CN116478129A - Quinoline compound and use thereof - Google Patents

Quinoline compound and use thereof Download PDF

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CN116478129A
CN116478129A CN202310060170.8A CN202310060170A CN116478129A CN 116478129 A CN116478129 A CN 116478129A CN 202310060170 A CN202310060170 A CN 202310060170A CN 116478129 A CN116478129 A CN 116478129A
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amino
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许柯
鲜于安今
李德尧
吴筱星
潘伟
周世强
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Shenzhen Moyuan Biotechnology Co ltd
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Shenzhen Moyuan Biotechnology Co ltd
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Abstract

The present invention relates to quinoline derivatives (I) which can be used as inhibitors of lactate dehydrogenase, to a process for their preparation and to their use. The invention further relates to pharmaceutical compositions comprising the quinoline derivatives.

Description

Quinoline compound and use thereof
RELATED APPLICATIONS
The present invention claims priority from the prior application filed on 1 month 21 2022 to the national intellectual property agency of China, having application number 202210083662.4, entitled "fluoro substituted quinoline Compounds as inhibitors of lactate dehydrogenase and uses thereof". The entirety of this prior application is incorporated by reference into this application.
Technical Field
The present invention relates to quinoline derivatives which can be used as inhibitors of lactate dehydrogenase, a process for their preparation and their use. The invention further relates to pharmaceutical compositions comprising the quinoline derivatives.
Background
Lactate Dehydrogenase (LDH) is a tetrameric enzyme belonging to the family of 2-hydroxy acid oxidoreductases that increases the rate of conversion of pyruvate to lactate and Nicotinamide Adenine Dinucleotide (NAD) H to nad+, which is commonly used by cells for anaerobic respiration and is therefore one of the important rate-limiting enzymes in the sugar metabolic pathway. Two different subunits of lactate dehydrogenase are encoded by two separate genes, LDHA and LDHB, respectively. LDHA is also known as the M subunit, found mainly in skeletal muscle; LDHB, also known as the H subunit, is found mainly in the heart. Since LDH is a tetrameric enzyme, LDH can also be composed of five isoenzymes via 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).
One of the important features of energy metabolism of tumor cells is the Warburg effect, i.e. under normal oxygen content, glucose metabolism is gradually changed to be dominant by glycolysis; wherein glucose is converted to lactic acid and Adenosine Triphosphate (ATP) is produced. The Warburg effect therefore suggests that the use of glucose by tumor cells is shifted from oxidative phosphorylation to glycolysis, which not only enhances glycolysis, but also inhibits oxidative phosphorylation of mitochondria.
Inhibition of energy metabolism, proliferation or invasion of tumor cells, and possibly reduction of drug resistance of tumor cells, is expected by inhibition of LDHA and inhibition or regulation of expression of LDHB. Thus, there is a need in the art to obtain drugs that target lactate dehydrogenase.
Disclosure of Invention
In view of the deficiencies in the prior art and/or the need in the art, it is an object of the present invention to provide a compound or derivative thereof and related pharmaceutical compositions that can be used as inhibitors of lactate dehydrogenase. This object is achieved by the subject matter described in the various aspects of the present application below.
In a first aspect, the present invention provides a compound of formula (I) or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, racemate, oxynitride, solvate, isotopic label, prodrug or metabolite thereof:
Wherein, the liquid crystal display device comprises a liquid crystal display device,
cy1 represents unsubstituted or optionally substituted by one, two or more R a Substituted C 3-20 Cycloalkyl, 3-14 membered heterocyclyl, C 6-20 Aryl or 5-to 20-membered heteroaryl,
R a may each be independently selected from the group consisting of: carboxyl, aminocarbonyl, C 1-12 Alkyl, halogen, nitro, cyano, hydroxy, -CO-C 1-12 Alkoxy, C 1-12 Alkoxy, -O-C 3-20 Cycloalkyl, -O-3-14 membered heterocyclyl, -O-C 6-20 Aryl, hydroxyaminocarbonyl, 3-14 membered heterocyclyl, 5-20 membered heteroaryl, C 1-12 Alkylsulfonyl, C 1-12 Alkylsulfonylaminocarbonyl, where R is a Can optionally be further oxo-or hydroxy-substituted, halogen, C 3-20 Cycloalkyl or 3-14 membered heterocyclyl,
cy2 represents notSubstituted or optionally substituted by one, two or more R' s b Substituted 3-20 membered heterocyclyl or C 6-20 Aryl or 5-to 20-membered heteroaryl,
R b can be each 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.
R 1 And R is 2 May each be independently selected from the group consisting of: hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Alkylamino, C 3-20 Cycloalkyl, C 3-20 Cycloalkyl C 1-12 Alkyl, C 1-12 Haloalkyl group C 3-20 Cycloalkyl, C 3-20 Halogenated cycloalkyl, C 6-20 Aryl, 3-14 membered heterocyclyl, C 6-20 aryl-C 1-12 Alkyl, C 1-12 Alkoxy C 1-12 Alkyl, cyano C 1-12 An alkyl group; alternatively, R 1 And R is 2 May form together with the nitrogen atom to which it is attached a 3-14 membered heterocyclyl optionally substituted by halogen or oxo or a 5-to 20-membered heteroaryl optionally substituted by halogen.
In some embodiments according to the invention, cy1 represents unsubstituted or optionally substituted with one, two or more R a Substituted C 3-12 Cycloalkyl or 3-14 membered heterocyclyl or C 6-14 Aryl or 5-14 membered heteroaryl. Preferably, R a Can 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-C 3-12 Heterocyclyl, -O-C 6-14 Aryl, hydroxyaminocarbonyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylaminocarbonyl, -SO 3 H or-SO 3 -C 1-6 Alkyl, wherein R is a Can optionally be further oxo-or hydroxy-substituted, halogen, C 3-12 Cycloalkyl or 3-14 membered heterocyclyl.
Preferably, cy1 represents 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.
Preferably, R a Can 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-C 3-12 Heterocyclyl, -O-C 6-14 Aryl, hydroxyaminocarbonyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylaminocarbonyl, -SO 3 H or-SO 3 -C 1-6 Alkyl, wherein R is a May optionally be further substituted with oxo or with hydroxy, fluoro, chloro, bromo, oxetanyl or cyclobutyl.
More preferably, cy1 represents unsubstituted or optionally substituted with one, two or more R a Substituted phenyl, pyridyl, thiazolyl, bicyclo [2.2.1]Heptyl, cyclohexyl, chromanyl.
More preferably, R a Independently of one another, selected from the group consisting of carboxyl, difluorophenoxy, difluorocyclohexyloxy, 5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl, 5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl, 2H-tetrahydropyranyl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazolyl, morpholinyl, morpholinomethyl, methanesulfonyl, methanesulfonylaminocarbonyl, 2-hydroxy-3, 4-dioxocyclobutanyl, 1-hydroxy-2, 2-trifluoroethyl, cyclobutyl, oxetanyl, oxetanylpiperazinyl, cyclobutylpiperidinyloxy, hydroxydioxocyclobutyl and/or hydroxyisoxazolyl.
Still more preferably, cy1 represents one, two or more R a Substituted phenyl, pyridin-2-yl, thiazol-2-yl, bicyclo [2.2.1]Hept-1-yl, cyclohexyl or chromanyl.
Still more preferably still the use of a modified starch,R a independently of each other selected from the group consisting of carboxy, 3, 5-difluorophenoxy, 4-difluorocyclohexyloxy, 5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl, 5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazol-5-yl, morpholin-4-ylmethyl, methanesulfonyl, methanesulfonylaminocarbonyl, 2-hydroxy-3, 4-dioxocyclobutan-1-yl, 1-hydroxy-2, 2-trifluoroethyl, cyclobutyl, oxetan-3-yl, 1- (oxetan-3-yl) piperidin-4-yloxy, 4- (oxetan-3-yl) piperazin-1-yl, 1-cyclobutylpiperidin-4-yloxy, 2-hydroxy-3, 4-dioxo-3-oxo and/or 5-isoxazol.
Most preferably, cy1 has the following structure:
in some embodiments according to the invention, cy1 may also be selected from the following structures:
in some embodiments according to the invention, cy1 is substituted with one or two R a Substitution; preferably, cy1 is substituted with at least one carboxyl group.
In some embodiments according to the invention, the compound of formula (I) has the structure of formula (IA), formula (IB), formula (IC) or formula (ID):
wherein R is 1 、R 2 、Cy1、Cy2、R a 、R b Is of the formula (I)Meaning of sense; h represents a number of 0, 1, 2 or 3, and i represents a number of 0, 1, 2 or 3.
In some embodiments according to the invention, cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted 3-14 membered heterocyclyl or C 6-14 Aryl or 5-14 membered heteroaryl.
Preferably, cy2 represents unsubstituted or optionally substituted by one, two or more R b Substituted phenyl, phenoxy, phenylthio, phenylamino, pyrimidinyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridinyl, benzopyranyl, benzothiopyranyl, pyrazolopyrimidinyl, dihydrofuropyrimidinyl, furopyrimidinyl, thiazolopyrimidinyl, imidazopyrimidinyl, dihydronaphthyridinyl or dihydrofuropyridinyl.
More preferably, cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridinyl, benzopyranyl, pyrazolopyrimidinyl, dihydrofuropyrimidinyl, dihydropyridinyl, imidazopyrimidinyl, dihydronaphthyridinyl or dihydrofuropyridinyl.
Still more preferably, cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridinyl, 4H-benzopyran-3-yl, 1H-pyrazolo [3,4-d]Pyrimidinyl, 2, 3-dihydrofuro [3,2-c ]]Pyrimidinyl, 1, 2-dihydropyridinyl, imidazo [1,2-c]Pyrimidinyl, 3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl or 2, 3-dihydrofuran [3,2-c ]]Pyridin-7-yl.
Preferably, R b Independently of one another 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.
More preferably, R b Independently of one another selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, halogen, aminocarbonyl, cyano and/or oxo.
Still more preferably, R b Independently of each other, selected from methyl, ethyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, aminocarbonyl, cyano, oxo and/or 2, 2-difluoroethoxy.
Most preferably, cy2 has the following structure:
in some embodiments according to the invention, cy2 may also be selected from the following structures:
in some embodiments according to the invention, R 1 And R is 2 May each be independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, C 1-6 Haloalkyl group C 3-12 Cycloalkyl, C 3-12 Halogenated cycloalkyl, C 6-14 Aryl, 3-12 membered heterocyclyl, C 6-14 aryl-C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 An alkyl group; alternatively, R 1 And R is 2 May form together with the nitrogen atom to which it is attached a 3-to 12-membered heterocyclyl optionally substituted by halogen or oxo or a 5-to 14-membered heteroaryl optionally substituted by halogen.
Preferably, R 1 And R is 2 May each be independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C 1-6 Haloalkyl group C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, C 3-12 Halogenated cycloalkyl, C 6-14 Aryl, 3-12 membered heterocyclyl, C 6-14 aryl-C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 An alkyl group; alternatively, R 1 And R is 2 May form together with the nitrogen atom to which it is attached a 3-8 membered heterocyclyl optionally substituted by halogen or oxo or a 5-to 10-membered heteroaryl optionally substituted by halogen.
More preferably, R 1 And R is 2 May each be independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, C 1-6 Haloalkyl group C 3-12 Cycloalkyl, C 3-6 Halogenated cycloalkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or a 5 or 6 membered heterocyclyl; alternatively, R 1 And R is 2 May form together with the nitrogen atom to which it is attached a 3-to 6-membered heterocyclic group optionally substituted by halogen or oxo.
Most preferably, R 1 And R is 2 May each be independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C 1-6 Haloalkyl group C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, 6-membered heterocyclyl or C 3-12 Halogenated cycloalkyl groups.
In some embodiments according to the invention, R 1 And R is 2 One of which represents hydrogen and the other represents hydrogen, cyclopropyl, 2-trifluoroethyl, methyl, propan-2-yl, tert-butyl, 1-trifluoromethyl-cyclopropyl-1-yl, 1-fluoro-cyclopropyl-1-yl, cyclobutyl, cyclopropylmethyl, cyanomethyl, tetrahydrofuran-3-yl, 2H-tetrahydropyran-4-yl, cyclohexyl, oxetan-3-yl or 2, 2-difluorocyclopropyl-1-yl.
In some embodiments according to the present invention, there is also provided a compound of formula (IIA) or (IIB) or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, racemate, oxynitride, solvate, isotopic label, prodrug or metabolite thereof:
Wherein R is 1 、R 2 Cy1, cy2 and R a Each independently having the meaning as defined herein, X and Y are each independently selected from CH or N, m represents 0, 1, 2 or 3, and L represents-SO 2 -or-C (=o) -.
In some embodiments according to the present invention, there is also provided a compound of formulae (IIC), (IID), (IIE) and (IIF), or a physiologically/pharmaceutically acceptable salt or ester thereof, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopic labels, prodrugs or metabolites thereof:
wherein R is 1 、R 2 Cy1, cy2 and R a Each independently having the meaning as defined herein, m represents 0, 1, 2 or 3, and L represents-SO 2 -or-C (=o) -.
In some embodiments according to the present invention, the compounds of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) and formula (IIF) may be selected from the following compounds:
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in a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE), formula (IIF) or a salt or ester thereof, a stereoisomer or tautomer, racemate, oxynitride, solvate, isotopic label, prodrug or metabolite thereof, as defined herein.
In some embodiments according to the present invention, the pharmaceutical composition according to the present invention may optionally further comprise at least one physiologically/pharmaceutically acceptable excipient.
In some embodiments according to the invention, the pharmaceutical composition according to the invention may optionally further comprise additional active ingredients. Such as anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogues, signal transduction pathway inhibitors; a non-receptor tyrosine kinase angiogenesis inhibitor; an immunotherapeutic agent; pro-apoptotic agents; and cell cycle signaling inhibitors.
In some embodiments according to the invention, the pharmaceutical composition according to the invention comprises a therapeutically effective amount of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) or formula (IIF) or a salt or ester thereof, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotopic label, prodrug or metabolite thereof.
In some embodiments according to the invention, the pharmaceutical composition according to the invention is an inhibitor of lactate dehydrogenase.
In some embodiments according to the invention, the pharmaceutical composition according to the invention is for use in preventing or treating a disease, disorder, syndrome and/or disorder selected from the group consisting of: autoimmune diseases or cancer. Autoimmune diseases include, but are not limited to: systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, vitiligo, alopecia areata, and the like. Examples of cancers include, but are not limited to: acute lymphoblastic leukemia, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumor (glioma), glioblastoma, bannayan-Zonana syndrome, cowden disease, lhemitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma, thyroid cancer, and the like.
According to the present invention, the pharmaceutical composition according to the present invention may be formulated into a dosage form suitable for administration by methods known in the art.
In a third aspect, the present invention provides the use of a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) or formula (IIF) according to the invention, or a salt or ester thereof, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotopic label, prodrug or metabolite thereof, in the manufacture of a medicament.
In some embodiments according to the invention, the medicament may optionally further comprise an additional active ingredient. Such as anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogues, signal transduction pathway inhibitors; a non-receptor tyrosine kinase angiogenesis inhibitor; an immunotherapeutic agent; pro-apoptotic agents; and cell cycle signaling inhibitors.
In some embodiments according to the invention, the agent is an inhibitor of lactate dehydrogenase, achieving the object of the invention by reducing LDHA and modulating expression of LDHB.
In some embodiments according to the invention, the medicament is for preventing or treating a disease, disorder, syndrome and/or disorder selected from the group consisting of: autoimmune diseases or cancer. Autoimmune diseases include, but are not limited to: systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, vitiligo, alopecia areata, and the like. Cancers include, but are not limited to: acute lymphoblastic leukemia, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumor (glioma), glioblastoma, bannayan-Zonana syndrome, cowden disease, lhemitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma, thyroid cancer, and the like.
According to the present invention, the medicament may be further formulated into a dosage form suitable for administration by methods known in the art.
In a fourth aspect, the present invention provides a method for treating or preventing a disease, condition, syndrome and/or disorder of autoimmune disease or cancer, the method comprising administering to a subject in need thereof a compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) or formula (IIF), or a salt or ester thereof, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotopic label, prodrug or metabolite thereof according to the present invention.
In some embodiments according to the invention, the disease, condition, syndrome, and/or disorder of an autoimmune disease comprises: 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, and the like.
In some embodiments according to the invention, the disease, condition, syndrome, and/or disorder of cancer comprises: acute lymphoblastic leukemia, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, and the like, brain tumor (glioma), glioblastoma, bannayan-Zonana syndrome, cowden disease, lhemitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma, and thyroid cancer.
Those skilled in the art will appreciate that features recited in the various aspects and embodiments of the invention can be freely combined in accordance with them as long as they do not conflict with each other or are incompatible therewith.
The beneficial effects of the invention are that
The invention provides an inhibitor of lactic dehydrogenase with a quinoline structure, which has better biological activity and pharmacokinetics.
Detailed Description
The present invention is described in further detail below.
The following terms used herein have the meanings explained below unless otherwise specified, and their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in tables, definitions of specific compounds in the examples and the like may be arbitrarily combined and combined with each other; terms not explained in detail should have the same meaning as commonly understood by those of skill in the art; both patent and non-patent documents, or materials that are otherwise disclosed in whole or in part herein are incorporated by reference.
For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato: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.
Terminology
The terms "comprising," "including," and/or "containing" are used herein as open-ended expressions, i.e., including the meaning of the present invention, but not excluding other aspects.
In this context, when describing one, two or more, more shall mean a situation of greater than 2, for example representing an integer situation of greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.
In this document, the term "optional (and/or ground)" means that the feature may or may not be present, meaning that the subsequently described event may or may not occur, thus including both cases where the event occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and thus includes the case of a heterocyclic group substituted with an alkyl group and a heterocyclic group not substituted with an alkyl group.
Herein, the expressions "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B and/or C", "X is A, B and/or C", etc. all express the same meaning, i.e. it means that X may be any one, two or more of A, B and C.
In this context, the term "unsubstituted" means that one or more hydrogen atoms on the atom, residue, group or moiety to which the term is attached are not replaced by other atoms or groups of atoms (i.e., substituents) other than hydrogen atoms, and thus the atom, residue, group or moiety retains its original structure. The term "(substituted)" means that one, two or more hydrogen atoms, preferably up to 5 hydrogen atoms, more preferably 1 to 3 hydrogen atoms in the group are each independently substituted with a corresponding number of substituents. When substituted with more than one substituent, the substituents are independent of each other, i.e., the more than one substituent may be identical to each other, but this is not exclusive of the possible identity. Unless specifically indicated, a substituent may be substituted at any substitutable position of the substituted group. When more than one position in a given formula can be substituted with one, two or more substituents, then the substituents may be independently substituted at those positions. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine possible or impossible substitutions experimentally or theoretically without undue effort.
In this context, the phrase "each independently of the other" should be understood as meaning that the individual individuals described are independent of each other and may be independently selected from the same or different options. For example, "each independently selected from each other" may mean that the specific options expressed by the same symbol in different groups do not affect each other; it may also be represented that the specific options expressed by the same symbols in the same group do not affect each other.
In this context, two or more groups of defined meaning are sometimes used in combination to describe a larger moiety, the combination describing a moiety that includes the two or more groups selected independently of one another to constitute a structural combination. For example, "alkylaryl" means "alkyl" and "aryl" linked together and the "alkyl" and the "aryl" each independently of the other have the meanings described for them separately, thereby together making up the combined group "alkylaryl".
Herein, it is sometimes described that a linker is in the middle part of the structure of the compound, connected to the rest of the compound by at least two connection sites. Markush variables listed for a linker are understood to be the divalent groups of that variable, i.e. "subunits". For example, if a linker is defined in the structure of a compound and "alkyl" or "aryl" is recited for the markush group definition of the linker, it is understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
Herein, the label "C x -C y "when used in conjunction with a group means the upper and lower ranges for 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 and up to twelve carbon atoms. Those skilled in the art will appreciate that such numbers do not include the number of carbon atoms contained on the substituents to which they are attached when such groups are otherwise substituted.
The expression "X-Y element" when used in combination with a cyclic group means the upper and lower limits of the number of ring atoms contained in the cyclic group. For example, a "3-20 membered" heterocyclyl refers to a heterocyclyl group containing a minimum of three ring atoms up to a maximum of twenty ring atoms. Those skilled in the art will appreciate that such numbers do not include the number of carbon atoms contained on the substituents to which such heterocyclyl groups are otherwise substituted.
In this context, the term "oxo" refers to a group substituted (=o) by an oxo group formed on an oxo carbon atom, nitrogen atom or sulfur atom.
Herein, the term "halogen" means fluorine, chlorine, bromine and/or iodine. Accordingly, the term "halo" refers to fluoro, chloro, bromo and/or iodo. Within the scope of this document, where an atom, residue, group or moiety is halogenated, the atom at the halogenated position may be mono-, di-or polysubstituted with halogen atoms up to full substitution.
The term "alkyl" means a straight or branched monovalent saturated aliphatic hydrocarbon group. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof.
The term "alkenyl" refers to a straight or branched chain monovalent unsaturated aliphatic hydrocarbon group containing one, two or more double bonds. It will be appreciated that where the alkenyl group comprises more than one double bond, the double bonds may be separated from each other or conjugated. Non-limiting examples of alkenyl groups 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-1-enyl, hex-5-enyl, (E) -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-methylbut-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-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.
The term "alkynyl" refers to a straight or branched monovalent unsaturated aliphatic hydrocarbon group containing one, two or more triple bonds. Non-limiting examples of alkynyl groups 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-methylpropan-2-ynyl, 2-methylbutan-3-ynyl, 1-methylbutan-2-ynyl, 3-methylbutan-1-ynyl, pent-4-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-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2, 2-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "alkylene" refers to a divalent group obtained by the additional removal of one hydrogen atom from an "alkyl" group. Similarly, "alkenylene" and "alkynylene" refer to divalent groups obtained by the additional removal of one hydrogen atom from "alkenyl" and "alkynyl", respectively.
The term "alk (yl) oxy" refers to an-O-alkyl group, wherein alkyl is as defined herein. Non-limiting examples of alkoxy groups include, for example: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like. Alkoxy groups may be unsubstituted or optionally substituted.
The term "carbocycle (group)" refers to a saturated or partially unsaturated, monocyclic or polycyclic, cyclic hydrocarbon group, a carbocycle 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, more preferably 3 to 6 carbon atoms. Carbocycles may be monocyclic or polycyclic, which may be saturated cycloalkyl or may optionally contain one, two or more double and/or triple bonds in the ring thereof, thereby forming a so-called cycloalkenyl or cycloalkynyl group. Saturated cyclic hydrocarbon groups or saturated carbocyclyl groups are also referred to as "cycloalkyl". Carbocyclyl or cyclic hydrocarbyl groups, where there are 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, and the like; non-limiting examples of polycyclic carbocycles include decalinyl, bicyclo [2.2.1] heptyl, or isobornyl.
The term "heterocyclic (group)" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent preferably containing 3 to 20 ring atoms, wherein one or more of the ring atoms is selected from N, O, NH, S, S (O) or S (O) 2 But does not include a ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1-4 are heteroatoms (e.g., 1, 2, 3, and 4); more preferably from 3 to 6 ring atoms (e.g., 3, 4, 5, 6). The heterocyclic group may be attached to the remainder of the molecule through any one of the carbon atoms or a nitrogen atom (if present) or an oxygen or sulfur atom (particularly in the case of onium salts). The heterocyclyl may include fused or bridged rings and/or spiro rings. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazepanyl, and the like, with piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups, but may also be benzo-fused heterocyclic groups such as dihydroisoquinolinyl. The heterocyclic group may be bicyclic, non-limiting examples of which include hexahydrocyclopenta [ c ] ]Pyrrol-2 (1H) -yl, hexahydropyrrolo [1,2-a ]]Pyrazin-2 (1H) -yl. The heterocyclic group may also be partially unsaturated, i.e., it may contain one or more double bonds, non-limiting examples of which include dihydrofuryl, dihydropyranyl, 2, 5-dihydro-1H-pyrrolyl、4H-[1,3,4]Thiadiazinyl, 4, 5-dihydrooxazolyl or 4H- [1,4]Thiazinyl, 4H-benzopyran-3-yl, 1H-pyrazolo [3,4-d ]]Pyrimidinyl, 2, 3-dihydrofuro [3,2-c ]]Pyrimidinyl, 1, 2-dihydropyridinyl, 3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl or 2, 3-dihydrofuran [3,2-c ]]Pyridin-7-yl.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, nitro, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl/aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated electron system, preferably a 6 to 14 membered or 6 to 10 membered ring, such as phenyl and naphthyl.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, hydrophobic, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups, preferably phenyl.
Herein, the term "heteroaryl/heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered), more preferably 5 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, thia-4H-pyrazolyl, and the like, and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, imidazo [1,2-c ] pyrimidinyl, and/or phenoxazinyl, and the like.
Heteroaryl/heteroaryl rings may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one, two or more groups selected independently of each other from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
Unless otherwise indicated, a heterocyclyl, heteroaryl or heteroaryl ring includes all possible isomeric forms thereof, for example positional isomers thereof. Thus, for some illustrative non-limiting examples, forms that may include substitution at one, two, or more of its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) or bonding to other groups include pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene include thiophen-2-yl, thienylene-2-yl, thiophen-3-yl and thienylene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.
