WO2024055992A1 - Tricyclic compound and use thereof - Google Patents

Tricyclic compound and use thereof Download PDF

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Publication number
WO2024055992A1
WO2024055992A1 PCT/CN2023/118565 CN2023118565W WO2024055992A1 WO 2024055992 A1 WO2024055992 A1 WO 2024055992A1 CN 2023118565 W CN2023118565 W CN 2023118565W WO 2024055992 A1 WO2024055992 A1 WO 2024055992A1
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compound
pharmaceutically acceptable
acceptable salt
formula
ring
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PCT/CN2023/118565
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French (fr)
Chinese (zh)
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胡治隆
唐锋
周峰
唐任宏
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南京再明医药有限公司
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Publication of WO2024055992A1 publication Critical patent/WO2024055992A1/en

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to tricyclic compounds, preparation methods thereof, pharmaceutical compositions containing the compounds, and their use in preventing or treating PI3K ⁇ -related diseases.
  • PI3K phosphatidylinositol-3-kinase
  • PI3K ⁇ phosphatidylinositol-3-kinase
  • PI3K ⁇ phosphatidylinositol-3-kinase
  • PI3K ⁇ phosphatidylinositol-3-kinase
  • PI3K ⁇ phosphatidylinositol-3-kinase
  • PI3K ⁇ mutations are related to malignant tumors; PI3K ⁇ can activate platelets and is related to the development of thrombotic diseases, and in PTEN-deficient tumors, PI3K ⁇ can promote the malignant transformation of tumors; PI3K ⁇ and PI3K ⁇ mainly exist in B cells and are associated with hematomas, Autoimmune diseases are closely related; PI3K signaling abnormalities include mutations and amplifications of PIK3CA, PIK3CB, AKT genes and loss of PTEN negative regulatory function, etc., and are associated with a variety of tumors including prostate cancer, breast cancer, endometrial cancer, lung cancer, and liver cancer , colon cancer, hematoma, lymphoma, etc. are closely related to the occurrence and development.
  • PI3K ⁇ plays an important role in the PI3K/AKT signaling pathway and regulates glucose metabolism, cell cycle, etc. downstream.
  • PI3K ⁇ mutation is considered to be one of the driving genes for tumorigenesis. Mutations lead to abnormal activation of the PI3K/ATK signaling pathway and promote the occurrence and development of tumors. The most important mutation types are H1047R, E545K and E542K. However, inhibiting wild-type PI3K ⁇ will cause blood sugar and insulin to rise, causing safety issues.
  • PI3K ⁇ inhibitors have been approved for HR+HER2- breast cancer.
  • target-related side effects especially hyperglycemia, affect safety and cause an increase in insulin, which will further weaken the efficacy of the drug.
  • the present disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof,
  • Ring A, Ring B, and Ring C are all single rings, independently selected from benzene rings, 5-6 membered heteroaromatic rings, 4-8 membered saturated or partially saturated heterocyclic rings, and C 4 -C 6 saturated or partially saturated heterocyclic rings.
  • Carbocyclic ring, the benzene ring, 5-6 membered heteroaromatic ring, 4-8 membered saturated or partially saturated heterocyclic ring and C 4 -C 6 saturated or partially saturated carbocyclic ring are optionally substituted by R X ;
  • Y 1 and Y 2 are independently selected from N and CH, and the CH is optionally substituted by R Y ;
  • Y 5 and Y 6 are independently selected from N and C;
  • Y 3 and Y 4 are independently selected from O, NH and CH 2 , and the NH and CH 2 are optionally substituted by R Y ;
  • n, p, q, t' are independently selected from 0, 1, 2, 3 and 4, and m and n are not 0 at the same time, and p and q are not 0 at the same time;
  • R 1 and R 2 are independently selected from halogen, CN, NO 2 , -OR, -SF 5 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O) 2 F, -S(O)R, -S(O)NR 2 , -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)
  • L is selected from the group consisting of a bond and a C 1 -C 4 alkylene group, in which 1-2 methylene units of the C 1 -C 4 alkylene group are optionally independently replaced by -CH(R)-, -C(R ) 2 -, C 3 -C 6 cycloalkylene, 3-6 membered heterocyclylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR) -, -N(R)C(NOR)-, -N(R)C(NCN)-, -N(R)S(O) 2 -, -O-, -C(O)-, -OC( O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 -replacement;
  • R is independently selected from H, deuterium, C 1 -C 6 alkyl, phenyl, 4-7 membered heterocyclyl and 5-6 membered heteroaryl, or two R connected to the same N and the N to which they are connected. Together, they form a 4-7-membered heterocyclyl group, and the C 1 -C 6 alkyl group, phenyl group, 4-7-membered heterocyclyl group and 5-6-membered heteroaryl group are optionally substituted by R';
  • R' is independently selected from oxo, deuterium, halogen, cyano, nitro, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.
  • Ring A, Ring B, and Ring C are all monocyclic rings, independently selected from benzene rings, 5-6 membered heteroaromatic rings, and 5-7 membered saturated or partially saturated heterocyclic rings. , 5-6 membered heteroaromatic rings and 5-7 membered saturated or partially saturated heterocyclic rings are optionally substituted by R
  • Selected from X 1 , X 2 are independently selected from C, CH and N, the CH is optionally substituted by R
  • t is selected from 0, 1, 2, and 3.
  • Y 1 and Y 5 are N, Y 6 is C, and Y 2 is CH, and the CH is optionally substituted by RY ; or Y 2 , Y 5 is N, Y 6 is C, Y 1 is CH, and the CH is optionally replaced by R Y ; or Y 2 and Y 6 are N, Y 5 is C, Y 1 is CH, and the CH is optionally replaced by R Y; R Y replaced.
  • m, n, p, q, t' are independently selected from 0, 1, and 2, and m and n are not 0 at the same time, and p and q are not 0 at the same time.
  • Cy is selected from
  • R 1 , R 2 are independently selected from phenyl, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, and 3-12
  • One-membered heterocyclyl, the phenyl, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl and 3-12 membered heterocyclyl are optionally replaced by R Z replaced.
  • R 1 , R 2 are independently selected from phenyl and 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are optionally substituted by RZ .
  • R 1 , R 2 are phenyl, and the phenyl is optionally substituted with R Z .
  • L is selected from a bond and a C 1 -C 4 alkylene group in which 1-2 methylene units are optionally independently replaced by -CH(R) -, -C(R) 2 -, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)S(O) 2 - , -O-, -C(O)-, -OC(O)-, -C(O)O-, -S(O)- or -S(O) 2 -replacement.
  • L is selected from C 1 -C 2 alkylene in which 1-2 methylene units are optionally independently replaced by -CH(R)-, -C(R) 2 -, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)S(O) 2 -, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S(O)- or -S(O) 2 -replacement.
  • L is selected from N(R)C(O) and N(R)C(O)N(R).
  • L is selected from N(R)C(O), such as NHC(O).
  • R' is independently selected from deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 3 -C 6 cycloalkyl.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from a compound of Formula (II) or a pharmaceutically acceptable salt thereof,
  • Ring A, Ring B, Ring C, R 1 , R 2 and L are as defined above.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from a compound of formula (III) or a pharmaceutically acceptable salt thereof,
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , m, n, p, q, t', R Y , R 1 , R 2 and L are as defined above.
  • a compound of the present disclosure is selected from the following compounds, or a pharmaceutically acceptable salt thereof:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) of the present disclosure or a specific compound as described above or Its pharmaceutically acceptable salt and pharmaceutically acceptable excipients.
  • the present disclosure provides a method for treating a disease mediated by PI3K ⁇ in a mammal, comprising administering to a mammal in need of the treatment, preferably a human, a therapeutically effective amount of a compound of formula (I) or the above specific compound or a pharmaceutically acceptable compound thereof. Acceptable salts, or pharmaceutical compositions thereof.
  • the present disclosure provides the use of the compound of formula (I) or the above-mentioned specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a PI3K ⁇ -mediated disease.
  • the present disclosure provides the use of the compound of formula (I) or the above-mentioned specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating PI3K ⁇ -mediated diseases.
  • the present disclosure provides compounds of formula (I) or the above-mentioned specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating PI3K ⁇ -mediated diseases.
  • the PI3K ⁇ -mediated disease is selected from cancer.
  • tautomer refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions.
  • Compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually yield a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and therefore the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S) )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the compounds of the present disclosure. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups.
  • the compounds of the present disclosure containing asymmetric atoms can be isolated in an optically active pure form or in a racemic form.
  • the optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. .
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • the term "optionally” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that description includes the occurrence Said event or circumstance and the non-occurrence of said event or circumstance.
  • the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), or polysubstituted. (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2, etc.) or completely substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3, etc.). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
  • any variable eg, R a , R b
  • its definition in each instance is independent. For example, if a group is replaced by 2 R b , there are independent options for each R b .
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • the direction of connection is arbitrary.
  • L 1 when the structural unit When L 1 is selected from “C 1 -C 3 alkylene-O", then L 1 can connect ring Q and R 1 in the direction from left to right to form “ring QC 1 -C 3 alkylene Group -OR 1 ”, you can also connect ring Q and R 1 from right to left to form “ring QOC 1 -C 3 alkylene group -R 1 ”.
  • substituents When a substituent's bond is cross-linked to a ring, the substituent can be bonded to any atom on the ring.
  • structural unit Indicates that R 5 can be substituted at any position on the benzene ring.
  • Cm - Cn refers to having an integer number of carbon atoms in the range of mn.
  • C 1 -C 10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula C n H 2n+1 , which alkyl group may be straight or branched.
  • C 1 -C 10 alkyl is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl "can be understood to mean
  • C 1 -C 3 alkyl is understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl” and other ranges, and the “C 1 -C 6 alkyl” may further include “ C 1 -C 3 alkyl”.
  • alkylene refers to a divalent group formed by further substitution of one hydrogen atom of an alkyl group, wherein alkyl is as defined above.
  • C 1 -C 3 alkylene means an alkylene group having 1, 2 or 3 carbon atoms.
  • C 1 -C 2 alkylene means an alkylene group having 1 or 2 carbon atoms, such as methylene or ethylene.
  • C 1 -C 4 alkylene may include “C 1 -C 3 alkylene” and "C 1 -C 2 alkylene”.
  • alkoxy refers to a group produced by losing a hydrogen atom on a hydroxyl group of a straight-chain or branched alcohol, and can be understood as “alkyloxy” or “alkyl-O-”.
  • C 1 -C 10 alkoxy is understood to mean “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”; the term “C 1 -C 6 alkoxy” It can be understood as “C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy group” may include the ranges of "C 1 -C 6 alkoxy group” and "C 1 -C 3 alkoxy group”.
  • the "C 1 -C 6 alkoxy group”"C 1 -C 3 alkoxy” may further be included.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond.
  • C 2 -C 10 alkenyl is understood to mean a straight-chain or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 2 -C 10 alkenyl” is preferably "C 2 -C 6 alkenyl", more preferably "C 2 -C 4 alkenyl", and even more preferably C 2 or C 3 alkenyl.
  • alkenyl group contains more than one double bond
  • the double bonds may be separated or conjugated to each other.
  • alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but- 1-alkenyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1- Alkenyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.
  • cycloalkyl refers to a fully saturated carbocyclic group that exists in the form of a single ring, a fused ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 20 membered.
  • C 3 -C 12 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms.
  • cycloalkyl group examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc.
  • C 3 -C 12 cycloalkyl may include “C 3 -C 6 cycloalkyl”, and the term “C 3 -C 6 cycloalkyl” is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring group, It has 3 to 6 ring carbon atoms, and specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.
  • cycloalkylene refers to a divalent group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the cycloalkyl group is as defined above.
  • C 3 -C 6 cycloalkylene refers to a cycloalkylene group having 3, 4, 5 or 6 ring carbon atoms.
  • cycloalkenyl refers to a non-aromatic carbocyclic group that has at least one double bond and is not fully saturated and exists in the form of a single ring, a fused ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 12 membered. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, and the like.
  • heterocyclyl refers to a fully saturated or partially saturated (not aromatic heteroaromatic as a whole) monocyclic, paracyclic, spirocyclic or bridged cyclic group containing 1 to 5 ring atoms.
  • Heteroatom or heteroatom group that is, an atomic group containing heteroatoms
  • 3-12 membered heterocyclyl refers to a heterocyclic group with 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, and its ring atoms contain 1-5 independent Selected from the heteroatoms or heteroatom groups described above.
  • “3-12-membered heterocyclyl” includes “4-7-membered heterocyclyl", wherein specific examples of 4-membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; 5-membered heterocyclyl Specific examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydroxazolyl or 2, 5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl , trithiyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-member
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrole-2(1H)-yl; 5,6-membered bicyclic groups. Specific examples include, but are not limited to, hexahydropyrro[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzo-fused cyclic group of the above-mentioned 4-7 membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolyl and the like.
  • "3-12-membered heterocyclyl” can also include “4-8-membered heterocyclyl", “5-7-membered heterocyclyl”, “3-7-membered heterocyclyl” and other ranges.
  • “4-8-membered heterocyclyl”"Cyclicgroup” may further include “4-7 membered heterocyclyl", “4-6 membered heterocyclyl”, “5-6 membered heterocyclyl”, “4-7 membered heterocycloalkyl", “4- Ranges include “6-membered heterocycloalkyl”, “5-6-membered heterocycloalkyl”, etc. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl groups are still non-aromatic as a whole.
  • heterocyclylene refers to a bivalent cyclic group formed by further substitution of one ring atom of the heterocyclyl group, wherein the heterocyclyl group is as defined above.
  • 3-6 membered heterocyclylene refers to a heterocyclylene group with the number of ring atoms being 3, 4, 5 or 6.
  • heterocycloalkyl refers to a fully saturated cyclic group that exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring, and the ring atoms of the ring contain 1-5 heteroatoms or heteroatom groups.
  • 4-10 membered heterocycloalkyl refers to a heterocycloalkyl group with a number of ring atoms of 4, 5, 6, 7, 8, 9 or 10, and its ring atoms contain 1 to 5 independently selected from the above The heteroatom or heteroatom group.
  • 4--10-membered heterocycloalkyl includes “4-7-membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thibutanyl; Specific examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydrofuranyl.
  • 6-membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydropyranyl thiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4- Dithianyl; specific examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxeppanyl or thiepanyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • Aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • C 6 -C 20 aryl is understood to mean an aryl group having 6 to 20 carbon atoms.
  • a ring with 6 carbon atoms for example phenyl; or a ring with 9 carbon atoms (“C 9 aryl”), for example indanyl or indenyl; or a ring with 10 or a ring of 13 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or is a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms.
  • a ring with 6 carbon atoms (“C 6 aryl”), for example phenyl; or a ring with 9 carbon atoms (“C 9 aryl”), for example indanyl or indenyl; or a ring with 10
  • a ring of 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, and the remaining ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, and the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S.
  • heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, etc. and their benzo derivatives, such as quinolyl, quinazole Phyllinyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • amino refers to the -NH group.
  • nitro refers to the -NO2 group.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.
  • composition refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds that are the same as those described herein, but in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature.
  • isotopes of open compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N respectively , 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured using methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, dragees, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg/kg body weight in single or divided doses.
  • the compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present disclosure.
  • the ratios expressed for mixed solvents are volumetric mixing ratios.
  • % refers to wt%.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10 -6 (ppm).
  • the solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration when half of the maximum inhibitory effect is achieved. concentration.
  • the eluent below can be composed of two or more solvents to form a mixed eluent.
  • the ratio is the volume ratio of each solvent.
  • “0 ⁇ 10% methanol/dichloromethane” means that the mixed eluent is used during the gradient elution process.
  • the volume ratio of methanol to methylene chloride is 0:100 ⁇ 10:100.
  • Step 1 Synthesis of 4-(3-nitropyridin-4-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester
  • Step 2 Synthesis of 6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert-butyl ester
  • Step 1 2-[(benzyloxy)carbonyl]-1,2,3,4,6,7,8,9-octahydropyrido[4',3':4,5]imidazo[3 ,Synthesis of 2-a]pyrazine-8-carboxylic acid-2-methylpropan-2-yl ester
  • Step 2 5-bromo-N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-2-fluoro-N-(4-methyl Synthesis of oxybenzyl)-3-nitrobenzamide
  • Step 3 6-Bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitroisoindolin-1-one synthesis
  • 6-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitroisoindolin-1-one (30g, 57.5 mmol, crude product) was dissolved in trifluoroacetic acid (150 mL), and triethylsilane (33.4 g, 288 mmol) was added. The reaction solution was stirred at 90°C for 5 hours. LCMS detects that the reaction is complete.
  • Step 5 Synthesis of 4-amino-6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)isoindolin-1-one
  • Step 6 N-(6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)- Synthesis of 3-fluoro-5-(trifluoromethyl)benzamide
  • Step 7 N-(6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl) Synthesis of benzamide:
  • reaction solution was concentrated to dryness under reduced pressure and beaten with petroleum ether (10 mL) to obtain the product 2-benzyl-8-(tert-butoxycarbonyl)-6,7,8,9-tetrahydropyrido[3',4 ':4,5]imidazo[1,2-a]pyrazine-2-ammonium bromide (400 mg, crude product).
  • reaction liquid was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the product 1,2,3,4,6,7-hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrido Azine-8(9H)-carboxylic acid tert-butyl ester (100 mg).
  • Step 4 2-(1-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzoylamino)-2-(4-methoxybenzyl) (yl)-3-oxoisoindolin-5-yl)-1,2,3,4,6,7-hexahydropyrido[3',4':4,5]imidazo[1,2 -Synthesis of pyrazine-8(9H)-carboxylic acid tert-butyl ester
  • Step 5 N-(3-(2-chloro-5-fluorophenyl)-6-(3,4,6,7,8,9-hexahydropyrido[3',4':4,5] Imidazo[1,2-a]pyrazin-2(1H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide Synthesis
  • LCMS detects that the reaction is complete.
  • the reaction solution was filtered and concentrated to dryness under reduced pressure, added with saturated aqueous sodium bicarbonate solution (5 mL), and extracted three times with ethyl acetate (5 mL*3).
  • the organic phase was dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and purified by preparative chromatography (Boston Prime C18 column, 5 ⁇ m silica, 30 mm diameter, 150 mm length; using water (containing 0.05% ammonia) and acetonitrile with decreasing polarity.
  • Example 2 N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2- a]pyrazine-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 2), (R) -N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrido Azin-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide and (S)-N-(3-( 2-Chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[
  • Step 2 N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a ]Pyrazine-8(9H)-yl))-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl )Synthesis of benzamide
  • reaction solution was stirred and reacted at 140°C for 1 hour.
  • LCMS detects that the reaction is complete.
  • Step 3 N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a Synthesis of ]pyrazine-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
  • Step 4 (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1 ,2-a]pyrazine-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide and (S)- N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine Synthesis of -8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
  • reaction solution is diluted with water (50.0mL), and then extracted with ethyl acetate (50.0mL*3).
  • the organic phase is washed with saturated brine, dried, filtered, and the filtrate is concentrated to obtain intermediate 2- (4-Bromo-2-methoxyphenyl)-4-(trifluoromethyl)-imidazole (10.0 g, crude).
  • reaction solution was directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 9-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza (30.0 mg, 72.8% yield).
  • Step 7 N-(3-(2-chloro-5-fluorophenyl)-6-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxynitrogen miscellaneous Synthesis of -9-yl)-2-(4-methoxyphenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
  • Step 8 N-(3-(2-chloro-5-fluorophenyl)-6-(5,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxaza Synthesis of -9-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
  • N-(3-(2-chloro-5-fluorophenyl)-6-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine -9-yl)-2-(4-methoxyphenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15.0 mg , 19.5 ⁇ mol) was dissolved in trifluoromethanesulfonic acid (20.0 ⁇ L) and trifluoroacetic acid (0.2 mL), and reacted at 80°C for 2 h. LCMS monitors that the raw material reaction is complete and the reaction is completed.
  • reaction solution was diluted with water (1.0mL), then adjusted to alkaline pH with 10% potassium carbonate solution, and then extracted with ethyl acetate (10.0mL*3).
  • the organic phase was concentrated to dryness, and the residue was subjected to reversed-phase high-performance liquid chromatography.
  • LCMS monitors the complete reaction of the raw materials.
  • the reaction solution is directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate (5,6-bis Hydrobenzo[f]imidazo[1,2-d][1,4]oxaza -9-yl)tert-butyl carbamate (40.0 mg, 78.2% yield).
  • Step 3 N-(3-(2-chloro-5-fluorophenyl)-6-((5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxy Aza -9-yl)amino)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide synthesis
  • Step 4 N-(3-(2-chloro-5-fluorophenyl)-6-((5,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxynitrogen miscellaneous Synthesis of -9-yl)amino)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
  • reaction solution was diluted with water (1.0mL), then adjusted to alkaline pH with 10% potassium carbonate solution, extracted with ethyl acetate (10.0mL*3), the organic phase was concentrated to dryness, and the residue was subjected to reversed-phase high-performance liquid chromatography.
  • Step 1 Synthesis of methyl 2-(3,5-dibromo-1H-pyrazol-1-yl)acetate
  • reaction solution was cooled to 25°C, water (100 mL) was added to quench, and extracted with ethyl acetate (100 mL). The organic phase was washed with water (100mL*2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 2-bromo-4. -Methylene-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxaza (1.2g, 56% yield).
  • Step 5 2'-Bromo-7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-d][1,4]oxaza ]
  • the reaction system was cooled to 25°C, quenched by adding water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated aqueous sodium chloride solution (100 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 2'-bromo-7',8'-bis. Hydrogen-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-d][1,4]oxaza ] (50 mg, 9.3% yield).
  • Step 6 4-Amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1, Synthesis of 3,2-dioxaborolan-2-yl)isoindolin-1-one
  • reaction solution was directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 4-amino-3-(2-chloro-5-fluoro).
