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WO2018133870A1 - 作为Caspase抑制剂的联环化合物 - Google Patents

作为Caspase抑制剂的联环化合物 Download PDF

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Publication number
WO2018133870A1
WO2018133870A1 PCT/CN2018/073721 CN2018073721W WO2018133870A1 WO 2018133870 A1 WO2018133870 A1 WO 2018133870A1 CN 2018073721 W CN2018073721 W CN 2018073721W WO 2018133870 A1 WO2018133870 A1 WO 2018133870A1
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Prior art keywords
pharmaceutically acceptable
compound
acceptable salt
tautomer
group
Prior art date
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PCT/CN2018/073721
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English (en)
French (fr)
Inventor
牟剑锋
吴松亮
贺海鹰
郭凤英
王川
李婕
黎健
陈曙辉
Original Assignee
正大天晴药业集团股份有限公司
南京明德新药研发股份有限公司
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Application filed by 正大天晴药业集团股份有限公司, 南京明德新药研发股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to AU2018209577A priority Critical patent/AU2018209577B2/en
Priority to CN201880007961.1A priority patent/CN110177774B/zh
Priority to US16/479,673 priority patent/US11434212B2/en
Priority to CN202110631394.0A priority patent/CN113354708B/zh
Priority to CA3050832A priority patent/CA3050832A1/en
Priority to EP18741759.7A priority patent/EP3572402B1/en
Priority to JP2019539922A priority patent/JP7113831B2/ja
Publication of WO2018133870A1 publication Critical patent/WO2018133870A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present application relates to a novel class of compounds as caspase inhibitors and pharmaceutically acceptable salts thereof, and to pharmaceutical compositions containing these compounds and methods of using such pharmaceutical compositions.
  • Necrotic cell death is one of the forms of cell death characterized by cell death due to pathological cell death caused by trauma or cell damage. Necrotic cell death is harmful to tissues, such as inflammation. In contrast, another physiological form of cell death occurs in an orderly, controlled manner. This ordered, controlled form of cell death is called apoptotic cell death (Barr, et al., Bio/Technology, 12: 487-497, 1994;
  • apoptotic cell death is an extremely important physiological process to maintain the normal development and dynamic balance of the organism.
  • caspase cyste aspartate-specific protease
  • Capase is a type of cysteine protease, and many important proteins in cells are its substrate. The process of apoptotic cell death involves the removal of fragments decomposed by the cells by caspase enzymes by other cells, or by macrophages or the like without causing inflammation or the like.
  • the present application provides a compound represented by the formula (I), a pharmaceutically acceptable salt thereof and a tautomer thereof,
  • Ring A is selected from a 5-membered heteroaryl or 6-membered heteroaryl group, which is optionally substituted by R;
  • Ring B is selected from phenyl or C 3-6 cycloalkyl, said phenyl or C 3-6 cycloalkyl being optionally substituted by R;
  • R is selected from halogen, OH, NH 2 , or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R 1 ;
  • R 1 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 .
  • the heteroatoms of Ring A are independently selected from O, S or N.
  • the number of heteroatoms of ring A is selected from 1, 2 or 3.
  • the above ring A is selected from the group consisting of oxazolyl, isoxazolyl, imidazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or pyridyl Azolyl.
  • the ring A is selected from the group consisting of
  • the above ring B is selected from phenyl or cyclohexyl, and the phenyl or cyclohexyl group is optionally substituted with R.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , or Me or Et optionally substituted with 1, 2 or 3 R 1 .
  • the above R 1 is selected from the group consisting of F, Cl or NH 2 .
  • R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , or Me or Et, optionally substituted with 1, 2 or 3 F.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 or CF 3 .
  • the above ring B is selected from the group consisting of:
  • Selected from The ring B is optionally substituted by R.
  • the compound of formula (I) of the present application is selected from the group consisting of a compound of formula (II),
  • ring A and ring B are as defined above.
  • the compound of Formula (I) of the present application is selected from the group consisting of:
  • Another object of the present application is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another object of the present application is to provide a use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the manufacture of a medicament for the treatment of a disorder associated with a caspase receptor.
  • Another object of the present application is to provide a method of treating a condition associated with a caspase receptor in a mammal comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Or a pharmaceutical composition thereof.
  • Another object of the present application is to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating a caspase receptor-related disorder.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention prepared from a compound having a particular substituent found herein 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.
  • the acid addition salt can be obtained by contacting a sufficient amount of an acid with a neutral form of such a compound in a neat solution or a suitable inert solvent.
  • Certain specific compounds of the present application contain basic and acidic functional groups which can be converted to any base or acid addition salt.
  • 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 pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from the parent compound containing an acidic functional group or a basic functional group.
  • 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.
  • the organic solvent is preferably a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the compounds provided herein also exist in the form of a prodrug.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the claimed compounds.
  • prodrugs can be converted to the compounds of the present application by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the present application may exist in unsolvated as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present application.
  • Certain compounds of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and individual isomers are included within the scope of this application.
  • Wedge-shaped solid and dashed keys Represents the absolute configuration of a stereocenter, using wavy lines a solid or dashed key representing a wedge
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified.
  • all tautomeric forms are included within the scope of this application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present application, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the application. 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 this application.
