WO2024002376A1 - 一类prmt5抑制剂及其用途 - Google Patents
一类prmt5抑制剂及其用途 Download PDFInfo
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- WO2024002376A1 WO2024002376A1 PCT/CN2023/105593 CN2023105593W WO2024002376A1 WO 2024002376 A1 WO2024002376 A1 WO 2024002376A1 CN 2023105593 W CN2023105593 W CN 2023105593W WO 2024002376 A1 WO2024002376 A1 WO 2024002376A1
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- 239000003112 inhibitor Substances 0.000 title description 2
- 101100434927 Caenorhabditis elegans prmt-5 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 42
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- 229910052736 halogen Inorganic materials 0.000 claims description 27
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- 125000003118 aryl group Chemical group 0.000 claims description 23
- 229910052805 deuterium Inorganic materials 0.000 claims description 23
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- 150000003839 salts Chemical class 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
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Classifications
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
Definitions
- the present invention relates to the field of pharmaceutical compounds. Specifically, the present invention provides a class of compounds for inhibiting PRMT5 and their use in pharmaceutical compositions.
- Epigenetic regulation of gene expression is an important biological determinant of protein production and cell differentiation and plays an important pathogenic role in many human diseases.
- Epigenetic regulation involves the heritable modification of genetic material without changing its nucleotide sequence.
- epigenetic regulation is mediated by selective and reversible modifications (e.g., methylation) of DNA and proteins (e.g., histones) that control conformational transitions between transcriptionally active and inactive states of chromatin.
- methyltransferases e.g., PRMT5
- PRMT5 plays a role in diseases such as proliferative, metabolic and hematological diseases.
- PRMT5 is a known cellular essential gene, and conditional PRMT5 knockout and siRNA knockdown studies have shown that PRMT5 inhibition in normal tissues is associated with a range of diseases (e.g., pancytopenia, infertility, skeletal muscle loss, cardiac hypertrophy). Therefore, new strategies are needed to exploit this metabolic vulnerability and preferentially target PRMT5 in MTAP-null tumors while sparing PRMT5 in normal tissues (MTAPWT).
- Targeting PRMT5 with MTA synergistic small molecule inhibitors can preferentially target the MTA-bound state of PRMT5, enriched in MTAP-null tumor cells, while providing a therapeutic index superior to normal cells with intact MTAP and low MTA levels.
- the purpose of the present invention is to provide a new class of small molecule compounds targeting PRMT5 in MTAP-ineffective tumors.
- a first aspect of the present invention provides a compound represented by the following formula I, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof:
- W is O or S
- X 1 and X 2 are each independently selected from the following group: CR, N; X 3 is N;
- L 1 is selected from the following group: chemical bond, -CHR-, -C(R)R-;
- Ring A is selected from the following group: substituted or unsubstituted 7-12 membered bridged ring (including carbocyclic ring or heterocyclic ring), substituted or unsubstituted 7-12 membered spiro ring (including carbocyclic ring or heterocyclic ring), substituted Or unsubstituted 8-12 membered fused bicyclic heterocyclyl (including carbocyclic or heterocyclic rings, preferably pentahexacyclic), substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl ( Preferably it is pentahexacyclic), or the A ring is a substituted or unsubstituted 3-7 membered carbocyclic ring or heterocyclic ring, a substituted or unsubstituted 5-6 membered aromatic ring or heteroaromatic ring;
- E ring is selected from the following group: substituted or unsubstituted 3-7 membered monoheterocycle, substituted or unsubstituted 7-12 membered bridged heterocycle, substituted or unsubstituted 7-12 membered spiroheterocycle, substituted or Unsubstituted 8-12 membered fused polycyclic heterocyclyl (such as fused bicyclic);
- R 8 is selected from the group consisting of: H, deuterium, halogen, cyano, alkynyl, SF 5 , amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, substituted or unsubstituted or halogenated C 1 -C 6 alkane group, substituted or unsubstituted or halogenated C 1 -C 6 alkoxy group, or R 8 is selected from the group consisting of: H, deuterium, halogen, cyano, alkynyl, SF 5 , amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, substituted or unsubstituted or halogenated C 1 -C 6 alkane group, substituted or unsubstituted or halogenated C 1 -C 6 alkoxy group, or R 8 is
- R 8 ' is selected from the following group: H, deuterium, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, unsubstituted or halogenated C 1 -C 6 alkyl, substituted or unsubstituted Benzene ring, substituted or unsubstituted 5-12-membered heteroaromatic ring, substituted or unsubstituted C 3 -C 10 carbocyclic ring (including saturated or partially unsaturated), substituted or unsubstituted 3-12-membered heteroaromatic ring Heterocycle (including saturated or partially unsaturated), or R 8 ' is selected from the following group: H, deuterium, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, unsubstituted or halogenated C 1 -C 6 alkyl, substituted or unsubstituted Benz
- Described L 3 is selected from the following group: chemical bond, -O-, -CHR-, -C(R)R-, carbonyl group, S, -NH-;
- Ring B is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring, substituted or unsubstituted C 3 -C 6 carbocyclic ring (including saturated or partially unsaturated) ), substituted or unsubstituted 3-7 membered heterocycle (including saturated or partially unsaturated);
- R 2 and R 2 ' are each independently selected from the following group: R 7 , -L 2 R 7 ; wherein, the L 2 is selected from the following group: -O-, -CHR-, -C(R)R- ; wherein R 7 is selected from the following group: hydrogen or none, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 6-10 aromatic ring, substituted or unsubstituted 5-12 membered hetero Aromatic rings, substituted or unsubstituted C 3 -C 10 carbocyclic rings (including saturated or partially unsaturated ones, including monocyclic rings, fused rings, spiro rings or bridged rings), substituted or unsubstituted 3-10 membered heterocyclic rings Ring (including saturated or partially unsaturated, including single ring, fused ring, spiro ring or bridged ring); n is 0, 1, 2 or 3;
- R 3 is selected from the group consisting of: H, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 6 alkyl;
- R 4 and R 5 together with the connected ring atoms form a 5-12 membered saturated or unsaturated ring, and the ring may be substituted or unsubstituted;
- R is H, deuterium, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl;
- the substitution means that the hydrogen atom on the corresponding group is replaced by one or more substituents selected from the following group: deuterium, tritium, halogen, hydroxyl, carboxyl, mercapto, benzyl , C 1 -C 12 alkoxycarbonyl group, C 1 -C 6 aldehyde group, amino group, C 1 -C 6 amide group, nitro group, cyano group, unsubstituted or halogenated C 1 -C 6 alkyl group, unsubstituted Pick Substituted or halogenated C 1 -C 6 alkyl-OC 1 -C 6 alkyl-, unsubstituted or halogenated C 1 -C 6 alkyl-OC 1 -C 6 alkyl-O-, unsubstituted or Halogenated C 1 -C 6 alkylene-OH, unsubstituted or halogenated C 3 -C 8 cyclo
- the Ra is selected from the following group:
- the R 9 is selected from the following group: deuterium, tritium, halogen, hydroxyl, carboxyl, unsubstituted or halogenated C 1 -C 6 alkyl, unsubstituted or halogenated C 1 -C 6 alkoxy , unsubstituted or substituted C 1 -C 6 alkyl -OH, -NH (unsubstituted or halogenated C 1 -C 6 alkyl), -N (unsubstituted or halogenated C 1 -C 6 alkyl ) 2 ; m is selected from 0, 1, 2 or 3; preferably, the R 9 is selected from the following group: deuterium, tritium, halogen, unsubstituted or halogenated C 1 -C 6 alkyl.
- the L 1 is -CHR-, -C(R)R-;
- Ring A is selected from the following group: substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl, Substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl;
- R 8 is selected from the following group: H, halogen, cyano, amino, alkynyl, SF 5 , hydroxyl, mercapto, aldehyde, carboxyl, unsubstituted Substituted or halogenated C 1 -C 6 alkyl,
- the B ring is selected from the following group: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-6 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 carbocyclic ring, a substituted or unsubstituted 3- 6-membered hetero
- the R 2 is selected from the following group: R 7 , -L 2 R 7 ; wherein the L 2 is selected from the following group: -O-, -CHR-, carbonyl, S, -NH-; wherein R 7 is selected from the following group: substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 6-10 aromatic ring, substituted or unsubstituted 5-12 membered heteroaryl ring.
- R 2 is an ortho-substituted 5- or 6-membered heteroaromatic ring, as shown in the following formula:
- the ortho-position substituent R 10 is selected from the group consisting of hydrogen, deuterium, halogen, halogenated or unhalogenated C 1 -C 3 alkyl, halogenated or unhalogenated C 1 -C 3 alkoxy;
- D ring is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring.
- D ring is selected from the following group:
- the L 1 is -CH 2 -, -CH(CH 3 )-; the A ring is selected from the following group:
- C ring is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring, substituted or unsubstituted C 3 -C 6 carbocyclic ring (including saturated or partially unsaturated case), substituted or unsubstituted 3-6 membered heterocycle (including saturated or partially unsaturated case);
- R 8 is And the B ring is selected from the following group: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-6 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 carbocyclic ring, a substituted or unsubstituted 3- 6-membered heterocycle; L 3 is selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or -NH-.
- the L 3 is a chemical bond.
- the B ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-6 membered heteroaromatic ring.
- R 2 is selected from the following group: R 7 , -(CHR)R 7 ; wherein R 7 is selected from the following group: hydrogen or none, substituted or unsubstituted C 1 -C 6 alkyl, substituted Or unsubstituted C 6-10 aromatic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted C 3 -C 8 carbocyclic ring (including saturated or partially unsaturated, including mono ring, fused ring, spiro ring or bridged ring), substituted or unsubstituted 3-8 membered heterocycle (including saturated or partially unsaturated, including single ring, fused ring, spiro ring or bridged ring).
- R 7 is selected from the following group: hydrogen or none, substituted or unsubstituted C 1 -C 6 alkyl, substituted Or unsubstituted C 6-10 aromatic ring, substituted or unsubstituted 5-12
- the compound has the structure shown in the following formula:
- Q is O, NH, CH 2 , or a chemical bond (i.e., is a five-membered ring);
- R 8 is defined as above;
- the R 8a and R 8b are each independently selected from the following group: H; or the R 8a and R 8b and the carbon atoms connected to them together constitute a 4-7 membered carbocyclic ring or heterocyclic ring;
- R 8a and R 8b are each independently H, the R 8a or R 8b can be optionally substituted by R 8 ; when the R 8a and R 8b and their attached carbon atoms are together When forming a 4- to 7-membered carbocyclic ring or heterocyclic ring, the R 8 may be located on the carbocyclic ring or heterocyclic ring.
- the R 3 is selected from the following group: H, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 6 alkyl.
- the R 2 is a substituted or unsubstituted 5-7 membered heteroaromatic ring; and the A ring is selected from the following group: a substituted or unsubstituted 5-6 membered aromatic ring or a heteroaromatic ring.
- a second aspect of the present invention provides a pharmaceutical composition containing a therapeutically effective amount
- the third aspect of the present invention provides a compound as described in any of the foregoing aspects, its racemate, optical isomer or pharmaceutically acceptable salt for preparation, treatment or prevention of gene level abnormalities or abnormal expression of PRMT5. (such as corresponding nucleic acid mutations, deletions, or ectopic or fusion or overexpression of the methyltransferase)-related diseases.
- PRMT5. such as corresponding nucleic acid mutations, deletions, or ectopic or fusion or overexpression of the methyltransferase
- the disease or disorder is selected from the group consisting of: ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer or bladder cancer.
- the halogen is F, Cl, Br or I.
- C1-C6 alkyl refers to a straight-chain or branched alkyl group with 1 to 6 carbon atoms, including without limitation methyl, ethyl, propyl, isopropyl, butyl, etc. ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
- C1-C6 alkoxy refers to a straight-chain or branched chain alkoxy group with 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, Isopropoxy and butoxy, etc.
- C2-C6 alkenyl refers to a straight-chain or branched alkenyl group containing one double bond with 2 to 6 carbon atoms, including without limitation vinyl, propenyl, butenyl , isobutenyl, pentenyl and hexenyl, etc.
- C2-C6 alkynyl refers to a straight-chain or branched-chain alkynyl group having 2 to 6 carbon atoms and containing a triple bond, including without limitation ethynyl, propynyl, butynyl base, isobutynyl, pentynyl and hexynyl, etc.
- C3-C10 cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, Hexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc.
- C3-C8 cycloalkyl “C3-C7 cycloalkyl”
- C3-C6 cycloalkyl have similar meanings.
- C3-C10 cycloalkenyl refers to a cyclic alkenyl group with 3 to 10 carbon atoms in the ring, including without limitation cyclopropenyl, cyclobutenyl, cyclopentenyl , cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecylene, etc.
- C3-C7 cycloalkenyl has a similar meaning.
