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WO2017177974A1 - 用于治疗纤维化和炎性疾病的含杂原子环丁烷取代基的吡啶酮衍生物 - Google Patents

用于治疗纤维化和炎性疾病的含杂原子环丁烷取代基的吡啶酮衍生物 Download PDF

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Publication number
WO2017177974A1
WO2017177974A1 PCT/CN2017/080599 CN2017080599W WO2017177974A1 WO 2017177974 A1 WO2017177974 A1 WO 2017177974A1 CN 2017080599 W CN2017080599 W CN 2017080599W WO 2017177974 A1 WO2017177974 A1 WO 2017177974A1
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group
pharmaceutically acceptable
acceptable salt
alkyl
compound according
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PCT/CN2017/080599
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English (en)
French (fr)
Inventor
施能扬
陈斌
张蕾
黎健
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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Priority to AU2017251555A priority Critical patent/AU2017251555B2/en
Priority to EP17781950.5A priority patent/EP3444247B1/en
Priority to RU2018139801A priority patent/RU2738844C2/ru
Priority to US16/093,376 priority patent/US10604513B2/en
Priority to JP2019505107A priority patent/JP6923634B2/ja
Priority to CN201780023642.5A priority patent/CN109311859B/zh
Priority to CA3020779A priority patent/CA3020779A1/en
Publication of WO2017177974A1 publication Critical patent/WO2017177974A1/zh
Anticipated expiration legal-status Critical
Priority to ZA2018/07404A priority patent/ZA201807404B/en
Ceased legal-status Critical Current

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    • 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
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel class of compounds for the treatment of fibrosis-related diseases, in particular to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • tissue fibrosis is an important cause of disability and death in many diseases. According to relevant statistics, 45% of patients who die from various diseases in the United States can be attributed to tissue fibrosis-related diseases.
  • the body organ consists of two parts: the main structure of the organ and the functional cells (such as the liver's parenchymal cells are hepatocytes), the interstitial cells are composed of interstitial cells and extracellular matrix (mainly collagen, proteoglycan, glycosaminoglycans).
  • the sugar, glycoprotein and elastin are composed and distributed between the parenchymal cells, mainly for mechanical support and connection.
  • the extracellular matrix can constitute a microenvironment that maintains the physiological activities of cells, is a bridge between cells, participates in a variety of physiological and pathological processes, and plays an important role in tissue repair and fibrosis. Any cause of injury can lead to degeneration, necrosis and inflammatory reactions in tissue cells. If the damage is small, the normal parenchymal cells surrounding the damaged cells will proliferate and repair, and this repair can completely restore normal structure and function. However, if the damage is large or the repeated damage exceeds the regenerative capacity of the surrounding parenchymal cells, the interstitial fibrous connective tissue (extracellular matrix) will repair a large amount of hyperplasia to the defect tissue, that is, pathological changes of fibrosis occur.
  • fibrosis is essentially a repair response after tissue damage to protect the relative integrity of tissues and organs.
  • the proliferating fibrous connective tissue repairs the defect, it does not have the structure and function of the original organ parenchymal cells. If this repair is overreacted, too strong, and out of control, it can cause fibrosis of the organs and cause a decline in the function of the organs.
  • fibrosis refers to the pathological process in which the parenchymal cells of the organ are necrotic due to inflammation, and the extracellular matrix in the tissue is abnormally increased and excessively deposited. The light becomes fibrosis, and the severe one causes structural damage and organ hardening.
  • pulmonary fibrosis and liver fibrosis are the most common.
  • Idiopathic Pulmonary Fibrosis is a typical chronic, progressive and fatal fibrotic interstitial pneumonia characterized by progressive dyspnea and progressive decline in lung function, which quickly leads to respiratory failure and death. At least 5 million people worldwide were sick in 2008. In 2010, there were only 130,000 to 500,000 people in the United States. About 48,000 new cases were reported each year, and about 40,000 people died each year from IPF. The incidence of IPF is estimated to be 4.6-7.4/100,000, and 3–35,000 new cases are diagnosed each year. The incidence of smoking is much greater than that of non-smokers, and the incidence of IPF can reach nearly 2.3% in people aged 20-40 years. The male incidence rate is higher than that of females. The 5-year individual survival rate of IPF is about 20%, and the mortality rate is much higher than many cancers. It is known as a cancer that is not cancer. Potential risk factors include occupational exposure and environmental pollution such as metals, animals, wood chips, smoking and smog.
  • IPF The pathogenesis of IPF is complex and generally thought to involve interaction between pro-inflammatory and pro-fibrotic pathways, but the exact mechanism is still unknown.
  • Roche's pirfenidone and Boehringer Ingelheim's nintedanib were first approved in the United States, and the annual sales peak of pirfenidone is estimated to reach $2 billion in 2019.
  • the prognosis of IPF is poor, and the treatment plan is scarce.
  • the launch of these two new drugs gives confidence in the progress of IPF disease, and these two drugs are likely to be used to treat other fibrotic diseases.
  • the majority of patients still have unmet medical needs, so the development of better IPF new drugs is receiving more and more attention.
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt thereof and a tautomer thereof,
  • X is selected from O, S and N(R);
  • R 2 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, or a C 1-6 alkyl group and C 1-6 optionally substituted by 1, 2 or 3 R Heteroalkyl
  • R 3 is selected from H or is selected from C 1-6 alkyl and C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, or a C 1-6 alkyl group and a C 1-6 hetero group optionally substituted by 1, 2 or 3 R alkyl;
  • Ring A is selected from the group consisting of a 5- to 10-membered aryl group and a 5- to 10-membered heteroaryl group;
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2;
  • n When m is different from n, it is selected from 0;
  • p is selected from 0, 1, 2 or 3;
  • R' is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , COOH, Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 , N(CH 3 ) 2 ;
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, or C 1- selected from 1, 2 or 3 R substituted. 3 alkyl.
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, or Me selected from the group consisting of 1, 2 or 3 R substitutions.
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, Me.
  • the above R 4 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, or C 1- selected from 1, 2 or 3 R substituted. 3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, NH(C 1-3 alkyl), N,N'-di(C 1-2 alkyl)amino.
  • R 4 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, or Me selected from the group consisting of 1, 2 or 3 R,
  • R 4 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, Me,
  • the ring A is selected from the group consisting of a 5- to 6-membered aryl group and a 5- to 9-membered heteroaryl group.
  • the ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, triazolyl, benzothienyl.
  • the structural unit From:
  • the structural unit structural unit From:
  • the structural unit Selected from Other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, or C 1- selected from 1, 2 or 3 R substituted. 3 alkyl, other variables are as defined above.
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, or Me selected from the group consisting of 1, 2 or 3 R, other The variables are as defined above.
  • R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, NO 2 , COOH, Me, and other variables are as defined above.
  • the above R 4 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, or C 1- selected from 1, 2 or 3 R substituted. 3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, NH(C 1-3 alkyl), N,N'-di(C 1-2 alkyl)amino, other variables as described above Defined.
  • R 4 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, or Me selected from the group consisting of 1, 2 or 3 R, Other variables are as defined above.
  • R 4 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, Me, Other variables are as defined above.
  • Ring A is selected from the group consisting of a 5- to 6-membered aryl group and a 5- to 9-membered heteroaryl group, and other variables are as defined above.
  • the ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, triazolyl, benzothienyl, other variables are as defined above.
  • the structural unit structural unit From: Other variables are as defined above.
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • R 2 , R 4 and p are as defined above.
  • the invention also provides a compound of the formula:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for treating a fibrosis-related disease.
  • the fibrosis-related disease refers to idiopathic pulmonary fibrosis.
