WO2019154053A1 - Inhibiteur d'iap et leur utilisation en médecine - Google Patents

Inhibiteur d'iap et leur utilisation en médecine Download PDF

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WO2019154053A1
WO2019154053A1 PCT/CN2019/072531 CN2019072531W WO2019154053A1 WO 2019154053 A1 WO2019154053 A1 WO 2019154053A1 CN 2019072531 W CN2019072531 W CN 2019072531W WO 2019154053 A1 WO2019154053 A1 WO 2019154053A1
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group
compound
alkyl
independently
aryl
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PCT/CN2019/072531
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English (en)
Chinese (zh)
Inventor
谢洪明
寇玉辉
蒋海港
黄仕海
张英俊
张健存
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广东东阳光药业有限公司
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Priority to CN201980008153.1A priority Critical patent/CN111655713B/zh
Publication of WO2019154053A1 publication Critical patent/WO2019154053A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the present invention relates to a novel compound which inhibits IAP (inhibitors of apoptosis proteins) and a salt thereof, a pharmaceutical composition thereof, and a process for the preparation thereof.
  • the invention further relates to the use of these compounds and their salts, and pharmaceutical compositions thereof, for the manufacture of a medicament for the treatment of a disease caused by an IAP disorder, in particular for the preparation of a medicament for the treatment of cancer or hepatitis B virus infection .
  • Apoptosis (programmed cell death) plays an important role in the development and homeostasis of all multicellular organisms. Changes in the apoptotic pathway are involved in many types of human lesions, including developmental disorders, cancer, autoimmune diseases, and neurodegenerative disorders. One mode of action of chemotherapeutic drugs is cell death through apoptosis.
  • Apoptosis is conserved between different species and is primarily performed by activated caspase, a family of caspase enzymes that have aspartate specificity in their stroma. Once activated, the effector caspase results in proteolytic cleavage of a broad spectrum of cellular targets that ultimately leads to cell death. Most of the caspase remains non-activated in normal viable cells that do not receive apoptosis. If caspase is aberrantly activated, their proteolytic activity can be inhibited by a family of evolutionarily conserved proteins called IAPs, inhibitors of apoptotic proteins.
  • IAPs family of evolutionarily conserved proteins
  • the IAP family of proteins inhibits apoptosis by preventing activation of the precursor caspase and inhibiting the enzymatic activity of mature caspase.
  • IAPs have been described in organisms (from fruit flies to humans) and are known to be overexpressed in many human cancers. IAP prevents apoptosis by directly interacting with caspase and neutralizing caspase.
  • the prototype IAP-XIAP and cIAP have three functional domains, called BIR1, 2, and 3 domains. It is believed that by inhibiting caspase, the BIR domain results in an anti-apoptotic effect, thereby inhibiting apoptosis.
  • Overexpression of XIAP in tumor cells has demonstrated that it provides protection against a variety of pre-apoptotic stimuli and increases tolerance to chemotherapy. For patients with acute myeloid leukemia, a strong correlation between XIAP protein levels and survival has been demonstrated.
  • Smac can neutralize XIAP by binding to a peptide binding pocket on the surface of BIR3, thereby eliminating the inhibitory effect of XIAP on apoptosis.
  • Smac essentially interacts with all IAPs that have been tested to date, including XIAP, c-IAP1, c-IAP2, ML-IAP and survivin.
  • Smac appears to be a major regulator of apoptosis. It has been shown that Smac not only enhances the proteolytic activation of the precursor caspase, but also enhances the enzymatic activity of mature caspase, both of which depend on their ability to physically interact with IAPs.
  • WO 2006091972 and WO2011002684 disclose a series of IAP inhibitor compounds useful for the treatment of cancer or hepatitis B virus infection, including the following structural compounds:
  • the present invention relates to a novel compound that inhibits IAP.
  • the compounds are useful in the treatment of diseases caused by IAP disorders, particularly cancer or hepatitis B virus infection.
  • the invention provides a compound having a structure as shown in formula (I), or a stereoisomer, geometric isomer, tautomer, oxynitride of the structure of formula (I) a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • n and n are each independently 1, 2, 3, 4, 5, 6 or 7;
  • r 1 and r 2 are each independently 0, 1, 2 or 3;
  • Ring A and Ring B are each independently an aryl or heteroaryl group
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, An aryl group, a heteroaryl group, a heterocyclic group or a carbocyclic group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, heterocyclic group and carbocyclic group are each independently optional The ground is replaced by 1, 2, 3 or 4 substituents selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl and amino ;
  • Each R 7 is independently an amino group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; wherein the amino group, the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each Independently optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino;
  • Each of R 8 and R 9 is independently H, D, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl,
  • the aryl and heteroaryl are each independently optionally 1, 2, 3 or 4 selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and Substituted by a substituent of an amino group.
  • Each R 7 is independently amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl; Amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl are each independently optionally 1, 2, 3 Or 4 selected from D, F, Cl, Br, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-4 alkoxy, C 6-10 Substituted by a substituent of an aryl group and an amino group;
  • Each of R 8 and R 9 is independently H, D, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered hetero An aryl group; wherein the amino group, C 1-6 alkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, C 6-10 aryl group and 5-6 membered heteroaryl group are each independently optional Ground, 1, 2, 3 or 4 selected from D, F, Cl, Br, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkane Substituents of an oxy group, a C 6-10 aryl group and an amino group are substituted.
  • Each R 7 is independently amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl or phenyl;
  • R 8 and R 9 are each independently H, D, amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl or phenyl;
  • Q 1a , Q 2a and Q 3a are each independently a bond, -CR 11 R 12 -, O, NR 11 or S, and Q 1a , Q 2a , Q 3a are not simultaneously a bond;
  • Q 1b , Q 2b and Q 3b are each independently a bond, -CR 11 R 12 -, O, NR 11 or S, and Q 1b , Q 2b , Q 3b are not simultaneously a bond;
  • R 11 and R 12 are each independently H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxane Hexacyclyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and phenyl;
  • t 1a and t 1b are each independently 0, 1, or 2;
  • t 2a and t 2b are each independently 0, 1, 2 or 3.
  • Ring A and Ring B are each independently C 6-10 aryl or 5-6 membered heteroaryl;
  • Ring A and Ring B are each independently of the following substructure:
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently H, D, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-6 membered heteroaryl, 3-7 membered heterocyclic or 3-7 membered carbon a cyclic group wherein the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 6-10 aryl group, 5-6 membered heteroaryl group
  • the 3-7 membered heterocyclic group or the 3-7 membered carbocyclic group are each independently optionally 1, 2, 3 or 4 selected from the group consisting of D, F, Cl, Br, hydroxy, C 1-4 alkyl, C Substituents of a 3-6
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently H, D, methyl, ethyl, or Propyl, isopropyl, n-butyl, isobutyl, methoxymethyl, ethoxymethyl, methylthiomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine Or a phenyl or pyridyl group, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxymethyl, ethoxymethyl, methylthio
  • the compound of the invention has a structure as shown in formula (II), or a stereoisomer, geometric isomer, tautomer, oxynitride, of a structural compound of formula (II), a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the compound of the present invention has a structure represented by formula (II-1), or a stereoisomer, geometric isomer, tautomer, or a structural compound of formula (II-1). Nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the compound of the invention has a structure, or formula, as represented by formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) Stereoisomers, geometric isomers, tautomerism of structural compounds represented by (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X) Body, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the compounds of the invention have the formulae (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX) a structure represented by -1) or (X-1), or formula (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1) Or (IX-1) or (X-1) a stereoisomer, geometric isomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or Prodrug,
  • the present invention provides a pharmaceutical composition comprising any one of the compound compounds of the present invention and a pharmaceutically acceptable adjuvant thereof.
  • the present invention provides the use of any one of the compounds of the present invention or a pharmaceutical composition of the present invention for the preparation of a medicament for preventing or treating a disease caused by an IAP disorder.
  • the disease caused by the IAP disorder is cancer or a hepatitis B virus infection.
  • the present invention provides any one of the compounds of the present invention or the pharmaceutical composition of the present invention for use in preventing or treating a disease caused by an IAP disorder in a patient.