  • 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 present application 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 is removed to provide Pure desired enantiomer.
  • a molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group)
  • the molecule is formed into a diastereomeric salt with a suitable optically active acid or base, and then passed through the art.
  • the diastereomer resolution is carried out by a conventionally known method, and then the pure enantiomer is recovered. Furthermore, 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 application may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). All isotopic compositional changes of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of the active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient.
  • Representative carriers include 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 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, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • 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.
  • C mn means having mn carbon atoms in this moiety.
  • C 3-10 cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.
  • the numerical range in this document refers to each integer in a given range.
  • C 1-10 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 Carbon atom, 9 carbon atoms or 10 carbon atoms.
  • 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.
  • substituents When a substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • 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).
  • 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” 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 containing a carbon atom.
  • 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). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • 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.
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, means a straight, branched or cyclic hydrocarbon.
  • the atomic group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as a Divalent (such as methylene) or polyvalent (such as methine), may include divalent or multivalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons, 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 -C 12 represents 1 to 12 carbons
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic hydrocarbyl groups, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 An aromatic hydrocarbon group such as a phenyl group, a naphthyl group 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, cyclohexyl, (cyclohexyl)methyl, cyclic A propylmethyl group, and a homologue or isomer of an atomic group such as n-pentyl, n-hexyl, n-heptyl or n-octyl.
  • the unsaturated hydrocarbon 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 isomers body.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • cycloalkyl includes any stable cyclic or polycyclic hydrocarbon radical, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent.
  • examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctyl, [4.4.0]bicyclodecyl, and the like.
  • halo or halogen, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the solvent used in the present application is commercially available.
  • the present application uses the following abbreviations: eq for equivalent, equivalent; NMM for N-methylmorpholine; DMSO for dimethyl sulfoxide; HOBt for 1-hydroxybenzotriazole; EDCI for 1-ethyl-( 3-dimethylaminopropyl)carbonyldiimide hydrochloride; TEMPO represents tetramethylpiperidine oxynitride; T3P represents propylphosphoric anhydride; DIPEA represents N,N-diisopropylethylamine.
  • Compounds are artificial or Software naming, commercially available compounds using the supplier catalog name.
  • the combined filtrate was poured into a three necked flask and maintaining the temperature at 0 °C, the CH 2 N 2- ether solution (370 mL of) were added to the flask under nitrogen, at 0 °C stirring continued for 20 minutes and warmed to 20 °C Stir for another 2 hours.
  • the reaction mixture was then cooled to 0.degree. C. and treated with H.sub.2 (30 mL, 35% acetic acid). and the mixture was stirred at 0[deg.] C. for 15 min.
  • the reaction mixture was extracted with ethyl acetate (500 mL) and water (400 mL). The organic phase was washed with water (400 mL), saturated sodium bicarbonate (400 mL) and brine (400 mL). After drying over anhydrous sodium sulfate, the title compound was obtained.
  • Examples 2-17 The compounds of Examples 2-17 were prepared by reference to the synthetic route of Example 1, replacing compound 1-b with a different intermediate acid.
  • Example 18 The compound of Example 18 was prepared by reference to the synthetic route of Example 1, substituting the intermediate 1-e for the compound 1-a.
  • This experiment used BioVision's Caspase Inhibitor Screening Kit to test the inhibitory activity of the test compound against Caspase.
  • test compound was diluted to a test concentration of 200* in DMSO, diluted to 2* test concentration with ddH 2 O, and added to a 384-well experimental plate at 12.5 ⁇ l per well.
  • Test compound and control compound were tested at 6 concentration points with test concentrations ranging from 1000 nM to 0.32 nM.
  • 1% DMSO containing ddH 2 O was added to the control wells, and a high concentration of control compound (final concentration: 5 ⁇ M) was added to the 100% inhibition control wells.
  • the fluorogenic substrate of the caspase enzyme was diluted 5-fold with 2X reaction buffer containing 10 mM DTT, and then added to a 384-well experimental plate at 6.25 ⁇ l per well.
  • the total reaction volume was 25 ⁇ l, the final concentration of the substrate was 50 ⁇ M, and the final concentration of DMSO was 0.5%. After the substrate was added, the 384-well experimental plate was incubated at 37 ° C for 30 minutes.
  • the fluorescence intensity (excitation light wavelength 400 nm, emission light wavelength 505 nm) was measured using a multi-function microplate reader. Fluorescence intensity was used to calculate the inhibitory effect of the compound on Caspase. Using GraphPad Prism software The compounds combined inhibition curve to calculate the 50 value IC.
  • Example 1 Compound number Caspase-1 Caspase-3 Caspase-8 Example 1 4.6 13.0 10.3 Example 2 5.3 29.6 24.6 Example 3 4.8 24.0 25.9 Example 4 4.1 11.4 11.7 Example 5 3.9 13.7 16.8 Example 6 6.0 24.5 19.9 Example 7 6.9 20.2 30.0 Example 8 5.5 21.8 18.0 Example 9 14.2 44.4 23.2 Example 10 6.6 22.0 16.3 Example 11 9.2 30.0 22.6 Example 12 6.7 21.0 17.9 Example 17 4.2 9.5 31.4 Example 18 7.5 26.1 62.1
  • the compound of the present application has a good inhibitory activity against Caspase enzyme.