  • the fibrosis-related disease refers to liver fibrosis.
  • C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ;
  • C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .
  • C 1-12 alkyl or heteroalkyl, C 3-12 cyclo or heterocycloalkyl, C 1-12 alkyl or heteroalkyl substituted by C 3-12 cycloalkyl or heterocycloalkyl includes, but is not limited to: C 1-12 alkyl, C 1-12 alkylamino, N,N-di(C 1-12 alkyl)amino, C 1-12 alkoxy, C 1-12 alkanoyl, C 1-12 alkoxy Carbonyl, C 1-12 alkylsulfonyl, C 1-12 alkylsulfinyl, C 3-12 cycloalkyl, C 3-12 cycloalkylamino, C 3-12 heterocycloalkylamino, C 3-12 Cycloalkoxy, C 3-12 cycloalkyl acyl, C 3-12 cycloalkyloxycarbonyl, C 3-12 cycloalkylsulfonyl, C 3-12 cycloalkylsulfinyl, 5-12
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • “Pharmaceutically acceptable salt” as used herein is a derivative of the compound of the present invention, wherein the salt is formed by salt formation with an acid or with a base.
  • the parent compound is modified.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • the compound may be labeled with a radioisotope, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy means an alkyl group as defined above having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, Imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C 1 -C 10 represents 1 to 10 carbons).
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl refers to cycloalkyl
  • heterocycloalkyl or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) , heterocyclic alkynyl, etc.) by themselves or in combination with other terms to mean cyclized “hydrocarbyl", "hetero
  • a heteroalkyl or heterocycloalkyl group such as a heteroalkyl group, a heterocycloalkyl group
  • a hetero atom may occupy a position at which the heterocyclic ring is attached to the rest of the molecule.
  • Examples of the cyclic hydrocarbon group include, but are not limited to, a ring. Pentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc.
  • Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2 -yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Figure 2 WX001 scores for improving tissue damage at the edge of pulmonary fibrosis
  • Step 1 Synthesis of Compound A-1_2.
  • Step 4 Synthesis of Compound A-1.
  • Step 1 Synthesis of Compound B-1_2.
  • Step 1 Synthesis of Compound C-1_2.
  • OBJECTIVE To examine the effects of compounds on the TNF- ⁇ in the blood of rats induced by LPS in vitro, and to evaluate the inhibitory effect of the compounds on LPS-induced TNF- ⁇ in rat blood.
  • Rat TNF-alpha Quantikine ELISA Kit R&D, #SRTA00
  • test compound solution having a concentration of 5 mM or 1 mM was prepared, and 40 ⁇ L (the final concentration of the compound was 0.5 or 0.1 mM) was added to a 48-well cell culture plate, respectively.
  • the rats were bled in the abdominal aorta (heparin anticoagulation).
  • Blood was added to a 48-well plate to which the test compound was added, 320 ⁇ L per well. Incubate in a 48-well plate at 37 ° C, remove it after 30 minutes of incubation, and add 40 ⁇ L of LPS solution (final concentration) 100 ug/mL), mix and place at 37 ° C to continue the incubation.
  • the 48-well plate was taken out, and the blood sample was transferred to a 1.5 mL centrifuge tube, centrifuged in a centrifuge (4,500 rpm, 4 ° C, 5 minutes), and the upper layer of plasma was separated, and 20 ⁇ L of each well was dispensed into a 96-well sample plate. Quickly freeze and store in a -80 ° C refrigerator. The next day, according to the kit instructions, the R&D ELISA kit was used to detect TNF- ⁇ levels in plasma samples. Data analysis was performed using EXCEL and Prism statistical software.
  • Example In vitro TNF- ⁇ inhibition rate Example In vitro TNF- ⁇ inhibition rate Pirfenidone* 51.4% WX004 89.5% WX001* 86.3% WX005 61.6% WX002 74.6% WX009* 51.5% WX003 84.7% WX011 78.8%
  • the "*" compound is detected at a concentration of 0.5 mM; the rest are 0.1 mM;
  • Model Left unilateral pulmonary pulmonary fibrosis model in SD rats: Rat tracheal injection of bleomycin (3 mg/kg in 1.5 ml/kg) replicated pulmonary fibrosis model
  • Grouping Number of animals Bleomycin (3.0mg/kg) Drug administration Dose and frequency Group-1 (Experiment 1) 7 injection NA NA Group-2 (Experiment 1) 7 injection Pirfenidone 50mpk, twice a day Group-3 (Experiment 1) 7 injection WX001 30mpk, twice a day Group-4 (Experiment 2) 7 injection WX002 50mpk, twice a day Group-5 (Experiment 2) 7 injection WX002 25mpk, twice a day
  • Test administration Oral administration was started on the day after modeling, and the frequency of administration was twice a day. Continuous administration for 14 days.
  • H&E staining pathological evaluation 1) pathological changes of left lung terminal bronchioles, 2) pathological changes of left pulmonary arterioles; pathological evaluation of Masson Trichrome staining: 3) area of left lung pulmonary fibrosis, 4) left Pulmonary pulmonary fibrosis score.

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Abstract

公开了一类用于治疗纤维化相关疾病的化合物，具体公开了式（I）所示化合物和其药学上可接受的盐。

Description