Unless otherwise indicated, the definitions of terms herein apply equally to expressions which include the terms, e.g. C 1-6 The definition of alkyl also applies to C 1-6 Alkyloxy (sometimes also referred to as C 1-6 Alkoxy), -N (C) 1-6 Alkyl group 2 、-NHC 1-6 Alkyl, -SO-C 1-6 Alkyl or-S (O) 2 -C 1-6 Alkyl groups, and the like.
As used herein, "physiologically/pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Physiologically/pharmaceutically acceptable salts include acid addition salts of the compounds of the invention having a nitrogen atom in the chain or ring that are sufficiently basic. Alternatively, the basic nitrogen-containing groups may be quaternized with the following agents: 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, and the like. As examples, physiologically/pharmaceutically acceptable salts include, but are not limited to, hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, methanesulfonate, formate, or meglumine salts, and the like.
Since the compounds of the present invention may have multiple salt-forming sites, the physiologically/pharmaceutically acceptable salts include not only salts formed at 1 of the salt-forming sites of the compounds of the present invention, but also salts formed at 2, 3 or all of the salt-forming sites. For this purpose, the molar ratio of the compound of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) or formula (IIF) to the cation of the root ion (anion) or base of the acid required for salification may vary within a wide range, for example may be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
As used herein, the term "nitroxide" refers to the oxidation of 1 or more than 1 nitrogen atom to form an N-oxide when the compound contains several nitrogen-containing functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding nitrogen-containing compound may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514) in which, for example, a nitrogen-containing compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as methylene chloride.
As used herein, the term "ester" refers to an in vivo hydrolysable ester formed from a compound containing a hydroxyl or carboxyl group. Such esters are, for example, physiologically/pharmaceutically acceptable esters which hydrolyze in the human or animal body to give the parent alcohol or acid. The compounds of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) or formula (IIF) of the present invention may contain a carboxyl group, and may form in vivo hydrolysable esters with suitable groups, including, but not limited to, alkyl, arylalkyl, and the like.
Depending on the position and nature of the different substituents, the compounds of the invention may also contain one or more asymmetric centers. The asymmetric carbon atoms may exist in either the (R) or (S) configuration, with only one asymmetric center, resulting in a racemic mixture, with multiple asymmetric centers, resulting in a diastereomeric mixture. In some cases, asymmetry may also be present due to the blocked rotation about a particular bond, for example, the center bond connects two substituted aromatic rings of a particular compound. Also, substituents may exist in cis or trans isomeric forms.
The compounds of the invention also include all of their respective possible stereoisomers, either in the form of a single stereoisomer or any mixture of any of the stereoisomers (e.g., R-isomer or S-isomer, or E-isomer or Z-isomer) in any ratio. Separation of individual stereoisomers (e.g., individual enantiomers or individual diastereomers) of the compounds of the invention may be accomplished by any suitable prior art method (e.g., chromatography, particularly, e.g., chiral chromatography).
The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.
In the present invention, the compounds according to the present invention also include isotopically-labeled compounds identical to those shown in formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) or formula (IIF), but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually naturally occurring. Examples of isotopes that can be incorporated into compounds of the invention include H, C, N, O, S, F and Cl isotopes, respectively, such as 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 32 P、 35 S、 18 F, F is a single crystal 36 Cl. The compounds of the invention, prodrugs thereof, or physiologically/pharmaceutically acceptable salts of the compounds or prodrugs, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Isotopically-labeled compounds according to the present invention can generally be prepared according to the methods described herein by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent. Certain isotopically-labeled compounds of the present invention, for example, are those into which a radioisotope (such as 3 H and 14 c) The compounds of (2) are useful in drug and/or substrate tissue distribution assays. Tritium (i.e. tritium) 3 H) And carbon 14 (i.e 14 C) Isotopes are particularly preferred for ease of preparation and detectability. Furthermore, with heavier isotopes (such as deuterium, i.e 2 H) Substitutions may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from higher metabolic stability, and thus may be preferred in certain circumstances. The compounds of the invention as claimed in the claims maySubstitution with deuterium or tritium is particularly limited. Furthermore, the presence of hydrogen in a substituent is not listed solely for the term deuterium or tritium and is not meant to exclude deuterium or tritium, but may equally well comprise deuterium or tritium.
The term "prodrug" or "prodrug" as used herein means a compound that is converted in vivo to a compound as shown in the aforementioned formula (I), formula (IA), formula (IB), formula (IC), formula (ID), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIE) or formula (IIF) or a specific compound. Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. Prodrugs of the invention may be esters, and in the present invention esters may be phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters as prodrugs. For example, one compound of the invention comprises a hydroxy/carboxy group, i.e., it can be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent.
In this context, the term "metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
Abbreviations for any protecting groups, amino acids and other compounds used in the present invention are, unless otherwise indicated, based on their commonly used, accepted abbreviations or with reference to IUPAC-IUB Commissionon Biochemical Nomen clature (see biochem.1972, 11:942-944).
As used herein, the term "solvate" refers to an association of one or more solvent molecules with 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. Thus, the term "hydrate" refers to an association of solvent molecules formed from water.
As used herein, the term "pharmaceutical composition" means a mixture comprising one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity. The term "physiologically/pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, etc., when administered to humans. The term "carrier" refers to a diluent, adjuvant, excipient, or matrix 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 and the like. Water and aqueous solutions saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly injectable solutions. Suitable drug carriers are described in "Remington' sPharmaceutical Sciences" of e.w. martin.
As used herein, the term "treating" any disease or disorder, in some embodiments refers to ameliorating the disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
In this context, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to achieve the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended use (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the regimen based on, whether to administer in combination with other compounds, the timing of administration, the organization of administration, and the physical delivery system carried.
In some embodiments according to the present invention, the pharmaceutical excipients may be excipients widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
Substances that may be used as physiologically/pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-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; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffer, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preserving and antioxidant agents.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The dosage form of the medicament of the invention can be selected according to specific conditions. Pharmaceutical dosage forms often consist of a drug, excipients and a container/sealing system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and may provide a means to achieve a desired drug release profile. Thus, the type of excipient added to a drug may depend on various factors, such as the physical and chemical characteristics of the drug, the route of administration, and the manufacturing steps. Pharmaceutically acceptable excipients are present in this field and include those listed in the various pharmacopoeias. (see U.S. Pharmacopeia (U.S.Pharmacopeia, USP), japanese Pharmacopeia (Japanese Pharmacopoeia, JP), european Pharmacopeia (European Pharmacopoeia, EP) and British Pharmacopeia (British pharmacopoeia, BP); U.S. food and drug administration (the U.S. food and Drug Administration, www.fda.gov) drug evaluation and research center (Centerfor Drug Evaluation and Research, CEDR) publications, such as Inactive ingredient guide (Inactive Ingredient Guide, 1996); pharmaceutical additives handbook written by Ash (Hand book of Pharmaceutical Additives, 2002), joint information resource company (Synapse Information Resources, inc., endiott NY; etc.).
The pharmaceutical compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a formulation for pharmaceutical use.
Suitable formulations will depend upon the route of administration desired. The administration route includes intravenous injection, transmucosal or nasal administration, oral administration, etc. For oral administration, the compounds may be formulated in liquid or solid dosage forms and 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, slurries, suspensions and emulsions.
Solid oral dosage forms may be obtained using excipients including fillers, disintegrants, binders (dry and wet), dissolution retarders, lubricants, glidants, anti-sticking agents, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavoring agents. These excipients may be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silica, sodium benzoate, sorbitol, starch, stearic acid or salts thereof, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth, vegetable oils (hydrogenated), and waxes. Ethanol and water may be used as granulation aids. In some cases it may be desirable to coat the tablet with, for example, a taste masking film, a gastric acid resistant film, or a delayed release film. Natural and synthetic polymers are often used in combination with colorants, sugars and organic solvents or water to coat tablets, resulting in dragees. When the capsule is preferred over a tablet, the drug powder, suspension or solution thereof may be delivered in the form of a compatible hard shell or soft shell capsule.
The therapeutically effective dose may be estimated first using various methods well known in the art. The initial dose used for animal studies may be based on the established effective concentration in the cell culture assay. The dosage range suitable for the human body can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention may be prepared as medicaments for oral administration.
The correct formulation, route of administration, dosage and interval of administration may be selected in consideration of the particularities of the individual condition according to methods known in the art.
Examples
The preparation method of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All technical solutions realized based on the present disclosure are included in the scope of the present disclosure.
Unless otherwise indicated, the experimental methods used in the following examples are all conventional in the art; reagents, materials, instruments, equipment, and the like used in the examples described below are all commercially available.
Reagents used
The starting materials and reagents in the examples of the present invention are known and commercially available, or may be synthesized using or according to literature reported in the art.
Instrument and apparatus and assay method
NMR was performed using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic instruments, and the measuring solvent contained deuterated dimethyl sulfoxide (DMSO-d 6), deuterated acetone (CD) 3 COCD 3 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), etc., the internal standard being Tetramethylsilane (TMS), the chemical shifts being measured in parts per million (ppm).
Liquid chromatography (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC was determined using an Agilent1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm column).
The thin layer chromatography silica gel plate is Qingdao GF254 silica gel plate, TLC is 0.15-0.20mm, and the preparation thin layer chromatography is 0.4-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as carrier.
Abbreviations or abbreviations
Boc: boc-group
Xantphos Pd G 4 : methane sulphonic acid (4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene) (2 '-methylamino-1, 1' -biphenyl-2-yl) palladium (II)
DIAD: diisopropyl azodicarboxylate
B 2 Pin 2 : diboric acid pinacol ester
AcOH: acetic acid
MeOH: methanol
NaOH: sodium hydroxide
DCM: dichloromethane (dichloromethane)
THF: tetrahydrofuran (THF)
t-BuOH: tert-butanol
Et 3 N: triethylamine
H 2 O: water and its preparation method
PE: petroleum ether
EA. EtOAc: acetic acid ethyl ester
KOAc: potassium acetate
NMP: n-methylpyrrolidone
DIEA: n, N-diisopropylethylamine
Na 2 SO 4 : sodium sulfate
HPLC: high performance liquid chromatography
Pre-HPLC: high performance liquid chromatography
Prep-TLC: preparative thin layer chromatography
And rt: room temperature
Example 1: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (1)
Step 1: synthesis of methyl 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (1-3)
4-chloro-N-cyclopropyl-7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (20 mg,0.05 mmol) and methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (19 mg,0.07 mmol) were added to AcOH (5 mL). Stir at room temperature overnight. Concentration under reduced pressure gave compound 1-3 (10 mg, 32%).
MS(ESI,pos.ion)m/z:682.2[M+1] + 。
Step 2: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (1)
3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid methyl ester (10 mg,0.01 mmol) was dissolved in MeOH (2 mL), THF (2 mL) and H 2 To a mixture of O (2 mL), naOH (2 mg,0.04 mmol) was added and the mixture was stirred at 45℃for 2 hours. Concentrating under reduced pressure to remove methanol and tetrahydrofuran, adding H 2 O (5 mL) was pH adjusted to about 5 with 1N HCl and filtered to give the crude product, which was purified by HPLC to give the title compound (2 mg, 18%).
MS(ESI,pos.ion)m/z:668.2[M+1] + 。
1 HNMR(DMSO-d 6 )δ:9.06(s,1H),8.64(s,1H),8.14(d,J＝1.6Hz,1H),7.58(dd,J＝13.7,1.4Hz,1H),7.37(s,1H),7.14-7.21(m,1H),6.92(tt,J＝9.3,2.1Hz,1H),6.79(t,J＝2.0Hz,1H),6.65(dd,J＝8.2,1.9Hz,2H),3.99(s,3H),3.97(s,3H),2.17-2.23(m,1H),0.38(br d,J＝6.9Hz,2H),0.32-0.36(m,2H).
Example 2: synthesis of 6- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -4- (3, 5-difluorophenoxy) picolinic acid (2)
Step 1: synthesis of dimethyl 4- (3, 5-difluorophenoxy) pyridine-2, 6-dicarboxylate (2-3)
Dimethyl 4-chloropyridine-2, 6-dicarboxylate (2.00 g,8.73 mmol), 3, 5-difluorophenol (1.36 g,10.48 mmol) and cesium carbonate (5.69 g,17.46 mmol) were added to DMF (20 mL). The reaction was carried out at 70℃for 2h. Adding H 2 O (100 mL), extracted with ethyl acetate (40 mL. Times.3), the combined organic phases were then washed with saturated NaCl solution (50 mL. Times.3), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave a yellow solid (2.00 g, 80%).
MS(ESI,pos.ion)m/z:324.1[M+1] + 。
Step 2: synthesis of 4- (3, 5-difluorophenoxy) -6- (methoxycarbonyl) picolinic acid (2-4)
Dimethyl 4- (3, 5-difluorophenoxy) pyridine-2, 6-dicarboxylate (1.70 g,4.95 mmol) and NaOH (237 mg,5.94 mmol) were added to a mixed solution of MeOH (16 ml) and THF (4 ml). The reaction was carried out at room temperature for 5 hours. The pH was adjusted to 5-6 with 2N hydrochloric acid, and a white solid precipitated, which was concentrated by filtration to give a white solid (1.6 g, 90%).
MS(ESI,pos.ion)m/z:310.1[M+1] + 。
Step 3: synthesis of methyl 6- ((tert-butoxycarbonyl) amino) -4- (3, 5-difluorophenoxy) picolinate (2-5)
4- (3, 5-Difluorophenoxy) -6- (methoxycarbonyl) picolinic acid (1.6 g,5.17 mmol) and Et 3 N (1.04 g,10.34 mmol) was added to a mixture of t-BuOH (4 ml) and dioxane (20 ml), and DPPA (2.84 g,10.34 mmol) was slowly added dropwise. The reaction was carried out at 80℃for 18h. Adding H 2 O (50 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases combined and then washed with saturated NaCl solution (50 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure. The crude product was isolated by column chromatography as a yellow solid (220 mg, 5%).
MS(ESI,pos.ion)m/z:381.2[M+1] + 。
Step 4: synthesis of methyl 6-amino-4- (3, 5-difluorophenoxy) picolinate (2-6)
Methyl 6- ((tert-butoxycarbonyl) amino) -4- (3, 5-difluorophenoxy) picolinate (220 mg,0.58 mmol) was added to HCl/dioxane (4N, 5 mL) and reacted at room temperature for 2h. Concentrating under reduced pressure, adding H to the residue 2 O (10 mL), adjusting pH to about 7 with saturated sodium bicarbonate solution, extracting with ethyl acetate (20 mL. Times.3), combining the organic phases, washing with saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave the product as a white solid (150 mg, 90%).
MS(ESI,pos.ion)m/z:281.1[M+1] +
Step 5: synthesis of methyl 6- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -4- (3, 5-difluorophenoxy) picolinate (2-8)
Methyl 6-amino-4- (3, 5-difluorophenoxy) picolinate (25 mg,0.089 mmol) and 4-chloro-N-cyclopropyl-7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (30 mg,0.068 mmol), cesium carbonate (42 mg,0.13 mmol), xantphos Pd G4 (6 mg, 0.006mmol) were added to dioxane (4 ml), nitrogen was displaced three times, stirred at 110℃for 5 hours, stirred to cool down completely to room temperature, water (10 ml) and ethyl acetate (15 ml) were added, the extract was dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was purified by Prep-TLC plate to give a yellow solid (16 mg, 30%).
MS(ESI,pos.ion)m/z:683.2[M+1] + 。
Step 6: synthesis of 6- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -4- (3, 5-difluorophenoxy) picolinic acid (2)
Methyl 6- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -4- (3, 5-difluorophenoxy) picolinate (16 mg,0.02 mmol) was added to MeOH (2 ml) and aqueous NaOH (2N, 0.5 ml) was added dropwise and stirred at room temperature for 1H, pH was adjusted to 5-6 by adding 2N hydrochloric acid solution, and then using H 2 O (10 ml) was diluted, ethyl acetate (10 ml) was extracted, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by Prep-HPLC to give the title compound (1.5 mg, 5%).
MS(ESI,pos.ion)m/z:669.2[M+1] + 。
1 HNMR(DMSO-d 6 )δ:12.55-13.19(m,1H),9.15(br s,1H),9.05(br s,1H),8.66(br s,1H),8.34-8.46(m,1H),8.17(br d,J＝1.0Hz,1H),7.59(br d,J＝14.8Hz,1H),7.11-7.26(m,2H),7.06(br s,2H),6.83(br s,1H),4.03(br s,3H),3.99(br s,3H),2.23(br d,J＝4.1Hz,1H),0.34(br s,4H).
Example 3: synthesis of 2- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) thiazole-4-carboxylic acid (3)
4-chloro-N-cyclopropyl-7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (30 mg, 0.07) and 2-aminothiazole-4-carboxylic acid (20 mg,0.13 mmol) were added to NMP (2 ml), DIEA (0.05 ml) was added last, reacted at 130℃for 1 hour, pH was adjusted to 5-6 with 2N hydrochloric acid, diluted with water (10 ml) and extracted with ethyl acetate (10 ml. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product concentrated under reduced pressure was filtered, followed by purification by Prep-HPLC to give the title compound (7 mg, 19%).
MS(ESI,pos.ion)m/z:547.1[M+1] + 。
1 HNMR(DMSO-d6)δ:8.53(s,1H),7.67(s,1H),7.16(s,1H),7.08-7.13(m,2H),3.98(s,3H),3.95-3.97(m,3H),0.78(br d,J＝5.7Hz,2H),0.68-0.74(m,2H).
Example 4: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- ((4, 4-difluorocyclohexyl) oxy) benzoic acid (4)
Step 1: synthesis of methyl 3- ((4, 4-difluorocyclohexyl) oxy) -5-nitrobenzoate (4-2)
Methyl 3-hydroxy-5-nitrobenzoate (650 mg,3.30 mmol), 4-difluorocyclohexyl-1-ol (450 mg,3.31 mmol) and PPh were reacted under nitrogen 3 (1.04 g,3.97 mmol) was added to anhydrous THF (20 mL), cooled to 0deg.C, DIAD (800 mg,3.96 mmol) was added dropwise, reacted at 0deg.C for 1h after the addition was completed, and then reacted at room temperature for 16h. After the reaction was completed, water (20 mL) and ethyl acetate (20 mL) were added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (40 mL), the organic phases were combined and then washed with saturated NaCl solution (60 mL), anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, separating the crude product by column chromatography (PE/EtOAc (v/v) =10/1),obtained as a white solid (700 mg, 67%).
Step 2: synthesis of methyl 3-amino-5- ((4, 4-difluorocyclohexyl) oxy) benzoate (4-3)
Methyl 3- ((4, 4-difluorocyclohexyl) oxy) -5-nitrobenzoate (700 mg,2.22 mmol) and Pd/C (70 mg) were added to MeOH (10 mL) and reacted at room temperature under a hydrogen atmosphere for 16h. After the reaction was complete, the filter cake was filtered and washed with MeOH (20 mL) and concentrated under reduced pressure to give the crude product as a white solid (550 mg, 86%).
MS(ESI,pos.ion)m/z:286.1[M+1] +
Step 3: synthesis of 3-amino-5- ((4, 4-difluorocyclohexyl) oxy) benzoic acid (4-4)
7-bromo-4-chloro-5-fluoroquinoline-3-carboxylic acid ethyl ester (215 mg,0.75 mmol) was added to MeOH (4 mL), and a solution of sodium hydroxide (40 mg,3.00 mmol) in water (1 mL) was added dropwise at room temperature and reacted at 45℃for 1.5h. After the completion of the reaction, hydrochloric acid (2N) was added dropwise to adjust the pH to about 6, water (20 mL) and ethyl acetate (20 mL) were added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (20 mL), the organic phases were combined and then washed with a saturated NaCl solution (30 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave the crude product as a white solid (200 mg, 98%).
MS(ESI,pos.ion)m/z:272.1[M+1] +
Step 4: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- ((4, 4-difluorocyclohexyl) oxy) benzoic acid (4)
3-amino-5- ((4, 4-difluorocyclohexyl) oxy) benzoic acid (14 mg,0.05 mmol) and 4-chloro-N-cyclopropyl-7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (20 mg,0.05 mmol) were added to acetic acid (2 mL) and reacted at room temperature for 16h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was separated by Pre-HPLC to give the title compound (10 mg, 29%).
MS(ESI,pos.ion)m/z:674.2[M+1]+。
1 H NMR(DMSO-d 6 )δ:9.04(s,1H),8.63(s,1H),8.50-8.57(m,1H),8.14(d,J＝1.6Hz,1H),7.55(dd,J＝13.4,1.4Hz,1H),7.11-7.16(m,1H),7.05(s,1H),6.75(t,J＝2.0Hz,1H),4.50(br s,1H),3.99(s,3H),3.96(s,3H),2.21(td,J＝6.5,3.8Hz,1H),1.65-1.97(m,8H),0.35-0.43(m,4H).
Example 5: synthesis of (1 r,4 r) -4- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) bicyclo [2.2.1] heptane-1-carboxylic acid (5)
Step 1: synthesis of methyl 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (5-3)
4-chloro-N-cyclopropyl-7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (10 mg,0.02 mmol) methyl (1 r,4 r) -4-aminobicyclo [2.2.1]Ethyl heptane-1-carboxylate (4 mg,0.02 mmol) and DIEA (6 mg,0.05 mmol) were added to NMP (2 mL). Microwave heating to 130 deg.C for reaction for 1 hr, adding H 2 O (20 mL) was diluted, extracted with EA (20 mL. Times.3), and washed with saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (DCM/MeOH (v/v) =30/1) to give a yellow solid (8 mg, 61%).
MS(ESI,pos.ion)m/z:572.3[M+1] + 。
Step 2: synthesis of (1 r,4 r) -4- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) bicyclo [2.2.1] heptane-1-carboxylic acid (5)
3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid methyl ester (30 mg,0.05 mmol) was dissolved in MeOH (2 mL), THF (2 mL) and H 2 To a mixture of O (2 mL), naOH (6 mg,0.16 mmol) was added and the mixture was stirred at 45℃for 2 hours. Concentrating under reduced pressure to remove methanol and tetrahydrofuran, adding H 2 O (5 mL) was adjusted to pH 5 with 1N HCl and filtered to give the crude product, which was purified using Prep-HPLC to give the title compound (9 mg, 29%).
MS(ESI,pos.ion)m/z:558.1[M+1] + 。
1 HNMR(DMSO-d 6 )δ:12.21(br s,1H),8.87(s,1H),8.67(s,1H),8.54(s,1H),8.00(s,1H),7.63(br d,J＝13.3Hz,1H),6.95(br s,1H),4.02(s,3H),3.98(s,3H),2.27(br d,J＝2.0Hz,1H),1.79-1.96(m,6H),1.65-1.74(m,2H),1.62(br d,J＝12.0Hz,2H),0.49-0.59(m,2H),0.41(br s,2H).
Example 6: synthesis of (1S, 3R) -3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) cyclohexane-1-carboxylic acid (6)
4-chloro-N-cyclopropyl-7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (10 mg,0.02 mmol), (1S, 3R) -3-aminocyclohexane-1-carboxylic acid (3 mg,0.02 mmol) and DIEA (6 mg,0.05 mmol) were added to NMP (2 mL). Microwave heating to 130 deg.C for reaction for 1 hr, adding H 2 O (10 mL) was diluted, extracted with EA (10 mL. Times.3), and washed with saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was purified by HPLC to give the title compound (2 mg, 16%).
MS(ESI,pos.ion)m/z:546.3[M+1] + 。
1 HNMR(DMSO-d 6 )δ:12.10(br s,1H),8.79(s,1H),8.65(s,1H),8.52(d,J＝1.5Hz,1H),8.00(d,J＝1.5Hz,1H),7.67(dd,J＝14.1,1.4Hz,1H),6.58(br s,1H),4.02(s,3H),3.99(s,3H),2.24-2.35(m,2H),2.03(br d,J＝11.5Hz,1H),1.92(br d,J＝3.3Hz,1H),1.74-1.86(m,2H),1.43(br d,J＝12.8Hz,1H),1.31(br t,J＝10.5Hz,2H),1.13-1.27(m,2H),0.49-0.56(m,2H),0.34-0.46(m,2H).
Example 7: synthesis of 3- ((7- (2-carbamoyl-4-cyanophenyl) -3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (7)
Step 1: synthesis of 4- (4, 5-tetramethyl-1, 3, 2-dioxaboronate-2-yl) isophthalonitrile (7-2)
Pd (dppf) Cl under the protection of nitrogen 2 (98 mg,0.12 mmol) was added to 4-bromoisophthalonitrile (500 mg,2.42 mmol), B 2 Pin 2 (6755 mg,2.66 mmol) and KOAc (719 mg,7.26 mmol) in dioxane (15 mL). Stir at 100 ℃ overnight. The reaction solution was cooled to room temperature, and H was used 2 O (50 mL) was diluted and EtOAc extracted (20 mL. Times.3). The combined organic phases were washed with saturated aqueous NaCl, anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give a white solid (150 mg, 24%).