  • the disease caused by the IAP disorder is cancer or a hepatitis B virus infection.
  • the present invention provides a method for preventing or treating a disease caused by an IAP disorder, comprising administering to a patient an effective therapeutic amount of any one of the compounds of the present invention or the pharmaceutical composition of the present invention.
  • the disease caused by the IAP disorder is cancer or a hepatitis B virus infection.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically relevant to the other components of the formulation and to the mammal being treated.
  • Salts of the compounds of the invention also include for the preparation or purification of formula (I), (II), (II-1), (III), (IV), (V), (VI), (VII), (VIII) ), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) Or an intermediate of the compound represented by (X-1), or formula (I), (II), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX) -1) or a salt of the enantiomer separated by the compound of (X-1), but not necessarily a pharmaceutically acceptable salt.
  • subject refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (eg, humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates eg, humans, males or females
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • a stable compound is a compound of a useful purity that can be isolated from the reaction mixture.
  • the compounds of the invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or, as in the examples, specific examples, subclasses, and ones encompassed by the invention Class of compounds.
  • substituents such as the compounds of the above formula, or, as in the examples, specific examples, subclasses, and ones encompassed by the invention Class of compounds.
  • substituents such as the compounds of the above formula, or, as in the examples, specific examples, subclasses, and ones encompassed by the invention Class of compounds.
  • substituents such as the compounds of the above formula, or, as in the examples, specific examples, subclasses, and ones encompassed by the invention Class of compounds.
  • substituents When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
  • the substituents described therein may be, but are not limited to, D, F, Cl, Br, hydroxyl, hydroxyl, cyano, COOH, amino, alkyl, carbocyclyl, heterocyclyl, heteroaryl, alkoxy Base and aryl, etc.
  • C 1-6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • C mn group used alone as a prefix means any group having from m to n carbon atoms, for example, a C 1-6 haloalkyl group means any group having from 1 to 6 carbon atoms; C 1- The 4- alkyl group means any group having 1 to 4 carbon atoms.
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein.
  • the alkyl group contains 1-10 carbon atoms; in some embodiments, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1- 4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl group when an alkyl group is clearly represented as a linking group, then the alkyl group represents a linked alkylene group, for example, a structural formula (C 6-10 aryl)-(C)
  • the C 1-6 alkyl group in the 1-6 alkyl)- is understood to be a C 1-6 alkylene group.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CHCH
  • heteroalkyl denotes the insertion of one or more heteroatoms in the middle of the alkyl chain, wherein the alkyl group and heteroatom have the meaning as described herein.
  • a heteroalkyl group contains from 1 to 10 carbon atoms, and in other embodiments, a heteroalkyl group contains from 1 to 8 carbon atoms.
  • a heteroalkyl group contains 1 -6 carbon atoms, in other embodiments, the heteroalkyl group contains 1-4 carbon atoms, and in other embodiments, the heteroalkyl group contains 1-3 carbon atoms.
  • Such examples include, but are not limited to, CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 SCH 2 -, CH 3 SCH 2 CH 2 -, (CH 3 ) 2 NCH 2 -, (CH 3 2 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 CH 2 -, and the like.
  • amino refers to "-NH 2 ".
  • halogen refers to F, Cl, Br or I.
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp 2 double bond, wherein the alkenyl group
  • the group may be optionally substituted with one or more substituents described herein, including the positioning of "cis” and “tans", or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-10 carbon atoms; in one embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2 4 carbon atoms.
  • alkynyl means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, in one embodiment, the alkynyl group contains 2 to 10 carbon atoms; the alkynyl group comprises 2 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like. .
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein.
  • the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms.
  • the alkoxy group can be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH
  • heterocyclyl and “heterocycle” are used interchangeably herein to refer to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from Nitrogen, sulfur and oxygen atoms, the ring may be fully saturated or contain one or more unsaturations, but none of the aromatic rings.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the heterocyclyl is a 3-7 membered heterocyclyl; in other embodiments, the heterocyclyl is a 4-7 membered heterocyclyl; in other embodiments, the heterocyclyl is a 3-6 membered heterocyclic group; in other embodiments, the heterocyclic group is a 4-6 membered heterocyclic group; in other embodiments, the heterocyclic group is a 5-6 membered heterocyclic group; In other embodiments, the heterocyclic group is a 5-membered heterocyclic group; in other embodiments, the heterocyclic group is a 6-membered heterocyclic group; in still other embodiments, the heterocyclic group is a 7-membered heterocyclic group.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, 1,3 -dioxocyclopentenyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, di Oxacyclyl, piperidinyl, morpholinyl, thiomorpholinyl, di Oxa
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group, a 1,1-dioxothiomorpholinyl group, and the like.
  • the heterocyclyl group can be optionally substituted with one or more substituents described herein.
  • Carbocyclyl refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 carbon atoms.
  • Carbon bicyclic groups include spirocarbon bicyclic groups and fused carbon bicyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • a "carbocyclyl” is a cycloalkyl.
  • a "carbocyclyl” or “carbocyclic” is a C3-10 carbocyclic or a 3-10 membered carbocyclic ring; in other embodiments, a “carbocyclyl” or “carbocyclic” is a C 3-7 carbocyclic group or a 3-7 membered carbocyclic ring; in other embodiments, a “carbocyclyl” or “carbocyclic ring” is a C 4-7 carbocyclic group or a 4 to 7 membered carbocyclic ring; In some embodiments, a "carbocyclyl” or “carbocyclic” is a C4-6 carbocyclyl or a 4-6 membered carbocyclic ring.
  • a "carbocyclyl” or “carbocyclic” is C. 3-6 carbocyclic or 3-6 membered carbocyclic ring.
  • Such examples further include, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl (1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl) 3-alkenyl), cyclopentadienyl (2,4-cyclopentadienyl, 1,3-cyclopentadienyl), cyclohexyl, cyclohexenyl (1-cyclohexyl-1-ene) , 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl), cyclohexadienyl (1,3-cyclohexadienyl, 1,4-cyclohexadienyl), Cycloheptyl,
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 carbon atoms.
  • a cycloalkyl group contains 3-6 carbon atoms, ie, a C3-6 cycloalkyl group.
  • Specific examples of the cycloalkyl group include, but are not limited to, a cyclopropane, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
  • the cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring system is aromatic Of the family, wherein each ring system comprises a ring of 3-7 atoms and one or more attachment points are attached to the remainder of the molecule.
  • the aryl group contains 6-10 carbon atoms, ie, a C6-10 aryl group. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene.
  • the aryl group may be independently and optionally substituted with one or more substituents described herein.
  • heteroaryl denotes a monocyclic, bicyclic and tricyclic ring system containing from 5 to 12 ring atoms, or from 5 to 10 ring atoms, or from 5 to 6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system comprises one or more heteroatoms (heteroatoms comprising nitrogen, phosphorus, oxygen or sulfur), wherein each ring system comprises a ring of 5-7 atoms and has one or more attachment points and molecules The rest are connected.
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”.
  • the heteroaryl group is a 5-6 membered heteroaryl; in other embodiments, the heteroaryl group is a 5 membered heteroaryl; in other embodiments, the heteroaryl The group is a 6-membered heteroaryl group.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • aryloxy means that the aryl group is attached to the remainder of the molecule through an oxygen atom. Wherein the aryl group has the meaning as described in the present invention. In one embodiment, the aryloxy group contains from 6 to 10 carbon atoms, i.e., a C6-10 aryloxy group. Examples of aryloxy groups include, but are not limited to, phenoxy, naphthyloxy, and the like. The aryloxy group can be optionally substituted with one or more substituents described herein.
  • haloalkyl denotes an alkyl group substituted by one or more halogens.
  • a haloalkyl group represents a haloalkyl group containing from 1 to 6 carbon atoms, ie, a C1-6 haloalkyl group; in other embodiments, a haloalkyl group represents a halo group of from 1 to 4 carbon atoms.
  • Such examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 1,2-dichloroethyl, 1,2-difluoroethyl, and the like.
  • hydroxyalkyl denotes an alkyl group substituted with one or more hydroxy groups.