  • Phenyl)-2-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Isoindolin-1-one (430 mg, 78.3% yield).
  • Step 7 4-Amino-3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo [1,5-d][1,4]oxaza Synthesis of ]-2'-yl)-2-(4-methoxybenzyl)isoindolin-1-one
  • reaction was carried out at 100°C for 12 hours.
  • LCMS monitored that the raw materials reacted completely and the reaction was completed.
  • the reaction solution was directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 4-amino-3-(2-chloro-5-fluoro).
  • Step 8 N-(3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[ 1,5-d][1,4]oxaza ]-2'-yl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
  • the solution is raised to room temperature and allowed to react for 2 hours.
  • LCMS monitors that the raw material reaction is complete and the reaction is completed.
  • Step 9 N-(3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[ 1,5-d][1,4]oxaza ]-2'-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
  • LCMS monitors that the raw material reaction is complete and the reaction is completed.
  • the reaction solution was diluted with water (1.0mL), then adjusted to alkaline pH with 10% potassium carbonate solution, extracted with ethyl acetate (10.0mL*3), the organic phase was concentrated to dryness, and the residue was subjected to reversed-phase high-performance liquid chromatography.
  • test examples were all prepared according to the methods of the above examples of the present disclosure.
  • the compounds in the test examples were determined based on the specific forms of the products prepared in the above examples.
  • Test Example 1 PIK3CA enzyme activity experiment
  • PIK3CA catalyzes the reaction of serine substrates (PI(4,5)P2 and phosphatidylserine (PS)), consuming ATP and producing ADP.
  • ADP-Glo TM reagent is then added to terminate the kinase reaction and consume the remaining ATP.
  • the added kinase The detection reagent converts ADP into ATP, which is then converted into light by luciferase.
  • the luminescence signal is positively correlated with the kinase activity, thus reflecting the enzymatic activity of PIK3CA.
  • the compound was gradient diluted with Echo650 and transferred to a 384-well white plate at 50 nL/well.
  • the starting concentration of the compound was 1000 nM, 3-fold gradient dilution, and 8 concentration points.
  • Lum max refers to the signal value of the well containing enzyme, reaction mixture and DMSO
  • Lum compound refers to the signal value of the well containing compound, enzyme and reaction mixture
  • OD min refers to the signal value of the well containing the reaction mixture and DMSO.
  • Test Example 2 MCF7/T47D/SKBR3 cell proliferation experiment
  • the cell proliferation assay is a direct homogeneous assay that determines the number of viable cells by detecting the ATP of viable cells. After the cells are incubated with the compound for a certain period of time, the detection reagent CellTilter-Glo is added. The luciferase in the detection reagent will react with ATP released by living cells to generate a light signal, thereby reflecting the compound's ability to inhibit cell proliferation.
  • T47D was purchased from ATCC and cultured using RPMI 1640 medium containing 10% FBS.
  • SKBR3 cells were purchased from Kangyuan Bochuang and cultured using McCoy's 5A medium containing 10% FBS.
  • MCF7 was purchased from ATCC and cultured in EMEM medium containing 10 ⁇ g/mL recombinant human insulin and 10% FBS.
  • MCF7/T47D/SKBR3 were seeded in 96-well transparent bottom white plates. Each cell was seeded on two plates. The number of cells was 2000/2500/3000 cells/well respectively. Place it in a 37°C, 5% CO 2 incubator. Incubate overnight.
  • the final reaction system is 100 ⁇ L, and the highest concentration point of the compound is 10 ⁇ M or 1 ⁇ M.
  • Lum max refers to the light signal value of the well containing cells and DMSO
  • Lum day0 refers to the light signal value on day 1
  • Lum compound refers to the light signal value of the well containing compound and cells
  • Lum min refers to the light signal value of the well containing culture medium and DMSO. The optical signal value of the hole.
  • XLfit software was used to fit to obtain the half growth inhibitory concentration (GI 50 ) of the compound.
  • the growth inhibition of tumor cells by the compounds of the present disclosure was measured through the above test, and the measured GI 50 value is shown in Table 2 below.
  • Test Example 3 Intracellular pAKT phosphorylation inhibitory activity experiment
  • the phosphorylated proteins in the cells are captured by the specific antibody-labeled acceptor beads and streptavidin-labeled donor beads in the AlphaLISA detection kit of PerkinElmer Company.
  • donor beads and acceptor beads are close to each other to generate signals, and the signal value is proportional to the phosphorylated protein content in the system.
  • T47D was purchased from ATCC and cultured using RPMI 1640 medium containing 10% FBS.
  • SKBR3 cells were purchased from Kangyuan Bochuang and cultured using McCoy's 5A medium containing 10% FBS.
  • Use the corresponding culture medium to adjust the cell density to 4*10 5 cells/mL, add 100 ⁇ L per well to a 96-well plate, and culture overnight in a 37°C, 5% CO 2 incubator. Add the compound to be tested to the cell culture plate and incubate for 2 hours at 37°C and 5% CO2 .
  • the final concentration of the compound is 10 ⁇ M starting from 3-fold dilution.
  • Inhibition rate (100-100*(Signal max -Signal compound )/(Signal max -Signal min ))%
  • Signal max refers to the AlphaLISA signal value of the cell lysate, acceptor beads and donor bead mixture wells containing 0.1% DMSO
  • Signal compound refers to the AlphaLISA signal of the cell lysate, acceptor beads and donor bead mixture wells containing the compound.
  • Value Signal min refers to the AlphaLISA signal value of the well containing the mixture of lysate, acceptor beads and donor beads.
  • the inhibitory activity of the compounds of the present disclosure on intracellular pAKT phosphorylation was measured through the above test, and the measured IC 50 values are shown in Table 3 below.

Abstract

The present disclosure relates to a tricyclic compound represented by formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and use thereof in preventing or treating a PI3Kα-related disease.

Description

三环化合物及其应用Tricyclic compounds and their applications
本公开要求2022年9月14日向中国国家知识产权局提交的，专利申请号为202211119158.1，发明名称为“三环化合物及其应用”的在先申请的权益和优先权。上述在先申请的全文通过引用的方式结合于本公开中。This disclosure requires the rights and priority of the prior application submitted to the State Intellectual Property Office of China on September 14, 2022, with the patent application number 202211119158.1 and the invention name "Tricyclic Compounds and Their Applications". The entire contents of the above-mentioned prior applications are incorporated into this disclosure by reference.
技术领域Technical field
本公开涉及三环化合物、其制备方法、含有该化合物的药物组合物、以及其在预防或治疗PI3Kα相关疾病中的用途。The present disclosure relates to tricyclic compounds, preparation methods thereof, pharmaceutical compositions containing the compounds, and their use in preventing or treating PI3Kα-related diseases.
背景技术Background technique
PI3K(磷脂酰肌醇-3-激酶)是一种脂激酶家族成员，是PI3K/AKT/mTOR信号通路的重要组成部分。PI3K研究最广泛的为I类PI3K，可分为PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ。PI3Kα的突变与恶性肿瘤有关；PI3Kβ能够激活血小板，与血栓性疾病的发展有关，并且在PTEN缺失的肿瘤中，PI3Kβ会促进肿瘤的恶变；PI3Kγ和PI3Kδ主要存在于B细胞中，与血液瘤、自身免疫性疾病密切有关；PI3K信号异常包括PIK3CA、PIK3CB、AKT基因的突变和扩增以及PTEN负调控功能的丧失等，与多种肿瘤包括***癌、乳腺癌、子宫内膜癌、肺癌、肝癌、结肠癌、血液瘤、淋巴瘤等的发生发展密切相关。PI3K (phosphatidylinositol-3-kinase) is a member of the lipid kinase family and an important component of the PI3K/AKT/mTOR signaling pathway. The most widely studied PI3K is class I PI3K, which can be divided into PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. PI3Kα mutations are related to malignant tumors; PI3Kβ can activate platelets and is related to the development of thrombotic diseases, and in PTEN-deficient tumors, PI3Kβ can promote the malignant transformation of tumors; PI3Kγ and PI3Kδ mainly exist in B cells and are associated with hematomas, Autoimmune diseases are closely related; PI3K signaling abnormalities include mutations and amplifications of PIK3CA, PIK3CB, AKT genes and loss of PTEN negative regulatory function, etc., and are associated with a variety of tumors including prostate cancer, breast cancer, endometrial cancer, lung cancer, and liver cancer , colon cancer, hematoma, lymphoma, etc. are closely related to the occurrence and development.
PI3Kα在PI3K/AKT信号通路发挥重要作用，下游调控了葡萄糖代谢、细胞周期等。PI3Kα突变被认为是肿瘤发生的驱动基因之一，突变导致PI3K/ATK信号通路异常活化，促进肿瘤的发生发展。最主要的突变类型是H1047R、E545K和E542K。但是抑制野生型PI3Kα，会引发血糖和胰岛素上升，引发安全性问题。目前针对HR+HER2-乳腺癌，PI3Kα抑制剂已获批，但是靶点相关的副作用，尤其是高血糖症，影响安全性的同时引发的胰岛素升高会进一步削弱药效。PI3Kα plays an important role in the PI3K/AKT signaling pathway and regulates glucose metabolism, cell cycle, etc. downstream. PI3Kα mutation is considered to be one of the driving genes for tumorigenesis. Mutations lead to abnormal activation of the PI3K/ATK signaling pathway and promote the occurrence and development of tumors. The most important mutation types are H1047R, E545K and E542K. However, inhibiting wild-type PI3Kα will cause blood sugar and insulin to rise, causing safety issues. Currently, PI3Kα inhibitors have been approved for HR+HER2- breast cancer. However, target-related side effects, especially hyperglycemia, affect safety and cause an increase in insulin, which will further weaken the efficacy of the drug.
提高药效和安全性是未满足的临床需求，因此开发仅对PI3Kα突变型有抑制作用的小分子抑制剂有潜力避免高血糖症的副作用，带来更好安全性的同时通过提升剂量达到更好的临床疗效。Improving drug efficacy and safety is an unmet clinical need. Therefore, the development of small molecule inhibitors that only inhibit PI3Kα mutants has the potential to avoid the side effects of hyperglycemia, bring better safety, and achieve better results by increasing the dose. Good clinical efficacy.
发明内容Contents of the invention
本公开涉及式(I)化合物或其药学上可接受的盐，
The present disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
Cy选自 Cy is selected from
环A、环B、环C均为单环，独立地选自苯环、5-6元杂芳环、4-8元饱和或部分饱和的杂环和C4-C6饱和或部分饱和的碳环，所述苯环、5-6元杂芳环、4-8元饱和或部分饱和的杂环和C4-C6饱和或部分饱和的碳环任选被RX取代；Ring A, Ring B, and Ring C are all single rings, independently selected from benzene rings, 5-6 membered heteroaromatic rings, 4-8 membered saturated or partially saturated heterocyclic rings, and C 4 -C 6 saturated or partially saturated heterocyclic rings. Carbocyclic ring, the benzene ring, 5-6 membered heteroaromatic ring, 4-8 membered saturated or partially saturated heterocyclic ring and C 4 -C 6 saturated or partially saturated carbocyclic ring are optionally substituted by R X ;
Y1、Y2独立地选自N和CH，所述CH任选被RY取代；Y 1 and Y 2 are independently selected from N and CH, and the CH is optionally substituted by R Y ;
Y5、Y6独立地选自N和C；Y 5 and Y 6 are independently selected from N and C;
Y3、Y4独立地选自O、NH和CH2，所述NH和CH2任选被RY取代；Y 3 and Y 4 are independently selected from O, NH and CH 2 , and the NH and CH 2 are optionally substituted by R Y ;
m、n、p、q、t’独立地选自0、1、2、3和4，且m和n不同时为0，p和q不同时为0； m, n, p, q, t' are independently selected from 0, 1, 2, 3 and 4, and m and n are not 0 at the same time, and p and q are not 0 at the same time;
R1、R2独立地选自卤素、CN、NO2、-OR、-SF5、-SR、-NR2、-S(O)2R、-S(O)2NR2、-S(O)2F、-S(O)R、-S(O)NR2、-S(O)(NR)R、-S(O)(NCN)R、-S(NCN)R、-C(O)R、-C(O)OR、-C(O)NR2、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2、-N(R)C(NR)NR2、-N(R)S(O)2NR2、-N(R)S(O)2R、-P(O)R2、-P(O)(R)OR、-B(OR)2、C1-C6烷基、苯基、萘基、5-10元杂芳基、C3-C12环烷基、C3-C12环烯基和3-12元杂环基，所述C1-C6烷基、苯基、萘基、5-10元杂芳基、C3-C12环烷基、C3-C12环烯基和3-12元杂环基任选被RZ取代；R 1 and R 2 are independently selected from halogen, CN, NO 2 , -OR, -SF 5 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O) 2 F, -S(O)R, -S(O)NR 2 , -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, -P(O)R 2 , -P(O)(R)OR, -B(OR) 2 , C 1 -C 6 alkyl, phenyl, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl and 3-12 membered heterocyclyl, wherein the C 1 -C 6 alkyl, phenyl, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl and 3-12 membered heterocyclyl are optionally substituted by R Z ;
L选自键和C1-C4亚烷基，所述C1-C4亚烷基中的1-2个亚甲基单元任选独立地被-CH(R)-、-C(R)2-、C3-C6亚环烷基、3-6元亚杂环基、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)C(NOR)-、-N(R)C(NCN)-、-N(R)S(O)2-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2-替换；L is selected from the group consisting of a bond and a C 1 -C 4 alkylene group, in which 1-2 methylene units of the C 1 -C 4 alkylene group are optionally independently replaced by -CH(R)-, -C(R ) 2 -, C 3 -C 6 cycloalkylene, 3-6 membered heterocyclylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR) -, -N(R)C(NOR)-, -N(R)C(NCN)-, -N(R)S(O) 2 -, -O-, -C(O)-, -OC( O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 -replacement;
RX、RY、RZ独立地选自氘、卤素、氧代、-CN、-NO2、-OR、-SF5、-SR、-NR2、-S(O)2R、-S(O)2NR2、-S(O)R、-S(O)NR2、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2、-N(R)C(NR)NR2、-N(R)S(O)2NR2、-N(R)S(O)2R、-P(O)R2、-P(O)(R)OR、-B(OR)2、C1-C6烷基、苯基、C3-C6环烷基、3-7元杂环基和5-6元杂芳基，所述C1-C6烷基、苯基、C3-C6环烷基、3-7元杂环基和5-6元杂芳基任选被R’取代； R ​ ​ ​ ​ ​ ​ (O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O )NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O) R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R , -P(O)R 2 , -P(O)(R)OR, -B(OR) 2 , C 1 -C 6 alkyl, phenyl, C 3 -C 6 cycloalkyl, 3-7 yuan Heterocyclyl and 5-6 membered heteroaryl, the C 1 -C 6 alkyl, phenyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are any Select to be replaced by R';
R独立地选自H、氘、C1-C6烷基、苯基、4-7元杂环基和5-6元杂芳基，或连接同一个N的两个R及其连接的N共同形成4-7元杂环基，所述C1-C6烷基、苯基、4-7元杂环基和5-6元杂芳基任选被R’取代；R is independently selected from H, deuterium, C 1 -C 6 alkyl, phenyl, 4-7 membered heterocyclyl and 5-6 membered heteroaryl, or two R connected to the same N and the N to which they are connected. Together, they form a 4-7-membered heterocyclyl group, and the C 1 -C 6 alkyl group, phenyl group, 4-7-membered heterocyclyl group and 5-6-membered heteroaryl group are optionally substituted by R';
R’独立地选自氧代、氘、卤素、氰基、硝基、氨基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、苯基、3-7元杂环基和5-6元杂芳基。R' is independently selected from oxo, deuterium, halogen, cyano, nitro, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.
在一些实施方案中，环A、环B、环C均为单环，独立地选自苯环、5-6元杂芳环和5-7元饱和或部分饱和的杂环，所述苯环、5-6元杂芳环和5-7元饱和或部分饱和的杂环任选被RX取代。In some embodiments, Ring A, Ring B, and Ring C are all monocyclic rings, independently selected from benzene rings, 5-6 membered heteroaromatic rings, and 5-7 membered saturated or partially saturated heterocyclic rings. , 5-6 membered heteroaromatic rings and 5-7 membered saturated or partially saturated heterocyclic rings are optionally substituted by R
在一些实施方案中，选自X1、X2独立地选自C、CH和N，所述CH任选地被RX取代，t选自0、1、2、3、4、5和6。In some embodiments, Selected from X 1 , X 2 are independently selected from C, CH and N, the CH is optionally substituted by R
在一些实施方案中，t选自0、1、2和3。In some embodiments, t is selected from 0, 1, 2, and 3.
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，Y1、Y5为N，Y6为C，Y2为CH，所述CH任选被RY取代；或Y2、 Y5为N，Y6为C，Y1为CH，所述CH任选被RY取代；或Y2、Y6为N，Y5为C，Y1为CH，所述CH任选被RY取代。In some embodiments, Y 1 and Y 5 are N, Y 6 is C, and Y 2 is CH, and the CH is optionally substituted by RY ; or Y 2 , Y 5 is N, Y 6 is C, Y 1 is CH, and the CH is optionally replaced by R Y ; or Y 2 and Y 6 are N, Y 5 is C, Y 1 is CH, and the CH is optionally replaced by R Y; R Y replaced.
在一些实施方案中，m、n、p、q、t’独立地选自0、1和2，且m和n不同时为0，p和q不同时为0。In some embodiments, m, n, p, q, t' are independently selected from 0, 1, and 2, and m and n are not 0 at the same time, and p and q are not 0 at the same time.
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，Cy选自 In some embodiments, Cy is selected from
在一些实施方案中，R1、R2独立地选自苯基、萘基、5-10元杂芳基、C3-C12环烷基、C3-C12环烯基和3-12元杂环基，所述苯基、萘基、5-10元杂芳基、C3-C12环烷基、C3-C12环烯基和3-12元杂环基任选被RZ取代。In some embodiments, R 1 , R 2 are independently selected from phenyl, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, and 3-12 One-membered heterocyclyl, the phenyl, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl and 3-12 membered heterocyclyl are optionally replaced by R Z replaced.
在一些实施方案中，R1、R2独立地选自苯基和5-6元杂芳基，所述苯基和5-6元杂芳基任选被RZ取代。In some embodiments, R 1 , R 2 are independently selected from phenyl and 5-6 membered heteroaryl, and the phenyl and 5-6 membered heteroaryl are optionally substituted by RZ .
在一些实施方案中，R1、R2为苯基，所述苯基任选被RZ取代。In some embodiments, R 1 , R 2 are phenyl, and the phenyl is optionally substituted with R Z .
在一些实施方案中，L选自键和C1-C4亚烷基，所述C1-C4亚烷基中的1-2个亚甲基单元任选独立地被-CH(R)-、-C(R)2-、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)S(O)2-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S(O)-或-S(O)2-替换。In some embodiments, L is selected from a bond and a C 1 -C 4 alkylene group in which 1-2 methylene units are optionally independently replaced by -CH(R) -, -C(R) 2 -, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)S(O) 2 - , -O-, -C(O)-, -OC(O)-, -C(O)O-, -S(O)- or -S(O) 2 -replacement.
在一些实施方案中，L选自C1-C2亚烷基，所述C1-C2亚烷基中的1-2个亚甲基单元任选独立地被-CH(R)-、-C(R)2-、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)S(O)2-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S(O)-或-S(O)2-替换。In some embodiments, L is selected from C 1 -C 2 alkylene in which 1-2 methylene units are optionally independently replaced by -CH(R)-, -C(R) 2 -, -N(R)-, -N(R)C(O)-, -N(R)C(NR)-, -N(R)S(O) 2 -, - O-, -C(O)-, -OC(O)-, -C(O)O-, -S(O)- or -S(O) 2 -replacement.
在一些实施方案中，L选自N(R)C(O)和N(R)C(O)N(R)。In some embodiments, L is selected from N(R)C(O) and N(R)C(O)N(R).
在一些实施方案中，L选自N(R)C(O)，例如NHC(O)。In some embodiments, L is selected from N(R)C(O), such as NHC(O).
在一些实施方案中，RX、RY、RZ独立地选自氘、卤素、-CN、-NO2、-OR、-SF5、-SR、-NR2、-S(O)2R、-S(O)2NR2、-S(O)R、-S(O)NR2、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2、-C(O)N(R)OR、-OC(O)R、C1-C6烷基、苯基、C3-C6环烷基、3-7元杂环基和5-6元杂芳基，所述C1-C6烷基、苯基、C3-C6环烷基、3-7元杂环基、5-6元杂芳基任选被R’取代。 In some embodiments , R ​ ​ , -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O)(NR)R, -C(O)R, -C(O)OR, - C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, C 1 -C 6 alkyl, phenyl, C 3 -C 6 cycloalkyl, 3-7 membered hetero Ring group and 5-6 membered heteroaryl group, the C 1 -C 6 alkyl group, phenyl group, C 3 -C 6 cycloalkyl group, 3-7 membered heterocyclic group, 5-6 membered heteroaryl group are optional Replaced by R'.
在一些实施方案中，RX、RY、RZ独立地选自氘、卤素和C1-C6烷基，所述C1-C6烷基任选被R’取代。 In some embodiments , R ​ ​
在一些实施方案中，R’独立地选自氘、卤素、C1-C3烷基、C1-C3烷氧基和C3-C6环烷基。In some embodiments, R' is independently selected from deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 3 -C 6 cycloalkyl.
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐选自式(II)化合物或其药学上可接受的盐，
In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from a compound of Formula (II) or a pharmaceutically acceptable salt thereof,
其中环A、环B、环C、R1、R2和L如上文定义。Wherein Ring A, Ring B, Ring C, R 1 , R 2 and L are as defined above.