- C1-C12 alkoxycarbonyl refers to an alkoxy group having 1 to 12 carbon atoms in the alkyl chain.
- Carbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
- C1-C12 alkylaminocarbonyl refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including without limitation methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, Isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl, etc.
- aromatic ring or “aryl” has the same meaning, and preferably "aryl” is “C6-C12 aryl” or “C6-C10 aryl”.
- aryl is “C6-C12 aryl” or “C6-C10 aryl”.
- C6-C12 aryl refers to an aromatic ring group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.
- C6-C10 aryl has a similar meaning.
- aromatic heterocycle or “heteroaryl” have the same meaning and refer to heteroaromatic groups containing one to more heteroatoms.
- Heteroatoms referred to here include oxygen, sulfur and nitrogen.
- the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
- Heteroaryl groups may be optionally substituted or unsubstituted.
- 3-12-membered heterocyclyl refers to a saturated or unsaturated 3-12-membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen on the ring, for example Dioxolyl etc.
- 3-7 membered heterocyclyl has a similar meaning.
- substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
- Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
- a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
- a cyclic substituent, such as heterocycloalkyl can be linked to another ring, such as cycloalkyl, to form a spirobicyclic system, for example, both rings having a common carbon atom.
- substituents contemplated by the present invention are those that are stable or chemically achievable.
- the substituents are for example (but not limited to): C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, Heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, C1-C12 alkoxycarbonyl, amino, alkoxy, C1-10 sulfonyl, etc. .
- C1-8 or similar expressions, it is meant that the group can have 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
- the present invention provides a class of compounds with PRMT5 regulatory activity:
- W is O or S
- X 1 and X 2 are each independently selected from the following group: CR, N; X 3 is N;
- L 1 is selected from the following group: chemical bond, -CHR-, -C(R)R-;
- Ring A is selected from the following group: substituted or unsubstituted 7-12 membered bridged ring (including carbocyclic ring or heterocyclic ring), substituted or unsubstituted 7-12 membered spiro ring (including carbocyclic ring or heterocyclic ring), substituted Or unsubstituted 8-12 membered fused bicyclic heterocyclyl (including carbocyclic or heterocyclic rings, preferably pentahexacyclic), substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl ( Preferably it is pentahexacyclic), or the A ring is a substituted or unsubstituted 3-7 membered carbocyclic ring or heterocyclic ring, a substituted or unsubstituted 5-6 membered aromatic ring or heteroaromatic ring;
- E ring is selected from the following group: substituted or unsubstituted 3-7 membered monoheterocycle, substituted or unsubstituted 7-12 membered bridged heterocycle, substituted or unsubstituted 7-12 membered spiroheterocycle, substituted or Unsubstituted 8-12 membered fused polycyclic heterocyclyl (such as fused bicyclic);
- R 8 is selected from the group consisting of: H, deuterium, halogen, cyano, alkynyl, SF 5 , amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, halogenated or unhalogenated C 1 -C 6 alkane group, halogenated or unhalogenated C 1 -C 6 alkoxy group, or R 8 is And when the A ring is a substituted or unsubstituted 3-7-membered carbocyclic ring or heterocyclic ring, a 5-6-membered aromatic ring or a heteroaromatic ring, the R 8 is
- R 8 ' is selected from the following group: H, deuterium, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, halogenated or unhalogenated C 1 -C 6 alkyl, substituted or unsubstituted benzene ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted C 3 -C 10 carbocyclic ring (including saturated or partially unsaturated), substituted or unsubstituted 3-12 membered Heterocycle (including saturated or partially unsaturated), or R 8 ' is selected from the following group: H, deuterium, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, halogenated or unhalogenated C 1 -C 6 alkyl, substituted or unsubstituted benzene ring, substituted or unsubstit
- Described L 3 is selected from the following group: chemical bond, -O-, -CHR-, -C(R)R-, carbonyl group, S, -NH-;
- Ring B is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring, substituted or unsubstituted C 3 -C 6 carbocyclic ring (including saturated or partially unsaturated) ), substituted or unsubstituted 3-7 membered heterocycle (including saturated or partially unsaturated);
- R 2 and R 2 ' are each independently selected from the following group: R 7 , -L 2 R 7 ; wherein, the L 2 is selected from the following group: -O-, -CHR-, -C(R)R- , ; wherein R 7 is selected from the following group: hydrogen or none, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 6-10 aromatic ring, substituted or unsubstituted 5-12 membered Heteroaromatic ring, substituted or unsubstituted C 3 -C 10 carbocyclic ring (including saturated or partially unsaturated, including monocyclic, fused ring, spiro ring or bridged ring), substituted or unsubstituted 3-10 membered Heterocycle (including saturated or partially unsaturated, including single ring, fused ring, spiro ring or bridged ring); n is 0, 1, 2 or 3;
- R 3 is selected from the group consisting of: H, deuterium, halogen, cyano, substituted or unsubstituted C 1 -C 6 alkyl;
- R 4 and R 5 together with the connected ring atoms form a 5-12 membered saturated or unsaturated ring, and the ring may be substituted or unsubstituted;
- R is H, deuterium, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl;
- the substitution means that the hydrogen atom on the corresponding group is replaced by one or more substituents selected from the following group: deuterium, tritium, halogen, hydroxyl, carboxyl, mercapto, benzyl , C 1 -C 12 alkoxycarbonyl group, C 1 -C 6 aldehyde group, amino group, C 1 -C 6 amide group, nitro group, cyano group, unsubstituted or halogenated C 1 -C 6 alkyl group, unsubstituted Substituted or halogenated C 1 -C 6 alkyl-OC 1 -C 6 alkyl-, unsubstituted or halogenated C 1 -C 6 alkyl-OC 1 -C 6 alkyl-O-, unsubstituted or Halogenated C 1 -C 6 alkylene-OH, unsubstituted or halogenated C 3 -C 8 cycloal
- compositions and methods of administration are provided.
- the compound of the present invention has excellent methyltransferase inhibitory activity
- the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the compound of the present invention are mainly Pharmaceutical compositions with active ingredients can be used to treat, prevent, and alleviate related diseases caused by abnormal activity or expression of methyltransferases (eg, PRMT5).
- methyltransferases eg, PRMT5
- the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
- the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 5-200 mg of the compound of the present invention/dose.
- the "dose" is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
- Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
- gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
- administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited.
- Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
- Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
- inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
- compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
- suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
- compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
- the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- the compounds of the present invention can be administered together with other small molecule compounds to form a PROTAC, or with other large molecule compounds such as monoclonal antibodies to form an ADC.
- a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
- a mammal such as a human
- the daily dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
- the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
- the raw materials can be obtained through commercial channels or prepared by methods already known or disclosed in the art.
- Normal phase chromatography is prepacked silica gel column or preparative thin layer chromatography.
- Silica gel chromatography columns are mainly glass columns or rapid preparation chromatographs.
- the mobile phase of normal phase chromatography is selected and proportioned from petroleum ether/ethyl acetate, dichloromethane/methanol or other suitable solvents for elution.
- Reversed-phase preparative liquid chromatography uses a C18 column, and is performed with a preparative liquid chromatograph or a rapid preparative chromatograph.
- a preparative liquid chromatography-mass spectrometry instrument is used for detection, with water/acetonitrile containing 0.1% hydrochloric acid, Water/acetonitrile, water/acetonitrile containing 0.1% ammonium bicarbonate, water/acetonitrile containing 0.1% formic acid, water/acetonitrile containing 0.1% ammonia, water/acetonitrile containing 0.1% trifluoroacetic acid, or other suitable solvent system as the mobile phase Perform gradient elution.
- the structures of intermediates and compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (LCMS).
- the nuclear magnetic resonance spectrometer used in nuclear magnetic resonance is Bruker Ascend 400 or Varian 400 or ZKNJ BIXI-1 300MHz or Bruker Avance III 400MHz or Bruker AVANCE Neo 400MHz.
- the solvent used is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol or other labeled deuterated solvents.
- Spectral data are reported in mode: chemical shift ⁇ (number of peak splits, coupling constant J (Hz), number of hydrogens).
- Tetramethylsilane was used as the internal standard for chemical shifts, and its chemical shift was set to zero ( ⁇ , 0 ppm).
- the meanings of some abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak).
- Method 1 Performed on an Agilent LC1260 system coupled with a 6120 single quadrupole mass spectrometer
- Method 2 Performed on an Agilent LC/MSD 1200 system coupled with a quadrupole mass spectrometer.
- the crude product was pulped with methyl tert-butyl methane for 60 minutes at 25 degrees Celsius (25.5 g). (2).
- the mother liquor was purified by column chromatography (silica, 50% tetrahydrofuran in petroleum ether) to obtain a yellow liquid, which was then slurried with methyl tert-butyl alcohol at 25 degrees Celsius for 60 minutes to obtain a yellow solid (8.23 grams).
- Step 4 7-Fluoro-1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (5)
- Step 5 4-((2,4-dimethoxybenzyl)amino)-7-fluoro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (6)
- Step 6 4-Amino-7-fluoro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (7)
- Step 7 4-Amino-7-fluoro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Intermediate A2)
- the residue was diluted with water to methanol 10:1 (300 ml) and filtered on diatomaceous earth.
- the filter cake was filtered with water to methanol 10:1 (300 ml). ml) and washed three times. All filtrates were combined and concentrated under reduced pressure to remove methanol.
- the pH of the residue was adjusted to 5-6 with acetic acid.
- the obtained slurry was stirred at 15 to 20 degrees Celsius for 12 hours, and the solid obtained was filtered under reduced pressure and washed with water. The solid was collected and freeze-dried to obtain a white solid.
- Step 3 8-bromo-7-chloro-1-methyl-5hydro-imidazole[1,5-a]quinoxalin-4-one (4)
- Step 4 7-Chloro-1-methyl-4-oxo-5H-imidazole[1,5-a]quinoxaline-8-carboxylic acid methyl ester (5)
- Step 5 7-Chloro-4-((2,4-dimethoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (6 )
- Step 6 7-chloro-4-((2,4-dimethoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Intermediate A3 )
- reaction solution was suction filtered, the filter cake was beaten with water, and dried under reduced pressure to obtain a brown solid 1,3-dimethyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8- Methyl formate (5) (460 mg, 1.62 mmol, 79.48% yield, 95.55% purity), the crude product was used directly in the next step without further purification.
- Step 4 Methyl 4-((2,4-dimethoxybenzyl)amino)-1,3-dimethylimidazo[1,5-a]quinoxaline-8-carboxylate
- Step 5 4-((2,4-dimethoxybenzyl)amino)-1,3-dimethylimidazo[1,5-a]quinoxaline-8-carboxylic acid
- reaction mixture was diluted with saturated ammonium chloride (10.0 mL) and ethanol (5.00 mL). The precipitate was collected, washed with water (10.0 mL), and then concentrated under reduced pressure to obtain 8-bromo-N-(4-methoxybenzyl)-3-methyl-4,5-dihydropyridine as a yellow solid.
- Azolo[1,5-a]quinoxalin-4-amine (5) (1.09 g, crude product).
- Step 5 4-Amino-3-methylpyrazolo[1,5-a]quinoxaline-8-carboxylic acid ethyl ester (7)
- Step 6 4-Amino-3-methylpyrazolo[1,5-a]quinoxaline-8-carboxylic acid (Intermediate A6)
- Step 3 7-Fluoro-4-hydroxy-3-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (5)
- Step 4 7-fluoro-4-((4-methoxybenzyl)amino)-3-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (6) to 7-
- BOP (19.2 g, 43.6 mmol, 2 equiv)
- DBU (16.5 g, 109 mmol, 16.4 mL, 5 equiv)
- PMBNH2 7.48 g, 54.5 mmol, 7.05 mL, 2.5 equiv).
- Step 5 4-Amino-7-fluoro-3-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (6)
- Step 6 4-Amino-7-fluoro-3-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Intermediate A7)
- Step 3 N-(pyrazolo[1,5-a]pyridin-2-ylmethyl)-1-(pyrimidin-2-yl)ethane-1-amine (Intermediate B1)
- Step 3 1-methyl-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-amine (intermediate B2)
- LCMS (ET63219-45-P1A1) showed complete consumption of Cpd.4 and several new peaks on LCMS.
- the reaction mixture was diluted with saturated aqueous Na 2 CO 3 solution (3.00 mL) and extracted with dichloromethane (2.00 mL ⁇ 4). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain a residue.
