WO2022063299A1 - 用作dhodh抑制剂的1,2,4-三唑酮衍生物 - Google Patents

用作dhodh抑制剂的1,2,4-三唑酮衍生物 Download PDF

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WO2022063299A1
WO2022063299A1 PCT/CN2021/120974 CN2021120974W WO2022063299A1 WO 2022063299 A1 WO2022063299 A1 WO 2022063299A1 CN 2021120974 W CN2021120974 W CN 2021120974W WO 2022063299 A1 WO2022063299 A1 WO 2022063299A1
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compound
pharmaceutically acceptable
general formula
alkyl
cycloalkyl
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French (fr)
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谢雨礼
樊后兴
钱立晖
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微境生物医药科技(上海)有限公司
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Priority to CN202180064073.5A priority Critical patent/CN116249702A/zh
Publication of WO2022063299A1 publication Critical patent/WO2022063299A1/zh

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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more particularly, to a new class of 1,2,4-triazolone derivatives, a preparation method thereof and the use of such compounds.
  • Dihydroorotate dehydrogenase is an iron-containing flavin-dependent enzyme, mainly present in the inner mitochondrial membrane, and is the key enzyme for de novo synthesis of pyrimidine nucleotides.
  • Pyrimidine nucleotides are the backbone components of DNA and RNA.
  • Orotic acid is a precursor for the synthesis of pyrimidine nucleotides.
  • DHODH catalyzes the dehydrogenation of dihydroorotic acid to convert it into orotic acid. Therefore, inhibition of DHODH can block the de novo synthesis of pyrimidine, resulting in DNA and RNA synthesis obstacles.
  • Intracellular pyrimidine nucleotides mainly come from de novo and salvage synthesis pathways.
  • pyrimidine nucleotides are mainly derived from the salvage that directly converts free pyrimidine bases to pyrimidine nucleotides, also known as the regenerative synthetic pathway.
  • the salvage pathway cannot maintain cell function or survival. Therefore, the de novo synthesis of pyrimidine nucleotides by DHODH is essential for the survival of such cells.
  • Inhibiting the activity of DHODH can selectively prevent such cells from having a large demand for pyrimidine nucleotides, thereby hindering the synthesis of biological macromolecules such as DNA, RNA, and glycoproteins, and inhibiting cell function or growth.
  • DHODH inhibitors targeting abnormally activated T, B cells and rapidly dividing cancer cells for the purpose of treating cancer, viral infections, autoimmune diseases (rheumatoid arthritis and multiple sclerosis), etc.
  • the development of DHODH has achieved initial success, such as the DHODH small-molecule inhibitors leflunomide/teriflunomide and buquina have been approved for the treatment of rheumatoid arthritis and multiple sclerosis.
  • these inhibitors have high lipid solubility and poor selectivity, and long-term use will cause great toxic and side effects. Therefore, the search for novel DHODH inhibitors with high efficiency and low side effects for the treatment of immune-related diseases and tumors has become a current research hotspot.
  • the present invention provides a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • n 0, 1 or 2;
  • X is -CH 2 -, -O-, -S-, -S(O)-, -S(O) 2 - or -N(R 5 )-;
  • R 1 is aryl or heteroaryl, which may be substituted by one or more of the following groups: halogen, OH, NH 2 , CN, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, halo-C1-C3 alkyl or halo-C1-C3 alkoxy;
  • R 2 is H or F
  • R 3 is C1-C3 alkyl or C3-C8 cycloalkyl
  • R 4 is C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl or C3-C6 cycloalkyl substituted C1-C3 alkyl;
  • R 5 is H, C1-C3 alkyl or C3-C6 cycloalkyl.
  • the isomers are optical isomers.
  • X is -CH 2 -, -O-, -S-, -S(O)-, -S(O) 2 -, -NH- , -N(Me)- or -N(Et)-; preferably X is -CH 2 -, -O-, -S-, -S(O)-, -S(O) 2 - or -N(Me )-, more preferably X is -CH2- or -O-, more preferably X is -CH2- .