Step 2: synthesis of 2- (4-chloro-3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-7-yl) -5-cyanobenzamide (7-4)
7-bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (30 mg,0.08 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaboronate-2-yl) isophthalonitrile (22 mg,0.09 mmol), K 2 CO 3 (33 mg,0.24 mmol) and Pd (PPh) 3 ) 4 (9 mg,0.01 mmol) was added dioxane (4 mL) and H 2 O (1 mL). Stirring is carried out for 1h at 80 ℃ under nitrogen atmosphere. The reaction solution was cooled to room temperature, and H was used 2 O (10 mL) was diluted and EtOAc extracted (10 mL. Times.3). The combined organic phases were washed with saturated aqueous NaCl, anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was purified by Prep-TLC to give a yellow solid (15 mg, 43%).
MS(ESI,pos.ion)m/z:445.1[M+1] + 。
Step 3: synthesis of 3- ((7- (2-carbamoyl-4-cyanophenyl) -3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (7)
2- (4-chloro-3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-7-yl) -5-cyanobenzamide (15 mg,0.03 mmol) and 3-amino-5- (3, 5-difluorophenoxy) benzoic acid (9 mg,0.03 mmol) were added to AcOH (2 mL) and stirred at 50℃for 2h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and purified by preparative chromatography Prep-HPLC to give the title compound (3 mg, 17%).
MS(ESI,pos.ion)m/z:674.1[M+1] + 。
1 HNMR(DMSO-d 6 )δ:12.47-13.76(m,1H),9.10(s,1H),8.62(br s,1H),8.55(br s,1H),8.08(br s,1H),8.03-8.06(m,1H),8.02(s,1H),7.97(s,1H),7.70(d,J＝8.0Hz,1H),7.65(s,1H),7.33-7.42(m,2H),7.18(s,1H),6.92-7.02(m,1H),6.80(br s,1H),6.67(dd,J＝8.2,1.8Hz,2H),2.23(br d,J＝3.4Hz,1H),0.34-0.44(m,4H).
Example 8: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -5-fluoro-7- (4-oxo-4H-benzopyran-3-yl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (8)
Step 1: synthesis of 7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (8-2)
7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (3.00 g,8.8 mmol), DMF (0.07 mL,0.88 mmol) and POCl 3 (6 mL,66 mmol) was added to toluene (30 mL) and reacted at 100℃for 18h. The reaction solution was concentrated under reduced pressure, and saturated NaHCO was used 3 And (5) washing. EtOAc (60 mL) was added and extracted sequentially with H 2 O (30 mL. Times.2) and saturated NaCl solution (30 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure. The crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =20/1) to give a yellow oil (1.50 g,4.2mmol, 47%).
Step 2: synthesis of 7-bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (8-4)
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1.00 g,2.9 mmol), TEA (1.2 mL,8.8 mmol) and cyclopropylamine (0.41 mL,5.8 mmol) were added to DCM (40 mL) at zero and reacted at 18℃for 1h. DCM (20 mL) was added for extraction, followed by H 2 O (10 mL. Times.2) and saturated NaCl solution (10 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure. The crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =4/1) to give a white solid (120 mg,0.33mmol, 11%).
MS(ESI,pos.ion)m/z:379.0[M+1] +
Step 3: synthesis of 4-chloro-N-cyclopropyl-5-fluoro-7- (4-oxo-4H-benzopyran-3-yl) quinoline-3-sulfonamide (8-6)
At N 2 7-bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (80 mg,0.21 mmol), K under protection 2 CO 3 (58 mg,0.42 mmol), (4-oxo-4H-benzopyran-3-yl) boronic acid (80 mg,0.42 mmol) and Pd (dppf) Cl 2 (15 mg,0.02 mmol) dioxane (5 mL) and H were added 2 O (1 mL) was reacted at 50℃for 2h. EtOAc (20 mL) was added and extracted sequentially with H 2 O (10 mL. Times.2) and saturated NaCl solution (10 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure. The crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =2/1) to give a yellow solid (30 mg,0.07mmol, 32%).
MS(ESI,pos.ion)m/z:445.0[M+1] +
Step 4: synthesis of 3-amino-5- (3, 5-difluorophenoxy) benzoic acid (8-8)
Methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (1 g,3.6 mmol) and LiOH. H 2 O (18 mL,18 mmol) was added MeOH (10 mL) and H 2 O (2 mL) was reacted at 25℃for 2h. The reaction was adjusted to ph=6 with 1N HCl solution, extracted with EtOAc (30 mL) and sequentially with H 2 O (50 mL. Times.2) and saturated NaCl solution (50 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure. The crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =2/1) to give a white solid (120 mg,0.45mmol, 13%).
MS(ESI,pos.ion)m/z:266.0[M+1] +
Step 5: synthesis of 4-chloro-N-cyclopropyl-5-fluoro-7- (4-oxo-4H-benzopyran-3-yl) quinoline-3-sulfonamide (8)
4-chloro-N-cyclopropyl-5-fluoro-7- (4-oxo-4H-benzopyran-3-yl) quinoline-3-sulfonamide (70 mg,0.16 mmol) and 3-amino-5- (3, 5-difluorophenoxy) benzoic acid (83 mg,0.31 mmol) were addedAcOH (5 mL) was reacted at 50℃for 1h. Concentrating under reduced pressure, and separating the crude product by high performance liquid chromatography (0.01 mol/LNH 4 HCO 3 : meCN (v/v) =31% -100%), the title compound (20 mg,0.03mmol, 19%), HPLC: 96.0%).
MS(ESI,pos.ion)m/z:674.1[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.08(s,1H),8.90(s,1H),8.60(s,1H),8.31(s,1H),8.21(dd,J＝8.0,1.5Hz,1H),7.92–7.86(m,1H),7.77(d,J＝8.3Hz,1H),7.64(d,J＝13.6Hz,1H),7.59(t,J＝7.5Hz,1H),7.34(s,1H),7.18(s,1H),6.98–6.90(m,1H),6.78(s,1H),6.67(dd,J＝8.4,2.1Hz,2H),2.27–2.19(m,1H),0.43–0.32(m,4H).
Example 9: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) benzoic acid (9)
Step 1: synthesis of 5- (((3-bromo-5-fluorophenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (9-2)
3-bromo-5-fluoroaniline (2.00 g,10.53 mmol) and 5- (methoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (2.16 g,11.58 mmol) were added to dioxane (20 mL). The reaction was carried out at room temperature for 2 hours. PE (20 mL) was added and filtered to give a yellow solid (3.28 g, 90%).
MS(ESI,neg.ion)m/z:343.8[M-1] + 。
Step 2: synthesis of 7-bromo-5-fluoroquinolin-4-ol (9-3)
5- (((3-bromo-5-fluorophenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (3.28 g,9.53 mmol) was added to diphenyl ether (20 mL). The reaction was carried out at 260℃for 30min. PE (20 mL) was added after cooling to room temperature and filtered to give a grey solid (2.12 g, 92%).
MS(ESI,pos.ion)m/z:243.8[M+1] + 。
Step 3: synthesis of 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (9-4)
7-bromo-5-fluoroquinolin-4-ol (1.00 g,4.13 mmol) was added to ClSO 3 H (10 mL). The reaction was carried out at 100℃for 16h. Cooled to room temperature and added dropwise to ice water, filtered and dried to give a grey solid (1.12 g, 80%).
MS(ESI,pos.ion)m/z:341.7[M+1] + 。
Step 4: synthesis of 7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (9-5)
7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (50 mg,0.15 mmol) was added to POCl 3 (1 mL), DMF (0.1 mL) and PhMe (4 mL) at 100deg.C for 5h. Concentrated under reduced pressure to give a crude product as a yellow oily liquid (50 mg, crude).
Step 5: synthesis of 7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide (9-6)
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (300 mg,0.84 mmol) and TEA (254 mg,2.51 mmol) were added to dry DCM (10 mL). Cyclopropylamine (48 mg,0.84 mmol) was added at 0deg.C and stirred at 0deg.C for 1 hour. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, and purifying the crude product by column chromatographySpectral separation (PE/EtOAc (v/v) =5/1) gave a yellow solid (120 mg, 38%).
MS(ESI,pos.ion)m/z:381.0[M+1] + 。
Step 6: synthesis of 4-chloro-N- (cyclopropylmethyl) -7- (2, 4-dimethoxypyrimidin-5-yl) quinoline-3-sulfonamide (9-7)
7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide (120 mg,0.32 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (58 mg,0.32 mmol) and K 2 CO 3 (109 mg,0.79 mmol) was added to a mixture of dioxane (8 mL) and water (2 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (37 mg,0.03 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 1h. Adding H 2 O (20 mL) was diluted, extracted with EA (20 mL. Times.3), and washed with saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give a yellow solid (44 mg, 32%).
MS(ESI,pos.ion)m/z:439.1[M+1] + 。
Step 7: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) benzoic acid (9)
4-chloro-N- (cyclopropylmethyl) -7- (2, 4-dimethoxypyrimidin-5-yl) quinoline-3-sulfonamide (40 mg,0.09 mmol), 3-aminobenzoic acid (13 mg,0.09 mmol) was added to AcOH (5 mL). Stir at room temperature overnight. Concentrated under reduced pressure, and the crude product was purified by HPLC to give the title compound (8 mg, 17%).
MS(ESI,pos.ion)m/z:540.1[M+1] + 。
1 HNMR(DMSO-d 6 )δ:9.04(s,1H),8.64(s,1H),8.52(s,1H),8.26(s,1H),8.13(d,J＝1.7Hz,1H),7.58(d,J＝7.6Hz,1H),7.51(dd,J＝13.5,1.8Hz,1H),7.45(t,J＝1.9Hz,1H),7.29(t,J＝7.8Hz,1H),7.04(dd,J＝7.8,2.5Hz,1H),4.00(s,3H),3.97(s,3H),2.21(dt,J＝6.5,3.1Hz,1H),0.39(ddd,J＝12.4,5.0,2.4Hz,4H).
Example 10: synthesis of 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N- (2, 2-trifluoroethyl) sulfonylamino) quinolin-4-yl) benzoic acid (10)
Step 1: synthesis of 7-bromo-5-fluoro-4-hydroxy-N- (2, 2-trifluoroethyl) quinoline-3-sulfonamide
7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (3.20 g,9.4 mmol) was dissolved in tetrahydrofuran (30.0 mL) under ice bath, and then trifluoroethylamine (3.66 mL,26.4 mmol) and methylammonium chloride (3.91 mL,28.2 mmol) were slowly added thereto, and the reaction was stirred at 37℃for 2 hours. After the completion of the reaction of the raw materials, 100-200 mesh silica gel (5.00 g) was added to the reaction solution, and the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by medium pressure liquid phase separation (methanol: methylene chloride=0% -8%) to obtain 7-bromo-5-fluoro-4-hydroxy-N- (2, 2-trifluoroethyl) quinoline-3-sulfonamide (1.58 g, 42%).
MS(ESI,pos.ion)m/z:[M+H]＝403.2
Step 2: synthesis of 4, 7-dichloro-5-fluoro-N- (2, 2-trifluoroethyl) quinoline-3-sulfonamide
7-bromo-5-fluoro-4-hydroxy-N- (2, 2-trifluoroethyl) quinoline-3-sulfonamide (1.58 g,3.92 mmol) was added in portions to phosphorus oxychloride (15.0 mL) at 37℃and the reaction solution was stirred at 100℃for 3 hours. After the reaction of the starting materials was completed, phosphorus oxychloride was removed from the solution by concentration under reduced pressure, and the resulting crude product was separated by medium pressure liquid phase (ethyl acetate: petroleum ether=0% -60%) to give 4, 7-dichloro-5-fluoro-N- (2, 2-trifluoroethyl) quinoline-3-sulfonamide (260 mg, 18.5%).
MS(ESI,pos.ion)m/z:[M+H]＝377.1
Step 3: synthesis of 3- ((7-chloro-5-fluoro-3- (N- (2, 2-trifluoroethyl) carbamoyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
4, 7-dichloro-5-fluoro-N- (2, 2-trifluoroethyl) quinoline-3-sulfonamide (100 mg,0.26 mmol) was dissolved in acetic acid (3.00 mL) at 37℃and 3-amino-5- [ (3, 5-difluorophenyl) oxy ] benzoic acid (105 mg,0.4 mmol) was further added thereto, and the reaction was stirred at room temperature for 18 hours. After the completion of the reaction of the starting materials, the solvent was removed by distillation under the reduced pressure to give 3- ((7-chloro-5-fluoro-3- (N- (2, 2-trifluoroethyl) carbamoyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (200 mg, 94%) as a crude product.
MS(ESI,pos.ion)m/z:[M+H]＝605.9
Step 4: synthesis of 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N- (2, 2-trifluoroethyl) amino) quinolin-4-yl) benzoic acid
3- ((7-chloro-5-fluoro-3- (N- (2, 2-trifluoroethyl) carbamoyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (200 mg,0.34 mmol) was dissolved in 1, 4-dioxane (2.00 mL) and water (0.40 mL) at 37℃followed by the addition of 1, 1-bis (diphenylphosphine) ferrocene palladium dichloride (24.1 mg,0.03 mmol) and potassium carbonate (228 mg,1.65 mmol), the solution was deoxygenated with a nitrogen balloon for 20 seconds, heated to 100℃by a microwave reactor and after the completion of the reaction of the starting materials, the reaction solution was filtered through celite, and the solvent was removed from the resulting filtrate by distillation under reduced pressure, and the resulting crude product was prepared by high pressure chromatography to give compound 10 (65.5 mg, 28%).
MS(ESI,pos.ion)m/z:[M+H]＝709.6
1 H NMR(400MHz,DMSO-d 6 )δ9.05(s,1H),8.64(s,1H),8.11(s,1H),7.56(d,J＝13.7Hz,1H),7.38(s,1H),7.16(s,1H),6.91(t,J＝9.3Hz,1H),6.64–6.63(m 3H),4.00(s,3H),3.98(s,3H)3.85–3.77(m,2H).
Example 11: synthesis of 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3-aminosulfonylquinolin-4-yl) amino) benzoic acid (11)
Step 1: synthesis of 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonamide
7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (4.00 g,11.75 mmol) was dissolved in tetrahydrofuran (80.0 mL) under ice bath, and then aqueous ammonia (7.24 mL,46.98 mmol) was slowly added to the solution, and the reaction was stirred at 37℃for 2 hours. After the raw materials are reacted completely, the reaction liquid is directly concentrated to obtain a crude product, and silica gel is added for sample mixing. Normal phase column chromatography (MeOH: dcm=0% -8%) afforded compound 11-2 (1.05 g, 27.84%).
MS(ESI,pos.ion)m/z:[M+H]＝320.8
Step 2: synthesis of 7-bromo-4-chloro-5-fluoroquinoline-3-sulfonamide
7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonamide (500 mg,1.56 mmol) was added in portions to phosphorus oxychloride (10.0 mL) at 37℃and the reaction stirred at 100℃for 18 hours. After the reaction of the starting materials was completed, phosphorus oxychloride was removed from the solution by concentration under reduced pressure, and the crude product obtained was separated by medium pressure liquid phase (EA: pe=0% -60%) to obtain a brown liquid (200 mg, 37.83%).
MS(ESI,pos.ion)m/z:[M+H]＝338.9
Step 3: synthesis of 4-chloro-7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonamide (50 mg,0.15 mmol) was added to 1, 4-dioxane (2.0 ml) and water (0.2 ml) at 37℃and potassium carbonate (61 mg,0.44 mmol), 2, 4-dimethoxypyrimidine-5-boronic acid (32 mg,0.18 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium (II) dichloride (22 mg,0.03 mmol) were added and reacted at 100℃for 1h. The reaction mixture was added with 5ml of water, the product was extracted with ethyl acetate (3 ml x 3), the organic phase was washed with saturated brine and the compound 11-4 (50 mg, 42.58%) was obtained by medium pressure liquid phase separation (EA: pe=0% -60%).
MS(ESI,pos.ion)m/z:[M+H]＝399.0
Step 4: synthesis of 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3-aminosulfonylquinolin-4-yl) amino) benzoic acid
4-chloro-7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (50 mg,0.13 mmol) and 3-amino-5- (3, 5-difluorophenoxy) benzoic acid (33 mg,0.13 mmol) were added to acetic acid (2.0 ml) at 37℃and reacted at 55℃for 16 hours. The reaction solution was concentrated directly, and 1ml of methanol was added for dissolution, and the obtained crude product was separated by medium pressure liquid phase (EA: pe=0% -60%) to obtain compound 11 (2.00 mg, 67%).
MS(ESI,pos.ion)m/z:[M+H]＝627.7
1HNMR(400MHz,DMSO)δ；9.13(s,1H),8.65(s,1H),8.55(s,1H),8.14(d,J＝7.6Hz,1H),7.92(s,1H),7.60(d,J＝13.6Hz,1H),7.57(s,1H),7.28(s,1H),7.14(t,J＝9.3Hz,1H),6.96(s,1H),6.94(s,1H),6.91(s,1H),6.68(dd,J＝8.4,2.0Hz,4H),4.00(d,J＝8.8Hz,6H)
Example 12: synthesis of 3- (3, 5-difluorophenoxy) -5- ((7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-isopropylsulfonylamino) quinolin-4-yl) amino) benzoic acid (12)
Step 1: synthesis of 7-bromo-5-fluoro-4-hydroxy-N-isopropylquinoline-3-sulfonamide
7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (5.00 g,14.7 mmol) was dissolved in tetrahydrofuran (50.0 mL) under ice bath, and triethylamine (10.2 mL,73.4 mmol) and isopropyl amine (5.0 mL,58.3 mmol) were slowly added thereto, and the reaction was stirred at 37℃for 2 hours. After the completion of the reaction of the raw materials, 100-200 mesh silica gel (5.00 g) was added to the reaction solution, and the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by medium pressure liquid phase separation (methanol: methylene chloride=0% -8%) to give compound 12-2 (3.20 g, 60%).
MS(ESI,pos.ion)m/z:[M+H]＝362.8
Step 2: synthesis of 7-bromo-4-chloro-5-fluoro-N-isopropylquinoline-3-sulfonamide
7-bromo-5-fluoro-4-hydroxy-N-isopropylquinoline-3-sulfonamide (1.50 g,4.12 mmol) was added in portions to phosphorus oxychloride (15.0 mL) at 37℃and the reaction stirred at 100℃for 18 hours. After the reaction of the starting materials was completed, phosphorus oxychloride was removed from the solution by concentration under reduced pressure, and the resulting crude product was separated by medium pressure liquid phase (EA: pe=0% -60%) to give 7-bromo-4-chloro-5-fluoro-N-isopropylquinoline-3-sulfonamide (220 mg, 13.9%) as a brown liquid.
MS(ESI,pos.ion)m/z:[M+H]＝382.8
Step 3: synthesis of 3- ((7-bromo-5-fluoro-3- (N-isopropylsulfamoyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
7-bromo-4-chloro-5-fluoro-N-isopropylquinoline-3-sulfonamide (220 mg,0.58 mmol) was dissolved in acetic acid (2.00 mL) at 37℃and 3-amino-5- [ (3, 5-difluorophenyl) oxy ] benzoic acid (153 mg,0.58 mmol) was added thereto, and the reaction was stirred at room temperature for 18 hours. After the completion of the reaction of the starting materials, the solvent was removed by distillation under the reduced pressure to give a crude product 3- ((7-bromo-5-fluoro-3- (N-isopropylaminosulfonyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (400 mg).
[MS(ESI,pos.ion)m/z:[M+H]＝610.0
Step 4: synthesis of 3- (3, 5-difluorophenoxy) -5- ((7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-isopropylsulfonylamino) quinolin-4-yl) amino) benzoic acid
3- ((7-bromo-5-fluoro-3- (N-isopropylsulfamoyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (400 mg,0.66 mmol), (2, 4-dimethoxypyrimidin-5-yl) boric acid (144 mg,0.79 mmol) was dissolved in 1, 4-dioxane (2.00 mL) and water (0.40 mL) at 37℃in a 5mL microwave tube, after which 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (48 mg,0.07 mmol) and potassium carbonate (271mg, 1.97 mmol) were added, the solution was deoxygenated with nitrogen balloon and reacted by a microwave reactor to 100℃for 30 min, after the reaction of the starting materials was completed, the reaction solution was filtered through celite, the solvent was removed by distillation under reduced pressure, and the resulting crude product was prepared by high pressure chromatography to give the title compound 12 (40.0 mg, 9.12%).
MS(ESI,pos.ion)m/z:[M+H]＝670.0
1 HNMR(400MHz,DMSO)δ9.09(s,1H),8.65(s,1H),8.52(s,1H),8.22(d,J＝7.5Hz,1H),8.14(s,1H),7.58(d,J＝13.7Hz,1H),7.38(s,1H),7.19(s,1H),6.93(t,J＝9.3Hz,1H),6.73(s,1H),6.66(dd,J＝8.3,2.0Hz,2H),4.00(d,J＝8.8Hz,6H),2.52(s,1H),0.91(d,J＝6.5Hz,6H).
Example 13: synthesis of 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-methylaminosulfonyl) quinolin-4-yl) amino) benzoic acid (13)
Step 1: synthesis of 5- ((3-bromo-5-fluorophenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione
3-bromo-5-fluoroaniline (10.0 g,52.6 mmol) was dissolved in 1, 4-dioxane (50 mL) at 37℃after which 5- (methoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (10.0 g,53.7 mmol) was added portionwise to the reaction mixture, this mixed solution was stirred at 37℃for 2 hours, a large amount of solids was observed to precipitate in the reaction mixture, after the completion of the reaction of the starting materials, petroleum ether (50 mL) was added to the reaction mixture and stirred for 5 minutes, after which the reaction mixture was filtered, the cake was washed twice with petroleum ether (20.0 mL), and the solid was freed from residual solvent by concentration under reduced pressure to give 5- ((3-bromo-5-fluorophenyl) amino) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (14.5 g, 80%).
MS(ESI,pos.ion)m/z:[M+H]＝344.1
Step 2: synthesis of 7-bromo-5-fluoroquinolin-4-ol
Diphenyl ether (20.0 mL) was placed in a 100mL single-port flask, the solution was heated to 200 ℃, 5- ((3-bromo-5-fluorophenyl) amino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (5.0 g,14.5 mmol) was added in portions to the solution and stirred at 200 ℃ for 30 minutes. The reaction solution was then cooled to room temperature, petroleum ether (20 mL) was added and stirred for 10 minutes, and filtered. The filter cake was washed twice with petroleum ether (10 mL) and the solid was concentrated under reduced pressure to remove residual solvent to give 7-bromo-5-fluoroquinolin-4-ol (2.5 g, 71%).
MS(ESI,pos.ion)m/z:[M+H]＝242.0
Step 3: synthesis of 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride
7-bromo-5-fluoroquinolin-4-ol (2.5 g,10.3 mmol) was added in portions to chlorosulfonic acid (20 mL) and the solution was stirred at 100deg.C for 16 hours. After the reaction of the starting materials was completed, the reaction solution was slowly and gradually added dropwise to ice water, a large amount of pale yellow solid was observed to precipitate in the water, the solid was filtered off by suction filtration, dissolved in acetonitrile (50.0 mL), and the solvent and the residual water were removed by distillation under reduced pressure to give 7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (4.6 g,13.5mmol, 98%).
MS(ESI,pos.ion)m/z:[M+H]＝340.5
Step 4: synthesis of 7-bromo-5-fluoro-4-hydroxy-N-methylquinoline-3-sulfonamide
7-bromo-5-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (3.0 g,8.8 mmol) was dissolved in tetrahydrofuran (15.0 mL) under ice-bath, and triethylamine (3.66 mL,26.4 mmol) and methylammonium chloride (3.66 mL,26.4 mmol) were slowly added thereto, and the reaction was stirred at 37℃for 2 hours. After the completion of the reaction of the raw materials, 100-200 mesh silica gel (5.0 g) was added to the reaction solution, and the solvent was removed by distillation under reduced pressure, and the obtained crude product was purified by medium pressure liquid phase separation (methanol: methylene chloride=10%) to obtain crude 7-bromo-5-fluoro-4-hydroxy-N-methylquinoline-3-sulfonamide (3.4 g, 98%).
MS(ESI,pos.ion)m/z:[M+H]＝335.1
Step 5: synthesis of 4, 7-dichloro-5-fluoro-N-methylquinoline-3-sulfonamide
7-bromo-5-fluoro-4-hydroxy-N-methylquinoline-3-sulfonamide (3.4 g,10.1 mmol) was added in portions to phosphorus oxychloride (25.0 mL) at 37℃and the reaction stirred at 100℃for 3 hours. After the reaction of the starting materials was completed, phosphorus oxychloride was removed from the solution by concentration under reduced pressure, and the resulting crude product was separated by medium pressure liquid phase (ethyl acetate: petroleum ether=0% -60%) to give 4, 7-dichloro-5-fluoro-N-methylquinoline-3-sulfonamide (200 mg, 6.4%).