- Step 3 N-ethyl-1-(pyrazolo[1,5-a]pyridin-2-yl)ethyl-1-amine (Intermediate B5)
- Step 3 2-methyl-N-((6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)propan-1-amine (Intermediate B6)
- Step 7 (E)-4-(((dimethylamino)methylene)amino)-3-methylpyrazolo[1,5-a]quinoxaline-8-carbonyl chloride (Intermediate A6- 1)
- Step 8 (E)-4-(((dimethylamino)methylene)amino)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)-N-((5 -(Trifluoromethyl)pyridin-2-yl)methyl)pyrazolo[1,5-a]quinoxaline-8-carboxamide (Intermediate A6-2)
- Step 9 4-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyridine Azolo[1,5-a]quinoxaline-8-carboxamide (Example 4)
- Step 1 4-(2,4-dimethoxybenzyl)amino)-N-ethyl-1,3-dimethyl-N-(5-(trifluoromethyl)pyridin-2-ylmethyl base)imidazo[1,5-a]quinoxaline-8-carboxamide (3)
- Step 2 4-Amino-N-ethyl-1,3-dimethyl-N-((5-trifluoromethyl)pyridin-2-ylmethyl)imidazo[1,5-a]quinoxal Phenoline-8-carboxamide (Example 15)
- reaction solution was concentrated to dryness under reduced pressure, added 10% sodium carbonate (10 ml), extracted with dichloromethane (10 ml*3), washed the combined organic phases with saturated brine (10 ml), dried over magnesium sulfate, filtered and concentrated.
- Step 1 7-chloro-4-[(2,4-dimethoxyphenyl)methylamino]-1-methyl-N-(1-methylpyrazol-4-yl)-N-[ [6-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]imidazo[1,5-a]quinoxaline-8-carboxamide (3)
- Step 2 4-amino-7-chloro-1-methyl-N-(1-methyl-1hydro-pyrazol-4-yl)-N-((6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-2-yl])methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Example 86)
- Step 2 4-Amino-7-fluoro-1-methyl-N-(2-methylpyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-ylmethyl)imidazole And[1,5-a]quinoxaline-8-carboxamide (Example 143)
- the target product was detected by LCMS.
- the reaction solution was purified by reversed-phase preparative liquid chromatography (formic acid conditions; Boston Prime C18 column, 150*30 mm*5 microns; mobile phase: [water (formic acid)-acetonitrile]; gradient: 15%-35% B, 10 minutes ) to obtain a yellow solid 4-amino-7-fluoro-1-methyl-N-(2-methylpyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-ylmethyl) Imidazo[1,5-a]quinoxaline-8-carboxamide (Example 143) (8 mg, 6.29% yield).
- the target product was detected by LCMS.
- Step 2 4-amino-N-(1,3-dimethyl-1H-pyrazol-4-yl)-1,7-dimethyl-N-((5-(trifluoromethyl)pyridine- 2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Example 188)
- Step 2 4-amino-N-(1,4-dimethyl-1H-imidazol-2-yl)-7-fluoro-1-methyl-N-((5-(trifluoromethyl)pyridine- 2-yl)methyl)imidazole[1,5-a]quinoxaline-8-carboxamide (Example 210)
- Step 2 4-amino-7-fluoro-1-methyl-1-methylpyrazol-5-yl)-N-(1-trifluoromethyl-1H-pyrazol-4-yl)methyl) Imidazo[1,5-a]quinoxaline-8-carboxamide (Example 213)
- Step 1 4-Fluoro-2-methyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]pyrazole-3-amine (3 ) Dissolve 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (1) (700 mg, 3.27 mmol, 1 equivalent) in methanol (14 ml), and add 4- Fluoro-1-methyl-1H-pyrazol-5-amine (2) (402.61 mg, 3.50 mmol, 1.07 equiv) and glacial acetic acid (255.18 mg, 4.25 mmol, 243.26 ⁇ L, 1.3 equiv), reacted in Stir for 1 hour at 25°C.
- Step 2 4-amino-7-fluoro-N-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-1-methyl-N-((6-(trifluoromethyl)) Imidazo[1,2-a]pyridin)-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Example 220)
- Step 1 (E)-4-(((dimethylamino)methylene)amino)-7-fluoro-3-methylimidazo[1,5-a]quinoxaline-8-carbonyl chloride (middle Body A7-1)
- Step 2 4-amino-7-fluoro-N-(1-methoxyprop-2-yl)-3-methyl-N-((6-(trifluoromethyl)imidazo[1,2- a]pyridin-2-yl)methyl)imidazole[1,5-a]quinoxaline-8-carboxamide (Example 287)
- the HCT116 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences.
- the MTAP gene was knocked out using CRISPR/Cas9 technology to obtain the HCT116-MTAP-KO cell line.
- McCoy'5A medium (Gibco, catalog number 16600082), fetal calf serum (Gibco, catalog number 10099141C), penicillin-streptomycin (Gibco, catalog number 15140122), trypsin (Gibco, catalog number 25200056), CellTiter -Glo detection kit (Promega, catalog number G7572), 384-well transparent flat-bottomed black-walled cell culture plate (Corning, catalog number 3764), ultra-micro sample dispenser (Tecan, catalog number D300e), multifunctional microplate reader (Biotek , catalog number SynergyHTX)
- HCT116 and HCT116-MTAP-KO cells are McCoy'5A medium + 10% fetal calf serum + 1% penicillin-streptomycin double antibody; ensure that they are always in the logarithmic growth phase and the cell viability rate greater than 95%.
- Compound-treated cells Add trypsin-digested HCT116 or HCT116-MTAP-KO cell suspension into a 384-well plate with the compound to be tested, 40 ⁇ L per well, that is, each well contains 100 cells, and the final DMSO concentration is 0.4 %. Place the cell culture plate in a 37°C, 5% carbon dioxide incubator for 6 days.
- A means IC 50 (nm) ⁇ 100
- B means 100 ⁇ IC 50 (nm) ⁇ 1000
- C means 1000 ⁇ IC 50 (nm) ⁇ 10000
- the first column is the cell proliferation inhibition rate HCT116MTAP WT IC 50 (nm)
- the second column is the cell proliferation inhibition rate HCT116-MTAP null IC 50 (nm)
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Abstract
本发明提供了一类具有甲基转移酶抑制活性的化合物,具体地,本发明提供了一类具有PRMT5抑制活性的化合物。所述的化合物是可以被用于制备治疗PRMT5活性相关的疾病的药物组合物。式 (I), 式(II)。
Description
本发明涉及药物化合物领域,具体地,本发明提供了一类用于抑制PRMT5的化合物,及其用于药物组合物的用途。
基因表达的表观遗传调控是蛋白质产生和细胞分化的重要生物学决定因素,在许多人类疾病中起着重要的致病作用。
表观遗传调控涉及遗传物质的可遗传修饰而不改变其核苷酸序列。通常,表观遗传调控由DNA和蛋白质(例如组蛋白)的选择性和可逆修饰(例如甲基化)介导,这些修饰控制染色质转录活性和非活性状态之间的构象转变。这些共价修饰可以由甲基转移酶(例如PRMT5)等酶控制,其中许多与可能导致人类疾病的特定遗传改变有关。PRMT5在增殖性疾病、代谢性疾病和血液疾病等疾病中发挥作用。
PRMT5是一种已知的细胞必需基因,条件性PRMT5敲除和siRNA敲除研究表明,正常组织中的PRMT5抑制与一系列疾病相关(例如,全血细胞减少症、不孕症、骨骼肌丧失、心脏肥大)。因此,需要新的策略来利用这种代谢脆弱性并优先针对MTAP无效肿瘤中的PRMT5,同时在正常组织中保留PRMT5(MTAPWT)。用MTA协同小分子抑制剂靶向PRMT5可以优先靶向PRMT5的MTA结合状态,富含MTAP无效肿瘤细胞,同时提供优于MTAP完整且MTA水平低的正常细胞的治疗指数。
因此,本领域需要提供新的靶向MTAP无效肿瘤中的PRMT5的小分子化合物。
发明内容
本发明的目的是提供一类新的靶向MTAP无效肿瘤中的PRMT5的小分子化合物。
本发明的第一方面,提供了一种如下式I所示的化合物,或其药学上可接受的立体异构体、盐或氘代产物:
其中,
Ra为
W为O或S;
X1、X2各自独立地选自下组:CR、N;X3为N;
所述的L1选自下组:化学键、-CHR-、-C(R)R-;
A环选自下组:取代或未取代的7-12元的桥环(包括碳环或杂环)、取代或未取代的7-12元的螺环(包括碳环或杂环)、取代或未取代的8-12元的稠合二环杂环基(包括碳环或杂环,优选为五并六环)、取代或未取代的7-10元的稠合二环杂芳基(优选为五并六环)、或所述的A环为取代或未取代的3-7元碳环或杂环、取代或未取代的5-6元芳环或杂芳环;
E环选自下组:取代或未取代的3-7元单杂环,取代或未取代的7-12元的桥杂环、取代或未取代的7-12元的螺杂环、取代或未取代的8-12元的稠合多环杂环基(如稠合二环);
R8选自下组:H、氘、卤素、氰基、炔基、SF5、氨基、硝基、羟基、巯基、醛基、羧基、取代或未取代或卤代的C1-C6烷基、取代或未取代或卤代的C1-C6烷氧基、或R8为
R8'选自下组:H、氘、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、未取代或卤代的C1-C6烷基、取代或未取代的苯环、取代或未取代的5-12元的杂芳环、取代或未取代的C3-C10碳环(包括饱和或部分不饱和的情况)、取代或未取代的3-12元的杂环(包括饱和或部分不饱和的情况)、或R8'为
所述的L3选自下组:化学键、-O-、-CHR-、-C(R)R-、羰基、S、-NH-;
B环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环(包括饱和或部分不饱和的情况)、取代或未取代的3-7元的杂环(包括饱和或部分不饱和的情况);
R2和R2'各自独立地选自下组:R7、-L2R7;其中,所述的L2选自下组:-O-、-CHR-、-C(R)R-;其中R7选自下组:氢或无、取代或未取代的C1-C6烷基、取代或未取代的C6-10的芳环、取代或未取代的5-12元的杂芳环、取代或未取代的C3-C10碳环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环)、取代或未取代的3-10元的杂环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环);n为0、1、2或3;
R3选自下组:H、氘、卤素、氰基、取代或未取代的C1-C6烷基;
R4和R5与相连的环原子共同形成5-12元饱和或不饱和环,且所述的环可以是取代或未取代的;
R为H、氘、卤素、取代或未取代的C1-C4烷基,取代或未取代的C1-C4烷氧基、取代或未取代C3-C6环烷基;
除非特别说明,上述各式中,所述的取代指对应基团上的氢原子被一个或多个选自下组的取代基所取代:氘、氚、卤素、羟基、羧基、巯基、苄基、C1-C12烷氧基羰基、C1-C6醛基、氨基、C1-C6酰胺基、硝基、氰基、未取代或卤代的C1-C6烷基、未取
代或卤代的C1-C6烷基-O-C1-C6烷基-、未取代或卤代的C1-C6烷基-O-C1-C6烷基-O-、未取代或卤代的C1-C6亚烷基-OH、未取代或卤代的C3-C8环烷基、C2-C10烯基、未取代或卤代的C1-C6烷氧基、C1-C6烷基-胺基、C6-C10芳基、五元或六元杂芳基、五元或六元非芳香性杂环基、-O-(C6-C10芳基)、-O-(五元或六元杂芳基)、C1-C12烷氨基羰基、未取代或卤代的C2-C10酰基、磺酰基(-SO2-OH)、磷酰基(-PO3-OH)、未取代或卤代的C1-C4烷基-S(O)2-、未取代或卤代C1-C4烷基-SO-、-SF6。
在另一优选例中,所述的Ra选自下组:
其中,所述的R9选自下组:氘、氚、卤素、羟基、羧基、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或取代的C1-C6烷基-OH、-NH(未取代或卤代的C1-C6烷基)、-N(未取代或卤代的C1-C6烷基)2;m选自0、1、2或3;较佳地,所述的R9选自下组:氘、氚、卤素、未取代或卤代的C1-C6烷基。
在另一优选例中,所述的L1为-CHR-、-C(R)R-;A环选自下组:取代或未取代的8-12元的稠合二环杂环基、取代或未取代的7-10元的稠合二环杂芳基;R8选自下组:H、卤素、氰基、氨基、炔基、SF5、羟基、巯基、醛基、羧基、未取代或卤代的C1-C6烷基、且B环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环、取代或未取代的3-6元的杂环;L3选自下组:化学键,-O-、-CHR-、羰基、S、或-NH-。
