 0.14 mmol) were added to acetic acid (2 mL), and the reaction was carried out at 50 °C for 1 hour. After completion of the reaction, it was concentrated to dryness under reduced pressure to give compound 7-3 (100 mg, 97%).

[0271] MS (ESI, pos. ion) m / z: 746.2 [M+1] + 。

[0272] Step 3: Synthesis of 5-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0273] Trifluoroacetic acid (2 mL) was added to a solution of 5-[(7-{2,4-bis[(2,2-difluoroethyl)oxy]pyrimidin-5-yl}-3-{[(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)amino]carbonyl}quinolin-4-yl)amino]-2-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid (100 mg, 0.13 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative chromatography (formic acid condition) to give compound 7 (30 mg, 35%).

[0274] MS (ESI, pos. ion) m / z: 662.1 [M+1] + 。

[0275] 11H NMR (DMSO-d6) δ: 11.30 (br s, 1H), 10.98 - 11.17 (m, 1H), 8.73 - 8.78 (m, 2H), 8.26 - 8.40 (m, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.91 (br d, J = 8.3 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 8.9, 2.6 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.60 (dt, J = 6.7, 3.3 Hz, 1H), 6.47 (dt, J = 6.7, 3.3 Hz, 1H), 6.33 (dt, J = 6.7, 3.4 Hz, 1H), 4.67 - 4.84 (m, 5H), 3.82 - 3.92 (m, 3H), 3.46 - 3.55 (m, 7H), 1.91 - 2.03 (m, 2H), 1.62 - 1.72 (m, 2H).

[0276] Example 8: Synthesis of 3 - ((7 - (5 - cyano - 2,3 - dihydrobenzofuran - 7 - yl) - 3 - (hydroxycarbamoyl)quinolin - 4 - yl)amino) - 5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)benzoic acid (8)

[0277]

[0278] Step 1: Synthesis of 7 - bromo - 2,3 - dihydrobenzofuran - 5 - carbaldehyde

[0279] 2,3 - Dihydrobenzofuran - 5 - carbaldehyde (2.54 mL, 20.25 mmol) and sodium acetate (1.99 g, 24.30 mmol) were added to a single - necked flask containing glacial acetic acid (40 mL). The reaction flask was cooled to 10 °C, and then bromine (2 mL, 40.50 mmol) was added. After addition, the mixture was stirred for 1 hour. Ice - water (100 mL) and saturated aqueous sodium thiosulfate solution (10 mL) were added to the reaction flask. The aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v)=10 / 1) to obtain the title compound 8 - 2 (3.7 g, 80%).

[0280] Step 2: Synthesis of 7 - bromo - 2,3 - dihydrobenzofuran - 5 - carbonitrile

[0281] 7-Bromo-2,3-dihydrobenzofuran-5-carbaldehyde (1.8 g, 7.93 mmol) and ammonia water (20 mL) were added to a single-necked flask containing tetrahydrofuran (20 mL), and then iodine (8.79 g, 19.82 mmol) was added in portions. After the addition, the reaction mixture was stirred overnight at 37 °C. Saturated aqueous sodium thiosulfate solution (100 mL) was added to the reaction flask, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 10 / 1) to obtain the title compound 8-3 (1.4 g, 79%).

[0282] Step 3: Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-5-carbonitrile

[0283] 7-Bromo-2,3-dihydrobenzofuran-5-carbonitrile (100 mg, 0.45 mmol), B 2 Pin 2 (227 mL, 0.89 mmol), and potassium acetate (131 mg, 1.34 mmol) were added to a single-necked flask containing DMF (5 mL). Under a nitrogen atmosphere, Pd(dppf)Cl 2 (29 mg, 0.04 mmol) was added, and then the nitrogen was replaced. The mixture was stirred at 130 °C for 1 hour. Water (10 mL) was added to the reaction flask, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 3 / 1) to obtain the title compound 8-4 (110 mg, 90%).

[0284] Step 4: Synthesis of 4-chloro-7-(5-cyano-2,3-dihydrobenzofuran-7-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide

[0285] 7-Bromo-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide (171 mg, 0.44 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-5-carbonitrile (100 mg, 0.37 mmol), and potassium carbonate (127 mg, 0.92 mmol) were added to a mixture of dioxane (8 mL) and water (2 mL). The nitrogen was replaced, and under a nitrogen stream, Pd(PPh 3 ) 4(43 mg, 0.04 mmol), then replace the nitrogen, and stir the reaction at 80 °C for 2 hours. Add H 2 O (20 mL) for dilution, extract with ethyl acetate (20 mL × 3), wash with saturated sodium chloride solution (20 mL), and dry with anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure, and separate the crude product by column chromatography (PE / EtOAc (v / v) = 5 / 1) to obtain the title compound 8-6 (150 mg, 90%).

[0286] MS (ESI, pos. ion) m / z: 450.1 [M+1] + .

[0287] Step 5: Synthesis of 3-((7-(5-cyano-2,3-dihydrobenzofuran-7-yl)-3-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0288] Add 4-chloro-7-(5-cyano-2,3-dihydrobenzofuran-7-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide (50 mg, 0.11 mmol) and 3-amino-5-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid (26 mg, 0.11 mmol) to acetic acid (5 mL). Stir at room temperature overnight. Concentrate under reduced pressure, and separate the crude product by column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain the title compound 8-7 (30 mg, 42%).

[0289] MS (ESI, pos. ion) m / z: 651.2 [M+1] + .

