WO2021000957A1 - Composé hétérocylique, composition pharmaceutique et utilisation associées - Google Patents

Composé hétérocylique, composition pharmaceutique et utilisation associées Download PDF

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WO2021000957A1
WO2021000957A1 PCT/CN2020/100252 CN2020100252W WO2021000957A1 WO 2021000957 A1 WO2021000957 A1 WO 2021000957A1 CN 2020100252 W CN2020100252 W CN 2020100252W WO 2021000957 A1 WO2021000957 A1 WO 2021000957A1
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group
substituted
groups
membered
hydrocarbon
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PCT/CN2020/100252
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English (en)
Chinese (zh)
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胡伟
杨艳青
祝力
张慧
吴伟
戴丽光
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北京国鸿生物医药科技有限公司
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Priority to CN202080044216.1A priority Critical patent/CN114127058A/zh
Publication of WO2021000957A1 publication Critical patent/WO2021000957A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present disclosure relates to heterocyclic compounds, specifically heterocyclic compounds for regulating CKI ⁇ -CDK7/9 kinase-mediated diseases.
  • Casein Kinase I ⁇ belongs to the serine/threonine protein kinase family, which participates in a variety of cellular physiological processes, and is closely related to the occurrence and development of some diseases.
  • CKI ⁇ binds to MDM2 and phosphorylates it to promote the binding of MDM2 to P53, thereby inhibiting the activity of P53. Loss of CKI ⁇ can cause DNA damage and P53 activation, so CKI ⁇ is a negative regulator of P53.
  • CKI ⁇ can act as a carcinogen.
  • the role of Lenalidomide in the treatment of pre-leukemia syndrome is to degrade CKI ⁇ .
  • Cyclin-dependent kinases are also a group of serine/threonine protein kinases, among which CDK7 and CDK9 are involved in cell transcription regulation and play an important role in transcription regulation.
  • CDK7 can phosphorylate Ser5 of RNA polymerase II
  • CDK9 can phosphorylate Ser 2, which leads to the activation of RNA polymerase II and promotes the extension of transcription.
  • Super enhancer is a special type of DNA fragment composed of non-coding regions of DNA.
  • the SE is enriched with high-density transcription factors, cofactors and enhancer apparent modification markers, which can regulate the expression of multiple genes , And play an important role in cell survival and differentiation characteristics.
  • SE-driven abnormally transcribed genes are essential to maintain the characteristics of tumor cells.
  • SE can promote the expression of key oncogenes and enrich disease-related mutations. It has great research value and has become a research hotspot in the field of biomedicine.
  • Richard A. Young proposed the concept of super-enhancers based on the research of enhancers at that time, and predicted: "'Super-enhancers' have broad research and development prospects and value, and will surely become the next golden target for drug development!
  • SE may provide new ideas for the development of treatment technologies for tumors, autoimmune diseases, diabetes and other complex diseases.
  • SE and the functional complex formed can affect the function of the super enhancer, and then affect the expression level of downstream regulatory genes, thereby playing a therapeutic role.
  • genes with super enhancers are very sensitive to the decline in the activity of key transcriptional regulatory factors such as cohesion factors, BRD4 and other chromatin modifiers, and CDK7 and other transcription device components. Therefore, targeting the CDK7/9 signaling pathway to down-regulate the transcription of SE regulatory genes, such as MCL-1, MYC, and Cyclin D1, and then down-regulate the level of body transcription, has become a hot spot for tumor therapy.
  • a main purpose of the present disclosure is to provide a heterocyclic compound or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotope label or isomer thereof, the structure of the heterocyclic compound is as follows :
  • R 1 is selected from a 3- to 9-membered substituted or unsubstituted cyclic group, and the substituent on the substituted cyclic group of R 1 is selected from halogen atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, and oxygen
  • substituent group a C 1 ⁇ C 8 hydrocarbon group, and a C 1 ⁇ C 8 substituted hydrocarbon group;
  • R 11 is selected from hydrogen, a substituted or unsubstituted cyclic group of 3 to 9 members, a C 3 to C 10 substituted hydrocarbon group, and the substituent of the C 3 to C 10 substituted hydrocarbon group is selected from 3 to 6 membered Substituted or unsubstituted cyclic group;
  • the substituents on the 3- to 6-membered and 3- to 9-membered substituted cyclic groups of R 11 are independently selected from substituted or unsubstituted halogen atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, C 1 ⁇ C 8 hydrocarbon group, C 2 ⁇ C 8 ester group, C 1 ⁇ C 8 acyloxy group, C 1 ⁇ C 8 hydrocarbon oxy group, C 1 ⁇ C 8 hydrocarbon thio group, C 1 ⁇ C 8 hydrocarbon amino group, C 1 ⁇ C 8 acyl group, C 1 ⁇ C 8 acylamino group, C 1 ⁇ C 8 sulfonyl group, C 1 ⁇ C 8 sulfonylamino group, 3-8 membered heterocyclic group
  • One or more of the group, the substituents in the 3- to 8-membered substituted heterocyclic group of R 11 are selected from halogen atoms, hydroxyl groups,
  • R 2 The structure of R 2 is as follows:
  • R 21 is selected from hydrogen, halogen atom, hydroxyl, mercapto, amino, cyano, methyl, halomethyl;
  • R 22 is selected from C 1 ⁇ C 8 hydrocarbon groups, C 1 ⁇ C 8 substituted hydrocarbon groups, R 23 is selected from substituted or unsubstituted C 1 ⁇ C 8 hydrocarbon groups, C 1 ⁇ C 8 hydrocarbon thio groups, C 1 ⁇ C 8 hydrocarbyloxy group; or, R 22 , R 23 and the carbon atom and nitrogen atom on the pyrazole ring to which they are connected together form a 3- to 8-membered substituted or unsubstituted heterocyclic group; wherein, R 22.