  • a hydroxyalkyl group represents a hydroxyalkyl group containing from 1 to 6 carbon atoms, ie, a C1-6 hydroxyalkyl group; in other embodiments, the hydroxyalkyl group is represented by from 1 to 4 A haloalkyl group of one carbon atom, i.e., a C 1-4 hydroxyalkyl group; in still other embodiments, a hydroxyalkyl group means a hydroxyalkyl group having from 1 to 3 carbon atoms, i.e., a C 1-3 hydroxyalkyl group.
  • Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, hydroxybutyrate Base, and so on.
  • alkoxyalkyl denotes an alkyl group substituted by one or more alkoxy groups.
  • the alkyl group represents an alkyl group substituted by a a C 1-3 alkoxy-C 1-4 alkyl group, i.e. a C 1-3 alkoxy-C 1-4 alkyl.
  • Such examples include, but are not limited to, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, methoxypropyl, and the like.
  • haloalkoxy denotes an alkoxy group substituted by one or more halogens.
  • a haloalkoxy group represents a haloalkyl group containing from 1 to 6 carbon atoms, ie, a C1-6 haloalkyl group; in other embodiments, a haloalkyl group represents from 1 to 4 carbon atoms.
  • a haloalkyl group, i.e., a C 1-4 haloalkyl group; in still other embodiments, a haloalkyl group means a haloalkyl group having from 1 to 3 carbon atoms, i.e., a C 1-3 haloalkyl group.
  • Such examples include, but are not limited to, trifluoromethoxy, difluoromethoxy, monofluoro substituted methoxy, 1,2-difluoroethoxy, and the like.
  • the substituent (R 1b ) n is bonded to the central ring by a bond to form a ring system (as shown in formula f) which represents n substituents R 1b which may be substituted on the ring or any reasonable The location is replaced.
  • the formula f represents that any position on the ring that may be substituted may be substituted by n substituents R 1b .
  • the ring system formed by the attachment of a substituent R 10a to the central ring A represents that the substituent R 10a can be substituted at any substitutable or any reasonable position on ring A.
  • the formula h represents that any position on the ring A which may be substituted may be substituted by the substituent R 10a , and the specific substitution is as shown by the formulas h1, h2, h3, h4.
  • a ring substituent can be attached to the remainder of the molecule through any attachable position on the ring.
  • piperidinyl comprises piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl.
  • the structural formulae described herein include all isomeric forms (eg, enantiomeric, diastereomeric, and geometric (or conformational)): for example, containing asymmetric centers R, S configuration, (Z), (E) isomer of double bond, and conformational isomer of (Z), (E).
  • isomeric forms eg, enantiomeric, diastereomeric, and geometric (or conformational): for example, containing asymmetric centers R, S configuration, (Z), (E) isomer of double bond, and conformational isomer of (Z), (E).
  • individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers thereof, or mixtures of geometric isomers (or conformational isomers) are within the scope of the invention.
  • the structural formulae and compounds described herein include all isomeric forms (eg, enantiomeric, diastereomeric, geometric or conformational), nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs.
  • isomeric forms eg, enantiomeric, diastereomeric, geometric or conformational
  • nitrogen oxides Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs.
  • individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrogen oxides, hydrates, solvates, metabolites, Compounds of pharmaceutically acceptable salts and prodrugs are also within the scope of the invention.
  • the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
  • protecting group refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups.
  • protecting group of an amino group refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • hydroxy protecting group refers to a substituent used to block or protect a hydroxyl group
  • suitable protecting groups include acetyl and silyl groups.
  • Carboxy protecting group means a substituent of a carboxy group used to block or protect the functionality of a carboxy group.
  • Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like.
  • a general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • prodrugs for a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • the compounds of the invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. portion. Many organic compounds exist in optically active forms, that is, they have the ability to rotate planes of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the molecular chiral center.
  • the prefix d, l or (+), (-) is used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
  • the chemical structures of these stereoisomers are the same, but their stereostructures are different.
  • a particular stereoisomer can be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers.
  • the 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers that lack optical activity.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • tautomer or "tautomeric form” means that the isomers of the structure of different energies can be converted into each other by a low energy barrier.
  • proton tautomers i.e., proton-shifted tautomers
  • the valence (valence) tautomer includes the interconversion of recombination bond electrons.
  • “Chirality” is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • the "hydrate” of the present invention means that the solvent molecule is an association formed by water.
  • the "nitrogen oxide” of the present invention means that when the compound contains several amine functional groups, one or more than one nitrogen atom can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514) wherein the amine compound and m-chloroperoxybenzoic acid (MCPBA) are, for example, in an inert solvent such as dichloromethane. reaction.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate means that the solvent molecule is an association formed by water.
  • any disease or condition as used in the present invention refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both.
  • “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the invention include isotopically enriched compounds of the invention, for example, those in which a radioisotope such as 3 H, 14 C and 18 F is present, or in which a non-radioactive isotope is present, such as 2 H and 13 C.
  • a radioisotope such as 3 H, 14 C and 18 F
  • a non-radioactive isotope such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy.
  • 18 F enriched compounds are particularly desirable for PET or SPECT studies.
  • the isotopically enriched compound of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the present invention.
  • the invention relates to the preparation of formula (I), (II), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX) , (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X- 1) An intermediate of the compound contained.
  • the invention relates to formula (I), (II), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1 A method of preparing, isolating and purifying a compound contained.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable adjuvant thereof.
  • adjuvants described herein include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof.
  • the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.
  • substitution of heavier isotopes may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index.
  • the oxime in the present invention is regarded as the formula (I), (II), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1) or (X-1) a substituent of the compound.
  • Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium.
  • the term "isotopic enrichment factor” refers to the ratio between the isotope abundance and the natural abundance of a given isotope. If a substituent of a compound of the invention is designated as hydrazine, the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation).
  • the present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D
  • the compound of the present invention can effectively treat diseases caused by IAP disorders as an IAP inhibitor, and can be used for the preparation of a medicament for preventing and treating cancer or hepatitis B virus infection.
  • the invention provides a compound having a structure as shown in formula (I), or a stereoisomer, geometric isomer, tautomer, oxynitride of the structure of formula (I) a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • m, n, r 1 , r 2 , R 1a , R 1b , ring A, ring B, R 10a , R 10b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a R 5b , R 6a and R 6b have the definitions as described in the present invention.
  • n and n are each independently 1, 2, 3, 4, 5, 6 or 7;
  • r 1 and r 2 are each independently 0, 1, 2 or 3;
  • Ring A and Ring B are each independently an aryl or heteroaryl group
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b are each independently H, D, alkyl, heteroalkyl, alkenyl, alkynyl, An aryl group, a heteroaryl group, a heterocyclic group or a carbocyclic group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, heterocyclic group and carbocyclic group are each independently optional The ground is replaced by 1, 2, 3 or 4 substituents selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl and amino ;
  • Each R 7 is independently an amino group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; wherein the amino group, the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each Independently optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino;
  • Each of R 8 and R 9 is independently H, D, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl,
  • the aryl and heteroaryl are each independently optionally 1, 2, 3 or 4 selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and Substituted by a substituent of an amino group.
  • Q 1a , Q 2a and Q 3a are each independently a bond, -CR 11 R 12 -, O, NR 11 or S, and Q 1a , Q 2a , Q 3a are not simultaneously a bond;
  • R 11 and R 12 are each independently H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxane Hexacyclyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and phenyl.
  • Q 1a , Q 2a and Q 3a are each independently a bond, -CR 11 R 12 -, O, NR 11 or S, and Q 1a , Q 2a , Q 3a are not simultaneously a bond;
  • R 11 and R 12 are each independently H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxane Hexacyclyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and phenyl.
  • Ring A and Ring B are each independently aryl or heteroaryl.
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently H, D, alkyl, heteroalkyl, Alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and carbon
  • the ring groups are each independently optionally 1, 2, 3 or 4 selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, heteroaryl and Substituted by a substituent of an amino group.
  • each R 7 is independently an amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl are each independently optionally 1, 2, 3 or 4 selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino Substituted by a substituent.