用于治疗纤维化和炎性疾病的含杂原子环丁烷取代基的吡啶酮衍生物 发明领域
本发明涉及新的一类用于治疗纤维化相关疾病的化合物，具体涉及式(Ⅰ)所示化合物或其药学上可接受的盐。
发明背景
全世界范围内，组织纤维化是许多疾病致残、致死的重要原因，据相关统计证明，美国因各种疾病致死的病人，其中有45％可归于组织纤维增生相关疾病。机体器官由两部分构成：实质指器官的主要结构和功能细胞(如肝脏的实质细胞是肝细胞)，间质由间质细胞和细胞外基质(主要有胶原蛋白、蛋白聚糖、糖胺聚糖、糖蛋白和弹性蛋白)构成，分布于实质细胞之间，主要起机械支撑和连接作用。此外细胞外基质能够构成维持细胞生理活动的微环境，是细胞间信号传导的桥梁，参与多种生理病理过程，在组织创伤修复和纤维化过程中起重要作用。无论任何原因引起损伤，均可导致组织细胞发生变性、坏死和炎症反应。如果损伤较小，损伤细胞周边正常实质细胞将增生修复，这种修复可完全恢复至正常的结构和功能。然而如果损伤较大或反复损伤超出了周围实质细胞的再生能力时，间质纤维结缔组织(细胞外基质)将大量增生对缺损组织进行修复，即发生纤维化的病理改变。因此，本质上纤维化是组织遭受损伤后的修复反应，以保护组织器官的相对完整性。增生的纤维结缔组织虽然修复了缺损，但却不具备原来器官实质细胞的结构和功能。如果这种修复反应过度、过强和失控时，就会引起器官的纤维化和导致器官的功能下降。由此可见，纤维化是指由于炎症导致器官实质细胞发生坏死，组织内细胞外基质异常增多和过度沉积的病理过程。轻者成为纤维化，重者引起组织结构破坏而发生器官硬化。在各种纤维化相关疾病中，以肺纤维化和肝纤维化最为常见。
特发性肺纤维化Idiopathic Pulmonary Fibrosis(IPF)是典型的慢性，渐进并致命的纤维化间质性肺炎，其特征在于渐进呼吸困难和肺功能逐渐下降，很快会导致呼吸衰竭而死亡。2008年全世界至少有500万人患病，2010年仅美国就有13-50万人患病，每年新增病例约48,000例，每年约4万人死于IPF。IPF的发病率估计为4.6-7.4/100,000，每年有3–3.5万新病例被确诊。吸烟的人发病率远远大于不吸烟的人，在烟龄为(20-40年)人群中IPF发病率可达到将近2.3％。男性发病率高于女性，IPF的5年个体存活率约为20％，死亡率远远高于许多癌症，被誉为不是癌症的癌症。潜在的风险因素包括职业暴露和环境污染，如金属，动物，木屑，吸烟和霧霾。
IPF的发病机制复杂，一般认为涉及促炎和促致纤维化途径之间的互动，然而确切的机制还是一个未知数。2014年罗氏的吡非尼酮(pirfenidone)和勃林格殷格翰的nintedanib在美国首次批准，吡非尼酮的年销售高峰估计在2019年可达20亿美元。目前IPF预后诊断差，治疗方案稀缺，这两个新药的上市给了IPF疾病进展一定的信心，而且这两个药很可能可用于治疗其他纤维化疾病。但是目前广大患者还有未满足的医疗需求，所以研发更好的IPF新药日益受到重视。
发明内容
本发明提供了式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体，
Figure PCTCN2017080599-appb-000001
其中，
X选自O、S和N(R)；
R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH，或选自任选被1、2或3个R取代的C1-6烷基和C1-6杂烷基；
R3选自H，或选自任选被1、2或3个R取代的C1-6烷基和C1-6杂烷基；
R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的C1-6烷基和C1-6杂烷基；
环A选自5～10元芳基和5～10元杂芳基；
m选自0、1或2；
n选自0、1或2；
m与n不同时选自0；
p选自0、1、2或3；
R选自H、F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2，或选自任选被1、2或3个R’取代的：C1-8烷基、C1-8杂烷基、C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-3烷基-；
R’选自F、Cl、Br、I、OH、CN、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2；
“杂”表示杂原子或杂原子团，选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、＝O、＝S、-O-N＝、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-和-N(R)C(＝O)N(R)-；以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2，或选自任选被1、2或3个R’取代的：C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、N,N’-二(C1-3烷基)氨基、C3-6环烷基、3～6元杂环烷基。
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2、Me、Et、CF3、CHF2、CH2F、NH(CH3)、N(CH3)2。
本发明的一些方案中，上述结构单元
Figure PCTCN2017080599-appb-000002
选自
Figure PCTCN2017080599-appb-000003
本发明的一些方案中，上述结构单元
Figure PCTCN2017080599-appb-000004
选自
Figure PCTCN2017080599-appb-000005
本发明的一些方案中，上述R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH，或选自任选被1、2或3个R取代的C1-3烷基。
本发明的一些方案中，上述R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH，或选自任选被1、2或3个R取代的Me。
本发明的一些方案中，上述R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH、Me。
本发明的一些方案中，上述R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的C1-3烷基、C1-3烷氧基、C1-3烷硫基、NH(C1-3烷基)、N,N’-二(C1-2烷基)氨基。
本发明的一些方案中，上述R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的Me、
Figure PCTCN2017080599-appb-000006
本发明的一些方案中，上述R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、
Figure PCTCN2017080599-appb-000007
Figure PCTCN2017080599-appb-000008
本发明的一些方案中，上述环A选自5～6元芳基和5～9元杂芳基。
本发明的一些方案中，上述环A选自苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、咪唑基、吡唑基、呋喃基、噻吩基、恶唑基、噻唑基、异恶唑基、异噻唑基、三唑基、苯并噻吩基。
本发明的一些方案中，上述结构单元
Figure PCTCN2017080599-appb-000009
选自：
Figure PCTCN2017080599-appb-000010
Figure PCTCN2017080599-appb-000011
本发明的一些方案中，上述结构单元结构单元
Figure PCTCN2017080599-appb-000012
选自：
Figure PCTCN2017080599-appb-000013
Figure PCTCN2017080599-appb-000014
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2，或选自任选被1、2或3个R’取代的：C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、N,N’-二(C1-3烷基)氨基、C3-6环烷基、3～6元杂环烷基，其他变量如上述所定义。
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2、Me、Et、CF3、CHF2、CH2F、NH(CH3)、N(CH3)2，其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017080599-appb-000015
选自
Figure PCTCN2017080599-appb-000016
其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017080599-appb-000017
选自
Figure PCTCN2017080599-appb-000018
其他变量如上述所定义。
本发明的一些方案中，上述R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH，或选自任选被1、2或3个R取代的C1-3烷基，其他变量如上述所定义。
本发明的一些方案中，上述R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH，或选自任选被1、2或3个R取代的Me，其他变量如上述所定义。
本发明的一些方案中，上述R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH、Me，其他变量如上述所定义。
本发明的一些方案中，上述R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的C1-3烷基、C1-3烷氧基、C1-3烷硫基、NH(C1-3烷基)、N,N’-二(C1-2烷基)氨基，其他变量如上述所定义。
本发明的一些方案中，上述R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的Me、
Figure PCTCN2017080599-appb-000019
其他变量如上述所定义。
本发明的一些方案中，上述R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、
Figure PCTCN2017080599-appb-000020
Figure PCTCN2017080599-appb-000021
其他变量如上述所定义。
本发明的一些方案中，上述环A选自5～6元芳基和5～9元杂芳基，其他变量如上述所定义。
本发明的一些方案中，上述环A选自苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、咪唑基、吡唑基、呋喃基、噻吩基、恶唑基、噻唑基、异恶唑基、异噻唑基、三唑基、苯并噻吩基，其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017080599-appb-000022
选自：
Figure PCTCN2017080599-appb-000023
Figure PCTCN2017080599-appb-000024
其他变量如上述所定义。
本发明的一些方案中，上述结构单元结构单元
Figure PCTCN2017080599-appb-000025
选自：
Figure PCTCN2017080599-appb-000026