  • mice were randomly divided into three groups of 3 male mice each.
  • the compound is formulated into the indicated formulation.
  • Oral formulations can be clarified or uniform suspensions. Animals were given a given dose of the preparation by intragastric administration.
  • the plasma sample was added to a centrifuge tube containing an anticoagulant, centrifuged at 3000 g for 15 min at 4 ° C, and the supernatant plasma was quickly frozen on dry ice and then stored in a -70 ⁇ 10 ° C refrigerator until LC-MS/MS analysis.
  • the blood outside the liver was blotted with absorbent paper, the weight of the liver was weighed, and then placed in liquid nitrogen to freeze.
  • the mixture was homogenized at 14000 rpm for 2 minutes in a volume ratio of 1:5 by adding MeOH/15 mM PBS (1:2). It was then stored in a -70 ⁇ 10 ° C freezer until LC-MS/MS analysis.
  • the following pharmacokinetic parameters were calculated using a log-linear trapezoidal method: elimination phase half-life (T 1/2 ), mean residence time of the drug in the body from 0 to the end of time (MRT 0-last ), 0 to unlimited time Mean residence time in the body (MRT 0-inf ), time from 0 o'clock to end time point - area under the plasma concentration curve (AUC 0-last ), 0 o'clock to infinity time - area under the plasma concentration curve (AUC 0-inf ) .
  • the pharmacokinetic parameters were calculated by the theoretical blood collection time and the theoretical administration concentration in the protocol.
  • the actual dosing concentration is within a range of ⁇ 20% from the theoretical concentration.
  • the actual blood collection time and the theoretical blood collection time deviation are in accordance with the relevant SOP (the point within 1 hour after administration is within ⁇ 1 minute, and the others are within 5% of the theoretical time).
  • Example 1 From the above Table 2, it can be seen that the reference compound IDN-6556 has a relatively small amount of liver exposure at different time points, and the curve area of the liver drug is lower.
  • the liver exposure of the compound shown in Example 1 was significantly improved compared to IDN-6556, which was about 5 times higher.
  • Example 1 also maintained a comparable liver/plasma time curve area ratio. If used to treat liver disease, high liver drug exposures make it possible for us to reduce the dose administered.
  • test compounds IDN-6556 and the compound of Example 1 in CCl 4 induced in male C57BL / 6 mice with chronic liver fibrosis model.
  • mice Male C57BL/6 mice were randomly divided into 7 groups, namely, the fake model group (group 1), the model group (group 2, vehicle po, qd), IDN-6556 (group 3, 3 mg/kg, po, bid), IDN-6556 (Group 4, 10 mg/kg, po, bid), Example 1 (Group 5, 3 mg/kg, po, bid), Example 1 (Group 6, 10 mg/kg, po, bid), Examples 1 (Group 7, 20 mg/kg, po, bid).
  • CCl 4 was formulated into a CCl 4 -olive oil mixed solution according to the dose with olive oil, orally orally for 3 weeks, and the pseudo model group was orally administered only the same volume of olive oil. Oral compounds were started on the day of modeling, twice a day for 28 days.
  • the pseudo model group and the model group were orally administered an equal volume of drug vehicle.
  • the animals were fasted for 6 hours, and the animals were euthanized and the liver was collected. Liver tissue was fixed in 10% formalin solution for histopathological analysis.
  • Table 3 is a liver pathology test score, by which it can be seen that IND-6556 and the different dose groups of Example 1 can significantly improve liver tissue damage caused by CCl 4 , and in addition, Example 1 is significantly inhibited compared with the model group. The formation of liver fibrosis (p ⁇ 0.01).
  • One-way ANOVA (one-way ANOVA): ### p ⁇ 0.001 vs. group 1; * p ⁇ 0.05 vs. group 2; *** p ⁇ 0.001 vs. group 2
  • T-test $ p ⁇ 0.05 vs. group 2; $$ p ⁇ 0.01 vs. group 2.
  • liver fibrosis of C57BL/6 mice was successfully induced by oral administration of CCl 4 .
  • Example 1 was superior to IND-6556 in this model.