  • each of R 8 and R 9 are independently H, D, amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl
  • the radical, heterocyclyl, aryl and heteroaryl are each independently optionally 1, 2, 3 or 4 selected from the group consisting of D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkane Substituents of oxy, aryl and amino groups are substituted.
  • Each R 7 is independently amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl; Amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl are each independently optionally 1, 2, 3 Or 4 selected from D, F, Cl, Br, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-4 alkoxy, C 6-10 Substituted by a substituent of an aryl group and an amino group;
  • Each of R 8 and R 9 is independently H, D, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered hetero An aryl group; wherein the amino group, C 1-6 alkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, C 6-10 aryl group and 5-6 membered heteroaryl group are each independently optional Ground, 1, 2, 3 or 4 selected from D, F, Cl, Br, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkane Substituents of an oxy group, a C 6-10 aryl group and an amino group are substituted.
  • the 3-7 membered heterocyclyl, C 6-10 aryl and C 1-6 alkyl are each independently
  • Q 1a , Q 2a and Q 3a are each independently a bond, -CR 11 R 12 -, O, NR 11 or S, and Q 1a , Q 2a , Q 3a are not simultaneously a bond;
  • R 11 and R 12 are each independently H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxane Hexacyclyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and phenyl.
  • the 3-7 membered heterocyclyl, C 6-10 aryl and C 1-6 alkyl are each independently
  • Q 1a , Q 2a and Q 3a are each independently a bond, -CR 11 R 12 -, O, NR 11 or S, and Q 1a , Q 2a , Q 3a are not simultaneously a bond;
  • R 11 and R 12 are each independently H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxane Hexacyclyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and phenyl.
  • each R 7 is independently amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl a group; wherein the amino group, C 1-6 alkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, C 6-10 aryl group and 5-6 membered heteroaryl group are each independently optionally 1, 2, 3 or 4 selected from D, F, Cl, Br, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-4 alkoxy Substituents of a C 6-10 aryl group and an amino group are substituted.
  • each R 8 and R 9 are independently H, D, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl Or a 5-6 membered heteroaryl group; wherein the amino group, C 1-6 alkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, C 6-10 aryl group and 5-6 membered hetero
  • the aryl groups are each independently optionally 1, 2, 3 or 4 selected from the group consisting of D, F, Cl, Br, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group Substituted by a C 1-4 alkoxy group, a C 6-10 aryl group and an amino group.
  • Each R 7 is independently amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl or phenyl;
  • R 8 and R 9 is independently H, D, amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl or phenyl;
  • Q 1a , Q 2a and Q 3a are each independently a bond, -CR 11 R 12 -, O, NR 11 or S, and Q 1a , Q 2a , Q 3a are not simultaneously a bond;
  • Q 1b , Q 2b and Q 3b are each independently a bond, -CR 11 R 12 -, O, NR 11 or S, and Q 1b , Q 2b , Q 3b are not simultaneously a bond;
  • R 11 and R 12 are each independently H, D, F, Cl, Br, hydroxy, cyano, COOH, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxane Hexacyclyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and phenyl;
  • t 1a and t 1b are each independently 0, 1, or 2;
  • t 2a and t 2b are each independently 0, 1, 2 or 3.
  • Ring A and Ring B are each independently C 6-10 aryl or 5-6 membered heteroaryl;
  • Ring A and Ring B are each independently of the following substructure:
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently H, D, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-6 membered heteroaryl, 3-7 membered heterocyclic or 3-7 membered carbon a cyclic group wherein the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 6-10 aryl group, 5-6 membered heteroaryl group
  • the 3-7 membered heterocyclic group or the 3-7 membered carbocyclic group are each independently optionally 1, 2, 3 or 4 selected from the group consisting of D, F, Cl, Br, hydroxy, C 1-4 alkyl, C Substituents of 3-6 cycl
  • R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b are each independently H, D, methyl, ethyl, or Propyl, isopropyl, n-butyl, isobutyl, methoxymethyl, ethoxymethyl, methylthiomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine Or a phenyl or pyridyl group, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxymethyl, ethoxymethyl, methylthio
  • the compound of the invention has a structure as shown in formula (Ia), or a stereoisomer, geometric isomer, tautomer, oxynitride, of a structural compound of formula (Ia), a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the compound of the invention has a structure as shown in formula (Ia-1), or a stereoisomer, geometric isomer, tautomer, or a structural compound of formula (Ia-I), Nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the compound of the invention has a structure as shown in formula (II), or a stereoisomer, geometric isomer, tautomer, oxynitride, of a structural compound of formula (II), a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the compound of the present invention has a structure represented by formula (II-1), or a stereoisomer, geometric isomer, tautomer, or a structural compound of formula (II-1). Nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the compound of the invention has a structure, or formula, as represented by formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) Stereoisomers, geometric isomers, tautomerism of structural compounds represented by (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X) Body, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the compounds of the invention have the formulae (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX) a structure represented by -1) or (X-1), or formula (III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1) Or (IX-1) or (X-1) a stereoisomer, geometric isomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or Prodrug,
  • the compound of the invention has a structure as shown in formula (IIIa), (IIIb), (IVa), (Va), (VIa) or (VIIa), or formula (IIIa), (IIIb), Stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable compounds of the structural compounds represented by (IVa), (Va), (VIa) or (VIIa)) Accepted salt or prodrug,
  • the compound of the invention has the formula (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1) Structure, or stereoisomers, geometry of structural compounds of formula (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1) Isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • the compounds of the invention have the structure of one of the following, or a stereoisomer, geometric isomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable Salt or prodrug,
  • the present invention provides a pharmaceutical composition comprising any one of the compound compounds of the present invention and a pharmaceutically acceptable adjuvant thereof.
  • the present invention provides the use of any one of the compounds of the present invention or a pharmaceutical composition of the present invention for the preparation of a medicament for preventing or treating a disease caused by an IAP disorder.
  • the present invention provides a compound of the present invention or a pharmaceutical composition of the present invention for use in preventing or treating a disease caused by an IAP disorder.
  • the invention provides a method for or treating a disease caused by an IAP disorder, the method comprising administering to a patient having a disease caused by an IAP disorder a pharmaceutically acceptable therapeutically effective amount of a compound or a compound of the invention
  • the pharmaceutical composition of the invention comprising administering to a patient having a disease caused by an IAP disorder a pharmaceutically acceptable therapeutically effective amount of a compound or a compound of the invention.
  • the disease caused by the IAP disorder of the invention is cancer or hepatitis B virus infection.
  • the cancer of the present invention includes, but is not limited to, rectal cancer, renal cancer, ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, melanoma, glioblastoma, acute myeloid leukemia. , small cell lung cancer, non-small cell lung cancer, rhabdomyosarcoma and basal cell carcinoma, and the like.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the invention, and as disclosed herein are included in the present invention. .
  • stereochemistry is indicated by a solid wedge or dashed line indicating a particular configuration, then the stereoisomers of the structure are defined and defined herein.
  • Nitrogen oxides of the compounds of the invention are also included within the scope of the invention.
  • the corresponding nitrogen-containing basic substance can be oxidized by using a usual oxidizing agent (for example, hydrogen peroxide) at elevated temperature, in the presence of an acid such as acetic acid, or by reacting with a peracid in a suitable solvent, for example, in methylene chloride.
  • a usual oxidizing agent for example, hydrogen peroxide
  • the oxynitride of the compound of the present invention is prepared by reacting with peracetic acid in ethyl acetate or methyl acetate or by reacting with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
  • the desired salt can be prepared by any suitable method provided in the literature, for example, using a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like.
  • organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranoic acid such as glucuronic acid and galactose Aldehydic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.
  • the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base such as ammonia (primary ammonia, secondary ammonia, tertiary ammonia), alkali metal hydroxide or alkaline earth. Metal hydroxide, and so on.
  • Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine Etc., and inorganic salts are obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the pharmaceutical composition of the present invention comprises the formula (I), (Ia), (Ia-1), (II), (II-1), (III), (IV), (V) , (VI), (VII), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1), (VII-1) , (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), A compound represented by IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa-1), a compound listed in the present invention, or a compound of the examples.
  • the amount of the compound in the composition of the present invention is effective for treating or alleviating a disease caused by an IAP disorder in a patient, including cancer, hepatitis B virus infection.
