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WO2023138674A1 - Composé n-hydroxyquinoléine carboxamide et son utilisation - Google Patents

Composé n-hydroxyquinoléine carboxamide et son utilisation Download PDF

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WO2023138674A1
WO2023138674A1 PCT/CN2023/073267 CN2023073267W WO2023138674A1 WO 2023138674 A1 WO2023138674 A1 WO 2023138674A1 CN 2023073267 W CN2023073267 W CN 2023073267W WO 2023138674 A1 WO2023138674 A1 WO 2023138674A1
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cancer
compound
disease
formula
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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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Meta Pharmaceutical Hk Ltd
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Meta Pharmaceutical Hk Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • 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
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to N-hydroxyquinoline carboxamide derivatives which can be used as inhibitors of lactate dehydrogenase, their preparation method and application.
  • the present invention also additionally relates to a pharmaceutical composition comprising the N-hydroxyquinoline carboxamide derivative.
  • Lactate dehydrogenase is a tetrameric enzyme belonging to the 2-hydroxyacid oxidoreductase family, which can increase the conversion rate of pyruvate to lactic acid and nicotinamide adenine dinucleotide (NAD) H to NAD+. It is usually used by cells for anaerobic respiration, so it is one of the important rate-limiting enzymes in the glucose metabolism pathway.
  • Two distinct subunits of lactate dehydrogenase are encoded by two separate genes, LDHA and LDHB.
  • LDHA also known as the M subunit
  • LDHB also known as the H subunit
  • LDH is a tetramerase
  • LDH can also be composed of five isoenzymes through M and H subunits: LDH-1 (4H, mainly found in the heart), LDH-2 (3H, 1M, mainly found in the reticuloendothelial system), LDH-3 (2H, 2M, mainly found in the lung), LDH-4 (1H, 3M, mainly found in the kidney) and LDH-5 (4M, mainly found in the liver and striated muscle).
  • Warburg effect whereby under normoxia, glucose metabolism gradually becomes dominated by glycolysis; in which glucose is converted to lactate and produces adenosine triphosphate (ATP). Therefore, the Warburg effect implies that tumor cells use glucose from oxidative phosphorylation to glycolysis, which not only enhances glycolysis, but also inhibits mitochondrial oxidative phosphorylation.
  • the purpose of the present invention is to provide a Compounds or derivatives thereof as inhibitors of lactate dehydrogenase and related pharmaceutical compositions. This object is achieved by the subject matter of the present application described in the following aspects.
  • the present invention provides a compound of formula (I) or a physiologically/pharmaceutically acceptable salt or ester thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites:
  • Cy1 represents a C 3-20 cycloalkyl group, a 3-14 membered heterocyclic group, a C 6-20 aryl group or a 5-20 membered heteroaryl group that is unsubstituted or optionally substituted by one, two or more R a ,
  • R a can each be independently selected from the following group: carboxyl, aminocarbonyl, C 1-12 alkyl, halogen, nitro, cyano, hydroxyl, -CO-C 1-12 alkoxy, C 1-12 alkoxy, -OC 3-20 cycloalkyl, -O-3-14 membered heterocyclyl, -OC 6-20 aryl, hydroxyaminocarbonyl, 3-14 membered heterocyclic group, 5-20 membered heteroaryl or C 1-12 alkylsulfonyl group, wherein R a can optionally be further oxo or substituted by hydroxyl or halogen,
  • Cy2 represents a 3-20 membered heterocyclic group or a C 6-20 aryl group or a 5-20 membered heteroaryl group that is unsubstituted or optionally substituted by one, two or more R b ,
  • R b may each be independently selected from C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, halogen, aminocarbonyl, cyano, nitro, C 1-12 alkoxycarbonyl and/or oxo.
  • Cy1 represents C 3-12 cycloalkyl or 3-14 membered heterocyclic group or C 6-14 aryl or 5-14 membered heteroaryl that is unsubstituted or optionally substituted by one, two or more R a .
  • R can be independently selected from carboxyl, aminocarbonyl, C 1-6 alkyl, halogen, nitro, cyano, hydroxyl, -CO-C 1-12 alkoxy, C 1-6 alkoxy, -OC 3-12 cycloalkyl, -O-3-14 membered heterocyclyl, -OC 3-12 halogenated cycloalkyl, -OC 6-14 aryl, hydroxyaminocarbonyl, 3-14 membered heterocyclic group, 5-14 membered heteroaryl , C 1-6 alkylsulfonyl, -SO 3 H or -SO 3 -C 1-6 alkyl, wherein R a may be optionally further substituted by oxo or hydroxy or halogen.
  • Cy1 represents phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, imidazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, thiadiazolyl, bicyclo[2.2.1]heptyl, cyclohexyl, chromanyl, unsubstituted or optionally substituted by one, two or more Ra .