  • the substituents on the heterocyclic group formed by R 23 are selected from substituted or unsubstituted: halogen atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, C 1 ⁇ C 8 hydrocarbon groups, C 2 -C 8 ester group, C 1 -C 8 acyloxy group, C 1 -C 8 hydrocarbyloxy group, C 1 -C 8 hydrocarbyl thio group, C 1 -C 8 hydrocarbylamino group, C 1 -C One or more of 8 acyl groups, C 1 ⁇ C 8 acylamino groups, C 1 ⁇ C 8 sulfonyl groups, and C 1 ⁇ C 8 sulfonylamino groups;
  • R 3 is selected from hydrogen, methyl, halogen atom or cyano group
  • R 4 is hydrogen, or, in the formula (I), R 4 and the nitrogen atom on the pyrimidine ring connected to it together form a five-membered or six-membered Heterocycle; or, R 3 , R 4 and the carbon atoms on the pyrimidine ring connected to them together form a five-membered or six-membered heterocycle;
  • R 5 is selected from fluorine or cyano
  • the substituent of the C 1 to C 8 substituted hydrocarbon group is selected from halogen atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, 3 to 6 membered cyclic hydrocarbon groups or heterocyclic groups, and C 2 to C 8 ester groups , C 1 -C 8 acyloxy group, C 1 -C 8 hydrocarbyloxy group, C 1 -C 8 hydrocarbyl thio group, C 1 -C 8 hydrocarbylamino group, C 1 -C 8 acyl group, C 1 One or more of ⁇ C 8 acylamino group, C 1 ⁇ C 8 sulfonyl group, C 1 ⁇ C 8 sulfonylamino group, and C 6 ⁇ C 8 aryl group;
  • the substituents in the substituted ester group, substituted acyloxy group, substituted hydrocarbyloxy group, substituted hydrocarbylthio group, substituted hydrocarbylamino group, substituted acyl group, substituted amido group, substituted sulfonyl group, and substituted sulfonylamino group are selected from halogen atoms, One or more of hydroxyl, mercapto, amino, cyano, oxo, and halomethyl.
  • One embodiment of the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above heterocyclic compounds or pharmaceutically acceptable salts, solvates, active metabolites, polymorphs, isotopic labels or isomers thereof, and A pharmaceutically acceptable carrier.
  • An embodiment of the present disclosure provides a heterocyclic compound or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotope label or isomer of any of the above heterocyclic compounds, or the above pharmaceutical composition Use in the treatment of malignant tumors.
  • the malignant tumor is selected from one or more of leukemia, colon cancer, rectal cancer, and lung cancer.
  • the heterocyclic compound according to one embodiment of the present disclosure has good CKI ⁇ -CDK7/9 inhibitory activity.
  • heterocyclic compound or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotope label or isomer thereof, the structure of the heterocyclic compound is as follows:
  • R 1 is selected from a 3- to 9-membered substituted or unsubstituted cyclic group, and the substituent on the R 1 ring may be a halogen atom, an amino group, a hydroxyl group, a mercapto group, a cyano group, an oxo group, C 1 ⁇ One or more of C 8 hydrocarbyl groups and C 1 ⁇ C 8 substituted hydrocarbyl groups;
  • R 11 is selected from hydrogen, a 3-9-membered substituted or unsubstituted cyclic group, a C 3 -C 10 substituted hydrocarbon group, and the substituent of the C 3 -C 10 substituted hydrocarbon group is selected from a 3- to 6-membered substituent Or unsubstituted cyclic group;
  • the substituent on the cyclic group of R 11 may be selected from halogen atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, and substituted or unsubstituted C 1 to C 8 hydrocarbon groups, C 2 to C 8 ester group, C 1 to C 8 acyloxy group, C 1 to C 8 hydrocarbyloxy group, C 1 to C 8 hydrocarbyl thio group, C 1 to C 8 hydrocarbyl amino group, C 1 to C 8 One or more of acyl group, C 1 ⁇ C 8 acylamino group, C 1 ⁇ C 8 sulfonyl group, C 1 ⁇ C 8 sulfonylamino group, and 3-8 membered heterocyclic group;
  • the substituents of the C 1 to C 8 substituted hydrocarbon groups are selected from halogen atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, 3 to 6 membered cyclic hydrocarbon groups or heterocyclic groups, C 2 to C 8 ester groups, and C 1 to C 8 acyloxy group, C 1 -C 8 hydrocarbyloxy group, C 1 -C 8 hydrocarbyl thio group, C 1 -C 8 hydrocarbylamino group, C 1 -C 8 acyl group, C 1 -C 8 One or more of acylamino, C 1 ⁇ C 8 sulfonyl group, C 1 ⁇ C 8 sulfonylamino group, and C 6 ⁇ C 8 aryl group;
  • the substituents in the substituted ester group, substituted acyloxy group, substituted hydrocarbyloxy group, substituted hydrocarbylamino group, substituted acyl group, substituted amido group, substituted sulfonyl group, substituted sulfonylamino group, and substituted heterocyclic group are selected from halogen atoms and hydroxyl groups.
  • R 2 The structure of R 2 is as follows:
  • R 21 can be hydrogen, halogen atom, hydroxyl, mercapto, amino, cyano, methyl, halomethyl;
  • R 22 can be a C 1 to C 8 hydrocarbon group, a C 1 to C 8 substituted hydrocarbon group, and R 23 can be a substituted or unsubstituted C 1 to C 8 hydrocarbon group, a C 1 to C 8 hydrocarbon group, or C 1 ⁇ C 8 hydrocarbyloxy group; or, R 22 , R 23 and the carbon atom and nitrogen atom on the pyrazole ring to which they are connected together form a substituted or unsubstituted 3-8 membered heterocyclic group; wherein, the heterocyclic ring
  • the substituents on the group can be selected from halogen atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, oxo groups, and substituted or unsubstituted C 1 ⁇ C 8 hydrocarbon groups, C 2 ⁇ C 8 ester groups , C 1 -C 8 acyloxy group, C 1 -C 8 hydrocarbyloxy group, C 1 -C 8 hydrocarbyl thio
  • the substituents of the C 1 to C 8 substituted hydrocarbon groups are selected from halogen atoms, amino groups, hydroxyl groups, mercapto groups, cyano groups, 3 to 6 membered cyclic hydrocarbon groups or heterocyclic groups, C 2 to C 8 ester groups, and C 1 to C 8 acyloxy group, C 1 -C 8 hydrocarbyloxy group, C 1 -C 8 hydrocarbyl thio group, C 1 -C 8 hydrocarbylamino group, C 1 -C 8 acyl group, C 1 -C 8 One or more of acylamino, C 1 ⁇ C 8 sulfonyl group, C 1 ⁇ C 8 sulfonylamino group, and C 6 ⁇ C 8 aryl group;
  • the substituents in the substituted ester group, substituted acyloxy group, substituted hydrocarbyloxy group, substituted hydrocarbylthio group, substituted hydrocarbylamino group, substituted acyl group, substituted amido group, substituted sulfonyl group, substituted sulfonylamino group, and substituted heterocyclic group are selected from One or more of halogen atoms, hydroxyl groups, mercapto groups, amino groups, cyano groups, oxo groups, and halogenated methyl groups;
  • R 3 is selected from hydrogen, methyl, halogen atom or cyano group (-CN), R 4 is hydrogen, or, in the formula (I), R 4 and the nitrogen atom on the pyrimidine ring connected to it together form five Or six-membered heterocyclic ring; or, R 3 , R 4 and the carbon atoms on the pyrimidine ring connected to them together form a substituted or unsubstituted five-membered or six-membered heterocyclic group.