Figure PCTCN2017080599-appb-000027
其他变量如上述所定义。
本发明的一些方案中，上述化合物、其药学上可接受的盐及其互变异构体，其选自：
Figure PCTCN2017080599-appb-000028
其中，
R2、R4和p如上述定义。
本发明还有一些方案是由上述变量任意组合而来。
本发明还提供了下式所示化合物：
Figure PCTCN2017080599-appb-000029
本发明的另一个目的在于提供一种药物组合物，其含有治疗有效量的上述化合物或其药学上可接受的盐和药学上可接受的载体。
本发明的另一个目的在于提供上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗纤维化相关疾病的药物中的应用。
本发明的一些方案中，上述纤维化相关疾病是指特发性肺纤维化。
本发明的一些方案中，上述纤维化相关疾病是指肝纤维化。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品 名时，意在指代其对应的商品或其活性成分。
C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。
C1-12烷基或杂烷基、C3-12环基或杂环烃基、被C3-12环烃基或杂环烃基取代的C1-12烷基或杂烷基包括但不限于：C1-12烷基、C1-12烷氨基、N,N-二(C1-12烷基)氨基、C1-12烷氧基、C1-12烷酰基、C1-12烷氧羰基、C1-12烷基磺酰基、C1-12烷基亚磺酰基、C3-12环烷基、C3-12环烷氨基、C3-12杂环烷氨基、C3-12环烷氧基、C3-12环烷基酰基、C3-12环烷基氧羰基、C3-12环烷基磺酰基、C3-12环烷基亚磺酰基、5～12元芳基或杂芳基、5～12元芳烷基或杂芳烷基；甲基、乙基、正丙基、异丙基、-CH2C(CH3)(CH3)(OH)、环丙基、环丁基、丙基亚甲基、环丙酰基、苄氧基、三氟甲基、氨甲基、羟甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基、乙氧基、乙酰基、乙磺酰基、乙氧羰基、二甲基氨基、二乙基氨基、二甲基氨基羰基、二乙基氨基羰基；N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S(＝O)2CH3,-CH2CH2CN,-CH2CH(OH)(CH3)2,-CH2CH(F)(CH3)2,-CH2CH2F,-CH2CF3,-CH2CH2CF3,-CH2CH2NH2,-CH2CH2OH,-CH2CH2OCH3,-CH2CH2CH2OCH3,-CH2CH2N(CH3)2,-S(＝O)2CH3,-CH2CH2S(＝O)2CH3,；和苯基、噻唑基、联苯基、萘基、环戊基、呋喃基、3-吡咯啉基、吡咯烷基、1,3-氧五环基、吡唑基、2-吡唑啉基、吡唑烷基、咪唑基、恶唑基、噻唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、4H-吡喃基、吡啶基、哌啶基、1,4-二氧六环基、吗啉基、哒嗪基、嘧啶基、吡嗪基、哌嗪基、1,3,5-三噻烷基、1,3,5-三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、嘌呤基、喹啉基、异喹啉基、噌啉基或喹喔啉基；
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方 式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
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)或C-14(14C)。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，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，结构单元
Figure PCTCN2017080599-appb-000030
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。
卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通 过氧桥连接的具有特定数目碳原子的上述烷基。C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。
术语“卤”或“卤素”是指氟、氯、溴和碘。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、 咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、苯基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的、单元或多元不饱和的，可以是单取代、二取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C10表示1至10个碳)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置(包括该烃基附着于分子其余部分的位置)。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂 烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代、二取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺 盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物经手工或者
Figure PCTCN2017080599-appb-000031
软件命名，市售化合物采用供应商目录名称。
附图说明：
图1：WX001对改善肺纤维化病灶区域内组织损伤评分
图2：WX001对改善肺纤维化病灶边缘的组织损伤评分
图3:WX002对改善肺纤维化病灶区域内组织损伤评分
图4：WX002对改善肺纤维化病灶边缘的组织损伤评分
图5：WX002对预防肺部纤维化面积的效果评分
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1：中间体A-1
Figure PCTCN2017080599-appb-000032
合成路线：
Figure PCTCN2017080599-appb-000033
步骤1：化合物A-1_2的合成。
在氮气保护下于10℃，向悬浮着钠氢(1.99g,49.83mmol)的无水DMF(75mL)溶液中滴加丙二酸二乙酯(6.57g,41.00mL)。滴加完成后，室温下搅拌反应0.5小时，然后滴加5-氯-2-硝基吡啶(5.00g,31.54mmol)的无水DMF(25mL)溶液。反应混合物缓慢升温至80℃，继续搅拌12小时。反应完成后，反应液用水(2300mL)稀释，然后EtOAc萃取(500mL*4)。合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂，所得残留物经层析柱分离纯化(洗脱剂：PE/EtOAc＝10/1到5/1)，得到桔红色固体化合物A-1_2(5.40g，收率60.66％)。1H NMR(400MHz,CDCl3)δ:8.63(d,J＝2.0Hz,1H),8.33-8.28(m,1H),8.26(d,J＝2.0Hz,1H),4.81(s,1H),4.33-4.21(m,4H),1.33-1.28(m,6H).
步骤2：化合物A-1_3的合成。
室温下，将化合物A-1_2(5.00g,17.71mmol)溶于无水DMF(50mL)中，加入碳酸钾固体(4.90g,35.42mmol)后，滴加碘甲烷(5.03g,35.42mmol)。混合物在25℃下搅拌1小时。反应完成后，反应液用水(900mL)稀释后，EtOAc萃取(200mL*3)。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂，所得残留物经层析柱分离纯化(洗脱剂：PE/EtOAc＝10/1)，得到黄色固体化合物A-1_3(5.25g，收率100％)。1H NMR(400MHz,CDCl3)δ:8.67(d,J＝2.0Hz,1H),8.25(d,J＝8.5Hz,1H),8.10(dd,J＝2.5,8.5Hz,1H),4.27(dq,J＝2.0,7.1Hz,4H),1.94(s,3H),1.28(t,J＝7.0Hz,6H).步骤3：化合物A-1_4的合成。
室温下，将化合物A-1_3(17.00g,60.23mmol)溶于EtOAc(150mL)中，加入10％湿钯碳(3.20g,3.01mmol)，混合物在40℃下于氢气氛围中(50psi)搅拌12小时。反应完成后，反应液过滤除去不溶物，催化剂用少量EtOAc(20mL*3)洗涤，滤液减压浓缩，所得桔黄色固体化合物A-1_4(13.70g，收率85.42％)可直接用于下一步合成，无需进一步纯化。1H NMR(400MHz,CDCl3)δ:7.83(d,J＝2.5Hz,1H),7.34(dd,J＝2.5,8.8Hz,1H),6.45-6.39(m,1H),5.99(s,2H),4.15(q,J＝7.0Hz,4H),1.74-1.66(m,3H),1.17(t,J＝7.0Hz,6H).
步骤4：化合物A-1的合成。
室温下，将化合物A-1_4(13.70g,51.45mmol)溶于70％的硫酸(92.00g,50.00mL)水溶液中，混合物降温到-5℃，慢慢滴加亚硝酸钠(4.30g,62.25mmol)的水(3.5mL)溶液，保证反应内温在0℃以下，混合物在-5℃下搅拌0.5小时，然后升温至室温，继续搅拌3小时。反应完成后，反应液加水(800mL)稀释，饱和Na2CO3水溶液调节pH至9～10，然后用EtOAc(200mL*4)萃取。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，旋蒸除去溶剂，所得残留物经层析柱分离纯化(洗脱剂：PE/EtOAc＝5/1至纯EtOAc)，得到棕黄色固体化合物A-1(11.00g，收率80％)。1H NMR(400MHz,CDCl3)δ:12.88(br.s.,1H),7.60(dd,J＝2.8,9.8Hz,1H),7.38(d,J＝3.0Hz,1H),6.57(d,J＝9.5Hz,1H),4.23(q,J＝6.9Hz,4H),1.76(s,3H),1.26(t,J＝7.0Hz,6H).
参考例2：中间体B-1
Figure PCTCN2017080599-appb-000034
合成路线：
Figure PCTCN2017080599-appb-000035
步骤1：化合物B-1_2的合成。
室温下，5-溴-2-甲氧基吡啶(15.00g,79.78mmol)和稀盐酸(6M，150mL)的混合物于100℃下搅拌20小时。反应完成后，混合物加水(600mL)稀释，用1M的氢氧化钠水溶液调节pH至中性，然后EtOAc(200mL*4)萃取。有机相合并，饱和食盐水(20mL)洗涤，无水Na2SO4干燥，过滤除去干燥剂，减压浓缩。残余物用混合溶剂(PE/EtOAc＝10/1，100mL)打浆，不溶物过滤收集，用PE(5mL*3)洗涤，减压干燥得到白色固体化合物B-1_2(10.42g，收率61.55％)。1H NMR(400MHz,CDCl3)δ:11.76(br s,1H),7.70(d,J＝3.0Hz,1H),7.56(dd,J＝2.5,9.5Hz,1H),6.36(d,J＝9.5Hz,1H).