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐选自式(III)化合物或其药学上可接受的盐，
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from a compound of formula (III) or a pharmaceutically acceptable salt thereof,
其中Y1、Y2、Y3、Y4、Y5、Y6、m、n、p、q、t’、RY、R1、R2和L如上文定义。Where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , m, n, p, q, t', R Y , R 1 , R 2 and L are as defined above.
在一些实施方案中，本公开的化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a pharmaceutically acceptable salt thereof:
另一方面，本公开提供药物组合物，其包含本公开的式(I)化合物或上述具体化合物或 其药学上可接受的盐和药学上可接受的辅料。In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) of the present disclosure or a specific compound as described above or Its pharmaceutically acceptable salt and pharmaceutically acceptable excipients.
另一方面，本公开提供治疗哺乳动物由PI3Kα介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)化合物或上述具体化合物或其药学上可接受的盐、或其药物组合物。On the other hand, the present disclosure provides a method for treating a disease mediated by PI3Kα in a mammal, comprising administering to a mammal in need of the treatment, preferably a human, a therapeutically effective amount of a compound of formula (I) or the above specific compound or a pharmaceutically acceptable compound thereof. Acceptable salts, or pharmaceutical compositions thereof.
另一方面，本公开提供式(Ⅰ)化合物或上述具体化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗PI3Kα介导的疾病的药物中的用途。On the other hand, the present disclosure provides the use of the compound of formula (I) or the above-mentioned specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a PI3Kα-mediated disease.
另一方面，本公开提供式(Ⅰ)化合物或上述具体化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗PI3Kα介导的疾病中的用途。On the other hand, the present disclosure provides the use of the compound of formula (I) or the above-mentioned specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating PI3Kα-mediated diseases.
另一方面，本公开提供预防或者治疗PI3Kα介导的疾病的式(Ⅰ)化合物或上述具体化合物或其药学上可接受的盐、或其药物组合物。On the other hand, the present disclosure provides compounds of formula (I) or the above-mentioned specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating PI3Kα-mediated diseases.
在一些实施方案中，PI3Kα介导的疾病选自癌症。In some embodiments, the PI3Kα-mediated disease is selected from cancer.
术语定义和说明Definitions and explanations of terms
除非另有说明，本公开中所用的术语具有下列含义，本公开中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the terms used in this disclosure have the following meanings. The definitions of groups and terms recorded in this disclosure include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and examples. The definitions of specific compounds, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in accordance with its ordinary meaning in the art. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
本文中表示连接位点。in this article Indicates the connection site.
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键表示一个立体中心的绝对构型，用黑实键和虚键表示一个立体中心的相对构型(如脂环化合物的顺反构型)。The schematic representation of racemic or enantiopure compounds herein is taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge and virtual wedge bonds are used Represents the absolute configuration of a stereocenter, using black real and imaginary bonds. Represents the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本公开包含化合物的所有互变异构形式。The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions. Compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually yield a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本公开化合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and therefore the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S) )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the compounds of the present disclosure. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups. These isomers and their mixtures involved in all substituents are also included in Within the definition of the compounds of the present disclosure. The compounds of the present disclosure containing asymmetric atoms can be isolated in an optically active pure form or in a racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. .
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced, and oxo does not occur on aromatic groups.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生 所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH2CH3)、单取代的(CH2CH2F、CH2CH2Cl等)、多取代的(CHFCH2F、CH2CHF2、CHFCH2Cl、CH2CHCl2等)或完全被取代的(CF2CF3、CF2CCl3、CCl2CCl3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that description includes the occurrence Said event or circumstance and the non-occurrence of said event or circumstance. For example, the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), or polysubstituted. (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2, etc.) or completely substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3, etc.). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
当任何变量(例如Ra、Rb)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个Rb所取代，则每个Rb都有独立的选项。When any variable (eg, R a , R b ) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. For example, if a group is replaced by 2 R b , there are independent options for each R b .
当一个连接基团的数量为0时，比如-(CH2)0-，表示该连接基团为键。When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
当其中一个变量选自化学键或不存在时，表示其连接的两个基团直接相连，比如A-L-Z中L代表键时表示该结构实际上是A-Z。When one of the variables is selected from a chemical bond or is absent, it means that the two groups it is connected to are directly connected. For example, when L in A-L-Z represents a bond, it means that the structure is actually A-Z.
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结构单元中的L1选自“C1-C3亚烷基-O”时，此时L1既可以按照与从左到右的方向连接环Q和R1构成“环Q-C1-C3亚烷基-O-R1”，也可以按照从右到左的方向连接环Q和R1构成“环Q-O-C1-C3亚烷基-R1”。When the linking group mentioned in this article does not specify the direction of connection, the direction of connection is arbitrary. For example, when the structural unit When L 1 is selected from "C 1 -C 3 alkylene-O", then L 1 can connect ring Q and R 1 in the direction from left to right to form "ring QC 1 -C 3 alkylene Group -OR 1 ”, you can also connect ring Q and R 1 from right to left to form “ring QOC 1 -C 3 alkylene group -R 1 ”.
当一个取代基的键交叉连接到一个环上时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元表示R5可在苯环上的任意一个位置发生取代。When a substituent's bond is cross-linked to a ring, the substituent can be bonded to any atom on the ring. For example, structural unit Indicates that R 5 can be substituted at any position on the benzene ring.
本文中的Cm-Cn是指具有m-n范围中的整数个碳原子。例如“C1-C10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。 Cm - Cn as used herein refers to having an integer number of carbon atoms in the range of mn. For example, "C 1 -C 10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
术语“烷基”是指通式为CnH2n+1的烃基，该烷基可以是直链或支链的。术语“C1-C10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；术语“C1-C6烷基”可理解为表示具有1至6个碳原子的烷基，具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C1-C3烷基”可理解为表示具有1至3个碳原子的直链或支链饱和烷基。所述“C1-C10烷基”可以包含“C1-C6烷基”或“C1-C3烷基”等范围，所述“C1-C6烷基”可以进一步包含“C1-C3烷基”。The term "alkyl" refers to a hydrocarbon group of the general formula C n H 2n+1 , which alkyl group may be straight or branched. The term "C 1 -C 10 alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl "can be understood to mean an alkyl group with 1 to 6 carbon atoms. Specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C 1 -C 3 alkyl" is understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C 1 -C 10 alkyl" may include "C 1 -C 6 alkyl" or "C 1 -C 3 alkyl" and other ranges, and the "C 1 -C 6 alkyl" may further include " C 1 -C 3 alkyl”.
术语“亚烷基”指烷基的一个氢原子进一步被取代形成的二价基团，其中烷基的定义如上所示。“C1-C3亚烷基”表示具有1、2或3个碳原子的亚烷基。术语“C1-C2亚烷基”表示具有1或2个碳原子的亚烷基，如亚甲基或亚乙基。优选地，“C1-C4亚烷基”可以包含“C1-C3亚烷基”和“C1-C2亚烷基”。The term "alkylene" refers to a divalent group formed by further substitution of one hydrogen atom of an alkyl group, wherein alkyl is as defined above. "C 1 -C 3 alkylene" means an alkylene group having 1, 2 or 3 carbon atoms. The term "C 1 -C 2 alkylene" means an alkylene group having 1 or 2 carbon atoms, such as methylene or ethylene. Preferably, "C 1 -C 4 alkylene" may include "C 1 -C 3 alkylene" and "C 1 -C 2 alkylene".
术语“烷氧基”是指直链或支链醇类失去羟基上的氢原子产生的基团，可理解为“烷基氧基”或“烷基-O-”。术语“C1-C10烷氧基”可理解为“C1-C10烷基氧基”或“C1-C10烷基-O-”；术语“C1-C6烷氧基”可理解为“C1-C6烷基氧基”或“C1-C6烷基-O-”。所述“C1-C10烷氧基”可以包含“C1-C6烷氧基”和“C1-C3烷氧基”等范围，所述“C1-C6烷氧基”可以进一步包含“C1-C3烷氧基”。The term "alkoxy" refers to a group produced by losing a hydrogen atom on a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C 1 -C 10 alkoxy" is understood to mean "C 1 -C 10 alkyloxy" or "C 1 -C 10 alkyl-O-"; the term "C 1 -C 6 alkoxy" It can be understood as "C 1 -C 6 alkyloxy" or "C 1 -C 6 alkyl-O-". The "C 1 -C 10 alkoxy group" may include the ranges of "C 1 -C 6 alkoxy group" and "C 1 -C 3 alkoxy group". The "C 1 -C 6 alkoxy group""C 1 -C 3 alkoxy" may further be included.
术语“烯基”是指由碳原子和氢原子组成的直链或支链的且具有至少一个双键的不饱和脂肪族烃基。术语“C2-C10烯基”可理解为表示直链或支链的不饱和烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，“C2-C10烯基”优选“C2-C6烯基”，进一步优选“C2-C4烯基”，更进一步优选C2或C3烯基。可理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或共轭。所述烯基的具体实例包括但不限于乙烯基、烯丙基、 (E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基或(Z)-1-甲基丙-1-烯基等。The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The term "C 2 -C 10 alkenyl" is understood to mean a straight-chain or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 2 -C 10 alkenyl" is preferably "C 2 -C 6 alkenyl", more preferably "C 2 -C 4 alkenyl", and even more preferably C 2 or C 3 alkenyl. It will be appreciated that where the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated to each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but- 1-alkenyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1- Alkenyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.
术语“环烷基”是指完全饱和的且以单环、稠合环、桥环或螺环等形式存在的碳环基团。除非另有指示，该碳环通常为3至20元环。术语“C3-C12环烷基”是指具有3、4、5、6、7、8、9、10、11或12个环碳原子的环烷基。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C3-C12环烷基”可以包含“C3-C6环烷基”，术语“C3-C6环烷基”可理解为表示饱和的单环或双环烃环基团，其具有3～6个环碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。The term "cycloalkyl" refers to a fully saturated carbocyclic group that exists in the form of a single ring, a fused ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 20 membered. The term "C 3 -C 12 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "C 3 -C 12 cycloalkyl" may include "C 3 -C 6 cycloalkyl", and the term "C 3 -C 6 cycloalkyl" is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring group, It has 3 to 6 ring carbon atoms, and specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.
术语“亚环烷基”是指环烷基的一个氢原子进一步被取代形成的二价基团，其中环烷基的定义如上所示。“C3-C6亚环烷基”是指具有3、4、5或6个环碳原子的亚环烷基。The term "cycloalkylene" refers to a divalent group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the cycloalkyl group is as defined above. "C 3 -C 6 cycloalkylene" refers to a cycloalkylene group having 3, 4, 5 or 6 ring carbon atoms.
术语“环烯基”是指具有至少一个双键的不完全饱和的且以单环、稠合环、桥环或螺环等形式存在的非芳香族碳环基。除非另有指示，该碳环通常为3至12元环。所述环烯基的具体实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基或环庚二烯基等。The term "cycloalkenyl" refers to a non-aromatic carbocyclic group that has at least one double bond and is not fully saturated and exists in the form of a single ring, a fused ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 12 membered. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, and the like.
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、并环、螺环或桥环基团，其环原子中含有1-5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-P(＝O)2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“3-12元杂环基”是指环原子数目为3、4、5、6、7、8、9、10、11或12的杂环基，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团。“3-12元杂环基”包括“4-7元杂环基”，其中，4元杂环基的具体实例包括但不限于氮杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-7元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“3-12元杂环基”还可以包含“4-8元杂环基”、“5-7元杂环基”、“3-7元杂环基”等范围，“4-8元杂环基”进一步可以包含“4-7元杂环基”、“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本公开中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。The term "heterocyclyl" refers to a fully saturated or partially saturated (not aromatic heteroaromatic as a whole) monocyclic, paracyclic, spirocyclic or bridged cyclic group containing 1 to 5 ring atoms. Heteroatom or heteroatom group (that is, an atomic group containing heteroatoms), the "heteroatom or heteroatom group" includes but is not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P) , boron atom (B), -S(=O) 2 -, -S(=O)-, -P(=O) 2 -, -P(=O)-, -NH-, -S(=O )(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "3-12 membered heterocyclyl" refers to a heterocyclic group with 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, and its ring atoms contain 1-5 independent Selected from the heteroatoms or heteroatom groups described above. "3-12-membered heterocyclyl" includes "4-7-membered heterocyclyl", wherein specific examples of 4-membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; 5-membered heterocyclyl Specific examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydroxazolyl or 2, 5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl , trithiyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include but are not limited to diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrole-2(1H)-yl; 5,6-membered bicyclic groups. Specific examples include, but are not limited to, hexahydropyrro[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused cyclic group of the above-mentioned 4-7 membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolyl and the like. "3-12-membered heterocyclyl" can also include "4-8-membered heterocyclyl", "5-7-membered heterocyclyl", "3-7-membered heterocyclyl" and other ranges. "4-8-membered heterocyclyl""Cyclicgroup" may further include "4-7 membered heterocyclyl", "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4- Ranges include "6-membered heterocycloalkyl", "5-6-membered heterocycloalkyl", etc. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl groups are still non-aromatic as a whole.
术语“亚杂环基”是指杂环基的一个环原子进一步被取代而形成的二价环状基团，其中，杂环基的定义如上所示。“3-6元亚杂环基”是指环原子数目为3、4、5或6的亚杂环基。The term "heterocyclylene" refers to a bivalent cyclic group formed by further substitution of one ring atom of the heterocyclyl group, wherein the heterocyclyl group is as defined above. "3-6 membered heterocyclylene" refers to a heterocyclylene group with the number of ring atoms being 3, 4, 5 or 6.
术语“杂环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的环状基团，其环的环原子中含有1-5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“4-10元杂环烷基”是指环原子数目为4、5、6、7、8、9或10的杂环烷基，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团。“4-10元杂环烷基”包括“4-7元杂环烷基”，其中，4元杂环烷基的具体实例包括但不限于吖丁啶基、噁丁环基或噻丁环基；5元杂环烷基的具体实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基或四氢吡唑基；6元杂环烷基的具体实例包括但不限于哌啶基、四氢吡喃基、四氢 噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基或1,4-二噻烷基；7元杂环烷基的具体实例包括但不限于氮杂环庚烷基、氧杂环庚烷基或硫杂环庚烷基。The term "heterocycloalkyl" refers to a fully saturated cyclic group that exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring, and the ring atoms of the ring contain 1-5 heteroatoms or heteroatom groups. (i.e. atomic groups containing heteroatoms), the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P), boron atoms (B ), -S(=O) 2 -, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O) NH-et al. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group with a number of ring atoms of 4, 5, 6, 7, 8, 9 or 10, and its ring atoms contain 1 to 5 independently selected from the above The heteroatom or heteroatom group. "4-10-membered heterocycloalkyl" includes "4-7-membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thibutanyl; Specific examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydrofuranyl. Hydropyrazolyl; specific examples of 6-membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydropyranyl thiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4- Dithianyl; specific examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxeppanyl or thiepanyl.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。术语“C6-C20芳基”可理解为具有6～20个碳原子的芳基。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基；或者具有13个碳原子的环(“C13芳基”)，例如芴基；或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。术语“C6-C10芳基”可理解为具有6～10个碳原子的芳基。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. Aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C 6 -C 20 aryl" is understood to mean an aryl group having 6 to 20 carbon atoms. In particular, a ring with 6 carbon atoms ("C 6 aryl"), for example phenyl; or a ring with 9 carbon atoms ("C 9 aryl"), for example indanyl or indenyl; or a ring with 10 or a ring of 13 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring of 13 carbon atoms ("C 13 aryl"), such as fluorenyl; or is a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl. The term "C 6 -C 10 aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. In particular, a ring with 6 carbon atoms ("C 6 aryl"), for example phenyl; or a ring with 9 carbon atoms ("C 9 aryl"), for example indanyl or indenyl; or a ring with 10 A ring of 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1-5个，优选1-3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1-3个，优选1-2个独立选自N、O和S的杂原子。The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, etc. and their benzo derivatives, such as quinolyl, quinazole Phyllinyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyl, etc. Aldyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
术语“卤”或“卤素”是指氟、氯、溴或碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”是指-OH基团。The term "hydroxy" refers to the -OH group.
术语“氰基”是指-CN基团。The term "cyano" refers to the -CN group.
术语“氨基”是指-NH2基团。The term "amino" refers to the -NH group.
术语“硝基”是指-NO2基团。The term "nitro" refers to the -NO2 group.
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，或(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate administration of the compounds of the present disclosure to an organism.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。The words "comprise" or "comprise" and their English variations such as compris or comprising can be understood as having an open, non-exclusive meaning, that is, "including but not limited to".
本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公 开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。The present disclosure also includes isotopically labeled compounds that are the same as those described herein, but in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature. Can be combined with the company Examples of isotopes of open compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N respectively , 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
某些同位素标记的本公开化合物(例如用3H及14C标记)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。Certain isotopically labeled compounds of the present disclosure (eg, labeled with 3 H and 14 C) can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present disclosure can be manufactured using methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, etc.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, dragees, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
本文所述的式(Ⅰ)化合物或上述具体化合物的所有施用方法中，每天给药的剂量为0.01mg/kg到200mg/kg体重，优选为0.05mg/kg到50mg/kg体重，更优选0.1mg/kg到30mg/kg体重，以单独或分开剂量的形式。In all administration methods of the compound of formula (I) described herein or the above specific compounds, the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg/kg body weight in single or divided doses.
本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present disclosure.
本公开具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本公开的化学变化及其所需的试剂和物料。为了获得本公开的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present disclosure are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, those skilled in the art sometimes need to modify or select synthetic steps or reaction procedures based on existing embodiments.
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本公开中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.本公开引用的所有参考文献整体上并入本公开。An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this disclosure). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this disclosure are incorporated into this disclosure in their entirety.
本公开采用下述缩略词：eq代表当量、等量；CBz代表苄氧羰基；Boc代表叔丁基羰基；DMSO代表二甲亚砜。This disclosure uses the following abbreviations: eq represents equivalent, equivalent; CBz represents benzyloxycarbonyl; Boc represents tert-butylcarbonyl; DMSO represents dimethyl sulfoxide.
具体实施方式Detailed ways
下面通过实施例对发明进行详细描述，但并不意味着对本公开的任何不利限制。本文已经详细地描述了本公开，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本公开精神和范围的情况下针对本公开具体实施方式进行各种改变将是显而易见的。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。The invention is described in detail below through examples, which do not mean any adverse limitations to the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof are also disclosed. For those skilled in the art, various changes will be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the disclosure. Obvious. All reagents used in this disclosure are commercially available and used without further purification.
除非另作说明，混合溶剂表示的比例是体积混合比例。Unless otherwise stated, the ratios expressed for mixed solvents are volumetric mixing ratios.
除非另作说明，否则，％是指wt％。 Unless otherwise stated, % refers to wt%.
化合物经手工或软件命名，市售化合物采用供应商目录名称。Compounds are manually or For software naming, commercially available compounds adopt supplier catalog names.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration when half of the maximum inhibitory effect is achieved. concentration.
下文的洗脱剂可由两种或多种溶剂形成混合洗脱剂，其比值为各溶剂的体积比，如“0～10％甲醇/二氯甲烷”表示梯度洗脱过程中，混合洗脱剂中的甲醇与二氯甲烷的体积用量比为0:100～10:100。The eluent below can be composed of two or more solvents to form a mixed eluent. The ratio is the volume ratio of each solvent. For example, "0~10% methanol/dichloromethane" means that the mixed eluent is used during the gradient elution process. The volume ratio of methanol to methylene chloride is 0:100~10:100.
中间体1
Intermediate 1
步骤1：4-(3-硝基吡啶-4-基)-3-氧代哌嗪-1-甲酸叔丁酯的合成Step 1: Synthesis of 4-(3-nitropyridin-4-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester
将4-氯-3-硝基吡啶(5.00g，31.5mmol)溶于N,N-二甲基甲酰胺(80mL)再加入1-Boc-3-哌嗪酮(7.58g，37.8mmol)和碳酸钾(8.72g，63.1mmol)。反应液于80℃搅拌反应5小时。LCMS检测反应完毕。反应液加入水(600mL)，用乙酸乙酯(1500mL)萃取三次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩至干，然后经柱层析纯化(二氧化硅，二氯甲烷：四氢呋喃＝3：1)得到产物4-(3-硝基吡啶-4-基)-3-氧代哌嗪-1-甲酸叔丁酯(1.30g)。Dissolve 4-chloro-3-nitropyridine (5.00g, 31.5mmol) in N,N-dimethylformamide (80mL) and add 1-Boc-3-piperazinone (7.58g, 37.8mmol) and Potassium carbonate (8.72g, 63.1mmol). The reaction solution was stirred and reacted at 80°C for 5 hours. LCMS detects that the reaction is complete. Water (600 mL) was added to the reaction solution, and extracted three times with ethyl acetate (1500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, dichloromethane : Tetrahydrofuran=3:1) to obtain the product 4-(3-nitropyridin-4-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.30g).
MS m/z(ESI):323.1[M+H]+；MS m/z(ESI):323.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ＝9.12(s,1H),8.95(d,J＝5.5Hz,1H),7.75(d,J＝5.3Hz,1H),4.09(s,2H),3.93(br t,J＝4.9Hz,2H),3.74(br t,J＝5.0Hz,2H),1.45(s,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.12 (s, 1H), 8.95 (d, J = 5.5Hz, 1H), 7.75 (d, J = 5.3Hz, 1H), 4.09 (s, 2H) ,3.93(br t,J＝4.9Hz,2H), 3.74(br t,J＝5.0Hz,2H), 1.45(s,9H).