在另一优选例中,所述的R2选自下组:R7、-L2R7;其中,所述的L2选自下组:-O-、-CHR-、羰基、S、-NH-;其中R7选自下组:取代或未取代的C1-C6烷基、取代或未取代的C6-10的芳环、取代或未取代的5-12元的杂芳环。
在另一优选例中,所述的R2为邻位取代的5、6元杂芳环,如下式:
邻位取代基R10选自下组:氢、氘、卤素、卤代或未卤代的C1-C3烷基,卤代或未卤代的C1-C3烷氧基;
D环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环,较佳地,D环选自下组:
在另一优选例中,所述的L1为-CH2-、-CH(CH3)-;A环选自下组:
其中,C环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环(包括饱和或部分不饱和的情况)、取代或未取代的3-6元的杂环(包括饱和或部分不饱和的情况);
或A环选自下组:
R8为且B环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环、取代或未取代的3-6元的杂环;L3选自下组:化学键,-O-、-CHR-、羰基、S、或-NH-。
在另一优选例中,所述的L3为化学键。
在另一优选例中,所述的B环为取代或未取代的苯环、或取代或未取代的5-6元的杂芳环。
在另一优选例中,R2选自下组:R7、-(CHR)R7;其中R7选自下组:氢或无、取代或未取代的C1-C6烷基、取代或未取代的C6-10的芳环、取代或未取代的5-12元的杂芳环、取代或未取代的C3-C8碳环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环)、取代或未取代的3-8元的杂环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环)。
在另一优选例中,所述的化合物具有如下式所示的结构:
其中,Q为O、NH、CH2,或化学键(即,为五元环);
R8的定义如上文中所述;
所述的R8a和R8b各自独立地选自下组:H;或所述的R8a和R8b及其相连的碳原子共同构成4-7元的碳环或杂环;
且当所述的R8a和R8b各自独立地为H时,所述的R8a或R8b可以任选地被R8取代;当所述的R8a和R8b及其相连的碳原子共同构成4-7元的碳环或杂环时,所述的R8可以位于该碳环或杂环上。
在另一优选例中,所述的R3选自下组:H、氘、卤素、氰基、、取代或未取代的C1-C6烷基。
在另一优选例中,所述的R2为取代或未取代的5-7元杂芳环;且所述的A环选自下组:取代或未取代的5-6元芳环或杂芳环、取代或未取代的7-10元的稠合二环杂芳基;所述的R8为CF3。
本发明的第二方面,提供了一种药物组合物,所述的药物组合物含有治疗有效量
的如前述任一方面所述的化合物、其可药用的盐、外消旋体、光学异构体、立体异构体或互变异构体中的一种或多种,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的第三方面,提供了一种如前述任一方面所述的化合物、其外消旋体、光学异构体或可药用盐在制备治疗或预防与PRMT5的基因水平异常或表达异常(如对应的核酸突变、缺失,或所述的甲基转移酶产生异位或融合或过高表达)相关的疾病的药物中的用途。
在另一优选例中,所述的疾病选自下组:所述疾病或病症卵巢癌、肺癌、淋巴癌、胶质母细胞瘤、结肠癌、黑色素瘤、胃癌、胰腺癌或膀胱癌。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明人通过广泛而深入的研究,首次意外地发现一类具有PRMT5调节作用的化合物。在此基础上完成了本发明。
术语
在本发明中,所述卤素为F、Cl、Br或I。
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。本发明中,如果没有特别指明,所有化学式意在涵盖可能的任何光学或几何异构体(例如R型、S型或外消旋体,或者烯烃的顺反异构体等)。
在本发明中,术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等;优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中,术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中,术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基,非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中,术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基,非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中,术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。
在本发明中,术语“C3-C10环烯基”是指在环上具有3至10个碳原子的环状烯基,非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环癸基烯等。术语“C3-C7环烯基”具有类似的含义。
在本发明中,术语“C1-C12烷氧羰基”是指在烷基链上具有1至12个碳原子的烷氧
羰基,非限制性地包括甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、叔丁氧羰基、苄氧羰基等。
在本发明中,术语“C1-C12烷氨基羰基”是指在烷基链上具有1至12个碳原子的烷氨基羰基,非限制性地包括甲氨基羰基、乙氨基羰基、丙氨基羰基、异丙氨基羰基、叔丁氨基羰基、苄氨基羰基、二甲氨基羰基等。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选地“芳基”为“C6-C12芳基”或“C6-C10芳基”。术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基,如苯基、萘基等。术语“C6-C10芳基”具有类似的含义。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“3-12元杂环基”是指在环上含有1~3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基,例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。环状取代基,例如杂环烷基,可以与另一个环相连,例如环烷基,从而形成螺二环系,例如,两个环具有一个共用碳原子。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基,芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、C1-C12烷氧羰基、氨基、烷氧基、C1-10磺酰基等。
当采用例如“C1-8”或类似表述时,指该基团可以具有1个、2个、3个、4个、5个、6个、7个、或8个碳原子。
当采用例如“3-12元”或类似表述时,指该基团可以具有3个、4个、5个、6个、7个、8个、9个、10个、11个、或12个作为环原子的碳原子或杂原子。
PRMT5调节剂化合物
本发明中提供了一类具有PRMT5调节活性的化合物:
其中,
Ra为
W为O或S;
X1、X2各自独立地选自下组:CR、N;X3为N;
所述的L1选自下组:化学键、-CHR-、-C(R)R-;
A环选自下组:取代或未取代的7-12元的桥环(包括碳环或杂环)、取代或未取代的7-12元的螺环(包括碳环或杂环)、取代或未取代的8-12元的稠合二环杂环基(包括碳环或杂环,优选为五并六环)、取代或未取代的7-10元的稠合二环杂芳基(优选为五并六环)、或所述的A环为取代或未取代的3-7元碳环或杂环、取代或未取代的5-6元芳环或杂芳环;
E环选自下组:取代或未取代的3-7元单杂环,取代或未取代的7-12元的桥杂环、取代或未取代的7-12元的螺杂环、取代或未取代的8-12元的稠合多环杂环基(如稠合二环);
R8选自下组:H、氘、卤素、氰基、炔基、SF5、氨基、硝基、羟基、巯基、醛基、羧基、卤代或未卤代的的C1-C6烷基、卤代或未卤代的C1-C6烷氧基、或R8为且当所述的A环为取代或未取代的3-7元碳环或杂环、5-6元芳环或杂芳环时,所述的R8为
R8'选自下组:H、氘、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、卤代或未卤代的C1-C6烷基、取代或未取代的苯环、取代或未取代的5-12元的杂芳环、取代或未取代的C3-C10碳环(包括饱和或部分不饱和的情况)、取代或未取代的3-12元的杂环(包括饱和或部分不饱和的情况)、或R8'为
所述的L3选自下组:化学键、-O-、-CHR-、-C(R)R-、羰基、S、-NH-;
B环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环(包括饱和或部分不饱和的情况)、取代或未取代的3-7元的杂环(包括饱和或部分不饱和的情况);
R2和R2'各自独立地选自下组:R7、-L2R7;其中,所述的L2选自下组:-O-、-CHR-、-C(R)R-、;其中R7选自下组:氢或无、取代或未取代的C1-C6烷基、取代或未取代的C6-
10的芳环、取代或未取代的5-12元的杂芳环、取代或未取代的C3-C10碳环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环)、取代或未取代的3-10元的杂环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环);n为0、1、2或3;
R3选自下组:H、氘、卤素、氰基、取代或未取代的C1-C6烷基;
R4和R5与相连的环原子共同形成5-12元饱和或不饱和环,且所述的环可以是取代或未取代的;
R为H、氘、卤素、取代或未取代的C1-C4烷基,取代或未取代的C1-C4烷氧基、取代或未取代C3-C6环烷基;
除非特别说明,上述各式中,所述的取代指对应基团上的氢原子被一个或多个选自下组的取代基所取代:氘、氚、卤素、羟基、羧基、巯基、苄基、C1-C12烷氧基羰基、C1-C6醛基、氨基、C1-C6酰胺基、硝基、氰基、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷基-O-C1-C6烷基-、未取代或卤代的C1-C6烷基-O-C1-C6烷基-O-、未取代或卤代的C1-C6亚烷基-OH、未取代或卤代的C3-C8环烷基、C2-C10烯基、未取代或卤代的C1-C6烷氧基、C1-C6烷基-胺基、C6-C10芳基、五元或六元杂芳基、五元或六元非芳香性杂环基、-O-(C6-C10芳基)、-O-(五元或六元杂芳基)、C1-C12烷氨基羰基、未取代或卤代的C2-C10酰基、磺酰基(-SO2-OH)、磷酰基(-PO3-OH)、未取代或卤代的C1-C4烷基-S(O)2-、未取代或卤代C1-C4烷基-SO-、-SF6。
药物组合物和施用方法
由于本发明化合物具有优异的甲基转移酶抑制的活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由于甲基转移酶(例如PRMT5)的活性或表达量异常引起的相关疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。在一些优选的实施方式中,本发明的化合物可以与其他小分子化合物一同形成PROTAC,或者与其他大分子化合物例如单抗共同形成ADC施用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选5~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
各个缩写的定义如下所示:
原料可以通过商业途径获得或者通过本领域已经已知或者公开的方法制备获得。
中间体和化合物的纯化采用正相或反向色谱法或者重结晶等常规的化学实验操作进行。正相色谱法为预装填硅胶色谱柱或者制备薄层色谱。硅胶色谱柱主要为玻璃柱或者快速制备色谱仪。正相色谱法的流动相从石油醚/乙酸乙酯,二氯甲烷/甲醇或者其它合适的溶剂中选择及配比进行洗脱。反相制备液相色谱采用C18柱,用制备型液相色谱仪或者快速制备色谱仪进行,214nM和254nM或者制备型液相色谱-质谱联用仪器检测,以含0.1%盐酸的水/乙腈、水/乙腈、含0.1%碳酸氢铵的水/乙腈、含0.1%甲酸的水/乙腈、含0.1%氨水/乙腈、含0.1%三氟乙酸的水/乙腈或者其它合适的溶剂体系作为流动相进行梯度洗脱。
中间体和化合物结构表征采用核磁共振(NMR)和质谱(LCMS)的方法。核磁共振所用到的核磁共振波谱仪为Bruker Ascend 400或者Varian 400或者ZKNJ BIXI-1 300MHz或者Bruker Avance III 400MHz或者Bruker AVANCE Neo 400MHz。所用溶剂为氘代二甲亚砜、氘代氯仿、氘代甲醇或者其它标注的氘代溶剂。光谱数据以模式报告:化学位移δ(峰裂数,耦合常数J(Hz),氢数目)。四甲基硅烷作为化学位移的内15标,并把它的化学位移定为零(δ,0ppm)。一些缩写的含义为:s(单峰),d(双重峰),t(三重峰),q(四重峰),m(多重峰),br(宽峰)。
中间体和化合物结构表征中液相色谱-质谱联用(LCMS)代表性的方法如下:
方法一:在偶联有6120单四级杆质谱仪的Agilent LC1260系统上进行
柱:Waters CORTECS C-18,2.7μm,4.6*30mm。溶剂A:0.05%甲酸水溶液,溶剂20B:0.05%甲酸的乙腈溶液,历时一分钟5%乙腈到95%乙腈,保持一分钟,共2.5分钟;流速:1.8mL/min;柱温40℃。
柱:XSelect CSH C18,3.5μm,4.6*50mm。溶剂A:0.05%氨水溶液,溶剂B:0.05%氨的乙腈溶液,历时一分钟内5%乙腈到95%乙腈,保持一分钟,共2.5分钟;流速:1.8mL/min;柱温40℃。
方法二:在偶联有四极杆质谱仪的Agilent LC/MSD 1200系统上进行。
柱:ODS2000(50×4.6mm,5μm)(ES(+)或(-)电离模式),温度30℃;流速1.5mL/min。
实施例合成通用方法:
通用方法:中间体A2的合成
合成路线:
步骤1:2,5-二氟-4-硝基苯甲酸甲酯(2)
将2,5-二氟-4-硝基苯甲酸(1)(50g,246.18毫摩尔,1当量)溶解在甲醇中(500毫升)再在0摄氏度下加入二氯亚砜(43.93克,369.28毫摩尔,26.79毫升,1.5当量)。反应液在40摄氏度下反应16小时。LCMS显示反应完全。反应液减压浓缩至干。加入300毫升的水稀释后用1升乙酸乙酯萃取三次。有机相用饱和食盐水(400毫升)洗涤,用无水硫酸镁干燥,过滤滤液减压浓缩至干.粗品在25摄氏度下用石油醚打浆60分钟得到白色固体2,5-二氟-4-硝基苯甲酸甲酯(2)(103克,474.38毫摩尔,96.35%收率)。HNMR:ES23714-64-P1A,1H NMR(400MHz,CHLOROFORM-d)δppm 7.89(td,J=9.51,5.63Hz,2H)4.00(s,3H)。19F NMR(376MHz,CHLOROFORM-d)δppm-110.27(s,1F)-121.56(m,1F)
步骤2:2-氟-5-(2-甲基-1H-咪唑-1-基)-4-硝基苯甲酸甲酯(3)
将2,5-二氟-4-硝基苯甲酸甲酯(2)(80克,368.45毫摩尔,1当量),2-甲基-1H-咪唑(36.30克,442.14毫摩尔,1.2当量)溶解在二甲基亚砜中(1.2升)。反应液在50摄氏度下反应16小时。LCMS显示反应完全。反应液中加入4升的水稀释后用乙酸乙酯4.5L萃取。有机相用饱和食盐水(3升)洗涤,用无水硫酸镁干燥,过滤滤液减压浓缩至干。粗品用甲基叔丁基谜在25摄氏度下打浆60分钟(25.5克)。(2).母液经柱层析色谱纯化(二氧化硅,50%四氢呋喃在石油醚中)得到黄色液体再经甲基叔丁基谜在25摄氏度下打浆60分钟得到黄色固体(8.23克).黄色固体2-氟-5-(2-甲基-1H-咪唑-1-基)-4-硝基苯甲酸甲酯(3)(25.5克,91.32毫摩尔,24.79%收率)2,5-二氟-4-硝基苯甲酸甲酯(2)(原料回收)(20.34克,93.68毫摩尔,25.43%收率)。黄色固体2-氟-5-(2-甲基-1H-咪唑-1-基)-4-硝基苯甲酸甲酯(3)(8.2克,29.07毫摩尔,7.89%收率,99%纯度)HNMR:ES23714-67-P1A1,1H NMR(400MHz,DMSO-d6)δppm 8.39(d,J=9.90Hz,1H)8.08-8.20(m,1H)7.23(d,J=1.32Hz,1H)6.92(s,1H)3.91(s,3H)2.12(s,3H)。19F NMR(376MHz,DMSO-d6)δppm-105.45(br s,1F)
步骤3:4-氨基-2-氟-5-(2-甲基-1H-咪唑-1-基)苯甲酸甲酯(4)
将2-氟-5-(2-甲基-1H-咪唑-1-基)-4-硝基苯甲酸甲酯(3)(13.9克,49.78毫摩尔,1当量)溶解在四氢呋喃中(300毫升),在氢气氛围下加入氢氧化钯碳(2.8克,49.78毫摩尔,20%纯度,1当量)。反应体系用氢气置换3次。反应液在氢气(1当量)(50psi)氛围下加热到50摄氏度反应32小时。LCMS显示反应完全。反应液在硅藻土上过滤,滤饼用300毫升乙酸乙酯洗四遍。滤液在减压下浓缩至干,得到灰色固体。粗品直接用于投下一步。4-氨基-2-氟-5-(2-甲基-1H-咪唑-1-基)苯甲酸甲酯(4)(12克,48.15毫摩尔,96.72%收率).1H NMR(400MHz,DMSO-d6)Shift 7.46(d,J=7.63Hz,1H),7.07(d,J=1.38Hz,1H),6.93(d,J=1.25Hz,1H),6.59(d,J=13.51Hz,1H),6.15(br s,2H),3.68-3.77(m,3H),2.01-2.12(m,3H).19F NMR(376MHz,DMSO-d6)Shift-109.31--108.47(m,1F).