  • R 5 is selected from fluorine or cyano.
  • the "*" at the end of the chemical bond in the structural formula means that it is connected to other atoms in the structure of formula (I) through the bond; unless otherwise specified, all references to “hydrocarbyl”, “substituted hydrocarbyl” and “cyclic group” in this specification
  • group “heterocyclic group”, etc. are all applicable to the following description of these groups; among them, the halogen atom can be fluorine, chlorine, bromine, iodine, etc.
  • the hydrocarbyl group includes an open-chain hydrocarbyl group, an alicyclic hydrocarbyl group (cyclic hydrocarbyl group), and an aryl group.
  • the open-chain hydrocarbon group includes straight-chain or branched alkyl, alkene, alkynyl and subunits; for example, the C 1 -C 8 alkyl group may be a straight-chain methyl, ethyl, or propyl group.
  • Butyl, pentyl, hexyl, etc. can also contain one methyl branch, two methyl branch, three methyl branch, four methyl branch, one ethyl branch, two ethyl C of the group branch, one propyl branch, one methyl branch and one ethyl branch, two methyl branch and one ethyl branch, or one methyl branch and two ethyl branch 1 to C 8 branched chain alkyl, the position of the branch can be located on the 1-position carbon, the 2-position carbon, the 3-position carbon, the 4-position carbon, the 5-position carbon, the 6-position carbon, and the 7-position carbon.
  • the carbon atom (C ⁇ ) represents the 1-position carbon, for example, the branched chain alkyl group can be isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 3-methyl-2-pentane Group, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, etc.
  • the alkene group may be linear or branched; the C 1 to C 8 alkene group of the branched structure may contain one methyl branch, two methyl branches, and three methyl groups. Branches, four methyl branches, one ethyl branch, two ethyl branches, one propyl branch, one methyl branch and one ethyl branch, two methyl branches and one ethyl branch Group branch, or one methyl branch and two ethyl branch; wherein, the position of the branch or double bond can be located at the 1-position carbon, 2-position carbon, 3-position carbon, 4-position carbon, 5-position carbon, On the 6-position carbon and the 7-position carbon (the carbon atom to be bonded (C ⁇ ) represents the 1-position carbon).
  • the alkene group may be a monoolefin group containing one double bond, such as vinyl, allyl, 2-enbutyl, etc., or a multiolefin group containing two or more double bonds.
  • the alkyne may be straight-chain or branched; the C 1 ⁇ C 8 alkyne group of the branched structure may contain one methyl branch, two methyl branch chains, and three methyl groups. Branches, four methyl branches, one ethyl branch, two ethyl branches, one propyl branch, one methyl branch and one ethyl branch, two methyl branches and one ethyl branch Base branch, or one methyl branch and two ethyl branch; wherein, the position of the branch or triple bond can be located at the 1-position carbon, 2-position carbon, 3-position carbon, 4-position carbon, 5-position carbon, On the 6-position carbon and the 7-position carbon (the carbon atom to be bonded (C ⁇ ) represents the 1-position carbon).
  • the alkynyl group can be a group formed by a saturated carbon atom losing one hydrogen atom, such as propargyl, or a group formed by a triple-bonded carbon atom losing one hydrogen atom, such as an ethynyl group (CH ⁇ C-);
  • the alkynyl group can be a monoalkynyl group containing a triple bond, such as ethynyl, propargyl, etc., or a polyalkynyl group containing two or more alkyne bonds.
  • a subunit refers to a group formed by losing two hydrogen atoms on the carbon atom of a hydrocarbon. It can have two valences concentrated on the same atom, or two valences connected to two Atomically.
  • the cyclic hydrocarbon group refers to a group formed by the loss of a hydrogen atom on the carbon on the alicyclic hydrocarbon ring. It can be a monovalent group formed by losing one hydrogen atom or a divalent group formed by losing two hydrogen atoms.
  • the alicyclic hydrocarbon may be a monocyclic ring, a spiro ring, a bridged ring, etc.
  • a spiro ring may be a dispiro, a trispiro, etc.
  • a bridged ring may be a bicyclic ring, a tricyclic ring, or the like.
  • the monovalent cyclic hydrocarbon group can be a saturated ring (cycloalkyl), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or an unsaturated group containing one or more double bonds.
  • Rings, such as cyclopentenyl and cyclopentadienyl; cyclosubunits can be cyclobutanyl, cyclopentaalkylene, cyclohexylene and the like with two valences attached to two atoms respectively.
  • the aryl group is a group formed by losing a hydrogen atom on the carbon on the benzene ring of an aromatic hydrocarbon, such as phenyl, tolyl, xylyl, and ethylphenyl.
  • the structural formula of the ester group can be -COOR, where R represents a hydrocarbyl group, and its type is suitable for the foregoing description of the hydrocarbyl group.
  • R represents a hydrocarbyl group
  • the ester group can be -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 , -COOCH(CH 3 )CH 3 and so on.
  • the structural formula of the acyloxy group can be RCOO-, where R represents a hydrocarbyl group, and its type is suitable for the foregoing description of the hydrocarbyl group.
  • the acyloxy group can be CH 3 COO-, CH 3 CH 2 COO -Wait.
  • the structural formula of the hydrocarbyloxy group may be RO-, where R represents a hydrocarbyl group, and its type is suitable for the foregoing description of the hydrocarbyl group;
  • the hydrocarbyloxy group may be an alkoxy group, such as methoxy (CH 3 O -), ethoxy (CH 3 CH 2 O-), propoxy (CH 3 CH 2 CH 2 O-), etc.;
  • the hydrocarbyloxy group may also be a cycloalkaneoxy group, such as cyclopropoxy (C 3 H 5 O-).
  • the structural formula of the hydrocarbylthio group can be RS-, where R represents a hydrocarbyl group, and its type is suitable for the foregoing description of the hydrocarbyl group;
  • the hydrocarbylthio group can be an alkylthio group, such as methylthio (CH 3 S -), ethylthio (CH 3 CH 2 S-), propylthio (CH 3 CH 2 CH 2 S-), etc.