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Abstract

一种如式(Ⅰ)所示的化合物、其药学上可接受的盐或其互变异构体，以及该化合物作为caspase抑制剂的应用。

Description

作为Caspase抑制剂的联环化合物
相关申请的引用
本申请要求于2017年01月23日向中华人民共和国国家知识产权局提交的第201710059063.8号中国专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请涉及一类作为caspase抑制剂的新的化合物及其药学上可接受的盐，本申请还涉及含有这些化合物的药物组合物和使用这类药物组合物的方法。
背景技术
哺乳动物细胞数量的控制在一定程度上由细胞繁殖和死亡之间的平衡决定。坏死性细胞死亡是细胞死亡形式之一，其特点在于细胞的死亡是由于外伤或细胞损坏所导致的病理性细胞死亡。坏死性细胞死亡对组织有危害，如导致发炎等。相反，另外一种细胞死亡的生理形式却是以有序、控制的方式进行。这种有序、控制的细胞死亡形式称为凋亡性细胞死亡(Barr，et al.，Bio/Technology，12：487-497，1994；Steller，et al.，267：1445-1449，1995)。通过凋亡性细胞死亡这种程序化的方式，生物体在不损害其他组织的情况下，消灭多余的细胞(其活动和存在已无需要的细胞)。因此，凋亡性细胞死亡是维持生物体正常发育及动态平衡的极为重要的生理过程。
有许多因素可以引起凋亡性细胞死亡。其中，最重要的因素是一类称为caspase的蛋白酶(cysteine aspartate-specific protease，已知有14种caspase蛋白酶)。Capase是一类半胱氨酸蛋白酶，细胞中的许多重要的蛋白质是它的作用底物。凋亡性细胞死亡的过程包括细胞在caspase酶作用下分解的碎片被其他的细胞吸收，或者被巨噬细胞等在不引发炎症等的情况下消灭。
发明内容
本申请提供了式(Ⅰ)所示的化合物、其药学上可接受的盐及其互变异构体，
Figure PCTCN2018073721-appb-000001
其中，
环A选自5元杂芳基或6元杂芳基，所述5元杂芳基或6元杂芳基任选地被R取代；
环B选自苯基或C 3-6环烷基，所述苯基或C 3-6环烷基任选地被R取代；
R选自卤素、OH、NH 2、或任选被1、2或3个R 1取代的C 1-3烷基；
R 1选自F、Cl、Br、I、OH、NH 2、NH(CH 3)或N(CH 3) 2。
本申请的一些方案中，环A的杂原子独立地选自O、S或N。
本申请的一些方案中，环A的杂原子的数目选自1、2或3。
本申请的一些方案中，上述环A选自噁唑基、异噁唑基、咪唑基、噻唑基、1,2,4-噁二唑基、1,3,4-噁二唑基或吡唑基。
本申请的一些方案中，上述环A选自
Figure PCTCN2018073721-appb-000002
Figure PCTCN2018073721-appb-000003
本申请的一些方案中，上述环B选自苯基或环己基，所述苯基或环己基任选地被R取代。
本申请的一些方案中，上述R选自F、Cl、Br、I、OH、NH 2，或任选被1、2或3个R 1取代的Me或Et。本申请的一些方案中，上述R 1选自F、Cl或NH 2。
本申请的一些方案中，上述R选自F、Cl、Br、I、OH、NH 2，或任选被1、2或3个F取代的Me或Et。
本申请的一些方案中，上述R选自F、Cl、Br、I、OH、NH 2或CF 3。
本申请的一些方案中，上述环B选自：
Figure PCTCN2018073721-appb-000004
Figure PCTCN2018073721-appb-000005
本申请的一些方案中，
Figure PCTCN2018073721-appb-000006
选自
Figure PCTCN2018073721-appb-000007
Figure PCTCN2018073721-appb-000008
Figure PCTCN2018073721-appb-000009
所述环B任选地被R取代。
本申请的一些方案中，
Figure PCTCN2018073721-appb-000010
选自
Figure PCTCN2018073721-appb-000011
Figure PCTCN2018073721-appb-000012
Figure PCTCN2018073721-appb-000013
本申请的一些方案中，
Figure PCTCN2018073721-appb-000014
选自
Figure PCTCN2018073721-appb-000015
Figure PCTCN2018073721-appb-000016
本申请的一些方案中，
Figure PCTCN2018073721-appb-000017
选自
Figure PCTCN2018073721-appb-000018
Figure PCTCN2018073721-appb-000019
Figure PCTCN2018073721-appb-000020
在一些实施方案中，本申请的式(Ⅰ)化合物选自式(II)所示的化合物，
Figure PCTCN2018073721-appb-000021
其中，环A、环B如上文中所定义。
在一些实施方案中，本申请的式(Ⅰ)化合物选自以下化合物：
Figure PCTCN2018073721-appb-000022
Figure PCTCN2018073721-appb-000023
本申请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式(Ⅰ)化合物或其药学上可接受的盐和药学上可接受的载体。
本申请的另一个目的在于提供式(Ⅰ)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caspase受体相关病症的药物中的应用。
本申请的另一个目的在于提供治疗哺乳动物caspase受体相关病症的方法，包括对需要该治疗的哺乳动物(优选人类)给予治疗有效量的式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物。
本申请的另一个目的在于提供预防或者治疗caspase受体相关病症的式(Ⅰ)化合物或其药学上可接受的盐。
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。
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”是指本申请化合物的盐，由本申请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。当本申请的化合物中含有相对酸性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本申请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。本申请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。