  • the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable adjuvant, such as any solvent, diluent, or other liquid excipient, dispersing agent, as employed herein. Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the particular target dosage form.
  • a pharmaceutically acceptable adjuvant such as any solvent, diluent, or other liquid excipient, dispersing agent, as employed herein.
  • suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc. suitable for the particular target dosage form.
  • a therapeutically effective amount of a compound of the invention especially formula (I), (Ia), (Ia-1), (II), (II-1), (III), (IV), V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX), (X), (III-1), (IV-1), (V- 1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (VIII-1), (IX-1), (X-1) , (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), ( The compound of VIa-1) or (VIIa-1) and a pharmaceutically acceptable salt thereof can be administered as an unprocessed chemical, and can also be provided as an active ingredient of a pharmaceutical composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, especially formula (I), (Ia), (Ia-1), (II), (II-1) , (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX), (X), (III-1) , (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (VIII-1), ( IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa- 1), (Va-1), (VIa-1) or (VIIa-1) a compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable adjuvants, including but not limited to a carrier , thinner or excipient, etc.
  • terapéuticaally effective amount refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit, such as a decrease in cancer cells. When administered alone as a separate active ingredient, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of the active ingredient which results in a therapeutic effect, whether administered sequentially or simultaneously.
  • a process for the preparation of a pharmaceutical formulation comprising the compounds of the invention, especially formula (I), (Ia), (Ia-1), (II), (II -1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX), (X), (III) -1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (VIII-1 ), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), a compound of (IVa-1), (Va-1), (VIa-1) or (VIIa-1) or a pharmaceutically acceptable salt thereof and one
  • pharmaceutically acceptable means a compound, a raw material, a composition and/or a dosage form which, within the scope of sound medical judgment, is suitable for contact with a patient's tissue without excessive toxicity or irritation. , allergies or other problems and complications commensurate with a reasonable benefit/risk ratio and effective for the intended use.
  • the amount of active ingredient combined with one or more adjuvants to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • the amount of active ingredient to be prepared in a single dosage form will vary depending on the condition to be treated, the severity of the disease, the time of administration, the route of administration, the rate
  • Preferred unit dosage forms are unit dosage forms containing a daily or divided dose of the active ingredient described herein, or a suitable fraction thereof. Treatment can be initiated with a small dose that is clearly below the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the best results are achieved in this case.
  • the level of concentration at which the compound is most desirably administered is generally effective to provide an effective anti-tumor effect without causing any harmful or toxic side effects.
  • the pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90%, of the active ingredient.
  • the pharmaceutical compositions of the invention may be, for example, in unit dosage form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
  • the compound of the present invention or a pharmaceutical composition thereof is preferably administered in an effective amount.
  • An effective amount is the amount of the formulation that produces the desired response, either alone or in combination with other drugs. This may only include temporarily slowing the progression of the disease, but preferably includes permanently preventing the progression of the disease or delaying the onset of the disease or preventing the appearance of the disease or condition. This can be monitored by conventional methods.
  • the dosage of active compound will range from about 0.01 mg/kg per day to 1000 mg/kg per day. It is contemplated that a daily dosage range of 50-500 mg/kg is preferred via intravenous, intramuscular or intradermal administration and one or several times.
  • Administration of a compound of the invention or a pharmaceutical composition thereof can be carried out simultaneously, after or before chemotherapy or radiation, as long as the chemotherapeutic agent or radiation renders the system susceptible to the compound of the invention or a pharmaceutical composition thereof.
  • the administration regimen of the compound of the present invention or a pharmaceutical composition thereof may be orally administered from 1 to 2 mg/day, preferably from 1 to 1000 mg/day, more preferably from 50 to 600 mg, in 2-4 times (preferably twice). / day to reduce tumor growth. Intermittent therapy (eg, three weeks in a week or four weeks in three weeks) can also be used.
  • compositions provided herein comprise a therapeutically effective amount of one or more of the formulae (I), (Ia), (Ia-1), (II), (II-1), (III) provided by the present invention, (IV), (V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX), (X), (III-1), (IV-1 ), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va a compound of -1), (VIa-1) or (VIIa-1) for use in preventing, treating or ameliorating a disease caused by an IAP disorder or associated with caspase activity, including caspase activity-9 activity One or more symptoms of the condition.
  • diseases or conditions include, but are not limited to, hyperpro
  • compositions are suitable for administration by any suitable route, for example by oral administration (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, dermal) Internal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion).
  • oral administration including buccal or sublingual
  • rectal including buccal or sublingual
  • nasal including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, dermal
  • Internal intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with carriers or excipients. Oral administration or injection administration is preferred.
  • suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia, tragacanth or sodium alginate), carboxymethylcellulose. , polyethylene glycol, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • a tablet is prepared by preparing a powdery mixture, granulating or pre-compacting, adding a lubricant and a disintegrating agent, and compressing into a tablet.
  • a powdery mixture for example carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone
  • a dissolution inhibitor for example paraffin
  • a powder mixture is prepared by mixing an absorption accelerator (quaternary salt) and/or an absorbent (for example, bentonite, kaolin or dicalcium phosphate).
  • the powdered mixture can be granulated by wetting with a binder such as syrup, starch syrup, acadiamucilage or cellulosic material or a solution of polymeric material.
  • a binder such as syrup, starch syrup, acadiamucilage or cellulosic material or a solution of polymeric material.
  • An alternative to granulation is that the powdered mixture can be passed through a tablet press, with the result that poorly formed agglomerates are broken down into granules.
  • the granules can be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent sticking to the die of the tablet press.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier which can be compressed into tablets without the need for granulation or pre-tabletting steps.
  • a protective or coating material consisting of a shellac seal coat, a sugar
  • formulations also include other ingredients commonly used in the art in connection with the type of formulation, such as those suitable for oral administration, which may include flavoring agents.
  • the pharmaceutical composition of the present invention is characterized by the formula (I), (Ia), (Ia-1), (II), (II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX), (X), (III-1), (IV-1), (V-1), (VI-1 ), (VII-1), (VIII-1), (IX-1), (X-1), (IIIa), (IIIb ), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1), (IVa-1), (Va-1), (VIa-1) or (VIIa a compound of the formula -1), a compound listed in the present invention, or a compound of the example, and a pharmaceutically acceptable adjuvant, an adjuvant such as a carrier, an adjuvant or an excipient, and the like.
  • the compounds of the compositions of the invention are useful in the prevention and treatment of
  • IAP disorders are not limited to hyperproliferative diseases, autoimmune diseases, psoriasis, hyperplasia, and restenosis.
  • autoimmune diseases include HIV virus infection, hepatitis B virus infection; proliferative diseases include tumor diseases (or cancer) (and/or any metastatic tumors).
  • the compounds of the present invention or pharmaceutical compositions thereof are useful in the manufacture of a medicament for the treatment of diseases which are particularly useful for the treatment of cancer, including tumors, such as skin cancer, breast cancer, brain cancer, cervical cancer, testicular cancer and the like. It is especially useful for the treatment of metastatic or malignant tumors. More particularly, cancers treatable by the compositions and methods of the invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, Head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer and thyroid cancer, and sarcoma.
  • tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, Head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer,
  • these compounds are useful in the treatment of cancer at the heart: sarcoma (vascular aneurysm, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibroids, lipomas and teratomas; lung cancer: bronchi Cancer (flat cells, undifferentiated small cells, undifferentiated large cells, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, cartilage hamartoma, mesothelioma; gastrointestinal site Cancer: esophageal cancer (flat cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (cancer, lymphoma, leiomyosarcoma), pancreatic cancer (catheter adenocarcinoma, insulinoma, glucagonoma, gas
  • the compound of the present invention or a pharmaceutical composition thereof can also be used for the preparation of a medicament for treating an HIV virus infection or a hepatitis B virus infection disease.
  • the compound of the present invention or a pharmaceutical composition thereof can effectively inhibit the expression of IAPs (inhibitors of apoptosis proteins) in hepatocytes, and promote the elimination of virus-specific T cell-mediated HBV DNA and HBV surface antigen, thereby curing chronic HBV infection.