步骤4:7-氟-1-甲基-4-氧-4,5-二氢咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(5)
在25摄氏度下将4-氨基-2-氟-5-(2-甲基-1H-咪唑-1-基)苯甲酸甲酯(4)(12克,48.15毫摩尔,1当量)加入1-甲基-2-吡咯烷酮,再加入1,1-羰基二咪唑(19.52克,120.37毫摩尔,2.5当量).反应液加热到115摄氏度反应16小时。LCMS显示反应完全。两个批次反应液合并处理。反应液中加入600毫升乙酸乙酯和600毫升的水在25摄氏度下打浆16小时。浆液在减压下过滤,滤饼用100毫升的乙酸乙酯洗。固体在减压下浓缩得到灰色固体7-氟-1-甲基-4-氧-4,5-二氢咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(5)(24.1克,87.56毫摩尔,86.60%收率)。粗品直接用于投下一步反应。1H NMR(400MHz,DMSO-d6)Shift 11.71(br s,1H),8.40(d,J=6.38Hz,1H),7.76(s,1H),7.08(d,J=11.38Hz,1H),3.88(s,3H),2.89(s,3H).19F NMR(376MHz,DMSO-d6)Shift-111.43--110.58(m,1F)
步骤5:4-((2,4-二甲氧基苄基)氨基)-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(6)
将7-氟-1-甲基-4-氧-4,5-二氢咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(5)(12.0克,43.60毫摩尔,1.0当量),2,4-二甲氧基苄胺(10.9克,65.19毫摩尔,9.82毫升,1.50当量)和1.8-二氮杂二环[5.4.0]十一烷-7-烯(19.92克,130.80毫摩尔,19.72毫升,3.0当量)加入乙腈中(240毫升)。在15~20摄氏度下分批加入苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(25.07克,56.68毫摩尔,1.3当量)。反应液微微放热,反应液变均匀,固体析出。氮气保护下反应液在15~20摄氏度下反应16小时。LCMS显示起始物料消耗完全并检测到的目标化合物。反应悬浮液在减压下过滤并用100毫升乙腈洗涤滤饼。收集固体并在减压下抽干得到灰白色固体4-((2,4-二甲氧基苄基)氨基)-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(6)(15.3克,36.05毫摩尔,82.68%收率).LCMS ES15882-1146-P1A:(ESI)m/z=425.3[M+1]+;RT=1.721min.1H NMR(400MHz,DMSO-d6)Shift 8.49(d,J=7.00Hz,1H),8.45(t,J=5.57Hz,1H),7.95(s,1H),7.23(d,J=12.51Hz,1H),7.18(d,J=8.38Hz,1H),6.58(d,J=2.38Hz,1H),6.47(dd,J=2.38,8.38Hz,1H),4.66(d,J=5.25Hz,2H),3.88(s,3H),3.82(s,3H),3.73(s,3H),2.93(s,3H).19F NMR(376.5MHz,DMSO-d6)Shift-113.02。
步骤6:4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(7)
将4-((2,4-二甲氧基苄基)氨基)-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(6)(16.3克,38.40毫摩尔,1.0当量)加入二氯甲烷(50毫升)中,再加入三氟乙酸(250毫升)。反应液加热到50摄氏度反应16小时。LCMS显示起始物料消耗完
全并检测到的目标化合。反应液在减压下浓缩至干,得到紫色固体4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(7)(28.3克,粗品)粗品直接用于投下一步反应。LCMS ES15882-1150-P1A:(ESI)m/z=275.3[M+1]+;RT=0.607min
步骤7:4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(中间体A2)
将4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(7)(上一步粗品)(28.3克,38.70毫摩尔,1当量)加入四氢呋喃(80毫升)和甲醇中(80毫升)。将氢氧化钠(7.74克,193.48毫摩尔,5当量)溶解在水中(80毫升)后加入反应液。反应液加热到50摄氏度反应4小时。LCMS检测到所需化合物。将反应液冷却到20摄氏度后,在减压下浓缩除去有机溶剂,残留物用水比甲醇10比1(300毫升)稀释后,在硅藻土上过滤,滤饼用水比甲醇10比1(300毫升)反复洗涤三次。合并所有的滤液,减压浓缩除去甲醇。残留物用醋酸调节pH至5~6。得到的浆液在15~20摄氏度下搅拌12小时,减压下过滤得到的固体用水洗涤。收集固体经冷冻干燥后得到白色固体。4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(中间体A2)(9.9克,37.55毫摩尔,97.05%收率,98.71%纯度)。LCMS ES15882-1154-P1C:(ESI)m/z=261.1[M+1]+;RT=0.422min。1H NMR(400MHz,DMSO-d6)Shift 13.15(br s,1H),8.53(d,J=7.04Hz,1H),7.85(s,1H),7.68(s,2H),7.16(d,J=12.10Hz,1H),2.94(s,3H)
通用方法:中间体A3的合成
合成路线:
步骤1:1-(5-溴-4-氯-2-硝基-苯基)-2-甲基-咪唑(2)
将1-溴-2-氯-5-氟-4-硝基苯(1)(3克,11毫摩尔,1当量)加入到2-甲基-1H-咪唑(1.2克,14毫摩尔,1.2当量)的乙腈(50毫升)溶液中,随后将碳酸钾(4克,29毫摩尔,2.5当量)加入到反应液中。升温到80摄氏度并搅拌16小时。检测到原料反应完全,目标产物生成。减压浓缩除去乙腈,加入水(40毫升),用乙酸乙酯萃取(3x 50毫升)。用无水硫酸镁干燥,过滤滤液减压浓缩至干,经柱层析色谱纯化(二氧化硅,35%四氢呋喃在石油醚中)得到白色固体1-(5-溴-4-氯-2-硝基-苯基)-2-甲
基-咪唑(2)(4克)。H NMR:1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.32(s,1H),7.22(d,J=1.32Hz,1H),6.91(d,J=1.32Hz,1H),2.08-2.23(m,3H).
步骤2:4-溴-5-氯-2-(2-甲基咪唑-1-基)苯胺(3)
将1-(5-溴-4-氯-2-硝基-苯基)-2-甲基-咪唑(2)(3.5克,11毫摩尔,1当量)溶解在水(8毫升),乙醇(16毫升)与四氢呋喃(16毫升)的混合溶液中,将氯化铵(8.9克,166毫摩尔,15当量)加入到反应液中,升温到70摄氏度把铁粉(2.5克,44毫摩尔,4当量)加入到反应液中。反应在90摄氏度下搅拌2小时。LC-MS检测到原料反应完全,目标产物生成。反应液在硅藻土下过滤并用乙酸乙酯洗涤(40毫升x3)。减压除去溶剂得到黑色固体4-溴-5-氯-2-(2-甲基咪唑-1-基)苯胺(3)(3.1克,10.8毫摩尔,98%产率)。H NMR:1H NMR(400MHz,DMSO-d6)δ7.41(s,1H),7.12(s,1H),7.07(s,1H),6.99(s,1H),5.45(s,2H),2.13(s,3H).