  • R 1 is: wherein Ra , Rb , Rc , Rd and Re are independently H, F, Cl, Me, Et, OMe, OEt, CHF2 , CF3 , OH, NH2 or CN.
  • R 3 is Me.
  • R 4 is Me, Et, CF 3
  • R4 is CF3 .
  • the compound of general formula (1) has one of the following structures:
  • the present invention also provides a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) of the present invention, or each isomer, each crystal form, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
  • the present invention also provides the compound represented by the general formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition for preparation Use in medicaments for the treatment, regulation or prevention of DHODH-related diseases.
  • the present invention also provides a method for treating, regulating or preventing DHODH-related diseases, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of its isomers and crystal forms , a pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition.
  • the DHODH-related disease is a DHODH-mediated related disease.
  • the DHODH-related disease is cancer.
  • the cancer is a solid tumor or a hematological tumor.
  • the cancer is leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, stomach cancer, Mesothelioma or all cancer metastases.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein.
  • the solvents, temperatures and other reaction conditions mentioned herein may vary.
  • Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources.
  • the compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following method A:
  • Method A comprises the following steps: firstly, the carboxyl group of compound A1 undergoes a chlorination reaction to generate acid chloride compound A2, compound A2 is further reacted with isopropanol under the action of a strong base to generate compound A3, and compound A3 and compound A4 are under alkaline conditions to generate compound A5 , Compound A6 reacts with compound A5 under strong basic conditions to obtain compound A7, and compound A7 reacts with suitable raw material R 1 NH 2 to obtain target compound A8.
  • n, X, R 1 , R 2 , R 3 and R 4 are as defined above.
  • “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
  • pharmaceutically acceptable salt refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound of general formula (1) with an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, etc.
  • propionic acid oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms.
  • the compound of the general formula (1) includes a crystalline form and can also be a polymorph.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl” alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”.
  • Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic.
  • the cycloalkyl group is monocyclic or bicyclic.
  • the ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form oxo or thiol groups.
  • Cycloalkyl also includes cycloalkylene.
  • the cycloalkyl group contains 0, 1 or 2 double bonds.
  • cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.
  • alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH3 , OCF3, CHF2O , CF3CH2O , i - PrO, n- PrO , i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group, which is monocyclic or polycyclic, eg, a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S, or N), which is monocyclic or polycyclic.
  • a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene pyridyl, pyrrolopyrimidinyl, 1H-pyrro[3,2-b]pyridyl, 1H-pyrro[2,3-c]pyridyl, 1H-pyrro[3,2-c]pyridyl, 1H- Pyrro[2,3-b]pyridyl,
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen-substituted appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, conditions may be attributable to or related to the administration.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers.
  • the number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides methods of treating diseases including, but not limited to, conditions involving DHODH (eg, cancer) using the compounds of general formula (1) or pharmaceutical compositions of the present invention.
  • diseases including, but not limited to, conditions involving DHODH (eg, cancer) using the compounds of general formula (1) or pharmaceutical compositions of the present invention.
  • methods for cancer treatment comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1).
  • the cancer is associated with the synthesis of DHODH.
  • the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective dose of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity .
  • “Compatibility” as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose,
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • AlMe3 represents trimethylaluminum
  • Ar represents argon
  • CDCl3 represents deuterated chloroform
  • (COCl) 2 represents oxalyl chloride
  • DCM represents dichloromethane
  • DMF represents dimethylformamide
  • DMSO for dimethyl sulfoxide
  • EA or EtOAc for ethyl acetate
  • h for hours
  • IPA for isopropanol
  • K2CO3 for potassium carbonate
  • KHMDS potassium bis(trimethylsilyl)amide
  • the target compounds 2-66 and 68-76 in Table 1 can be obtained.
  • Determination of DHODH enzymatic activity was determined by cascade reaction to determine its ability to catalyze the oxidation of natural substrate DHO (dihydroorotic acid) to orotate, while reducing coenzyme Q.
  • the enzymatic activity of DHODH was indirectly detected by measuring the ability of coenzyme Q to reduce the chromogenic substrate DCIP.