本申请的药学上可接受的盐可由含有酸性官能团或碱性官能团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，所述有机溶剂优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本申请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申请的化合物。此外，前药可以在体内环境中通过化学或生化方法被转换到本申请的化合物。
本申请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，都包含在本申请的范围之内。
本申请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申请的范围之内。
除非另有说明，用楔形的实线键和虚线键
Figure PCTCN2018073721-appb-000024
表示一个立体中心的绝对构型，用波浪线
Figure PCTCN2018073721-appb-000025
表示楔形的实线键或虚线键
Figure PCTCN2018073721-appb-000026
当本文所述化合物含有烯属双键或其它几何不对称中心时，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申请的范围之内。
本申请的化合物可以存在特定的几何或立体异构体形式。本申请设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-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申请的范围之内。 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，均包括在本申请的范围之内。
可以通过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。如果想得到本申请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，其中将所得的非对映体混合物分离，并且将辅助基团脱去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，使所述分子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)。
本申请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)。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
术语“药学上可接受的载体”是指能够递送本申请有效量活性物质、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的载体、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。对于本申请中的口服剂型，组合物中的一种活性物质的“有效量”是指与该组合物中的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“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须出现的，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。
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，可以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。
本文所用的C m-n指该部分中具有m-n个碳原子。例如，“C 3-10环烷基”指该环烷基具有3-10个碳原子。本文中的数字范围，是指给定范围中的各个整数。例如“C 1-10”指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
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。
当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018073721-appb-000027
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018073721-appb-000028
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018073721-appb-000029
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018073721-appb-000030
所述连接基团、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。
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，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。
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。
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、芳基等)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(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，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C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“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烃基，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，例如苯基、萘基等。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、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。不饱和烃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“烷基”用于表示直链或支链的饱和烃基，可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)、乙基(Et)、丙基(如，n-丙基和异丙基)、丁基(如，n-丁基、异丁基、s-丁基、t-丁基)、戊基(如，n-戊基、异戊基、新戊基)等。