  • the hydrocarbylthio group can also be a cycloalkylthio group, such as cyclopropylthio (C 3 H 5 S-).
  • the structural formula of the hydrocarbon amino group can be RNH- or RR'N-, wherein R and R'both represent a hydrocarbon group, and the type is suitable for the foregoing description of the hydrocarbon group;
  • the hydrocarbon amino group can be an alkylamino group, such as methyl Amino (CH 3 NH-), ethylamino (CH 3 CH 2 NH-), propylamino (CH 3 CH 2 CH 2 NH-), etc.
  • the structural formula of the sulfonyl group may be RSO 2 -, where R represents a hydrocarbyl group, and its type is suitable for the foregoing description of the hydrocarbyl group; for example, the sulfonyl group may be methylsulfonyl (CH 3 SO 2 -), Ethylsulfonyl (CH 3 CH 2 SO 2 -), propanesulfonyl (CH 3 CH 2 CH 2 SO 2 -), etc.
  • the structural formula of the sulfonylamino group may be RSO 2 NH-, where R represents a hydrocarbyl group, and its kind is suitable for the foregoing description of the hydrocarbyl group; for example, the sulfonylamino group may be methylsulfonylamino (CH 3 SO 2 NH-), ethylsulfonamido (CH 3 CH 2 SO 2 NH-), propanesulfonamido (CH 3 CH 2 CH 2 SO 2 NH-), etc.
  • the cyclic group may be a carbocyclic group or a heterocyclic group.
  • a carbocyclic group refers to a carbocyclic compound having one or more carbon atoms on the ring.
  • the cyclic group may be a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, a seven-membered ring, or an eight-membered ring.
  • the heteroatom in the heterocyclic group can be nitrogen (N), oxygen (O), sulfur (S), when the heteroatom is sulfur, it can be further divided into sulfur atom, sulfonyl (-SO) 2 -), sulfinyl (-SO-), the total number of heteroatoms can be 1-8, for example 2, 3, 4, 5, 6, 7.
  • the carbocyclic group may be an alicyclic group (i.e., the aforementioned cyclic hydrocarbon group) or an aromatic group (i.e., the aforementioned aryl group).
  • the heterocyclic group can be an aliphatic heterocyclic group, an aromatic heterocyclic group; an aliphatic heterocyclic group can be a saturated ring, a ring containing one double bond, or a ring containing multiple double bonds (such as two ), for example, the aliphatic heterocyclic group can be a three-membered ring of oxirane group, azide group, four-membered ⁇ -propiolactone group, ⁇ -lactam group, five-membered ⁇ -butane Lactone, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, six-membered caprolactam, piperidinyl, etc.; aromatic heterocyclic groups can be, for example, five-membered furyl, thienyl, pyrrolyl, thiazolyl , Imidazolyl, six-membered pyridyl, pyrimidinyl,
  • a cyclic group can be a monocyclic group, a bridged ring group, or a spirocyclic group; a monocyclic group is a monocyclic compound whose ring carbon atoms or heteroatoms lose one or more of them.
  • a bridged ring group is a group formed by a carbon atom or heteroatom on the ring of a bridged ring compound losing one or more hydrogen atoms connected to it.
  • a spiro ring group is a spiro ring A group formed when a carbon atom or heteroatom on a compound ring loses one or more hydrogen atoms connected to it.
  • the bridging ring group may be a bicyclic group, a tricyclic group, a tetracyclic group, etc.
  • the spiro group may be a dispiro group, a trispiro group, or the like.
  • substituted ester group, substituted acyloxy group, substituted hydrocarbyloxy group, substituted hydrocarbyl thio group, substituted hydrocarbylamino group, substituted acyl group, substituted amide group, substituted sulfonyl group, substituted sulfonylamino group refers to: ester group, The hydrogen atom connected to the carbon atom in the acyloxy group, hydrocarbyloxy group, hydrocarbylthio group, hydrocarbylamino group, acyl group, amido group, sulfonyl group, and sulfonylamino group is substituted by a substituent.
  • one of the substituents in the substituted ester group, substituted acyloxy group, substituted hydrocarbyloxy group, substituted hydrocarbyl thio group, substituted hydrocarbylamino group, substituted acyl group, substituted amide group, substituted sulfonyl group, and substituted sulfonylamino group The number can be one or multiple, such as two, three, four, five, six, etc.
  • the substituents in the substituted ester group, substituted acyloxy group, substituted hydrocarbyloxy group, substituted hydrocarbyl thio group, substituted hydrocarbylamino group, substituted acyl group, substituted amide group, substituted sulfonyl group, and substituted sulfonylamino group may be Halogen atoms, hydroxyl groups, mercapto groups, amino groups, cyano groups, halogenated methyl groups, etc.
  • the substituent in the substituted hydrocarbon group is a halogen atom, such as fluorine, chlorine, bromine, and iodine.
  • the number of substituents can be one, two, three, or fully substituted. That is, all hydrogen atoms in the hydrocarbyl group are substituted by substituents, for example, the halogenated methyl group may be CH 2 F-, CHF 2 -, CF 3 -, CClF 2 -, and the like.
  • the substituent in the substituted hydrocarbon group may contain 1 to 6 carbon atoms, for example, 2, 3, 4, or 5 carbon atoms.
  • the substituent in the substituted hydrocarbyl group may be a substituted or unsubstituted ester group, acyloxy group, hydrocarbyloxy group, hydrocarbylamino group, acyl group, acylamino group, sulfonyl group, sulfonylamino group, aryl group, cycloalkyl group , Heterocyclic group.
  • the substituted hydrocarbyl group includes a substituted cyclic hydrocarbyl group, and the substituent in the substituted cyclic hydrocarbyl group may be cyclopropyl, cyclobutyl, etc.
  • the substituted hydrocarbon group may be CF 3 -, CHF 2 CH 2 -, HOCH 2 -, CH 3 OOCCH 2 -, CH 3 COOCH 2 -, CH 3 OCH 2 -, CH 3 NHCH 2 -, HCOCH 2 -, HCONHCH 2 -, CH 3 SO 2 CH 2 -, phCH 2 -, etc.
  • the substituted hydrocarbon group can be one of the following structures:
  • the substituted cyclic group means that the hydrogen atom connected to the carbon atom or heteroatom on the ring is replaced by a substituent.
  • the number of substituents can be one or more, for example, two. , Three, four, five, six, etc.
  • the substituted cyclic group may be a substituted carbocyclic group or a substituted heterocyclic group, and the substituted carbocyclic group may be a substituted cycloalkyl group.