MS(ESI,pos.ion)m/z:[M+H]＝309.4
Step 6: synthesis of 3- ((7-chloro-5-fluoro-3- (N-methylaminosulfonyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
4, 7-dichloro-5-fluoro-N-methylquinoline-3-sulfonamide (100 mg,0.32 mmol) was dissolved in acetic acid (2.00 mL) at 37℃and 3-amino-5- [ (3, 5-difluorophenyl) oxy ] benzoic acid (86 mg,0.32 mmol) was added thereto, and the reaction was stirred at room temperature for 18 hours. After the reaction of the starting materials was completed, the solvent was removed by distillation under reduced pressure, and the resulting crude product was purified by thick preparative silica gel plate (dichloromethane: methanol=10:1) to give 3- ((7-chloro-5-fluoro-3- (N-methylaminosulfonyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (100 mg, 57%).
MS(ESI,pos.ion)m/z:[M+H]＝573.9
Step 7: synthesis of 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-methylaminosulfonyl) quinolin-4-yl) amino) benzoic acid
3- ((7-chloro-5-fluoro-3- (N-methylaminosulfonyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (50 mg,0.09 mmol) dissolved in 1, 4-dioxane (1.00 mL) and water (0.20 mL) were added to a 5mL microwave tube, followed by 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride (13 mg,0.02 mmol), potassium carbonate (38 mg,0.28 mmol), the solution was deoxygenated with a nitrogen balloon for 20 seconds, heated to 100℃by a microwave reactor for 30 minutes, after the reaction of the starting materials was completed, the resulting filtrate was filtered through celite, the solvent was removed by distillation under reduced pressure, and the resulting crude product was prepared by high pressure chromatography to give 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-methylaminosulfonyl) quinolin-4-yl) amino) benzoic acid (25 mg, 42%).
MS(ESI,pos.ion)m/z:[M+H]＝641.6
1 H NMR(400MHz,DMSO-d 6 )δ9.02(s,1H),8.63(s,1H),8.12(s,1H),7.55(s,1H),7.35(s,1H),7.15(s,1H),6.90(t,J＝9.3Hz,1H),6.72–6.61(m,3H),4.00(s,6H),3.99(s,3H),2.68(s,3H).
Example 14: synthesis of 3- ((3- (N-cyclobutylsulfamoyl) -7- (2, 4-dimethoxyphenyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (14)
Step 1: synthesis of 7-bromo-4-chloro-N- (cyclobutyl) -5-fluoroquinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (500 mg,1.39 mmol) and TEA (423 mg,4.18 mmol) were added to dry DCM (10 mL). Cyclobutylamine (89 mg,1.25 mmol) was added at 0deg.C and stirred at 0deg.C for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed on column chromatography (PE/EtOAc (v/v) =5/1) to give compound 14-6 (33 mg, 6%).
MS(ESI,pos.ion)m/z:392.9[M+1] + 。
Step 2: synthesis of methyl 3- ((3- (N-cyclobutylsulfamoyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
7-bromo-4-chloro-N- (cyclobutyl) -5-fluoroquinoline-3-sulfonamide (33 mg,0.084 mmol), methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (28 mg,0.1 mmol) was added to AcOH (3 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 14-7 (42 mg, 79%).
MS(ESI,pos.ion)m/z:636.2[M+1] + 。
Step 3: synthesis of methyl 3- ((3- (N-cyclobutylsulfamoyl) -7- (2, 4-dimethoxyphenyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
Methyl 3- ((3- (N-Cyclobutylaminosulfonyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (42 mg,0.066 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (18 mg,0.099 mmol) and K 2 CO 3 (32 mg,0.226 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (7 mg, 0.006mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure to give compound 14-8 (60 mg)Crude product).
MS(ESI,pos.ion)m/z:696.2[M+1] + 。
Step 4: synthesis of 3- ((3- (N-cyclobutylsulfamoyl) -7- (2, 4-dimethoxyphenyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
Methyl 3- ((3- (N-cyclobutylsulfamoyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (60 mg, crude) and lithium hydroxide (35.9 mg,0.9 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at room temperature for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give Compound 14 (9.5 mg).
MS(ESI,pos.ion)m/z:682.1[M+1] + 。
1H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),8.65(s,1H),8.61-8.51(m,2H),8.14(s,1H),7.59(br d,J＝13.8Hz,1H),7.38(s,1H),7.19(s,1H),6.99-6.88(m,1H),6.72-6.62(m,3H),4.00(d,J＝9.3Hz,6H),3.76-3.63(m,1H),1.83(br d,J＝6.8Hz,2H),1.68(br t,J＝9.8Hz,2H),1.51-1.34(m,2H)。
Example 15: synthesis of 3- ((3- (N-cyclopropylmethylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (15)
Step 1: synthesis of 7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g,1.39 mmol) and TEA (846 mg,8.36 mmol) were added to dry DCM (10 mL). Cyclopropylmethylamine (160 mg,2.252 mmol) was added at 0deg.C and stirred at 0deg.C for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 15-6 (79 mg, 5%).
MS(ESI,pos.ion)m/z:392.9[M+1] + 。
Step 2: synthesis of methyl 3- ((3- (N-cyclopropylmethylaminosulfonyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide (79 mg,0.201 mmol), methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (67 mg,0.24 mmol) was added to AcOH (3 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 15-7 (51 mg, 40%).
MS(ESI,pos.ion)m/z:636.0[M+1] + 。
Step 3: synthesis of methyl 3- ((3- (N-cyclopropylmethylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
Methyl 3- ((3- (N-cyclopropylmethylaminosulfonyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (51 mg,0.08 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (22 mg,0.12 mmol) and K 2 CO 3 (32 mg,0.226 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (9 mg,0.008 mmol) and then replaced with nitrogen and the reaction stirred at 100deg.C for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to give compound 15-8 (90 mg, crude product).
MS(ESI,pos.ion)m/z:695.8[M+1] + 。
Step 4: synthesis of 3- ((3- (N-cyclopropylmethylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
Methyl 3- ((3- (N-cyclopropylmethylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (90 mg, crude) and lithium hydroxide (35.9 mg,0.9 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at room temperature for 16h. Concentrated under reduced pressure, diluted with H2O (3 mL), adjusted to pH 5-6 with 1M HCl, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product purified by HPLC to give compound 15 (10.5 mg, 51%).
MS(ESI,pos.ion)m/z:682.1[M+1] + 。
1H NMR(400MHz,DMSO-d6)δ:9.08(br s,1H),8.64(s,1H),8.53(br s,1H),8.30(br s,1H),8.13(br s,1H),7.57(br d,J＝12.7Hz,1H),7.34(s,1H),7.16(s,1H),6.92(br t,J＝9.4Hz,1H),6.77-6.56(m,3H),3.99(d,J＝8.1Hz,6H),2.73(br d,J＝6.8Hz,2H),0.71(br s,1H),0.33-0.17(m,2H),-0.04(br d,J＝4.6Hz,2H)。
Example 16: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxyphenyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (16)
Step 1: synthesis of methyl 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxyphenyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
Methyl 3- ((3- (N-cyclopropylaminosulfonyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (38 mg,0.061 mmol), 2, 4-dimethoxyphenylboronic acid (17 mg,0.093 mmol) and K 2 CO 3 (32 mg,0.226 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (7 mg, 0.006mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to give compound 16-8 (100 mg, crude product).
MS(ESI,pos.ion)m/z:680.3[M+1] + 。
Step 2: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxyphenyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
Will 3- ((3- (N-Ring)Propyl aminosulfonyl) -7- (2, 4-dimethoxyphenyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid methyl ester (100 mg, crude) and lithium hydroxide (35.9 mg,0.9 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at 30℃for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give Compound 16 (3.6 mg).
MS(ESI,pos.ion)m/z:666.1[M+1] + 。
1 HNMR(400MHz,DMSO-d6)δ：9.05(s,1H),8.58(s,1H),8.49(br s,1H),8.00(s,1H),7.44(br d,J＝8.7Hz,2H),7.35(s,1H),7.16(s,1H),6.93(br t,J＝9.2Hz,1H),6.79(s,1H),6.75-6.61(m,4H),3.83(d,J＝9.3Hz,6H),2.21(br s,1H),0.48-0.29(m,4H)。
Example 17: synthesis of 3- (3-cyclopropylaminosulfonyl) -5-fluoro-7-phenylquinolin-4-amino) -5- (3, 5-difluorophenoxy) benzoic acid (17)
Step 1: synthesis of 4-chloro-N-cyclopropyl-5-fluoro-7-phenylquinoline-3-sulfonamide
7-bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (50 mg,0.132 mmol), tetrakis triphenylphosphine palladium (15 mg,0.01 mmol), potassium carbonate (37 mg,0.26 mmol) and phenylboronic acid (16 mg,0.13 mmol) were dissolved in a mixed solution of dioxane/water (4:1, 2 mL) and stirred at 80℃for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, water (10 mL) and ethyl acetate (10 mL) were added to extract a fraction, and the organic phase was washed with a saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by preparative silica gel plate (PE/ea=1/1) to give compound 17-2 (17 mg, 32%).
MS(ESI,pos.ion)m/z:377.1[M+1] + 。
Step 2 Synthesis of 3- (3-cyclopropylaminosulfonyl) -5-fluoro-7-phenylquinolin-4-amino) -5- (3, 5-difluorophenoxy) benzoic acid
4-chloro-N-cyclopropyl-5-fluoro-7-phenylquinoline-3-sulfonamide (10 mg,0.02 mmol) and 3-amino-5- (3, 5-difluorophenoxy) benzoic acid (12 mg,0.04 mmol) were dissolved in acetic acid (2 mL) and stirred at 37℃for 12 hours. After completion of the reaction, concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 3- (3-cyclopropylsulfonylamino) -5-fluoro-7-phenylquinolin-4-amino) -5- (3, 5-difluorophenoxy) benzoic acid (6 mg, 22%).
MS(ESI,pos.ion)m/z:606.1[M+1] + 。
1 HNMR(DMSO-d 6 )δ:9.04(s,1H),8.53-8.66(m,1H),8.24(s,1H),8.17(s,1H),7.89(d,J＝7.4Hz,2H),7.65(br d,J＝13.6Hz,1H),7.51-7.59(m,2H),7.43-7.50(m,1H),7.35(s,1H),7.19(s,1H),6.86-6.96(m,1H),6.72(br s,1H),6.58-6.66(m,2H),2.19-2.26(m,1H),0.32-0.45(m,4H).
Example 18: synthesis of 3- (7- (2, 4-bis (2, 2-difluoroethoxy) pyrimidin-5-yl) -3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (18)
Step 1: synthesis of 7- (2, 4-bis (2, 2-difluoroethoxy) pyrimidin-5-yl) -4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide
At N 2 7-bromo-4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (100 mg,0.26 mmol), potassium carbonate (73 mg,0.53 mmol), (2, 4-bis (2, 2-difluoroethoxy) pyrimidin-5-yl) boronic acid (75 mg,0.26 mmol) and 1, 1-bis (diphenylphosphine) ferrocene palladium dichloride (19 mg,0.03 mmol) were added to dioxane (10 mL) and water (2 mL) and reacted at 50℃for 1 hour. Ethyl acetate (10 mL) was added thereto for extraction, followed by washing with water (20 ml×2) and saturated sodium chloride solution (20 mL), drying over anhydrous sodium sulfate, and concentrating under reduced pressure. The crude product was chromatographed by column chromatography (petroleum ether/ethyl acetate (v/v) =2/1) to give compound 18-2 (40 mg, 28%).
MS(ESI,pos.ion)m/z:539.0[M+1] +
Step 2: synthesis of 3- (7- (2, 4-bis (2, 2-difluoroethoxy) pyrimidin-5-yl) -3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
7- (2, 4-bis (2, 2-difluoroethoxy) pyrimidin-5-yl) -4-chloro-N-cyclopropyl-5-fluoroquinoline-3-sulfonamide (40 mg,0.074 mmol) and 3-amino-5- (3, 5-difluorophenoxy) benzoic acid (39 mg,0.15 mmol) were added to acetic acid (5 mL) and reacted at 18℃for 18 hours. Concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography (0.01 mol/L formic acid: acetonitrile (v/v) =0% -90%), to give compound 18 (1.6 mg, 2.8%).
MS(ESI,pos.ion)m/z:768.1[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.03(s,1H),8.78(s,1H),8.67(s,1H),8.16(s,1H),7.57(d,J＝14.1Hz,1H),7.30(s,1H),7.15(s,1H),6.89(t,J＝9.3Hz,1H),6.61(d,J＝6.0Hz,5H),4.84–4.67(m,4H),2.21–2.20(m,1H),0.41–0.40(m,4H).
Example 19: synthesis of 3- ((3- (N- (tetrahydrofuran-3-yl) sulfamoyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (19)
Step 1: synthesis of 7-bromo-4-chloro-5-fluoro-N- (tetrahydrofuran-3-yl) quinoline-3-sulfonamide
To dried DCM (10 mL) was added 7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g,1.39 mmol) and TEA (846 mg,8.36 mmol), 3-aminotetrahydrofuran (194 mg,2.23 mmol) was added at 0deg.C and stirred at 0deg.C for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed on column chromatography (PE/EtOAc (v/v) =5/1) to give compound 19-6 (52 mg, 4%).
MS(ESI,pos.ion)m/z:408.8[M+1] + 。
Step 2: synthesis of methyl 3- ((3- (N- (tetrahydrofuran-3-yl) sulfamoyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
7-bromo-4-chloro-5-fluoro-N- (tetrahydrofuran-3-yl) quinoline-3-sulfonamide (52 mg,0.127 mmol), methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (42.7 mg,0.153 mmol) was added to AcOH (3 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 19-7 (30 mg, 36%).
MS(ESI,pos.ion)m/z:651.7[M+1] + 。
Step 3: synthesis of methyl 3- ((3- (N- (tetrahydrofuran-3-yl) sulfamoyl) -7- (2, 4-dimethoxy pyrimidin-5-yl) -5-fluoro-quinolin-4-yl) amino) -5- (3, 5-difluoro-phenoxy) benzoate
Methyl 3- ((3- (N- (tetrahydrofuran-3-yl) sulfamoyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (30 mg,0.046 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (12.7 mg,0.069 mmol) and K 2 CO 3 (32 mg,0.226 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (5 mg,0.04 mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave a brown oil (50 mg, crude).
MS(ESI,pos.ion)m/z:712.3[M+1] + 。
Step 4: synthesis of 3- ((3- (N- (tetrahydrofuran-3-yl) sulfamoyl) -7- (2, 4-dimethoxy pyrimidin-5-yl) -5-fluoro quinolin-4-yl) amino) -5- (3, 5-difluoro-phenoxy) benzoic acid
Methyl 3- ((3- (N- (tetrahydrofuran-3-yl) sulfamoyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (50 mg, crude) and lithium hydroxide (28.6 mg,1.2 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at 30℃for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, the pH was adjusted to 5-6 by addition of an appropriate amount of 1M HCl, and the mixture was quenched with EA (3 mL. Times.3)) Extraction, concentration under reduced pressure, and purification of the crude product by HPLC gave compound 19 (1.88 mg).
MS(ESI,pos.ion)m/z:698.1[M+1] + 。
1H NMR(400MHz,DMSO-d6)δ:9.09(s,1H),8.64(s,1H),8.60-8.45(m,2H),8.14(s,1H),7.58(br d,J＝14.2Hz,1H),7.37(s,1H),7.17(s,1H),6.93(br t,J＝9.4Hz,1H),6.75(br s,1H),6.65(dd,J＝2.0,8.4Hz,2H),3.99(d,J＝7.9Hz,6H),3.81(br s,1H),3.62(q,J＝7.5Hz,1H),3.57-3.48(m,2H),1.83(br dd,J＝7.0,13.3Hz,1H),1.54(br s,1H)。
Example 20: synthesis of N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (methanesulfonamide) phenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (20)
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Step 1: synthesis of 1-bromo-3- (3, 5-difluorophenoxy) -5-nitrobenzene
3, 5-Difluorobenzeneboronic acid (6.9 g,43.70 mmol) and 3-bromo-5-nitrophenol (10.00 g,45.88 mmol), cu (OAc) 2 (8.33 g,45.88 mmol), DMAP (6.67 g,54.62 mmol), and molecular sieves 4A (6.9 g,43.7 mmol) were added to dichloromethane (250 mL). The reaction was carried out at 30℃under oxygen for 16h. Sequentially with H 2 O (100 mL. Times.2) and saturated NaCl solution (200 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 20-2 (5.7 g, 39.52%).
1 H NMR (400 MHz, deuterated chloroform) δ=8.18 (t, j=1.8 hz, 1H), 7.80 (t, j=2.1 hz, 1H), 7.55-7.48 (m, 1H), 6.71 (tt, j=2.3, 8.8hz, 1H), 6.65-6.54 (m, 2H)
Step 2: synthesis of 1- (3, 5-difluorophenoxy) -3-iodo-5-nitrobenzene
1-bromo-3- (3, 5-difluorophenoxy) -5-nitrobenzene (2.0 g,6.06 mmol) and CuI (115.40 g,605.91 mmol) ) NaI (2.72 g,18.18 mmol), 1, 10-phenanthroline (172.37 g,1.21 mmol), cs 2 CO 3 (3.95 g,12.12 mmol) was added to dioxane (50 mL). The reaction was carried out at 100℃for 16h. PE (20 mL) was added after cooling to room temperature and filtered to give compound 20-3 (1.5 g, 65.65%).
1 H NMR (400 MHz, deuterated chloroform) δ=8.36 (t, j=1.7 hz, 1H), 7.83 (t, j=2.1 hz, 1H), 7.70 (dd, j=1.5, 2.2hz, 1H), 6.73-6.69 (m, 1H), 6.60-6.57 (m, 2H)
Step 3: synthesis of 1- (3, 5-difluorophenoxy) -3- (methylsulfonyl) -5-nitrobenzene
1- (3, 5-difluorophenoxy) -3-iodo-5-nitrobenzene (0.7 g,1.86 mmol) and MeSO 2 - Na + (379.02 mg,3.71 mmol), L-proline (42.74 mg,371.27 mmol), cuI (35.35 mg,185.64 mmol), K 2 CO 3 (51.31 mg,371.27 mmol) was added to DMSO (20 mL). The reaction was carried out at 80℃for 16h. Add EtOAc (20 mL) to dilute and use H in sequence 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =4/1) to give compound 20-4 (120 mg, 19.63%).
Step 4: synthesis of 1- (3, 5-difluorophenoxy) -3- (methylsulfonyl) -5-aminobenzene
1- (3, 5-difluorophenoxy) -3- (methylsulfonyl) -5-nitrobenzene (100 mg,303.70 mmol), fe (84.80 mg,1.52 mmol), NH 4 Cl (243.68 mg,4.56 mmol), etOH (1 mL), THF (1 mL) and H are added 2 O (0.5 mL) was reacted at 90℃for 2h. Add EtOAc (4 mL) to dilute and use H in sequence 2 O (2 mL. Times.2) and saturated NaCl solution (10 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 20-5 (51 mg, 56.11%).
Step 5: synthesis of 7-bromo-N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (methylsulfonyl) phenyl) amino) -5-fluoro-quinoline-3-sulfonamide
7-bromo-4-chloro-N-cyclopropyl-5-fluoro-quinoline-3-sulfonamide (65 mg,171.22 mmol) and 1- (3, 5-difluorophenoxy) -3- (methylsulfonyl) -5-aminobenzene (51.24 mg,171.22 mmol) were added to dry AcOH (2 mL). Stirring for 1h at 80 ℃. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 20-6 (52.7 mg, 47.91%).
MS(ESI,pos.ion)m/z:643.6[M+1] + 。
Step 6: synthesis of N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (methylsulfonyl) phenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide
7-bromo-N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (methylsulfonyl) phenyl) amino) -5-fluoro-quinoline-3-sulfonamide (52.7 mg,82.03 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (18.11 mg,98.43 mmol) and K 2 CO 3 (124.71 mg,902.31 mmol) was added to a mixture of dioxane (5 mL) and water (1 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (9.48 mg,8.20 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 3h. Adding H 2 O (5 mL) was diluted, extracted with EA (5 mL. Times.3), and washed with saturated NaCl solution (5 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 20 (167 mg, crude).
MS(ESI,pos.ion)m/z:702.69[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝9.10(s,1H),8.76(br s,1H),8.65(s,1H),8.51(br s,1H),8.17(s,1H),7.62(br d,J＝13.6Hz,1H),7.37(s,1H),7.19(s,1H),6.97(br t,J＝9.4Hz,1H),6.84-6.67(m,2H),6.84-6.66(m,1H),3.99(d,J＝8.0Hz,6H),3.21(s,3H),2.23(br s,1H),0.36(br d,J＝8.5Hz,4H)
Example 21: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) -N-hydroxybenzoamide (21)
Step 1: synthesis of methyl 3- ((7-bromo-3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
7-bromo-4-chloro-N-cyclopropyl-5-fluoro-quinoline-3-sulfonamide (630 mg,1.66 mmol) and methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (552 mg,1.99 mmol) were added to acetic acid (5 mL). The reaction was carried out at 80℃for 1h. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 21-2 (430 mg, 42%).
Step 2: synthesis of 3- ((7-bromo-3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
Methyl 3- ((7-bromo-3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (100 mg,160 mmol) and lithium hydroxide (18 mg,480 mmol) were added to methanol (1 mL) and water (0.2 mL), and to methanol (2 mL). The reaction was carried out at 37℃for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 3-4, extracted with EA (2 mL. Times.3), concentrated under reduced pressure, cooled to room temperature, and PE (20 mL) was added to filter to give compound 21-3 (80 mg, crude).
Step 3: synthesis of 3- ((7-bromo-3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) -N- ((tetrahydrofuran-2H-pyran-2-yl) oxy) benzamide
3- ((7-bromo-3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (80 mg,131.5 mmol) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (15.4 mg,131.5 mmol), 1-propylphosphoric acid cyclic anhydride (62.76 mg,197.24 mmol), TEA (26.61 mg,262.99 mmol) were added to dioxane (2 mL). The reaction was carried out at 50℃for 16h. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 21-4 (61 mg, 66%).
MS(ESI,pos.ion)m/z:708.5[M+1] + 。
1 H NMR (400 MHz, deuterated chloroform) δ=8.55 (t, j=1.6 hz, 1H), 8.10 (t, j=2.1 hz, 1H), 7.91 (dd, j=1.5, 2.3hz, 1H), 6.78 (tt, j=2.3, 8.8hz, 1H), 6.69-6.57 (m, 2H), 3.16 (s, 3H)
Step 4: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (difluorophenoxy) -N- ((tetrahydrofuran-2H-pyran-2-yl) oxy) benzamide
3- ((7-bromo-3- (N-cyclopropylaminosulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) -N- ((tetrahydrofuran-2H-pyran-2-yl) oxy) benzamide (61 mg,86.22 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (19 mg,103.46 mmol) and K 2 CO 3 (138.21 mg,1 mmol) was added to a mixture of dioxane (5 mL) and water (1 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (9.96 mg,8.62 mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 5h. Adding H 2 O (5 mL) was diluted, extracted with EA (5 mL. Times.3), and washed with saturated NaCl solution (5 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave a brown oil (126 mg, crude).
MS(ESI,pos.ion)m/z:767.7[M+1] + 。
Step 5: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) -N-hydroxybenzoamide
3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (difluorophenoxy) -N- ((tetrahydrofuran-2H-pyran-2-yl) oxy) benzamide (126 mg, crude) and TFA (770 mg,6.75 mmol) were added to dry DCM (2 mL). Concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 21 (19.66 mg, 17.5%).
MS(ESI,pos.ion)m/z:683.6[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝11.49-10.98(m,1H),9.05(br s,2H),8.64(s,2H),8.13(s,1H),7.56(br d,J＝13.6Hz,1H),7.22(s,1H),7.10(s,1H),6.94(br t,J＝9.3Hz,1H),6.75(s,1H),6.66(dd,J＝2.1,8.4Hz,2H),4.00(s,3H),3.98(s,2H),3.99-3.97(m,1H),2.22(quin,J＝5.1Hz,1H),0.37(br s,4H)
Example 22: synthesis of 3- ((3- (N-cyclobutylsulfamoyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (22)
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Step 1: synthesis of 7-bromo-4-chloro-N- (cyclobutyl) quinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (500 mg,1.39 mmol) and TEA (423 mg,4.18 mmol) were added to dry DCM (10 mL). Cyclobutylamine (89 mg,1.25 mmol) was added at 0deg.C and stirred at 0deg.C for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 22-2 (33 mg, 6%).
MS(ESI,pos.ion)m/z:392.9[M+1] + 。
1 H NMR (400 MHz deuterated chloroform) δ:9.42-9.35 (m, 1H), 8.21 (t, j=1.5 hz, 1H), 7.54 (dd, j=1.9, 11.4hz, 1H), 3.87 (sxt, j=8.4 hz, 1H), 2.14-2.02 (m, 2H), 1.95-1.77 (m, 2H), 1.69-1.57 (m, 2H).
Step 2: synthesis of methyl 3- ((3- (N-cyclobutylsulfamoyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
7-bromo-4-chloro-N- (cyclobutyl) quinoline-3-sulfonamide (33 mg,0.084 mmol), methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (28 mg,0.1 mmol) was added to AcOH (3 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 22-3 (42 mg, 79%).