步骤3:8-溴-7-氯-1-甲基-5氢-咪唑[1,5-a]喹恶啉-4-酮(4)
将4-溴-5-氯-2-(2-甲基咪唑-1-基)苯胺(3)(3克,10.5毫摩尔,1当量)和1,1-羰基二咪唑(2.6克,15.7毫摩尔,1.5当量)依次溶解在1,2-二氯苯(30毫升)溶液中。反应液在130摄氏度下搅拌16小时。LC-MS检测到原料反应完全,目标产物生成。反应液在乙酸乙酯和水(2/1 15毫升)的溶液中搅拌30分钟后过滤得到滤饼,滤饼在真空下浓缩得到黑色固体8-溴-7-氯-1-甲基-5氢-咪唑[1,5-a]喹恶啉-4-酮(4)(2.2克,7毫摩尔,67%产率)。H NMR:1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.33(d,J=3.30Hz,2H),2.83(s,3H)
步骤4:7-氯-1-甲基-4-氧代-5H-咪唑[1,5-a]喹喔啉-8-羧酸甲酯(5)
将8-溴-7-氯-1-甲基-5氢-咪唑[1,5-a]喹恶啉-4-酮(4)(500毫克,1.6毫摩尔,1当量)溶解在乙醇(5毫升)溶液中加入1.8-二氮杂二环[5.4.0]十一十一烷-7-烯(365毫克,2.4毫摩尔,362微升,1.5当量)置换三次氮气,将四氟硼酸三丁基磷(46毫克,160微摩尔,0.1当量),六羰基钼(232毫克,880微摩尔,118微升,0.55当量)和醋酸钯(36毫克,160微摩尔,0.1当量)。反应在90摄氏度下搅拌两小时。LC-MS检测原料反应完全,目标产物生成。将反应液减压除去乙醇,加入水(10毫升),用乙酸乙酯30毫升(10毫升*3)萃取。用无水硫酸镁干燥,过滤,减压浓缩至干。通过柱层析色谱纯化(二氧化硅,30%四氢呋喃在石油醚中)得到黄色固体7-氯-1-甲基-4-氧代-5H-咪唑[1,5-a]喹喔啉-8-羧酸甲酯(5)(500毫克)。
步骤5:7-氯-4-((2,4-二甲氧基苄基)氨基)-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸甲酯(6)
将7-氯-1-甲基-4-氧代-5H-咪唑[1,5-a]喹喔啉-8-羧酸甲酯(5)(480毫克,1.6毫摩尔,1当量)溶解在乙腈中(5毫升)加入2,4-二甲氧基苄胺(341毫克,2毫摩尔,306微升,1.3当量),苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(1克,2.4毫摩尔,1.5当量)和1.8-二氮杂二环[5.4.0]十一十一烷-7-烯(1.2克,7.9毫摩尔,1.2毫升,5当量)。反应在室温下搅拌16小时。LC-MS检测原料反应完全,目标产物生成。将反应液减压除去乙腈,加入水(8毫升),用乙酸乙酯30毫升(10毫升*3)萃取。用无水硫酸镁干燥,过滤,减压浓缩至干。通过柱层析色谱纯化(二氧化
硅,30%四氢呋喃在石油醚中)得到黄色固体7-氯-4-((2,4-二甲氧基苄基)氨基)-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸甲酯(6)(500毫克,1.1毫摩尔,70%产率)。
步骤6:7-氯-4-((2,4-二甲氧基苄基)氨基)-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(中间体A3)
将7-氯-4-((2,4-二甲氧基苄基)氨基)-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸甲酯(6)(500毫克,1.1毫摩尔,1当量)溶解在水(5毫升)和乙醇(5毫升)中,加入氢氧化钠(132毫克,3.3毫摩尔,3当量)。反应液在50摄氏度下搅拌5小时。LCMS检测原料反应完全,目标产物生成。反应液加入6摩尔盐酸(0.5毫升)减压浓缩至干,粗品直接用于下一步,得到白色固体7-氯-4-((2,4-二甲氧基苄基)氨基)-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(中间体A3)(350毫克,820微摩尔,74.6%产率)。
通用方法:中间体A4的合成
合成路线:
步骤1:3-(2,4-二甲基咪唑-1-基)-4-硝基苯甲酸甲酯
将3-氟-4-硝基苯甲酸甲酯(1)(2.00克,10.04毫摩尔,1当量)加到乙腈中(40当量)加碳酸钾(4.16克,30.13毫摩尔,3当量)和2,4-二甲基-1H-咪唑(2)(965毫克,10.04毫摩尔,1当量),反应液85摄氏度反应16小时。LC-MS显示原料消耗完全,目标产物生成。反应液减压浓缩至干,残留物用二氯甲烷(80当量)稀释,过滤,滤液用硫酸镁干燥,过滤,减压浓缩至干得黄色固体3-(2,4-二甲基咪唑-1-基)-4-硝基苯甲酸甲酯(3)(2.6克,9.45毫摩尔,94.05%产率),粗品直接用于下一步,不需要进一步纯化。
步骤2:4-氨基-3-(2,4-二甲基咪唑-1-基)苯甲酸甲酯
将3-(2,4-二甲基咪唑-1-基)-4-硝基苯甲酸甲酯(3)(2.5克,9.08毫摩尔,1当量)溶解在乙醇(20当量),四氢呋喃(20当量)和水(10当量)中,室温下加铁粉(5.07克,90.82毫摩尔,10当量)和氯化铵(2.43克,45.41毫摩尔,5当量)。反应液90摄氏度反应16小时。LC-MS显示原料消耗完全,目标产物生成。反应液过滤,减压浓缩至干,残留物用水稀释(50当量),用乙酸乙酯萃取(40当量*3),合并有机相用硫酸镁干燥,过滤,减压浓缩至干得黄色固体4-氨基-3-(2,4-二甲基咪唑-1-基)苯甲酸甲酯(4)(1.9克,6.13毫摩尔,67.49%产率,79.13%纯度),粗品直接用于下一步,不需要进一步纯化。LCMS:ES19974-375-P1C2,(ESI)m/z=246.1[M+1]+;RT=0.61min,purity:79.13%
步骤3:1,3-二甲基-4-氧代-4,5-二氢咪唑并[1,5-a]喹喔啉-8-甲酸甲酯
4-氨基-3-(2,4-二甲基咪唑-1-基)苯甲酸甲酯(4)(500毫克,2.04毫摩尔,1当量)和1,1-羰基二咪唑(495毫克,3.06毫摩尔,1.5当量)溶解在1,2-二氯苯中(10当量),反应液在氮气保护下120摄氏度反应16小时。LC-MS显示原料消耗完全,目标产物生成。反应液抽滤,滤饼用水打浆,减压干燥得棕色固体1,3-二甲基-4-氧代-4,5-二氢咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(5)(460毫克,1.62毫摩尔,79.48%产率,95.55%纯度),粗品直接用于下一步,不需要进一步纯化。
LCMS:ES19974-392-P1B1,(ESI)m/z=272.0[M+1]+;RT=0.61min,purity:95.55%
步骤4:4-((2,4-二甲氧基苄基)氨基)-1,3-二甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯
将二甲基-4-氧代-4,5-二氢咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(5)(700毫克,2.58毫摩尔,1当量)溶在乙腈中(25当量)加苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(1.83g,4.13毫摩尔,1.6当量)和1.8-二氮杂二环[5.4.0]十一十一烷-7-烯(1.96g,12.90毫摩尔,1.94当量,5当量),反应液室温反应0.5小时,将(2,4-二甲氧基苯基)甲胺(647.2毫克,3.87毫摩尔,583.1微升,1.5当量)加到反应液中,反应液50摄氏度反应15.5小时。LC-MS显示原料消耗完全,目标产物生成。反应液过滤,滤饼减压干燥得棕色固体4-((2,4-二甲氧基苄基)氨基)-1,3-二甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(6)(900毫克,2.08毫摩尔,80.57%产率,97.13%纯度),粗品直接用于下一步,不需要进一步纯化。LCMS:ES19974-397-P1B1,(ESI)m/z=421.1[M+1]+;RT=0.78min,purity:97.13%
步骤5:4-((2,4-二甲氧基苄基)氨基)-1,3-二甲基咪唑并[1,5-a]喹喔啉-8-羧酸
将4-((2,4-二甲氧基苄基)氨基)-1,3-二甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(6)(850毫克,2.02毫摩尔,1当量)溶解在甲醇(10当量),四氢呋喃(10当量)和水中(5当量)加氢氧化锂(424.2毫克,10.11毫摩尔,5当量)。反应液50摄氏度反应16小时。LC-MS显示原料消耗完全,目标产物生成。反应液减压浓缩至干,残留物加醋酸调节pH=6-7,过滤,滤饼减压干燥得棕色固体4-((2,4-二甲氧基苄基)氨基)-1,3-二甲基咪唑并[1,5-a]喹喔啉-8-羧酸(中间体A4)(800毫克,1.97毫摩尔,97.37%产率),粗品直接用于下一步,不需要进一步纯化。
通用方法:中间体A6的合成
合成路线:
步骤1:N-(4-溴-2-氟苯基)-4-甲基-1H-吡唑-5-甲酰胺(3)
向4-溴-2-氟苯胺(5.78g,30.4mmol,1当量)和4-甲基-1H-吡唑-5-甲酸(4.60g,36.5mmol,1.2当量)在Py(120mL)中的溶液中添加POCl3(4.66g,30.4mmol,2.82mL,1eq)在0℃下搅拌1h。LC-MS(ET63399-4-R1A1)显示起始材料完全消耗,并检测到一个具有所需m/z的主峰。将反应混合物用冰水(200mL)猝灭,然后用乙酸乙酯(60mL×6)萃取。将合并的有机层用盐水(30.0mL)洗涤,经Na 2SO 4干燥,过滤并减压浓缩,得到残余物。将粗产物用乙酸乙酯(50.0mL)研磨,得到呈白色固体的N-(4-溴-2-氟苯基)-4-甲基-1H-吡唑-5-甲酰胺(3)(7.09g,23.8mmol,78.2%产率)。1H NMR(400MHz,DMSO-d6)δ13.26(br s,1H)9.52(s,1H)7.92(t,J=8.52Hz,1H)7.70(s,1H)7.62(dd,J=10.31,1.85Hz,1H)7.41(br d,J=8.70Hz,1H)2.25(s,3H).LC-MS;[MH]+298.0
步骤2:8-溴-3-甲基吡唑并[1,5-a]喹喔啉-4(5H)-酮(4)
向N-(4-溴-2-氟苯基)-4-甲基-1H-吡唑-5-甲酰胺(3)(7.09g,23.8mmol,1当量)在DMA(70mL)中的溶液中添加NaH(1.43g,35.7mmol,60%纯度,1.5当量)。将混合物在120℃搅拌16小时。LC-MS显示起始材料完全消耗,并且一个主峰具有所需的m/z。将反应混合物用饱和氯化铵(300mL)淬灭,收集沉淀物并用水(50mL)洗涤,然后减压浓缩,得到呈白色固体状的8-溴-3-甲基吡唑并[1,5-a]喹喔啉-4(5H)-酮(4)(6.50g,粗品)。1H NMR(400MHz,DMSO-d6)δ8.11(d,J=2.00Hz,1H)7.91(s,1H)7.52(dd,J=8.63,2.00Hz,1H)7.28(d,J=8.63Hz,1H)2.42(s,3H).LC-MS;[MH]+278.0
步骤3:8-溴-N-(4-甲氧基苄基)-3-甲基-4,5-二氢吡唑并[1,5-a]喹喔啉-4-胺(5)
向8-溴-3-甲基吡唑并[1,5-a]喹喔啉-4(5H)-酮(4)(1.00g,3.60mmol,1当量)在MeCN(10.0mL)中的溶液中添加PMBNH 2(1.23g,8.99mmol,1.16mL,2.5当量)、BOP(3.18g,7.19mmol,2当量))和DBU(2.74克,18.0毫摩尔,2.71毫升,5当量)。将混合物在50℃搅拌16小时。LC-MS显示起始材料完全消耗,并且一个主峰具有所需的m/z。将反应混合物用饱和氯化铵(10.0mL)和乙醇(5.00mL)稀释。收集沉淀物并用水(10.0mL)洗涤,然后减压浓缩,得到呈黄色固体状的8-溴-N-(4-甲氧基苄基)-3-甲基-4,5-二氢吡唑并[1,5-a]喹喔啉-4-胺(5)(1.09g,粗品)。1H NMR(400MHz,DMSO-d6)δ8.20(d,J=1.88Hz,1H)7.95(s,1H),7.44-7.48(m,2H)7.38(d,J=8.63Hz,2H)7.28(br s,1H)6.87(d,J=8.75Hz,2H)4.70(d,J=5.88Hz,2H)3.71(s,3H)2.53(s,3H).LC-MS;[MH]+399.0
步骤4:8-溴-3-甲基吡唑并[1,5-a]喹喔啉-4-胺(6)
将8-溴-N-(4-甲氧基苄基)-3-甲基-4,5-二氢吡唑并[1,5-a]喹喔啉-4-胺(5)(500mg,1.26mmol,1当量)在TFA(5mL)中的溶液在60℃搅拌12小时。LC-MS显
示起始材料完全消耗,并且一个主峰具有所需的m/z。将反应混合物减压浓缩,得到化合物8-溴-3-甲基吡唑并[1,5-a]喹喔啉-4-胺(6)(400mg,粗品),为黄色固体。LC-MS:[MH]+277.0
步骤5:4-氨基-3-甲基吡唑并[1,5-a]喹喔啉-8-甲酸乙酯(7)
向8-溴-3-甲基吡唑并[1,5-a]喹喔啉-4-胺(6)(400mg,1.08mmol,1当量)的EtOH(4mL)溶液中添加Mo(CO)6(143mg,541umol,72.9uL,0.5当量)、DBU(659mg,4.33mmol,652uL,4eq)、(t-Bu)3PBF4(94.2mg,325umol,0.3eq)和Pd(OAc)2(36.5mg,162umol,0.15eq)。将混合物在90℃搅拌12小时。LC-MS(ET63399-28-R1A1)显示起始材料完全消耗并且检测到所需的质量。将反应混合物用饱和氯化铵(10mL)和乙醇(10mL)稀释。收集沉淀并用水(10.0mL)洗涤,然后减压浓缩以得到呈黄色固体的4-氨基-3-甲基吡唑并[1,5-a]喹喔啉-8-甲酸乙酯(7)(250mg,925umol,85.4%产率)。LC-MS;[MH]+271.1
步骤6:4-氨基-3-甲基吡唑并[1,5-a]喹喔啉-8-甲酸(中间体A6)