步骤2：6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-甲酸叔丁酯的合成Step 2: Synthesis of 6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert-butyl ester
将4-(3-硝基吡啶-4-基)-3-氧代哌嗪-1-甲酸叔丁酯(1.20g，3.72mmol)溶于冰醋酸(10mL)再加入铁粉(2.08g，37.2mmol)。反应液于80℃搅拌反应1小时。LCMS检测反应完毕。反应液过滤，滤液加入水(100mL)稀释，用二氯甲烷萃取(300mL)，有机相经饱和碳酸氢钠(200mL)萃取，加入硫酸镁干燥过滤，滤液减压浓缩至干，然后经柱层析纯化(二氧化硅，二氯甲烷：甲醇＝10：1)得到产物6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-甲酸叔丁酯(500mg)。Dissolve 4-(3-nitropyridin-4-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (1.20g, 3.72mmol) in glacial acetic acid (10mL) and add iron powder (2.08g, 37.2mmol). The reaction solution was stirred at 80°C for 1 hour. LCMS detects that the reaction is complete. The reaction solution was filtered, the filtrate was diluted with water (100 mL), extracted with dichloromethane (300 mL), the organic phase was extracted with saturated sodium bicarbonate (200 mL), magnesium sulfate was added to dry it and filtered, the filtrate was concentrated under reduced pressure to dryness, and then passed through the column layer Analytical purification (silica, dichloromethane:methanol=10:1) gave the product 6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine- 8(9H)-tert-butyl formate (500 mg).
MS m/z(ESI):275.2[M+H]+；MS m/z(ESI):275.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ＝8.88(s,1H),8.34(d,J＝5.5Hz,1H),7.58(d,J＝5.5Hz,1H),4.83(s,2H),4.23-4.20(m,2H),3.94-3.91(m,2H),1.46(s,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.88 (s, 1H), 8.34 (d, J = 5.5Hz, 1H), 7.58 (d, J = 5.5Hz, 1H), 4.83 (s, 2H) ,4.23-4.20(m,2H),3.94-3.91(m,2H),1.46(s,9H).
中间体2
Intermediate 2
步骤1：2-[(苄基氧基)羰基]-1,2,3,4,6,7,8,9-八氢吡啶并[4',3':4,5]咪唑并[3,2-a]吡嗪-8-甲酸-2-甲基丙-2-基酯的合成Step 1: 2-[(benzyloxy)carbonyl]-1,2,3,4,6,7,8,9-octahydropyrido[4',3':4,5]imidazo[3 ,Synthesis of 2-a]pyrazine-8-carboxylic acid-2-methylpropan-2-yl ester
将1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(100mg，359μmol)溶于四氢呋喃(1mL)和水(0.25mL)，随后加入碳酸氢钠(90.5mg，1.08mmol)和氯甲酸苄酯(91.9mg，539μmol)。反应液于25℃搅拌反应16小时。LCMS检测反应完毕。反应液减压浓缩至干，然后经柱层析纯化(二氧化硅，二氯甲烷：甲醇＝10：1)得到产物2-[(苄基氧基)羰基]-1,2,3,4,6,7,8,9-八氢吡啶并[4',3':4,5]咪唑并[3,2-a]吡嗪-8-甲酸-2-甲基丙-2-基酯(120mg)。1,2,3,4,6,7-Hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert-butyl ester (100 mg, 359 μmol) was dissolved in tetrahydrofuran (1 mL) and water (0.25 mL), followed by addition of sodium bicarbonate (90.5 mg, 1.08 mmol) and benzyl chloroformate (91.9 mg, 539 μmol). The reaction solution was stirred at 25°C for 16 hours. LCMS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, dichloromethane:methanol=10:1) to obtain the product 2-[(benzyloxy)carbonyl]-1,2,3,4 ,6,7,8,9-octahydropyrido[4',3':4,5]imidazo[3,2-a]pyrazine-8-carboxylic acid-2-methylpropan-2-yl ester (120mg).
MS m/z(ESI):413.2[M+H]+；MS m/z(ESI):413.2[M+H] + ;
步骤2：3,4,6,7,8,9-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-2(1H)-羧酸苄酯的合成Step 2: 3,4,6,7,8,9-Hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylic acid benzyl Synthesis of esters
将2-[(苄基氧基)羰基]-1,2,3,4,6,7,8,9-八氢吡啶并[4',3':4,5]咪唑并[3,2-a]吡嗪-8-甲酸-2-甲基丙-2-基酯(120mg，291μmol)溶于无水甲醇(2mL)，随即加入盐酸/二氧六环(1mL，4M)。 反应液于25℃搅拌反应2小时。LCMS检测反应完毕。反应液减压浓缩至干，得到产物3,4,6,7,8,9-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-2(1H)-羧酸苄酯(60mg)。2-[(Benzyloxy)carbonyl]-1,2,3,4,6,7,8,9-octahydropyrido[4',3':4,5]imidazo[3,2 -a]pyrazine-8-carboxylic acid-2-methylpropan-2-yl ester (120 mg, 291 μmol) was dissolved in anhydrous methanol (2 mL), and then hydrochloric acid/dioxane (1 mL, 4M) was added. The reaction solution was stirred and reacted at 25°C for 2 hours. LCMS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the product 3,4,6,7,8,9-hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-2 (1H)-Carboxylic acid benzyl ester (60 mg).
MS m/z(ESI):313.1[M+H]+；MS m/z(ESI):313.1[M+H] + ;
中间体3
Intermediate 3
步骤1：5-溴-2-氟-3-硝基苯甲酸的合成Step 1: Synthesis of 5-bromo-2-fluoro-3-nitrobenzoic acid
将2-氟-3-硝基苯甲酸(23.0g，124mmol)溶于硫酸(200mL)中，再加入二溴海因(17.8g，62.2mmol)。反应液于85℃搅拌反应2小时。LCMS检测反应完毕。在0℃下，将反应液缓慢加入冰水(1.5L)中，搅拌并过滤，滤渣减压浓缩至干，得到产物5-溴-2-氟-3-硝基苯甲酸(30.0g)。2-Fluoro-3-nitrobenzoic acid (23.0g, 124mmol) was dissolved in sulfuric acid (200mL), and dibromohydantoin (17.8g, 62.2mmol) was added. The reaction solution was stirred at 85°C for 2 hours. LCMS detects that the reaction is complete. The reaction solution was slowly added to ice water (1.5L) at 0°C, stirred and filtered, and the filter residue was concentrated to dryness under reduced pressure to obtain the product 5-bromo-2-fluoro-3-nitrobenzoic acid (30.0g).
1H NMR(400MHz,DMSO-d6)δ＝8.54(dd,J＝2.8,6.0Hz,1H),8.29(dd,J＝2.8,5.5Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.54 (dd, J = 2.8, 6.0 Hz, 1H), 8.29 (dd, J = 2.8, 5.5 Hz, 1H).
步骤2：5-溴-N-(2-(叔丁基氨基)-1-(2-氯-5-氟苯基)-2-氧乙基)-2-氟-N-(4-甲氧基苄基)-3-硝基苯甲酰胺的合成Step 2: 5-bromo-N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxoethyl)-2-fluoro-N-(4-methyl Synthesis of oxybenzyl)-3-nitrobenzamide
将2-氯-5-氟苯甲醛(18.8g，119mmol)溶于甲醇(350mL)，氮气保护下依次加入对甲氧基苄胺(16.3g，119mmol)和5-溴-2-氟-3-硝基苯甲酸(32g，121mmol)和叔丁基异氰(9.87g，119mmol)。反应液于25℃搅拌反应2小时。LCMS检测反应完毕。反应液减压浓缩至干，然后经柱层析纯化(二氧化硅，石油醚：乙酸乙酯＝5：1)得到产物5-溴-N-(2-(叔丁基氨基)-1-(2-氯-5-氟苯基)-2-氧乙基)-2-氟-N-(4-甲氧基苄基)-3-硝基苯甲酰胺(66g)。Dissolve 2-chloro-5-fluorobenzaldehyde (18.8g, 119mmol) in methanol (350mL), and add p-methoxybenzylamine (16.3g, 119mmol) and 5-bromo-2-fluoro-3 under nitrogen protection. - Nitrobenzoic acid (32g, 121mmol) and tert-butyl isocyanate (9.87g, 119mmol). The reaction solution was stirred and reacted at 25°C for 2 hours. LCMS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, petroleum ether: ethyl acetate = 5:1) to obtain the product 5-bromo-N-(2-(tert-butylamino)-1- (2-Chloro-5-fluorophenyl)-2-oxyethyl)-2-fluoro-N-(4-methoxybenzyl)-3-nitrobenzamide (66 g).
1H NMR(400MHz,DMSO-d6)δ＝8.53(br,1H),8.31-8.17(m,1H),7.91(s,1H),7.69-7.48(m,1H),7.30-7.01(m,3H),6.96-6.73(m,2H),6.62-6.60(m,2H),5.42-5.10(m,1H),4.56-4.21(m,1H),3.65(d,J＝6.3Hz,3H),1.34-1.17(m,9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.53 (br, 1H), 8.31-8.17 (m, 1H), 7.91 (s, 1H), 7.69-7.48 (m, 1H), 7.30-7.01 (m ,3H),6.96-6.73(m,2H),6.62-6.60(m,2H),5.42-5.10(m,1H),4.56-4.21(m,1H),3.65(d,J＝6.3Hz,3H ),1.34-1.17(m,9H).
步骤3：6-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧苄基)-4-硝基异二氢吲哚-1-酮的合成Step 3: 6-Bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitroisoindolin-1-one synthesis
将5-溴-N-(2-(叔丁基氨基)-1-(2-氯-5-氟苯基)-2-氧乙基)-2-氟-N-(4-甲氧基苄基)-3-硝基苯甲酰胺(20g，32.0mmol)溶于乙腈(150mL)，加入2-叔丁基-1,1,3,3-四甲基胍(8.22g，48.0mmol)。反应液于50℃搅拌反应3小时。LCMS检测反应完毕。反应液减压浓缩至干，得到产物6-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧苄基)-4-硝基异二氢吲哚-1-酮(30g，粗品)。5-Bromo-N-(2-(tert-butylamino)-1-(2-chloro-5-fluorophenyl)-2-oxyethyl)-2-fluoro-N-(4-methoxy Benzyl)-3-nitrobenzamide (20g, 32.0mmol) was dissolved in acetonitrile (150mL), and 2-tert-butyl-1,1,3,3-tetramethylguanidine (8.22g, 48.0mmol) was added . The reaction solution was stirred at 50°C for 3 hours. LCMS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure to obtain the product 6-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitroisodihydrogen Indole-1-one (30g, crude product).
MS m/z(ESI):521.0；523.0[M+H]+；MS m/z(ESI):521.0;523.0[M+H] + ;
步骤4：6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧苄基)-4-硝基异二氢吲哚-1-酮的合成Step 4: Synthesis of 6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitroisoindolin-1-one
将6-溴-3-(2-氯-5-氟苯基)-3-羟基-2-(4-甲氧苄基)-4-硝基异二氢吲哚-1-酮(30g，57.5mmol，粗品)溶于三氟醋酸(150mL)，加入三乙基硅烷(33.4g，288mmol)。反应液于90℃搅拌反应5小时。LCMS检测反应完毕。反应液减压浓缩至干，然后经柱层析纯化(二氧化硅，石油醚：二氯甲烷＝1：10)得到产物6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧苄基)-4-硝基异二氢吲哚-1-酮(7.5g)。6-bromo-3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitroisoindolin-1-one (30g, 57.5 mmol, crude product) was dissolved in trifluoroacetic acid (150 mL), and triethylsilane (33.4 g, 288 mmol) was added. The reaction solution was stirred at 90°C for 5 hours. LCMS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, petroleum ether: dichloromethane = 1:10) to obtain the product 6-bromo-3-(2-chloro-5-fluorophenyl)- 2-(4-methoxybenzyl)-4-nitroisoindolin-1-one (7.5 g).
MS m/z(ESI):505.0[M+H]+；MS m/z(ESI):505.0[M+H] + ;
步骤5：4-氨基-6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)异吲哚啉-1-酮的合成 Step 5: Synthesis of 4-amino-6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)isoindolin-1-one
将6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧苄基)-4-硝基异二氢吲哚-1-酮(7.5g，14.8mmol)溶于无水乙醇(80mL)和乙酸(10mL)，加入氯化铵(5.55g，104mmol)，升温至50℃加入铁粉(5.80g，104mmol)。反应液于80℃搅拌反应1小时。LCMS检测反应完毕。反应液过滤并减压浓缩至干，然后经柱层析纯化(二氧化硅，石油醚：乙酸乙酯＝3：1)得到产物4-氨基-6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)异吲哚啉-1-酮(5g)。6-Bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitroisoindolin-1-one (7.5g, 14.8mmol) Dissolve in absolute ethanol (80 mL) and acetic acid (10 mL), add ammonium chloride (5.55 g, 104 mmol), heat to 50°C and add iron powder (5.80 g, 104 mmol). The reaction solution was stirred at 80°C for 1 hour. LCMS detects that the reaction is complete. The reaction solution was filtered and concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, petroleum ether: ethyl acetate = 3:1) to obtain the product 4-amino-6-bromo-3-(2-chloro-5 -Fluorophenyl)-2-(4-methoxybenzyl)isoindolin-1-one (5 g).
MS m/z(ESI):476.9[M+H]+；MS m/z(ESI):476.9[M+H] + ;
步骤6：N-(6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成Step 6: N-(6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)- Synthesis of 3-fluoro-5-(trifluoromethyl)benzamide
将3-氟-5-三氟甲基苯甲酸(455mg，2.19mmol)溶于无水二氯甲烷(6mL)，加入草酰氯(427mg，3.36mmol)和N,N二甲基甲酰胺(0.1mL)，反应液于80℃搅拌反应1小时，反应液减压浓缩至干备用。将4-氨基-6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)异吲哚啉-1-酮(1g，2.11mmol)溶于乙腈(7mL)，加入吡啶(266mg，3.36mmol)，将上述减压浓缩至干的产物溶于乙腈(3mL)，缓慢滴加到上述反应液。反应液于25℃搅拌反应16小时。LCMS检测反应完毕。反应液过滤并减压浓缩至干，然后经柱层析纯化(二氧化硅，石油醚：乙酸乙酯＝3：1)得到产物N-(6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(500mg)。Dissolve 3-fluoro-5-trifluoromethylbenzoic acid (455mg, 2.19mmol) in anhydrous dichloromethane (6mL), add oxalyl chloride (427mg, 3.36mmol) and N,N dimethylformamide (0.1 mL), the reaction solution was stirred at 80°C for 1 hour, and the reaction solution was concentrated under reduced pressure to dryness for later use. Dissolve 4-amino-6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)isoindolin-1-one (1 g, 2.11 mmol) in acetonitrile (7 mL), add pyridine (266 mg, 3.36 mmol), and the product concentrated to dryness under reduced pressure was dissolved in acetonitrile (3 mL), and slowly added dropwise to the above reaction solution. The reaction solution was stirred at 25°C for 16 hours. LCMS detects that the reaction is complete. The reaction solution was filtered and concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, petroleum ether: ethyl acetate = 3:1) to obtain the product N-(6-bromo-3-(2-chloro-5- Fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (500 mg).
MS m/z(ESI):664.9,666.9[M+H]+；MS m/z(ESI):664.9,666.9[M+H] + ;
步骤7：N-(6-溴-3-(2-氯-5-氟苯基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成：Step 7: N-(6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl) Synthesis of benzamide:
将N-(6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(500mg，751μmol)溶于无水三氟乙酸(3.08g，27.0mmol)，加入三氟甲磺酸(340mg，2.27mmol)，反应液于80℃搅拌反应1小时。LCMS检测反应完毕。反应液过滤并减压浓缩至干，加入饱和碳酸氢钠(20mL)，用乙酸乙酯萃取三次(50mL*3)。有机相用无水硫酸镁干燥，减压浓缩至干，得到产物N-(6-溴-3-(2-氯-5-氟苯基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(400mg)。取N-(6-溴-3-(2-氯-5-氟苯基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(100mg)经制备色谱纯化(Boston Prime C18柱，5μm二氧化硅，30mm直径，150mm长度；使用水(含有0.05％氨水)和乙腈的极性递减(48％-68％)的混合物作为洗脱液)得到产物N-(6-溴-3-(2-氯-5-氟苯基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(15mg)。N-(6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3- Fluoro-5-(trifluoromethyl)benzamide (500 mg, 751 μmol) was dissolved in anhydrous trifluoroacetic acid (3.08 g, 27.0 mmol), trifluoromethanesulfonic acid (340 mg, 2.27 mmol) was added, and the reaction solution was heated to 80 The reaction was stirred for 1 hour. LCMS detects that the reaction is complete. The reaction solution was filtered and concentrated to dryness under reduced pressure, saturated sodium bicarbonate (20 mL) was added, and extracted three times with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to obtain the product N-(6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxoisoindolin-4-yl )-3-fluoro-5-(trifluoromethyl)benzamide (400 mg). Take N-(6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzyl The amide (100 mg) was purified by preparative chromatography (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile of decreasing polarity (48%-68%) as eluents. Deliquidation) to obtain the product N-(6-bromo-3-(2-chloro-5-fluorophenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl base) benzamide (15 mg).
MS m/z(ESI):544.8,546.8[M+H]+；MS m/z(ESI):544.8,546.8[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ＝10.56(br s,1H),9.30(br s,1H),7.96(br d,J＝8.3Hz,1H),7.82(d,J＝1.3Hz,1H),7.77-7.68(m,2H),7.64(s,1H),7.32(dd,J＝5.3,8.8Hz,1H),7.09(dt,J＝2.9,8.3Hz,1H),5.97(br s,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.56 (br s, 1H), 9.30 (br s, 1H), 7.96 (br d, J = 8.3Hz, 1H), 7.82 (d, J = 1.3Hz ,1H),7.77-7.68(m,2H),7.64(s,1H),7.32(dd,J＝5.3,8.8Hz,1H),7.09(dt,J＝2.9,8.3Hz,1H),5.97( br s,1H).
实施例1:N-(3-(2-氯-5-氟苯基)-6-(3,4,6,7,8,9-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)-1-氧代异二氢吲哚-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物1)的合成
Example 1: N-(3-(2-chloro-5-fluorophenyl)-6-(3,4,6,7,8,9-hexahydropyrido[3',4':4,5 ]Imidazo[1,2-a]pyrazin-2(1H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzyl Synthesis of Amide (Compound 1)
步骤1：2-苄基-8-(叔丁氧基羰基)-6,7,8,9-四氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-2-溴化铵的合成Step 1: 2-Benzyl-8-(tert-butoxycarbonyl)-6,7,8,9-tetrahydropyrido[3',4':4,5]imidazo[1,2-a] Synthesis of pyrazine-2-ammonium bromide
将6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(300mg，1.09mmol)溶于甲苯(5mL)中，再加入溴化苄(206mg，1.20mmol)。反应液于80℃搅拌反应16小时。LCMS检测反应完毕。反应液减压浓缩至干，用石油醚(10mL)打浆，得到产物2-苄基-8-(叔丁氧基羰基)-6,7,8,9-四氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-2-溴化铵(400mg，粗品)。6,7-Dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert-butyl ester (300mg, 1.09mmol) was dissolved in To toluene (5 mL), benzyl bromide (206 mg, 1.20 mmol) was added. The reaction solution was stirred at 80°C for 16 hours. LCMS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure and beaten with petroleum ether (10 mL) to obtain the product 2-benzyl-8-(tert-butoxycarbonyl)-6,7,8,9-tetrahydropyrido[3',4 ':4,5]imidazo[1,2-a]pyrazine-2-ammonium bromide (400 mg, crude product).
步骤2：2-苄基-1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯的合成Step 2: 2-benzyl-1,2,3,4,6,7-hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H )-Synthesis of tert-butyl carboxylate
将2-苄基-8-(叔丁氧基羰基)-6,7,8,9-四氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-2-溴化铵(400mg，0.9mmol)溶于乙醇(8mL)，0℃下加入硼氢化钠(140mg，3.70mmol)。反应液于25℃搅拌反应16小时。LCMS检测反应完毕。反应液加入丙酮(10mL)，搅拌反应20分钟，反应液减压浓缩至干，然后经柱层析纯化(二氧化硅，二氯甲烷：甲醇＝10：1)得到产物2-苄基-1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(200mg)。2-Benzyl-8-(tert-butoxycarbonyl)-6,7,8,9-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine -2-Ammonium bromide (400 mg, 0.9 mmol) was dissolved in ethanol (8 mL), and sodium borohydride (140 mg, 3.70 mmol) was added at 0°C. The reaction solution was stirred at 25°C for 16 hours. LCMS detects that the reaction is complete. Acetone (10 mL) was added to the reaction solution, and the reaction was stirred for 20 minutes. The reaction solution was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, dichloromethane: methanol = 10:1) to obtain the product 2-benzyl-1. ,2,3,4,6,7-Hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert-butyl ester (200mg ).
MS m/z(ESI):369.1[M+H]+；MS m/z(ESI):369.1[M+H] + ;
步骤3：1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯的合成Step 3: 1,2,3,4,6,7-Hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert. Synthesis of butyl ester
将2-苄基-1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(200mg，543μmol)溶于乙酸乙酯(10mL)，加入湿钯/碳(100mg，10％纯度)和湿氢氧化钯/碳(100mg，142μmol，20％纯度)。氢气(15PSI)氛围下反应液于25℃搅拌反应16小时。LCMS检测反应完毕。反应液过滤，滤液减压浓缩至干，得到产物1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(100mg)。2-Benzyl-1,2,3,4,6,7-hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)- Tert-butyl carboxylate (200 mg, 543 μmol) was dissolved in ethyl acetate (10 mL), and wet palladium on carbon (100 mg, 10% purity) and wet palladium hydroxide on carbon (100 mg, 142 μmol, 20% purity) were added. The reaction solution was stirred and reacted at 25°C for 16 hours under a hydrogen gas (15 PSI) atmosphere. LCMS detects that the reaction is complete. The reaction liquid was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the product 1,2,3,4,6,7-hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrido Azine-8(9H)-carboxylic acid tert-butyl ester (100 mg).