步骤2：化合物B-1_3的合成。
氮气保护于室温下，向化合物B-1_2(10.40g,59.77mmol)的无水甲苯(400mL)溶液中，加入碳酸银(24.72g,89.66mmol)和苄溴(10.22g,59.77mmol)，混合物于110℃搅拌20小时。反应完成后，反应液用硅藻土过滤除去不溶物，滤饼用二氯甲烷(20mL*5)洗涤，所得滤液减压浓缩。残余物经层析柱分离纯化(洗脱剂：PE/EtOAc＝10/1)，得到白色固体化合物B-1_3(15.00g，收率95％)。1H NMR(400MHz,CDCl3)δ:8.22(d,J＝2.0Hz,1H),7.66(dd,J＝2.5,8.5Hz,1H),7.48-7.42(m,2H),7.39(br t,J＝7.3Hz,2H),7.34(br d,J＝7.0Hz,1H),6.73(d,J＝8.5Hz,1H),5.35(s,2H).
步骤3：化合物B-1_4的合成。
氮气保护于-70℃下，向化合物B-1_3(2.00g,7.57mmol)的无水THF(20mL)溶液中，逐滴加入2.5M的正丁基锂(3.21mL,8.02mmol)溶液，立即形成黄色悬浊液，混合物于-70℃下搅拌0.5小时。然后在相同温度下，滴加氧杂环丁酮(0.60g,8.33mmol)的THF(6mL)溶液，混合物于-70℃下搅拌1小时。反应完成后，反应液用饱和NH4Cl(5mL)水溶液淬灭，加水(50mL)稀释，EtOAc萃取(30mL*3)。合并有机相，饱和食盐水(10mL)洗涤，无水Na2SO4干燥。过滤除去干燥剂，减压浓缩。残余物经层析柱分离(洗脱剂：PE/EtOAc＝10/1到1/1)，得到白色固体化合物B-1_4(1.80g，收率92.42％)。1H NMR(400MHz,CDCl3)δ:8.40(d,J＝2.5Hz,1H),7.83(dd,J＝2.5,8.5Hz,1H),7.49-7.44(m,2H),7.41-7.36(m,2H),7.35-7.31(m,1H),6.87(d,J＝8.5Hz,1H),5.40(s,2H),4.92-4.88(m,4H),2.60(br s,1H).
步骤4：化合物B-1的合成。
室温下，将化合物B-1_4(1.40g,5.44mmol)溶于EtOAc(30mL)中，加入10％湿钯碳(580mg,544umol)，混合物在25℃下于氢气氛围中(15psi)搅拌1小时。反应完成后，反应液过滤除去不溶物，催化剂用DCM/MeOH混合溶剂(10:1，50mL*3)洗涤，滤液减压浓缩，所得白色固体化合物B-1(800.00mg，收率87.97％)可直接用于下一步合成，无需进一步纯化。1H NMR(400MHz,CDCl3)δ:7.71(dd,J＝2.8,9.3Hz,1H),7.43(d,J＝2.5Hz,1H),6.45(d,J＝9.5Hz,1H),4.74-4.70(m,2H),4.69-4.65(m,2H).
参考例3：中间体C-1
Figure PCTCN2017080599-appb-000036
合成路线：
Figure PCTCN2017080599-appb-000037
步骤1：化合物C-1_2的合成。
氮气保护于10℃下，向丙二酸叔丁基乙酯(46.36g,246.31mmol)的DMSO(125mL)的溶液中加入60％的钠氢(9.85g,246.31mmol)，反应液升温于15℃搅,拌0.5小时，然后再滴加5-溴-2-硝基吡啶(25.00g,123.16mmol)，反应液升温于80℃搅,拌5小时。TLC监测反应完成，反应混合物用饱和氯化铵(150mL)水溶液淬灭，EtOAc(200mL)萃取。有机相用水(150mL)和饱和食盐水(150mL)洗涤，无水Na2SO4干燥，过滤除去干燥剂，旋蒸至干。黄色油状残余物C-1_2(65g)无需纯化，作为粗品直接用于下一步。
步骤2：化合物C-1_3的合成。
室温下，向化合物C-1_2(65.00g,209.47mmol)的无水DCM(200mL)溶液中，加入三氟醋酸(200mL,2.70mol)溶液，混合液于40℃搅拌反应1.5小时。TLC监测反应完成后，反应液直接减压浓缩至干。残余物溶于200mL的EtOAc，用饱和NaHCO3水溶液(150mL)以及饱和食盐水(150mL)洗涤，有机相经无水Na2SO4干燥，过滤除去干燥剂，所得滤液减压浓缩。残余物经层析柱分离纯化(洗脱剂：PE/EtOAc＝10/1到3/1)，得到白色固体化合物C-1_3(16.70g，收率96.42％)。1H NMR(400MHz,CDCl3)δ:8.56(d,J＝2.13Hz,1H)8.26(d,J＝8.28Hz,1H)8.01(dd,J＝8.34,2.20Hz,1H)4.21(q,J＝7.07Hz,2H)3.79(s,2H)1.29(t,J＝7.09Hz,3H).
步骤3：化合物C-1_4的合成。
室温下，向化合物C-1_3(15.60g,74.22mmol)的乙醇(156mL)溶液中，加入10％的Pd/C(1.56g)， 混合物于15℃在氢气氛围下(15psi)搅拌11.5小时。LCMS监测反应完成后，反应液过滤除去不溶物，滤液减压下浓缩至干，得到红褐色油状化合物C-1_4(13.05g，收率96.98％)。1H NMR(400MHz,CDCl3)δ:7.77(d,J＝1.96Hz,1H)7.26(dd,J＝8.44,2.45Hz,1H)6.40(d,J＝8.44Hz,1H)5.82(s,2H)4.06(q,J＝7.13Hz,2H)3.44(s,2H)2.41-2.59(m,4H)1.18(t,J＝7.09Hz,3H).
步骤4：化合物C-1的合成。
80℃下，向化合物C-1_4(10.00g,55.49mmol)的醋酸(625mL)溶液中，于10分钟内滴加亚硝酸钠(16.46g,238.62mmol)的水溶液(18.75mL)，混合物于80℃搅拌0.5小时后，加入50mL水，然后继续搅拌2小时。LCMS监测反应完成后，反应液减压下浓缩，残余物溶于EtOAc(100mL)中，过滤除去不溶物，滤饼用少量EtOAc洗涤知道成为白色固体，滤液减压下浓缩至干。重新用EtOAc溶解后再过滤，重复几次同样的操作以除去粗产物中的无机盐。粗品用100mL的EtOA溶解后，用饱和NaHCO3水溶液洗至水相至中性(pH＝7～8)。有机相经无水Na2SO4干燥，过滤浓缩。残余物溶于20mL的EtOAc中，不溶物过滤，得到黄色固体化合物C-1(7.50g，收率74.59％)。1H NMR(400MHz,CDCl3)δ:11.47(br s,1H)7.34(dd,J＝9.29,2.64Hz,1H)7.26(d,J＝2.13Hz,1H)6.30(d,J＝9.41Hz,1H)4.08(q,J＝7.15Hz,2H)3.43(s,2H)1.19(t,J＝7.09Hz,3H).
实施例1：WX001
Figure PCTCN2017080599-appb-000038
合成路线：
Figure PCTCN2017080599-appb-000039
步骤1：化合物WX001-2的合成
室温于氧气氛围下，向化合物A-1(10.90g,40.78mmol)和苯硼酸(5.02g,41.19mmol)的无水DCM(130mL)溶液中加入醋酸铜(7.41g,40.78mmol)，三乙胺(8.25g,81.56mmol)和粉末状4A分子筛(2.20g)，混合物在室温下搅拌12小时。反应完毕后，过滤除去不溶物，固体用DCM(100mL*4)洗涤。滤液合并后，减压浓缩至干。残余物用层析柱纯化(洗脱剂：PE/EtOAc，从10:1到1:1)，得到黄色固体化合物WX001-2(13.00g，收率：92.84％)。1H NMR(400MHz,CDCl3)δ:7.55-7.47(m,3H),7.44(d,J＝7.5Hz,1H),7.39(d,J＝7.5Hz,2H),7.35(d,J＝2.5Hz,1H),6.65(d,J＝9.5Hz,1H),4.25(q,J＝7.0Hz,4H),1.76(s,3H),1.28(t,J＝7.0Hz,6H).