  • R a can be independently selected from carboxyl, aminocarbonyl, C 1-6 alkyl, halogen, nitro, cyano, hydroxyl, -CO-C 1-12 alkoxy, C 1-6 alkoxy, -OC 3-12 cycloalkyl, -O-3-6 membered heterocyclyl, -OC 3-12 halocycloalkyl, -OC 6-14 aryl, hydroxyaminocarbonyl, 5 or 6 membered heterocyclyl, 5 or 6 membered heteroaryl, C 1-6 alkylsulfonyl, -SO 3 H or -SO 3 -C 1-6 alkyl, wherein R a can optionally be further oxo Or substituted by hydroxy, fluorine, chlorine or bromine.
  • Cy1 represents phenyl, pyridyl, thiazolyl, bicyclo[2.2.1]heptyl, cyclohexyl, chromanyl which are unsubstituted or optionally substituted by one, two or more R a .
  • R a is independently selected from carboxyl, difluorophenoxy, difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 2H-tetrahydropyranyl, 2H-tetrahydropyranyloxy, hydroxyaminocarbonyl, 1H-tetrazolyl, methanesulfonyl, 2-hydroxy-3,4-dioxocyclobutane, 1-hydroxy-2,2,2-trifluoroethyl and/or hydroxyiso Oxazolyl.
  • Cy1 represents phenyl, pyridin-2-yl, thiazol-2-yl, bicyclo[2.2.1]hept-1-yl, cyclohexyl or chromanyl substituted by one, two or more Ra .
  • R is independently selected from carboxyl, 3,5-difluorophenoxy, 4,4-difluorocyclohexyloxy, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 2H-tetrahydropyran-4-yl, 2H-tetrahydropyran-4-yloxy, hydroxyaminocarbonyl, 1H-tetrazol-5-yl, methanesulfonyl, 2-hydroxy-3,4-dioxocyclobutane-1 -yl, 1-hydroxy-2,2,2-trifluoroethyl and/or 3-hydroxyisoxazol-5-yl.
  • Cy1 has the following structure:
  • Cy1 is substituted by one or two R a ; preferably, Cy1 is substituted by at least one carboxyl group.
  • Cy1 is phenyl substituted by at least one carboxyl group, which may be optionally substituted by one, two or more R a .
  • the compound of formula (I) has the following structure of formula (I-1):
  • Cy2 has the definition herein
  • R a has the definition herein independently of each other
  • n represents 0, 1, 2, 3 or 4.
  • R a is tetrahydro-2H-pyran-4-yl and n is 1.
  • Cy2 represents a 3-14 membered heterocyclic group or a C 6-14 aryl group or a 5-14 membered heteroaryl group which is unsubstituted or optionally substituted by one, two or more R b .
  • Cy represents phenyl, phenoxy, phenylthio, phenylamino, pyrimidinyl, pyridyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, benzopyranyl, benzothiopyranyl, pyrazolopyrimidinyl, dihydrofuropyrimidinyl, furopyrimidinyl, thiazolopyrimidinyl or imidazopyrimidinyl, unsubstituted or optionally substituted by one, two or more R.
  • Cy represents phenyl, phenoxy, phenylamino, pyrimidinyl, pyridyl, benzopyranyl, pyrazolopyrimidinyl, dihydrofuropyrimidinyl, dihydropyridinyl or imidazopyrimidinyl, which is unsubstituted or optionally substituted by one, two or more R b .
  • Cy2 represents unsubstituted or optionally replaced by one, two or more R b Substituted phenyl, phenoxy, phenylamino, pyrimidyl, pyridyl, 4H-benzopyran-3-yl, 1H-pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydrofuro[3,2-c]pyrimidinyl, 1,2-dihydropyridyl, imidazo[1,2-c]pyrimidinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-[1,4]dioxin a[2,3-c]pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridyl, 2,3-dihydrofuro[3,2-c]pyridyl or 3,4-dihydro-1,5-naphthyridin-1(2H)
  • R b are independently selected from C 1-12 alkyl, C 1-12 alkoxy, C 1-12 haloalkyl, C 1-12 haloalkoxy, halogen, aminocarbonyl, cyano, nitro, C 1-12 alkoxycarbonyl and/or oxo.
  • R b are independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, halogen, aminocarbonyl, cyano and/or oxo.
  • Rb are independently selected from among methyl, ethyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, chloro, fluoro, aminocarbonyl, cyano, oxo and/or 2,2-difluoroethoxy.
  • Cy2 has the following structure:
  • Cy2 is an unsubstituted 3-14 membered heterocyclic group, preferably 3,4-dihydro-1,5-naphthyridin-1(2H)-yl.
  • the compound of formula (I) has the following structure of formula (I-2):
  • Cy1 has the definition herein.
  • R a is tetrahydro-2H-pyran-4-yl and n is 1.
  • the compound of formula (I) is selected from the following compounds:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a salt or ester thereof, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites thereof.
  • the pharmaceutical composition according to the present invention may also optionally contain at least one physiologically/pharmaceutically acceptable excipient.
  • the pharmaceutical composition according to the present invention may also optionally contain additional active ingredients.