MS m/z(ESI):279.2[M+H]+；MS m/z(ESI):279.2[M+H] + ;
步骤4：2-(1-(2-氯-5-氟苯基)-7-(3-氟-5-(三氟甲基)苯甲酰氨基)-2-(4-甲氧基苄基)-3-氧代异吲哚啉-5-基)-1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯的合成Step 4: 2-(1-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzoylamino)-2-(4-methoxybenzyl) (yl)-3-oxoisoindolin-5-yl)-1,2,3,4,6,7-hexahydropyrido[3',4':4,5]imidazo[1,2 -Synthesis of pyrazine-8(9H)-carboxylic acid tert-butyl ester
将1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(50mg，180μmol)和N-(6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧苄基)-1-氧代异二氢吲哚-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(150mg，180μmol，80％纯度)溶于叔戊醇(1mL)，氮气氛围下加入叔丁醇钠(51.8mg，539μmol)和甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(15.0mg，18.0μmol)。反应液于130℃搅拌反应1小时。LCMS检测反应完毕。反应液减压浓缩至干，然后经柱层析纯化(二氧化硅，二氯甲烷：甲醇＝10：1)得到产物2-(1-(2-氯-5-氟苯基)-7-(3-氟-5-(三氟甲基)苯甲酰氨基)-2-(4-甲氧基苄基)-3-氧代异吲哚啉-5-基)-1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(110mg)。1,2,3,4,6,7-Hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert-butyl ester (50 mg, 180 μmol) and N-(6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindoline-4- (150 mg, 180 μmol, 80% purity) was dissolved in tert-amyl alcohol (1 mL), and sodium tert-butoxide (51.8 mg, 539 μmol) was added under nitrogen atmosphere. and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl )Palladium(II) (15.0 mg, 18.0 μmol). The reaction solution was stirred and reacted at 130°C for 1 hour. LCMS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and then purified by column chromatography (silica, dichloromethane:methanol=10:1) to obtain the product 2-(1-(2-chloro-5-fluorophenyl)-7- (3-Fluoro-5-(trifluoromethyl)benzoylamino)-2-(4-methoxybenzyl)-3-oxoisoindolin-5-yl)-1,2,3 , 4,6,7-hexahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert-butyl ester (110 mg).
MS m/z(ESI):863.2[M+H]+；MS m/z(ESI):863.2[M+H] + ;
步骤5：N-(3-(2-氯-5-氟苯基)-6-(3,4,6,7,8,9-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)-1-氧代异二氢吲哚-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成Step 5: N-(3-(2-chloro-5-fluorophenyl)-6-(3,4,6,7,8,9-hexahydropyrido[3',4':4,5] Imidazo[1,2-a]pyrazin-2(1H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide Synthesis
将2-(1-(2-氯-5-氟苯基)-7-(3-氟-5-(三氟甲基)苯甲酰氨基)-2-(4-甲氧基苄基)-3-氧代异吲哚啉-5-基)-1,2,3,4,6,7-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(100mg，11.6μmol，10％纯度)溶于三氟乙酸(0.5mL，6.7mmol)，加入三氟甲磺酸(0.05mL，0.57mmol)，反应液于80℃搅拌反应1小时。LCMS检测反应完毕。反应液过滤并减压浓缩至干，加入饱和碳酸氢钠水溶液(5mL)，用乙酸乙酯萃取三次(5mL*3)。有机相用无水硫酸镁干燥，减压浓缩至干，经制备色谱纯化(Boston Prime C18柱，5μm二氧化硅，30mm直径，150mm长度；使用水(含有0.05％氨水)和乙腈的极性递减(35％-55％)的混合物作为洗脱液)得到产物N-(3-(2-氯-5-氟苯基)-6-(3,4,6,7,8,9-六氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-2(1H)-基)-1-氧代异二氢吲哚-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物1，1.01mg)。2-(1-(2-Chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzoylamino)-2-(4-methoxybenzyl) -3-Oxoisoindolin-5-yl)-1,2,3,4,6,7-hexahydropyrido[3',4':4,5]imidazo[1,2-a ] Pyrazine-8(9H)-carboxylic acid tert-butyl ester (100 mg, 11.6 μmol, 10% purity) was dissolved in trifluoroacetic acid (0.5 mL, 6.7 mmol), and trifluoromethanesulfonic acid (0.05 mL, 0.57 mmol) was added , the reaction solution was stirred and reacted at 80°C for 1 hour. LCMS detects that the reaction is complete. The reaction solution was filtered and concentrated to dryness under reduced pressure, added with saturated aqueous sodium bicarbonate solution (5 mL), and extracted three times with ethyl acetate (5 mL*3). The organic phase was dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and purified by preparative chromatography (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length; using water (containing 0.05% ammonia) and acetonitrile with decreasing polarity. (35%-55%) mixture as eluent) to obtain the product N-(3-(2-chloro-5-fluorophenyl)-6-(3,4,6,7,8,9-hexahydro Pyrido[3',4':4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-1-oxoisoindolin-4-yl)-3- Fluoro-5-(trifluoromethyl)benzamide (Compound 1, 1.01 mg).
MS m/z(ESI):643.1[M+H]+；MS m/z(ESI):643.1[M+H] + ;
1H NMR(400MHz,CD3OD)δ＝7.74-7.61(m,3H),7.45(s,1H),7.28(dd,J＝4.8,8.3Hz,1H),7.15(s,1H),7.07-6.94(m,1H),6.75-5.99(m,1H),4.97(br s,1H),4.33(s,2H),4.01(s,2H), 3.91(br t,J＝5.4Hz,2H),3.84(br t,J＝5.3Hz,2H),3.25(br t,J＝5.4Hz,2H),2.81(br s,2H)。 1 H NMR (400MHz, CD 3 OD) δ = 7.74-7.61 (m, 3H), 7.45 (s, 1H), 7.28 (dd, J = 4.8, 8.3Hz, 1H), 7.15 (s, 1H), 7.07 -6.94(m,1H),6.75-5.99(m,1H),4.97(br s,1H),4.33(s,2H),4.01(s,2H), 3.91(br t,J＝5.4Hz,2H), 3.84(br t,J＝5.3Hz,2H), 3.25(br t,J＝5.4Hz,2H), 2.81(br s,2H).
实施例2：N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物2)，(R)-N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺和(S)-N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成
Example 2: N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2- a]pyrazine-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 2), (R) -N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrido Azin-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide and (S)-N-(3-( 2-Chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)- Synthesis of 1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
步骤1：6,7,8,9-四氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪盐酸盐的合成Step 1: Synthesis of 6,7,8,9-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine hydrochloride
将6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-羧酸叔丁酯(200mg，729μmol)溶于甲醇(2mL)，再加入4M盐酸二氧六环(2mL)。反应液于25℃搅拌反应2小时。反应液减压浓缩至干得产物6,7,8,9-四氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪盐酸盐(200mg)。Dissolve 6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)-carboxylic acid tert-butyl ester (200 mg, 729 μmol) in methanol (2 mL), and then add 4M dioxane hydrochloride (2 mL). The reaction solution was stirred and reacted at 25°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain the product 6,7,8,9-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine hydrochloride (200 mg).
1H NMR(400MHz,DMSO-d6)δ＝9.54(s,1H),8.80-8.70(m,1H),8.43-8.32(m,1H),4.78(br s,2H),4.68(br t,J＝5.4Hz,2H),3.80(br s,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.54 (s, 1H), 8.80-8.70 (m, 1H), 8.43-8.32 (m, 1H), 4.78 (br s, 2H), 4.68 (br t ,J＝5.4Hz,2H),3.80(br s,2H).
步骤2：N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基))-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成Step 2: N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a ]Pyrazine-8(9H)-yl))-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl )Synthesis of benzamide
将6,7,8,9-四氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪盐酸盐(157mg,745μmol)和N-(6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(200mg,300μmol)溶于叔戊醇(4mL)，再在氮气条件下加入甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(50.24mg,60.08μmol,0.2eq)和叔丁醇钠(86.60mg,901.13μmol,3eq)。反应液于140℃搅拌反应1小时。LCMS检测反应完毕。反应液减压浓缩，然后经柱层析纯化(二氧化硅，二氯甲烷：甲醇＝10：1)得到产物N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基))-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(150mg)。6,7,8,9-Tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine hydrochloride (157 mg, 745 μmol) and N-(6-bromo -3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoro Methyl)benzamide (200 mg, 300 μmol) was dissolved in tert-amyl alcohol (4 mL), and then methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (50.24 mg, 60.08 μmol, 0.2 eq) and sodium tert-butoxide (86.60 mg, 901.13 μmol,3eq). The reaction solution was stirred and reacted at 140°C for 1 hour. LCMS detects that the reaction is complete. The reaction solution was concentrated under reduced pressure, and then purified by column chromatography (silica, dichloromethane:methanol=10:1) to obtain the product N-(3-(2-chloro-5-fluorophenyl)-6-(6 ,7-Dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazin-8(9H)-yl))-2-(4-methoxybenzyl) -1-Oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (150 mg).
MS m/z(ESI):759.2[M+H]+；MS m/z(ESI):759.2[M+H] + ;
步骤3：N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成Step 3: N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a Synthesis of ]pyrazine-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基))-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(150mg,198μmol)溶于三氟乙酸(1.5mL)再加入三氟甲磺酸(0.15mL)。反应液80℃搅拌反应1小时。LCMS检测反应完毕。反 应液减压浓缩至干，然后经制备液相色谱纯化(WatersXbridge BEH C18柱：5μm二氧化硅，30mm直径，100mm长度；使用水(0.05％氨水)和乙腈的极性递减(25％-45％)的混合物作为洗脱液)纯化得到N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物2，17.82mg)。N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrido Azine-8(9H)-yl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzene Formamide (150 mg, 198 μmol) was dissolved in trifluoroacetic acid (1.5 mL) and trifluoromethanesulfonic acid (0.15 mL) was added. The reaction solution was stirred at 80°C for 1 hour. LCMS detects that the reaction is complete. opposite The solution was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography (WatersXbridge BEH C18 column: 5 μm silica, 30 mm diameter, 100 mm length; using water (0.05% ammonia) and acetonitrile with decreasing polarity (25%-45 %) as the eluent) was purified to obtain N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5] Imidazo[1,2-a]pyrazine-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide ( Compound 2, 17.82 mg).
MS m/z(ESI):639.3[M+H]+；MS m/z(ESI):639.3[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ＝10.45(s,1H),9.12-9.02(m,2H),8.43(d,J＝5.5Hz,1H),7.95(br d,J＝8.5Hz,1H),7.82-7.65(m,3H),7.42(d,J＝2.3Hz,1H),7.33-7.24(m,2H),7.08(br d,J＝3.0Hz,1H),6.64(br s,1H),5.91(br s,1H),4.89(d,J＝2.0Hz,2H),4.40(s,2H),4.12-4.03(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.45 (s, 1H), 9.12-9.02 (m, 2H), 8.43 (d, J = 5.5Hz, 1H), 7.95 (br d, J = 8.5Hz ,1H),7.82-7.65(m,3H),7.42(d,J＝2.3Hz,1H),7.33-7.24(m,2H),7.08(br d,J＝3.0Hz,1H),6.64(br s,1H),5.91(br s,1H),4.89(d,J=2.0Hz,2H),4.40(s,2H),4.12-4.03(m,2H).
步骤4：(R)-N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺和(S)-N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成Step 4: (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1 ,2-a]pyrazine-8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide and (S)- N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine Synthesis of -8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(14.12mg，22.10μmol)经手性分离(DAICEL CHIRALPAK IG，10μm二氧化硅，30mm直径，250mm长度，使用乙醇(含有0.1％氨水)保持极性(60％-60％)的混合物作为洗脱液)得到(R)-N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺和(S)-N-(3-(2-氯-5-氟苯基)-6-(6,7-二氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-8(9H)-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物2A，3.97mg，第一个峰，保留时间1.046分钟；化合物2B，2.34mg，第二个峰，保留时间1.797分钟)。N-(3-(2-chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine -8(9H)-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (14.12 mg, 22.10 μmol) was chiral separated (DAICEL CHIRALPAK IG, 10μm silica, 30mm diameter, 250mm length, using ethanol (containing 0.1% ammonia) to maintain polarity (60%-60%) mixture as eluent) to obtain (R)-N-(3-( 2-Chloro-5-fluorophenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-8(9H)- base)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide and (S)-N-(3-(2-chloro-5-fluoro Phenyl)-6-(6,7-dihydropyrido[3',4':4,5]imidazo[1,2-a]pyrazin-8(9H)-yl)-1-oxo Isoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 2A, 3.97 mg, first peak, retention time 1.046 minutes; compound 2B, 2.34 mg, second peak peak, retention time 1.797 minutes).
第一个峰，保留时间1.046分钟：The first peak, retention time 1.046 minutes:
MS m/z(ESI):639.3[M+H]+；MS m/z(ESI):639.3[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ＝10.47(s,1H),9.12-9.01(m,1H),8.96-8.85(m,1H),8.37-8.32(m,1H),7.91(br d,J＝1.5Hz,1H),7.78-7.70(m,1H),7.70-7.66(m,1H),7.65-7.61(m,1H),7.43(s,1H),7.32-7.24(m,2H),7.12-7.04(m,1H),6.02-5.76(m,1H),4.88-4.80(m,2H),4.38-4.32(m,2H),4.09-4.03(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.47 (s, 1H), 9.12-9.01 (m, 1H), 8.96-8.85 (m, 1H), 8.37-8.32 (m, 1H), 7.91 (br d,J＝1.5Hz,1H),7.78-7.70(m,1H),7.70-7.66(m,1H),7.65-7.61(m,1H),7.43(s,1H),7.32-7.24(m, 2H),7.12-7.04(m,1H),6.02-5.76(m,1H),4.88-4.80(m,2H),4.38-4.32(m,2H),4.09-4.03(m,2H).
第二个峰，保留时间1.797分钟：The second peak, retention time 1.797 minutes:
MS m/z(ESI):639.1[M+H]+；MS m/z(ESI):639.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ＝10.47-10.42(m,1H),9.12-8.98(m,1H),8.95-8.87(m,1H),8.40-8.31(m,1H),7.98-7.89(m,1H),7.79-7.70(m,1H),7.68(s,1H),7.64(d,J＝5.7Hz,1H),7.41(d,J＝2.2Hz,1H),7.32-7.24(m,2H),7.10-7.04(m,1H),6.04-5.75(m,1H),4.91(s,2H),4.39-4.27(m,2H),4.13-4.00(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.47-10.42 (m, 1H), 9.12-8.98 (m, 1H), 8.95-8.87 (m, 1H), 8.40-8.31 (m, 1H), 7.98 -7.89(m,1H),7.79-7.70(m,1H),7.68(s,1H),7.64(d,J＝5.7Hz,1H),7.41(d,J＝2.2Hz,1H),7.32- 7.24(m,2H),7.10-7.04(m,1H),6.04-5.75(m,1H),4.91(s,2H),4.39-4.27(m,2H),4.13-4.00(m,2H).
实施例3、N-(3-(2-氯-5-氟苯基)-6-(5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂-9-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物3)的合成
Example 3, N-(3-(2-chloro-5-fluorophenyl)-6-(5,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxynitrogen miscellaneous Synthesis of -9-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 3)
步骤1：2-(4-溴-2-甲氧苯基)-4-(三氟甲基)-咪唑的合成Step 1: Synthesis of 2-(4-bromo-2-methoxyphenyl)-4-(trifluoromethyl)-imidazole
将1,1-二溴-3,3,3-三氟丙酮(12.6g,46.5mmol)溶于水(25.0mL)中，再加入乙酸钠(3.8g,46.5mmol)，然后于100℃下反应1h，然后冷却至室温，再将4-溴-2-甲氧基苯甲醛(5.0g,23.3mmol)溶于甲醇(50.0mL)和氨水(825.4mg,25.0mL)中，逐滴加入到冷却的反应液中，再于100℃下反应6h。LCMS监测原料反应完全，反应结束，反应液加水(50.0mL)稀释，再用乙酸乙酯(50.0mL*3)萃取，有机相用饱和食盐水洗涤，干燥，过滤，滤液浓缩得到中间体2-(4-溴-2-甲氧苯基)-4-(三氟甲基)-咪唑(10.0g，粗品)。Dissolve 1,1-dibromo-3,3,3-trifluoroacetone (12.6g, 46.5mmol) in water (25.0mL), then add sodium acetate (3.8g, 46.5mmol), and then incubate at 100°C React for 1 hour, then cool to room temperature, then dissolve 4-bromo-2-methoxybenzaldehyde (5.0g, 23.3mmol) in methanol (50.0mL) and ammonia (825.4mg, 25.0mL), and add it dropwise In the cooled reaction solution, react at 100°C for 6 hours. LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution is diluted with water (50.0mL), and then extracted with ethyl acetate (50.0mL*3). The organic phase is washed with saturated brine, dried, filtered, and the filtrate is concentrated to obtain intermediate 2- (4-Bromo-2-methoxyphenyl)-4-(trifluoromethyl)-imidazole (10.0 g, crude).
LC-MS(ESI):m/z＝321.0[M+H]+ LC-MS(ESI):m/z＝321.0[M+H] +
步骤2：5-溴-2-(4-(三氟甲基)-咪唑-2-基)苯酚的合成Step 2: Synthesis of 5-bromo-2-(4-(trifluoromethyl)-imidazol-2-yl)phenol
将2-(4-溴-2-甲氧基苯基)-4-(三氟甲基)-咪唑(8.6g,26.8mmol)溶于二氯甲烷(80.0mL)中，于0℃下加入三溴化硼(20.1g,80.4mmol,7.7mL)，然后于室温反应12h。TLC监测原料反应完全，反应结束。反应液用二氯甲烷稀释，再用饱和碳酸氢钠溶液洗涤有机相，然后有机相用饱和食盐水洗涤，干燥，过滤，滤液浓缩，直接硅胶(200-300目)拌样，柱层析纯化(石油醚/乙酸乙酯梯度洗脱)，得到中间体5-溴-2-(4-(三氟甲基)-咪唑-2-基)苯酚(4.0g,48.6％收率)。Dissolve 2-(4-bromo-2-methoxyphenyl)-4-(trifluoromethyl)-imidazole (8.6g, 26.8mmol) in dichloromethane (80.0mL) and add at 0°C Boron tribromide (20.1g, 80.4mmol, 7.7mL), and then reacted at room temperature for 12h. TLC monitors that the raw material reaction is complete and the reaction is completed. The reaction solution was diluted with dichloromethane, and then the organic phase was washed with saturated sodium bicarbonate solution, and then the organic phase was washed with saturated brine, dried, filtered, and the filtrate was concentrated, directly mixed with silica gel (200-300 mesh), and purified by column chromatography. (Petroleum ether/ethyl acetate gradient elution), the intermediate 5-bromo-2-(4-(trifluoromethyl)-imidazol-2-yl)phenol (4.0 g, 48.6% yield) was obtained.
步骤3：2-(4-溴-2-羟基苯基)-咪唑-4-羧酸的合成Step 3: Synthesis of 2-(4-bromo-2-hydroxyphenyl)-imidazole-4-carboxylic acid
将5-溴-2-(4-(三氟甲基)-咪唑-2-基)苯酚(2.0g,6.5mmol)溶于乙醇(45.0mL)和水(5.0mL)中，再加入氢氧化钠(2.6g,65.1mmol)，于90℃下反应2h。LCMS监测原料反应完全，反应结束。反应液用稀盐酸调节pH至酸性，再用乙酸乙酯进行萃取，有机相干燥，浓缩得到中间体2-(4-溴-2-羟基苯基)-咪唑-4-羧酸(2.0g，粗品)。Dissolve 5-bromo-2-(4-(trifluoromethyl)-imidazol-2-yl)phenol (2.0g, 6.5mmol) in ethanol (45.0mL) and water (5.0mL), then add hydroxide Sodium (2.6g, 65.1mmol), react at 90°C for 2h. LCMS monitors that the raw material reaction is complete and the reaction is completed. The pH of the reaction solution was adjusted to acidic with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the intermediate 2-(4-bromo-2-hydroxyphenyl)-imidazole-4-carboxylic acid (2.0g, Crude).
LC-MS(ESI):m/z＝283.0[M+H]+ LC-MS(ESI):m/z＝283.0[M+H] +
步骤4：5-溴-2-(1H-咪唑-2-基)苯酚的合成Step 4: Synthesis of 5-bromo-2-(1H-imidazol-2-yl)phenol
将2-(4-溴-2-羟基苯基)-咪唑-4-羧酸(0.6g,2.1mmol)溶于二苯醚(6.0mL)中，于260℃下反应2h。LCMS监测原料反应完全，反应结束。反应液自然冷却至室温，向反应液中加入二氯甲烷(20.0mL)稀释，然后硅胶(200-300目)拌样，柱层析纯化(石油醚/乙酸乙酯梯度洗脱)，得到中间体5-溴-2-(1H-咪唑-2-基)苯酚(0.2g,39.5％收率)。Dissolve 2-(4-bromo-2-hydroxyphenyl)-imidazole-4-carboxylic acid (0.6g, 2.1mmol) in diphenyl ether (6.0mL), and react at 260°C for 2h. LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution was naturally cooled to room temperature. Dichloromethane (20.0 mL) was added to the reaction solution to dilute it. Then, the sample was mixed with silica gel (200-300 mesh) and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 5-Bromo-2-(1H-imidazol-2-yl)phenol (0.2 g, 39.5% yield).