步骤2：化合物WX001-3的合成
0℃于氮气保护下，向化合物WX001-2(10.00g，29.12mmol)的MeOH(150mL)溶液中分批加入硼氢化钠(5.51g，145.60mmol)，混合物缓慢升温至25℃搅拌12小时。反应完成后，反应液倒入DCM(1500mL)中，并于室温搅拌1小时。过滤除去不溶物，滤液减压浓缩至干。残余物用层析柱纯化(洗脱剂：DCM/MeOH＝50/1到10/1)，得到白色固体粉末状化合物WX001-3(3.00g，收率39.73％)。1H NMR(400MHz,CDCl3)δ:7.55(dd,J＝2.8,9.5Hz,1H),7.50-7.38(m,4H),7.35(d,J＝7.3Hz,2H),6.60(d,J＝9.5Hz,1H),3.71(q,J＝11.3Hz,4H),1.10(s,3H).
步骤3：化合物WX001的合成
室温于氮气保护下，向化合物WX001-3(500.00mg,1.93mmol)，三苯基磷(1.01g,3.86mmol)和福美锌(900.00mg,2.94mmol)的无水THF(15mL)溶液中滴加偶氮二甲酸二乙酯DEAD(672.00mg,3.86mmol)，混合物在30℃下搅拌20小时。反应完毕后，反应液中加入MeOH(50mL)，过滤除去不溶物，滤饼用MeOH(10mL*2)洗涤。滤液合并后，减压浓缩至干。残余物用层析柱纯化(洗脱剂：PE/EtOAc，从10:1到纯EtOAc)，得到化合物WX001(280.00mg，收率60.13％)。1H NMR(400MHz,CDCl3)δ:7.59(dd,J＝2.6,9.7Hz,1H),7.54-7.47(m,2H),7.47-7.41(m,1H),7.38(d,J＝7.3Hz,2H),7.14(d,J＝2.8Hz,1H),6.74(d,J＝9.5Hz,1H),4.80(d,J＝5.8Hz,2H),4.61(d,J＝5.8Hz,2H),1.67(s,3H).
实施例2：WX002
Figure PCTCN2017080599-appb-000040
合成路线：
Figure PCTCN2017080599-appb-000041
步骤1：化合物WX002-2的合成
室温于氮气保护下，向化合物A-1(500.00mg,1.87mmol)和3-溴噻吩(304.88mg,1.87mmol)的无水dioxane(12mL)溶液中加入碘化亚铜(356.14mg,1.87mmol)，N,N’-二甲基-trans-环己二胺(427.07mg,3.74mmol)和碳酸钾(516.91mg,3.74mmol)，混合物在100℃下搅拌12小时。反应完毕后，反应液用水(50mL)稀释，EtOAc(50mL)萃取。有机相用5％的氨水(20mL*3)洗涤，至有机相成为亮黄色，且水相无蓝色洗出为止。水相再次用EtOAc(30mL*2)萃取，有机相合并，减压浓缩至干。残余物用层析柱纯化(洗脱剂：PE/EtOAc，从10/1到3/1)，得到黄色固体化合物WX002-2(550.00mg，收率：84.18％)。1H NMR(400MHz,CDCl3)δ:7.49(dd,J＝2.6,9.7Hz,1H),7.44-7.37(m,3H),7.25(br d,J＝5.3Hz,1H),6.63(d,J＝9.8Hz,1H),4.25(q,J＝7.2Hz,4H),1.77(s,3H),1.28(t,J＝7.2Hz,6H).
步骤2：化合物WX002-3的合成
0℃于氮气保护下，向化合物WX002-2(2.95g，8.44mmol)的MeOH(45mL)溶液中分批加入硼氢化钠(1.60g，42.20mmol)，混合物缓慢升温至25℃搅拌12小时。反应完成后，反应液倒入DCM(450mL)中，并于室温搅拌1小时。过滤除去不溶物，滤液减压浓缩至干。残余物用层析柱纯化(洗脱剂：DCM/MeOH＝50/1到10/1)，得到白色固体粉末状化合物WX002-3(950.00mg，收率42.42％)。1H NMR(400MHz,DMSO-d6)δ:7.76-7.72(m,1H),7.67-7.58(m,2H),7.42(d,J＝2.5Hz,1H),7.31-7.27(m,1H),6.45(d,J＝9.5Hz,1H),4.65(br s,2H),3.56-3.49(m,2H),3.48-3.42(m,2H),1.11(s,3H).
步骤3：化合物WX002的合成
室温于氮气保护下，向化合物WX002-3(900.00mg,3.39mmol)，三苯基磷(1.78g,6.78mmol)和福美锌(1.60g,5.22mmol)的无水THF(25mL)溶液中滴加偶氮二甲酸二乙酯DEAD(1.18g,6.78mmol)，混合物在30℃下搅拌20小时。反应完毕后，反应液中加入MeOH(50mL)，过滤除去不溶物，固体用MeOH(10mL*2)洗涤。滤液合并后，减压浓缩至干。残余物用层析柱纯化(洗脱剂：PE/EtOAc，从10:1到纯EtOAc)，得到混有少量三苯氧磷的黄色固体粗产物。粗产物用混合溶剂PE/EtOAc(1:1,10mL)打浆1小时，过滤收集固体，滤饼用PE(5mL*2)洗涤，所得固体真空干燥，得到化合物WX002(280.00mg，收率87.50％)。1H NMR(400MHz,CDCl3)δ:7.60(dd,J＝2.5,9.5Hz,1H),7.46-7.39(m,2H),7.27-7.22(m,2H),6.78(d,J＝9.5Hz,1H),4.80(d,J＝6.0Hz,2H),4.63(d,J＝5.8Hz,2H),1.72-1.65(m,1H),1.69(s,2H).
参照实施例2中的合成方法，合成下表中各实施例。
表1
Figure PCTCN2017080599-appb-000042
Figure PCTCN2017080599-appb-000043
实施例8：WX008
Figure PCTCN2017080599-appb-000044
合成路线：
Figure PCTCN2017080599-appb-000045
步骤1：化合物WX008的合成
室温于氧气氛围下，向化合物B-1(400.00mg,2.39mmol)和苯硼酸(300.00mg,2.46mmol)的无水DCM(20mL)溶液中加入醋酸铜(434.10mg,2.39mmol)，三乙胺(483.69mg,4.78mmol)和粉末状4A分子筛(200.00mg)，混合物在30℃下搅拌16小时。反应完毕后，过滤除去不溶物，固体用DCM(30mL*3)洗涤。滤液合并后，减压浓缩至干。残余物用层析柱纯化(洗脱剂：PE/EtOAc，从5:1到纯EtOAc)，得到化合物WX008(420.00mg，收率：72.24％)。1H NMR(400MHz,CDCl3)δ:7.79(dd,J＝2.5,9.5Hz,1H),7.55(d,J＝2.5Hz,1H),7.50-7.39(m,3H),7.33(d,J＝7.0Hz,2H),6.73(d,J＝9.5Hz,1H),4.84(d,J＝7.3Hz,2H),4.74(d,J＝7.3Hz,2H).