向4-氨基-3-甲基吡唑并[1,5-a]喹喔啉-8-甲酸乙酯(7)(250mg,925umol,1当量)在EtOH(3mL)和H 2O(1mL)中的溶液中添加LiOH·H 2O(116mg,2.77mmol,3当量)。将混合物在25℃搅拌12小时。LC-MS(ET63399-32-R1A1)显示起始材料完全消耗并且检测到所需的质量。将反应混合物浓缩,用水(10mL)稀释,用DCM(10.0mL×3)洗涤以除去杂质。用1M HCl调节水相至pH=5,收集沉淀并通过制备型HPLC纯化(柱:Phenomenex Luna C18 75*30mm*3um;流动相:[水(FA)-ACN];B%:1%-35%,8分钟,UV 220nm和254nm),得到呈黄色固体的4-氨基-3-甲基吡唑并[1,5-a]喹喔啉-8-甲酸(中间体A6)(60.0mg,248umol,26.8%产率)。1H NMR(400MHz,DMSO-d6)δ12.94(br s,1H)8.67(d,J=1.96Hz,1H)7.96(s,1H)7.89(dd,J=8.44,1.96Hz,1H)7.52(d,J=8.44Hz,1H)7.19(br s,2H)2.49(br s,3H).LC-MS,[MH]+243.1
通用方法:中间体A7的合成
合成路线:
步骤1:2-氟-5-(4-甲基-1H-咪唑-1-基)-4-硝基苯甲酸甲酯(3)
将2,5-二氟-4-硝基苯甲酸甲酯(20.0g,92.1mmol,1当量)和5-甲基-1H-咪唑(7.56g,92.1mmol,1当量)在DMSO(200mL)中的混合物在50℃搅拌12小时。LCMS显示剩余起始材料并检测到所需质量。将残余物用H 2O(400mL)稀释并用EtOAc(200mL×3)萃取。将合并的有机层用盐水(200mL)洗涤,经Na 2SO 4干燥,过滤并减压浓缩,得到残余物。将残余物通过柱色谱法(SiO 2,石油醚/乙酸乙酯=20/1至0/1)纯化,得到呈黄色固体的化合物2-氟-5-(4-甲基-1H-咪唑-1-基)-4-硝基苯甲酸甲酯(9.30g,33.3mmol,34.2%产率)。LC-MS(ESI)m/z=280.1[M+H]+
步骤2:4-氨基-2-氟-5-(4-甲基-1H-咪唑-1-基)苯甲酸甲酯(4)
向2-氟-5-(4-甲基-1H-咪唑-1-基)-4-硝基苯甲酸甲酯(9.30g,33.3mmol,1当量)和NH 4Cl(26.7g,499mmol,15当量)在EtOH(90.0mL)/THF(90.0mL)/H 2O(45.0mL)中的溶液中添加Fe粉末(7.44克,133毫摩尔,4当量)。将混合物在80℃搅拌2小时。LCMS显示起始材料已消耗并且检测到所需质量。过滤反应混合物,用水(300mL)稀释滤液并用EtOAc(200mL×3)萃取。将合并的有机层用盐水(100mL)洗涤,用Na 2SO 4干燥,减压浓缩,得到化合物4-氨基-2-氟-5-(4-甲基-1H-咪唑-1-基)苯甲酸甲酯(8.00g,32.1mmol,95.2%收率),为黄色固体。LC-MS(ESI)m/z=250.0[M+H]+
步骤3:7-氟-4-羟基-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(5)
将4-氨基-2-氟-5-(4-甲基-1H-咪唑-1-基)苯甲酸甲酯(500mg,2.01mmol,1eq)和CDI(487mg,2.41mmol,1.2eq)放入微波管中的1,2-二氯苯(20.0mL)中。将密封管在微波下于150℃加热3小时。进行11次平行反应,LCMS显示起始材料已消耗并且检测到所需质量。过滤反应混合物,减压干燥滤饼,得到残余物。将粗产物与MTBE(20.0mL)在25℃下研磨30分钟以得到呈黄色固体的7-氟-4-羟基-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(6.00g,21.80mmol,85.0%收率)。LC-MS(ESI)m/z=276.0[M+H]+
步骤4:7-氟-4-((4-甲氧基苄基)氨基)-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(6)向7-氟-4-羟基-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯5(6.00g,21.8mmol,1当量)在MeCN(120mL)中的溶液中添加BOP(19.2g,43.6mmol,2当量)、DBU(16.5g,109mmol,16.4mL,5当量))和PMBNH2(7.48克,54.5毫摩尔,7.05毫升,2.5当量)。将混合物在70℃搅拌16小时,LCMS显示起始材料完全消耗并且检测到所需质量。将反应混合物用饱和氯化铵(20.0mL)稀释。滤饼用水(10.0mL)洗涤并减压浓缩,得到呈黄色固体的7-氟-4-((4-甲氧基苄基)氨基)-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯6(5.00g,12.6mmol,50.0%产率)。LC-MS(ESI)m/z=395.1[M+H]+
步骤5:4-氨基-7-氟-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯(6)
将7-氟-4-((4-甲氧基苄基)氨基)-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯6(2.00g,5.07mmol,1当量)在TFA(20.0mL)中的溶液在75℃搅拌16小时。LCMS显示起始材料已消耗并且检测到所需质量。将反应混合物减压浓缩,得到呈黄色固体状的4-氨基-7-氟-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯7(1.39g,粗品)。LC-MS(ESI)m/z=275.0[M+H]+
步骤6:4-氨基-7-氟-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸(中间体A7)
向4-氨基-7-氟-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸甲酯7(1.39g,5.07mmol,1当量)在EtOH(15mL)/H2O(5.00mL)中的溶液中添加LiOH(638mg,15.2mmol,3当量)。
将混合物在25℃搅拌12小时。LCMS表明起始材料已消耗并且检测到具有所需质量的一个主峰。将反应混合物用H 2O(20.0mL)稀释并用(DCM 10.0mL×2)萃取以除去杂质。用2M HCl将水层调节至pH=6,收集沉淀物并减压干燥,得到呈白色固体的4-氨基-7-氟-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸(中间体A7)(1.30g,5.00mmol,98.5%产率)。1H NMR(400MHz,DMSO-d6)δ13.15(br s,1H),9.12(s,1H),8.56(br d,J=6.4Hz,1H),7.35(br s,2H),7.13(br d,J=12.1Hz,1H),2.62(s,3H).LC-MS(ESI)m/z=261.0[M+H]+
通用方法:中间体B1的合成
合成路线:
步骤1:N-甲氧基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺(1)
向吡唑并[1,5-a]吡啶-2-羧酸(2.0g,12.3mmol)和HATU(7.0g,18.5mmol)的DMF(100mL)溶液中加入Et3N(6.2g,61.7mmol)和甲氧基(甲基)胺(1.9g,30.83mmol),25℃。然后将混合物在25℃搅拌12小时。用水(100mL)淬灭反应,然后用EA(100mL×3)萃取。有机溶液用盐水(100mL)洗涤。有机相用Na 2 SO 4干燥并过滤。减压浓缩滤液。将残余物通过硅胶色谱法纯化,用MeOH的DCM溶液在20分钟内从0%洗脱到10%,得到N-甲氧基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺(2.01g,79%产率)为黄色固体。LC-MS:Rt=1.049min,(ESI)m/z.[M+H]+206.1;C10H11N3O2.
步骤2:吡唑并[1,5-a]吡啶-2-甲醛(3)
在-60℃向N-甲氧基-N-甲基吡唑并[1,5-a]吡啶-2-甲酰胺(1.5g,7.31mmol)的THF(20mL)溶液中加入LiAlH4(439mg,10.96mmol)。然后将混合物在-60℃搅拌2小时。用水(40mL)淬灭反应并过滤。减压浓缩滤液。将残余物通过硅胶色谱法纯化,用DCM中的MeOH在20分钟内从0%洗脱到10%,得到黄色油状的吡唑并[1,5-a]吡啶-2-甲醛(450mg,42%产率)。LC-MS:Rt=1.071min,(ESI)m/z.[M+H]+147.1;C8H6N2O
步骤3:N-(吡唑并[1,5-a]吡啶-2-基甲基)-1-(嘧啶-2-基)乙烷-1-胺(中间体B1)
向吡唑并[1,5-a]吡啶-2-甲醛(100mg,0.68mmol)的MeOH(5mL)溶液中加入1-(嘧啶-2-基)乙胺(126mg,1.03mmol)和NaBH3CN(86毫克,1.37毫摩尔),在25℃下反应。然后将混合物在25℃搅拌2小时。用水(1mL)淬灭反应,减压浓缩溶剂。将残余物通过硅胶色谱法纯化,用MeOH的DCM溶液在20分钟内从0%洗脱到5%,得到N-(吡唑并[1,5-a]吡啶-2-基甲基)-1-(嘧啶-2-基)乙胺(中间体B1)(40毫克,23%产率),为黄色油状物。LC-MS:Rt=0.521min,(ESI)m/z.[M+H]+254.2;C14H15N5
通用方法:中间体B2合成
合成路线:
步骤1:2-二氯甲基-6-三氟甲基咪唑并[1,2-a]吡啶(3)
5-(三氟甲基)吡啶-2-胺(1)(30克,185毫摩尔,1当量),氯苯(450毫升)和1,1,3-三氯-2-丙酮(45克,277毫摩尔,1.5当量)的混合物在135摄氏度反应4小时。LCMS检测到目标产物生成。反应液用碳酸钠调pH到8左右,用乙酸乙酯萃取(500毫升*3),合并有机相拥硫酸镁干燥,过滤滤液减压浓缩至干,经柱层析色谱纯化(二氧化硅,15%乙酸乙酯在石油醚中)得到黄色固体2-二氯甲基-6-三氟甲基咪唑并[1,2-a]吡啶(3)(30克,111毫摩尔,60%产率)。H NMR:ES19506-784-P1A,1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.27(s,1H),7.79(d,J=9.68Hz,1H),7.65(s,1H),7.56(dd,J=1.65,9.57Hz,1H).
步骤2:6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(4)
将2-二氯甲基-6-三氟甲基咪唑并[1,2-a]吡啶(3)(30克,111毫摩尔,1当量),水(600毫升)碳酸钙(33克,334毫摩尔,3当量)升温至100摄氏度反应2小时。LCMS检测到目标产物生成。反应液加硅藻土和乙酸乙酯(600毫升),室温搅拌30分钟,过滤,用乙酸乙酯萃取(600毫升*2)。合并有机相拥硫酸镁干燥,过滤,滤液减压浓缩至干得棕色固体6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(4)(35克),粗品直接用于下一步,不需要进一步纯化。H NMR:ES19506-789-P1A1,1H NMR(400MHz,CHLOROFORM-d)δ10.09-10.29(m,1H),8.59(s,1H),8.27(s,1H),7.82(br d,J=9.46Hz,1H),7.44(br d,J=9.02Hz,1H).
步骤3:1-甲基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)-1H-吡唑-4-胺(中间体B2)
向6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(4)(100mg,467umol,1当量)在DCM(2.00mL)中的溶液中添加KOAc(91.7mg,934umol,2当量)和1-甲基-1H-吡唑-4-胺(45.4mg,467umol,1当量)在-5℃下,将反应混合物在-5℃下搅拌1小时。然后添加NaBH(OAc)3(198mg,934umol,2当量)并在-5℃下再搅拌3小时。LCMS(ET63219-45-P1A1)显示Cpd.4完全消耗并且LCMS上显示几个新峰。将反应混合物用饱和Na 2 CO 3水溶液(3.00mL)稀释并用二氯甲烷(2.00mL×4)萃取。将合并的有机层用Na 2 SO 4干燥,减压浓缩,得到残余物。通过制备型TLC(乙酸乙酯/甲醇=8/1)纯化残余物,得到呈黄色固体的1-甲基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)-1H-吡唑-4-胺(中间体B2)(80.0mg,271umol,58.0%产率)。1H NMR(400
MHz,CDCl3)δ8.47(s,1H),7.69(d,J=9.5Hz,1H),7.64(s,1H),7.35(d,J=1.5,9.5Hz,1H),7.30(s,2H),6.97(s,1H),4.39(s,2H),3.81(s,3H);LC-MS,[MH]+217.0.
通用方法:中间体B3的合成
合成路线:
步骤1:1,3-二甲基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)-1H-吡唑-4-胺(中间体B3)
将6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(4)(10克,46毫摩尔,1当量)和1,3-二甲基吡唑-4-胺(6克,56毫摩尔,1.2当量)溶解在二氯甲烷(150毫升)中,加醋酸(3克,56毫摩尔,3毫升,1.2当量),反应液在25摄氏度反应1小时,加三乙酰氧基硼氢化钠(25克,117毫摩尔,2.5当量),反应液在25摄氏度反应3小时,LCMS检测到目标产物生产。反应液用200毫升碳酸氢钠萃灭,用乙酸乙酯萃取(150毫升*2)。合并有机相用400毫升饱和食盐水洗涤,硫酸镁干燥,过滤,滤液减压浓缩至干。经柱层析色谱纯化(二氧化硅,35%乙酸乙酯:乙醇(3:1)在石油醚中)得到棕色固体1,3-二甲基-N-(6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)-1H-吡唑-4-胺(中间体B3)(14克,45毫摩尔,97%产率)。H NMR:ES19506-795-P1A,1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),7.92(s,1H),7.67(d,J=9.46Hz,1H),7.41(dd,J=1.76,9.46Hz,1H),6.93(s,1H),4.56(br s,1H),4.17(br d,J=3.96Hz,2H),3.52-3.61(m,3H),2.04(s,3H).LCMS:ES19506-795-P1B,(ESI)m/z=310.3(M+1)+,RT=0.64min.