  • the reaction substrate DHO was added to initiate the reaction, and the enzyme activity was determined by measuring the depletion of DCIP by measuring the absorbance at 600 nm at regular intervals.
  • the inhibition rate of DHODH enzyme activity of the compounds with different concentrations was calculated, and the IC 50 value of the half effective inhibitor concentration was calculated.
  • the screening results are shown in Table 2.
  • Example 78 Determination of antiproliferative activity of THP-1 cells
  • THP-1 cells were planted in a 384-well plate (Fisher 142762), 3000 cells per well. On the second day, the compound diluted in gradient was added. After adding the compound for 72 hours, CellTiter-Lumi (Biyuntian C0068XL) was added to measure the content of ATP in the cells. The cell growth condition was evaluated, and the IC 50 of the compound for inhibiting cell growth was calculated. The screening results are shown in Table 2.
  • Example 79 Determination of anti-proliferative activity of MV-4-11 cells
  • MV-4-11 cells were seeded in a 384-well plate (Fisher 142762), 3000 cells per well, and the compound diluted in gradient was added on the second day. After adding the compound for 72 hours, CellTiter-Lumi (Biyuntian C0068XL) was added to measure the ATP level in the cells. content, to evaluate the cell growth, and to calculate the IC 50 of the compound for inhibiting cell growth. The screening results are shown in Table 2.
  • the compound of the present invention has a strong inhibitory activity against DHODH enzyme activity, and the compound also has a strong anti-proliferation activity on tumor cells THP-1 and MV-4-11.

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Abstract

本发明涉及用作DHODH抑制剂的1,2,4-三唑酮衍生物。具体地，本发明涉及通式(1)所示的化合物及其制备方法，以及通式(1)化合物及其各光学异构体、各晶型、药学上可接受的盐作为DHODH抑制剂在治疗DHODH相关疾病中的应用。

Description

用作DHODH抑制剂的1,2,4-三唑酮衍生物
本申请要求申请日为2020年9月28日的中国申请CN202011042241.4的优先权。本申请引用上述中国申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及一类新型1,2,4-三唑酮衍生物，及其制备方法和该类化合物的用途。
背景技术
二氢乳清酸脱氢酶(Dihydroorotate Dehydrogenase,DHODH)是一种含铁的黄素依赖性酶，主要存在于线粒体内膜上，是从头合成嘧啶核苷酸的关键酶。嘧啶核苷酸是DNA和RNA的骨架成分。乳清酸是合成嘧啶核苷酸的前体。DHODH催化二氢乳清酸发生脱氢作用，使其转化为乳清酸。因此抑制DHODH，可以阻断嘧啶的从头合成，致使DNA和RNA合成障碍。
细胞内的嘧啶核苷酸主要来自于从头合成和补救合成途径。对于正常分化的静息细胞，嘧啶核苷酸主要来源于将游离嘧啶碱基直接转换为嘧啶核苷酸的补救又称再生合成途径。但对于病理条件下代谢旺盛的T，B淋巴细胞或者快速分裂的癌症细胞，补救途径生成的嘧啶核苷酸无法维持细胞的功能或生存。因此，依赖DHODH从头合成嘧啶核苷酸，对这类细胞的存活至关重要。抑制DHODH的活性能够选择性阻止这类细胞对嘧啶核苷酸的大量需求，进而阻碍DNA、RNA、糖蛋白等生物大分子的合成，抑制细胞功能或生长。