LC-MS(ESI):m/z＝239.0[M+H]+ LC-MS(ESI):m/z＝239.0[M+H] +
步骤5：9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂的合成Step 5: 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza Synthesis
将5-溴-2-(1H-咪唑-2-基)苯酚(0.1g,418.3μmol)溶于N,N-二甲基甲酰胺(1.0mL)中，再 加入碳酸钾(173.4mg,1.3mmol)和1,2-二溴乙烷(102.2mg,543.8μmol)，然后于100℃下反应12h。LCMS监测原料反应完全，反应结束。向反应液中加入水(10.0mL)稀释，再用乙酸乙酯(10.0mL*3)进行萃取，有机相干燥浓缩，直接硅胶(200-300目)拌样，柱层析纯化(石油醚/乙酸乙酯梯度洗脱)，得到中间体9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂(88.0mg,39.7％收率)。Dissolve 5-bromo-2-(1H-imidazol-2-yl)phenol (0.1g, 418.3μmol) in N,N-dimethylformamide (1.0mL), and then Potassium carbonate (173.4 mg, 1.3 mmol) and 1,2-dibromoethane (102.2 mg, 543.8 μmol) were added, and then reacted at 100°C for 12 h. LCMS monitors that the raw material reaction is complete and the reaction is completed. Add water (10.0 mL) to the reaction solution to dilute, then extract with ethyl acetate (10.0 mL*3), dry and concentrate the organic phase, mix the sample directly with silica gel (200-300 mesh), and purify by column chromatography (petroleum ether/ Gradient elution with ethyl acetate), the intermediate 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza was obtained (88.0 mg, 39.7% yield).
LC-MS(ESI):m/z＝265.0[M+H]+ LC-MS(ESI):m/z＝265.0[M+H] +
步骤6：9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂的合成Step 6: 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo [1,2-d][1,4]oxaza Synthesis
将9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂(35.0mg,132.0μmol)溶于二氧六环(1.0mL)中，再加入乙酸钾(38.9mg,396.1μmol)、双三苯基膦二氯化钯(27.8mg,39.6μmol)、联硼酸频那醇酯(67.1mg,264.1μmol)，然后在氮气条件下，于100℃下反应2h。LCMS监测原料反应完全，反应结束。反应液直接浓缩至干，硅胶(200-300目)拌样，柱层析纯化(石油醚/乙酸乙酯梯度洗脱)，得到中间体9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂(30.0mg,72.8％收率)。9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza (35.0 mg, 132.0 μmol) was dissolved in dioxane (1.0 mL), and then potassium acetate (38.9 mg, 396.1 μmol), bistriphenylphosphine palladium dichloride (27.8 mg, 39.6 μmol), and diboric acid were added. Pinacol ester (67.1 mg, 264.1 μmol) was then reacted at 100°C for 2 h under nitrogen conditions. LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution was directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 9-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza (30.0 mg, 72.8% yield).
LC-MS(ESI):m/z＝313.1[M+H]+ LC-MS(ESI):m/z＝313.1[M+H] +
步骤7：N-(3-(2-氯-5-氟苯基)-6-(5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-2-(4-甲氧基苯基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成Step 7: N-(3-(2-chloro-5-fluorophenyl)-6-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxynitrogen miscellaneous Synthesis of -9-yl)-2-(4-methoxyphenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将N-(6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(30.0mg,45.1μmol)和9-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂(18.3mg,58.6μmol)溶于二氧六环(0.6mL)和水(30.0μL)中，再加入碳酸钠(14.3mg,135.2μmol)，双三苯基膦二氯化钯(7.3mg,9.0μmol)，在氮气条件下于100℃反应2h。LCMS监测原料反应完全，反应结束。反应液直接浓缩至干，硅胶(200-300目)拌样，柱层析纯化(二氯甲烷/甲醇梯度洗脱)，得到中间体N-(3-(2-氯-5-氟苯基)-6-(5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-2-(4-甲氧基苯基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(30.0mg,86.4％收率)。N-(6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3- Fluoro-5-(trifluoromethyl)benzamide (30.0 mg, 45.1 μmol) and 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza (18.3mg, 58.6μmol) was dissolved in dioxane (0.6mL) and water (30.0μL), then sodium carbonate (14.3mg, 135.2μmol), bistriphenylphosphine palladium dichloride (7.3mg, 9.0 μmol), reacted at 100°C for 2 h under nitrogen. LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution was directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (dichloromethane/methanol gradient elution) to obtain the intermediate N-(3-(2-chloro-5-fluorophenyl) )-6-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza -9-yl)-2-(4-methoxyphenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (30.0 mg , 86.4% yield).
LC-MS(ESI):m/z＝771.1[M+H]+ LC-MS(ESI):m/z＝771.1[M+H] +
步骤8：N-(3-(2-氯-5-氟苯基)-6-(5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂-9-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成Step 8: N-(3-(2-chloro-5-fluorophenyl)-6-(5,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxaza Synthesis of -9-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将N-(3-(2-氯-5-氟苯基)-6-(5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)-2-(4-甲氧基苯基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(15.0mg,19.5μmol)溶于三氟甲磺酸(20.0μL)和三氟乙酸(0.2mL)中，于80℃下反应2h。LCMS监测原料反应完全，反应结束。反应液用水(1.0mL)稀释，再用10％碳酸钾溶液调节pH为碱性，再用乙酸乙酯(10.0mL*3)萃取，有机相浓缩至干，残留物经反相高效液相色谱(色谱柱：spherical-C18；流动相：A为水(含有0.1％甲酸)；B为乙腈，B％：50％-90％，40mL/min)制备得到N-(3-(2-氯-5-氟苯基)-6-(5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂-9-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物3，2.0mg,15.8％收率)。N-(3-(2-chloro-5-fluorophenyl)-6-(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine -9-yl)-2-(4-methoxyphenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (15.0 mg , 19.5 μmol) was dissolved in trifluoromethanesulfonic acid (20.0 μL) and trifluoroacetic acid (0.2 mL), and reacted at 80°C for 2 h. LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution was diluted with water (1.0mL), then adjusted to alkaline pH with 10% potassium carbonate solution, and then extracted with ethyl acetate (10.0mL*3). The organic phase was concentrated to dryness, and the residue was subjected to reversed-phase high-performance liquid chromatography. (Column: spherical-C18; mobile phase: A is water (containing 0.1% formic acid); B is acetonitrile, B%: 50%-90%, 40mL/min) N-(3-(2-chloro- 5-Fluorophenyl)-6-(5,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxaza -9-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (Compound 3, 2.0 mg, 15.8% yield).
LC-MS(ESI):m/z＝651.1[M+H]+ LC-MS(ESI):m/z＝651.1[M+H] +
1H NMR(400MHz,CD3OD)δ8.37(d,J＝8.4Hz,1H),8.09(d,J＝1.7Hz,1H),7.82(s,1H),7.72-7.63(m,3H),7.54-7.48(m,1H),7.47-7.42(m,1H),7.31-7.24(m,2H),7.13(d,J＝1.2Hz,1H),7.04-6.96(m,1H),6.67(s,1H),6.24(s,1H),4.59-4.41(m,4H). 1 H NMR (400MHz, CD 3 OD) δ8.37(d,J＝8.4Hz,1H),8.09(d,J＝1.7Hz,1H),7.82(s,1H),7.72-7.63(m,3H ),7.54-7.48(m,1H),7.47-7.42(m,1H),7.31-7.24(m,2H),7.13(d,J＝1.2Hz,1H),7.04-6.96(m,1H), 6.67(s,1H),6.24(s,1H),4.59-4.41(m,4H).
实施例4、N-(3-(2-氯-5-氟苯基)-6-((5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)氨基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物4)的合成
Example 4, N-(3-(2-chloro-5-fluorophenyl)-6-((5,6-dihydrobenzo[f]imidazo[1,2-d][1,4] Oxaza Synthesis of -9-yl)amino)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 4)
步骤1：(5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)氨基甲酸叔丁酯的合成Step 1: (5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza Synthesis of -9-yl)tert-butyl carbamate
将9-溴-5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂(45.0mg,169.7μmol)溶于二氧六环(1.0mL)中，再加入氨基甲酸叔丁酯(29.8mg,254.6μmol)以及碳酸铯(110.6mg,339.5μmol)，2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-异丙基-1,1'-联苯(18.2mg,33.9μmol)，甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(30.8mg,33.9μmol)，然后于氮气条件下，100℃下反应10h。LCMS监测原料反应完全，反应结束，反应液直接浓缩干，硅胶(200-300目)拌样，柱层析纯化(石油醚/乙酸乙酯梯度洗脱)，得到中间体(5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)氨基甲酸叔丁酯(40.0mg,78.2％收率)。9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza (45.0 mg, 169.7 μmol) was dissolved in dioxane (1.0 mL), and then added tert-butyl carbamate (29.8 mg, 254.6 μmol) and cesium carbonate (110.6 mg, 339.5 μmol), 2-(dicyclohexyl) Phosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-1,1'-biphenyl (18.2 mg, 33.9 μmol), methanesulfonic acid (2-bicyclo Hexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2 -base) palladium (II) (30.8 mg, 33.9 μmol), and then reacted at 100°C for 10 h under nitrogen conditions. LCMS monitors the complete reaction of the raw materials. When the reaction is completed, the reaction solution is directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate (5,6-bis Hydrobenzo[f]imidazo[1,2-d][1,4]oxaza -9-yl)tert-butyl carbamate (40.0 mg, 78.2% yield).
LC-MS(ESI):m/z＝246.1[M-56+H]+ LC-MS(ESI):m/z＝246.1[M-56+H] +
步骤2：5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-胺的合成Step 2: 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza -Synthesis of 9-amines
将(5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)氨基甲酸叔丁酯(30.0mg,99.6μmol)溶于二氯甲烷(0.1mL)和三氟乙酸(0.1mL)中，然后于室温反应1h。LCMS监测原料反应完全，反应结束，反应液用二氯甲烷稀释，再用饱和碳酸氢钠溶液洗涤，有机相干燥浓缩，得到中间体5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-胺(35.0mg,粗品)。(5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza -9-yl)tert-butyl carbamate (30.0 mg, 99.6 μmol) was dissolved in dichloromethane (0.1 mL) and trifluoroacetic acid (0.1 mL), and then reacted at room temperature for 1 h. LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution is diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase is dried and concentrated to obtain the intermediate 5,6-dihydrobenzo[f]imidazo[1, 2-d][1,4]oxaza -9-amine (35.0 mg, crude product).
LC-MS(ESI):m/z＝202.1[M+H]+ LC-MS(ESI):m/z＝202.1[M+H] +
步骤3：N-(3-(2-氯-5-氟苯基)-6-((5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)氨基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺的合成Step 3: N-(3-(2-chloro-5-fluorophenyl)-6-((5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxy Aza -9-yl)amino)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide synthesis
将N-(6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-1-氧代异二氢吲哚-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(65.0mg,97.6μmol)，5,6-二氢苯并[f]咪唑并[1，2-d][1,4]氧氮杂-9-胺(19.6mg,97.6μmol)溶于二氧六环(1.0mL)中，再加入甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(17.7mg,19.5μmol)，2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-异丙基-1,1'-联苯(10.5mg,19.5μmol)，碳酸铯(63.6mg,195.2μmol)。LCMS监测原料反应完全，反应结束。反应液直接浓缩干，硅胶(200-300目)拌样，柱层析纯化(二氯甲烷/甲醇梯度洗脱)，得到中间体N-(3-(2-氯-5-氟苯基)-6-((5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)氨基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(45.0mg,58.6％收率)。N-(6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3 -Fluoro-5-(trifluoromethyl)benzamide (65.0 mg, 97.6 μmol), 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine -9-amine (19.6mg, 97.6μmol) was dissolved in dioxane (1.0mL), and then added methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4 ',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (17.7 mg, 19.5 μmol), 2- (Dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-isopropyl-1,1'-biphenyl (10.5 mg, 19.5 μmol), cesium carbonate (63.6 mg,195.2μmol). LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution was directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (dichloromethane/methanol gradient elution) to obtain the intermediate N-(3-(2-chloro-5-fluorophenyl)) -6-((5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza -9-yl)amino)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide ( 45.0 mg, 58.6% yield).
LC-MS(ESI):m/z＝786.2[M+H]+ LC-MS(ESI):m/z＝786.2[M+H] +
步骤4：N-(3-(2-氯-5-氟苯基)-6-((5,6-二氢苯并[f]咪唑[1,2-d][1,4]氧氮杂-9-基)氨基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺合成Step 4: N-(3-(2-chloro-5-fluorophenyl)-6-((5,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxynitrogen miscellaneous Synthesis of -9-yl)amino)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将N-(3-(2-氯-5-氟苯基)-6-((5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)氨基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(25.0mg,31.8μmol)溶于三氟乙酸(0.5mL)和三氟甲磺酸(50μL)中，于80℃下反应1h。LCMS监测原料反应完全， 反应结束。反应液用水(1.0mL)稀释，再用10％碳酸钾溶液调节pH为碱性，再用乙酸乙酯(10.0mL*3)萃取，有机相浓缩至干，残留物经反相高效液相色谱(色谱柱：spherical-C18；流动相：A为水(含有0.1％甲酸)；B为乙腈，B％：50％-90％，40mL/min)制备得到N-(3-(2-氯-5-氟苯基)-6-((5,6-二氢苯并[f]咪唑并[1,2-d][1,4]氧氮杂-9-基)氨基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物4，2.0mg,9.4％收率)。N-(3-(2-chloro-5-fluorophenyl)-6-((5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine -9-yl)amino)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide ( 25.0 mg, 31.8 μmol) was dissolved in trifluoroacetic acid (0.5 mL) and trifluoromethanesulfonic acid (50 μL), and reacted at 80°C for 1 h. LCMS monitors the complete reaction of raw materials. The reaction is over. The reaction solution was diluted with water (1.0mL), then adjusted to alkaline pH with 10% potassium carbonate solution, extracted with ethyl acetate (10.0mL*3), the organic phase was concentrated to dryness, and the residue was subjected to reversed-phase high-performance liquid chromatography. (Column: spherical-C18; mobile phase: A is water (containing 0.1% formic acid); B is acetonitrile, B%: 50%-90%, 40mL/min) N-(3-(2-chloro- 5-Fluorophenyl)-6-((5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxaza -9-yl)amino)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 4, 2.0 mg, 9.4% yield).
LC-MS(ESI):m/z＝666.1[M+H]+ LC-MS(ESI):m/z＝666.1[M+H] +
1H NMR(400MHz,CD3OD)δ8.13(d,J＝8.8Hz,1H),7.71-7.60(m,3H),7.56(d,J＝2.0Hz,1H),7.31(d,J＝2.0Hz,1H),7.29-7.23(m,1H),7.14(d,J＝1.3Hz,1H),7.03(d,J＝1.3Hz,1H),7.01-6.96(m,1H),6.95-6.91(m,1H),6.88(d,J＝2.3Hz,1H),6.67(s,1H),6.13(s,1H),4.49-4.33(m,4H). 1 H NMR (400MHz, CD 3 OD) δ8.13(d,J＝8.8Hz,1H),7.71-7.60(m,3H),7.56(d,J＝2.0Hz,1H),7.31(d,J ＝2.0Hz,1H),7.29-7.23(m,1H),7.14(d,J＝1.3Hz,1H),7.03(d,J＝1.3Hz,1H),7.01-6.96(m,1H),6.95 -6.91(m,1H),6.88(d,J＝2.3Hz,1H),6.67(s,1H),6.13(s,1H),4.49-4.33(m,4H).
实施例5、N-(3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]-2'-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物5)的合成
Example 5, N-(3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo [1,5-d][1,4]oxaza Synthesis of ]-2'-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 5)
步骤1：2-(3,5-二溴-1H-吡唑-1-基)乙酸甲酯的合成Step 1: Synthesis of methyl 2-(3,5-dibromo-1H-pyrazol-1-yl)acetate
将起始原料3,5-二溴吡唑(5g,22.1mmol)溶于无水N,N-二甲基甲酰胺(50mL)，氮气保护下，依次加入碘化钠(330mg,2.2mmol)，碳酸钾(10g,72.6mmol)和氯甲酸甲酯(3.6g,33.2mmol)，25℃反应16h。LCMS显示原料反应完全。加入水(200mL)淬灭，乙酸乙酯(100mL*3)萃取。有机相依次用饱和氯化钠水溶液(100mL)和水(100mL)洗涤。有机相用无水硫酸钠干燥，减压蒸出溶剂，得到中间体2-(3,5-二溴-1H-吡唑-1-基)乙酸甲酯(6.0g,91％收率)。The starting material 3,5-dibromopyrazole (5g, 22.1mmol) was dissolved in anhydrous N,N-dimethylformamide (50mL). Under nitrogen protection, sodium iodide (330mg, 2.2mmol) was added in sequence. , Potassium carbonate (10g, 72.6mmol) and methyl chloroformate (3.6g, 33.2mmol) were reacted at 25°C for 16h. LCMS showed that the starting material was completely reacted. Add water (200mL) to quench, and extract with ethyl acetate (100mL*3). The organic phase was washed successively with saturated aqueous sodium chloride solution (100 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the intermediate methyl 2-(3,5-dibromo-1H-pyrazol-1-yl)acetate (6.0 g, 91% yield).
LC-MS(ESI):m/z＝296.9[M+H]+。LC-MS (ESI): m/z=296.9[M+H] + .
步骤2：2-(3,5-二溴-1H-吡唑-1-基)乙烷-1-醇的合成Step 2: Synthesis of 2-(3,5-dibromo-1H-pyrazol-1-yl)ethane-1-ol
将中间体2-(3,5-二溴-1H-吡唑1-基)乙酸甲酯(3.0g，10.1mmol)溶于无水甲醇(30mL)，降温至0℃，分批加入硼氢化钠(800mg,21.1mmol)，反应体系升温至25℃反应16h。LCMS显示原料反应完全。反应体系中滴加饱和氯化铵水溶液(100mL)淬灭，二氯甲烷(100mL*3)萃取。有机相用无水硫酸钠干燥，减压蒸出溶剂，得到中间体2-(3,5-二溴-1H-吡唑-1-基)乙烷-1-醇(3.0g)。Dissolve the intermediate 2-(3,5-dibromo-1H-pyrazol 1-yl)acetic acid methyl ester (3.0g, 10.1mmol) in anhydrous methanol (30mL), cool to 0°C, and add hydroboration in batches Sodium (800 mg, 21.1 mmol), the reaction system was heated to 25°C and reacted for 16 hours. LCMS showed that the starting material was completely reacted. Saturated ammonium chloride aqueous solution (100 mL) was added dropwise to the reaction system to quench, and dichloromethane (100 mL*3) was extracted. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the intermediate 2-(3,5-dibromo-1H-pyrazol-1-yl)ethane-1-ol (3.0 g).
LC-MS(ESI):m/z＝268.9[M+H]+。 LC-MS (ESI): m/z=268.9[M+H] + .
步骤3：1-(2-(烯丙氧基)乙基)-3,5-二溴-1H-吡唑的合成Step 3: Synthesis of 1-(2-(allyloxy)ethyl)-3,5-dibromo-1H-pyrazole
将化合物2-(3,5-二溴-1H-吡唑-1-基)乙烷-1-醇(3.0g,11.1mmol)溶于无水四氢呋喃(50mL)，降温至0℃，氮气保护下，分批加入氢化钠(800mg，20.0mmol 60％分散在矿物油中)，保温反应30min。向反应体系里缓慢滴加3-溴丙烯(1.5g，12.4mmol)，升温至25℃反应2h。LCMS显示原料反应完全。反应体系中加入饱和氯化铵水溶液(100mL)淬灭，乙酸乙酯(100mL*3)萃取。有机相用无水硫酸钠干燥，减压蒸出溶剂，得到中间体1-(2-(烯丙氧基)乙基)-3,5-二溴-1H-吡唑(2.9g,84％收率)。Dissolve compound 2-(3,5-dibromo-1H-pyrazol-1-yl)ethane-1-ol (3.0g, 11.1mmol) in anhydrous tetrahydrofuran (50mL), cool to 0°C, and protect with nitrogen Then, add sodium hydride (800 mg, 20.0 mmol 60% dispersed in mineral oil) in batches, and keep the reaction for 30 minutes. Slowly add 3-bromopropene (1.5g, 12.4mmol) dropwise into the reaction system, raise the temperature to 25°C and react for 2 hours. LCMS showed that the starting material was completely reacted. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction system to quench, and extracted with ethyl acetate (100 mL*3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the intermediate 1-(2-(allyloxy)ethyl)-3,5-dibromo-1H-pyrazole (2.9g, 84% yield).
LC-MS(ESI):m/z＝308.9[M+H]+。LC-MS (ESI): m/z=308.9[M+H] + .
步骤4：2-溴-4-亚甲基-4,5,7,8-四氢吡唑并[1,5-d][1,4]氧氮杂的合成Step 4: 2-Bromo-4-methylene-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxaza Synthesis
将中间体1-(2-(烯丙氧基)乙基)-3,5-二溴-1H-吡唑(2.9g，9.36mmol)溶于无水N,N-二甲基甲酰胺(50mL)，氮气保护下，依次加入醋酸钯(110mg,0.49mmol)，三苯基磷(260mg,0.99mmol)，醋酸钾(3.0g,30.6mmol)，四丁基溴化铵(3.0g,9.3mmol)，反应体系升温至90℃反应18h。LCMS显示原料反应完全。反应液降温至25℃，加入水(100mL)淬灭，乙酸乙酯(100mL)萃取。有机相用水(100mL*2)洗涤，无水硫酸钠干燥，减压蒸出溶剂，残留物用硅胶柱层析(石油醚/乙酸乙酯梯度洗脱)纯化，得到中间体2-溴-4-亚甲基-4,5,7,8-四氢吡唑并[1,5-d][1,4]氧氮杂(1.2g,56％收率)。The intermediate 1-(2-(allyloxy)ethyl)-3,5-dibromo-1H-pyrazole (2.9g, 9.36mmol) was dissolved in anhydrous N,N-dimethylformamide ( 50mL), under nitrogen protection, add palladium acetate (110mg, 0.49mmol), triphenylphosphorus (260mg, 0.99mmol), potassium acetate (3.0g, 30.6mmol), tetrabutylammonium bromide (3.0g, 9.3 mmol), the reaction system was heated to 90°C and reacted for 18 hours. LCMS showed that the starting material was completely reacted. The reaction solution was cooled to 25°C, water (100 mL) was added to quench, and extracted with ethyl acetate (100 mL). The organic phase was washed with water (100mL*2), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 2-bromo-4. -Methylene-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxaza (1.2g, 56% yield).