MS(ESI,pos.ion)m/z:636.2[M+1] + 。
Step 3: synthesis of methyl 3- ((3- (N-cyclobutylsulfamoyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
Methyl 3- ((3- (N-Cyclobutylaminosulfonyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (42 mg,0.066 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (18 mg,0.099 mmol) and K 2 CO 3 (32mg,0.226mmol) Into a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (7 mg, 0.006mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure gave compound 22-4 (60 mg, crude).
MS(ESI,pos.ion)m/z:696.2[M+1] + 。
Step 4: synthesis of 3- ((3- (N-cyclobutylsulfamoyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
Methyl 3- ((3- (N-cyclobutylsulfamoyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (60 mg, crude) and lithium hydroxide (35.9 mg,0.9 mmol) were added to methanol (4 mL) and water (0.5 mL) and stirred at room temperature for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 22 (9.5 mg, 7%).
MS(ESI,pos.ion)m/z:682.1[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),8.65(s,1H),8.61-8.51(m,2H),8.14(s,1H),7.59(br d,J＝13.8Hz,1H),7.38(s,1H),7.19(s,1H),6.99-6.88(m,1H),6.72-6.62(m,3H),4.00(d,J＝9.3Hz,6H),3.76-3.63(m,1H),1.83(br d,J＝6.8Hz,2H),1.68(br t,J＝9.8Hz,2H),1.51-1.34(m,2H)。
Example 23: synthesis of N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (2, 2-trifluoro-1-hydroxyethyl) phenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (23)
Step 1: synthesis of methyl 3- (3, 5-difluorophenoxy) -5-nitrobenzoate
3-methoxycarbonyl-5-nitrobenzoic acid (5.00 g,22.23 mmol) and 3, 5-difluorophenol (3.04 g,23.34 mmol), cu (OAc) (4.24 g,23.34 mmol), 4A MS (5.00 g,22.23 mmol) and DMAP (3.39 g,27.78 mmol) were added to dichloromethane (200 mL), replaced with three oxygen portions and reacted at 30℃for 16h under oxygen. Filtering with celite, adding aqueous solution (100 mL) to the filtrate, quenching, washing sequentially with EtOAc (100 mL x 2) and saturated NaCl solution (100 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 23-2 (3.27 g, 47.58%).
MS(ESI,neg.ion)m/z:312.2[M+1] + 。
1H NMR (400 MHz, deuterated chloroform) δ=8.68-8.63 (m, 1H), 8.06 (t, j=2.2 hz, 1H), 8.01 (dd, j=1.3, 2.3hz, 1H), 6.70 (dt, j=2.1, 4.4hz, 1H), 6.62-6.56 (m, 2H), 3.99 (s, 3H)
Step 2: synthesis of (3- (3, 5-difluorophenoxy) -5-nitrobenzyl alcohol
Methyl 3- (3, 5-difluorophenoxy) -5-nitrobenzoate (2.00 g,6.47 mmol) was added to tetrahydrofuran (20 mL), liBH4 (281.79 mg,12.94 mmol) was added at 0deg.C and the reaction was continued for 2h at 37deg.C. Quench with saturated NH4Cl solution (100 mL), wash sequentially with EtOAc (100 mL x 2) and saturated NaCl solution (100 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed on column chromatography (PE/EtOAc (v/v) =5/1) to give compound 23-3 (570 mg, 31.34%).
MS(ESI,neg.ion)m/z:345.8[M+1] + 。
1 H NMR (400 MHz, deuterated chloroform) δ:11.18 (br d, j=13.4 hz, 1H), 8.56 (d, j=13.9 hz, 1H), 7.23 (s, 1H), 7.15 (td, j=1.8, 7.8hz, 1H), 6.94 (td, j=2.0, 9.2hz, 1H), 1.76 (s, 6H).
Step 3: synthesis of (3- (3, 5-difluorophenoxy) -5-nitrobenzaldehyde
(3- (3, 5-difluorophenoxy) -5-nitrobenzyl alcohol (570 mg,2.03 mmol) and Dess-Martin (1.29 g,3.04 mmol) were added to dichloromethane (10 mL) and reacted at 30 ℃16h. Quenched with aqueous (10 mL), washed sequentially with EtOAc (10 mL x 2) and saturated NaCl solution (10 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 23-4 (387 mg, 68.38%).
MS(ESI,neg.ion)m/z:282.2[M+1] + 。
1H NMR (400 MHz, deuterated chloroform) delta=10.13-10.03 (m, 1H), 8.51 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.85 (s, 1H), 6.73-6.71 (m, 1H), 6.80-6.68 (m, 1H), 4.04-3.93 (m, 1H)
Step 4: synthesis of 1- (3, 5-difluorophenoxy) -5-nitrophenyl) -2, 2-trifluoroethanol
(3- (3, 5-difluorophenoxy) -5-nitrobenzaldehyde (387 mg,1.39 mmol) and TMSCF 3 (256.23 mg,1.8 mmol) CsF (210.56 mg,1.39 mmol), TBAF (36.24 mg,138.61 mmol) was added to THF (3 mL). The reaction was carried out at 30℃for 2h. Quenched with aqueous (10 mL), washed sequentially with EtOAc (10 mL x 2) and saturated NaCl solution (10 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 23-5 (280 mg, 57.85%).
MS(ESI,pos.ion)m/z:350.2[M+1] + 。
1H NMR (400 MHz, deuterated chloroform) δ=8.24-8.15 (m, 1H), 7.90 (br d, j=1.9 hz, 1H), 7.56 (s, 1H), 6.75-6.64 (m, 1H), 6.59 (br dd, j=1.8, 7.6hz, 2H), 5.18 (br d, j=2.6 hz, 1H)
Step 5: synthesis of 1- (3, 5-difluorophenoxy) -5-aminophenyl) -2, 2-trifluoroethanol
1- (3, 5-difluorophenoxy) -5-nitrophenyl) -2, 2-trifluoroethanol (175 mg,501.13 mmol) and Fe (139.93 mg,2.51 mmol), NH4Cl (402.09 mg,7.52 mmol) were added to EtOH (2 ml) and THF (2 ml), H 2 O (1 ml) was reacted at 90℃for 2 hours. Quenched with aqueous (10 mL), washed sequentially with EtOAc (10 mL x 2) and saturated NaCl solution (10 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 23-6 (120 mg, 75.01%).
MS(ESI,pos.ion)m/z:350.2[M+1] + 。
1H NMR (400 MHz, deuterated chloroform) δ=8.24-8.15 (m, 1H), 7.90 (br d, j=1.9 hz, 1H), 7.56 (s, 1H), 6.75-6.64 (m, 1H), 6.59 (br dd, j=1.8, 7.6hz, 2H), 5.18 (br d, j=2.6 hz, 1H)
Step 6: synthesis of 7-bromo-N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (2, 2-trifluoroethyl-1-hydroxyethyl) phenyl) amino) -5-fluoroquinoline-3-sulfonamide
1- (3, 5-difluorophenoxy) -5-aminophenyl) -2, 2-trifluoroethanol (72.32 mg,226.54 mmol) and 7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide (86 mg,226.54 mmol) were added to acetic acid (2 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 23-7 (49 mg, 32.65%).
MS(ESI,pos.ion)m/z:663.4[M+1] + 。
Step 7: synthesis of N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (2, 2-trifluoro-1-hydroxyethyl) phenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide
7-bromo-N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (2, 2-trifluoroethyl-1-hydroxyethyl) phenyl) amino) -5-fluoroquinoline-3-sulfonamide (49 mg,73.97 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (16.33 mg,88.77 mmol) and K 2 CO 3 (112.46 mg,813.71 mmol) was added to a mixture of dioxane (5 mL) and water (1 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (8.55 mg,7.4 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 16h. Adding H 2 O (5 mL) was diluted, extracted with EA (5 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 23 (15.81 mg).
MS(ESI,pos.ion)m/z:722.6[M+1] + 。
1H NMR(400MHz,DMSO-d6)δ＝9.03(s,1H),8.66-8.53(m,3H),8.14-8.10(m,1H),7.52(br d,J＝14.3Hz,1H),6.95-6.86(m,4H),6.72-6.60(m,3H),5.12(br t,J＝6.8Hz,1H),3.99(d,J＝6.0Hz,6H),2.17(br d,J＝3.8Hz,1H),0.41-0.33(m,4H)
Example 24: synthesis of N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (3-hydroxyisoxazol-5-yl) phenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (24)
Step 1: synthesis of ethyl 3- (3, 5-difluorophenoxy) -5-nitrophenyl) propiolate
1- (3, 5-difluorophenoxy) -3-iodo-5-nitrobenzene (1.00 g,2.65 mmol), ethyl propiolate (260.16 mg,2.65 mmol), cuI (25.25 mg,132.60 mmol), pd (PPh) 3 ) 2 Cl 2 (93.07mg,132.60mmol),K 2 CO 3 (733.05 mg,5.30 mmol) was added to DCM (30 mL). The reaction was carried out at 37℃for 16h. Filtration, concentration of the filtrate under reduced pressure, and column chromatography of the crude product (PE/EtOAc (v/v) =3/1) gave compound 24-2 (760 mg, 82.6%).
1 H NMR (400 MHz, deuterated chloroform) δ=8.36 (t, j=1.6 hz, 1H), 8.24-8.15 (m, 2H), 7.94 (t, j=2.2 hz, 1H), 7.82 (td, j=2.1, 7.8hz, 1H), 7.70 (d, j=1.3 hz, 1H), 7.51 (d, j=1.4 hz, 2H), 6.78-6.66 (m, 2H), 6.65-6.54 (m, 5H), 4.33 (q, j=7.1 hz, 2H), 1.37 (t, j=7.1 hz, 3H)
Step 2: synthesis of ethyl 3- (3, 5-difluorophenoxy) -5-aminophenyl) propiolate
Ethyl 3- (3, 5-difluorophenoxy) -5-nitrophenyl) propiolate (726 mg,2.09 mmol), iron powder (583.75 mg,10.45 mmol), ammonium chloride (1.68 g,31.36 mmol) were added to a mixed solvent of ethanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL). The reaction was carried out at 90℃for 16h. Cooled to room temperature, diluted with water (3 mL), extracted with EtOAc (3 ml×3), washed with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure, and separating the crude product by column chromatography (PE/EtOAc (v/v) =1/1) to give compound 24-3 (200 mg, 30.15%)
Step 3: synthesis of ethyl 3- (3- ((7-bromo-3- (N-cyclopropylsulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) phenyl) propynoate
7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide (100 mg,263.41 mmol), ethyl 3- (3, 5-difluorophenoxy) -5-aminophenyl) propynoate (83.58 mg,263.41mmol,1 eq) was added to AcOH (4 mL). Stirred at 75℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 24-4 (62 mg, 35.64%).
MS(ESI,pos.ion)m/z:661.4[M+1] + 。
Step 4: synthesis of ethyl 3- (3- ((3- (N-cyclopropylsulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) phenyl) propiolate
Ethyl 3- (3- ((7-bromo-3- (N-cyclopropylsulfonyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) phenyl) propynoate (62 mg,93.87 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (25.90 mg,140.81 mmol), K 2 CO 3 (142.72 mg,1.03 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (10.85 mg,9.39 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 1h. Adding H 2 O (3 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure gave compound 24-5 (123 mg, crude).
MS(ESI,pos.ion)m/z:720.6[M+1] + 。
Step 5: synthesis of N-cyclopropyl-4- ((3- (3, 5-difluorophenoxy) -5- (3-hydroxyisoxazol-5-yl) phenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide
NaOH (68.36 mg,1.71 mmol) was added to H2O (0.5 mL) and hydroxylamine hydrochloride (35.63 mg,512.72 mmol) was added slowly in portions after 10 minutes, ethyl 3- (3- ((3- (N-cyclopropylsulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) phenyl) propynoate (123 mg, crude) was added to methanol (5 mL). The reaction was stirred at 30℃for 16h. Adding H 2 O (5 mL) was diluted, extracted with EA (5 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 24 (5.29 mg).
MS(ESI,pos.ion)m/z:707.6[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝11.48(s,1H),9.09-9.02(m,1H),8.70-8.49(m,3H),8.19-8.08(m,1H),7.67-7.54(m,1H),7.37(s,1H),7.22(s,1H),6.91(br d,J＝9.3Hz,2H),6.67-6.57(m,3H),4.02-3.97(m,6H),2.24(br s,1H),0.51-0.30(m,4H)
Example 25: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) -1H-tetrazol-5-ylbenzene (25)
Step 1: synthesis of 3- (3, 5-difluorophenoxy) -5-nitrobenzonitrile
3-hydroxy-5-nitro-benzonitrile (1.00 g,6.10 mmol), 3, 5-difluorophenylboronic acid (0.92 g,5.82 mmol), copper acetate (1.11 g,6.10 mmol), DMAP (0.89 g,7.30 mmol) and 4A MS (6.9 g) were added to DCM (30 mL). The reaction was carried out at 37℃for 16h. Filtration, concentration of the filtrate under reduced pressure, and column chromatography of the crude product (PE/EtOAc (v/v) =3/1) gave compound 25-2 (0.26 g, 16%).
MS(ESI,neg.ion)m/z:277.2[M-1] + 。
1 H NMR (400 MHz, deuterated chloroform) δ:8.32-8.25 (m, 1H), 8.06 (t, J=2.1 Hz, 1H), 7.59 (dd, J=1.3, 2.3Hz, 1H), 6.78 (tt, J=2.3, 8.8Hz, 1H), 6.68-6.57 (m, 2H)
Step 2: synthesis of 5- (3, 5-difluorophenoxy) -5-nitrophenyl) -1H-tetrazole
3- (3, 5-difluorophenoxy) -5-nitrobenzonitrile (150 mg,0.54 mmol), ammonium chloride (145 mg,2.71 mmol), naN 3 (160 mg,2.46 mmol) was added to DMF (5 mL). The reaction was carried out at 95℃for 16h. Cooling to room temperature, pouring H 2 Diluted in O (20 mL), extracted with EtOAc (10 mL. Times.3), washed with saturated NaCl solution (20 mL), and dried Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =1/1) to give compound 25-3 (270 mg, crude).
MS(ESI,pos.ion)m/z:319.9[M+1] + 。
Step 3: synthesis of 3- (3, 5-difluorophenoxy) -5- (1H-tetrazol-5-yl) aniline
5- (3, 5-difluorophenoxy) -5-nitrophenyl) -1H-tetrazole(270 mg, crude), iron powder (236 mg,4.21 mmol), ammonium chloride (678 mg,12.8 mmol) were added to a mixed solvent of ethanol (1 mL), tetrahydrofuran (1 mL) and water (0.5 mL). The reaction was carried out at 90℃for 2h. Cooled to room temperature, diluted with water (3 mL), extracted with EtOAc (3 ml×3), washed with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =1/1) to give compound 25-4 (390 mg, crude).
MS(ESI,pos.ion)m/z:632.1[M+1] + 。
Step 4: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) -1H-tetrazol-5-yl benzene
7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide (100 mg,0.265 mmol), 3- (1H-tetrazol-5-yl) -5- (3, 5-difluorophenoxy) aniline (76 mg,0.263 mmol) was added to AcOH (4 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 25-5 (79 mg, 47%).
MS(ESI,pos.ion)m/z:633.1[M+1] + 。
Step 5: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) -1H-tetrazol-5-ylbenzene
3- ((3- (N-cyclopropylaminosulfonyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) -1H-tetrazol-5-ylbenzene (79 mg,0.125 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (34 mg,0.187 mmol) and K 2 CO 3 (130 mg,0.94 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (14 mg,0.01 mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 5h. Adding H 2 O (3 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 25 (15.28 mg, 16.9%).
MS(ESI,pos.ion)m/z:692.2[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ：9.03(s,1H),8.63(s,1H),8.11(d,J＝1.5Hz,1H),7.60-7.18(m,6H),6.94-6.84(m,1H),6.66(dd,J＝2.1,8.5Hz,2H),6.46(t,J＝2.1Hz,1H),4.02-3.92(m,6H),0.47-0.29(m,4H)。
Example 26: synthesis of N-cyclopropyl-4- ((3- ((4, 4-difluorocyclohexyl) oxy) -5- (5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-ylphenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (26)
Step 1: synthesis of methyl 3- (4, 4-difluorocyclohexyloxy) -5-nitrobenzoate
Methyl 3-hydroxy-5-nitrobenzoate (1.00 g,5.07 mmol), 4-difluorocyclohexanol (690.56 g,5.07 mmol), triphenylphosphine (1.60 g,6.09 mmol), DIAD (1.23 g,6.09 mmol) were added to DCM (30 mL). The reaction was carried out at 37℃for 16h. Filtration, concentration of the filtrate under reduced pressure, and column chromatography of the crude product (PE/EtOAc (v/v) =10/1) gave a white solid (580 mg, 36.27%).
Step 2: synthesis of 3- (4, 4-difluorocyclohexyloxy) -5-nitrobenzoyl hydrazine
Methyl 3- (4, 4-difluorocyclohexyloxy) -5-nitrobenzoate (580 mg,1.84 mmol) and hydrazine hydrate (793 mg,12.67 mmol) were added to EtOH (20 mL). The reaction was carried out at 90℃for 5h. Cooled to room temperature, filtered, and the solid was collected to give crude compound 26-3 (580 mg, crude).
1 H NMR (400 MHz, deuterated chloroform) δ=8.12 (s, 1H), 7.90 (d, j=2.1 hz, 1H), 7.71 (s, 1H), 7.51 (br s, 1H), 4.68 (br s, 1H), 2.14-1.96 (m, 8H)
Step 3: synthesis of 5- (3- ((4, 4-difluorocyclohexyloxy) -5-nitrobenzene) -1,3, 4-oxadiazol-2 (3H) -one
3- (4, 4-Difluorocyclohexyloxy) -5-nitrobenzoyl hydrazine (580 mg,1.84 mmol), CDI (596.60 mg,3.68 mmol), triethylamine (558.47 mg,5.52 mmol) were added to a tetrahydrofuran (5 mL) solvent. The reaction was carried out at 60℃for 16h. Concentrated under reduced pressure, and the crude product was chromatographed on column (DCM/MeOH (v/v) =10/1) to give compound 26-4 (480 mg, 76.45%).
1 H NMR (400 MHz, deuterated chloroform) δ=8.32 (t, j=1.6 hz, 1H), 7.88 (t, j=2.1 hz, 1H), 7.68 (dd, j=1.4, 2.4hz, 1H), 4.68 (br d, j=2.5 hz, 1H), 2.15-1.96 (m, 8H)
Step 4: synthesis of 5- (3-amino-5- (((4, 4-difluorocyclohexyl) oxy)) phenyl) -1,3, 4-oxadiazol-2 (3H) -one
5- (3- ((4, 4-Difluorocyclohexyloxy) -5-nitrophenyl) -1,3, 4-oxadiazol-2 (3H) -one (100 mg,293.03 mmol), tin dichloride dihydrate (264.48 mg,1.17 mmol) was added to ethanol (2 mL) solvent and reacted at.70℃for 1H, cooled to room temperature, diluted with water (3 mL), extracted with EtOAc (3 mL. Times.3), washed with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed on column (DCM/MeOH (v/v) =10/1) to give compound 26-5 (120 mg, crude).
MS(ESI,pos.ion)m/z:312.2[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝6.64(s,1H),6.57(s,1H),6.39(t,J＝1.9Hz,1H),5.54(br s,1H),4.50(br d,J＝3.0Hz,1H),4.08-3.99(m,1H),2.03-1.85(m,8H)
Step 5: synthesis of 7-bromo-N-cyclopropyl-4- ((3- ((4, 4-difluorocyclohexyl) oxy) -5- (5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-ylphenyl) amino) -5-fluoroquinoline-3-sulfonamide
7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide (70 mg,184.39 mmol), 5- (3-amino-5- (((4, 4-difluorocyclohexyl) oxy) phenyl) -1,3, 4-oxadiazol-2 (3H) -one (57.4 mg,184.39 mmol) was added to AcOH (2 mL) and stirred at 80 ℃ for 1 hour.
MS(ESI,pos.ion)m/z:655.4[M+1] + 。
Step 6: synthesis of N-cyclopropyl-4- ((3- ((4, 4-difluorocyclohexyl) oxy) -5- (5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-ylphenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide
7-bromo-N-cyclopropyl-4- ((3- ((4, 4-difluorocyclohexyl) oxy) -5- (5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-ylphenyl) amino) -5-fluoroquinoline-3-sulfonamide (55.5 mg, 84)8 mmol), (2, 4-dimethoxypyrimidin-5-yl) boric acid (15.6 mg,84.8 mmol) and K 2 CO 3 (128.92 mg,932.84 mmol) was added to a mixture of dioxane (2 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (9.80 mg,8.48 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 1h. Adding H 2 O (3 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 26 (17.16 mg, 28.35%).
MS(ESI,pos.ion)m/z:714.6[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝12.84(br s,1H),9.07(s,1H),8.64(s,1H),8.57(br d,J＝7.8Hz,2H),8.17(s,1H),7.56(br d,J＝13.6Hz,1H),7.05(s,1H),6.92(s,1H),6.78(s,1H),4.52(br s,1H),3.98(d,J＝7.5Hz,6H),2.23(br s,1H),2.05-1.73(m,8H),0.43-0.38(m,4H),0.47-0.38(m,1H)
Example 27: synthesis of N-cyclopropyl-4- ((3- ((4, 4-difluorocyclohexyl) oxy) -5- (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) phenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide (27)
Step 1: synthesis of 3- (4, 4-difluorophenoxy) -5-nitrobenzonitrile
3-hydroxy-5-nitrobenzonitrile (1.00 g,6.09 mmol), 4-difluorocyclohexanol (829.52 g,6.09 mmol), triphenylphosphine (1.92 g,7.31 mmol), DIAD (1.48 g,7.31 mmol) were added to DCM (30 mL). The reaction was carried out at 37℃for 16h. Filtration, concentration of the filtrate under reduced pressure, and column chromatography of the crude product (PE/EtOAc (v/v) =10/1) gave compound 27-2 (900 mg, 52.33%).
Step 2: synthesis of (Z) -3- ((4, 4-difluorophenoxy) -N' -hydroxy-5-nitrobenzeneimine
3- (4, 4-difluorophenoxy) -5-nitrobenzonitrile (500 mg,1.77 mmol) and hydroxylamine in 50% water (1.17 g,17.72 mmol) were added to EtOH (10 mL). The reaction was carried out at 90℃for 3 hours. Cooled to room temperature, filtered, and the solid was collected to give crude compound 27-3 (600 mg, crude).
1 H NMR (400 MHz, deuterated chloroform) δ=8.08 (t, j=1.5 hz, 1H), 7.79 (t, j=2.1 hz, 1H), 7.58-7.49 (m, 1H), 4.64 (br d, j=2.8 hz, 1H), 2.30-1.89 (m, 8H)
Step 3: synthesis of 3- (3- ((4, 4-difluorophenoxy) -5-nitrophenyl) -1,2, 4-oxadiazol-5 (4H) -one
(Z) -3- ((4, 4-difluorophenoxy) -N' -hydroxy-5-nitrobenzoimine (500 mg,1.59 mmol), CDI (514.32 mg,3.17 mmol), triethylamine (481.44 mg,4.76 mmol) were added to tetrahydrofuran (5 mL) solvent and reacted at 60℃for 16h, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (DCM/MeOH (v/v) =10/1) to give compound 27-4 (440 mg, 81.40%).
1 H NMR (400 MHz, deuterated chloroform) δ=8.27 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 4.70 (br s, 1H), 2.19-1.95 (m, 8H)
Step 4: synthesis of 3- (3-amino-5- ((4, 4-difluorophenoxy) nitrophenyl) -1,2, 4-oxadiazol-5 (4H) -one
3- (3- ((4, 4-difluorophenoxy) -5-nitrophenyl) -1,2, 4-oxadiazol-5 (4H) -one (100 mg,293.03 mmol), tin dichloride dihydrate (264.48 mg,1.17 mmol) was added to ethanol (2 mL) solvent and reacted at.70℃for 1H, cooled to room temperature, diluted with water (3 mL), extracted with EtOAc (3 mL. Times.3), washed with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed on column (DCM/MeOH (v/v) =10/1) to give compound 27-5 (120 mg, crude).
MS(ESI,pos.ion)m/z:312.2[M+1] + 。
Step 5: synthesis of 7-bromo-N-cyclopropyl-4- ((3- ((4, 4-difluorophenoxy) -5- (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-2-ylphenyl) amino) -5-fluoroquinoline-3-sulfonamide
7-bromo-4-chloro-N- (cyclopropylmethyl) quinoline-3-sulfonamide (70 mg,184.39 mmol), 5- (3-amino-5- ((4, 4-difluorophenoxy) phenyl) -1,2, 4-oxadiazol-2 (3H) -one (57.4 mg,184.39 mmol) was added to AcOH (2 mL) and stirred at 75 ℃ for 1 hour.
MS(ESI,pos.ion)m/z:655.4[M+1] + 。
Step 6: synthesis of N-cyclopropyl-4- ((3- ((4, 4-difluorocyclohexyl) oxy) -5- (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) phenyl) amino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinoline-3-sulfonamide
7-bromo-N-cyclopropyl-4- ((3- ((4, 4-difluorophenoxy) -5- (5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-2-ylphenyl) amino) -5-fluoroquinoline-3-sulfonamide (27.7 mg,42.33 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (11.68 mg,63.49 mmol) and K 2 CO 3 (64.35 mg,465.58 mmol) was added to a mixture of dioxane (2 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (4.89 mg,4.23 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 5h. Adding H 2 O (3 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 27 (1.30 mg, 4.31%).