  • the substituent of the substituted cyclic group may be a substituted or unsubstituted C 1 -C 8 hydrocarbyl group, C 1 -C 6 ester group, C 1 -C 6 acyloxy group, C 1 to C 6 hydrocarbyloxy group, C 1 to C 6 hydrocarbyl amino group, C 1 to C 6 acyl group, C 1 to C 6 acylamino group, C 1 to C 6 sulfonyl group, C 1 to C 6 Sulfonylamino, C 6 to C 8 aryl, C 3 to C 8 cyclic hydrocarbon group, C 3 to C 8 heterocyclic group.
  • the substituent of the substituted cyclic group may contain 2, 3, 4, 5, 6 or 7 carbon atoms, and/or contain 1 to 8 heteroatoms, such as 2, 3, 4, 5, 6, 7 heteroatoms, the heteroatoms can be nitrogen (N), oxygen (O), sulfur (S).
  • the substituent of the substituted heterocyclic group may be a halogen atom, a hydroxyl group, a mercapto group, an amino group, a cyano group, an oxo group, a halogenated methyl group, and the like.
  • R 1 may be a substituted or unsubstituted four-membered ring, five-membered ring, six-membered ring, seven-membered ring, or eight-membered ring (monocyclic) alkylene group.
  • the substituent on the R 1 ring can be a C 2 to C 7 hydrocarbon group, a C 2 to C 7 substituted hydrocarbon group, for example, a hydrocarbon group containing 3, 4, 5, or 6 carbon atoms, substituted Hydrocarbyl.
  • R 1 is a cycloalkylene group with a molecular formula of C n H 2n-2 , and n is 4, 5, 6, 7 or 8.
  • R 1 is a bicyclic alkylene group with a molecular formula of C n H 2n-4 , and n is an integer of 5 to 8, such as 5, 6, 7, 8 and the like.
  • R 1 is a bicyclic alkylene group (bridged ring), wherein one of the carbons connected to the amino groups on both sides may be one on the ring, and the other is a substituent on the ring.
  • the carbons connected to both amino groups in R 1 when all located on the ring, it includes cis-isomer and trans-isomer.
  • R 1 can be one of the following structures:
  • R 11 may be a 4, 5, 6, 7 or 8 membered substituted or unsubstituted cyclic group.
  • R 11 can be a substituted hydrocarbon group containing 4, 5, 6, 7, 8 or 9 carbon atoms, and the substituent of the substituted hydrocarbon group can be a substituted or unsubstituted 3, 4, 5, or 6 member Cyclic groups such as cyclobutyl, monofluorocyclobutyl, difluorocyclobutyl, oxetanyl, substituted cyclopiperidinyl and the like.
  • R 11 may be one selected from the following structures (C 3 -C 10 substituted hydrocarbon groups):
  • R represents a substituent, and the group represented by it applies to the description of the substituent on the carbocyclic or heterocyclic ring in the R 11 group.
  • R 11 is a substituted cyclic group, wherein the substituents on the carbocyclic or heterocyclic ring may be one or multiple, such as two, three, four, five, six Wait.
  • R 11 is a substituted cyclic group, wherein the substituent on the carbocyclic or heterocyclic ring may be a hydrocarbon group containing 1 to 8 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group may be 2. , 3, 4, 5, 6, 7.
  • R 11 is a substituted cyclic group, wherein the substituent on the carbocyclic or heterocyclic ring may be a substituted hydrocarbon group containing 1 to 8 carbon atoms, for example, the number of carbon atoms in the substituted hydrocarbon group may be For 2, 3, 4, 5, 6, 7.
  • R 11 is a substituted cyclic group, wherein the substituent on the carbocyclic or heterocyclic ring may be a substituted or unsubstituted ester group containing 1 to 8 carbon atoms, an acyloxy group, a hydrocarbon oxygen
  • the number of carbon atoms in the above-mentioned substituent may be 2, 3, 4, 5, 6, or 7.
  • R 11 is a substituted cyclic group, wherein the substituent on the carbocyclic or heterocyclic ring can be a 3- to 8-membered substituted or unsubstituted heterocyclic group, for example, a four-membered or five-membered heterocyclic group.
  • R 11 is a bridged ring group, and its structure can be one of the following formulas:
  • R represents a substituent on the ring, and the group represented by it is applicable to the description of the substituent on the carbocyclic or heterocyclic ring in the R 11 group.
  • R 11 is a spiro ring group, and its structure can be one of the following formulas:
  • R represents a substituent on the ring, and the group represented by it applies to the description of the substituent on the carbocyclic or heterocyclic ring in the R 11 group.
  • the cyclic group of R 11 may be a saturated carbocyclic group, such as a cycloalkyl group, or a carbocyclic group containing a double bond or a triple bond, such as a cyclohexenyl group.
  • the cyclic group of R 11 may be a substituted or unsubstituted three-membered carbocyclic group, four-membered carbocyclic group, five-membered carbocyclic group, six-membered carbocyclic group, three-membered Heterocyclic groups, four-membered heterocyclic groups, five-membered heterocyclic groups, six-membered heterocyclic groups, and seven-membered heterocyclic groups.
  • the three-membered carbocyclic group of R 11 can be cyclopropyl; the four-membered carbocyclic group can be cyclobutyl or alkenylcyclobutyl; the five-membered carbocyclic group can be cyclopentyl ;
  • the six-membered carbocyclic group can be cyclohexyl;
  • the three-membered heterocyclic group can be an oxirane group, a cycloazaethane group, or an sulfide group;
  • the four-membered heterocyclic group can be azetidine Group, oxetanyl group, thietanyl group, ⁇ -propiolactone group, ⁇ -lactam group;
  • five-membered heterocyclic group can be ⁇ -butyrolactone group, tetrahydrofuranyl group, tetrahydrothienyl group, Tetrahydropyrrolyl;
  • R 11 is a substituted four-membered, six-membered carbocyclic or heterocyclic group, and the substituent is located on the para-carbon atom or heteroatom containing the carbon atom of the connecting bond (bond with *).
  • the unsubstituted or substituted four-membered carbocyclic group can be one of the following structures:
  • the unsubstituted or substituted four-membered heterocyclic group can be one of the following structures:
  • the unsubstituted or substituted five-membered carbocyclic or heterocyclic group can be one of the following structures:
  • R represents a substituent located on the ring, and the group represented by it applies to the description of the substituent on the carbocyclic or heterocyclic ring in the R 11 group.
  • R can be any carbon atom on the tetrahydrofuran ring Substituents.