  • additional active ingredients are, for example, antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; and inhibitors of cell cycle signaling.
  • the pharmaceutical composition according to the present invention comprises a therapeutically effective amount of a compound of formula (I) or a salt or ester thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites.
  • the pharmaceutical composition according to the invention is an inhibitor of lactate dehydrogenase.
  • the pharmaceutical composition according to the present invention is used for preventing or treating a disease, disease, syndrome and/or disorder selected from the group, or for relieving the symptoms of a disease, disease, syndrome and/or disorder selected from the group consisting of autoimmune disease or cancer.
  • Autoimmune diseases include but are not limited to: systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, vitiligo, alopecia areata, etc.
  • cancers include, but are not limited to: acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumor (glioma), glioblastoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma, and thyroid cancer etc.
  • the pharmaceutical composition according to the present invention can be made into a dosage form suitable for administration by methods known in the art type.
  • the present invention provides the compounds of formula (I) or their salts or esters according to the present invention, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites in the preparation of medicines.
  • the medicament may also optionally contain additional active ingredients.
  • additional active ingredients are, for example, antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; and inhibitors of cell cycle signaling.
  • the drug is an inhibitor of lactate dehydrogenase, and achieves the purpose of the present invention by inhibiting the activity of LDHA and regulating or inhibiting the activity of LDHB, especially improving the inhibitory selectivity for LDHA/LDHB.
  • the medicament is used for preventing or treating a disease, disease, syndrome and/or disorder selected from the group, or for relieving symptoms of a disease, disease, syndrome and/or disorder selected from the group consisting of autoimmune disease or cancer.
  • Autoimmune diseases include but are not limited to: systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, vitiligo, alopecia areata, etc.
  • Cancers include, but are not limited to: acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, brain tumor (glioma), glioblastoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma and thyroid cancer, etc. .
  • the drug can be further prepared into a dosage form suitable for administration by methods known in the art.
  • the present invention provides a method for treating or preventing a disease, condition, syndrome and/or disorder of an autoimmune disease or cancer, the method comprising administering to an individual in need thereof a compound of formula (I) according to the present invention or a salt or ester thereof, stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites thereof.
  • the diseases, diseases, syndromes and/or disorders of autoimmune diseases include: systemic lupus erythematosus, multiple sclerosis, asthma, psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, uveitis, atopic dermatitis, vitiligo, alopecia areata, etc.
  • cancer diseases, illnesses, syndromes and/or disorders include: acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, etc., brain tumor (glioma), glioblastoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colon cancer, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, prostate cancer, sarcoma, and thyroid cancer.
  • acute lymphoblastic leukemia acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer, pancreatic cancer, lung cancer, etc.
  • brain tumor glioma
  • glioblastoma Bannayan-Zonana syndrome
  • Cowden disease Lhermitt
  • the invention provides an inhibitor of lactate dehydrogenase with N-hydroxyquinoline formamide structure, which has better biological activity and pharmacokinetic properties.
  • the compounds of the present invention have excellent selectivity for the modulation of LDHA/LDHB.
  • more/kind shall refer to a situation greater than 2, for example, an integer situation greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10/kind.
  • heterocyclic group optionally substituted with an alkyl group means that the alkyl group may but need not be present, thus including the case of a heterocyclic group substituted with an alkyl group and a heterocyclic group not substituted with an alkyl group.
  • the term "unsubstituted (of)” means that one or some hydrogen atoms on the atom, residue, group or moiety used in conjunction with this term are not replaced by other atoms or atomic groups (i.e., substituents) other than hydrogen atoms, so that the atom, residue, group or moiety maintains its original structure.
  • substituents i.e., substituents
  • (substituted) means that one, two or more hydrogen atoms, preferably up to 5 hydrogen atoms, more preferably 1-3 hydrogen atoms in a group are each independently substituted with a corresponding number of substituents.
  • substituents When substituted by more than one substituent, these substituents are independent of each other, that is, the more than one substituent may be the same as each other, but the possible same situation is not excluded. Unless specifically stated otherwise, a substituent may substitute at any substitutable position of the substituent. When more than one position in a given formula can be substituted by one, two or more substituents, then these substituents can independently substitute at those positions. It goes without saying that substituents are only in their possible chemical positions, and that a person skilled in the art can determine possible or impossible substitutions experimentally or theoretically without undue effort.
  • independently of each other should be understood as that the described individuals are independent of each other and can be independently selected from the same or different options.
  • independently selected from each other can mean that in different groups, the specific options expressed by the same symbol do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbol do not affect each other.
  • alkylaryl means “alkyl” and “aryl” linked together and each of the “alkyl” and the “aryl” independently of each other have the meanings described for them respectively, thereby together constituting the combined group "alkylaryl”.
  • a linker is sometimes described as being in the middle of a compound structure, connected to the rest of the compound through at least two attachment points.
  • a Markush variable recited for a linker is to be understood as a divalent group, ie "subunit", of that variable. For example, if a linker is defined in a compound structure and the Markush group definition for that linker recites “alkyl” or “aryl,” it is understood that the “alkyl” or “aryl” represent an attached alkylene or arylene group, respectively.