实施例9：WX009
Figure PCTCN2017080599-appb-000046
合成路线：
Figure PCTCN2017080599-appb-000047
步骤1：化合物WX009的合成
室温于氮气保护下，向化合物B-1(400.00mg,2.39mmol)和3-溴噻吩(401.36mg,2.46mmol)的无水dioxane(20mL)溶液中加入碘化亚铜(455.18mg,2.39mmol)，N,N’-二甲基-trans-环己二胺(545.83mg,4.78mmol)和碳酸钾(660.64mg,4.78mmol)，混合物在100℃下搅拌16小时。反应完毕后，反应液趁热过滤，滤饼用EtOAc(30mL*3)洗涤。有机相用5％的氨水(20mL*3)洗涤，至有机相成为亮黄色，且水相无蓝色洗出为止。水相再次用EtOAc(20mL*2)萃取，有机相合并，减压浓缩至干。残余物用层析柱纯化(洗脱剂：PE/EtOAc，从5/1到纯EtOAc)，得到化合物WX009(520.00mg，收率：87.28％)。1H NMR(400MHz,CDCl3)δ:7.78(dd,J＝2.6,9.4Hz,1H),7.61(d,J＝2.3Hz,1H),7.39-7.32(m,2H),7.16(dd,J＝1.4,5.1Hz,1H),6.69(d,J＝9.3Hz,1H),4.82(d,J＝7.3Hz,2H),4.67(d,J＝7.3Hz,2H).
实施例10：WX010
Figure PCTCN2017080599-appb-000048
合成路线：
Figure PCTCN2017080599-appb-000049
步骤1：化合物WX010的合成
0℃于氮气保护下，向化合物WX008(200.00mg，822.17umol)的无水DCM(5mL)溶液中加入二乙胺基三氟化硫DAST(245.82mg，1.51mmol)，混合物于0℃下搅拌2小时。反应完成后，反应液小心倒 入冰水(30mL)中淬灭，DCM萃取(20mL*3)。有机相合并，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥。过滤除去干燥剂后，滤液减压浓缩至干。残余物用制备TLC分离纯化，得到化合物WX010(180.00mg，收率89.26％)。1H NMR(400MHz,CDCl3)δ:7.50(dd,J＝2.3,9.5Hz,1H),7.45-7.32(m,4H),7.29(d,J＝7.0Hz,2H),6.66(d,J＝9.5Hz,1H),5.00-4.89(m,2H),4.78-4.67(m,2H).
参照实施例10中的合成方法，合成下表中实施例。
表2
Figure PCTCN2017080599-appb-000050
实施例12：WX012
Figure PCTCN2017080599-appb-000051
合成路线：
Figure PCTCN2017080599-appb-000052
步骤1：化合物WX012-2的合成
室温于氮气保护下，向化合物C-1(2.00g,11.04mmol)和3-溴噻吩(1.98g,12.14mmol)的无水二氧六环(50mL)溶液中加入碘化亚铜(2.10g,11.04mmol)，N,N’-二甲基-trans-环己二胺(2.92g,33.11mmol)和磷酸钾(3.51g,16.56mmol)，混合物在110℃下搅拌4小时。TLC监测反应完毕后，反应液 趁热过滤，滤液减压浓缩至干。残余物经柱层析(PE:EA＝4:1to 1:4)纯化，得到黄色油状化合物WX012-2(2.65g，收率：90.51％)。1H NMR(400MHz,CDCl3)δ:7.75(br s,1H)7.66(br s,2H)7.43(br d,J＝9.29Hz,1H)7.29(br d,J＝4.65Hz,1H)6.48(br d,J＝9.29Hz,1H)4.10(q,J＝7.05Hz,2H)3.51(s,2H)1.20(br t,J＝6.97Hz,3H).
步骤2：化合物WX012-3的合成
-10℃下，向乙醇钠(56.86mg,835.51umol)和多聚甲醛(1.13g,12.53mmol)的无水THF(50mL)溶液中滴加化合物WX012-2(2.20g,8.36mmol)的THF(20mL)溶液，混合物在0℃下搅拌4小时。LCMS监测原料未消耗完全，补加四批次乙醇钠(56.86mg,835.51umol)，混合物在15℃下搅拌40小时。TLC监测反应完毕后，反应液过滤除去不溶物，滤液减压浓缩至干。残余物经制备HPLC(碱性)纯化，得到浅黄色油状化合物WX012-3(0.29g，收率：10.73％)。
步骤4：化合物WX012-4的合成
室温于氮气保护下，向化合物WX012-3(290.00mg,896.82umol)，三苯基磷(1.18g,4.48mmol)和福美锌(891.38mg,2.91mmol)的无水THF(10mL)溶液中滴加偶氮二甲酸二乙酯DEAD(780.93mg,4.48mmol)，混合物在15℃下搅拌12小时。LCMS监测反应完毕后，反应液过滤除去不溶物，滤液减压浓缩至干。残余物用制备TLC(展开剂：PE/EtOAc＝1/2)纯化，得到黄色固体化合物WX012-4粗品(300mg，含30％三苯氧磷)。
步骤5：化合物WX012的合成
室温下，向粗品WX012-4(300mg,0.98mmol)的乙醇(5mL)溶液中加入LiOH.H2O(412.28mg,9.82mmol)的水溶液(5mL)，混合物在15℃下搅拌1小时。LCMS监测反应完毕后，反应液经1M的HCl水溶液调节pH至5～6，用EtOAc(20mL*3)萃取，有机相合并，减压浓缩至干。残余物用制备HPLC(酸性)纯化，得到白色固体化合物WX012(10mg，收率3.7％)。
各实施例的NMR和MS数据
表3
Figure PCTCN2017080599-appb-000053
Figure PCTCN2017080599-appb-000054
实验例1：生物活性实验
主要任务:体外评价化合物对内毒素(LPS)诱导大鼠血液中TNF-α的影响
实验目的：在体外检测化合物对LPS诱导大鼠血液中TNF-α的影响，评估化合物对大鼠血液中LPS诱导TNF-α的抑制作用。
实验材料:
Sprague Dawley大鼠(雄性,210～260g,上海斯莱克)
Rat TNF-alpha Quantikine ELISA Kit(R&D,#SRTA00)
实验操作：
配制浓度为5mM或1mM的待测化合物溶液，分别在48孔细胞培养板中加入40μL(化合物终浓度为0.5或0.1mM)。大鼠用异氟烷麻醉后，于腹主动脉采血(肝素抗凝)。将血液加入已加好待测化合物的48孔板中，每孔320μL。48孔板放置于37℃孵育，孵育30分钟后取出，加入40μL LPS溶液(终浓度 100ug/mL)，混匀后放置于37℃中继续孵育。5小时后取出48孔板，血样转移至1.5mL离心管中，置于离心机中离心(4,500rpm,4℃,5分钟)，分离上层得血浆，20μL每孔分装于96孔样品板后速冻，保存在-80℃冰箱。第二天按照试剂盒说明书操作用R&D ELISA试剂盒进行血浆样品中TNF-α水平检测。用EXCEL和Prism统计软件进行数据分析。
实验结果总结：
表4
实施例 体外TNF-α抑制率 实施例 体外TNF-α抑制率
吡非尼酮* 51.4％ WX004 89.5％
WX001* 86.3％ WX005 61.6％
WX002 74.6％ WX009* 51.5％
WX003 84.7％ WX011 78.8％
注：“*”化合物检测浓度为0.5mM；其余均为0.1mM；
结论：在体外TNF-α抑制活性检测实验中，化合物WX001(0.5mM)、WX002、WX003、WX004、WX011在0.1mM终浓度能够显著抑制LPS诱导的TNF-α水平，对TNF-α的抑制率显著高于同剂量原研药吡非尼酮。
实验例2：体内药效实验
实验目的：测试化合物对博来霉素诱导SD大鼠肺纤维化的预防性治疗作用
实验材料：
动物：雄性SD大鼠，35只
模型：SD大鼠左侧单侧肺肺纤维化模型：大鼠气管注射博来霉素(3mg/kg in 1.5ml/kg)复制肺纤维化模型
造模剂：博来霉素(BLM)
实验过程：
1.实验分组：共进行了两次药效实验，除共有的模型组与阳性参照物吡非尼酮组，供试化合物分为三组，即模型组(Group-1,n＝7,Vehicle)，阳性对照药物(group-2,n＝7,吡非尼酮)；受试药物WX001组(Group-3，n＝7)，受试药物WX002高剂量组(Group-4，n＝7)，受试药物WX002低剂量组(Group-5，n＝7)(表5)。
表5
分组 动物数 博来霉素(3.0mg/kg) 给药化合物 剂量及频率
Group-1(实验一) 7 注射 NA NA
Group-2(实验一) 7 注射 吡非尼酮 50mpk,每天两次
Group-3(实验一) 7 注射 WX001 30mpk,每天两次
Group-4(实验二) 7 注射 WX002 50mpk,每天两次
Group-5(实验二) 7 注射 WX002 25mpk,每天两次
2.试验给药：造模后当日开始口服给药，给药频率为每天两次。连续给药14天。