  • the proliferative disease may also be a hyperproliferative condition such as leukemia, hyperplasia, fibrosis (especially pulmonary fibrosis, but also other types of fibrosis such as fibrosis of the kidney), blood vessels Formation, psoriasis, atherosclerosis, and intravascular smooth muscle hyperplasia such as stenosis or restenosis after angioplasty.
  • a hyperproliferative condition such as leukemia, hyperplasia, fibrosis (especially pulmonary fibrosis, but also other types of fibrosis such as fibrosis of the kidney), blood vessels Formation, psoriasis, atherosclerosis, and intravascular smooth muscle hyperplasia such as stenosis or restenosis after angioplasty.
  • tumor disease When referring to a tumor, tumor disease, cancer or cancer, it additionally or additionally implies a metastatic tumor in the original organ or tissue and/or any other site, regardless of the location of the tumor and/or metastases.
  • the compounds of the invention may be administered alone or in combination with other anticancer agents, such as compounds that inhibit tumor angiogenesis, such as protease inhibitors, epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, and the like.
  • anticancer agents such as compounds that inhibit tumor angiogenesis, such as protease inhibitors, epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, and the like.
  • Cytotoxic drugs such as antimetabolites, such as purines and pyrimidine mimicking antimetabolites; anti-mitotic agents such as microtubule-stabilizing drugs and anti-mitotic alkaloids; platinum-coordinating complexes; antitumor antibiotics; Agents such as nitrogen mustard and nitrosourea; endocrine drugs such as adrenocortical steroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin releasing hormone agonists and somatostatin analogues And compounds that target enzymes or receptors that are overexpressed and/or involved in a particular metabolic pathway that is upregulated in tumor cells, such as ATP and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinases Inhibitors such as serine, threonine and tyrosine kinase inhibitors, such as Abelson protein tyrosine kinases and various growth factors , their receptor
  • the compound or pharmaceutical composition of the present invention when administered in combination, there are two ways: 1) the compound or pharmaceutical composition of the present invention is separately formulated with other active agents that can be used in combination, and the two dosage forms may be the same or Differently, it can be used sequentially or simultaneously; when used, the first drug has not lost its effective effect in vivo when the second drug is administered; 2) the compound or pharmaceutical composition of the present invention can be combined
  • the other active drugs used are prepared as a single preparation and administered simultaneously.
  • the invention further relates to a method of promoting apoptosis in rapidly proliferating cells, the method comprising the step of combining a rapidly proliferating cell with an effective amount of a pro-apoptotic cell that binds to a Smac binding site of a XIAP and/or cIAP protein
  • the compounds or compositions of the invention may be administered with a chemotherapeutic agent and/or with radiation therapy, immunotherapy and/or photodynamic therapy to promote apoptosis and enhance the chemistry The effectiveness of therapy, radiation therapy, immunotherapy and/or photodynamic therapy.
  • an “effective amount” or “effective amount” of a compound or pharmaceutically acceptable composition of the invention refers to an effective amount to treat or ameliorate the severity of one or more of the conditions mentioned herein.
  • the compounds and compositions can be administered in any amount and in any route of administration effective to treat or reduce the severity of the disease. The exact amount required will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of infection, specific factors, mode of administration, and the like.
  • the compound or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.
  • the compounds of the invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I), (Ia), (Ia-1), (II), II-1), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (VIII), (IX), (X), III-1), (IV-1), (V-1), (VI-1), (VII-1), (VIII-1), (IX-1), (X-1), (VIII- 1), (IX-1), (X-1), (IIIa), (IIIb), (IVa), (Va), (VIa), (VIIa), (IIIa-1), (IIIb-1) , (IVa-1), (Va-1), (VIa-1) or (VIIa-1).
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • the reagents were purchased from commercial suppliers such as Lingkai Pharmaceuticals, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated.
  • the general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
  • Anhydrous tetrahydrofuran is obtained by refluxing with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, N,N-dimethylacetamide and petroleum ether were previously dried over anhydrous sodium sulfate.
  • reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe.
  • the glassware is dry.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh
  • Silica gel 300-400 mesh
  • TMS 0.25 ppm
  • chloroform 7.25 ppm
  • MS data was measured with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C) Agilent 6320 Series LC-MS spectrometer, G1329A autosampler and G1315B DAD detector applied For analysis, the ESI source was applied to an LC-MS spectrometer.
  • MS mass spectrometry
  • Both spectrometers are equipped with an Agilent Zorbax SB-C18 column measuring 2.1 x 30 mm, 5 ⁇ m.
  • the injection volume was determined by sample concentration; the flow rate was 0.6 mL/min; the peak of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phase was a 0.1% formic acid acetonitrile solution (Phase A) and a 0.1% formic acid ultrapure aqueous solution (Phase B).
  • the compound of the formula (I) when versus When it is the same fragment, the compound of the formula (I) can be obtained according to the synthesis procedure of the synthesis scheme 1.
  • Pg is an amino protecting group, preferably Cbz; hal is Cl, Br, preferably Br; and alkyl is C 1-4 alkyl, preferably tert-butyl.
  • the compound of the formula (I-1) is first reacted with oxalyl chloride, and then the obtained acid chloride product and the compound (I-2) are subjected to a Grignard reagent such as ethylmagnesium bromide to give the compound (I-3).
  • Compound (I-3) gives compound (I-4) under the action of a reducing agent such as sodium borohydride.
  • Compound (I-4) gives compound (I-5) under the action of a halogenating reagent such as NBS.
  • the compound (I-5) is subjected to a coupling reaction with the compound (I-6) under the action of a catalyst such as (dppf) 2 PdCl 2 to obtain a compound (I-7).
  • Compound (I-7) is subjected to deamination protection under suitable conditions (e.g., Pd/C catalysis under H 2 conditions) to give compound (I-8).
  • the compound (I-8) is subjected to a coupling reaction with a compound (I-9) under a coupling agent (e.g., DMT-MM) to give a compound (I-10).
  • Compound (I-10) is deaminated under acidic conditions (e.g., TFA) to give compound (I).
  • the compound of the formula (IIIA) can be obtained according to the synthesis procedure of the synthesis scheme 2.
  • Pg is each independently an amino protecting group, preferably Cbz; hal is Cl, Br, preferably Br; and alkyl is C 1-4 alkyl, preferably tert-butyl.
  • the compound of the formula (IIIA-1) is first reacted with oxalyl chloride, and then the obtained acid chloride product and the compound (IIIA-2) are subjected to a Grignard reagent such as ethylmagnesium bromide to give the compound (IIIA-3).
  • Compound (IIIA-3) gives compound (IIIA-4) under the action of a reducing agent such as sodium borohydride.
  • Compound (IIIA-4) gives compound (IIIA-5) under the action of a halogenating reagent such as NBS.
  • the compound (IIIA-5) is subjected to a coupling reaction with the compound (IIIA-6) under the action of a catalyst such as (dppf) 2 PdCl 2 to obtain a compound (IIIA-7).
  • Compound (IIIA-7) is subjected to deamination protection under suitable conditions (e.g., Pd/C catalysis under H 2 conditions) to give compound (IIIA-8).
  • the compound (IIIA-8) and the compound (IIIA-9) are subjected to a coupling reaction under the action of a coupling agent such as DMT-MM to obtain a compound (IIIA-10).
  • Compound (IIIA-10) is deaminated under acidic conditions (e.g., TFA) to give compound (IIIA-11).
  • Compound (IIIA) is obtained under basic conditions (e.g., LiOH).
  • the compound of the formula (IIIA1) when versus When it is the same fragment, the compound of the formula (IIIA1) can be obtained according to the synthesis procedure of Synthesis Scheme 3.
  • Pg is each independently an amino protecting group, preferably Cbz; hal is Cl, Br, preferably Br; and alkyl is C 1-4 alkyl, preferably tert-butyl.
  • the compound of the formula (IIIA1-1) is first reacted with oxalyl chloride, and then the obtained acid chloride product and the compound (IIIA-2) are subjected to a Grignard reagent such as ethylmagnesium bromide to give the compound (IIIA1-3).
  • the compound (IIIA1-3) is subjected to a reducing agent such as sodium borohydride to give the compound (IIIA1-4).