  • C x -C y when used in conjunction with a group, represents the upper and lower ranges of the number of carbon atoms contained in the group.
  • C1 - C12 " alkyl refers to an alkyl group containing a minimum of one carbon atom up to a maximum of twelve carbon atoms.
  • substituents attached to these groups when they are otherwise substituted.
  • X-Y member When the expression "X-Y member" is used in conjunction with a cyclic group, it represents the range of the upper limit and the lower limit of the number of ring atoms contained in the cyclic group.
  • a “3-20 membered" heterocyclyl refers to a heterocyclyl group that contains a minimum of three ring atoms up to a maximum of twenty ring atoms. Those skilled in the art can understand that such numbers do not include the number of carbon atoms contained in the substituents attached to these heterocyclic groups when they are additionally substituted.
  • halogen denotes fluorine, chlorine, bromine and/or iodine.
  • halo refers to fluoro, chloro, bromo and/or iodo.
  • the atom at the halogenated position can be monosubstituted, disubstituted or polysubstituted up to fully substituted by a halogen atom.
  • alkyl denotes a linear or branched monovalent saturated aliphatic hydrocarbon group.
  • alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-hept
  • alkenyl refers to a linear or branched monovalent unsaturated aliphatic hydrocarbon group containing one, two or more double bonds. It is understood that where an alkenyl group contains more than one double bond, said double bonds may be separated from each other or conjugated.
  • alkenyl include vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z )-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (E)-he
  • alkynyl refers to a linear or branched monovalent unsaturated aliphatic hydrocarbon group containing one, two or more triple bonds.
  • alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-
  • alkylene refers to a divalent group obtained by removing one additional hydrogen atom from “alkyl”.
  • alkenylene and alkynylene refer to divalent groups obtained by removing one additional hydrogen atom from “alkenyl” and “alkynyl”, respectively.
  • alk(yl)oxy refers to -O-alkyl, wherein alkyl is as defined herein.
  • alkoxy include, for example, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Alkoxy groups can be unsubstituted or optionally substituted.
  • carbocycle (base) refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group.
  • the carbocycle may contain 3 to 20 carbon atoms, preferably 3 to 12 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms.
  • the carbocycle can be monocyclic or polycyclic, it can be a saturated cycloalkyl group or it can optionally contain one, two or more double and/or triple bonds in its ring, thus forming a so-called cycloalkenyl or cycloalkynyl group.
  • a saturated cyclic hydrocarbon group or a saturated carbocyclyl group is also referred to as "cycloalkyl”.
  • a carbocyclic group or a cyclic hydrocarbon group has a plurality of rings
  • these rings may form a spiro ring, condensed ring and bridged ring structure.
  • monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, cyclooctatetraenyl, and the like
  • non-limiting examples of polycyclic carbocycles include decahydronaphthyl, norbornyl, or isobornyl.
  • heterocyclic (group) refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which preferably contains 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms or atomic groups selected from N, O, NH, S, S(O) or S(O) , excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms (eg 1, 2, 3 and 4); more preferably it contains 3 to 6 ring atoms (eg 3, 4, 5, 6).
  • the heterocyclyl group may be attached to the remainder of the molecule through any of said carbon atoms or a nitrogen atom (if present) or an oxygen or sulfur atom (particularly in the case of onium salt formation).
  • the heterocyclyl group may include fused or bridged rings and/or spirocyclic rings.
  • Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, homopiperazinyl, diazacyclic Heptyl, etc., preferably piperidinyl and pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups, and may also be benzo-fused heterocyclic groups such as dihydroisoquinolinyl.
  • the heterocyclyl group may be bicyclic, non-limiting examples of which include hexahydrocyclopenta[c]pyrrol-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl.
  • a heterocyclyl group may also be partially unsaturated, i.e.
  • the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.
  • aryl/aromatic ring refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated electron system, preferably 6 to 14 or 6 to 10 membered rings, such as phenyl and naphthyl.
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.
  • 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 (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered.
  • heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc.
  • indolyl isoindolyl, etc.
  • pyridyl pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolyl, etc.; Phenoxazinyl, etc.
  • the heteroaryl/heteroaryl ring may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one, two or more groups independently of each other selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • a heterocyclyl, heteroaryl or heteroaryl ring includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridin-2-yl pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridinylene -4-yl
  • thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl
  • C 1-6 alkyloxy also sometimes referred to as C 1-6 alkoxy
  • C 1-6 alkyloxy also sometimes referred to as C 1-6 alkoxy
  • -N(C 1-6 alkyl) 2 -NHC 1-6 alkyl
  • -SO-C 1-6 alkyl or -S(O) 2 -C 1-6 alkyl and the like.
  • physiologically/pharmaceutically acceptable salt refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • Physiologically/pharmaceutically acceptable salts include acid addition salts of sufficiently basic compounds of the invention having nitrogen atoms in the chain or ring.