[0290] Step 6: Synthesis of 3-((7-(5-cyano-2,3-dihydrobenzofuran-7-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0291] Dissolve 3-((7-(5-cyano-2,3-dihydrobenzofuran-7-yl)-3-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (20 mg, 0.03 mmol) in dichloromethane (3 mL), then add trifluoroacetic acid (1 mL), and stir the mixture at room temperature for 2 hours. After the reaction, concentrate under reduced pressure, and purify the crude product by preparative HPLC to obtain the title compound 8 (2.5 mg, 13%).

[0292] MS(ESI,pos.ion)m / z:567.3[M+1] + 。

[0293] 1 HNMR(DMSO-d 6 )δ:12.17 - 13.64(m,1H),11.39(br s,1H),9.69 - 10.23(m,1H),9.14(br s,1H),8.81(s,1H),8.42(s,1H),8.05(s,2H),7.91(br d,J=8.3Hz,1H),7.77(s,1H),7.14(br s,2H),6.86(br s,1H),4.78(t,J=8.8Hz,2H),4.49 - 4.60(m,1H),3.81(dt,J=11.5,4.3Hz,2H),3.42 - 3.47(m,4H),1.89 - 1.96(m,2H),1.56(qd,J=8.8,4.6Hz,2H).

[0294] Example 9: Synthesis of 5 - ({3 - [(hydroxyamino)carbonyl]-7-(5 - methyl - 2,3 - dihydro[1,4]dioxino[3,2 - c]pyridin - 8 - yl)quinolin - 4 - yl}amino)-3-(3,4,5,6 - tetrahydro - 2H - pyran - 4 - yloxy)benzoic acid (9)

[0295]

[0296] Step 1: Synthesis of 3 - ((7 - bromo - 3 - (ethoxycarbonyl)quinolin - 4 - yl)amino)-5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)benzoic acid

[0297] Ethyl 7 - bromo - 4 - chloroquinoline - 3 - carboxylate (640 mg, 2.03 mmol) and tert - butyl 5 - amino - 3 - (3,4,5,6 - tetrahydro - 2H - pyran - 4 - yloxy)benzoate (600 mg, 2.05 mmol) were added to acetic acid (4 mL), and the mixture was stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude title compound (1046 mg, 99%).

[0298] MS(ESI,pos.ion)m / z:516.5[M+1] + 。

[0299] Step 2: Synthesis of ethyl 7 - bromo - 4 - ((3 - (tert - butoxycarbonyl)-5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)phenyl)amino)quinoline - 3 - carboxylate

[0300] At 0 °C, N,N'-dicyclohexylcarbodiimide (400 mg, 1.94 mmol) was added to a solution of 3-((7-bromo-3-(ethoxycarbonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (500 mg, 0.97 mmol), tert-butanol (0.28 mL, 2.91 mmol), and 4-dimethylaminopyridine (118 mg, 0.97 mmol) in dichloromethane (5 mL). Subsequently, the temperature was raised to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was diluted with H 2 O (10 mL) and extracted with EA (15 mL × 3). The organic layer was washed with saturated brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA (v / v) = 2 / 1) to give the title compound 9-3 (520 mg, 93%).

[0301] MS (ESI, pos. ion) m / z: 573.1 [M+1] + .

[0302] Step 3: Synthesis of ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate

[0303] Under a nitrogen atmosphere, Pd(dppf)Cl 2 (66 mg, 0.09 mmol) was added to a solution of ethyl 7-bromo-4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)quinoline-3-carboxylate (520 mg, 0.91 mmol), bis(pinacolato)diboron (0.47 mL, 1.82 mmol), and potassium acetate (267 mg, 2.73 mmol) in dimethyl sulfoxide (6 mL). The reaction was carried out at 100 °C for 4 hours. After the reaction was completed, the reaction mixture was diluted with H 2 O (30 mL) and extracted with EA (15 mL × 3). The organic layer was washed with saturated brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA (v / v) = 2 / 1 - 1 / 10) to give the title compound 9-4 (525 mg, 93%).

[0304] MS (ESI, pos. ion) m / z: 619.2 [M+1] + .

[0305] Step 4: Synthesis of Ethyl 4-((3-(tert-Butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(5-methyl-2,3-dihydro[1,4]dioxino[3,2-c]pyridin-8-yl)quinoline-3-carboxylate

[0306] Under a nitrogen atmosphere, to a solution of ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate (100 mg, 0.19 mmol), 8-bromo-5-methyl-2,3-dihydro[1,4]dioxino[3,2-c]pyridine (43 mg, 0.19 mmol), and potassium carbonate (77 mg, 0.56 mmol) in dioxane (2 mL) was added tetrakis(triphenylphosphine)palladium (21 mg, 0.02 mmol), and the reaction was carried out at 80 °C for 1 hour. After completion of the reaction, the reaction mixture was diluted with H 2 O (10 mL) and extracted with EA (15 mL × 3). The organic layer was washed with saturated brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography (PE / EA (v / v) = 1 / 3) to give the title compound 9-5 (30 mg, 25%).

[0307] MS (ESI, pos. ion) m / z: 642.3 [M+1] + .

[0308] Step 5: Synthesis of 5-{[3-(Ethoxycarbonyl)-7-(5-methyl-2,3-dihydro[1,4]dioxino[3,2-c]pyridin-8-yl)quinolin-4-yl]amino}-3-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic Acid

[0309] To a solution of ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(5-methyl-2,3-dihydro[1,4]dioxino[3,2-c]pyridin-8-yl)quinoline-3-carboxylate (30 mg, 0.05 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at 37 °C for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give compound 9-6 (27 mg, 98%).