除非另有规定，术语“环烷基”包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷基、[4.4.0]二环癸烷基等。
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。
本申请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申请的实施例。
本申请所使用的溶剂可经市售获得。本申请采用下述缩略词：eq代表当量、等量；NMM代表N-甲基吗啡啉；DMSO代表二甲亚砜；HOBt代表1-羟基苯并三唑；EDCI代表1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐；TEMPO代表四甲基哌啶氮氧化物；T3P代表丙基磷酸酐；DIPEA代表N,N-二异丙基乙胺。
化合物经人为或者
Figure PCTCN2018073721-appb-000031
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，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，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
制备例1：化合物1-a的制备
Figure PCTCN2018073721-appb-000032
步骤1：化合物A-3的合成
将化合物A-1(30.00g，92.78mmol，1.00eq)和4-甲基吗啉(15.02g，148.45mmol，16.33mL，1.60eq)在-10℃氮气保护下溶于四氢呋喃(468mL)中，慢慢滴加化合物A-2(19.01g，139.17mmol，18.28mL，1.50eq)，并保持温度在-10℃下搅拌40分钟。将反应混合物过滤，并用四氢呋喃(200mL)洗涤滤饼。合并的滤液倒入一个三口烧瓶中并保持温度在0℃，将CH 2N 2-乙醚溶液(370mL)在氮气保护下加入到该烧瓶中，在0℃下继续搅拌20分钟并升温至20℃再搅拌2小时。然后反应混合物继续冷却到0℃，并用HBr(30mL，35％乙酸溶液)处理，该混合物在0℃搅拌15分钟，升温至20℃继续搅拌45分钟。反应完毕后，反应混合物采用乙酸乙酯(500mL)和水(400mL)进行萃取分液。有机相继续用水(400mL)、饱和碳酸氢钠溶液(400mL)和饱和食盐水(400mL)洗涤。经无水硫酸钠干燥后浓缩得到粗产物，该粗品经由柱层析纯化得到无色油状化合物A-3(30.00g，收率：76％)。
步骤2：化合物A-5的合成
将化合物A-3(25.00g，62.46mmol，1.00eq)和A-4(12.45g，74.95mmol，1.20eq)溶于DMF(350.00mL)中，在氮气保护下加入KF(14.52g，249.84mmol，5.85mL，4.00eq)，该反应在20℃下搅拌15小时。反应完全后，加入500mL乙酸乙酯，并用饱和碳酸氢钠(350mL)、水(350mL)和饱和食盐水(350mL)洗涤。有机相经无水硫酸钠干燥后浓缩得到粗品，粗品经由柱层析(石油醚:乙酸乙酯＝1:0-3:1)纯化得到化合物A-5(18.00g，收率：56％)。
步骤3：化合物A-6的合成
将化合物A-5(9.50g，19.57mmol，1.00eq)加入到甲醇(30.00mL)和四氢呋喃(30.00mL)的混合溶剂中，保持温度为0℃向其中加入硼氢化钠(2.96g，78.28mmol，4.00eq)，加料完毕反应混合物在25℃下搅拌1小时。反应完毕后，反应混合物加入到水(200mL)中，并加入NH 4Cl(200mL，aq，10％)，然后采用乙酸乙酯(500mL*3)进行萃取。合并的有机相经由水(500mL)、食盐水(500mL)洗涤，并用无水硫酸钠进行干燥、过滤得到无色油状化合物A-6(9.00g，粗品)，该产品未经纯化直接用于下一步反应。
步骤4：化合物A-7的合成
将化合物A-6(9.00g，18.46mmol，1.00eq)溶于甲醇(500.00mL)中，向其中加入Pd-C(10％，2.5g)。该混合物用氢气置换3次并保持压力为15psi，保持温度为25℃下搅拌4小时。反应完全后过滤、浓缩得到黄色油状化合物A(6.10g，粗品)，该产品未经纯化直接用于下一步反应。
步骤5：化合物A-9的合成
将化合物A-7(6.10g，17.2mmol，1.00eq)和化合物A-8(3.85g，17.2mmol，1.00eq)溶于乙酸乙酯溶液中(100mL)，先后加入T 3P(16.42g，25.8mmol，1.50eq，50％乙酸乙酯溶液)和DIPEA(4.44g，34.4mmol，2.0eq)，25℃下搅拌4小时。向反应液中加入水(50mL)淬灭，分液。有机相分别用饱和碳酸氢钠(50mL)、水(50mL)、饱和食盐水(50mL)洗涤一次。有机相经无水硫酸钠干燥，浓缩得粗产品。粗产品经柱层析分离(乙酸乙酯:石油醚＝1:20-1:2)的产品化合物A-9(3.50g，收率：36.5％)；LCMS m/z＝581.2[M+Na] +。
步骤6：化合物1-a的合成
将化合物A-9(3.30g，5.91mmol，1.00eq)溶于甲醇(33.0mL)和THF(33.0mL)的混合溶剂中，向其中加入Pd-C(10％，330mg)。该混合物用氢气置换3次并保持压力为15psi，保持温度为25℃下搅拌2小时。反应完全后过滤、浓缩得到黄色油状化合物A(2.18g，4.50mmol，收率：76.2％)，该产品未经纯化直接用于下一步反应；LCMS m/z＝425.2[M+H] +。
制备例2：化合物1-e的制备(参考化合物1-a的制备路线，采用手性对映异构体替换化合物A-1)
Figure PCTCN2018073721-appb-000033
实施例1：(S)-3-((S)-2-(5-(2-氯苯基)异噁唑-3-甲酰胺基)丙酰胺基)-4-氧代-5-(2,3,5,6-四氟苯氧基)戊酸(化合物1)
Figure PCTCN2018073721-appb-000034
步骤1：化合物1-c的合成
将化合物1-b(100.00mg，447.21μmol，1.00eq)溶于二氯甲烷(10.00mL)，向其中加入化合物NMM(135.71mg，1.34mmol,147.51μL，3.00eq)、HOBt(82.78mg,612.67μmol，1.37eq)、EDCI(117.45mg，612.67μmol，1.37eq)和化合物1-a(189.79mg，447.21μmol，1.00eq)。将该反应液在25℃下搅拌4小时。反应完全后，反应液直接浓缩得到粗品，粗品经快速硅胶柱层析(石油醚:乙酸乙酯＝4:1)得到无色油状化合物1-c。LCMS m/z＝652.3[M+Na] +。
步骤2：化合物1-d的合成
将化合物1-c(220.00mg，349.22μmol，1.00eq)溶于二氯甲烷(10.00mL)，向其中加入二乙酰氧基碘苯(435.31mg，1.35mmol，3.87eq)和TEMPO(54.92mg，349.22μmol，1.00eq)。该反应液在25℃下搅拌15小时。反应完全后，向反应液中加入二氯甲烷(20mL)，该溶液先后用水(20mL)、饱和碳酸氢钠(20mL)和食盐水(20mL)洗涤。有机相经无水Na 2SO 4干燥、过滤、浓缩得到粗品。粗品经快速硅胶柱层析(石油醚:乙酸乙酯＝7:3)得到淡黄色油状化合物1-d。LCMS m/z＝650.1[M+Na] +。