  • the unsubstituted or substituted six-membered carbocyclic group can be one of the following structures:
  • the unsubstituted or substituted six-membered heterocyclic group can be one of the following structures:
  • R 11 may be one of the following structures:
  • R 22 and R 23 may be C 1 to C 8 hydrocarbon groups, C 1 to C 8 substituted hydrocarbon groups, C 1 to C 8 hydrocarbon thio groups, C 1 to C 8 substituted hydrocarbon sulfur groups, respectively.
  • the number of can be 2, 3, 4, 5, 6, 7.
  • R 22 can be methyl, ethyl or halomethyl.
  • R 23 is a C 2 -C 6 substituted alkyl group, and the substituent is a fluorine atom, a chlorine atom, and/or a hydroxyl group, and/or a cyclopropyl group.
  • R 23 is a hydrocarbylthio group or a hydrocarbyloxy group
  • the hydrocarbyl group connected to the sulfur or oxygen on the hydrocarbylthio group or the hydrocarbyloxy group may be a 3- to 6-membered cyclic hydrocarbon group, such as 4-membered or 5-membered, It can further be a 3-6 membered cycloalkyl group, for example, R 23 can be cyclopropylthio (C 3 H 5 S-), cyclobutylthio (C 4 H 7 S-), cyclopentylthio (C 5 H 9 S-), cyclopropoxy (C 3 H 5 O-), cyclobutoxy (C 4 H 7 O-), cyclopentyloxy (C 5 H 9 O-), etc.
  • R 23 can be one of the following structures:
  • R 22 , R 23 and the carbon atom and nitrogen atom on the pyrazole ring connected thereto can jointly form a substituted or unsubstituted 4-membered, 5-membered, 6-membered or 7-membered heterocyclic group.
  • the heterocyclic ring formed by R 22 and R 23 may be an aliphatic heterocyclic ring or an aromatic heterocyclic ring.
  • a heterocyclic group may contain no double bond, one double bond, and two Double bond or five-membered or six-membered nitrogen heterocycle with aromatic characteristics.
  • the heterocyclic ring formed by R 22 and R 23 may be a monocyclic ring, a bridged ring, or a spiro ring, such as a bicyclic ring, a tricyclic ring, a dispiro, a trispiro, and the like.
  • the substituent on the substituted heterocyclic group formed by R 22 and R 23 may be a substituted or unsubstituted hydrocarbon group containing 2, 3, 4, 5, 6 or 7 carbon atoms; or It is a substituted or unsubstituted ester group, acyloxy group, hydrocarbyloxy group, hydrocarbylamino group, acyl group, acylamino group, sulfonyl group, and sulfonylamino group containing 2, 3, 4, 5, 6 or 7 carbon atoms.
  • the substituents on the substituted heterocyclic group formed by R 22 and R 23 may be one or more, such as two, three, or four; the types of substituents may be fluorine, methyl , Methylene, trifluoromethyl, cyano, cyclopropyl, etc.
  • R 2 is selected from one of the following structures:
  • R 3 can be hydrogen, methyl, fluorine, chlorine or cyano.
  • the heterocyclic ring formed by R 3 and R 4 may be an aliphatic heterocyclic ring or an aromatic heterocyclic ring.
  • the five-membered heterocyclic ring formed by R 3 , R 4 and the pyrimidine ring may be one of thiophene, furan, pyrrole, pyrazole, and imidazole.
  • the six-membered heterocyclic ring formed by R 3 , R 4 and the pyrimidine ring may be one of pyridine, pyrazine, pyrimidine, and pyridazine.
  • the substituents in the substituted heterocyclic group formed by R 3 , R 4 and the pyrimidine ring may be halogen atoms, hydroxyl groups, mercapto groups, amino groups, cyano groups, oxo groups, and halogenated methyl groups. One or more.
  • R 3 and R 4 together form one of the following structures:
  • R 4 and the nitrogen atom on the pyrimidine ring connected to it together form a substituted or unsubstituted five-membered or six-membered heterocyclic ring, such as pyrrole ring, thiazole ring, imidazole ring, pyridine ring, pyrazine ring , Pyrimidine ring, etc.
  • the substituent on the substituted five-membered or six-membered heterocyclic ring formed by R 4 and the nitrogen atom on the pyrimidine ring connected to it may be a halogen atom, a hydroxyl group, a mercapto group, an amino group, a cyano group, One or more of oxo group and halomethyl group.
  • R 4 and the nitrogen atom on the pyrimidine ring connected to it together form a five-membered ring in the following structure, wherein the R 1 and R 2 structural groups are abbreviated in the following formula:
  • X is selected from hydrogen, fluorine, chlorine, methyl or cyano (-CN).
  • the heterocyclic compound of one embodiment of the present disclosure has good CKI ⁇ -CDK7/9 inhibitory activity and tumor cell inhibitory activity, has better safety in normal cells, and has good oral bioavailability, and is continuously administered to animals Demonstrates better safety, has a strong synergistic effect when combined with the p53 activator APR-246, and can be used to regulate CKI ⁇ -CDK7/9 kinase-mediated diseases.
  • the heterocyclic compound according to an embodiment of the present disclosure can be used to treat malignant tumors, especially leukemia, colon cancer, rectal cancer, lung cancer and the like.
  • One embodiment of the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above heterocyclic compounds or a pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotope label or isomer thereof, And a pharmaceutically acceptable carrier.
  • the aforementioned pharmaceutical composition may be an anti-tumor drug.
  • the compound II undergoes an amination reaction to generate compound III;
  • the related reaction formula is as follows, where X1 and X2 represent halogen atoms, X1 and X2 can be the same or different, X1 and/or X2 can be Br, Cl, F, etc.; R 11 , R 2 , R 3 , R 4 The structure shown is the same as the structure of R 11 , R 2 , R 3 , and R 4 in formula (I).
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reaction or other problems or complications, it is commensurate with a reasonable benefit/risk ratio.
  • pharmaceutical composition refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component or agent.
  • the pharmaceutically acceptable chemical component or agent is the “carrier”, which helps For introducing the compound into cells or tissues, it includes, but is not limited to, stabilizers, diluents, suspending agents, thickeners, and/or excipients.
  • salts in the present disclosure may refer to metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. .
  • metal salts include, but are not limited to, alkali metal salts, such as sodium salt, potassium salt, etc.; alkaline earth metal salts, such as calcium salt, magnesium salt, barium salt, aluminum salt, and the like.
  • Non-limiting examples of salts formed with organic bases include, but are not limited to, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, Dicyclohexylamine and other salts.
  • Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, lactic acid, fumaric acid, mandelic acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, Salts formed by methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
  • salts can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • solvate refers to a physical aggregate formed by a compound in the present disclosure and one or more solvent molecules. This physical aggregate includes varying degrees of ions and covalent bonds, such as hydrogen bonds. It has been shown that this solvate can be separated, for example, when one or more solvent molecules are mixed in the crystal lattice.
  • Solvate includes both the solvent phase and the separable solvate. There are many examples of corresponding solvates, including ethanol solvates, methanol solvates and the like.
  • “Hydrate” is a solvate that uses water (H 2 O) molecules as a solvent.
  • One or more of the compounds in this disclosure can be prepared as solvates at will. The preparation of solvates is well known. For example, M.
  • active metabolite refers to an active derivative of the compound formed when the compound is metabolized.
  • polymorph refers to a compound of the present disclosure that exists in different crystal lattice forms.
  • isotopic label refers to a compound of the present disclosure that is isotopically labeled.
  • the isotopes in the compounds of the present disclosure may include various isotopes of elements such as H, C, N, O, P, F, S, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 S.
  • the term "isomer” refers to isomers produced by different arrangements of atoms in a molecule in space.
  • the compounds of the present disclosure contain structures such as asymmetric or chiral centers and double bonds. Therefore, the compounds of the present disclosure may include optical isomers, geometric isomers, tautomers, atropisomers and other isomers.
  • the body forms, these isomers and their single isomers, racemates, etc. are all included in the scope of the present disclosure.
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral resolution, chiral synthesis or chiral reagents or other conventional techniques. body.
  • it can be converted into diastereomers by reacting with an appropriate optically active substance (such as a chiral alcohol or Mosher ⁇ s Moss acid chloride), and then separated and converted (such as hydrolyzed) into the corresponding single isomer body.
  • an appropriate optically active substance such as a chiral alcohol or Mosher ⁇ s Moss acid chloride
  • separation can also be performed by a chromatographic column.
  • compositions can be prepared in a manner well known in the pharmaceutical field, and they can be administered or administered by various routes, depending on whether local or systemic treatment is required and the area to be treated. It can be delivered locally (for example, transdermal, skin, eye, and mucous membranes including intranasal, vaginal and rectal delivery), lung (for example, by inhalation or insufflation of powder or aerosol, including through a nebulizer; intratracheal, intranasal), Oral or parenteral administration.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intracerebroventricular administration.
  • the pharmaceutical composition herein includes but is not limited to the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid Or it can be dissolved in a liquid vehicle), ointment, soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaging powders.
  • heterocyclic compound according to an embodiment of the present disclosure will be further described with reference to specific examples.
  • Step B Preparation of 4'H,6'H spiro[cyclopropane-1,5'-pyrrolo[1,2-b]pyrazole]
  • Step C Preparation of 3'-bromo 4'H,6'H spiro[cyclopropane-1,5'-pyrrolo[1,2-b]pyrazole]
  • Step D 3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'H, 6'H spiro[cyclopropane-1, Preparation of 5'-pyrrolo[1,2-b]pyrazole]
  • Step E 3'-(2-chloro-5-fluoropyrimidin-4-yl)-4'H,6'H spiro[cyclopropane-1,5'-pyrrolo[1,2-b]pyrazole]
  • Step F (1r,4r)-N 1 -(5-fluoro-4-(4'H,6'H spiro[cyclopropane-1,5'-pyrrolo[1,2-b]pyrazole]- 3'-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine preparation
  • Step A Preparation of tert-butyl (1-methyl-1H-pyrazol-3-yl)carbamate
  • Step B Preparation of tert-butyl (5-(cyclopropyl(hydroxy)methyl)-1-methyl-1H-pyrazol-3-yl)carbamate
  • Step D Preparation of tert-butyl (5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)carbamate
  • Step E Preparation of tert-butyl (4-bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl)carbamate
  • Step F (5-(Cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl)-1H-pyrazol-3-yl) t-butyl carbamate
  • Step G (4-(2-Chloro-5-fluoropyrimidin-4-yl)-5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3-yl) tert-butyl carbamate Preparation
  • Step H (4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-5-fluoropyrimidin-4-yl)-5-(cyclopropylmethyl)-1-methyl
  • Step I (1 r ,4 r )-N 1 -(4-(3-amino-5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoro Preparation of pyrimidin-2-yl)cyclohexane-1,4-diamine
  • Step A Preparation of cyclopropyl (1-methyl-1H-pyrazol-5-yl) methanol
  • Step D 5-(Cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-2-yl)- Preparation of 1H-pyrazole
  • Step F 2-Chloro-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-9-(tetrahydro-2H-pyran-2-yl) Preparation of -9H-purine
  • Step G (1r,4r)-N 1 -(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-9-(tetrahydro-2H-pyridine (Pan-2-yl)-9H-purin-2-yl)cyclohexyl-1,4-diamine
  • Step H (1r,4r)-N 1 -(6-(5-cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-9H-purin-2-yl)cyclohexyl
  • Step A tert-Butyl 3-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5- Preparation of fluoropyrimidin-2-yl)amino)cyclohexyl)amino)azetidine-1-carboxylate
  • Step B (1r,4r)-N 1 -(azetidin-3-yl)-N 4 -(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazole -4-yl)-5-fluoropyrimidin-2-yl)cyclohexyl-1,4-diamine
  • the core of the screening platform is MSA based on microfluidic chip technology, which applies the basic concepts of capillary electrophoresis to a microfluidic environment.
  • the experimental substrate is a polypeptide with a fluorescent label. Under the catalysis of the enzyme in the reaction system, the substrate is converted into a product, and the charge on the substrate changes accordingly. MSA uses the difference in charge between the substrate and the product to separate the two and detect them separately.
  • the compound powder was dissolved in 100% DMSO to prepare a 10 mM stock solution.
  • the initial test concentration of the compound is 1000 nM, 3-fold gradient dilution, 10 concentrations, and multiple well detection.
  • PHA-793887 Selleckchem, Cat. S1487)
  • Dinaciclib Selleckchem, Cat. S2768
  • Fitting the dose-response curve take the log value of the concentration as the X-axis, and the percentage inhibition rate on the Y-axis. Use the analysis software GraphPad Prism 5 log(inhibitor) vs.response-Variable slope to fit the dose-response curve to obtain each compound IC 50 value for inhibition of enzyme activity.