MS(ESI,pos.ion)m/z:714.6[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ＝9.06(s,1H),8.63(s,2H),8.28(s,1H),8.15(s,1H),7.56(br d,J＝13.8Hz,2H),6.96(br d,J＝8.0Hz,2H),6.62(s,1H),4.52(br s,1H),3.98(d,J＝7.5Hz,6H),2.24(br d,J＝3.5Hz,1H),1.92-1.65(m,8H),0.43-0.39(m,4H)
Example 28: synthesis of 3- ((3- (N-cyclopropylsulfonylamino) -7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (28)
Step 1: synthesis of 2, 3-dihydrofuran [3,2-c ] pyridine
4-Chlorofuran- [3,2-c ] pyridine (4.00 g,26.05 mmol) and wet palladium on carbon (500 mg,26.01 mmol) were added to a methanol solution (50 mL), replaced 3 times with nitrogen and hydrogen, respectively, and the mixture was reacted under hydrogen balloon (15 Psi) at room temperature for 2 hours. After the completion of the reaction, the mixture was filtered to give 28-2 (3 g, crude product).
MS(ESI,pos.ion)m/z:122.1[M+1] + 。
Step 2: synthesis of 7-bromo-2, 3-dihydrofuran [3,2] pyridine
2, 3-dihydrofuran [3,2-c ]]Pyridine (1.8 g,14.86 mmol) and NBS (3.44 g,19.32 mmol) were added separately to concentrated sulfuric acid (30 mL) in an ice salt bath (0deg.C). The reaction was carried out at 25℃for 16h. After the reaction, the reaction solution was added dropwise to 150mL of a 2M sodium hydroxide solution under ice salt bath conditions, and the pH of the reaction solution was adjusted to 8 to 9. Extracted with EA (50 mL. Times.3), washed with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed on column chromatography (PE/EtOAc (v/v) =1/3) to give compound 28-3 (1.3 g, 43.74%).
MS(ESI,neg.ion)m/z:201.9[M+1] +
Step 3: synthesis of (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) boronic acid
7-bromo-2, 3-dihydrofuran [3,2 ]]Pyridine (500 mg,2.5 mmol), bis (1S, 2S,3R, 5S) (+) -pinanediol diboron ester (1.16 g,3.25 mmol), potassium acetate (490.62 mg,5.00 mmol) and Pd (dppf) Cl 2 (182.90 mg,249.96 mmol) was added anhydrous to dioxane (8 mL), nitrogen was substituted 3 times, and the reaction mixture was reacted at 100℃for 16 hours. After completion of the reaction, the mixture was diluted with water (10 mL), extracted with EA (10 ml×3), washed with saturated NaCl solution (10 mL), and dried Na 2 SO 4 Dried, concentrated under reduced pressure by filtration, and the crude product was purified by HPLC to give compound 28-4 (120 mg, 29.10%).
MS(ESI,neg.ion)m/z:165.8[M+1] + 。
Step 4: synthesis of methyl 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 3-dihydrofuran [3,2-c ] pyridin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
Methyl 3- ((3- (N-cyclopropylaminosulfonyl) -7-bromo-5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (75 mg,0.120 mmol), 2, 3-dihydrofuran-pyridine borate (29.82 mg,0.181 mmol) and K 2 CO 3 (49.98 mg,0.362 mmol) and water (0) 5 mL) of the mixture, the air in the reaction system was replaced with nitrogen, and Pd (dppf) Cl was added under a nitrogen flow 2 (8.82 mg,0.12 mmol) and then replaced with nitrogen, the reaction was stirred at 100℃for 16h. Concentrating the reaction solution in vacuum to remove part of dioxane, adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to give compound 28-5 (150 mg, crude).
MS(ESI,pos.ion)m/z:663.1[M+1] + 。
Step 5: synthesis of 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 3-dihydrofuran [3,2-c ] pyridin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
Methyl 3- ((3- (N-cyclopropylaminosulfonyl) -7- (2, 3-dihydrofuran pyridin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (150 mg, crude) and lithium hydroxide (108.42 mg,4.53 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 30℃for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 28 (3.58 mg).
MS(ESI,pos.ion)m/z:649.1[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),8.71(s,1H),8.49-8.64(m,2H),8.40(s,1H),8.34(s,1H),7.74(br d,J＝13.30Hz,1H),7.37(s,1H),7.17(s,1H),6.86-6.95(m,1H),6.78(br s,1H),6.64(dd,J＝2.13,8.41Hz,2H),4.79(t,J＝8.91Hz,2H),3.50(br s,2H),2.22(br d,J＝4.02Hz,1H),0.33-0.40(m,4H)。
Example 29: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydro-2H-pyran-4-yl) sulfonylamino) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid (29)
Step 1: synthesis of methyl 3- ((7-bromo-3- (N-tetrahydro-2H-pyran-4-yl) -5-fluoroquinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate
7-bromo-4-chloro-5-fluoro-N- (tetrahydro-2H-pyran-4-yl) quinoline-3-sulfonamide (275 mg,649.07 mmol) and methyl 3-amino-5- ((tetrahydro-2H-pyran-4-etheryl) benzoate (195.72 mg,778.88 mmol) were added to AcOH (2 mL) and stirred for 1 hour at 80 ℃ concentrated under reduced pressure, and the crude product was isolated by column chromatography (PE/EtOAc (v/v) =2/1) to give compound 29-2 (260 mg, 62.74%).
MS(ESI,pos.ion)m/z:639.5[M+1] + 。
Step 2: synthesis of methyl 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (N-tetrahydro-2H-pyran-4-yl) sulfonyl) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate
Methyl 3- ((7-bromo-3- (N-tetrahydro-2H-pyran-4-yl) -5-fluoroquinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate (260 mg,407.2 mmol), 2, 3-dihydrofuran-pyridine boronate (260 mg,1.58 mmol) and K 2 CO 3 (224.58 mg,1.63 mmol) was added to a mixture of DMF (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (dppf) Cl was added under a nitrogen flow 2 (29.8 mg,40.72 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 1h. Concentrating the reaction solution in vacuum to remove part of dioxane, adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 29-3 (300 mg, crude).
MS(ESI,pos.ion)m/z:679.7[M+1] + 。
Step 3: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydro-2H-pyran-4-yl) sulfonylamino) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid
3- ((7- (2, 3-dihydrofuran [3, 2-c)]Methyl pyridin-7-yl) -5-fluoro-3- (N- (tetrahydro-2H-pyran-4-yl) sulfonylamino) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate (150 mg, crude) and lithium hydroxide (108.42 mg,4.53 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at room temperature for 16H. Concentrating under reduced pressure, adding H 2 Diluting with O (3 mL), adding appropriate amount ofThe pH was adjusted to 5-6 with 1M HCl, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to afford compound 29 (7.28 mg).
MS(ESI,pos.ion)m/z:665.7[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝9.10(s,1H),8.71(s,1H),8.49-8.33(m,4H),8.16(s,1H),7.72(br d,J＝13.8Hz,1H),7.12(s,1H),7.03(s,1H),6.72(s,1H),4.79(t,J＝8.9Hz,2H),4.53-4.41(m,1H),3.80-3.69(m,2H),3.63(br d,J＝11.5Hz,2H),3.06(br t,J＝10.7Hz,2H),1.84(br d,J＝11.3Hz,2H),1.55-1.45(m,4H),1.38-1.25(m,2H)
Example 30: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydro-2H-pyran-4-yl) sulfonylamino) quinolin-4-yl) amino) -N- (methylsulfonyl) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzamide (30)
Step 1: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydro-2H-pyran-4-yl) sulfonylamino) quinolin-4-yl) amino) -N- (methylsulfonyl) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzamide
3- ((7- (2, 3-dihydrofuran [3, 2-c)]Pyridin-7-yl) -5-fluoro-3- (N- (tetrahydro-2H-pyran-4-yl) sulfonylamino) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid (80 mg,120.36 mmol), methanesulfonamide (22.90 mg,240.71 mmol), EDCI (46.14 mg,240.71mmol,2 eq) and DMAP (14.70 mg,120.36 mmol) were added to DCM (5 mL). Stirred at 30℃for 2 hours. Concentrating under reduced pressure, and adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 30 (25.5 mg).
MS(ESI,pos.ion)m/z:742.8[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝9.11(s,1H),8.74(s,1H),8.51-8.31(m,4H),7.72(d,J＝15.1Hz,1H),7.23(s,1H),7.11(s,1H),6.69(s,1H),4.81(t,J＝8.9Hz,2H),4.50(td,J＝4.3,8.4Hz,1H),3.81-3.71(m,2H),3.64(br d,J＝11.5Hz,2H),3.41(br s,2H),3.33-3.21(m,6H),3.12-3.00(m,2H),1.86(br d,J＝12.0Hz,2H),1.51(br t,J＝12.3Hz,4H),1.38-1.25(m,2H).
Example 31: synthesis of 3- ((3- (N-cyclohexylsulfonylamino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid (31)
Step 1: synthesis of 7-bromo-4-chloro-N-cyclohexylamino-fluoroquinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (2 g,5.57 mmol) and TEA (2.82 mg,27.86 mmol) were added to dry DCM (30 mL). Cyclohexylamine (552.5 mg,5.57 mmol) was added at 0deg.C and stirred at 0deg.C for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 31-2 (73 mg, 3.11%).
MS(ESI,pos.ion)m/z:421.0[M+1] + 。
Step 2: synthesis of methyl (3- ((7-bromo-3-N-cyclohexylsulfamoyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
7-bromo-4-chloro-N- (cyclohexylamino) fluoroquinoline-3-sulfonamide (73 mg,0.173 mmol), methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (48.34 mg,0.173 mmol) was added to AcOH (3 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed on column (PE/EtOAc (v/v) =5/1) to give compound 31-3 (43.8 mg, 38%).
MS(ESI,pos.ion)m/z:664.0[M+1] + 。
Step 3: synthesis of methyl 3- ((3- (N-cyclohexylsulfonylamino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
(3- ((7-bromo-3-N-cyclohexylsulfamoyl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy)) Methyl benzoate (43.8 mg,0.066 mmol), (2, 4-dimethoxypyrimidin-5-yl) boric acid (18.19 mg,0.099 mmol) and K 2 CO 3 (32 mg,0.226 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (7.62 mg, 0.006mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure gave compound 31-4 (70 mg, crude).
MS(ESI,pos.ion)m/z:724.3[M+1] + 。
Step 4: synthesis of 3- ((3- (N-cyclohexylsulfonylamino) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoic acid
Methyl 3- ((3- (N-Cyclohexylsulfamoyl) -7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoroquinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (70 mg, crude) and lithium hydroxide (35.9 mg,0.9 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at 30℃for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give Compound 31 (9.37 mg).
MS(ESI,pos.ion)m/z:710.3[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ：9.09(s,1H),8.65(s,1H),8.54(s,1H),8.23(br d,J＝7.78Hz,1H),8.14(s,1H),7.59(br d,J＝14.05Hz,1H),7.36(s,1H),7.18(s,1H),6.94(br t,J＝9.41Hz,1H),6.73(s,1H),6.61-6.68(m,1H),6.61-6.68(m,1H),6.65(dd,J＝2.01,8.28Hz,2H),4.00(s,2H),3.99-4.03(m,1H),3.96-3.99(m,1H),3.96-3.99(m,1H),3.98(s,3H),3.01(br s,1H),1.33-1.57(m,1H),1.33-1.57(m,5H),0.93-1.12(m,5H)。
Example 32: synthesis of 3- (3, 5-difluorophenoxy) -5- ((7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N- (tetrahydropyran-4-yl) sulfamoyl) quinolin-4-yl) amino) benzoic acid (32)
Step 1: synthesis of 7-bromo-4-chloro-5-fluoro-N- (tetrahydropyran) quinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (2 g,5.57 mmol) and TEA (2.82 g,27.86 mmol) were added to dry DCM (30 mL). Further cyclopentylamine epoxy (0.563 g,5.57 mmol) was added at 0deg.C and stirred at 0deg.C for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 32-2 (560 mg, 11.36%).
MS(ESI,pos.ion)m/z:422.9[M+1] + 。
Step 2: synthesis of methyl 3- ((7-bromo-5-fluoro-3- (N- (tetrahydropyran-4-yl) aminosulfonyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
7-bromo-4-chloro-5-fluoro-N- (tetrahydropyran) quinoline-3-sulfonamide (63 mg,0.148 mmol), methyl 3-amino-5- (3, 5-difluorophenoxy) benzoate (41.25 mg,0.148 mmol) was added to AcOH (3 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 32-3 (38 mg, 39.35%).
MS(ESI,pos.ion)m/z:666.1[M+1] + 。
Step 3: synthesis of methyl 3- (3, 5-difluorophenoxy) -5- ((7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N- (tetrahydropyran-4-ylamino) sulfonyl) quinolin-4-yl) amino) benzoate
Methyl 3- ((7-bromo-5-fluoro-3- (N- (tetrahydropyran-4-yl) sulfamoyl) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (38.1 mg,0.057 mmol), (2, 4-dimethoxypyrimidin-5-yl) boric acid (15.77 mg,0.086 mmol) and K 2 CO 3 (86.91 mg, 0.6278 mmol) was added to a mixed solution of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (6.61 mg,0.0057 mmol) and then replaced with nitrogen, and the reaction was stirred at 100℃for 1h. Adding H 2 Dilution with O (5 mL)EA (3 mL. Times.3) extraction, and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure gave compound 32-4 (60 mg, crude).
MS(ESI,pos.ion)m/z:726.3[M+1] + 。
Step 4: synthesis of 3- (3, 5-difluorophenoxy) -5- ((7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N- (tetrahydropyran-4-yl) aminosulfonyl) quinolin-4-yl) amino) benzoic acid
Methyl 3- (3, 5-difluorophenoxy) -5- ((7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N- (tetrahydropyran-4-yl) sulfamoyl) quinolin-4-yl) amino) benzoate (60 mg, crude) and lithium hydroxide (39.6 mg,1.65 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at 30℃for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 32 (7.51 mg).
MS(ESI,pos.ion)m/z:712.2[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.11(s,1H),8.64(s,1H),8.52(s,1H),8.38(br d,J＝7.03Hz,1H),8.13(s,1H),7.58(br d,J＝13.55Hz,1H),7.37(s,1H),7.17(s,1H),6.93(br t,J＝9.41Hz,1H),6.77(s,1H),6.61-6.72(m,2H),4.00(s,3H),3.98(s,3H),3.62(br d,J＝11.80Hz,2H),3.18-3.25(m,1H),3.02-3.14(m,2H),1.44-1.55(m,1H),1.48(br d,J＝11.29Hz,2H),1.22-1.36(m,2H)。
Example 33: synthesis of 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-oxetan-3-yl) sulfamoyl) quinolin-4-yl) amino) benzoic acid (33)
Step 1: synthesis of (7-bromo-4-chloro-5-fluoro-N- (oxetan-3-yl) quinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (2 g,5.57 mmol) and TEA (2.82 mg,27.86 mmol) were added to dry DCM (30 mL). Oxetan-3 amine (407.21 mg,5.57 mmol) was added at 0deg.C andstirred at 0℃for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 33-2 (150 mg, 6.81%).
MS(ESI,pos.ion)m/z:394.8[M+1] + 。
Step 2: synthesis of methyl 3- ((7-bromo-5-fluoro-3- (N- (oxetan-3-yl) sulfonylamino) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate
Methyl (7-bromo-4-chloro-5-fluoro-N- (oxetan-3-yl) quinoline-3-sulfonamide (100 mg,0.252 mmol), 3-amino-5- (3, 5-difluorophenoxy) benzoate (70.58 mg,0.252 mmol) was added to AcOH (3 mL), stirred at 80 ℃ for 1 hour, concentrated under reduced pressure, and the crude product was isolated by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 33-3 (92 mg, 57%).
MS(ESI,pos.ion)m/z:637.9[M+1] + 。
Step 3: synthesis of methyl 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-oxetan-3-yl) sulfamoyl) quinolin-4-yl) amino) benzoate
Methyl 3- ((7-bromo-5-fluoro-3- (N- (oxetan-3-yl) sulfonylamino) quinolin-4-yl) amino) -5- (3, 5-difluorophenoxy) benzoate (92.9 mg,0.145 mmol), (2, 4-dimethoxypyrimidin-5-yl) boronic acid (40.15 mg,0.218 mmol) and K 2 CO 3 (226.7 mg,1.65 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (16.82 mg,0.0145 mmol) and then replaced with nitrogen and the reaction stirred at 100deg.C for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 33-4 (130 mg, crude).
MS(ESI,pos.ion)m/z:698.2[M+1] + 。
Step 4: synthesis of 3- (3, 5-difluorophenoxy) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-oxetan-3-yl) aminosulfonyl) quinolin-4-yl) amino) benzoic acid
Methyl 3- (3, 5-difluorophenol) -5- (7- (2, 4-dimethoxypyrimidin-5-yl) -5-fluoro-3- (N-oxetan-3-yl) aminosulfonyl) quinolin-4-yl) amino) benzoate (130 mg, crude) and lithium hydroxide (89.26 mg,3.73 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at 30℃for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 33 (1.08 mg).
MS(ESI,pos.ion)m/z:684.2[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.02(br s,1H),8.64(s,1H),8.53(br s,1H),8.08-8.22(m,1H),7.57(br d,J＝14.56Hz,1H),7.33(br s,1H),7.16(br s,1H),6.87-6.99(m,1H),6.74(br s,1H),6.66(br d,J＝7.78Hz,2H),4.45(br s,3H),4.26(br s,2H),4.00(d,J＝3.01Hz,3H),3.98(d,J＝3.01Hz,3H)。
Example 34: synthesis of 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3-aminosulfonyl quinolin-4-yl) amino) -5-morpholinobenzoic acid (34)
Step 1: synthesis of 7-bromo-4-chloro-5-fluoro-N- (4-methoxyphenyl-methyl) quinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g,2.79 mmol) and TEA (845.6 mg,8.36 mmol) were added to dry DCM (20 mL). 4-Methoxyphenylmethylamine (800 mg,0.305 mmol) was added thereto at 0℃and stirred at 0℃for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 34-2 (100 mg, 7.8%).
MS(ESI,pos.ion)m/z:460.7[M+1] + 。
Step 2: synthesis of methyl 3- ((7-bromo-5-fluoro-3- (N-4-methoxybenzyl) aminosulfonyl) quinolin-4-yl) amino) -5-morpholinylbenzoate
7-bromo-4-chloro-5-fluoro-N- (4-methoxyphenyl-methyl) quinoline-3-sulfonamide (100 mg,0.217 mmol), 3-amino-5-morpholinylbenzoic acid methyl ester (61.67 mg,0.261 mmol) was added to AcOH (4 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =1/1) to give compound 34-3 (65 mg, 45.31%).
MS(ESI,pos.ion)m/z:661.1[M+1] + 。
Step 3: synthesis of methyl 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (N- (4-methoxybenzyl) aminosulfonyl) quinolin-4-yl) amino) -5-morpholinylbenzoate
Methyl 3- ((7-bromo-5-fluoro-3- (N-4-methoxybenzyl) sulfonyl) quinolin-4-yl) amino) -5-morpholinylbenzoate (65 mg,0.091 mmol), 2, 4-diethylpyrimidine borate (42.88 mg,0.136 mmol) and K 2 CO 3 (125.7 mg,0.909 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (10.51 mg,0.009 mmol) and then replaced with nitrogen and the reaction stirred at 100deg.C for 1h. Concentrating the reaction solution in vacuum to remove part of dioxane, adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 34-4 (100 mg, crude).
MS(ESI,pos.ion)m/z:714.5[M+1] + 。
Step 4: synthesis of 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (N- (4-methoxybenzyl) aminosulfonyl) quinolin-4-yl) amino) -5-morpholinylbenzoic acid
Methyl 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (N- (4-methoxybenzyl) aminosulfonyl) quinolin-4-yl) amino) -5-morpholinylbenzoate (100 mg, crude) and lithium hydroxide (67.01 mg,4.53 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at room temperature for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, a proper amount of 1M HCl was added to adjust the pH to 5-6, EA (3 mL. Times.3) was used for extraction, and concentration under reduced pressure gave compound 34-5 (140 mg, crude).
MS(ESI,pos.ion)m/z:701.2[M+1] + 。
Step 5: synthesis of 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3-aminosulfonyl quinolin-4-yl) amino) -5-morpholinobenzoic acid
3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (N- (4-methoxybenzyl) sulfamoyl) quinolin-4-yl) amino) -5-morpholinylbenzoic acid (140 mg, crude) and trifluoroacetic acid (68.34 mg,0.599 mmol) were added to anhydrous dichloromethane (2 mL) and stirred at room temperature for 16h. Concentrated under reduced pressure, and the crude product was purified by direct HPLC to give compound 34 (19.5 mg, 16.8%).
MS(ESI,pos.ion)m/z:581.3[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ：7.39(br d,J＝12.55Hz,1H),7.14(s,1H),6.83(s,1H),6.72(br s,1H),3.64-3.69(m,4H),3.01(br s,4H),2.93(q,J＝7.53Hz,2H),2.68-2.75(m,2H),1.32(t,J＝7.53Hz,3H),1.09-1.15(m,3H)。
Example 35: synthesis of 3- ((7- (2, 3-dihydrofuran (3, 2-c) pyridin-7-yl) -5-fluoro-3-sulfonylamino-4-quinolinyl) amino) -5- (morpholinomethyl) benzoic acid (35)
Step 1: synthesis of 7-bromo-4-chloro-N- (4-methoxyphenyl-methyl) quinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g,2.79 mmol) and TEA (845.6 mg,8.36 mmol) were added to dry DCM (20 mL). 4-Methoxyphenylmethylamine (800 mg,0.305 mmol) was added thereto at 0℃and stirred at 0℃for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 35-2 (100 mg, 7.8%).
MS(ESI,pos.ion)m/z:460.7[M+1] + 。
Step 2: synthesis of methyl 3- ((7-bromo-5-fluoro-3- ((4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- (morpholinomethyl) benzoate
7-bromo-4-chloro-N- (4-methoxyphenyl-methyl) quinoline-3-sulfonamide (100 mg,0.21 mmol), methyl 3-amino-5- (morpholinomethyl) benzoate (65.34 mg,0.261 mmol) was added to AcOH (4 mL) and stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 35-3 (85 mg, 58.1%).
MS(ESI,pos.ion)m/z:675.0[M+1] + 。
Step 3: synthesis of methyl 3- ((7- (2, 3-dihydrofuran (3, 2-c) pyridin-7-yl) -5-fluoro-3- (N- (4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- (morpholinomethyl) benzoate
Methyl 3- ((7-bromo-5-fluoro-3- ((4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- (morpholinomethyl) benzoate (85 mg,0.126 mmol), 2, 3-dihydrofuran [3,2-c ]]Pyridine-7-boronic acid (31.23 mg,0.189 mmol) and K 2 CO 3 (200 mg,1.45 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (dppf) Cl was added under a nitrogen flow 2 (9.23 mg,0.0126 mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 1h. Concentrating the reaction solution in vacuum to remove part of dioxane, adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to give 35-4 (200 mg, crude product).
MS(ESI,pos.ion)m/z:714.1[M+1] + 。
Step 4: synthesis of 3- ((7- (2, 3-dihydrofuran (3, 2-c) pyridin-7-yl) -5-fluoro-3- (N- (4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- (morpholinomethyl) benzoic acid
Methyl 3- ((7- (2, 3-dihydrofuran (3, 2-c) pyridin-7-yl) -5-fluoro-3- (N- (4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- (morpholinomethyl) benzoate (200 mg, crude) and lithium hydroxide (65 mg,2.51 mmol) were added to methanol (3 mL) and water (1 mL) and stirred at 30℃for 16h. Reduction ofConcentrating under pressure, adding H 2 O (3 mL) was diluted, a proper amount of 1M HCl was added to adjust the pH to 5-6, EA (3 mL. Times.3) was used for extraction, and concentration under reduced pressure gave compound 35-5 (140 mg, crude).
MS(ESI,pos.ion)m/z:699.8[M+1] + 。
Step 5: synthesis of 3- ((7- (2, 3-dihydrofuran (3, 2-c) pyridin-7-yl) -5-fluoro-3-sulfonylamino-4-quinolinyl) amino) -5- (morpholinomethyl) benzoic acid
3- ((7- (2, 3-Dihydrofuran (3, 2-c) pyridin-7-yl) -5-fluoro-3- (N- (4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- (morpholinomethyl) benzoic acid (140 mg, crude) and trifluoroacetic acid (68.34 mg,0.599 mmol) were added to anhydrous dichloromethane (2 mL) and stirred at room temperature for 16h. Concentrated under reduced pressure, and the crude product was purified by direct HPLC to give compound 35 (7.37 mg, 4.45%).