步骤3：化合物1的合成
将化合物1-d(210.00mg，334.41μmol，1.00eq)溶于二氯甲烷(4.00mL)，向其中加入三氟乙酸(1.54g，13.51mmol，1.00mL，40.39eq)。该反应液在25℃下搅拌3小时。反应完全后，反应液浓缩得到粗品。粗品经prep-HPLC(三氟乙酸条件)纯化，冻干后得到化合物1。 1H NMR(400MHz,DMSO-d 6)δ12.47(br s,1H),9.01(br s,1H),8.67(br s,1H),7.96(dd,J＝2.26,7.28Hz,1H),7.72(d,J＝7.39Hz,1H),7.48-7.65(m,3H),7.38(s,1H),5.02-5.42(m,2H),4.62(d,J＝6.02Hz,1H),4.40-4.54(m,1H),2.73-2.85(m,1H),2.52-2.65(m,1H),1.37(d,J＝7.03Hz,3H)；LCMS m/z＝572.1[M+H] +。
实施例2-17：参考实施例1的合成路线，采用不同的中间体酸替换化合物1-b，制备实施例2-17的化合物。
Figure PCTCN2018073721-appb-000035
Figure PCTCN2018073721-appb-000036
实施例18：参考实施例1的合成路线，采用中间体1-e替换化合物1-a制备实施例18的化合物。
Figure PCTCN2018073721-appb-000037
实施例2-13以及实施例17-18的核磁和质谱数据如下：
Figure PCTCN2018073721-appb-000038
Figure PCTCN2018073721-appb-000039
实验例1：化合物体外对Caspase酶的抑制活性检测
实验目的：
本实验使用BioVision的Caspase抑制剂筛选试剂盒测试受试化合物对Caspase酶的抑制活性。
实验材料：
1)试剂盒：
Caspase-1抑制剂筛选试剂盒(BioVision#K151-100)
Caspase-3抑制剂筛选试剂盒(BioVision#K153-100)
Caspase-8抑制剂筛选试剂盒(BioVision#K158-100)
注：每个caspase酶学实验使用其对应的试剂盒内的试剂。每个酶分别用550μl对应的2X反应缓冲液 溶解分装储存于-80℃。
2)黑色384孔板(PerkinElmer#6007279)
3)仪器：多功能酶标仪Molecular Devices(型号SpectraMax M2e)
实验方法：
1)将化合物用DMSO倍比稀释至200*测试浓度，用ddH 2O稀释到2*测试浓度后以每孔12.5μl加入384孔实验板中。测试化合物和对照化合物测试6个浓度点，测试浓度范围为：1000nM-0.32nM。0％抑制对照孔中加入含1％DMSO的ddH 2O，100％抑制对照孔中加入高浓度对照化合物(终浓度为：5μM)。
2)配制含10mM DTT的2X反应缓冲液。将caspase酶储存液用含10mM DTT的2X反应缓冲液稀释5倍后以每孔6.25μl加入到384孔实验板中。混匀后将酶和化合物于37℃孵育30分钟。
3)将caspase酶的荧光底物用含10mM DTT的2X反应缓冲液稀释5倍后以每孔6.25μl加入到384孔实验 板中。反应总体积为25μl，底物终浓度为50μM，DMSO终浓度为0.5％。加入底物后，384孔实验板置于37℃孵育30分钟。
4)使用多功能酶标仪测定荧光强度(激发光波长400nm，发射光波长为505nm)。荧光强度用于计算化合物对Caspase酶的抑制作用。使用GraphPad Prism软件对化合物抑制曲线进行拟合并计算IC 50值。
实验结果：
供试化合物的实验结果见表1。
表1.供试化合物酶学活性测试结果
化合物编号 Caspase-1 Caspase-3 Caspase-8
实施例1 4.6 13.0 10.3
实施例2 5.3 29.6 24.6
实施例3 4.8 24.0 25.9
实施例4 4.1 11.4 11.7
实施例5 3.9 13.7 16.8
实施例6 6.0 24.5 19.9
实施例7 6.9 20.2 30.0
实施例8 5.5 21.8 18.0
实施例9 14.2 44.4 23.2
实施例10 6.6 22.0 16.3
实施例11 9.2 30.0 22.6
实施例12 6.7 21.0 17.9
实施例17 4.2 9.5 31.4
实施例18 7.5 26.1 62.1
实验结论：
从上表1可以看出，本申请化合物具有良好的Caspase酶的抑制活性。
实验例2：小鼠药代动力学研究
实验目的：
本实验旨在研究化合物口服给药后在雄性C57BL/6J小鼠血浆与肝脏中的药代动力学情况。
实验方法：
将小鼠随机分为三组，每组3只雄性小鼠。将化合物配制为指定制剂。口服制剂可以为澄清或者均一混悬液。动物分别灌胃给予指定剂量制剂。
动物在给药后30分钟、2小时及6小时的3个时间点从颈静脉穿刺采集全血样品，每个样品大约25μL；同时每个时间点采集肝脏。
将血浆样品加入含有抗凝剂的离心管中，4℃，3000g离心15min，取上清血浆于干冰上快速冷冻，然后保存在-70±10℃冰箱中直到进行LC-MS/MS分析。
将肝脏外的血液用吸水纸吸干，称量肝脏的重量，然后放置在液氮中冷冻。按照1:5的体积重量比加入MeOH/15mM PBS(1:2)在14000rpm下匀浆2分钟。然后保存在-70±10℃冰箱中直到进行LC-MS/MS分析。
数据处理：
使用WinNonlin TM Version 6.3.0(Pharsight，Mountain View，CA)药动学软件，以非房室模型对化合物的血浆药物浓度数据进行处理。达峰浓度(C max)和达峰时间(T max)以及可定量末时间，从血药浓度-时间图中直接获得。
使用对数线性梯形法计算下列药代动力学参数：消除相半衰期(T 1/2)，0点到末端时间点药物在体内的平均滞留时间(MRT 0-last)，0点到无限时间药物在体内的平均滞留时间(MRT 0-inf)，0点到末端时间点时间-血浆浓度曲线下面积(AUC 0-last)，0点到无限时间-血浆浓度曲线下面积(AUC 0-inf)。
对于小于BQL的个体血浆浓度，出现在T max前作为0计算，出现在T max后的直接排除。所有参数及比值以三位有效数字的形式报告。
本实验以方案中的理论采血时间与理论给药浓度计算药动学参数。实际给药浓度与理论浓度偏差在±20％的范围内。实际采血时间与理论采血时间偏差符合相关SOP(给药后1小时以内的点在±1分钟范围内，其它均在理论时间5％以内)。
实验结果：
供试化合物的实验结果见表2。
表2.供试化合物药代动力学研究
Figure PCTCN2018073721-appb-000040
实验结论：