LC-MS(ESI):m/z＝229.0[M+H]+。LC-MS (ESI): m/z=229.0[M+H] + .
步骤5：2'-溴-7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]Step 5: 2'-Bromo-7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-d][1,4]oxaza ]
将三甲基碘化亚砜(1.4g,6.4mmol)溶于无水二甲基亚砜(10mL)，氮气保护下，加入叔丁醇钾(750mg,6.7mmol)，25℃反应30min。滴加化合物2-溴-4-亚甲基-4,5,7,8-四氢吡唑并[1,5-d][1,4]氧氮杂(500mg,2.2mmol)的无水二甲基亚砜(5.0mL)溶液，反应体系升温至50℃反应16h。LCMS显示原料反应完全。反应体系降温至25℃，加入水(100mL)淬灭，乙酸乙酯(100mL)萃取，有机相依次用饱和氯化钠水溶液(100mL)和水(100mL)洗涤。有机相用无水硫酸钠干燥，减压蒸出溶剂，残留物用硅胶柱层析(石油醚/乙酸乙酯梯度洗脱)纯化，得到中间体2'-溴-7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂](50mg,9.3％收率)。Dissolve trimethylsulfoxide iodide (1.4g, 6.4mmol) in anhydrous dimethylsulfoxide (10mL), add potassium tert-butoxide (750mg, 6.7mmol) under nitrogen protection, and react at 25°C for 30 minutes. Add dropwise the compound 2-bromo-4-methylene-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]oxaza (500mg, 2.2mmol) solution in anhydrous dimethyl sulfoxide (5.0mL), the reaction system was heated to 50°C and reacted for 16h. LCMS showed that the starting material was completely reacted. The reaction system was cooled to 25°C, quenched by adding water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated aqueous sodium chloride solution (100 mL) and water (100 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 2'-bromo-7',8'-bis. Hydrogen-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-d][1,4]oxaza ] (50 mg, 9.3% yield).
步骤6：4-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)异吲哚啉-1-酮的合成Step 6: 4-Amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1, Synthesis of 3,2-dioxaborolan-2-yl)isoindolin-1-one
将4-氨基-6-溴-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)异吲哚啉-1-酮(500mg,1.05mmol)溶于1,4-二氧六环(5.0mL)中，再依次加入醋酸钾(309mg,3.15mmol)，联硼酸频那醇酯(400mg,1.58mmol)，1,1'-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(86mg,105μmol)，在氮气条件下于100℃下反应6h，LCMS监测原料反应完全，反应结束。反应液直接浓缩至干，硅胶(200-300目)拌样，柱层析纯化(石油醚/乙酸乙酯梯度洗脱)，得到中间体4-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)异吲哚啉-1-酮(430mg,78.3％收率)。Dissolve 4-amino-6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)isoindolin-1-one (500 mg, 1.05 mmol) in To 1,4-dioxane (5.0 mL), potassium acetate (309 mg, 3.15 mmol), pinacol diborate (400 mg, 1.58 mmol), and 1,1'-bis(diphenylphosphine) were added in sequence. ) Ferrocene]palladium (II) dichloride dichloromethane complex (86 mg, 105 μmol) was reacted at 100°C for 6 hours under nitrogen conditions. LCMS monitored that the raw material reaction was complete and the reaction was completed. The reaction solution was directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 4-amino-3-(2-chloro-5-fluoro). Phenyl)-2-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Isoindolin-1-one (430 mg, 78.3% yield).
LC-MS(ESI):m/z＝523.2[M+H]+ LC-MS(ESI):m/z＝523.2[M+H] +
步骤7：4-氨基-3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]-2'-基)-2-(4-甲氧基苄基)异吲哚啉-1-酮的合成Step 7: 4-Amino-3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo [1,5-d][1,4]oxaza Synthesis of ]-2'-yl)-2-(4-methoxybenzyl)isoindolin-1-one
将4-氨基-3-(2-氯-5-氟苯基)-2-(4-甲氧基苄基)-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂硼烷-2-基)异吲哚啉-1-酮(105mg,200μmol)，2'-溴-7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂环庚烷](105mg,430μmol)，磷酸钾(183mg,861μmol)，[1,1'-双(二叔丁基膦)二茂铁]二氯化钯(II)(19mg,29μmol)溶于1,4-二氧六环(1.5mL)和水(0.3mL)混合溶液中，在氮气条件下于100℃下反应12h，LCMS监测原料反应完全，反应结束。反应液直接浓缩至干，硅胶(200-300目)拌样，柱层析纯化(石油醚/乙酸乙酯梯度洗脱)，得到中间体4-氨基-3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]-2'-基)-2-(4-甲氧基苄基)异吲哚啉-1-酮(100mg,62.4％收率)。4-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3, 2-dioxaboraborane-2-yl)isoindolin-1-one (105 mg, 200 μmol), 2'-bromo-7',8'-dihydro-5'H-spiro[cyclopropane- 1,4'-pyrazolo[1,5-d][1,4]oxazepine] (105 mg, 430 μmol), potassium phosphate (183 mg, 861 μmol), [1,1'-bis(di Tert-butylphosphine) ferrocene] palladium (II) dichloride (19 mg, 29 μmol) was dissolved in a mixed solution of 1,4-dioxane (1.5 mL) and water (0.3 mL), and the solution was dissolved under nitrogen. The reaction was carried out at 100°C for 12 hours. LCMS monitored that the raw materials reacted completely and the reaction was completed. The reaction solution was directly concentrated to dryness, mixed with silica gel (200-300 mesh), and purified by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the intermediate 4-amino-3-(2-chloro-5-fluoro). Phenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-d][1,4]oxaza ]-2'-yl)-2-(4-methoxybenzyl)isoindolin-1-one (100 mg, 62.4% yield).
步骤8：N-(3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂 ]-2'-基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺Step 8: N-(3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[ 1,5-d][1,4]oxaza ]-2'-yl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将4-氨基-3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]-2'-基)-2-(4-甲氧基苄基)异吲哚啉-1-酮(100mg,179μmol)溶于无水吡啶(1.0mL)中；然后0℃下,向反应液中缓慢加3-氟-5-(三氟甲基)苯甲酰氯(36μL,233μmol)，滴加完毕后升至室温反应2h。LCMS监测原料反应完全，反应结束。反应液用碳酸氢钠饱和溶液调节pH＝7-8，再用乙酸乙酯进行萃取，有机相干燥，过滤，滤液浓缩得到中间体N-(3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]-2'-基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(190mg，粗品)。4-Amino-3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1 ,5-d][1,4]oxaza ]-2'-yl)-2-(4-methoxybenzyl)isoindolin-1-one (100 mg, 179 μmol) was dissolved in anhydrous pyridine (1.0 mL); then, add to the reaction solution at 0°C Slowly add 3-fluoro-5-(trifluoromethyl)benzoyl chloride (36 μL, 233 μmol) into the solution. After the dropwise addition is completed, the solution is raised to room temperature and allowed to react for 2 hours. LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution was adjusted to pH=7-8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated to obtain the intermediate N-(3-(2-chloro-5-fluorophenyl)) -6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-d][1,4]oxaza ]-2'-yl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide ( 190 mg, crude product).
LC-MS(ESI):m/z＝749.2[M+H]+ LC-MS(ESI):m/z＝749.2[M+H] +
步骤9：N-(3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]-2'-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺Step 9: N-(3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[ 1,5-d][1,4]oxaza ]-2'-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide
将N-(3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]-2'-基)-2-(4-甲氧基苄基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(100.0mg,133μmol)溶于三氟甲磺酸(100.0μL)和三氟乙酸(1mL)中，于80℃下反应2h。LCMS监测原料反应完全，反应结束。反应液用水(1.0mL)稀释，再用10％碳酸钾溶液调节pH为碱性，再用乙酸乙酯(10.0mL*3)萃取，有机相浓缩至干，残留物经反相高效液相色谱(色谱柱：spherical-C18；流动相：A为水(含有0.1％甲酸)；B为乙腈，B％：50％-90％，40mL/min)制备得到N-(3-(2-氯-5-氟苯基)-6-(7',8'-二氢-5'H-螺[环丙烷-1,4'-吡唑并[1,5-d][1,4]氧氮杂]-2'-基)-1-氧代异吲哚啉-4-基)-3-氟-5-(三氟甲基)苯甲酰胺(化合物5，10.0mg,11.9％收率)。N-(3-(2-chloro-5-fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1, 5-d][1,4]oxaza ]-2'-yl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide ( 100.0 mg, 133 μmol) was dissolved in trifluoromethanesulfonic acid (100.0 μL) and trifluoroacetic acid (1 mL), and reacted at 80°C for 2 h. LCMS monitors that the raw material reaction is complete and the reaction is completed. The reaction solution was diluted with water (1.0mL), then adjusted to alkaline pH with 10% potassium carbonate solution, extracted with ethyl acetate (10.0mL*3), the organic phase was concentrated to dryness, and the residue was subjected to reversed-phase high-performance liquid chromatography. (Column: spherical-C18; mobile phase: A is water (containing 0.1% formic acid); B is acetonitrile, B%: 50%-90%, 40mL/min) N-(3-(2-chloro- 5-Fluorophenyl)-6-(7',8'-dihydro-5'H-spiro[cyclopropane-1,4'-pyrazolo[1,5-d][1,4]oxynitrogen miscellaneous ]-2'-yl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (Compound 5, 10.0 mg, 11.9% yield).
LC-MS(ESI):m/z＝629.1[M+H]+ LC-MS(ESI):m/z＝629.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.00(s,1H),7.96(d,J＝8.5Hz,1H),7.91(s,1H),7.77(d,J＝9.1Hz,1H),7.70(s,1H),7.32(dd,J＝8.9,5.1Hz,1H),7.14-7.04(m,1H),6.73(s,1H),5.99(s,1H),4.54-4.40(m,2H),3.95-3.84(m,2H),3.57(s,2H),1.09-1.01(m,1H),1.00-0.94(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.17 (s, 1H), 8.00 (s, 1H), 7.96 (d, J = 8.5Hz, 1H), 7.91 (s, 1H), 7.77 (d, J＝9.1Hz,1H),7.70(s,1H),7.32(dd,J＝8.9,5.1Hz,1H),7.14-7.04(m,1H),6.73(s,1H),5.99(s,1H ),4.54-4.40(m,2H),3.95-3.84(m,2H),3.57(s,2H),1.09-1.01(m,1H),1.00-0.94(m,2H).
19F NMR(376MHz,DMSO-d6)δ-61.34,-109.65. 19 F NMR (376MHz, DMSO-d6) δ-61.34,-109.65.
生物学活性及相关性质测试例Biological activity and related property test examples
以下测试例中的化合物均根据本公开上述实施例的方法制备获得，测试例化合物根据上文实施例制得的产物具体形式确定。The compounds in the following test examples were all prepared according to the methods of the above examples of the present disclosure. The compounds in the test examples were determined based on the specific forms of the products prepared in the above examples.
测试例1：PIK3CA酶活性实验Test Example 1: PIK3CA enzyme activity experiment
实验原理：Experimental principle:
PIK3CA催化丝氨酸底物(PI(4,5)P2和磷脂酰丝氨酸(PS))反应，消耗ATP并产生ADP，随后加入ADP-GloTM试剂以终止激酶反应并消耗完剩余的ATP，加入的激酶检测试剂将ADP转化成ATP，然后ATP再被荧光素酶转化成光。发光信号与激酶活性正相关，从而反映PIK3CA的酶活性。PIK3CA catalyzes the reaction of serine substrates (PI(4,5)P2 and phosphatidylserine (PS)), consuming ATP and producing ADP. ADP-Glo TM reagent is then added to terminate the kinase reaction and consume the remaining ATP. The added kinase The detection reagent converts ADP into ATP, which is then converted into light by luciferase. The luminescence signal is positively correlated with the kinase activity, thus reflecting the enzymatic activity of PIK3CA.
实验仪器：laboratory apparatus:
Perkin Elmer公司Envision酶标仪Perkin Elmer Envision microplate reader
Eppendorf公司5810R离心机Eppendorf 5810R centrifuge
Beckman公司Echo650纳升转移***Beckman Echo650 Nano Transfer System
实验材料：

Experimental Materials:

实验方法：experimental method:
化合物用Echo650进行梯度稀释，并以50nL/孔转移至384孔白板内，化合物起始浓度为1000nM，3倍梯度稀释，8个浓度点。每孔加入2μL的酶(其中PIK3CA[E545K]/PIK3R1、PIK3CA[H1047R]/PIK3R1、PIK3CA[E542K]/PIK3R1为5ng/孔，PIK3CA/PIK3R1为25ng/孔)，1000rpm离心30秒，在冰上孵育30分钟。随后每孔加入含有ATP/PI(4,5)P2:PS的反应混合物(终浓度分别为100μM、25μM的PI(4,5)P2和200μM的PS)，1000rpm离心30秒，室温孵育60分钟。每孔加入5μL ADP-Glo，1000rpm离心30秒，室温孵育40分钟。每孔加入10μL ADP-Glo检测底物，1000rpm离心30秒，室温孵育30分钟。最后使用酶标仪Envision读取信号值(Lum)，计算抑制率：
抑制率＝(100-100*(Lummax-Lum化合物)/(Lummax-Lummin))％The compound was gradient diluted with Echo650 and transferred to a 384-well white plate at 50 nL/well. The starting concentration of the compound was 1000 nM, 3-fold gradient dilution, and 8 concentration points. Add 2 μL of enzyme to each well (of which PIK3CA[E545K]/PIK3R1, PIK3CA[H1047R]/PIK3R1, PIK3CA[E542K]/PIK3R1 is 5ng/well, PIK3CA/PIK3R1 is 25ng/well), centrifuge at 1000rpm for 30 seconds, and place on ice Incubate for 30 minutes. Then, a reaction mixture containing ATP/PI(4,5)P2:PS was added to each well (final concentrations were 100 μM, 25 μM PI(4,5)P2, and 200 μM PS respectively), centrifuged at 1000 rpm for 30 seconds, and incubated at room temperature for 60 minutes. . Add 5 μL ADP-Glo to each well, centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 40 minutes. Add 10 μL ADP-Glo detection substrate to each well, centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 30 minutes. Finally, use the microplate reader Envision to read the signal value (Lum) and calculate the inhibition rate:
Inhibition rate = (100-100*(Lum max -Lum compound )/(Lum max -Lum min ))%
其中，Lummax指含有酶、反应混合物和DMSO的孔的信号值，Lum化合物指含有化合物、酶和反应混合物的孔的信号值。ODmin指含反应混合物和DMSO的孔的信号值。Among them, Lum max refers to the signal value of the well containing enzyme, reaction mixture and DMSO, and Lum compound refers to the signal value of the well containing compound, enzyme and reaction mixture. OD min refers to the signal value of the well containing the reaction mixture and DMSO.
然后，使用XLfit软件拟合得到化合物的IC50值。Then, use XLfit software to fit and obtain the IC 50 value of the compound.
本公开化合物对PIK3CA酶活性的抑制作用通过以上的试验进行测定，测得的IC50值见下表1。The inhibitory effect of the disclosed compounds on PIK3CA enzyme activity was measured through the above test, and the measured IC 50 values are shown in Table 1 below.
表1
Table 1
测试例2：MCF7/T47D/SKBR3细胞增殖实验Test Example 2: MCF7/T47D/SKBR3 cell proliferation experiment
实验原理：Experimental principle:
细胞增殖实验是通过检测活细胞的ATP来确定存活细胞数的直接匀相测定法。细胞与化合物孵育一定时间后，加入检测试剂CellTilter-Glo。检测试剂中的荧光素酶会和活细胞释放的ATP反应，产生光信号，从而反映化合物对细胞增殖的抑制能力。The cell proliferation assay is a direct homogeneous assay that determines the number of viable cells by detecting the ATP of viable cells. After the cells are incubated with the compound for a certain period of time, the detection reagent CellTilter-Glo is added. The luciferase in the detection reagent will react with ATP released by living cells to generate a light signal, thereby reflecting the compound's ability to inhibit cell proliferation.
实验仪器：laboratory apparatus:
Perkin Elmer公司Envision酶标仪Perkin Elmer Envision microplate reader
Eppendorf公司5810R离心机Eppendorf 5810R centrifuge
ESCO CCL-170B-8二氧化碳培养箱ESCO CCL-170B-8 carbon dioxide incubator
实验材料：

Experimental Materials:

实验方法：experimental method:
T47D购自ATCC，使用含有10％FBS的RPMI 1640培养基进行细胞培养。SKBR3细胞购自康源博创，使用含有10％FBS的McCoy’s 5A培养基进行细胞培养。MCF7购自ATCC，使用含有10μg/mL重组人胰岛素以及10％FBS的EMEM培养基进行细胞培养。分别将MCF7/T47D/SKBR3种于96孔透明底白板中，每个细胞种两块板，细胞数分别为2000/2500/3000个细胞/孔，放置在37℃，5％CO2培养箱中过夜培养。分别取出第一块96孔透明底白板，每孔加入50μL CellTiter-Glo试剂，震荡混匀。在37℃，5％CO2培养箱中孵育10分钟，使用Envision酶标仪读取信号值，作为第0天的读值。将浓度为10mM的化合物母液在96孔圆底板中用DMSO进行3倍稀释，再分别用对应的细胞培养基进一步稀释至10倍终浓度。取出第二块96孔透明底白板，加入10μL 10倍终浓度的化合物，在37℃，5％CO2培养箱中培养约144小时。最终反应体系为100μL，化合物最高浓度点为10μM或1μM。孵育结束后，每孔加入50μL CellTiter-Glo试剂，震荡混匀。在培养箱中孵育10分钟，然后使用Envision酶标仪读取光信号值(Lum)，并结合第0天的光信号值(Lumday0)计算抑制率：
抑制率＝(100*((Lummax-Lumday0)-(Lum化合物-Lumday0))/((Lummax-Lumday0)-(Lummin-
Lumday0)))％T47D was purchased from ATCC and cultured using RPMI 1640 medium containing 10% FBS. SKBR3 cells were purchased from Kangyuan Bochuang and cultured using McCoy's 5A medium containing 10% FBS. MCF7 was purchased from ATCC and cultured in EMEM medium containing 10 μg/mL recombinant human insulin and 10% FBS. MCF7/T47D/SKBR3 were seeded in 96-well transparent bottom white plates. Each cell was seeded on two plates. The number of cells was 2000/2500/3000 cells/well respectively. Place it in a 37°C, 5% CO 2 incubator. Incubate overnight. Take out the first 96-well transparent bottom white plate, add 50 μL CellTiter-Glo reagent to each well, and shake to mix. Incubate for 10 minutes in a 37°C, 5% CO2 incubator, and read the signal value using an Envision microplate reader as the reading on day 0. The compound stock solution with a concentration of 10 mM was diluted 3-fold with DMSO in a 96-well round-bottom plate, and then further diluted with the corresponding cell culture medium to a final concentration of 10-fold. Take out the second 96-well transparent bottom white plate, add 10 μL of the compound at 10 times the final concentration, and culture it in a 37°C, 5% CO2 incubator for about 144 hours. The final reaction system is 100 μL, and the highest concentration point of the compound is 10 μM or 1 μM. After the incubation, add 50 μL CellTiter-Glo reagent to each well and shake to mix. Incubate in the incubator for 10 minutes, then use an Envision microplate reader to read the light signal value (Lum), and combine it with the light signal value on day 0 (Lum day0 ) to calculate the inhibition rate:
Inhibition rate=(100*((Lum max -Lum day0 )-(Lum compound -Lum day0 ))/((Lum max -Lum day0 )-(Lum min -
Lum day0 )))%
其中，Lummax指含有细胞和DMSO孔的光信号值，Lumday0指第0天的光信号值，Lum化 合物指含有化合物和细胞的孔的光信号值，Lummin指含有培养基和DMSO的孔的光信号值。Among them, Lum max refers to the light signal value of the well containing cells and DMSO, Lum day0 refers to the light signal value on day 0, Lum compound refers to the light signal value of the well containing compound and cells, and Lum min refers to the light signal value of the well containing culture medium and DMSO. The optical signal value of the hole.
然后，使用XLfit软件拟合得到化合物的半数生长抑制浓度(GI50)。Then, XLfit software was used to fit to obtain the half growth inhibitory concentration (GI 50 ) of the compound.
本公开化合物对肿瘤细胞的生长抑制通过以上的试验进行测定，测得的GI50值如下表2所示。The growth inhibition of tumor cells by the compounds of the present disclosure was measured through the above test, and the measured GI 50 value is shown in Table 2 below.
表2
Table 2
测试例3：细胞内pAKT磷酸化抑制活性实验Test Example 3: Intracellular pAKT phosphorylation inhibitory activity experiment
实验原理简介：靶细胞与化合物共同孵育后，细胞中的磷酸化蛋白被PerkinElmer公司AlphaLISA检测试剂盒中特异性抗体标记的受体珠和链霉亲和素标记的供体珠所捕获。在磷酸化蛋白存在的情况下，供体珠和受体珠相互靠近产生信号，信号值与体系中的磷酸化蛋白含量成正比。Introduction to the experimental principle: After the target cells are incubated with the compound, the phosphorylated proteins in the cells are captured by the specific antibody-labeled acceptor beads and streptavidin-labeled donor beads in the AlphaLISA detection kit of PerkinElmer Company. In the presence of phosphorylated proteins, donor beads and acceptor beads are close to each other to generate signals, and the signal value is proportional to the phosphorylated protein content in the system.