[0310] MS (ESI, pos. ion) m / z: 586.2 [M+1] + .

[0311] Step 6: Synthesis of 5-({3-[(hydroxyamino)carbonyl]-7-(5-methyl-2,3-dihydro[1,4]dioxino[3,2-c]pyridin-8-yl)quinolin-4-yl}amino)-3-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid

[0312] 5-{[3-(Ethoxycarbonyl)-7-(5-methyl-2,3-dihydro[1,4]dioxino[3,2-c]pyridin-8-yl)quinolin-4-yl]amino}-3-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid (27 mg, 0.05 mmol), lithium hydroxide (0.01 mL, 0.18 mmol), and aqueous hydroxylamine solution (1 mL) were added to methanol (3 mL), and the mixture was stirred overnight at 37 °C. After the reaction was completed, it was adjusted to neutral with 1 M aqueous hydrochloric acid, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative chromatography (formic acid condition) to obtain Compound 9 (10 mg, 38%).

[0313] MS(ESI,pos.ion)m / z:574.2[M+1] + 。

[0314] 1 HNMR(DMSO-d6)δ:10.18(br s,1H),8.89(s,1H),8.09(d,J=1.8Hz,1H),8.04(s,1H),7.81(br d,J=8.9Hz,1H),7.55(br d,J=8.5Hz,1H),7.09(s,1H),7.03-7.07(m,1H),6.56(br s,1H),4.46(dt,J=8.2,4.3Hz,1H),4.39(s,4H),3.75-3.81(m,2H),3.43(br s,2H),2.35-2.38(m,3H),1.86-1.93(m,2H),1.48-1.57(m,2H).

[0315] The synthesis method of 8-bromo-5-methyl-2,3-dihydro[1,4]dioxino[3,2-c]pyridine in Step 4 is as follows:

[0316] Step 7: Synthesis of 3-(benzyloxy)-2-methyl-4H-pyran-4-one

[0317] Dissolve 3-hydroxy-2-methyl-4H-pyran-4-one (20.00 g, 158.59 mmol) in acetone (500 mL), add potassium carbonate (22.00 g, 317.18 mmol), and dropwise add PMBCl (24.84 g, 317.18 mmol) with stirring. The reaction solution is refluxed and stirred overnight. The reaction solution is concentrated under reduced pressure, and the concentrated solution is diluted with DCM (300 mL), washed successively with water (100 mL × 2) and saturated brine (100 mL × 2), and the combined organic phases are dried with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product is separated by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain 3-(benzyloxy)-2-methyl-4H-pyran-4-one as a yellow oil (20.00 g, 51%).

[0318] MS (ESI, pos. ion) m / z: 217.3 [M+1] + 。

[0319] Step 8: Synthesis of 3-(benzyloxy)-2-methylpyridin-4(1H)-one

[0320] In a high-pressure autoclave, dissolve 3-(benzyloxy)-2-methyl-4H-pyran-4-one (2.80 g, 40.61 mmol) in acetonitrile (20 mL), add ammonia water (20 mL), and stir the reaction solution at 90 °C overnight. The reaction solution is concentrated under reduced pressure, and the concentrated solution is diluted with EA (100 mL), washed successively with water (20 mL × 2) and saturated brine (20 mL × 2), and the combined organic phases are dried with anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product is separated by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain 3-(benzyloxy)-2-methylpyridin-4(1H)-one (2.30 g, 23%).

[0321] MS (ESI, pos. ion) m / z: 216.3 [M+1] + 。

[0322] Step 9: Synthesis of 3-(benzyloxy)-5-bromo-2-methylpyridin-4(1H)-one

[0323] Dissolve 3-(benzyloxy)-2-methylpyridin-4(1H)-one (2.80 g, 11.42 mmol) in acetonitrile, add NBS (2.50 g, 13.70 mmol), and stir the reaction solution at room temperature for 6 h. The reaction solution is concentrated under reduced pressure, and the concentrated solution is diluted with DCM (100 mL), washed successively with water (20 mL × 2) and saturated brine (20 mL × 2), and the combined organic phases are dried with anhydrous Na2 SO 4 It was dried, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain 3-(benzyloxy)-5-bromo-2-methylpyridin-4(1H)-one as a pale yellow oil (2.30 g, 62%).

[0324] MS (ESI, pos. ion) m / z: 294.0 [M+1] + 。

[0325] Step 10: Synthesis of 5-bromo-2-methylpyridine-3,4-diol

[0326] 3-(Benzyloxy)-5-bromo-2-methylpyridin-4(1H)-one (1.80 g, 5.55 mmol) was dissolved in TFA (5 mL), and the mixture was stirred at 60 °C for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain the crude product 5-bromo-2-methylpyridine-3,4-diol (1.30 g, 74%), which was directly used in the next step of the reaction.