MS(ESI,pos.ion)m/z:580.1[M+1] + 。
1H NMR(400MHz,METHANOL-d4)δ:9.13(s,1H),8.59(s,1H),8.31(d,J＝19.07Hz,2H),7.68(s,1H),7.48-7.59(m,2H),7.07(s,1H),4.82-4.87(m,2H),3.53-3.63(m,6H),3.39(t,J＝8.78Hz,2H),2.50(br s,4H)。
Example 36: synthesis of 3- (7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3-aminosulfonylquinolin-4-yl) amino) -5- (1- (oxetan-3-yl) piperidin-4-yl) oxy) benzoic acid (36)
Step 1: synthesis of 7-bromo-4-chloro-5-fluoro-N- (4-methoxyphenyl-methyl) quinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g,2.79 mmol) and TEA (845.6 mg,8.36 mmol) were added to dry DCM (20 mL). 4-Methoxyphenylmethylamine (800 mg,0.305 mmol) was added thereto at 0℃and stirred at 0℃for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 36-2 (100 mg, 7.8%).
MS(ESI,pos.ion)m/z:460.7[M+1] + 。
Step 2: synthesis of methyl 3- ((7-bromo-5-fluoro-3- (N- (4-methoxybenzyl) sulfonylamino) quinolin-4-yl) amino) -5- (1- (oxetan-3-yl) piperidin-4-yl) oxy) benzoate
7-bromo-4-chloro-5-fluoro-N- (4-methoxyphenyl-methyl) quinoline-3-sulfonamide (100 mg,0.217 mmol), methyl 3-amino-5- (1- (oxetan-3-yl) -piperidin-4-yl) oxybenzoate (79.97 mg,0.261 mmol) was added to AcOH (4 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 36-3 (100 mg, 63.01%).
MS(ESI,pos.ion)m/z:731.2[M+1] + 。
Step 3: synthesis of methyl 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (N- (4-methoxybenzyl) sulfamoyl) quinolin-4-yl) amino) -5- (1- (oxetan-3-yl) piperidin-4-yl) oxy) benzoate
Methyl 3- ((7-bromo-5-fluoro-3- (N- (4-methoxybenzyl) sulfonylamino) quinolin-4-yl) amino) -5- (1- (oxetan-3-yl) piperidin-4-yl) oxy) benzoate (100 mg,0.137 mmol), 2, 4-diethylpyrimidine borate (64.6 mg,0.205 mmol) and K 2 CO 3 (18.74 mg,0.137 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (15.84 mg,0.014 mmol) and then replaced with nitrogen, the reaction was stirred at 100deg.C for 1h. Concentrating the reaction solution in vacuum to remove part of dioxane, adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure to give compound 36-4 (180 mg, crude product).
MS(ESI,pos.ion)m/z:785.3[M+1] + 。
Step 4: synthesis of 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (N- (4-methoxybenzyl) aminosulfonyl) quinolin-4-yl) amino) -5- (1- (oxetan-3-yl) piperidin-4-yl) oxy) benzoic acid
3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (N- (4-methoxybenzyl) ammonia) Methyl (180 mg, crude) and lithium hydroxide (54.9 mg,2.29 mmol) of methylsulfonyl) quinolin-4-yl) amino) -5- (1- (oxetan-3-yl) piperidin-4-yl) oxy) benzoate were added to methanol (3 mL) and water (0.5 mL) and stirred at 30℃for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 36-5 (150 mg, crude).
MS(ESI,pos.ion)m/z:771.4[M+1] + 。
Step 5: synthesis of 3- (7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3-aminosulfonylquinolin-4-yl) amino) -5- (1- (oxetan-3-yl) piperidin-4-yl) oxy) benzoic acid
3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (N- (4-methoxybenzyl) sulfamoyl) quinolin-4-yl) amino) -5- (1- (oxetan-3-yl) piperidin-4-yl) oxy) benzoic acid (150 mg, crude) and trifluoroacetic acid (68.34 mg,0.599 mmol) were added to anhydrous dichloromethane (2 mL) and stirred at room temperature for 16h. Concentrated under reduced pressure, and the crude product was purified by direct HPLC to give compound 36 (16.23 mg, 12.81%).
MS(ESI,pos.ion)m/z:651.4[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.14(s,1H),8.63(s,1H),8.55(br s,1H),7.98(br s,1H),7.93(s,1H),7.43(br d,J＝12.55Hz,1H),7.07(s,1H),6.99(s,1H),6.68(s,1H),4.48(t,J＝6.53Hz,2H),4.36(t,J＝6.15Hz,2H),4.30(br s,1H),2.93(q,J＝7.53Hz,2H),2.73(q,J＝7.36Hz,2H),2.54(br s,1H),2.41(br s,2H),1.94-2.05(m,2H),1.82(br s,2H),1.55(br d,J＝8.28Hz,2H),1.32(t,J＝7.53Hz,3H),1.13(t,J＝7.53Hz,3H)。
Example 37: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3-aminosulfonyl quinolin-4-yl) amino) -5- (4- (oxetan-3-yl) piperazin-1-yl) benzoic acid (37)
Step 1: synthesis of 1-tert-butyloxycarbonyl-4- (3- (methoxycarbonyl) -5-nitro) piperazine
Methyl 3-bromo-5-nitrobenzoate (1.5 g,5.77 mmol), N-BOC piperazine (1.29 g,6.93 mmol), cs 2 CO 3 (3.76 g,11.54 mmol) was added to dry dioxane (20 mL). The air in the reaction system was replaced with nitrogen, and Ruphos Pd G was added under a nitrogen flow 3 (241 mg,0.288 mmol) and then replaced with nitrogen, stirring for 16 hours at 100deg.C under nitrogen. Filtration, concentration of the filtrate under reduced pressure, and column chromatography of the crude product (PE/EtOAc (v/v) =3/1) gave compound 37-2 (1.6 g, 75.9%).
MS(ESI,pos.ion)m/z:310.2[M-55] + 。
Step 2: synthesis of methyl 3-nitro-5- (piperazin-1-yl) benzoate
1-tert-butyloxycarbonyl-4- (3- (methoxycarbonyl) -5-nitrobenzene) piperazine (1.6 g,4.38 mmol) and dioxane hydrochloride (4M, 20 mL) were added to MeOH (5 mL). Stirred at 25℃for 1 hour. Concentrating under reduced pressure to give Compound 37-3 (1.5 g, crude).
MS(ESI,pos.ion)m/z:266.0[M+1] + 。
Step 3: synthesis of methyl 3-nitro-5- (4- (oxetan-3-yl) piperazin-1-yl) benzoate
Methyl 3-nitro-5- (piperazin-1-yl) benzoate (1.5 g, crude), 3-oxetanone (815 g,11.32 mmol), triethylamine (1.14 g,11.26 mmol) and sodium borohydride acetate (2.4 g,11.32 mmol) were added to dichloromethane (15 mL) and the reaction stirred at 30℃for 16 hours. Adding H 2 O (20 mL) was diluted, extracted with dichloromethane (15 mL. Times.3), and washed with saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed on column chromatography (PE/EtOAc (v/v) =1/1) to give compound 37-4 (1.35 g).
MS(ESI,pos.ion)m/z:322.2[M+1] + 。
Step 4: synthesis of methyl 3-amino-5- (4- (oxetan-3-yl) piperazin-1-yl) benzoate
3-nitro-5- (4- (oxa-cyclic) ringMethyl butan-3-yl) piperazin-1-yl benzoate (1.35 g,4.21 mmol), iron powder (1.17 g,2.09 mmol) and ammonium chloride (3.37 g,63 mmol) were added to a mixed solution of ethanol (5 mL), tetrahydrofuran (5 mL) and water (2.5 mL), and stirred at 90℃for 2 hours. Filtering, adding H into the filtrate 2 O (10 mL) was diluted, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was chromatographed on column (PE/EtOAc (v/v) =3/1) to give compound 37-5 (1.0 g, 81.7%).
MS(ESI,pos.ion)m/z:292.3[M+1] + 。
Step 5: synthesis of methyl 3- ((7-bromo-5-fluoro-3- (N- (4-methoxyphenyl) sulfamide) quinolin-4-yl) amino) -5- (4- (oxetan-3-yl) piperazin-1-yl) benzoate
Methyl 3-amino-5- (4- (oxetan-3-yl) piperazin-1-yl) benzoate (91.3 mg,0.31 mmol), 7-bromo-4-chloro-5-fluoro-N- (4-methoxyphenyl) quinoline-3-sulfonamide (120 mg,0.26 mmol) was added to AcOH (3 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =1/1) to give compound 37-6 (99 mg, 53%).
MS(ESI,pos.ion)m/z:716.1[M+2] + 。
Step 6: synthesis of methyl 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (4-methoxyphenyl) sulfamide) quinolin-4-yl) amino) -5- (4- (oxetan-3-yl) piperazin-1-yl) benzoate
Methyl 3- ((7-bromo-5-fluoro-3- (N- (4-methoxyphenyl) sulfamide) quinolin-4-yl) amino) -5- (4- (oxetan-3-yl) piperazin-1-yl) benzoate (99 mg,0.138 mmol), (2, 3-dihydrofuran [3, 2-c)]Pyridine) boronic acid (68.5 mg, 0.418 mmol) and K 2 CO 3 (38 mg,0.276 mmol) was added to a mixture of DMF (4 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (dppf) Cl was added under a nitrogen flow 2 (10 mg,0.014 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (5 mL), anhydrous Na 2 SO 4 Drying and concentrating under reduced pressure gave compound 37-7 (200 mg, crude).
MS(ESI,pos.ion)m/z:755.3[M+1] + 。
Step 7: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (4-methoxyphenyl) sulfamide) quinolin-4-yl) amino) -5- (4- (oxetan-3-yl) piperazin-1-yl) benzoic acid
3- ((7- (2, 3-dihydrofuran [3, 2-c)]Methyl pyridin-7-yl) -5-fluoro-3- (N- (4-methoxyphenyl) sulfamide) quinolin-4-yl) amino) -5- (4- (oxetan-3-yl) piperazin-1-yl) benzoate (150 mg, crude) and lithium hydroxide (25.4 mg,1.06 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 30℃for 1h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, a proper amount of 1M HCl was added to adjust the pH to 5-6, EA (3 mL. Times.3) was used for extraction, and the mixture was concentrated under reduced pressure to give Compound 37-8 (200 mg, crude).
MS(ESI,pos.ion)m/z:741.3[M+1] + 。
Step 8: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3-aminosulfonyl quinolin-4-yl) amino) -5- (4- (oxetan-3-yl) piperazin-1-yl) benzoic acid
3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (4-methoxyphenyl) sulfamide) quinolin-4-yl) amino) -5- (4- (oxetan-3-yl) piperazin-1-yl) benzoic acid (200 mg, crude), trifluoroacetic acid (0.5 mL,27 mmol) was added to dichloromethane (5 mL). Stirred at 25℃for 16 hours. Concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 37 (2.85 mg).
MS(ESI,pos.ion)m/z:620.8[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.08(s,1H),8.71(s,1H),8.46(br s,1H),8.39(s,1H),8.32(s,1H),7.96(br s,1H),7.68(br d,J＝13.3Hz,1H),7.14(s,1H),6.74(s,2H),4.79(t,J＝8.9Hz,2H),4.53(t,J＝6.7Hz,2H),4.43(t,J＝6.0Hz,2H),3.11(br s,4H),2.33(br s,5H)。
Example 38: synthesis of 3- (1-cyclobutylpiperidin-4-yl) oxy) -5- (7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3-aminosulfonylquinolin-4-yl) amino) benzoic acid (38)
Step 1: synthesis of 7-bromo-4-chloro-N- (4-methoxyphenyl-methyl) quinoline-3-sulfonamide
7-bromo-4-chloro-5-fluoroquinoline-3-sulfonyl chloride (1 g,2.79 mmol) and TEA (845.6 mg,8.36 mmol) were added to dry DCM (20 mL). 4-Methoxyphenylmethylamine (800 mg,0.305 mmol) was added thereto at 0℃and stirred at 0℃for 2 hours. DCM (20 mL) was added for dilution, followed by H 2 O (20 mL. Times.2) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 38-2 (100 mg, 7.8%).
MS(ESI,pos.ion)m/z:460.7[M+1] + 。
Step 2: synthesis of methyl 3- ((7-bromo-5-fluoro-3- ((4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- ((1-cyclobutyl-4-piperidinyl) oxy) benzoate
Methyl 7-bromo-4-chloro-5-fluoro-N- (4-methoxyphenyl-methyl) quinoline-3-sulfonamide (100 mg,0.217 mmol), 3-amino-5- ((1- (cyclobutyl) -4-piperidinyl) oxy) benzoate (79.97 mg,0.261 mmol) was added to AcOH (4 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 38-3 (150 mg, 92.01%).
MS(ESI,pos.ion)m/z:729.3[M+1] + 。
Step 3: synthesis of methyl 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- ((4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- ((1-cyclobutyl-4-piperidinyl) oxy) benzoate
Methyl 3- ((7-bromo-5-fluoro-3- ((4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- ((1-cyclobutyl-4-piperidinyl) oxy) benzoate (150 mg,0.206 mmol), 2, 4-diethylpyrimidine borate (97.17 mg,0.309 mmol) and K 2 CO 3 (28.49 mg,0.206 mmol) was added to a mixture of dioxane (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (PPh) was added under a nitrogen flow 3 ) 4 (23.82 mg,0.0206 mmol) and then replaced by nitrogen, the reaction was stirred at 100℃for 1h. Concentrating the reaction solution in vacuum to remove part of dioxane, adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 38-4 (150 mg, crude).
MS(ESI,pos.ion)m/z:784.3[M+1] + 。
Step 4: synthesis of 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- ((4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- ((1-cyclobutyl-4-piperidinyl) oxy) benzoic acid
Methyl 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- ((4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- ((1-cyclobutyl-4-piperidinyl) oxy) benzoate (150 mg, crude) and lithium hydroxide (60.2 mg,2.52 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 30 ℃ for 16h. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 38-5 (200 mg, crude).
MS(ESI,pos.ion)m/z:768.8[M+1] + 。
Step 5: synthesis of 3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- (sulfonyl) -4-quinolinyl) amino) -5- ((1-cyclobutyl-4-piperidinyl) oxy) benzoic acid
3- ((7- (2, 4-diethylpyrimidin-5-yl) -5-fluoro-3- ((4-methoxyphenyl) methylaminosulfonyl) -4-quinolinyl) amino) -5- ((1-cyclobutyl-4-piperidinyl) oxy) benzoic acid (200 mg, crude) and trifluoroacetic acid (68.34 mg,0.599 mmol) were added to anhydrous dichloromethane (2 mL) and stirred at room temperature for 16h. Concentrated under reduced pressure, and the crude product was purified by direct HPLC to give compound 38 (6.95 mg, 4.12%).
MS(ESI,pos.ion)m/z:629.2[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.14(s,1H),8.63(s,1H),8.56(br s,1H),7.90-8.03(m,3H),7.43(br d,J＝12.55Hz,1H),7.06(s,1H),7.01(s,1H),6.65(s,1H),4.24(br s,1H),2.93(q,J＝7.61Hz,2H),2.74(q,J＝7.53Hz,2H),1.90(br s,5H),1.65-1.83(m,5H),1.45-1.62(m,4H),1.32(t,J＝7.53Hz,3H),1.14(t,J＝7.40Hz,3H).
Example 39: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid (39)
Step 1: synthesis of methyl 3- ((7-bromo-5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate
7-bromo-4-chloro-5-fluoro-N- (tetrahydrofuran-3-yl) quinoline-3-sulfonamide (100 mg,0.244 mmol) and methyl 3-amine-5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate (147 mg,0.586 mmol) were added to acetic acid (3 mL). Stirred at 80℃for 1 hour. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 39-2 (100 mg, 65.6%).
MS(ESI,pos.ion)m/z:625.0[M+1] + 。
Step 2: synthesis of methyl 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate
Methyl 3- ((7-bromo-5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate (100 mg,0.16 mmol), (2, 3-dihydrofuran [3, 2-c)]Pyridin-7-yl) boronic acid (102 mg,0.62 mmol) and K 2 CO 3 (88 mg,0.64 mmol) was added to a mixture of DMF (3 mL) and water (0.5 mL), the air in the reaction system was replaced with nitrogen, and Pd (dppf) Cl was added under a nitrogen flow 2 (11.7 mg,0.016 mmol) and then replaced with nitrogen, the reaction was stirred at 80℃for 1h. Adding H 2 O (5 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave compound 39-3 (207 mg, crude).
MS(ESI,pos.ion)m/z:665.3[M+1] + 。
Step 3: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid
3- ((7- (2, 3-dihydrofuran [3, 2-c)]Methyl pyridin-7-yl) -5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate (207 mg, crude) and lithium hydroxide (7.46 mg,0.31 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at 50℃for 16H. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give Compound 39 (9.5 mg).
MS(ESI,pos.ion)m/z:651.1[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.08(br s,1H),8.71(s,1H),8.59(br s,1H),8.40(s,2H),8.35(br s,1H),7.71(br d,J＝13.9Hz,1H),7.13(s,1H),7.05(s,1H),6.70(s,1H),4.80(t,J＝8.9Hz,2H),4.46(td,J＝4.3,8.4Hz,1H),3.86(br s,1H),3.77-3.70(m,2H),3.68-3.47(m,7H),2.02-1.75(m,4H),1.61-1.45(m,3H)。
Example 40: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -N- (methylsulfonyl) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzamide (40)
Step 1: synthesis of 3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -N- (methylsulfonyl) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzamide
3- ((7- (2, 3-dihydrofuran [3,2-c ] pyridin-7-yl) -5-fluoro-3- (N- (tetrahydrofuran-3-yl) sulfonamide) quinolin-4-yl) amine) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid (300 mg, crude), EDCI (176.8 mg,0.92 mmol), DMAP (56.3 mg,0.46 mmol), triethylamine (93.3 mg,0.92 mmol), methanesulfonamide (87.7 mg,0.92 mmol) was added to dichloromethane (10 mL). Stirred at 30℃for 2 hours. Concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 40 (12.2 mg).
MS(ESI,pos.ion)m/z:728.3[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ:9.12-9.04(m,1H),8.72(s,1H),8.62(br d,J＝7.0Hz,1H),8.46-8.38(m,2H),8.35(s,1H),7.70(br d,J＝13.3Hz,1H),7.22(s,1H),7.13(s,1H),6.71-6.56(m,1H),4.80(br t,J＝8.9Hz,2H),4.54-4.33(m,1H),3.88-3.65(m,7H),3.27-3.11(m,7H),1.95-1.78(m,3H),1.66-1.43(m,3H)。
Example 41: synthesis of 3- ((7- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -3-sulfonylamino-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid (41)
Step 1: synthesis of methyl 3-nitro-5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate
Methyl 3-hydroxy-5-nitrobenzoate (2.00 g,10.14 mmol) and 4-tetrahydropyranol (1.04 g,10.14 mmol), PPh 3 (3.19 g,12.17 mmol) DIAD (2.46 g,12.17 mmol) was added to DCM (50 mL) and reacted at room temperature for 16h. Adding H 2 O (30 mL) was diluted, extracted with EA (30 mL. Times.3), and washed with saturated NaCl solution (30 mL), anhydrous Na 2 SO 4 The crude product was dried and chromatographed on column (PE/EtOAc (v/v) =5/1) and concentrated under reduced pressure to give compound 41-2 (3 g of crude product).
Step 2: synthesis of methyl 3-amino-5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate
Methyl 3-nitro-5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate (1 g,3.56 mmol), iron powder (992.76 mg,17.78 mmol), ammonium chloride (2.85 g,53.33 mmol) were added to a mixed solvent of ethanol (10 mL), tetrahydrofuran (10 mL) and water (5 mL). The reaction was carried out at 90℃for 16h. Cooled to room temperature, diluted with water (30 mL), extracted with EtOAc (30 ml×3), washed with saturated NaCl solution (30 mL), and anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =5/1) to give compound 41-3 (710 mg, 79.47%)
1 H NMR (400 MHz deuterated chloroform) δ=7.02-6.95 (m, 2H), 6.45 (t, j=2.3 hz, 1H), 4.52 (tt, j=3.8, 7.8hz, 1H), 4.14 (q, j=7.3 hz, 1H), 4.05-3.95 (m, 2H), 3.90 (s, 3H), 3.60 (ddd, j=3.1, 8.3,11.7hz,2H),2.09-2.02(m,2H),1.79(dtd,J＝3.9,8.3,12.8Hz,2H)
Step 3: synthesis of 7-bromo-4-hydroxyquinoline-3-sulfonyl chloride
4-hydroxy-7-bromoquinoline (10 g,44.63 mmol) was added to chlorosulfonic acid (100 mL), and the reaction mixture was reacted at 100℃for 16h. After completion of the reaction, the mixture was diluted with water (100 mL) and filtered to give crude compound 41-5 (15 g crude product)
1 H NMR(400MHz,DMSO-d 6 )δ＝8.92(s,1H),8.26-8.09(m,2H),7.78(dd,J＝1.7,8.8Hz,1H),7.89-7.72(m,1H)
Step 4: synthesis of 7-bromo-4-chloroquinoline-3-sulfonyl chloride
7-bromo-4-hydroxyquinoline-3-sulfonyl chloride (10 g,31.0 mmol) was added to phosphorus oxychloride (100 mL), and the reaction solution was reacted at 100℃for 3 hours. Concentrating under reduced pressure after the reaction is finished to obtain a compound 41-6 (14.77 g crude product)
1 H NMR (400 MHz deuterated chloroform) δ=9.58 (s, 1H), 8.78-8.61 (m, 1H), 8.49 (d, j=9.1 hz, 1H), 8.21-8.01 (m, 1H)
Step 5: synthesis of 7-bromo-4-chloro-N- (4-methoxybenzyl) quinoline-3-sulfonamide
7-bromo-4-chloroquinoline-3-sulfonyl chloride (2 g,5.86 mmol), p-methoxybenzylamine (643.64 mg,4.69 mmol), TEA (2.97 g,29.3 mmol) was added to DCM (50 mL). Stirred at 0℃for 2 hours. Concentrated under reduced pressure, and the crude product was chromatographed by column chromatography (PE/EtOAc (v/v) =3/1) to give compound 41-7 (620 mg, 23.95%).
MS(ESI,pos.ion)m/z:442.7[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝9.06(s,1H),8.81(t,J＝6.3Hz,1H),8.37(d,J＝1.8Hz,1H),8.19(d,J＝9.0Hz,1H),7.99(dd,J＝2.0,9.0Hz,1H),6.98(d,J＝8.8Hz,2H),6.44(d,J＝8.8Hz,2H),4.11(d,J＝6.5Hz,2H),3.43-3.39(m,3H)
Step 6: synthesis of methyl 3- ((7-bromo-3- (N- (4-methoxybenzyl) sulfamoyl) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate
7-bromo-4-chloro-N- (4-methoxybenzyl) quinoline-3-sulfonamide (300 mg,679.15 mmol), 3-amino-5- ((tetrahydro-2H-pyran-4-yloxy) benzoic acid methyl ester (204.79 mg,814.98 mmol) was added to AcOH (2 mL), stirred at 80 ℃ for 2 hours, concentrated under reduced pressure, and the crude product was isolated by column chromatography (PE/EtOAc (v/v) =4/1) to give compound 41-8 (100 mg, 22.43%).
MS(ESI,pos.ion)m/z:657.5[M+1] + 。
Step 7: synthesis of methyl 3- ((7- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -3- (N- (4-methoxybenzyl) aminosulfonyl) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate
Methyl 3- ((7-bromo-3- (N- (4-methoxybenzyl) sulfamoyl) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate (90 mg,137.08 mmol), 1,2,3, 4-tetrahydro-1, 5-naphthyridine (23.91 mg,178.21 mmol) and Cs 2 CO 3 (89.33 mg,274.16 mmol) was added to dioxane (2 mL), the air in the reaction system was replaced with nitrogen, ruPhos Pd G2 (10.65 mg,13.71 mmol) was added under a nitrogen flow, then replaced with nitrogen, and the reaction was stirred at 80℃for 1h. Adding H 2 O (3 mL) dilution, extraction with EA (3 mL. Times.3), and washing with saturated NaCl solution (3 mL), anhydrous Na 2 SO 4 The crude product was dried and chromatographed by column chromatography (PE/EtOAc (v/v) =4/1), concentrating under reduced pressure to give compound 41-9 (176 mg, crude).
MS(ESI,pos.ion)m/z:710.8[M+1] + 。
Step 8: synthesis of 3- ((7- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -3- (N- (4-methoxybenzyl) aminosulfonyl) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid
Methyl 3- ((7- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -3- (N- (4-methoxybenzyl) sulfamoyl) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoate (176 mg, crude) and lithium hydroxide (130.64 mg,5.45 mmol) were added to methanol (3 mL) and water (0.5 mL) and stirred at room temperature for 16H. Concentrating under reduced pressure, adding H 2 O (3 mL) was diluted, an appropriate amount of 1M HCl was added to adjust the pH to 5-6, extracted with EA (3 mL. Times.3), concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 41-10 (160 mg, crude).