实验仪器：Envision酶标仪(Perkin Elmer公司)，5810R离心机(Eppendorf公司)，BSD-YX3400恒温摇床(Boxun公司)，HeracellVIOS 250i培养箱(Thermo公司)。Experimental instruments: Envision microplate reader (Perkin Elmer Company), 5810R centrifuge (Eppendorf Company), BSD-YX3400 constant temperature shaker (Boxun Company), HeracellVIOS 250i incubator (Thermo Company).
实验材料：
Experimental Materials:
实验方法：T47D购自ATCC，使用含有10％FBS的RPMI 1640培养基进行细胞培养。SKBR3细胞购自康源博创，使用含有10％FBS的McCoy’s 5A培养基进行细胞培养。用相应的培养基调整细胞密度至4*105cells/mL，每孔100μL加入96孔板中，在37℃、5％CO2培养箱中培养过夜。将待测化合物加入细胞培养板中，37℃，5％CO2孵育2h，化合物的终浓度为10μM起始，3倍稀释。去除细胞上清，每孔加入50μL细胞裂解液(即胰酶-EDTA溶液(0.25％)，含酚红)，在摇床上室温振荡10min。按照检测试剂盒说明书配制受体珠混合物。转移10μL细胞裂解物或裂解液至384孔板中，加入5μL前述配制的受体珠混合物，1000rpm离心30s，振荡1-2min，室温避光孵育1h。再加入5μL供体珠混合物，离心振荡1-2min，室温避光孵育过夜。将384孔板于1000rpm下离心30s，用Envision酶标仪读取发光信号值(Ex:680nm,Em:615nm)，并使用XLfit软件拟合计算抑制率和半数抑制浓度(IC50)。Experimental methods: T47D was purchased from ATCC and cultured using RPMI 1640 medium containing 10% FBS. SKBR3 cells were purchased from Kangyuan Bochuang and cultured using McCoy's 5A medium containing 10% FBS. Use the corresponding culture medium to adjust the cell density to 4*10 5 cells/mL, add 100 μL per well to a 96-well plate, and culture overnight in a 37°C, 5% CO 2 incubator. Add the compound to be tested to the cell culture plate and incubate for 2 hours at 37°C and 5% CO2 . The final concentration of the compound is 10 μM starting from 3-fold dilution. Remove the cell supernatant, add 50 μL of cell lysis solution (i.e., trypsin-EDTA solution (0.25%), containing phenol red) to each well, and shake on a shaker at room temperature for 10 min. Prepare the receptor bead mixture according to the instructions of the detection kit. Transfer 10 μL of cell lysate or lysate to a 384-well plate, add 5 μL of the receptor bead mixture prepared above, centrifuge at 1000 rpm for 30 s, shake for 1-2 min, and incubate at room temperature in the dark for 1 h. Then add 5 μL of donor bead mixture, centrifuge and shake for 1-2 min, and incubate overnight at room temperature in the dark. Centrifuge the 384-well plate at 1000 rpm for 30 s, read the luminescence signal value (Ex: 680nm, Em: 615nm) with an Envision microplate reader, and use XLfit software to fit and calculate the inhibition rate and half inhibitory concentration (IC 50 ).
数据分析：data analysis:
根据以下公式计算抑制率：
抑制率＝(100-100*(Signalmax-Signal化合物)/(Signalmax-Signalmin))％Calculate the inhibition rate according to the following formula:
Inhibition rate = (100-100*(Signal max -Signal compound )/(Signal max -Signal min ))%
其中，Signalmax指含有0.1％DMSO的细胞裂解物、受体珠及供体珠混合物孔的AlphaLISA信号值，Signal化合物指含有化合物的细胞裂解物、受体珠及供体珠混合物孔的AlphaLISA信号值，Signalmin指含有裂解液、受体珠及供体珠混合物孔的AlphaLISA信号值。Among them, Signal max refers to the AlphaLISA signal value of the cell lysate, acceptor beads and donor bead mixture wells containing 0.1% DMSO, and Signal compound refers to the AlphaLISA signal of the cell lysate, acceptor beads and donor bead mixture wells containing the compound. Value, Signal min refers to the AlphaLISA signal value of the well containing the mixture of lysate, acceptor beads and donor beads.
本公开化合物对细胞内pAKT磷酸化的抑制活性通过以上的试验进行测定，测得的IC50值如下表3所示。The inhibitory activity of the compounds of the present disclosure on intracellular pAKT phosphorylation was measured through the above test, and the measured IC 50 values are shown in Table 3 below.
表3化合物对pAKT信号抑制的IC50
Table 3 IC 50 of compounds inhibiting pAKT signal

Claims (28)

  1. 式(I)化合物或其药学上可接受的盐，
    A compound of formula (I) or a pharmaceutically acceptable salt thereof,
    其中，in,
    Cy选自 Cy is selected from
    环A、环B、环C均为单环，独立地选自苯环、5-6元杂芳环、4-8元饱和或部分饱和的杂环和C4-C6饱和或部分饱和的碳环，所述苯环、5-6元杂芳环、4-8元饱和或部分饱和的杂环和C4-C6饱和或部分饱和的碳环任选被RX取代；Ring A, Ring B, and Ring C are all single rings, independently selected from benzene rings, 5-6 membered heteroaromatic rings, 4-8 membered saturated or partially saturated heterocyclic rings, and C 4 -C 6 saturated or partially saturated heterocyclic rings. Carbocyclic ring, the benzene ring, 5-6 membered heteroaromatic ring, 4-8 membered saturated or partially saturated heterocyclic ring and C 4 -C 6 saturated or partially saturated carbocyclic ring are optionally substituted by R X ;
    Y1、Y2独立地选自N和CH，所述CH任选被RY取代；Y 1 and Y 2 are independently selected from N and CH, and the CH is optionally substituted by R Y ;
    Y5、Y6独立地选自N和C；Y 5 and Y 6 are independently selected from N and C;
    Y3、Y4独立地选自O、NH和CH2，所述NH和CH2任选被RY取代；Y 3 and Y 4 are independently selected from O, NH and CH 2 , and the NH and CH 2 are optionally substituted by R Y ;
    m、n、p、q、t’独立地选自0、1、2、3和4，且m和n不同时为0，p和q不同时为0；m, n, p, q, t' are independently selected from 0, 1, 2, 3 and 4, and m and n are not 0 at the same time, and p and q are not 0 at the same time;
    R1、R2独立地选自卤素、CN、NO2、-OR、-SF5、-SR、-NR2、-S(O)2R、-S(O)2NR2、-S(O)2F、-S(O)R、-S(O)NR2、-S(O)(NR)R、-S(O)(NCN)R、-S(NCN)R、-C(O)R、-C(O)OR、-C(O)NR2、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2、-N(R)C(NR)NR2、-N(R)S(O)2NR2、-N(R)S(O)2R、-P(O)R2、-P(O)(R)OR、-B(OR)2、C1-C6烷基、苯基、萘基、5-10元杂芳基、C3-C12环烷基、C3-C12环烯基和3-12元杂环基，所述C1-C6烷基、苯基、萘基、5-10元杂芳基、C3-C12环烷基、C3-C12环烯基和3-12元杂环基任选被RZ取代；R 1 and R 2 are independently selected from halogen, CN, NO 2 , -OR, -SF 5 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S( O) 2 F, -S(O)R, -S(O)NR 2 , -S(O)(NR)R, -S(O)(NCN)R, -S(NCN)R, -C( O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R) C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R , -P(O)R 2 , -P(O)(R)OR, -B(OR) 2 , C 1 -C 6 alkyl, benzene base, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl and 3-12 membered heterocyclyl, the C 1 -C 6 alkyl, benzene Base, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl and 3-12 membered heterocyclyl are optionally substituted by R Z ;
    L选自键和C1-C4亚烷基，所述C1-C4亚烷基中的1-2个亚甲基单元任选独立地被-CH(R)-、-C(R)2-、C3-C6亚环烷基、3-6元亚杂环基、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)C(NOR)-、-N(R)C(NCN)-、-N(R)S(O)2-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2-替换；RX、RY、RZ独立地选自氘、卤素、氧代、-CN、-NO2、-OR、-SF5、-SR、-NR2、-S(O)2R、-S(O)2NR2、-S(O)R、-S(O)NR2、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2、-N(R)C(NR)NR2、-N(R)S(O)2NR2、-N(R)S(O)2R、-P(O)R2、-P(O)(R)OR、-B(OR)2、C1-C6烷基、苯基、C3-C6环烷基、3-7元杂环基和5-6元杂芳基，所述C1-C6烷基、苯基、C3-C6环烷基、3-7元杂环基和5-6元杂芳基任选被R’取代；L is selected from the group consisting of a bond and a C 1 -C 4 alkylene group, in which 1-2 methylene units of the C 1 -C 4 alkylene group are optionally independently replaced by -CH(R)-, -C(R ) 2 -, C 3 -C 6 cycloalkylene, 3-6 membered heterocyclylene, -N(R)-, -N(R)C(O)-, -N(R)C(NR) -, -N(R)C(NOR)-, -N(R)C(NCN)-, -N(R)S(O) 2 -, -O-, -C(O)-, -OC( O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 -replacement; RX , RY , RZ are independently selected from deuterium, halogen, oxo , -CN, -NO 2 , -OR, -SF 5 , -SR, -NR 2 , -S(O) 2 R , -S(O) 2 NR 2 , -S(O)R, -S(O )NR 2 , -S(O)(NR)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC( O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R )C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R , -P(O)R 2 , -P(O)(R)OR , -B(OR) 2 , C 1 -C 6 alkyl, phenyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, the C 1 -C 6 alkyl, phenyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted by R';
    R独立地选自H、氘、C1-C6烷基、苯基、4-7元杂环基和5-6元杂芳基，或连接同一个N的两个R及其连接的N共同形成4-7元杂环基，所述C1-C6烷基、苯基、4-7元杂环基和5-6元杂芳基任选被R’取代；R is independently selected from H, deuterium, C 1 -C 6 alkyl, phenyl, 4-7 membered heterocyclyl and 5-6 membered heteroaryl, or two R connected to the same N and the N to which they are connected. Together, they form a 4-7-membered heterocyclyl group, and the C 1 -C 6 alkyl group, phenyl group, 4-7-membered heterocyclyl group and 5-6-membered heteroaryl group are optionally substituted by R';
    R’独立地选自氧代、氘、卤素、氰基、硝基、氨基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、苯基、3-7元杂环基和5-6元杂芳基。R' is independently selected from oxo, deuterium, halogen, cyano, nitro, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, phenyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl.
  2. 权利要求1所述的式(I)化合物或其药学上可接受的盐，其中，环A、环B、环C均为单环，独立地选自苯环、5-6元杂芳环和5-7元饱和或部分饱和的杂环，所述苯环、5-6元杂 芳环和5-7元饱和或部分饱和的杂环任选被RX取代。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A, ring B and ring C are all single rings, independently selected from benzene rings, 5-6 membered heteroaromatic rings and 5-7 membered saturated or partially saturated heterocyclic ring, the benzene ring, 5-6 membered heterocyclic ring Aromatic rings and 5-7 membered saturated or partially saturated heterocyclic rings are optionally substituted by R
  3. 权利要求1或2所述的式(I)化合物或其药学上可接受的盐，其中，选自X1、X2独立地选自C、CH和N，所述CH任选地被RX取代，t选自0、1、2、3、4、5和6。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, Selected from X 1 , X 2 are independently selected from C, CH and N, the CH is optionally substituted by R
  4. 权利要求3所述的式(I)化合物或其药学上可接受的盐，其中，t选自0、1、2和3。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein t is selected from 0, 1, 2 and 3.
  5. 权利要求3所述的式(I)化合物或其药学上可接受的盐，其中，选自 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein, Selected from
  6. 权利要求1或2所述的式(I)化合物或其药学上可接受的盐，其中，选自 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, Selected from
  7. 权利要求1-6任一项所述的式(I)化合物或其药学上可接受的盐，其中，Y1、Y5为N，Y6为C，Y2为CH，所述CH任选被RY取代；或Y2、Y5为N，Y6为C，Y1为CH，所述CH任选被RY取代；或Y2、Y6为N，Y5为C，Y1为CH，所述CH任选被RY取代。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Y 1 and Y 5 are N, Y 6 is C, Y 2 is CH, and the CH is optional Substituted by R Y ; or Y 2 and Y 5 are N, Y 6 is C, Y 1 is CH, and the CH is optionally substituted by R Y ; or Y 2 and Y 6 are N, Y 5 is C, Y 1 is CH, which CH is optionally substituted by R Y.
  8. 权利要求1-7任一项所述的式(I)化合物或其药学上可接受的盐，其中，m、n、p、q、t’独立地选自0、1和2，且m和n不同时为0，p和q不同时为0。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein m, n, p, q, t' are independently selected from 0, 1 and 2, and m and n is 0 when they are not at the same time, and p and q are 0 when they are not at the same time.
  9. 权利要求1-8任一项所述的式(I)化合物或其药学上可接受的盐，其中，选自 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein, Selected from
  10. 权利要求1-9任一项所述的式(I)化合物或其药学上可接受的盐，其中，R1、R2独立地选自苯基、萘基、5-10元杂芳基、C3-C12环烷基、C3-C12环烯基和3-12元杂环基，所述苯基、萘基、5-10元杂芳基、C3-C12环烷基、C3-C12环烯基和3-12元杂环基任选被RZ取代。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 1 and R 2 are independently selected from phenyl, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl and 3-12 membered heterocyclyl, the phenyl, naphthyl, 5-10 membered heteroaryl, C 3 -C 12 cycloalkyl , C 3 -C 12 cycloalkenyl and 3-12 membered heterocyclyl are optionally substituted by R Z.
  11. 权利要求10所述的式(I)化合物或其药学上可接受的盐，其中，R1、R2独立地选自苯基和5-6元杂芳基，所述苯基和5-6元杂芳基任选被RZ取代。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, wherein R 1 and R 2 are independently selected from phenyl and 5-6 membered heteroaryl, and the phenyl and 5-6 Metaheteroaryl groups are optionally substituted with RZ .
  12. 权利要求11所述的式(I)化合物或其药学上可接受的盐，其中，R1、R2为苯基，所述苯基任选被RZ取代。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 11, wherein R 1 and R 2 are phenyl groups, and the phenyl group is optionally substituted by R Z.
  13. 权利要求1-12任一项所述的式(I)化合物或其药学上可接受的盐，其中，L选自键和C1-C4亚烷基，所述C1-C4亚烷基中的1-2个亚甲基单元任选独立地被-CH(R)-、-C(R)2-、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)S(O)2-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S(O)-或-S(O)2-替换。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein L is selected from the group consisting of bonds and C 1 -C 4 alkylene, and the C 1 -C 4 alkylene 1-2 methylene units in the base are optionally independently replaced by -CH(R)-, -C(R) 2 -, -N(R)-, -N(R)C(O)-, - N(R)C(NR)-, -N(R)S(O) 2 -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S (O)-or-S(O) 2 -replacement.
  14. 权利要求13所述的式(I)化合物或其药学上可接受的盐，其中，L选自C1-C2亚烷基，所述C1-C2亚烷基中的1-2个亚甲基单元任选独立地被-CH(R)-、-C(R)2-、-N(R)-、-N(R)C(O)-、-N(R)C(NR)-、-N(R)S(O)2-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S(O)-或-S(O)2-替换。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein L is selected from C 1 -C 2 alkylene, 1-2 of the C 1 -C 2 alkylene The methylene unit is optionally independently substituted by -CH(R)-, -C(R) 2 -, -N(R)-, -N(R)C(O)-, -N(R)C(NR )-, -N(R)S(O) 2 -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S(O)- or -S (O) 2 - Substitution.
  15. 权利要求14所述的式(I)化合物或其药学上可接受的盐，其中，L选自N(R)C(O)和N(R)C(O)N(R)。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, wherein L is selected from the group consisting of N(R)C(O) and N(R)C(O)N(R).
  16. 权利要求15所述的式(I)化合物或其药学上可接受的盐，其中，L选自N(R)C(O)。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 15, wherein L is selected from N(R)C(O).
  17. 权利要求16所述的式(I)化合物或其药学上可接受的盐，其中，L选自NHC(O)。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 16, wherein L is selected from NHC(O).
  18. 权利要求1-17任一项所述的式(I)化合物或其药学上可接受的盐，其中，RX、RY、RZ独立地选自氘、卤素、-CN、-NO2、-OR、-SF5、-SR、-NR2、-S(O)2R、-S(O)2NR2、-S(O)R、-S(O)NR2、-S(O)(NR)R、-C(O)R、-C(O)OR、-C(O)NR2、-C(O)N(R)OR、-OC(O)R、C1-C6烷基、苯基、C3-C6环烷基、3-7元杂环基和5-6元杂芳基，所述C1-C6烷基、苯基、C3-C6环烷基、3-7元杂环基、5-6元杂芳基任选被R’取代。The compound of formula ( I ) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein R -OR, -SF 5 , -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -S(O )(NR)R, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, C 1 -C 6 alkyl, phenyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl, the C 1 -C 6 alkyl, phenyl, C 3 -C 6 Cycloalkyl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are optionally substituted by R'.
  19. 权利要求18所述的式(I)化合物或其药学上可接受的盐，其中，RX、RY、RZ独立地选自氘、卤素和C1-C6烷基，所述C1-C6烷基任选被R’取代。 The compound of formula ( I) or a pharmaceutically acceptable salt thereof according to claim 18, wherein R -C 6 alkyl is optionally substituted by R'.
  20. 权利要求1-19任一项所述的式(I)化合物或其药学上可接受的盐，其中，R’独立地选自氘、卤素、C1-C3烷基、C1-C3烷氧基和C3-C6环烷基。The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R' is independently selected from deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 Alkoxy and C 3 -C 6 cycloalkyl.
  21. 权利要求1-20任一项所述的式(I)化合物或其药学上可接受的盐，选自式(II)化合物或其药学上可接受的盐，
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 is selected from the group consisting of compounds of formula (II) or a pharmaceutically acceptable salt thereof,
    其中环A、环B、环C、R1、R2和L如权利要求1-20任一项所定义。Wherein Ring A, Ring B, Ring C, R 1 , R 2 and L are as defined in any one of claims 1-20.
  22. 权利要求1-20任一项所述的式(I)化合物或其药学上可接受的盐，选自式(III)化合物或其药学上可接受的盐，
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 is selected from the group consisting of compounds of formula (III) or a pharmaceutically acceptable salt thereof,
    其中Y1、Y2、Y3、Y4、Y5、Y6、m、n、p、q、t’、RY、R1、R2和L如权利要求1-20任一项所定义。Wherein Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , m, n, p, q, t', R Y , R 1 , R 2 and L are as claimed in any one of claims 1 to 20 definition.
  23. 化合物或其药学上可接受的盐，所述化合物选自以下：
    A compound or a pharmaceutically acceptable salt thereof, the compound being selected from the following:
  24. 药物组合物，其包含权利要求1-23任一项所述的化合物或其药学上可接受的盐和药学上可接受的辅料。A pharmaceutical composition comprising the compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
  25. 治疗哺乳动物由PI3Kα介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的权利要求1-23任一项所述的化合物或其药学上可接受的盐、或权利要求24所述的药物组合物。A method of treating a PI3Kα-mediated disease in a mammal, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof to a mammal in need of the treatment, preferably a human. Or the pharmaceutical composition of claim 24.
  26. 权利要求1-23任一项所述的化合物或其药学上可接受的盐、或权利要求24所述的药物组合物在制备预防或者治疗PI3Kα介导的疾病的药物中的用途。The use of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 24 in the preparation of a medicament for preventing or treating PI3Kα-mediated diseases.
  27. 权利要求1-23任一项所述的化合物或其药学上可接受的盐、或权利要求24所述的药物组合物在预防或者治疗PI3Kα介导的疾病中的用途。Use of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 24 in preventing or treating PI3Kα-mediated diseases.
  28. 预防或者治疗PI3Kα介导的疾病权利要求1-23任一项所述的化合物或其药学上可接受的盐、或权利要求24所述的药物组合物。 Preventing or treating PI3Kα-mediated diseases The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24.
PCT/CN2023/118565 2022-09-14 2023-09-13 Tricyclic compound and use thereof WO2024055992A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108349996A (en) * 2015-09-08 2018-07-31 豪夫迈·罗氏有限公司 Tricyclic PI3K inhibitor compounds and its application method
WO2021222556A1 (en) * 2020-04-29 2021-11-04 Relay Therapeutics, Inc. PI3K-α INHIBITORS AND METHODS OF USE THEREOF
CN114874234A (en) * 2021-02-05 2022-08-09 江苏先声药业有限公司 Tricyclic compound serving as KRAS G12C inhibitor and application thereof
WO2023081757A1 (en) * 2021-11-03 2023-05-11 Relay Therapeutics, Inc. Pi3k-alpha inhibitors and methods of making and using the same
CN116655602A (en) * 2022-07-12 2023-08-29 苏州浦合医药科技有限公司 PI3K alpha allosteric inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108349996A (en) * 2015-09-08 2018-07-31 豪夫迈·罗氏有限公司 Tricyclic PI3K inhibitor compounds and its application method
WO2021222556A1 (en) * 2020-04-29 2021-11-04 Relay Therapeutics, Inc. PI3K-α INHIBITORS AND METHODS OF USE THEREOF
CN114874234A (en) * 2021-02-05 2022-08-09 江苏先声药业有限公司 Tricyclic compound serving as KRAS G12C inhibitor and application thereof
WO2023081757A1 (en) * 2021-11-03 2023-05-11 Relay Therapeutics, Inc. Pi3k-alpha inhibitors and methods of making and using the same
CN116655602A (en) * 2022-07-12 2023-08-29 苏州浦合医药科技有限公司 PI3K alpha allosteric inhibitors

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