从上表2可知参考化合物IDN-6556不同时间段的肝脏暴露量比较小，肝脏药时曲线面积较低。实施例1所示的化合物肝脏暴露较IDN-6556有明显的改善，约为其5倍。同时，实施例1还保持了相当的肝脏/血浆药时曲线面积比。如果用于治疗肝脏疾病，高肝脏药物暴露量为我们降低给药剂量带来了可能。
实验例3：小鼠体内药效学研究
实验目的：
测试化合物IDN-6556和实施例1化合物在CCl 4诱导的雄性C57BL/6小鼠慢性肝纤维化模型中的治疗作用。
实验方法：
将雄性C57BL/6小鼠随机分为7组，即假模型组(组1)、模型组(组2，溶媒p.o.，q.d)、IDN-6556(组3，3mg/kg，p.o.，bid)、IDN-6556(组4，10mg/kg，p.o.，bid)、实施例1(组5，3mg/kg，p.o.，bid)、实施例1(组6，10mg/kg，p.o.，bid)、实施例1(组7，20mg/kg，p.o.，bid)。将CCl 4根据剂量用橄榄油配制成CCl 4-橄榄油混合溶液，每周三次口服造模，持续4周；假模型组仅口服给予相同体积的橄榄油。造模当天开始口服化合物，每天两次，共给药28天，假模型组以及模型组口服给予等体积的药物溶媒。末次给药结束次日，动物禁食6小时后，动物实施安乐死，采集肝脏。肝脏组织固定于10％福尔马林溶液中，进行组织病理学分析。
实验结果：
表3是肝脏病理学检测评分，通过该表可见IND-6556和实施例1不同剂量组均能显著改善由CCl 4引起的肝组织损伤，此外实施例1与模型组相比还显著性地抑制了肝纤维化的形成(p<0.01)。
表3：肝脏病理学检测(mean±sem)
Figure PCTCN2018073721-appb-000041
One-way ANOVA(单因素方差分析)： ###p<0.001vs.组1； *p<0.05vs.组2； ***p<0.001vs.组2
T-test(T-检验)： $p<0.05vs.组2； $$p<0.01vs.组2。
实验结论：
结果显示经CCl 4口服成功诱导C57BL/6小鼠肝纤维化。不同剂量的IDN-6556，每天两次口服28天显著性地抑制CCl 4诱导的肝组织损伤，特别是炎细胞浸润；但是，未见明确的抑制肝纤维化的作用。不同剂量的实施例1，每天两次口服28天显著性地抑制CCl 4诱导的肝组织损伤，特别是炎细胞浸润，同时可见显著性地抑制肝纤维化的作用。总体来说实施例1在该模型中的药效作用要优于IND-6556。

Claims (16)

  1. 式(Ⅰ)所示的化合物、其药学上可接受的盐或其互变异构体，
    Figure PCTCN2018073721-appb-100001
    其中，
    环A选自5元杂芳基或6元杂芳基，所述5元杂芳基或6元杂芳基任选地被R取代；
    环B选自苯基或C 3-6环烷基，所述苯基或C 3-6环烷基任选地被R取代；
    R选自卤素、OH、NH 2，或任选被1、2或3个R 1取代的C 1-3烷基；
    R 1选自F、Cl、Br、I、OH、NH 2、NH(CH 3)或N(CH 3) 2。
  2. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中，环A的杂原子独立地选自O、S或N，环A的杂原子的数目选自1、2或3。
  3. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中，环A选自噁唑基、异噁唑基、咪唑基、噻唑基、1,2,4-噁二唑基、1,3,4-噁二唑基或吡唑基。
  4. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中，环A选自
    Figure PCTCN2018073721-appb-100002
    Figure PCTCN2018073721-appb-100003
  5. 根据权利要求1-4任意一项所述的化合物、其药学上可接受的盐或其互变异构体，其中，环B选自苯基或环己基，所述苯基或环己基任选地被R取代。
  6. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中，R选自F、Cl、Br、I、OH、NH 2，或任选被1、2或3个R 1取代的Me或Et。
  7. 根据权利要求6所述的化合物、其药学上可接受的盐或其互变异构体，其中，R选自F、Cl、Br、I、OH、NH 2或CF 3。
  8. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中，环B选自
    Figure PCTCN2018073721-appb-100004
    Figure PCTCN2018073721-appb-100005
  9. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中，
    Figure PCTCN2018073721-appb-100006
    选自
    Figure PCTCN2018073721-appb-100007
    Figure PCTCN2018073721-appb-100008
    所述环B任选地被R取代。
  10. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中，
    Figure PCTCN2018073721-appb-100009
    选自
    Figure PCTCN2018073721-appb-100010
    Figure PCTCN2018073721-appb-100011
  11. 根据权利要求10所述的化合物、其药学上可接受的盐或其互变异构体，其中，
    Figure PCTCN2018073721-appb-100012
    选自
    Figure PCTCN2018073721-appb-100013
  12. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中，
    Figure PCTCN2018073721-appb-100014
    选自
    Figure PCTCN2018073721-appb-100015
  13. 下式所示的化合物、其药学上可接受的盐或其互变异构体：
    Figure PCTCN2018073721-appb-100016
    Figure PCTCN2018073721-appb-100017
  14. 一种药物组合物，其含有治疗有效量的根据权利要求1-13任意一项所述的化合物、其药学上可接受的盐或其互变异构体和药学上可接受的载体或赋形剂。
  15. 根据权利要求1-13任意一项所述的化合物、其药学上可接受的盐或其互变异构体或者根据权利要求14所述的药物组合物在制备治疗caspase受体相关病症的药物中的应用。
  16. 治疗哺乳动物caspase受体相关病症的方法，包括对需要该治疗的哺乳动物给予治疗有效量的权利要求1-13任意一项所述的化合物、其药学上可接受的盐或其互变异构体或者根据权利要求14所述的药物组合物。
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