[0327] MS (ESI, pos. ion) m / z: 204.1 [M+1] + 。

[0328] Step 11: Synthesis of 8-bromo-5-methyl-2,3-dihydro-[1,4]dioxino[2,3-c]pyridine

[0329] 5-Bromo-2-methylpyridine-3,4-diol (1.30 g, 6.37 mmol) was dissolved in DMF (30 mL), potassium carbonate (2.60 g, 19.20 mmol) was added, and the reaction solution was stirred at 60 °C for 1 h. Then 1,2-dibromoethane (2.40 g, 12.74 mmol) was added, and the temperature was raised to 90 °C and stirred for 12 h. The reaction solution was diluted with EA (50 mL), washed successively with water (10 mL × 2) and saturated brine (10 mL × 2), and the combined organic phase was dried with anhydrous Na 2 SO 4 It was dried, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain 8-bromo-5-methyl-2,3-dihydro-[1,4]dioxino[2,3-c]pyridine as a white solid (0.69 g, 47%).

[0330] MS (ESI, pos. ion) m / z: 230.1 [M+1] +

[0331] Example 10: Synthesis of 5-{[7-(2,3-dihydro[1,4]dioxino[3,2-b]pyridin-8-yl)-3-[(hydroxyamino)carbonyl]quinolin-5-yl]amino}-3-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid (10)

[0332]

[0333]

[0334] Step 1: Synthesis of 2,3-dihydro[1,4]dioxino[3,2-b]pyridine

[0335] Dissolve pyridine-2,3-diol (2.00 g, 18.00 mmol) in acetonitrile (40 mL), add 1-bromo-2-chloroethane (5.16 g, 36.00 mmol), potassium carbonate (19.90 g, 144.01 mmol), and sodium iodide (0.27 g, 1.80 mmol). N 2 Protect, reflux and stir the reaction solution overnight. Filter the reaction solution, concentrate the filtrate, dilute the concentrated solution with EA (40 mL), and wash it successively with water (20 mL × 2) and saturated brine (20 mL). Combine the organic phases and dry them with anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (PE / EA (v / v) = 1 / 1) to obtain 2,3-dihydro[1,4]dioxino[3,2-b]pyridine as a colorless transparent oil (10-2, 560 mg, 23%).

[0336] MS (ESI, pos. ion) m / z: 138.1 [M+1] + .

[0337] Step 2: Synthesis of 8-bromo-2,3-dihydro[1,4]dioxino[3,2-b]pyridine

[0338] Dissolve 2,3-dihydro[1,4]dioxino[3,2-b]pyridine (650 mg, 4.74 mmol) in THF (3 mL), N 2Protection was carried out. The temperature was lowered to -78 °C, and n-butyllithium (6.00 mL, 9.48 mmol) was slowly added dropwise to the reaction solution. After stirring for 30 min, 1,2-dibromo-1,1,2,2-tetrafluoroethane (1230 mg, 4.74 mmol) was slowly added dropwise again, and the reaction solution was stirred for 30 min. The reaction solution was restored to room temperature, quenched with saturated ammonium chloride solution (12 mL), adjusted to pH = 7 - 8, and extracted with EA (40 mL × 2). The organic phases were combined. The organic phase was washed once with water (20 mL) and saturated brine (20 mL) in sequence. The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (PE / EA (v / v) = 3 / 1) to obtain 8-bromo-2,3-dihydro[1,4]dioxino[3,2-b]pyridine (10-3, 592 mg, 58%).

[0339] MS (ESI, pos. ion) m / z: 216.0 [M+1] +

[0340] Step 3: Synthesis of ethyl 7-(2,3-dihydro[1,4]dioxino[3,2-b]pyridin-8-yl)-5-[(3-{[(2-methylpropan-2-yl)oxy]carbonyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)phenyl)amino]quinoline-3-carboxylate

[0341] Under a nitrogen atmosphere, to a solution of ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate (168 mg, 0.32 mmol), 8-bromo-2,3-dihydro[1,4]dioxino[3,2-b]pyridine (69 mg, 0.32 mmol), and potassium carbonate (133 mg, 0.96 mmol) in dioxane (5 mL) was added tetrakis(triphenylphosphine)palladium (31 mg, 0.03 mmol), and the reaction was carried out at 80 °C for 1 hour. After the reaction was completed, the reaction mixture was diluted with H 2 O (10 mL) and extracted with EA (15 mL × 3). The organic layer was washed with saturated brine (5 mL), dried over anhydrous Na 2 SO 4 and filtered, then concentrated under reduced pressure. The residue was purified by preparative chromatography (PE / EA (v / v) = 1 / 3) to obtain the title compound 10-5 (50 mg, 25%).

[0342] MS (ESI, pos. ion) m / z: 628.3 [M+1] + .

[0343] Step 4: Synthesis of 3-(7-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3-(ethoxycarbonyl)quinolin-5-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0344] Dissolve ethyl 7-(2,3-dihydro[1,4]dioxino[3,2-b]pyridin-8-yl)-5-[(3-{[(2-methylpropan-2-yl)oxy]carbonyl}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)phenyl)amino]quinoline-3-carboxylate (50 mg, 0.08 mmol) in DCM (3 mL), add TFA (1 mL), and stir at room temperature for 1 h. Concentrate the reaction solution under reduced pressure, and prepare the crude product by Pre-TLC (DCM / MeOH (v / v) = 10 / 1) to obtain 3-(7-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3-(ethoxycarbonyl)quinolin-5-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (10 - 6, 38.0 mg, 84%).