利用这一特性，以治疗癌症、病毒性感染、自身免疫性疾病(类风湿关节炎和多发性硬化)等为目的，靶向异常激活的T，B细胞以及快速分裂的癌症细胞的DHODH抑制剂的研发，已初见成效，例如DHODH小分子抑制剂来氟米特/特立氟胺和布奎那已被批准用于治疗类风湿性关节炎和多发性硬化症。然而这些抑制剂脂溶性高、选择性差，长期使用会产生很大的毒副作用。因此，寻找新型高效、副作用小的DHODH抑制剂用于治疗免疫相关疾病及肿瘤已经成为当前研究的热点。
发明内容
本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2021120974-appb-000001
通式(1)中：
n为0、1或2；
X为-CH 2-、-O-、-S-、-S(O)-、-S(O) 2-或-N(R 5)-；
R 1为芳基或杂芳基，所述芳基和杂芳基可被1个或多个下述基团所取代：卤素、OH、NH 2、CN、C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、卤代C1-C3烷基或卤代C1-C3烷氧基；
R 2为H或F；
R 3为C1-C3烷基或C3-C8环烷基；
R 4为C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、卤代C1-C6烷基或C3-C6环烷基取代C1-C3烷基；
R 5为H、C1-C3烷基或C3-C6环烷基。
在另一优选例中，所述的异构体为光学异构体。
在另一优选例中，其中所述通式(1)中，X为-CH 2-、-O-、-S-、-S(O)-、-S(O) 2-、-NH-、-N(Me)-或-N(Et)-；优选X为-CH 2-、-O-、-S-、-S(O)-、-S(O) 2-或-N(Me)-，更优选X为-CH 2-或-O-，更优选X为-CH 2-。
在另一优选例中，其中所述通式(1)中，R 1为：
Figure PCTCN2021120974-appb-000002
Figure PCTCN2021120974-appb-000003
Figure PCTCN2021120974-appb-000004
其中R a、R b、R c、R d和R e独立为H、F、Cl、Me、Et、OMe、OEt、CHF 2、CF 3、OH、NH 2或CN。
在另一优选例中，其中所述通式(1)中，R 3为Me。
在另一优选例中，其中所述通式(1)中，R 4为Me、Et、CF 3、
Figure PCTCN2021120974-appb-000005
Figure PCTCN2021120974-appb-000006
优选R 4为CF 3。
在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：
Figure PCTCN2021120974-appb-000007
Figure PCTCN2021120974-appb-000008
Figure PCTCN2021120974-appb-000009
Figure PCTCN2021120974-appb-000010
Figure PCTCN2021120974-appb-000011
本发明还提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
本发明还提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防DHODH相关疾病的药物中的应用。
本发明还提供了治疗、调节或预防DHODH相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。
在另一具体实施例中，所述的DHODH相关疾病为DHODH介导的相关疾病。
在另一具体实施例中，所述的DHODH相关疾病为癌症。
在另一具体实施例中，所述的癌症为实体瘤或血液瘤。
在另一具体实施例中，所述的癌症为白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、前列腺癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始 物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式(1)化合物可采用下列方法A制备：
方法A
方法A包含下列步骤：首先化合物A1的羧基进行氯化反应生成酰氯化合物A2，化合物A2进一步在强碱作用下和异丙醇反应生成化合物A3，化合物A3和化合物A4在碱性条件下生成化合物A5，化合物A6在强碱性条件下反应后，再和化合物A5反应得到化合物A7，化合物A7和合适的原料R 1NH 2反应得到目标化合物A8。
Figure PCTCN2021120974-appb-000012