  • Example 59 11 20 Example 62 2.6 7.4 Example 63 3.7 2.7 Example 64 NA 3.4 Example 65 2.8 3.3 Example 66 5.1 7.0 Example 68 4.8 4.2
  • This test uses the ADP-Glo TM Kinase Assay (Promega, Cat.V9102) kit to test the IC 50 value of the compound to inhibit CKI ⁇ kinase activity.
  • This kit is used to quantitatively detect the formation of ADP in the kinase reaction and is a homogeneous reaction system. The newly generated ADP in the reaction system is converted into ATP, and luciferin reacts to emit fluorescence under the action of ATP and luciferase. Fluorescence signal is positively correlated with ADP concentration, that is, kinase activity.
  • the compound powder was dissolved in 100% DMSO (Sigma, Cat. D8418) to prepare a 10 mM stock solution.
  • the initial test concentration of the compound is 10,000nM, 3-fold dilution, 10 concentrations, and multiple well detection.
  • Staurosporine MCE, Cat.HY-15141 was used as a positive control compound.
  • Compounds, substrates, kinases, etc. are all pre-diluted with enzyme reaction solution (40mM Tris, PH7.5; 20mM MgCl2; 0.1mg/ml BSA; 50mMDTT). Mix 5 nl of the compound with gradient dilution and 2.5 ⁇ l of CK1a1 (Signalchem, Cat.
  • Example number CKI ⁇ IC 50 (nM) Example number CKI ⁇ IC 50 (nM)
  • Example 1 THZ1 >10000 A86 a 483.5 Example 1 812.7 Example 3 99.5 Example 4 181.6 Example 5 475.6 Example 7 424.1 Example 8 146.9 Example 11 824.3 Example 14 672.6 Example 15 225.1 Example 16 305 Example 18 149.1 Example 19 487.4 Example 20 829.7 Example 21 967.2 Example 22 1052 Example 24 923.6 Example 31 94.8 Example 32 231.4 Example 33 160.0 Example 34 101.1 Example 35 52 Example 41 1088 Example 63 269.4 Example 64 80.0 Example 65 83.5 Example 66 237.9
  • a A86 is the compound in patent CN108137562A
  • CCG Luminescent Cell Viability Assay
  • the cells in the 96-well plate with the drug added were placed under 37°C, 5% CO 2 , and 95% humidity for 72 hours, and then CTG analysis was performed. Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes. Add an equal volume of CTG solution to each well. Shake on an orbital shaker for 5 minutes to lyse the cells. Place the cell plate at room temperature for 20 minutes to stabilize the luminescence signal. The luminescence value was read and processed by SpectraMax multi-label microplate detector (MD, 2104-0010A).
  • GraphPad Prism 5.0 software was used to analyze the data, and non-linear S-curve regression was used to fit the data to obtain a dose-response curve, and the IC 50 value was calculated accordingly.
  • Cell survival rate (%) (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) ⁇ 100%.
  • Table 3 Inhibitory activity of compounds on tumor cells and normal cells (IC 50 )
  • a A51/A86 are compounds in patent CN108137562A
  • the male SD rats were divided into groups, 3 rats in each group, and the suspensions (5 mg/kg) of the compound of the examples were administered orally orally in a single gavage.
  • the animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration.
  • Blood was collected 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration.
  • Use a small animal anesthesia machine to anaesthetize with isoflurane and collect 0.3 mL of whole blood through the fundus venous plexus, and place it in a heparin anticoagulation tube.
  • the sample is centrifuged at 4°C and 4000 rpm for 5 min.
  • the plasma is transferred to a centrifuge tube and placed at -80 Store at °C until analysis.
  • the plasma samples were extracted by protein precipitation, and the extract was analyzed by LC/MS/MS.
  • mice were divided into 5 groups, each with 6 mice, once a day, orally administered for 14 consecutive days, and observe the changes in body weight
  • A51 is a compound in patent CN108137562A; b is a di-p-toluenesulfonate

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Abstract

L'invention concerne un composé hétérocyclique ou un sel, un solvate, un métabolite actif, un polymorphe, un marqueur isotopique ou un isomère de celui-ci pharmaceutiquement acceptables, et son/leur utilisation, la structure du composé hétérocyclique étant telle que représentée dans la formule (I) ou (II). Le composé hétérocyclique présente une bonne activité inhibitrice de CKIα-CDK7/9.
PCT/CN2020/100252 2019-07-04 2020-07-03 Composé hétérocylique, composition pharmaceutique et utilisation associées WO2021000957A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016058544A1 (fr) * 2014-10-16 2016-04-21 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
CN105849099A (zh) * 2013-10-18 2016-08-10 达纳-法伯癌症研究所股份有限公司 周期蛋白依赖性激酶7(cdk7)的多环抑制剂
CN106559991A (zh) * 2014-06-19 2017-04-05 阿里亚德医药股份有限公司 用于激酶抑制的杂芳基化合物
CN108137562A (zh) * 2015-08-04 2018-06-08 耶路撒冷希伯来大学伊森姆研究发展有限公司 吡唑嘧啶衍生物及其用途
CN110475771A (zh) * 2017-02-01 2019-11-19 耶路撒冷希伯来大学伊森姆研究发展有限公司 治疗癌症的ck1和/或irak1抑制剂n1-(4-(5-(环丙基甲基)-1-甲基-1h-吡唑-4-基)吡啶-2-基)环己烷-1,4-二胺衍生物和相关化合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105849099A (zh) * 2013-10-18 2016-08-10 达纳-法伯癌症研究所股份有限公司 周期蛋白依赖性激酶7(cdk7)的多环抑制剂
CN106559991A (zh) * 2014-06-19 2017-04-05 阿里亚德医药股份有限公司 用于激酶抑制的杂芳基化合物
WO2016058544A1 (fr) * 2014-10-16 2016-04-21 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
CN108137562A (zh) * 2015-08-04 2018-06-08 耶路撒冷希伯来大学伊森姆研究发展有限公司 吡唑嘧啶衍生物及其用途
CN110475771A (zh) * 2017-02-01 2019-11-19 耶路撒冷希伯来大学伊森姆研究发展有限公司 治疗癌症的ck1和/或irak1抑制剂n1-(4-(5-(环丙基甲基)-1-甲基-1h-吡唑-4-基)吡啶-2-基)环己烷-1,4-二胺衍生物和相关化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MINZEL, WALEED ET AL.,: "Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models Kinases CDK7/9 Control AML in Preclinical Models", CELL, vol. 175, no. 1,, 20 September 2018 (2018-09-20), XP085481131, DOI: 20200916094519X *

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