[0345] MS (ESI, pos. ion) m / z: 572.3 [M + 1] + 。

[0346] Step 5: Synthesis of 3-(7-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0347] Dissolve 3-(7-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3-(ethoxycarbonyl)quinolin-5-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (38 mg, 0.07 mmol) in MeOH (3 mL), add aqueous hydroxylamine solution (1 mL, 50%) and lithium hydroxide (12 mg, 0.27 mmol), and stir the reaction solution at room temperature overnight. Adjust the pH = 5 - 6 with dilute hydrochloric acid solution (2N), and purify the crude product by preparative HPLC to obtain a pale yellow solid 3-(7-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (Compound 10, 3.2 mg, 8%).

[0348] MS (ESI, pos. ion) m / z: 559.3 [M + 1] + 。

[0349] 1 HNMR (DMSO-d6) δ: 12.57 - 13.14 (m, 1H), 11.16 - 11.75 (m, 1H), 9.58 - 9.67 (m, 1H), 9.04 - 9.32 (m, 1H), 8.83 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.95 (br d, J = 8.8 Hz, 1H), 7.84 (d, J = 5.1 Hz, 1H), 7.70 (br d, J = 8.6 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.08 (br s, 2H), 6.77 (s, 1H), 4.50 - 4.56 (m, 1H), 4.48 (dd, J = 5.1, 2.6 Hz, 2H), 4.28 - 4.34 (m, 2H), 3.80 (dt, J = 11.5, 4.2 Hz, 2H), 3.38 - 3.47 (m, 2H), 1.84 - 1.94 (m, 2H), 1.49 - 1.60 (m, 2H), 1.23 (br s, 1H).

[0350] Example 11: Synthesis of 3 - ((7 - (2,3 - Dihydrofuro[3,2 - c]pyridin - 7 - yl) - 3 - (hydroxycarbamoyl)quinolin - 4 - yl)amino) - 5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)benzoic acid (11)

[0351]

[0352] Step 1: Synthesis of 7 - bromo - 4 - chloro - 3 - quinolinecarbonyl chloride

[0353] 7 - Bromo - 4 - hydroxyquinoline - 3 - carboxylic acid (4 g, 14.92 mmol) was slowly added to a solution of phosphorus oxychloride (20 mL) with stirring. The reaction was carried out in an oil bath at 100 °C for 5 h. After the reaction, it was directly concentrated under reduced pressure. The crude product was triturated with toluene (20 mL) and washed and dried with dichloromethane to obtain the title compound 11 - 2 (6.4 g, crude product).

[0354] Step 2: Synthesis of 7 - bromo - 4 - chloro - N - ((tetrahydro - 2H - pyran - 2 - yl)oxy)quinoline - 3 - carboxamide

[0355] 7-Bromo-4-chloro-3-quinolinecarbonyl chloride (3.2 g, 8.39 mmol) was slowly added to a solution of DCM (20 mL). Triethylamine (2.55 g, 25.18 mmol) was added dropwise under an ice-salt bath at 0 °C. After magnetic stirring for 10 min, o-(tetrahydro-2H-pyran)-2-ylhydroxylamine (786.72 mg, 6.72 mmol) was added at 0 °C. Finally, the mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was diluted with H 2 O (20 mL), extracted with DCM (20 mL * 3), washed with saturated NaCl solution, and dried over anhydrous Na 2 SO 4 . It was filtered and concentrated under reduced pressure. The crude product was separated by column chromatography (PE / EtOAc (v / v) = 1 / 1) to obtain the title compound 11-3 (1.3 g, 40.16%).

[0356] MS (ESI, pos. ion) m / z: 386.9 [M + H] + .

[0357] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.89 (s, 1H), 8.84 - 8.97 (m, 1H), 8.40 (d, J = 1.76 Hz, 1H), 8.24 (d, J = 9.04 Hz, 1H), 8.00 (dd, J = 2.01, 9.03 Hz, 1H), 5.11 (s, 1H), 3.88 - 4.08 (m, 1H), 3.58 (br d, J = 11.29 Hz, 1H), 1.75 (br s, 3H), 1.45 - 1.64 (m, 3H).

[0358] Step 3: Synthesis of methyl 3-((7-bromo-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0359] 7-Bromo-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide (300 mg, 0.778 mmol) was added to a solution of acetic acid (5 mL). Methyl 3-amino-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (390.95 mg, 1.56 mmol) was added. The reaction solution was stirred at 80 °C for 2 h. After the reaction was completed, it was directly concentrated under reduced pressure. The crude product was separated by column chromatography (DCM / MeOH (v / v) = 10 / 1) to obtain the title compound 11-4 (150 mg, 37.34%).

[0360] MS(ESI,pos.ion)m / z:518.0[M+H] + 。

[0361] Step 4: Synthesis of methyl 3-((7-(2,3-dihydrofuro[3,2-c]pyridin-7-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate

[0362] Methyl 3-((7-bromo-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (150 mg, 0.290 mmol) was added to a solution of DMF (3 mL) and H 2 O (1 mL), then (2,3-dihydrofuro[3,2-c]pyridin-7-yl)boronic acid (119.80 mg, 0.726 mmol) and potassium carbonate (401.5 mg, 2.91 mmol) were added. The reaction solution was purged with nitrogen three times, then Pd(dppf)Cl 2 (21.26 mg, 0.021 mmol) palladium catalyst was added. The reaction solution was purged with nitrogen three times again, and finally the reaction solution was reacted at 80 °C for 16 hours. After the reaction was completed, the reaction solution was diluted with water H 2 O (5 mL), extracted with EtOAc (3 mL * 3), washed with saturated NaCl solution, and dried over anhydrous Na 2 SO 4 The crude product was directly subjected to the next reaction to obtain the title compound 11-5 (200 mg, crude product).