  • basic nitrogen-containing groups can be quaternized with lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and dipentyl sulfates; 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.
  • 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.
  • the physiologically/pharmaceutically acceptable salts include not only the salts formed on one of the salt-forming sites of the compounds of the present invention, but also the salts formed on 2, 3 or all of the salt-forming sites.
  • the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid required for salt formation or the cation of the base can vary within a relatively large range, for example, it can be 4:1-1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
  • nitrogen oxide means that when the compound contains several nitrogen-containing functional groups, one or more nitrogen atoms can be oxidized to form N-oxides.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings.
  • the corresponding nitrogen-containing compounds can be treated with oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • oxidizing agents such as hydrogen peroxide or peracids such as peroxycarboxylic acids
  • N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514) by reacting a nitrogen-containing compound with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane.
  • MCPBA m-
  • esters refers to in vivo hydrolyzable esters of compounds containing hydroxyl or carboxyl groups. Such esters are, for example, physiologically/pharmaceutically acceptable esters which hydrolyze in the human or animal body to yield the parent alcohol or acid.
  • the compound of formula (I) of the present invention contains a carboxyl group, which can form in vivo hydrolyzable esters with suitable groups, such groups include, but are not limited to, alkyl, arylalkyl and the like.
  • the compounds of the invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms can exist in the (R) or (S) configuration, with only one asymmetric center giving racemic mixtures and with multiple asymmetric centers giving diastereomeric mixtures. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the central bond connecting two substituted aromatic rings of a particular compound.
  • substituents may exist in cis or trans isomeric form.
  • the compounds of the present invention also include all possible stereoisomers of each of them, be it a single stereoisomer or the stereoisomer isomers (such as R-isomer or S-isomer, or E-isomer or Z-isomer) in any ratio in the form of any mixture.
  • Separation of single stereoisomers (eg single enantiomers or single diastereomers) of compounds of the invention may be achieved by any suitable prior art method (eg chromatography, in particular eg chiral chromatography).
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • the compounds according to the invention also include isotopically labeled compounds which are identical to those shown in formula (I), but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the usual naturally occurring atomic mass or mass number.
  • isotopes that may be incorporated into the compounds of the invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F, and 36 Cl , respectively.
  • Isotopically labeled compounds according to the 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 invention eg, compounds incorporating radioactive isotopes such as3H and14C , are useful in drug and/or substrate tissue distribution assays.
  • Tritium (ie, 3H ) and carbon-14 (ie, 14C ) isotopes are particularly preferred for ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium, i.e. H , may afford certain therapeutic advantages derived from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances.
  • the compounds of the present invention as claimed in the claims may specifically limit the substitution of deuterium or tritium.
  • the hydrogen appearing in the substituent, the term deuterium or tritium is not listed separately, does not mean deuterium or tritium is excluded, but deuterium or tritium can also be included.
  • prodrug or “prodrug” means that the compound is transformed into the compound represented by the aforementioned formula (I) or the specific compound in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure.
  • the prodrugs of the present invention can be esters, and esters can be used as prodrugs in the present invention include phenyl esters, aliphatic esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl/carboxyl group, which can be acylated to give a prodrug form of the compound.
  • Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups.
  • Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the present invention includes Metabolites of compounds include metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
  • 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, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association of solvent molecules with water.
  • the term "pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • physiologically/pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, etc., when administered to a human.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • Such 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, especially for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • any disease or condition means, in some embodiments thereof, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, “treating” refers to preventing or delaying the onset, development or worsening of a disease or condition.
  • the term "effective amount” or “therapeutically effective amount” refers to an amount of the compound of the present invention sufficient to achieve the intended use, including but not limited to the treatment of diseases as defined below.
  • a therapeutically effective amount may vary depending on factors such as the intended application (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, and the mode of administration, etc., which can be readily determined by one of ordinary skill in the art.
  • the specific dosage will vary depending on the particular compound selected, the dosing regimen employed, whether it is administered in combination with other compounds, the timing of administration, the tissue administered and the physical delivery system employed.
  • the pharmaceutical adjuvant can be an adjuvant widely used in the field of pharmaceutical production.
  • the excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to make the active ingredient dissolve at a desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition administration.
  • the pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients of the composition.
  • Described pharmaceutical adjuvant can comprise one or more in the following adjuvant: binding agent, auxiliary Suspending agents, emulsifying agents, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents and sweeteners.
  • binding agent auxiliary Suspending agents, emulsifying agents, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents and sweeteners.
  • Substances which may be used as physiologically/pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, 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, polyvinyl-polyethylene Oxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; Oleate and
  • compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, milling, encapsulating, entrapping or freeze-drying processes.
  • the dosage form of the medicine of the present invention can be selected according to specific conditions.
  • a pharmaceutical dosage form often consists of a drug, excipients and a container/closure system.
  • excipients also known as inactive ingredients
  • Pharmaceutical excipients exist in the art and include those listed in various pharmacopoeias. (See U.S.