上述反应方程式中，n、X、R 1、R 2、R 3和R 4的定义如前所述。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体 的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，通式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，通式(1)化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。 必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。
除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。
除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级炔基，例如乙炔基、1-丙炔基或1-丁炔基。
除非另有规定，“环烷基”是指非芳香族烃环系统(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫离子基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。
除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一 个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。
除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的。例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环烷基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基、吡咯并嘧啶基、1H-吡咯[3,2-b]吡啶基、1H-吡咯[2,3-c]吡啶基、1H-吡咯[3,2-c]吡啶基、1H-吡咯[2,3-b]吡啶基、
Figure PCTCN2021120974-appb-000013
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为单键。
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。
除非另有说明，用楔形实线键
Figure PCTCN2021120974-appb-000014
和楔形虚线键
Figure PCTCN2021120974-appb-000015
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021120974-appb-000016
和直形虚线键
Figure PCTCN2021120974-appb-000017
表示立体中心的相对构型，用波浪线
Figure PCTCN2021120974-appb-000018
表示楔形实线键
Figure PCTCN2021120974-appb-000019
或楔形虚线键
Figure PCTCN2021120974-appb-000020
或用波浪线
Figure PCTCN2021120974-appb-000021
表示直形实线键
Figure PCTCN2021120974-appb-000022
或直形虚线键
Figure PCTCN2021120974-appb-000023
除非另有说明，用
Figure PCTCN2021120974-appb-000024
表示单键或双键。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可 以归因于或与给药有关的情况。
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明通式(1)化合物或药物组合物治疗疾病的方法，包括但不限于涉及DHODH的病况(例如癌症)。
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)化合物的药物组合物。在一些实施例中，癌症与DHODH的合成相关。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于白血病、乳腺 癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、前列腺癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021120974-appb-000025
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除 了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
具体实施方式
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词：AlMe 3代表三甲基铝；Ar代表氩气；CDCl 3代表氘代氯仿；(COCl) 2代表草酰氯；DCM代表二氯甲烷；DMF代表二甲基甲酰胺；DMSO代表二甲基亚砜；EA或EtOAc代表乙酸乙酯；h代表小时；IPA代表异丙醇；K 2CO 3代表碳酸钾；KHMDS代表双(三甲基硅)氨基钾；LC-MS代表液相-质谱；mL代表毫升；min代表分钟；MS代表质谱；Na 2SO 4代表硫酸钠；NMR代表核磁共振；PE代表石油醚；py代表吡啶；THF代表四氢呋喃。