3.实验动物生理观察：检测动物体重变化(每天给药前测量一次体重)；监测试验周期内动物死亡率。
4.连续给药14天后各组动物安乐死，左肺肺内福尔马林灌注固定，测量灌注后左肺体积和重量，肺病理相关检测(表6)。
表6
分组 动物数 H&E Masson Thrichrome染色
Group-1(实验一) 7 需要 需要
Group-2(实验一) 7 需要 需要
Group-3(实验一) 7 需要 需要
Group-4(实验二) 7 需要 需要
Group-5(实验二) 7 需要 需要
实验结果测定：
左肺组织病理学检测：H&E染色病理评价：1)左肺终末细支气管病理变化，2)左肺细小动脉病理变化；Masson Trichrome染色病理评价：3)左肺肺纤维化面积，4)左肺肺纤维化评分。
实验结果总结：
二次药效试验结果表明：WX001对改善肺纤维化病灶区域内和边缘的组织损伤有很好的效果(图1&2)，WX002对于改善肺纤维化病灶区域内和边缘的组织损伤同样有很好的效果(图3&4)，并且具有很好的预防肺部纤维化形成的药效(图5)，相比参照化合物吡非尼酮，无论是同剂量100mpk组还是低剂量50mpk组，都达到了较吡非尼酮更好的药效。

Claims (21)

  1. 式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体，
    Figure PCTCN2017080599-appb-100001
    其中，
    X选自O、S和N(R)；
    R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH，或选自任选被1、2或3个R取代的C1-6烷基和C1-6杂烷基；
    R3选自H，或选自任选被1、2或3个R取代的C1-6烷基和C1-6杂烷基；
    R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的C1-6烷基和C1-6杂烷基；
    环A选自5～10元芳基和5～10元杂芳基；
    m选自0、1或2；
    n选自0、1或2；
    m与n不同时选自0；
    p选自0、1、2或3；
    R选自H、F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2，或选自任选被1、2或3个R’取代的：
    C1-8烷基、C1-8杂烷基、C3-6环烷基、3～6元杂环烷基、C3-6环烷基-C1-3烷基-；
    R’选自F、Cl、Br、I、OH、CN、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2；
    “杂”表示杂原子或杂原子团，选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、＝O、＝S、-O-N＝、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-和-N(R)C(＝O)N(R)-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物、其药学上可接受的盐及其互变异构体，其中，R选自H、F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2，或选自任选被1、2或3个R’取代的：C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、N,N’-二(C1-3烷基)氨基、C3-6环烷基、3～6元杂环烷基。
  3. 根据权利要求2所述化合物、其药学上可接受的盐及其互变异构体，其中，R选自H、F、Cl、Br、I、OH、CN、NH2、COOH、C(＝O)NH2、Me、Et、CF3、CHF2、CH2F、NH(CH3)、N(CH3)2。
  4. 根据权利要求1～3任意一项所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
    Figure PCTCN2017080599-appb-100002
    选自
    Figure PCTCN2017080599-appb-100003
  5. 根据权利要求4所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
    Figure PCTCN2017080599-appb-100004
    选自
    Figure PCTCN2017080599-appb-100005
  6. 根据权利要求1或2所述化合物、其药学上可接受的盐及其互变异构体，其中，R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH，或选自任选被1、2或3个R取代的C1-3烷基。
  7. 根据权利要求6所述化合物、其药学上可接受的盐及其互变异构体，其中，R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH，或选自任选被1、2或3个R取代的Me。
  8. 根据权利要求7所述化合物、其药学上可接受的盐及其互变异构体，其中，R2选自F、Cl、Br、I、OH、NH2、CN、NO2、COOH、Me。
  9. 根据权利要求1～3任意一项所述化合物、其药学上可接受的盐，及其互变异构体，其中，R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的C1-3烷基、C1-3烷氧基、C1-3烷硫基、NH(C1-3烷基)、N,N’-二(C1-2烷基)氨基。
  10. 根据权利要求9所述化合物、其药学上可接受的盐及其互变异构体，其中，R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH，或选自任选被1、2或3个R取代的Me、
    Figure PCTCN2017080599-appb-100006
  11. 根据权利要求10所述化合物、其药学上可接受的盐及其互变异构体，其中，R4选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、
    Figure PCTCN2017080599-appb-100007
  12. 根据权利要求1～3任意一项所述化合物、其药学上可接受的盐及其互变异构体，其中，环A选自5～6元芳基和5～9元杂芳基。
  13. 根据权利要求12所述化合物、其药学上可接受的盐及其互变异构体，其中，环A选自苯基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吡咯基、咪唑基、吡唑基、呋喃基、噻吩基、恶唑基、噻唑基、异恶唑基、异噻唑基、三唑基、苯并噻吩基。
  14. 根据权利要求13所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元
    Figure PCTCN2017080599-appb-100008
    选自：
    Figure PCTCN2017080599-appb-100009
  15. 根据权利要求11或14所述化合物、其药学上可接受的盐及其互变异构体，其中，结构单元结构单元
    Figure PCTCN2017080599-appb-100010
    选自：
    Figure PCTCN2017080599-appb-100011
  16. 根据权利1～15任意一项所述化合物、其药学上可接受的盐及其互变异构体，其选自：
    Figure PCTCN2017080599-appb-100012
    其中，
    R2、R4、和P如权利要求1～15所定义。
  17. 下式所示化合物：
    Figure PCTCN2017080599-appb-100013
  18. 一种药物组合物，其含有治疗有效量的根据权利要求1～17任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  19. 根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐或根据权利要求18所述的药物组合物在制备治疗纤维化相关疾病的药物中的应用。
  20. 根据权利要求所述的应用，其中，纤维化病症是指特发性肺纤维化。
  21. 根据权利要求所述的应用，其中，纤维化病症是指肝纤维化。
PCT/CN2017/080599 2016-04-14 2017-04-14 用于治疗纤维化和炎性疾病的含杂原子环丁烷取代基的吡啶酮衍生物 Ceased WO2017177974A1 (zh)

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WO2025209440A1 (zh) * 2024-04-02 2025-10-09 广州嘉越医药科技有限公司 一种吡啶酮衍生物的药物组合物及其应用

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