[0363] MS(ESI,pos.ion)m / z:557.2[M+H] + 。

[0364] Step 5: Synthesis of 3-((7-(2,3-dihydrofuro[3,2-c]pyridin-7-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid

[0365] Methyl 3-((7-(2,3-dihydrofuro[3,2-c]pyridin-7-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (200 mg, 0.359 mmol) was added to methanol (3 mL), then 1 mL of 2M lithium hydroxide solution was added, and the reaction was carried out at 37 °C for 2 h. After the reaction was completed, part of the methanol was concentrated under reduced pressure, then the pH was adjusted to 6 - 7 with 1M dilute hydrochloric acid solution, and then diluted with water (5 mL). It was extracted with EtOAc (5 mL * 3), washed with saturated NaCl solution, and dried over anhydrous Na2 SO 4 It was dried, concentrated under reduced pressure, and the crude product was purified by HPLC to obtain Compound 11 (2.6 mg, 1.25%).

[0366] MS (ESI, pos. ion) m / z: 543.2 [M+1] + 。

[0367] 1 H NMR (400 MHz, DMSO-d6) δ = 11.48 (s, 1H), 9.63 (br s, 1H), 9.20 (br s, 1H), 8.82 (s, 1H), 8.66 (s, 1H), 8.38 (s, 2H), 7.98 - 7.83 (m, 2H), 7.07 (br d, J = 7.3 Hz, 2H), 6.77 (s, 1H), 4.77 (t, J = 8.9 Hz, 2H), 4.57 - 4.46 (m, 1H), 3.85 - 3.72 (m, 2H), 3.49 - 3.41 (m, 4H), 1.91 (br d, J = 9.3 Hz, 2H), 1.63 - 1.44 (m, 2H)

[0368] Example 12: Synthesis of 3 - ((7-(3,4 - Dihydro - 1,5 - naphthyridin - 1(2H)-yl)-3-(hydroxycarbamoyl)quinolin - 4 - yl)amino)-5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)benzoic acid (12)

[0369]

[0370] Step 1: Synthesis of Ethyl 7 - bromo - 4 - ((3-(tert - butoxycarbonyl)-5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)phenyl)amino)quinoline - 3 - carboxylate

[0371] Ethyl 7 - bromo - 4 - chloroquinoline - 3 - carboxylate (300 mg, 0.95 mmol) was added to a reaction flask containing acetic acid (5 mL). Then tert - butyl 3 - amino - 5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)benzoate (280 mg, 0.95 mmol) was added. The reaction mixture was stirred at 50 °C for 1 hour. After completion of the reaction, it was concentrated under reduced pressure, and the crude product was triturated with ethyl acetate (15 mL) to obtain ethyl 7 - bromo - 4 - ((3-(tert - butoxycarbonyl)-5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)phenyl)amino)quinoline - 3 - carboxylate (300 mg, 40.4%).

[0372] MS (ESI, pos. ion) m / z: 570.2 [M+1] + 。

[0373] Step 2: Synthesis of Ethyl 4-((3-(tert-Butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)quinoline-3-carboxylate

[0374] Ethyl 7-bromo-4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)quinoline-3-carboxylate (200 mg, 0.35 mmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (56 mg, 0.42 mmol) and cesium carbonate (285 mg, 0.87 mmol) were dissolved in a reaction flask containing dioxane (5 mL). After purging the system with nitrogen three times, Xphos Palladacycle Gen.4 (30 mg, 0.03 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 3 hours. After completion of the reaction, it was concentrated under reduced pressure. The crude product was purified by preparative silica gel plate (DCM:MeOH = 20:1) to obtain ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)quinoline-3-carboxylate (64 mg, 29.3%).

[0375] MS(ESI,pos.ion) m / z: 625.3 [M+1] + 。

[0376] Step 3: Synthesis of 3-{[3-(Ethoxycarbonyl)-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinolin-4-yl]amino}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid

[0377] Ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)quinoline-3-carboxylate (70 mg, 0.11 mmol) was dissolved in a reaction flask containing dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 2 hours. After completion of the reaction, it was concentrated under reduced pressure. The crude product was purified by preparative silica gel plate (DCM:MeOH = 0:1) to obtain 3-{[3-(ethoxycarbonyl)-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinolin-4-yl]amino}-5-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid (45 mg, 70.6%).

[0378] MS(ESI,pos.ion) m / z: 569.2 [M+1]+ 。

[0379] Step 4: Synthesis of 3 - ((7 - (3,4 - dihydro - 1,5 - naphthyridin - 1(2H) - yl) - 3 - (hydroxycarbamoyl)quinolin - 4 - yl)amino) - 5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)benzoic acid

[0380] Dissolve 3 - {[3 - (ethoxycarbonyl) - 7 - (1,2,3,4 - tetrahydropyrido[3,2 - b]pyridin - 1 - yl)quinolin - 4 - yl]amino} - 5 - (3,4,5,6 - tetrahydro - 2H - pyran - 4 - yloxy)benzoic acid (30 mg, 0.05 mmol) in a reaction flask containing methanol (1.8 mL), then add aqueous hydroxylamine solution (0.6 mL, 50%) and lithium hydroxide monohydrate (9 mg, 0.21 mmol). The reaction solution is stirred at 25 °C for 3 hours. After the reaction is completed, the pH value is adjusted to about 7 with aqueous hydrochloric acid solution, filtered, and the filtrate is purified by preparative high - performance liquid chromatography (formic acid system) to obtain 3 - ((7 - (3,4 - dihydro - 1,5 - naphthyridin - 1(2H) - yl) - 3 - (hydroxycarbamoyl)quinolin - 4 - yl)amino) - 5 - ((tetrahydro - 2H - pyran - 4 - yl)oxy)benzoic acid (Compound 12, 18 mg, 61.4%).