  • Compound (IIIA1-4) gives compound (IIIA1-5) under the action of a halogenating reagent such as NBS.
  • the compound (IIIA1-5) is subjected to a coupling reaction with the compound (IIIA1-6) under the action of a catalyst such as (dppf) 2 PdCl 2 to obtain a compound (IIIA1-7).
  • Compound (IIIA1-7) is subjected to deamination protection under suitable conditions (e.g., Pd/C catalysis under H 2 conditions) to give compound (IIIA1-8).
  • the compound (IIIA1-8) and the compound (IIIA1-9) are subjected to a coupling reaction under the action of a coupling agent such as DMT-MM to obtain a compound (IIIA1-10).
  • the compound (IIIA1-10) is deaminated under acidic conditions (e.g., TFA) to give the compound (IIIA1-11).
  • Compound (IIIA1-11) gives compound (IIIA1) under basic conditions (e.g., LiOH).
  • the compound of the formula (I) can be obtained according to the synthesis procedure of the synthesis scheme 4.
  • Pg is an amino protecting group, preferably Cbz; hal is Cl, Br, preferably Br; and alkyl is C 1-4 alkyl, preferably tert-butyl.
  • hal is Cl, Br, preferably Br; and alkyl is C 1-4 alkyl, preferably tert-butyl.
  • alkyl is C 1-4 alkyl, preferably tert-butyl.
  • formula (I-4) is protected to give a compound of deaminated compound (I-11) under suitable conditions (e.g., Pd / C catalyst under conditions H 2).
  • the compound (I-11) is subjected to a coupling reaction with a compound (I-9) under a coupling agent (e.g., DMT-MM) to give a compound (I-12).
  • a coupling agent e.g., DMT-MM
  • the compound (I-12) is subjected to a halogenation reaction under suitable conditions such as the presence of oxalyl chloride to give the compound (I-13).
  • the compound (I-13) is subjected to a coupling reaction with the compound (I-6) under the action of a catalyst such as (dppf) 2 PdCl 2 to obtain a compound (I-14).
  • Compound (I-14) is subjected to deamination protection under suitable conditions (e.g., Pd/C catalysis under H 2 conditions) to give compound (I-15).
  • the compound (I-15) and the compound (I-16) are subjected to a coupling reaction under the action of a coupling agent such as DMT-MM to obtain a compound (I-10).
  • Compound (I-10) is deaminated under acidic conditions (e.g., TFA) to give compound (I).
  • the compound of the formula (IIIA) when versus When not the same fragment, the compound of the formula (IIIA) can be obtained according to the synthetic procedure of Synthesis Scheme 5.
  • Pg is an amino protecting group, preferably Cbz; hal is Cl, Br, preferably Br; and alkyl is C 1-4 alkyl, preferably tert-butyl.
  • the compound of formula (IIIA-4) deaminated to give protected compound (IIIA-12) under suitable conditions (e.g., Pd / C catalyst under conditions H 2).
  • the compound (IIIA-12) is subjected to a coupling reaction with the compound (IIIA-9) under the action of a coupling agent such as DMT-MM to obtain a compound (IIIA-13).
  • the compound (IIIA-13) is subjected to a halogenation reaction under suitable conditions such as the presence of oxalyl chloride to give the compound (IIIA-14).
  • the compound (IIIA-14) is subjected to a coupling reaction with the compound (IIIA-6) under the action of a catalyst such as (dppf) 2 PdCl 2 to obtain a compound (IIIA-15).
  • Compound (IIIA-15) is subjected to deamination protection under suitable conditions (e.g., Pd/C catalysis under H 2 conditions) to give compound (IIIA-16).
  • the compound (IIIA-16) and the compound (IIIA-17) are subjected to a coupling reaction under the action of a coupling agent such as DMT-MM to obtain a compound (IIIA-10).
  • a coupling agent such as DMT-MM
  • Compound (IIIA-10) is deaminated under acidic conditions (e.g., TFA) to give compound (IIIA-11).
  • Compound (IIIA) is obtained under basic conditions (e.g., LiOH).
  • the compound of the formula (IIIA1) can be obtained according to the synthesis procedure of Synthesis Scheme 3.
  • Pg is an amino protecting group, preferably Cbz; hal is Cl, Br, preferably Br; and alkyl is C 1-4 alkyl, preferably tert-butyl.
  • the compound (IIIA1-12) is subjected to a coupling reaction with the compound (IIIA1-9) under the action of a coupling agent such as DMT-MM to obtain a compound (IIIA1-13).
  • the compound (IIIA1-13) is subjected to a halogenation reaction under suitable conditions such as the presence of oxalyl chloride to give the compound (IIIA1-14).
  • the compound (IIIA1-14) is subjected to a coupling reaction with the compound (IIIA1-6) under the action of a catalyst such as (dppf) 2 PdCl 2 to obtain a compound (IIIA1-15).
  • the compound (IIIA1-15) is subjected to deamination protection under suitable conditions (e.g., Pd/C catalysis under H 2 conditions) to give the compound (IIIA1-16).
  • the compound (IIIA1-16) and the compound (IIIA1-17) are subjected to a coupling reaction under the action of a coupling agent such as DMT-MM to obtain a compound (IIIA1-10).
  • the compound (IIIA1-10) is deaminated under acidic conditions (e.g., TFA) to give the compound (IIIA1-11).
  • Compound (IIIA1-11) gives compound (IIIA1) under basic conditions (e.g., LiOH).
  • the synthesis of the compound 3-2 can be carried out by referring to the synthesis of the step 6 of Example 11, wherein the starting material 11-6 is replaced with the starting material 3-1.
  • Compound 4-1 (160 mg, 0.22 mmol) can be obtained by the synthesis of the compound 1-10 of Example 1, using (S)-6-((6-fluoro-1H-indol-3-yl)methyl) -5-Azaspiro[2.4]heptane-5-carboxylic acid benzyl ester and (S)-2-((6-fluoro-1H-indol-3-yl)methyl)pyrrolidine-1-carboxylic acid benzyl ester Prepared by reaction under trifluoroacetic acid conditions, EA (10 mL), Pd/C (10%) (53 mg) were sequentially added to the reaction flask. H 2 gas catalyzed, stirred at rt overnight. Filtration, EA, EtOH elution, EtOAc (EtOAc/EtOAc)
  • the synthesis of Compound 7-2 can be carried out by referring to the synthesis of Step 6 of Example 11, wherein starting material 11-6 is replaced with starting material 7-1.
  • the synthesis of Compound 9-2 can be carried out by referring to the synthesis of Step 6 of Example 11, wherein starting material 11-6 is replaced with starting material 9-1.
  • the synthesis of Compound 10-2 can be carried out by referring to the synthesis of Step 6 of Example 11, wherein starting material 11-6 is replaced with starting material 10-1.
  • the synthesis of the compound 13-2 can be carried out by referring to the synthesis of the step 6 of Example 11, wherein the starting material 11-6 is replaced with the starting material 13-1, and the starting material 11-7 is the starting material 13-7 (the compound 13-7 can be referred to the compound 11-7). Synthetic) alternative.
  • the synthesis of the compound 14-2 can be carried out by referring to the synthesis of the step 6 of Example 11, wherein the starting material 11-6 is replaced by the starting material 13-1, and the starting material 11-7 is used as the starting material 14-7 (the compound 14-7 can be referred to the compound 11-7). Synthetic) alternative.
  • Compound 28-1 (500 mg, 0.595 mmol, can be obtained by the synthesis of the compound 27-5 of Example 27, wherein the starting material 27-4 is (2R,4S)-4-acetoxy-2-((2-bromo) -5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)methyl)pyrrolidine-1-carboxylate instead), EA (25 mL), Pd/C (10%, 200 mg) was added to the reaction flask in sequence. H 2 catalysis, stirring at rt overnight. Filtration, EA, EtOH washing, spin-drying, column chromatography, EA as eluent to give a pale yellow solid, 250 mg, yield 73%.
  • the starting material 27-4 is (2R,4S)-4-acetoxy-2-((2-bromo) -5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)methyl)pyrrolidine-1-
  • IC50 50% inhibitory concentration of cell proliferation in SK-OV-3 human ovarian cancer and in MDA-MB-231 human breast cancer was tested by CTG method.