  • compositions of the invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into preparations for pharmaceutical use.
  • Administration routes include intravenous injection, transmucosal or nasal administration, oral administration, and the like.
  • the compounds can be formulated in liquid or solid dosage forms and as immediate or controlled/sustained release formulations.
  • Suitable dosage forms for oral ingestion by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, sugar-coated Syrups, ointments, suspensions and emulsions.
  • Solid oral dosage forms can be obtained using excipients including fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring agents and flavoring agents.
  • excipients including fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring agents and flavoring agents.
  • excipients may be of synthetic or natural origin.
  • excipients examples include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or salts thereof, sugars (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated) and waxes. Ethanol and water can be used as granulation aids.
  • Dragees are produced by combining natural and synthetic polymers with coloring agents, sugar and organic solvents or water to coat tablets.
  • capsules When capsules are preferred over tablets, they can be delivered as pharmaceutical powders, suspensions or solutions in compatible hard or soft shell capsules.
  • a therapeutically effective dose can be estimated initially using various methods well known in the art. Initial dosages for animal studies can be based on effective concentrations established in cell culture assays. A dosage range suitable for humans can be determined, for example, using data obtained from animal studies and cell culture assays.
  • the compounds of the present invention may be formulated for oral administration.
  • Proper formulations, administration routes, doses and administration intervals can be selected according to methods known in the art, taking into account the particularities of individual conditions.
  • NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic analyzers.
  • the determination solvents included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), etc.
  • DMSO-d6 deuterated dimethyl sulfoxide
  • CD3COCD3 deuterated acetone
  • CD3OD deuterated chloroform
  • CD3OD deuterated methanol
  • LC-MS Liquid chromatography-mass chromatography
  • Qingdao GF254 silica gel plates were used for thin-layer chromatography, 0.15-0.20mm for TLC, and 0.4mm-0.5mm for preparative thin-layer chromatography.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • Xantphos Pd G 4 (4,5-bisdiphenylphosphine-9,9-dimethylxanthene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate
  • DIAD Diisopropyl azodicarboxylate
  • PE petroleum ether
  • Step 2 Synthesis of ethyl 4-chloro-7-(2,4-dimethoxypyrimidin-5-yl)quinoline-3-carboxylate (1-4)
  • Step 3 Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(ethoxycarbonyl)quinolin-4-yl)amino)benzoic acid (1-6)
  • Step 4 Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(hydroxyaminocarbonyl)quinolin-4-yl)amino)benzoic acid (1)
  • Step 1 Synthesis of 3-((4,4-difluorocyclohexyl)oxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(ethoxycarbonyl)quinolin-4-yl)amino)benzoic acid (2-3)
  • Step 2 Synthesis of 3-((4,4-difluorocyclohexyl)oxy)-5-((7-(2,4-dimethoxypyrimidin-5-yl)-3-(hydroxyaminocarbonyl)quinolin-4-yl)amino)benzoic acid (2)
  • Step 1 Synthesis of 3-((7-bromo-3-(ethoxycarbonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (3-5)
  • Step 2 Synthesis of 3-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(ethoxycarbonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (3-7)
  • Step 3 Synthesis of 3-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxyaminocarbonyl)quinolin-4-yl)amino)-5-(3,5-difluorophenoxy)benzoic acid (3)
  • Step 3 Synthesis of 3-(3,5-difluorophenoxy)-5-((7-(4-oxo-4H-benzopyran-3-yl)-3-(((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)benzoic acid
  • Step 4 Synthesis of 3-(3,5-difluorophenoxy)-5-((3-(hydroxycarbamoyl)-7-(4-oxo-4H-benzopyran-3-yl)quinolin-4-yl)amino)benzoic acid
  • Step 3 Synthesis of methyl 2-((4,4-difluorocyclohexyl)oxy)-5-nitrobenzoate
  • diisopropyl azodicarboxylate (3.85g, 19.02mmol) was added to a solution of methyl 2-hydroxy-5-nitrobenzoate (2.50g, 12.68mmol), 4,4-difluorocyclohexane-1-ol (1.73g, 12.68mmol) and triphenylphosphine (4.99g, 19.02mmol) in tetrahydrofuran (15mL).
  • tetrahydrofuran 15mL
  • Step 4 Synthesis of methyl 5-amino-2-((4,4-difluorocyclohexyl)oxy)benzoate
  • iron powder (3.45g, 61.85mmol) was added to a solution of methyl 2-((4,4-difluorocyclohexyl)oxy)-5-nitrobenzoate (3.90g, 12.37mmol) and ammonium chloride (6.62g, 123.70mmol) in water (4mL) and ethanol (20mL), and reacted at 90°C for 4 hours.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-8 (6.00 g, crude product).
  • Step 6 Synthesis of ethyl 7-bromo-4-chloroquinoline-3-carboxylate
  • lithium hydroxide (10.40g, 247.97mmol) was added to ethyl 7-bromo-4-chloroquinoline-3-carboxylate (7.80g, 24.80 mmol) in water (25 mL) and tetrahydrofuran (30 mL), react at 25°C for 18 hours.