MS(ESI,pos.ion)m/z:696.8[M+1] + 。
Step 9: synthesis of 3- ((7- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -3-sulfonylamino-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid
3- ((7- (3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl) -3- (N- (4-methoxybenzyl) sulfonyl) quinolin-4-yl) amino) -5- ((tetrahydro-2H-pyran-4-yl) oxy) benzoic acid (160 mg, crude) was added to DCM (3 mL) and TFA (0.5 mL) and stirred at room temperature for 16H. Concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 41 (1.17 mg, 0.88%).
MS(ESI,pos.ion)m/z:576.63[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ＝9.02(s,1H),8.28(s,1H),8.03(d,J＝3.5Hz,1H),7.78(br s,2H),7.60(s,1H),7.57(d,J＝9.3Hz,1H),7.40-7.35(m,2H),7.11(s,1H),7.06-7.02(m,2H),6.72(s,1H),4.52(s,1H),3.80-3.74(m,4H),3.45(br s,2H),2.90(t,J＝6.4Hz,2H),2.08-2.01(m,2H),1.90(br d,J＝12.0Hz,2H),1.55(br s,2H),1.24(s,2H)
Example 42: synthesis of 5- { [ 3-carbamoyl-7- (1, 2,3, 4-tetrahydropyridin [3,2-b ] pyridin-1-yl) quinolin-4-yl ] amino } -3- (3, 4,5, 6-tetrahydro-2H-pyran-4-yloxy) benzoic acid (42)
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Step 1 Synthesis of 7-bromo-4- [ (ethoxymethyl) oxy ] quinoline-3-carboxylic acid ethyl ester
To 7-bromo-4-hydroxyquinoline-3-carboxylic acid ethyl ester (300 mg,1.01 mmol) and [ (chloromethyl) oxy group]To dichloromethane (5 mL) of ethane (191 mg,2.03 mmol) was added N, N-diisopropylethylamine (390 mg,3.04 mmol), and the mixture was stirred at room temperature for 2h. After the reaction, the reaction mixture was treated with H 2 O (5 mL) was diluted and extracted with dichloromethane (10 mL. Times.3). The organic layer was washed with saturated brine (10 mL), and dried over Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave compound 42-2 (335 mg, 93%).
MS(ESI,pos.ion)m/z:354.0[M+1] + 。
Step 2 Synthesis of ethyl 4- [ (ethoxymethyl) oxy ] -7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carboxylate
To ethyl 7-bromo-4- [ (ethoxymethyl) oxy ] quinoline-3-carboxylate (315 mg,0.89 mmol), 1,2,3, 4-tetrahydropyrido [3,2-b ] pyridine (131 mg,0.98 mmol), cesium carbonate (869 mg,2.67 mmol) and 1, 4-dioxane (6 mL) were added Xphos Palladacycle Gen.4 (76 mg,0.09 mmol) under nitrogen atmosphere, and the reaction was carried out at 100℃overnight. After the reaction was completed, the mixture was filtered, and the cake was washed with methylene chloride (20 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA (v/v) =2/1-1/10) to give compound 42-3 (263 mg, 72%).
MS(ESI,pos.ion)m/z:408.6[M+1] + 。
Step 3 Synthesis of ethyl 4-hydroxy-7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carboxylate
Ethyl 4- [ (ethoxymethyl) oxy ] -7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carboxylate (263 mg,0.65 mmol) was added to an ethanol solution of hydrochloric acid (5 mL,10 mol/L) and stirred overnight at 60 ℃. After completion of the reaction, the mixture was concentrated under reduced pressure to give compound 42-4 (225 mg, 99%).
MS(ESI,pos.ion)m/z:350.1[M+1] + 。
Step 4 Synthesis of 4-hydroxy-7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carboxylic acid
Ethyl 4-hydroxy-7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carboxylate (225 mg,0.64 mmol) and potassium hydroxide (180 mg,3.22 mmol) were added to water (4 mL) and refluxed overnight. After the reaction was completed, the pH was adjusted to neutrality with one mol/liter of aqueous hydrochloric acid, and the solid was filtered, washed with water (10 mL) and the cake was dried to give compound 42-5 (175 mg, 84%).
MS(ESI,pos.ion)m/z:322.2[M+1] + 。
Step 5 Synthesis of 4-chloro-7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carbonyl chloride
4-hydroxy-7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carboxylic acid (175 mg,0.54 mmol) was added to phosphorus oxychloride (3 mL) and reacted at 100℃for 1h. After the completion of the reaction, the reaction mixture was concentrated to dryness to give Compound 42-6 (195 mg, 99%).
Step 6 Synthesis of 4-chloro-7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carboxamide
To a mixed solution of 1, 4-dioxane solution (10 mL,0.4 mol/L) and tetrahydrofuran (5 mL) of ammonia at 0deg.C was added dropwise 4-chloro-7- (1, 2,3, 4-tetrahydropyrido [3, 2-b)]A solution of pyridin-1-yl) quinoline-3-carbonyl chloride (195 mg,0.54 mmol) in tetrahydrofuran (5 mL) was reacted at 0℃for 0.5h. After completion of the reaction, water (10 mL) was added to dilute the mixture, the resulting extract was extracted with methylene chloride (20 mL. Times.3), and the organic layer was washed with saturated brine (10 mL) and dried Na 2 SO 4 Drying, filtration, and concentration under reduced pressure gave compound 42-7 (120 mg, 65%). MS (ESI, pos.ion) m/z 339.5[ M+1 ]] + 。
Step 7 Synthesis of 5- { [ 3-carbamoyl-7- (1, 2,3, 4-tetrahydropyridin [3,2-b ] pyridin-1-yl) quinolin-4-yl ] amino } -3- (3, 4,5, 6-tetrahydro-2H-pyran-4-oxy) benzoic acid
4-chloro-7- (1, 2,3, 4-tetrahydropyrido [3,2-b ] pyridin-1-yl) quinoline-3-carboxamide (50 mg,0.15 mmol) and 5-amino-3- (3, 4,5, 6-tetrahydro-2H-pyran-4-yloxy) benzoic acid (35 mg,0.15 mmol) were added to acetic acid (2 mL) and reacted at 50℃for 1H. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by preparative chromatography (formic acid condition) to give compound 42 (35 mg, 44%).
MS(ESI,pos.ion)m/z:540.2[M+1] + 。
1 HNMR(DMSO-d6)δ:12.93(br s,1H),10.37(s,1H),8.95(s,1H),8.21(br s,1H),7.98-8.02(m,1H),7.71(d,J＝9.3Hz,1H),7.64(br s,1H),7.58(d,J＝2.1Hz,1H),7.35(dd,J＝9.3,2.1Hz,1H),7.32(dd,J＝8.3,0.9Hz,1H),7.09(s,1H),7.06(s,1H),7.02(dd,J＝8.3,4.6Hz,1H),6.78-6.81(m,1H),4.54(dt,J＝8.4,4.3Hz,1H),3.75-3.83(m,4H),3.41-3.46(m,2H),2.91(t,J＝6.5Hz,2H),2.06(quin,J＝6.1Hz,2H),1.86-1.95(m,2H),1.47-1.61(m,2H).
Biological examples
Inhibition activity test of LDHA
1. Preparing a 200-fold dilution of the test compound: starting from a 2mM test compound concentration, 3-fold gradient dilutions were made in DMSO, comprising 10 concentration gradients, each prepared with 2 duplicate wells.
2. 200-fold negative controls (100% DMSO) were prepared.
3. mu.L of the diluted test compound was pipetted into 49. Mu.L of 1-fold tween-20 buffer to give a 4-fold diluted test compound working solution.
4. After sealing the plates were shaken on a shaker for 15 minutes.
5. To 384-well plates (784075, greiner) 5. Mu.L of the 4-fold diluted working solution of the compound prepared in step 4 was added.
6. A 4-fold dilution of LDHA solution was prepared on ice. mu.L of 4-fold diluted LDHA solution was added to 384-well plates.
7. The plates were sealed and incubated at room temperature for 15 minutes in the dark.
8. A 4-fold dilution of the substrate solution was prepared: beta-NADH and sodium pyruvate were dissolved in 1-fold tween-20 buffer.
9. To 384-well plates, 5. Mu.L of the substrate solution prepared in step 8 was added at 4-fold dilution.
10. After centrifugation of 384 plates at 1000rpm for 1 min, incubation was carried out in an incubator at 25℃for 30 min protected from light.
11. Preparation of 4-fold diluted detection solution: diaphorase and resazurin were dissolved in 1-fold tween-20 buffer.
12. To 384-well plates, 5. Mu.L of the 4-fold diluted detection solution prepared in step 11 was added.
13. After centrifugation of 384 plates at 1000rpm for 1 min, incubation was carried out in an incubator at 25℃for 20 min in the absence of light.
14. EX540-EM590 data was read with PHERAstar FSX.
The compound of the invention has better LDHA inhibition activity, and data obtained by representative compounds of the invention are shown in table 1:
TABLE 1
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(2) Liver microsome stability
Preheating 5mM MgCl 2 (pH 7.41). A100. Mu.L acetonitrile solution of the test compound (0.1 mM) was prepared. mu.L of 500. Mu.M chloramphenicol standard additive solution (1.5. Mu.L) and 18.75. Mu.L of liver microsomes (20 mg/mL) were added to 479.75. Mu.L of the MgCl 2 In a buffer solution. The liver microsome solution was dispensed into experimental plates at different time points (0, 5, 15, 30, 45 min) and pre-incubated for 5min at 37 ℃. Then, 150. Mu.L of acetonitrile solution of the test compound was added to the above-mentioned test plate. MgCl for formulating (6 mM,5 mg/mL) NADPH 2 The buffer solution was ready for use. After 5 minutes, 15 minutes, 30 minutes and 45 minutes, respectively, the reaction of the corresponding plate was quenched, and after 10 minutes of shaking ((600 rpm), the plate was centrifuged for 15 minutes (6000 rmp), 80. Mu.L of the supernatant was taken and 140. Mu.L of pure water was added at the same time, and the final solution was analyzed by LC/MS.
The compound of the invention has better liver microsome stability, and the data obtained by the representative compound of the invention are as follows:
TABLE 2
Wherein the structure of GSK808A is
(3) Selectivity of
Selectivity mainly refers to the selectivity of the compound for LDHA inhibitory activity relative to LDHB, i.e., the selectivity is obtained by dividing the inhibitory activity of LDHB by the inhibitory activity of LDHA
Inhibitory Activity test of LDHA see priority text
The inhibitory activity of LDHB was tested as follows:
1) Preparing a 200-fold dilution of the test compound: starting from a 2mM test compound concentration, 3-fold gradient dilutions were made in DMSO, comprising 10 concentration gradients, each prepared with 2 duplicate wells.
2) 200-fold negative controls (100% DMSO) were prepared.
3) mu.L of the diluted test compound was pipetted into 49. Mu.L of 1-fold tween-20 buffer to give a 4-fold diluted test compound working solution.
4) After sealing the plates were shaken on a shaker for 15 minutes.
5) To 384-well plates (784075, greiner) 5. Mu.L of the 4-fold diluted working solution of the compound prepared in step 4 was added.
6) A 4-fold dilution of LDHB solution was prepared on ice. mu.L of 4-fold diluted LDHB solution was added to 384-well assay plates.
7) The plates were sealed and incubated at room temperature for 15 minutes in the dark.
8) A 4-fold dilution of the substrate solution was prepared: beta-NADH and sodium pyruvate were dissolved in 1-fold tween-20 buffer.
9) To 384-well plates, 5. Mu.L of the substrate solution prepared in step 8 was added at 4-fold dilution.
10 384-well plates were centrifuged at 1000rpm for 1 min and incubated in an incubator at 25℃for 30 min in the absence of light.
11 Preparing a 4-fold diluted detection solution: diaphorase and resazurin were dissolved in 1-fold tween-20 buffer.
12 5. Mu.L of the detection solution prepared in step 11 was added to 384-well plates at 4-fold dilution.
13 384-well plates were centrifuged at 1000rpm for 1 min and incubated in an incubator at 25℃for 20 min in the absence of light.
EX540-EM590 data read with PHERAstar FSX
The compounds of the invention have better selectivity, and the selectivity of the exemplary compounds of the invention is as follows:
TABLE 3 Table 3
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in the present specification and the features of the different embodiments or examples can be freely combined and combined by one skilled in the art without contradiction.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (13)

1. A compound of formula (I) or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer thereof, a racemate, a nitrogen oxide, a solvate, an isotopic label, a prodrug or a metabolite thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
cy1 represents unsubstituted or optionally substituted by one, two or more R a Substituted C 3-20 Cycloalkyl, 3-14 membered heterocyclyl, C 6-20 Aryl or 5-to 20-membered heteroaryl,
R a each independently of the others is selected from the group: carboxyl, aminocarbonyl, C 1-12 Alkyl, halogen, nitro, cyano, hydroxy, -CO-C 1-12 Alkoxy, C 1-12 Alkoxy, -O-C 3-20 Cycloalkyl, -O-3-14 membered heterocyclyl, -O-C 6-20 Aryl, hydroxyaminocarbonyl, 3-14 membered heterocyclyl, 5-20 membered heteroaryl, C 1-12 Alkylsulfonyl, C 1-12 Alkylsulfonylaminocarbonyl, where R is a Can optionally be further oxo-or hydroxy-substituted, halogen, C 3-20 Cycloalkyl or 3-14 membered heterocyclyl,
cy2 represents unsubstituted or optionally substituted by one, two or more R b Substituted 3-20 membered heterocyclyl or C 6-20 Aryl or 5-to 20-membered heteroaryl,
R b each independently of the others is 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.
R 1 And R is 2 Each independently of the others is selected from the group: hydrogen, C 1-12 Alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy, C 1-12 Alkylamino, C 3-20 Cycloalkyl, C 3-20 Cycloalkyl C 1-12 Alkyl, C 1-12 Haloalkyl group C 3-20 Cycloalkyl, C 3-20 Halogenated cycloalkyl, C 6-20 Aryl, 3-14 membered heterocyclyl, C 6-20 aryl-C 1-12 Alkyl, C 1-12 Alkoxy C 1-12 Alkyl, cyano C 1-12 An alkyl group; alternatively, R 1 And R is 2 May form together with the nitrogen atom to which it is attached a 3-14 membered heterocyclyl optionally substituted by halogen or oxo or a 5-to 20-membered heteroaryl optionally substituted by halogen.
2. A compound of formula (I) according to claim 1 or a physiologically/pharmaceutically acceptable salt or ester thereof, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopic labels, prodrugs or metabolites thereof, wherein
Cy1 represents unsubstituted or optionally substituted by one, two or more R a Substituted C 3-12 Cycloalkyl or 3-14 membered heterocyclyl or C 6-14 Aryl or 5-14 membered heteroaryl; preferably, cy1 represents unsubstituted or optionally substitutedOne, two or more R a Substituted phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, imidazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, thiadiazolyl, bicyclo [2.2.1 ] ]Heptyl, cyclohexyl, chromanyl; more preferably, cy1 represents unsubstituted or optionally substituted with one, two or more R a Substituted phenyl, pyridyl, thiazolyl, bicyclo [2.2.1]Heptyl, cyclohexyl, chromanyl; still more preferably, cy1 represents one, two or more R a Substituted phenyl, pyridin-2-yl, thiazol-2-yl, bicyclo [2.2.1]Hept-1-yl, cyclohexyl or chromanyl; and
R a independently of one another 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-C 3-12 Heterocyclyl, -O-C 6-14 Aryl, hydroxyaminocarbonyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylaminocarbonyl, -SO 3 H or-SO 3 -C 1-6 Alkyl, wherein R is a Optionally further oxo or hydroxy, halogen, C 3-12 Cycloalkyl or 3-14 membered heterocyclyl; preferably, R a Independently of one another 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-C 3-12 Heterocyclyl, -O-C 6-14 Aryl, hydroxyaminocarbonyl, 5-or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, C 1-6 Alkylsulfonyl, C 1-6 Alkylsulfonylaminocarbonyl, -SO 3 H or-SO 3 -C 1-6 Alkyl, wherein R is a Optionally further substituted by oxo or by hydroxy, fluoro, chloro, bromo, oxetanyl or cyclobutyl; more preferably, R a Independently of each other selected from the group consisting of carboxyl, difluorophenoxy, difluorocyclohexyloxy, 5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl, 5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl, 2H-tetrahydropyranyl, 2H-tetrahydropyran-4-yloxyHydroxy aminocarbonyl, 1H-tetrazolyl, morpholinyl, morpholinylmethyl, methanesulfonyl, methanesulfonylaminocarbonyl, 2-hydroxy-3, 4-dioxocyclobutanyl, 1-hydroxy-2, 2-trifluoroethyl, cyclobutyl, oxetanyl piperidinyloxy, oxetanylpiperazinyl, cyclobutylpiperidinyloxy, hydroxydioxocyclobutyl and/or hydroxyisoxazolyl; still more preferably, R a Independently of each other selected from the group consisting of carboxy, 3, 5-difluorophenoxy, 4-difluorocyclohexyloxy, 5-oxo-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl, 5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazol-5-yl, morpholin-4-ylmethyl, methanesulfonyl, methanesulfonylaminocarbonyl, 2-hydroxy-3, 4-dioxocyclobutan-1-yl, 1-hydroxy-2, 2-trifluoroethyl, cyclobutyl, oxetan-3-yl, 1- (oxetan-3-yl) piperidin-4-yloxy, 4- (oxetan-3-yl) piperazin-1-yl, 1-cyclobutylpiperidin-4-yloxy, 2-hydroxy-3, 4-dioxo-3-oxo and/or 5-isoxazol.
3. The compound of formula (I) according to claim 1 or 2, or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotopic label, prodrug or metabolite thereof, wherein,
cy2 represents unsubstituted or optionally substituted by one, two or more R b Substituted 3-14 membered heterocyclyl or C 6-14 Aryl or 5-14 membered heteroaryl; preferably, cy2 represents unsubstituted or optionally substituted by one, two or more R b Substituted phenyl, phenoxy, phenylthio, phenylamino, pyrimidinyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridinyl, benzopyranyl, benzothiopyranyl, pyrazolopyrimidinyl, dihydrofuropyrimidinyl, furopyrimidinyl, thiazolopyrimidinyl, imidazopyrimidinyl, dihydronaphthyridinyl or dihydrofuropyridinyl; more preferably, cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy,Phenylamino, pyrimidinyl, pyridinyl, benzopyranyl, pyrazolopyrimidinyl, dihydrofuropyrimidinyl, dihydropyridinyl, imidazopyrimidinyl, dihydronaphthyridinyl or dihydrofuropyridinyl; still more preferably, cy2 represents unsubstituted or optionally substituted with one, two or more R b Substituted phenyl, phenoxy, phenylamino, pyrimidinyl, pyridinyl, 4H-benzopyran-3-yl, 1H-pyrazolo [3,4-d]Pyrimidinyl, 2, 3-dihydrofuro [3,2-c ]]Pyrimidinyl, 1, 2-dihydropyridinyl or imidazo [1,2-c ]]Pyrimidinyl, 3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl or 2, 3-dihydrofuran [3,2-c ]]Pyridin-7-yl;
R b independently of one another 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; more preferably, R b Independently of one another selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, halogen, aminocarbonyl, cyano and/or oxo; still more preferably, R b Independently of each other, selected from methyl, ethyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, aminocarbonyl, cyano, oxo and/or 2, 2-difluoroethoxy.
4. A compound of formula (I) or a physiologically/pharmaceutically acceptable salt or ester thereof as claimed in any one of claims 1 to 3, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopic labels, prodrugs or metabolites thereof, wherein
Cy1 is selected from the following structures:
5. the compound of formula (I) or a physiologically/pharmaceutically acceptable salt or ester thereof as claimed in claim 1 to 4, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopic labels, prodrugs or metabolites thereof, wherein,
cy2 is selected from the following structures:
6. a compound of formula (I) according to claim 1 to 5 or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, racemate, oxynitride, solvate, isotopic label, prodrug or metabolite thereof,
wherein R is 1 And R is 2 Each independently of the others is selected from the group: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, C 1-6 Haloalkyl group C 3-12 Cycloalkyl, C 3-12 Halogenated cycloalkyl, C 6-14 Aryl, 3-12 membered heterocyclyl, C 6-14 aryl-C 1-6 Alkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 An alkyl group; alternatively, R 1 And R is 2 May form together with the nitrogen atom to which it is attached a 3-12 membered heterocyclyl optionally substituted with halogen or oxo or a 5-to 14-membered heteroaryl optionally substituted with halogen; preferably, R 1 And R is 2 Each independently of the others is selected from the group: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C 1-6 Haloalkyl group C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, C 3-12 Halogenated cycloalkyl, C 6-14 Aryl, 3-12 membered heterocyclyl, C 6-14 aryl-C 1-6 Alkyl, cyano C 1-6 Alkyl or C 1-6 Alkoxy C 1-6 An alkyl group; alternatively, R 1 And R is 2 Can form together with the nitrogen atom to which they are attached an optionally halogen-containing groupSubstituted or oxo 3-8 membered heterocyclyl or 5-to 10-membered heteroaryl optionally substituted with halo; more preferably, R 1 And R is 2 Each independently of the others is selected from the group: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-6 Alkyl, C 1-6 Haloalkyl group C 3-12 Cycloalkyl, C 3-6 Halogenated cycloalkyl, cyano C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or a 5 or 6 membered heterocyclyl; alternatively, R 1 And R is 2 Can form together with the nitrogen atom to which it is attached a 3-to 6-membered heterocyclyl optionally substituted with halogen or oxo; most preferably, R 1 And R is 2 Each independently of the others is selected from the group: hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl, C 1-6 Haloalkyl group C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl, 6-membered heterocyclyl or C 3-12 Halogenated cycloalkyl; or alternatively, the process may be performed,
R 1 and R is 2 One of which represents hydrogen and the other represents hydrogen, cyclopropyl, 2-trifluoroethyl, methyl, propan-2-yl, tert-butyl, 1-trifluoromethyl-cyclopropan-1-yl, 1-fluoro-cyclopropan-1-yl, cyclobutyl, cyclopropylmethyl, cyanomethyl, tetrahydropyran-4-yl, tetrahydrofuran-3-yl, 2H-tetrahydropyran-4-yl, cyclohexyl, oxetan-3-yl or 2, 2-difluorocyclopropan-1-yl.
7. The compound of formula (I) or a physiologically/pharmaceutically acceptable salt or ester thereof as claimed in any one of claims 1 to 7, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopic labels, prodrugs or metabolites thereof, wherein,
the compound of formula (I) has the structure of formula (IA), formula (IB), formula (IC) or formula (ID):
wherein R is 1 、R 2 、Cy1、Cy2、R a 、R b Having the meaning defined in formula (I); h represents a number of 0, 1, 2 or 3 (preferably 0, 1 or 2), and i represents a number of 0, 1, 2 or 3 (preferably 0, 1 or 2).
8. A compound of formula (IIA) or (IIB) or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotopic label, prodrug or metabolite thereof:
wherein R is 1 、R 2 Cy1, cy2 and R a Each independently having the meaning as defined for the compounds of the formula (I) in any of claims 1 to 7, X and Y are each independently of the other selected from CH or N, m represents 0, 1, 2 or 3, L represents-SO 2 -or-C (=o) -.
9. The compound of formula (IIA) or formula (IIB) according to claim 8, or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, racemate, oxynitride, solvate, isotopic label, prodrug or metabolite thereof, wherein the compound has the structure of formula (IIC), formula (IID), formula (IIE) or formula (IIF):
10. A compound according to any one of claims 1 to 9, or a physiologically/pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, a racemate, a nitrogen oxide, a solvate, an isotopic label, a prodrug or a metabolite thereof, wherein the compound is selected from the group consisting of:
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11. a pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10 or a salt or ester thereof, a stereoisomer or tautomer, a racemate, a nitrogen oxide, a solvate, an isotopic label, a prodrug or a metabolite thereof; the pharmaceutical composition optionally comprises at least one physiologically/pharmaceutically acceptable excipient and/or additional active ingredient.
12. Use of a compound of formula (I) or a salt or ester thereof according to any one of claims 1 to 10, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotopic labels, prodrugs or metabolites thereof, for the preparation of a medicament, preferably, said medicament is an inhibitor of lactate dehydrogenase; more preferably, the medicament is for preventing or treating a disease, disorder, syndrome and/or disorder selected from the group consisting of, or for alleviating the symptoms of a disease, disorder, syndrome and/or disorder selected from the group consisting of: autoimmune diseases or cancers; still more preferably, the autoimmune disease is selected from 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., and/or the cancer is selected from acute lymphoblastic leukemia, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumor (glioma), glioblastoma, bannayan-Zonana syndrome, cowden's disease, lhermitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma, and thyroid cancer.
13. A method for the treatment or prophylaxis of a disease, condition, syndrome and/or disorder of autoimmune disease or cancer, which method comprises administering to a subject in need thereof a compound of formula (I) or a salt or ester thereof, a stereoisomer or tautomer, racemate, nitrogen oxide, solvate, isotopic label, prodrug or metabolite thereof according to any one of claims 1 to 10; preferably, the autoimmune disease is selected from 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., and/or the cancer is selected from acute lymphoblastic leukemia, acute myelogenous leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumor (glioma), glioblastoma, bannayan-Zonana syndrome, cowden's disease, lhermitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma, and thyroid cancer.
CN202310060170.8A 2022-01-21 2023-01-19 Quinoline compound and use thereof Pending CN116478129A (en)

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