[0381] MS(ESI, pos.ion) m / z: 556.2 [M + 1] + 。

[0382] 1 HNMR(DMSO - d6) δ: 12.07 - 13.41(m, 1H), 11.06 - 11.64(m, 1H), 9.49 - 9.79(m, 1H), 8.88 - 9.43(m, 1H), 8.73(s, 1H), 8.15(s, 1H), 8.00(dd, J = 4.4, 0.8 Hz, 1H), 7.76(br d, J = 9.2 Hz, 1H), 7.59(d, J = 2.4 Hz, 1H), 7.39(dd, J = 9.2, 2.4 Hz, 1H), 7.31(dd, J = 8.4, 1.2 Hz, 1H), 6.98 - 7.13(m, 3H), 6.73 - 6.80(m, 1H), 4.47 - 4.58(m, 1H), 3.74 - 3.85(m, 4H), 3.42 - 3.49(m, 2H), 2.92(t, J = 6.5 Hz, 2H), 2.06(quin, J = 6.2 Hz, 2H), 1.87 - 1.97(m, 2H), 1.50 - 1.62(m, 2H).

[0383] Other compounds of the present invention can be prepared by methods similar to those described in the above examples (with appropriate modifications if necessary).

[0384] Biological Examples

[0385] (1) Inhibitory activity test of LDHA

[0386] 1. Prepare the test compound diluted 200 times: Starting from a concentration of 2 mM of the test compound, perform a 3-fold serial dilution with DMSO, including 10 concentration gradients, and prepare 2 replicates for each concentration.

[0387] 2. Prepare a 200-fold negative control (100% DMSO).

[0388] 3. Pipette 1 μL of the diluted test compound into 49 μL of 1-fold tween-20 buffer to obtain a 4-fold diluted working solution of the test compound.

[0389] 4. After sealing the plate, shake the experimental plate on an oscillator for 15 minutes.

[0390] 5. Add 5 μL of the 4-fold diluted compound working solution prepared in step 4 to a 384-well experimental plate (784075, Greiner).

[0391] 6. Prepare a 4-fold diluted LDHA solution on ice. Add 5 μL of the 4-fold diluted LDHA solution to the 384-well experimental plate.

[0392] 7. After sealing the plate, incubate the experimental plate in the dark at room temperature for 15 minutes.

[0393] 8. Prepare a 4-fold diluted substrate solution: Dissolve β-NADH and sodium pyruvate in 1-fold tween-20 buffer.

[0394] 9. Add 5 μL of the 4-fold diluted substrate solution prepared in step 8 to the 384-well experimental plate.

[0395] 10. Centrifuge the 384-well experimental plate at 1000 rpm for 1 minute and then incubate it in the dark in a 25 °C incubator for 30 minutes.

[0396] 11. Prepare a 4-fold diluted detection solution: Dissolve diaphorase and resazurin in 1-fold tween-20 buffer.

[0397] 12. Add 5 μL of the 4-fold diluted detection solution prepared in step 11 to the 384-well experimental plate.

[0398] 13. Centrifuge the 384-well experimental plate at 1000 rpm for 1 minute and then incubate it in the dark in a 25 °C incubator for 20 minutes.

[0399] 14. Read the EX540-EM590 data using PHERAstar FSX.

[0400] The compounds of the present invention have good LDHA inhibitory activity. The data obtained from the representative compounds of the present invention are shown in Table 1:

[0401] Table 1

[0402]

[0403]

[0404] (2) Hepatic microsomal stability

[0405] Preheat the buffer solution of 5 mM MgCl 2 (pH 7.41). Prepare a 100 μL acetonitrile solution of the compound to be tested (0.1 mM). Take 1.5 μL of the 500 μM chloramphenicol standard addition solution and 18.75 μL of hepatic microsomes (20 mg / mL) and add them to 479.75 μL of the above MgCl 2 buffer solution. Distribute the hepatic microsome solution into the experimental plates at different time points (0, 5, 15, 30, 45 min), and pre-incubate at 37 °C for 5 minutes. Then add 150 μL of the acetonitrile solution of the compound to be tested to the above experimental plates. Prepare the MgCl 2 buffer solution of (6 mM, 5 mg / mL) NADPH for standby. Then add 15 μL of the NADPH solution to the above experimental plates to start timing. After 5 minutes, 15 minutes, 30 minutes, and 45 minutes respectively, quench the reactions of the corresponding experimental plates, shake for 10 minutes (600 rpm), then centrifuge for 15 minutes (6000 rmp), take 80 μL of the supernatant and add 140 μL of pure water at the same time, and analyze the final solution by LC / MS. The compounds of the present invention have good hepatic microsomal stability. The results obtained from the representative compounds of the present invention are shown in Table 2 below.

[0406] Table 2

[0407]

[0408] The structure of GSK808A is:

[0409] (3) Selectivity test

[0410] The selectivity in this test refers to the selectivity of the compound to be tested for LDHA inhibitory activity relative to LDHB, that is, the selectivity value is obtained by dividing the inhibitory activity of LDHB by the inhibitory activity of LDHA.