  • the pH of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid (50 mL), and the solid precipitated out.
  • the crude product filter cake was obtained by filtration, and compound 5-12 (6.30 g, 89%) was obtained after drying.
  • Step 8 Synthesis of 7-bromo-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide
  • Step 9 Synthesis of 7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-4-chloro-N-((tetrahydro-2H-pyran-2-yl)oxy)quinoline-3-carboxamide
  • Step 10 Synthesis of 5-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)-2-((4,4-difluorocyclohexyl)oxy)benzoic acid
  • Step 11 Synthesis of 5-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-2-((4,4-difluorocyclohexyl)oxy)benzoic acid
  • Trifluoroacetic acid (219 mg, 01.92 mmol) was added to 5-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)-2-((4,4-difluorocyclohexyl)oxy)benzoic acid (150 mg, 0.19 mmol) in THF furan (2 mL) solution at 60°C for 18 hours. The reaction solution was concentrated under reduced pressure.
  • diisopropyl azodicarboxylate 1076mg, 5.33mmol was added to methyl 3-hydroxy-5-nitrobenzoate (700mg, 3.55mmol), tetrahydro-2H-pyran-4-ol (362mg, 3.55mmol) and triphenylphosphine (1396mg, 5.33mmol) in tetrahydrofuran (10mL) were reacted at 25°C for 1 hour under nitrogen protection.
  • Step 3 Synthesis of methyl 3-amino-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoate
  • Step 5 Synthesis of 3-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-methyl)oxy)benzoic acid
  • the crude product was separated by prep-HPLC (mobile phase: A is 0.225% aqueous formic acid, B is acetonitrile; flow rate: 30ml/min wavelength: 220nm and 254nm) to obtain the title compound 6 (30mg, 11%).
  • Step 1 Synthesis of 7- ⁇ 2,4-bis[(2,2-difluoroethyl)oxy]pyrimidin-5-yl ⁇ -4-chloro-N-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)quinoline-3-carboxamide
  • Step 2 Synthesis of 5-[(7- ⁇ 2,4-bis[(2,2-difluoroethyl)oxy]pyrimidin-5-yl ⁇ -3- ⁇ [(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)amino]carbonyl ⁇ quinolin-4-yl)amino]-2-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid
  • Step 3 Synthesis of 5-((7-(2,4-bis(2,2-difluoroethoxy)pyrimidin-5-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid
  • Step 3 Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-5-carbonitrile
  • Step 4 Synthesis of 4-chloro-7-(5-cyano-2,3-dihydrobenzofuran-7-yl)-N-((tetrahydrofuran-2H-pyran-2-yl)oxy)quinoline-3-carboxamide
  • Step 5 Synthesis of 3-((7-(5-cyano-2,3-dihydrobenzofuran-7-yl)-3-(((tetrahydrofuran-2H-pyran-2-yl)oxy)carbamoyl)quinolin-4-yl)amino)-5-((tetrahydrofuran-2H-pyran-4-yl)oxy)benzoic acid
  • Step 6 Synthesis of 3-((7-(5-cyano-2,3-dihydrobenzofuran-7-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid
  • Step 1 Synthesis of 3-((7-bromo-3-(ethoxycarbonyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid
  • Step 2 Synthesis of ethyl 7-bromo-4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)quinoline-3-carboxylate
  • Step 3 Synthesis of ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate
  • Step 4 Synthesis of ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(5-methyl-2,3-dihydro[1,4]dioxino[3,2-c]pyridin-8-yl)quinoline-3-carboxylate
  • Step 5 Synthesis of 5- ⁇ [3-(ethoxycarbonyl)-7-(5-methyl-2,3-dihydro[1,4]dioxeno[3,2-c]pyridin-8-yl)quinolin-4-yl]amino ⁇ -3-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid
  • Step 6 Synthesis of 5-( ⁇ 3-[(hydroxyamino)carbonyl]-7-(5-methyl-2,3-dihydro[1,4]dioxano[3,2-c]pyridin-8-yl)quinolin-4-yl ⁇ amino)-3-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid
  • Step 11 Synthesis of 8-bromo-5-methyl-2,3-dihydro-[1,4]dioxino[2,3-c]pyridine
  • Step 3 Synthesis of ethyl 7-(2,3-dihydro[1,4]dioxino[3,2-b]pyridin-8-yl)-5-[(3- ⁇ [(2-methylpropan-2-yl)oxy]carbonyl]-5-(3,4,5,6-tetrahydro-2H-pyran-4-oxy)phenyl)amino]quinoline-3-carboxylate
  • Step 4 Synthesis of 3-(7-(2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-8-yl)-3-(ethoxycarbonyl)quinolin-5-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoic acid
  • Step 5 Synthesis of 3-(7-(2,3-dihydro-[1,4]dioxano[2,3-b]pyridin-8-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)oxy)benzoic acid
  • Step 3 Synthesis of methyl 3-((7-bromo-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate
  • Step 4 Synthesis of methyl 3-((7-(2,3-dihydrofuro[3,2-c]pyridin-7-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate
  • Step 5 Synthesis of 3-((7-(2,3-dihydrofuro[3,2-c]pyridin-7-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid
  • Step 1 Synthesis of ethyl 7-bromo-4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)quinoline-3-carboxylate
  • Ethyl 7-bromo-4-chloroquinoline-3-carboxylate 300 mg, 0.95 mmol was added to a reaction flask containing acetic acid (5 mL). Further tert-butyl 3-amino-5-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (280 mg, 0.95 mmol) was added. The reaction solution was stirred at 50° C. for 1 hour.