  • Cell line SK-OV-3 was purchased from Shanghai Institute of Biological Sciences, Chinese Academy of Sciences
  • Cell line MDA-MB-231 was purchased from ATCC
  • Cells in the exponential growth phase were collected and viable cell counts were performed using a Vi-Cell XR cytometer.
  • the cell suspension was adjusted to the appropriate concentration with the corresponding medium.
  • 90 ⁇ L of the cell suspension was added to each well in a 96-well cell culture plate to a final cell concentration of 2000 cells/well.
  • test compound was dissolved in DMSO to a 20 mM stock solution.
  • a 4X series of gradient dilutions was prepared using stock solutions and corresponding solvents. The medium was then diluted 100 times each. Finally, 10 ⁇ L of the corresponding 10-fold solution was added to each well of each cell, and each drug concentration was 3 replicate wells.
  • concentration of the test compound used in the final test ranged from 0.153 to 10000 nM: the test compound was diluted, and the final concentration of DMSO per well was 0.1%. . Incubate for 72 hours at 37 ° C in a 5% CO 2 incubator.
  • Vsample/Vvehicle control x100% The average of the solvent control group.
  • S-type dose-survival curves were plotted and the IC50 values were calculated using the GraphPad Prism 5.0 software using a non-linear regression model.
  • the compounds 1, 2, and 4 of the present invention have strong inhibitory activity against SK-OV-3 human ovarian cancer cells, and the IC50 values are all in the range of 1-10 nM. Therefore, the compound of the present invention has a strong inhibitory activity against the proliferation of SK-OV-3 human ovarian cancer cells.
  • Table 2 shows that the compound of the present invention has a strong inhibitory activity against MDA-MB-231 human breast cancer cell proliferation.
  • the 50% inhibitory concentration (IC50) of cell proliferation in Molm13 human acute myelomonocytic leukemia was tested by CTG method.
  • FBS fetal calf serum
  • Cells in the exponential growth phase were collected and viable cell counts were performed using a cytometer.
  • the cell suspension was adjusted to the appropriate concentration with the corresponding medium.
  • 90 ⁇ L of the cell suspension was added to each well in a 96-well cell culture plate to a final cell concentration of 3000 cells/well.
  • test compound was dissolved in DMSO to a 10 mM stock solution.
  • a 3X series of gradient dilutions was prepared using stock solutions and corresponding solvents. The medium was then diluted 100 times each. Finally, 10 ⁇ L of the corresponding 10-fold solution was added to each well of each cell, and each drug concentration was 3 replicate wells.
  • concentration of the test compound used in the final test ranged from 1.52 to 10000 nM: the test compound was diluted, and the final concentration of DMSO per well was 0.1%. . Incubate for 72 hours at 37 ° C in a 5% CO 2 incubator.
  • Vsample/Vvehicle control x100% The average of the solvent control group.
  • S-type dose-survival curves were plotted and the IC50 values were calculated using the GraphPad Prism 5.0 software using a non-linear regression model.
  • Table 3 shows that the compound of the present invention has a strong inhibitory activity against the proliferation of Molm13 human acute myelomonocytic leukemia cells.
  • the inhibitory effect of the compound on the cIAP1-BIR3 target was evaluated based on fluorescence polarization binding experiments.
  • the inhibitory effect of the small molecule compound on the binding ability of the cIAP1-BIR3 protein to the fluorescent marker SM5F was examined by a drug screening system based on a fluorescence polarization binding assay.
  • the protein is fluorescently polarized in combination with a fluorescent label, and the fluorescence polarization value (mP) is detected by an Envision plate reader to reflect the degree of binding of the protein to the fluorescent label.
  • the positive compound Birinapant (10 mM stock solution) was diluted 10-fold to 1000 ⁇ M with 100% DMSO, and the test compound (10 mM stock solution) was diluted 100-fold to 100 ⁇ M in a 384-dilution plate (3657, corning) at 1:3. Equal dilutions were made such that the gradient concentrations of the positive compounds were: 1000, 333.3, 111.1, 37.04, 12.34, 4.12, 1.37, 0.46, 0.15, 0.051, 0 ⁇ M. Gradient concentrations of the test compounds: 100, 33.3, 11.1, 3.704, 1.234, 0.412, 0.137, 0.046, 0.015, 0.005, 0 ⁇ M.
  • step c) Transfer 5 ⁇ L of the compound solution (prepared in step b) to a 384-dilution plate containing 45 ⁇ L of 1X reaction buffer, shake well and centrifuge at 1000 rpm.
  • step d) Transfer 2 ⁇ L of the compound solution (prepared in step c) to a 384 reaction plate (prepared in step a), centrifuge at 1000 rpm and incubate at 25 ° C for 15 minutes.
  • step e) Transfer 10 ⁇ L of fluorescent label (prepared in step 2.2.1.3) to a 384 reaction plate, centrifuge at 1000 rpm and incubate at 25 ° C for 60 minutes.
  • the positive compound and the test compound were in the reaction system, and the final concentration gradients were 10000, 3333.3, 1111.1, 370.3, 123.5, 41.4, 13.7, 4.6, 1.5, 0.51, 0 nM. 1000, 333.3, 111.1, 37.04, 12.34, 4.12, 1.37, 0.46, 0.15, 0.051, 0 nM.
  • the final concentration of DMSO was 1%.
  • f) Read the mP value using the Envision Multifunction Reader. The mP value size was used to characterize the degree of binding of the cIAP1-BIR3 protein to the fluorescent marker SM5F.
  • g) Using a nonlinear fitting formula to obtain the IC50 (half inhibitory concentration) of the compound. The specific experimental results are shown in Table 4.
  • Table 4 shows that the compound of the present invention has strong inhibitory activity against the cIAP1-BIR3 protein.

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Abstract

L'invention concerne un nouveau composé inhibiteur d'IAP et son utilisation. En particulier, la présente invention concerne un composé qui est un inhibiteur d'IAP, ou un stéréoisomère, un tautomère, un oxyde d'azote, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. La présente invention concerne également l'utilisation du composé et de la composition pharmaceutique de celui-ci dans la préparation d'un médicament pour le traitement ou la prévention de maladies provoquées par un trouble d'IAP, en particulier l'utilisation de celui-ci dans la préparation d'un médicament pour le traitement ou la prévention de cancers ou d'une infection par le virus de l'hépatite B.
PCT/CN2019/072531 2018-02-09 2019-01-21 Inhibiteur d'iap et leur utilisation en médecine WO2019154053A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014361A1 (fr) * 2004-07-02 2006-02-09 Genentech, Inc. Inhibiteurs de pai
CN101128425A (zh) * 2005-02-25 2008-02-20 泰特拉洛吉克药业公司 Iap二聚体抑制剂
CN101516904A (zh) * 2006-07-24 2009-08-26 泰特拉洛吉克药业公司 二聚的iap拮抗剂
CN102471275A (zh) * 2009-07-02 2012-05-23 泰特拉洛吉克药业公司 Smac模拟物
WO2012080260A1 (fr) * 2010-12-13 2012-06-21 Novartis Ag Inhibiteurs iap dimériques
CN108440507A (zh) * 2017-02-16 2018-08-24 南京圣和药业股份有限公司 作为细胞凋亡蛋白抑制剂的化合物及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014361A1 (fr) * 2004-07-02 2006-02-09 Genentech, Inc. Inhibiteurs de pai
CN101128425A (zh) * 2005-02-25 2008-02-20 泰特拉洛吉克药业公司 Iap二聚体抑制剂
CN101516904A (zh) * 2006-07-24 2009-08-26 泰特拉洛吉克药业公司 二聚的iap拮抗剂
CN102471275A (zh) * 2009-07-02 2012-05-23 泰特拉洛吉克药业公司 Smac模拟物
WO2012080260A1 (fr) * 2010-12-13 2012-06-21 Novartis Ag Inhibiteurs iap dimériques
CN108440507A (zh) * 2017-02-16 2018-08-24 南京圣和药业股份有限公司 作为细胞凋亡蛋白抑制剂的化合物及其应用

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