[0411] For the test of the inhibitory activity of LDHA, refer to the above text.

[0412] The inhibitory activity test of LDHB is as follows

[0413] 1. Prepare the test compound diluted 200-fold: Starting from the concentration of 2 mM of the test compound, perform 3-fold serial dilutions with DMSO, including 10 concentration gradients, and prepare 2 replicates for each concentration.

[0414] 2. Prepare a 200-fold negative control (100% DMSO).

[0415] 3. Pipette 1 μL of the diluted test compound into 49 μL of 1-fold tween-20 buffer to obtain a 4-fold diluted working solution of the test compound.

[0416] 4. After sealing the plate, shake the experimental plate on an oscillator for 15 minutes.

[0417] 5. Add 5 μL of the 4-fold diluted compound working solution prepared in step 4 to a 384-well experimental plate (784075, Greiner).

[0418] 6. Prepare a 4-fold diluted LDHB solution on ice. Add 5 μL of the 4-fold diluted LDHB solution to the 384-well experimental plate.

[0419] 7. After sealing the plate, incubate the experimental plate in the dark at room temperature for 15 minutes.

[0420] 8. Prepare a 4-fold diluted substrate solution: Dissolve β-NADH and sodium pyruvate in 1-fold tween-20 buffer.

[0421] 9. Add 5 μL of the 4-fold diluted substrate solution prepared in step 8 to the 384-well experimental plate.

[0422] 10. Centrifuge the 384-well experimental plate at 1000 rpm for 1 minute and then incubate it in the dark at 25 °C in an incubator for 30 minutes.

[0423] 11. Prepare a 4-fold diluted detection solution: Dissolve diaphorase and resazurin in 1-fold tween-20 buffer.

[0424] 12. Add 5 μL of the 4-fold diluted detection solution prepared in step 11 to the 384-well experimental plate.

[0425] 13. Centrifuge the 384-well experimental plate at 1000 rpm for 1 minute and then incubate it in the dark at 25 °C in an incubator for 20 minutes.

[0426] Read the EX540-EM590 data using PHERAstar FSX and calculate the selectivity. The results are shown in Table 3 below.

[0427] Table 3

[0428]

[0429] In the description of this specification, expressions such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0430] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof: Wherein, Cy1 represents an unsubstituted or optionally substituted by one, two or more R a substituted phenyl; R a each independently selected from carboxyl, -O-C 5-6 cycloalkyl, -O-5-6-membered heterocyclic group, -O-C 6-10 aryl, or 5-6-membered heterocyclic group, wherein R a is optionally further substituted by oxo or by fluorine, chlorine or bromine; Cy2 represents an unsubstituted or optionally substituted 6- to 12-membered heterocyclic group with one, two or more Rs b substituents; R b Each independently selected from C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, cyano, nitro and / or oxo.

2. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to claim 1, Wherein, Cy2 represents an unsubstituted or optionally substituted 6-10 membered heteroaryl group with one, two or more R b substituents; Cy1, R b has the same definition as in claim 1.

3. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to claim 1, Wherein, Cy1 represents an unsubstituted or optionally substituted by one, two or more R a substituted phenyl group; R a each independently selected from carboxyl, difluorophenoxy, difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 2H-tetrahydropyranyloxy; Cy2 represents an unsubstituted or optionally substituted pyrimidinyl, benzopyranyl, benzothiopyranyl group by one, two or more R b substituents; R b Each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano and / or oxo.

4. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to claim 1, Wherein, Cy1 represents a phenyl group substituted by one, two or more Rs a substituted phenyl; Cy2 represents an unsubstituted or optionally substituted pyrimidinyl or benzopyranyl group by one, two or more R b substituents.

5. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to claim 1, Wherein, Cy2 represents an unsubstituted or optionally substituted by one, two or more R b substituted pyrimidinyl, 4H-chromen-3-yl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydrofuro[3,2-c]pyridinyl or 3,4-dihydro-1,5-naphthyridin-1(2H)-yl.

6. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to claim 1, Wherein, R a each independently selected from carboxyl, 3,5-difluorophenoxy, 4,4-difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 2H-tetrahydropyran-4-yloxy; R b Each independently selected from methyl, ethyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, cyano, oxo and / or 2,2-difluoroethoxy.

7. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to claim 1, Where Cy1 has the following structure:

8. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to claim 1, Where Cy2 has the following structure:

9. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the compound of formula (I) has the structure of formula (I-1) below: Wherein, n represents 0, 1, 2, 3 or 4.

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

11. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the compound of formula (I) has the structure of formula (I-2) below:

12. The compound of formula (I) or a physiologically / pharmaceutically acceptable salt thereof according to claim 1, Wherein, The compound of formula (I) is selected from the following compounds:

13. A pharmaceutical composition comprising the compound of formula (I) or a salt thereof according to any one of claims 1 to 12.

14. The pharmaceutical composition according to claim 13, which optionally comprises at least one physiologically / pharmaceutically acceptable excipient.

15. Use of the compound of formula (I) or a salt thereof according to any one of claims 1 to 12 in the preparation of a drug, wherein the drug is an inhibitor of lactate dehydrogenase.

16. The use according to claim 15, Characterized in that, The drug is used for preventing or treating autoimmune diseases or cancers, the autoimmune diseases are selected from systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, and / or, the cancers are selected from acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin 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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