  • Step 2 Synthesis of ethyl 4-((3-(tert-butoxycarbonyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)quinoline-3-carboxylate
  • Step 3 Synthesis of 3- ⁇ [3-(ethoxycarbonyl)-7-(1,2,3,4-tetrahydropyrido[3,2-b]pyridin-1-yl)quinolin-4-yl]amino ⁇ -5-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid
  • Step 4 Synthesis of 3-((7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran)4-yl)oxy)benzoic acid
  • the filtrate was purified by preparative high performance liquid chromatography (formic acid system) to obtain 3-((7-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-3-(hydroxycarbamoyl)quinolin-4-yl)amino)-5-((tetrahydro-2H-pyran)4-yl)oxy)benzoic acid (compound 12, 1 8 mg, 61.4%).
  • test compound prepared a 200-fold dilution of the test compound: starting from a concentration of 2 mM test compound, perform 3-fold serial dilution with DMSO, including 10 concentration gradients, and prepare 2 replicate wells for each concentration.
  • a buffer solution of 5 mM MgCl 2 (pH 7.41) was pre-warmed.
  • a 100 ⁇ L acetonitrile solution of the compound to be tested (0.1 mM) was prepared. Take 1.5 ⁇ L of 500 ⁇ M chloramphenicol standard supplement and 18.75 ⁇ L of liver microsomes (20 mg/mL) and add to 479.75 ⁇ L of the above MgCl 2 buffer solution.
  • the liver microsomal solution was distributed to assay plates at different time points (0, 5, 15, 30, 45 min) and pre-incubated at 37°C for 5 min. Then add 150 ⁇ L of acetonitrile solution of the compound to be tested to the above experimental plate.
  • GSK808A The structure of GSK808A is:
  • the selectivity in this test refers to the selectivity of the test compound for the inhibitory activity of LDHA relative to LDHB, that is, the inhibitory activity of LDHB is divided by the inhibitory activity of LDHA to obtain the selectivity value.
  • the inhibitory activity of LDHB was tested as follows
  • test compound prepared a 200-fold dilution of the test compound: starting from a concentration of 2 mM test compound, perform 3-fold serial dilution with DMSO, including 10 concentration gradients, and prepare 2 replicate wells for each concentration.

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Abstract

La présente invention concerne un dérivé de N-hydroxyquinoléine carboxamide (I), son procédé de préparation et son utilisation. La présente invention concerne en outre une composition pharmaceutique contenant le dérivé de N-hydroxyquinoléine carboxamide.
PCT/CN2023/073267 2022-01-21 2023-01-19 Composé n-hydroxyquinoléine carboxamide et son utilisation Ceased WO2023138674A1 (fr)

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CN1890234A (zh) * 2003-12-23 2007-01-03 辉瑞大药厂 新颖的喹啉衍生物
WO2012061557A2 (fr) * 2010-11-05 2012-05-10 Glaxosmithkline Llc Composés chimiques
WO2013096151A1 (fr) * 2011-12-22 2013-06-27 Glaxosmithkline Llc Composés chimiques

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WO2013096153A1 (fr) * 2011-12-22 2013-06-27 Glaxosmithkline Llc Composés chimiques
CN111788193B (zh) * 2018-03-13 2023-04-04 广东东阳光药业有限公司 Pd-1/pd-l1类小分子抑制剂及其在药物中的应用
BR112020019824A2 (pt) * 2018-03-29 2021-01-05 Board Of Regents, The University Of Texas System Composto de fórmula estrutural i ou um sal do mesmo, composição farmacêutica, método de inibição de cbp, método de inibição de p300, método de tratamento de uma doença mediada por cbp, método de tratamento de uma doença mediada por p300 e método para alcançar um efeito em um paciente
CN110938068B (zh) * 2019-11-06 2022-12-23 广东东阳光药业有限公司 N-(吗啉-2-基甲基)酰胺衍生物及其用途

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CN1890234A (zh) * 2003-12-23 2007-01-03 辉瑞大药厂 新颖的喹啉衍生物
WO2012061557A2 (fr) * 2010-11-05 2012-05-10 Glaxosmithkline Llc Composés chimiques
WO2013096151A1 (fr) * 2011-12-22 2013-06-27 Glaxosmithkline Llc Composés chimiques

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