实施例1(S)-N-(2-氯-6-氟苯基)-5-氟-6-(3-氧代-5,6,7,8-四氢-[1,2,4]三唑[4,3-a]吡啶-2(3H)-基)-2-(((1,1,1-三氟丙烷-2-基)氧基)烟酰胺(化合物1)的合成
Figure PCTCN2021120974-appb-000026
合成路线：
Figure PCTCN2021120974-appb-000027
步骤1：化合物1-1的合成
100mL三口瓶中加入2,6-二氯-5-氟烟酸(2.1g,10.0mmol),THF(50mL)和DMF(73mg,1.0mmol)，混合液用Ar置换保护后，冰浴降温至0～5℃，缓慢滴加(COCl) 2(1.52g,12mmol)的THF(5mL)溶液。滴加完毕，混合液升至室温搅拌2h。LC-MS检测反应完 成后，混合液减压浓缩得粗产物1-1(2.42g,收率100％)，不经纯化直接投入下步反应。
步骤2：化合物1-2的合成
100mL单口瓶中加入上步所得粗产物1-1(2.42g,10.0mmol)和THF(50mL)，Ar置换后用冰浴冷却，滴加异丙醇(1.2g,20mmol)/吡啶(1.2g,15.2mmol)的THF(10mL)混合溶液，滴加完毕，混合液升至室温搅拌反应2h。LC-MS检测反应完成后，体系加入EA(50mL)和H 2O(100mL)，搅拌，分液，有机相用饱和氯化钠溶液(50mL)洗涤，无水Na 2SO 4干燥，浓缩，残留物经柱层析纯化(PE/EA＝10/0 to 10/1)得无色油状产物1-2(2.14g,收率85％)，ESI-MS m/z:252[M+H] +。
步骤3：化合物1-3的合成
100mL单口瓶中加入1-2(2.10g,8.333mmol)，DMSO(40mL)，5,6,7,8-四氢-[1,2,4]三唑[4,3-a]吡啶-3(2H)-酮(1.27g,9.17mmol)和无水K 2CO 3(1.72g,12.5mmol)，氩气置换后升温至80℃搅拌反应4h。LC-MS检测反应完成后，体系加入EA(60mL)和H 2O(60mL)，搅拌，分液，水相用EA(30mL)萃取，合并有机相用饱和氯化钠溶液(30mL*2)洗涤,无水Na 2SO 4干燥，浓缩，残留物经柱层析纯化(PE/EA＝1/0 to 1/1)后得类白色固体产物1-3(2.12g,收率72％)，ESI-MS m/z:355[M+H] +。
步骤4：化合物1-4的合成
100mL三口瓶中加入(S)-1,1,1-三氟丙烷-2-醇(228mg,2.0mmol)和干燥THF(5mL)，Ar保护下冰盐浴降温至-10～-20℃，后滴加KHMDS(2.5mL,1M in THF,2.5mmol)，滴加完毕，混合液保持在-10～-20℃搅拌30min。后在-10℃以下化合物1-3(355mg,1.0mmol)的THF(5mL)溶液，滴加完毕，混合液保温搅拌反应5h。LC/LC-MS检测反应完成后，混合物加入EA(20mL)，饱和氯化铵溶液(20mL)淬灭反应，搅拌，分液，水相用EA(20mL)萃取，合并有机相用饱和氯化钠溶液(20mL*2)洗涤，无水Na 2SO 4干燥，浓缩，残留物经柱层析纯化(PE/EA＝1/10 to 1/3)得棕色油状产物1-4(134mg,收率:31％),ESI-MS m/z:433[M+H] +。
步骤5：化合物1的合成
50mL三口瓶中加入2-氯-6-氟苯胺(90mg,0.62mmol)和干燥DCM(5mL)，氩气保护下室温滴加三甲基铝(0.31mL,2M in甲苯,0.62mmol)，滴加完毕，混合液室温搅拌30min，后加入化合物1-4(134mg,0.31mmol)的DCM(2mL)溶液，混合物升温至50℃搅拌反应过夜。LC-MS检测原料基本消失后，体系加水(5mL)淬灭，分液，水相再用DCM(10mL)萃取，合并有机相，浓缩，残留物经pre-TLC纯化(EA/PE＝1/1)得淡棕色固体产物1(42mg,收率26％)。
1H NMR(400MHz,CDCl 3)δ:9.51(s,1H),8.14(d,J＝11.3Hz,1H),7.37(dt,J＝8.0,1.4 Hz,1H),7.24-7.19(m,1H),7.05(ddd,J＝9.6,8.1,1.7Hz,1H),4.93(h,J＝6.2Hz,1H),3.42(m,2H),2.08-2.02(m,2H),1.67(m,4H),1.56(d,J＝6.5Hz,3H)；LC-MS:518[M+H] +.
实施例2(S)-N-(2-氯-6-氟苯基)-5-氟-6-(3-氧代-5,6-二氢-3H-[1,2,4]三唑并[3,4-c][1,4]恶嗪-2(8H)-基)-2-((1,1,1-三氟丙-2-基)氧基)烟酰胺(化合物67)的合成
Figure PCTCN2021120974-appb-000028
合成路线：
Figure PCTCN2021120974-appb-000029
以1-2和2,5,6,8-四氢-3H-[1,2,4]三唑并[3,4-c][1,4]恶嗪-3-酮为原料，参照实施例1中类似的合成方法得到目标化合物67。
1H NMR(400MHz,Chloroform-d)δ9.04(s,1H),8.49(d,J＝9.6Hz,1H),7.24–7.16(m,2H),7.11–7.03(m,1H),5.87(p,J＝6.4Hz,1H),4.70(s,2H),4.02(dd,J＝6.1,4.6Hz,2H),3.75(t,J＝5.3Hz,2H),1.61(d,J＝6.5Hz,3H).
实施例3-76化合物2-66，68-76的合成
使用合成方法A，采用不同原料，可以得到表1中目标化合物2-66，68-76。
表1
Figure PCTCN2021120974-appb-000030
Figure PCTCN2021120974-appb-000031
Figure PCTCN2021120974-appb-000032
Figure PCTCN2021120974-appb-000033
Figure PCTCN2021120974-appb-000034
Figure PCTCN2021120974-appb-000035
Figure PCTCN2021120974-appb-000036
实施例77 DHODH酶活性的测定
DHODH酶活的测定通过级联反应测定其催化天然底物DHO(二氢乳清酸)氧化为乳清酸，同时还原辅酶Q的能力。通过测定辅酶Q还原显色底物DCIP的能力间接检测DHODH的酶活。化合物与酶反应混合物温孵育5分钟后，加入反应底物DHO启动反应， 定时通过测定600nm处吸收检测DCIP的耗竭测定酶活。与对照组相比，计算不同浓度化合物的DHODH酶活抑制率，计算出半数有效抑制剂浓度IC 50值，筛选结果见表2。
实施例78:THP-1细胞抗增殖活性测定
THP-1细胞种植于384孔板(Fisher 142762)中，每孔3000个，第二日加入梯度稀释的化合物，加入化合物72h后，加入CellTiter-Lumi(碧云天C0068XL)测量细胞中ATP的含量，评价细胞生长的情况，计算化合物抑制细胞生长的IC 50，筛选结果见表2。
实施例79:MV-4-11细胞抗增殖活性测定
MV-4-11细胞种植于384孔板(Fisher 142762)中，每孔3000个，第二日加入梯度稀释的化合物，加入化合物72h后，加入CellTiter-Lumi(碧云天C0068XL)测量细胞中ATP的含量，评价细胞生长的情况，计算化合物抑制细胞生长的IC 50，筛选结果见表2。
表2本发明化合物对DHODH酶的抑制活性，以及THP-1细胞和MV-4-11细胞的抗增殖活性
Figure PCTCN2021120974-appb-000037
Figure PCTCN2021120974-appb-000038
A表示IC 50≤50nM
B表示50nM≤IC 50≤0.5μM
C表示IC 50>0.5μM
从表2数据可知，本发明化合物抑制DHODH酶活的活性很强，同时化合物对肿瘤细胞THP-1和MV-4-11也具有很强的抗增殖活性。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (10)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2021120974-appb-100001
    通式(1)中：
    n为0、1或2；
    X为-CH 2-、-O-、-S-、-S(O)-、-S(O) 2-或-N(R 5)-；
    R 1为芳基或杂芳基，所述芳基和杂芳基可被1个或多个下述基团所取代：卤素、OH、NH 2、CN、C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、卤代C1-C3烷基或卤代C1-C3烷氧基；
    R 2为H或F；
    R 3为C1-C3烷基或C3-C8环烷基；
    R 4为C1-C6烷基、C3-C8环烷基、C2-C6烯基、C2-C6炔基、卤代C1-C6烷基或C3-C6环烷基取代C1-C3烷基；
    R 5为H、C1-C3烷基或C3-C6环烷基。
  2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，X为-CH 2-、-O-、-S-、-S(O)-、-S(O) 2-、-NH-、-N(Me)-或-N(Et)-。
  3. 如权利要求1-2中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为：
    Figure PCTCN2021120974-appb-100002
    Figure PCTCN2021120974-appb-100003
    其中R a、R b、R c、R d和R e独立为H、F、Cl、Me、Et、OMe、OEt、CHF 2、CF 3、OH、NH 2或CN。
  4. 如权利要求1-3中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 3为Me。
  5. 如权利要求1-4中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 4为Me、Et、CF 3、
    Figure PCTCN2021120974-appb-100004
    Figure PCTCN2021120974-appb-100005
  6. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2021120974-appb-100006
    Figure PCTCN2021120974-appb-100007
    Figure PCTCN2021120974-appb-100008
    Figure PCTCN2021120974-appb-100009
    Figure PCTCN2021120974-appb-100010
  7. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-6中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
  8. 一种如权利要求1-6中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求7所述的药物组合物在制备治疗DHODH相关疾病的药物中的应用。
  9. 如权利要求8所述的应用，其特征在于，所述的DHODH相关疾病为癌症。
  10. 如权利要求9所述的应用，其特征在于，所述癌症为实体瘤或血液瘤。
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CN110023302A (zh) * 2016-10-27 2019-07-16 拜耳股份有限公司 用作dhodh抑制剂的2,4,5-三取代的1,2,4-三唑酮
WO2020144638A1 (en) * 2019-01-11 2020-07-16 Janssen Biotech, Inc. Dihydroorotate dehydrogenase inhibitors

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CN110023302A (zh) * 2016-10-27 2019-07-16 拜耳股份有限公司 用作dhodh抑制剂的2,4,5-三取代的1,2,4-三唑酮
WO2020144638A1 (en) * 2019-01-11 2020-07-16 Janssen Biotech, Inc. Dihydroorotate dehydrogenase inhibitors

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