通用方法:中间体B5的合成
合成路线:
步骤1:吡唑并[1,5-a]吡啶-2-甲酸(2)
向吡唑并[1,5-a]吡啶-2-甲酸(10.0g,61.67mmol,1当量)和HATU(28.14g,74.01mmol,1.2当量)、DIEA(31.88g,246.69mmol,4当量)在DCM(500mL)中的溶
液中添加N,O-二甲基羟胺盐酸盐(12.03克,123.35毫摩尔,2当量)。将混合物在25℃搅拌16小时。LCMS(ET63565-18-P1A)表明起始材料完全消耗并且检测到产物。将反应混合物减压浓缩,得到残余物。通过柱色谱法(石油醚/乙酸乙酯=1/1至0/1)纯化残余物,得到呈白色固体的化合物吡唑并[1,5-a]吡啶-2-甲酸(2)(12.1g,58.9mmol,产率95.6%)。1H NMR(400MHz,CHLOROFORM-d)δ8.49(d,J=7.1Hz,1H),7.57(d,J=8.9Hz,1H),7.15(dd,J=7.3,8.4Hz,1H),7.00(s,1H),6.85(t,J=6.9Hz,1H),3.79(s,3H),3.49(s,3H);LC-MS,[MH]+206.22.
步骤2:1-(吡唑并[1,5-a]吡啶-2-基)乙烷-1-酮(3)
氮气气氛下,在-60℃下向吡唑并[1,5-a]吡啶-2-甲酸(2)(2g,9.75mmol,1当量)的THF(20.0mL)溶液中添加MeLi(11.70mL,1.2当量),然后将混合物在25℃下搅拌16小时。LCMS(ET63565-13-P1A1)表明起始材料完全消耗并且检测到产物。将残余物通过柱色谱法(石油醚/乙酸乙酯=50/1至3/1)纯化,得到呈白色固体的1-(吡唑并[1,5-a]吡啶-2-基)乙烷-1-酮(3)(277mg,1.73mmol,17.7%收率)。LC-MS,[MH]+161.1.
步骤3:N-乙基-1-(吡唑并[1,5-a]吡啶-2-基)乙-1-胺(中间体B5)
将1-(吡唑并[1,5-a]吡啶-2-基)乙烷-1-酮(3)(0.1g,624.33umol,1eq)和乙胺(112.58mg,2.50mmol,163.39uL,4eq)在DCM(2mL)中的混合物在-60℃搅拌0.5h,然后在0℃下将NaBH 4(264.64mg,1.25mmol,2当量)添加到混合物中并在N 2气氛下在25℃下搅拌16小时。LCMS(ET63565-9-P1A2)表明起始材料完全消耗并且检测到产物。将反应混合物用H2O(5mL)淬灭,并用DCM(5mL×3)稀释,将合并的有机层减压浓缩,得到残余物。通过制备型TLC(DCM:MeOH=10:1)纯化残余物以得到呈白色固体的N-乙基-1-(吡唑并[1,5-a]吡啶-2-基)乙-1-胺(中间体B5)(50mg,264umol,42.3%收率)。1H NMR(400MHz,CHLOROFORM-d)δ8.39(br d,J=6.9Hz,1H),7.46(br d,J=8.5Hz,1H),7.12-7.03(m,1H),6.70(br t,J=6.8Hz,1H),6.44(s,1H),4.13(br d,J=6.8Hz,1H),3.32-3.21(m,1H),2.77-2.56(m,2H),1.53(d,J=6.6Hz,4H),1.17-1.14(m,3H):LC-MS,[MH]+190.1.
通用方法:中间体B6的合成
合成路线:
步骤1:2-(二氯甲基)-6-(三氟甲基)-1H-苯并[d]咪唑(3)
将4-(三氟甲基)苯-1,2-二胺(5g,28.3mmol,1eq)和2,2-二氯乙酸(7.32g,56.7mmol,4.66mL,2eq)在HCl(125mL)(4M)中的混合物在100℃下搅拌10分钟。16小时。LCMS(ET60224-68-P1A)显示Cpd.1被消耗并且检测到所需的质量。过滤反应混合物并用水洗涤滤饼。将合并的滤液用DCM(20ml*3)萃取。将合并的有机层用
盐水(100mL)洗涤,经MgSO4干燥,过滤并减压浓缩,得到残余物。将残余物通过柱色谱法(石油醚/乙酸乙酯=20/1至5/1)纯化,得到呈黄色油状的化合物2-(二氯甲基)-6-(三氟甲基)-1H-苯并[d]咪唑(3)(4.4g,16.3mmol,收率57.6%)。1H NMR(400MHz,CHLOROFORM-d)δ8.01(s,1H),7.79(d,J=8.6Hz,1H),7.66(d,J=8.2Hz,1H),7.26(s,1H);LCMS:[M+H]+268.9
步骤2:6-(三氟甲基)-1H-苯并[d]咪唑-2-甲醛(4)
向2-(二氯甲基)-6-(三氟甲基)-1H-苯并[d]咪唑(3)(1g,3.72mmol,1当量)在H 2O(20mL)中的悬浮液中添加CaCO3(1.12g,11.1mmol,3当量)。将混合物在100℃搅拌8小时。LCMS(ET60224-74-P1B)显示Cpd.3被消耗并且检测到所需的质量。将反应混合物用H2O(50mL)稀释并用乙酸乙酯(30mL×3)萃取。将合并的有机层减压浓缩,得到呈白色固体的6-(三氟甲基)-1H-苯并[d]咪唑-2-甲醛(4)(310mg,1.45mmol,38.9%产率)。(1H NMR(400MHz,DMSO-d6)δ14.28-13.59(m,1H),10.02(s,1H),8.40-8.30(m,2H),8.23-8.05(m,3H),8.00(dd,J=5.4,8.5Hz,1H),7.89(br s,1H),7.83-7.61(m,3H),7.34(br d,J=7.9Hz,1H),7.27(d,J=7.6Hz,1H);LCMS:[M+H]+215.2
步骤3:2-甲基-N-((6-(三氟甲基)-1H-苯并[d]咪唑-2-基)甲基)丙-1-胺(中间体B6)
在25℃下,向6-(三氟甲基)-1H-苯并[d]咪唑-2-甲醛(4)(0.31g,1.45mmol,1当量)和2-甲基丙-1-胺(105mg,1.45mmol,143uL,1当量)在DCM(6.2mL)中的溶液中添加KOAc(170mg,1.74mmol,1.2eq)。将混合物在25℃搅拌0.5小时,然后在25℃将NaBH(OAc)3(398mg,1.88mmol,1.3当量)添加至上述混合物,将混合物在25℃搅拌15.5小时。LCMS(ET60224-77-P1A)显示Cpd.4被消耗并且检测到所需的质量。将反应混合物用H2O(10mL)稀释并用DCM(2mL×3)萃取。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤并减压浓缩,得到残余物。通过制备型TLC(石油醚/乙酸乙酯=0/1)纯化残余物,得到呈无色油状的2-甲基-N-((6-(三氟甲基)-1H-苯并[d]咪唑-2-基)甲基)丙-1-胺(中间体B6)(100mg,368umol,25.4%收率,100%纯度)。1H NMR(400MHz,CHLOROFORM-d)7.80(s,1H),7.56(d,J=8.4Hz,1H),7.43(d,J=8.5Hz,1H),4.07(s,2H),2.45(d,J=6.8Hz,2H),1.82-1.68(m,1H),0.89(d,J=6.6Hz,6H);LCMS:[M+H]+272.0
通用方法:中间体B7的合成
步骤:2-甲基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)丙-1-胺(中间体B7)
向2-甲基丙-1-胺(68.3mg,933umol,92.8uL,1当量)和6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(0.2g,933umol,1当量)在DCM(4mL)中的溶液中添加KOAc(109mg,1.12mmol,1.2当量)在25℃下,将混合物在25℃下搅拌0.5小时,
然后在25℃下将NaBH(OAc)3(257mg,1.21mmol,1.3当量)添加到上述混合物中,将混合物25℃搅拌15.5小时。LCMS(ET60224-75-P1A)显示Cpd.4被消耗并且检测到所需的质量。将反应混合物用H2O(10mL)稀释并用DCM(2mL×3)萃取以除去杂质。将水层用饱和Na2CO3碱化至pH=8,然后用DCM(10mL*3)萃取。将合并的有机层经MgSO4干燥,过滤并减压浓缩,得到呈无色油状的中间体2-甲基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)丙-1-胺(中间体B7)(108mg,398umol,42.6%收率,100%纯度)。1H NMR(400MHz,CHLOROFORM-d)δ8.49(s,1H),7.70-7.62(m,2H),7.33(br d,J=9.2Hz,1H),4.01(s,2H),2.54(d,J=6.7Hz,2H),1.84(quind,J=6.6,13.3Hz,1H),0.97(d,J=6.6Hz,6H);LC-MS,[MH]+272.0.
实施例4的合成
步骤7:(E)-4-(((二甲氨基)亚甲基)氨基)-3-甲基吡唑并[1,5-a]喹喔啉-8-碳酰氯(中间体A6-1)
向4-氨基-3-甲基吡唑并[1,5-a]喹喔啉-8-甲酸(中间体A6)(50.0mg,206umol,1当量)在DCM(2mL)中的溶液中添加HCl/二恶烷(4M)。将混合物在25℃搅拌0.5小时。然后将反应混合物浓缩,用己烷(10mL×3)蒸,并冷却至0℃。在0℃滴加草酰二氯(157mg,1.24mmol,108uL,6当量)和DMF(3.02mg,41.3umol,3.18uL,0.2当量)。将混合物在0℃搅拌2小时。在MeOH中取出样品。LC-MS显示检测到所需质量的甲酯。将混合物减压浓缩,得到残余物。将残余物用正己烷(5mL)研磨,然后减压浓缩,得到呈黄色固体的(E)-4-(((二甲氨基)亚甲基)氨基)-3-甲基吡唑并[1,5-a]喹喔啉-8-碳酰氯(中间体A6-1)(50.0mg,158umol,76.7%产率)。LC-MS,[MH]+243.1
步骤8:(E)-4-(((二甲基氨基)亚甲基)氨基)-3-甲基-N-(1-(嘧啶-2-基)乙基)-N-((5-(三氟甲基)吡啶-2-基)甲基)吡唑并[1,5-a]喹喔啉-8-甲酰胺(中间体A6-2)
向(E)-4-(((二甲氨基)亚甲基)氨基)-3-甲基吡唑并[1,5-a]喹喔啉-8-碳酰氯(中间体A6-1)(50.0mg,158umol,1eq)和DIEA(81.9mg,633umol,110uL,4eq)的THF(2mL)溶液中添加Int.6(44.7mg,158umol,1当量)在0℃。将混合物在0℃搅拌2小时。LC-MS显示起始材料完全消耗并且检测到所需的质量。将混合物减压浓缩,得到(E)-4-(((二甲基氨基)亚甲基)氨基)-3-甲基-N-(1-(嘧啶-2-基)乙基)-N-((5-(三氟甲基)
吡啶-2-基)甲基)吡唑并[1,5-a]喹喔啉-8-甲酰胺(中间体A6-2)(61.0mg,109umol,68.6%收率),为黄色固体。LC-MS,[MH]+562.2.
步骤9:4-氨基-3-甲基-N-(1-(嘧啶-2-基)乙基)-N-((5-(三氟甲基)吡啶-2-基)甲基)吡唑并[1,5-a]喹喔啉-8-甲酰胺(实施例4)
将(E)-4-(((二甲基氨基)亚甲基)氨基)-3-甲基-N-(1-(嘧啶-2-基)乙基)-N-((5-(三氟甲基)吡啶-2-基)甲基)吡唑并[1,5-a]喹喔啉-8-甲酰胺(中间体A6-2)(60.0mg,107umol,1eq)在NH3/MeOH(2mL)中的溶液在70℃搅拌2小时。LC-MS显示起始材料完全消耗并且检测到所需的质量。将反应混合物减压浓缩,得到残余物。残余物通过制备型HPLC纯化(柱:Waters Xbridge Prep OBD C18 150*40mm*10um;流动相:[水(NH4HCO3)-ACN];B%:25%-65%,8分钟,UV 220&254nm),得到白色固体状的4-氨基-3-甲基-N-(1-(嘧啶-2-基)乙基)-N-((5-(三氟甲基)吡啶-2-基)甲基)吡唑并[1,5-a]喹喔啉-8-甲酰胺(实施例4)(19.2mg,37.9umol,35.48%产率,100%纯度)。1H NMR(400MHz,DMSO-d6)δ8.84(br s,1H)8.79(br d,J=4.63Hz,2H)8.28(br s,1H)8.13(br d,J=6.75Hz,1H)7.80-8.01(m,1H)7.49-7.72(m,3H)7.29-7.47(m,1H)6.99(br s,2H)5.43(br s,1H)4.92(br d,J=17.01Hz,1H)4.52(br d,J=16.51Hz,1H)2.50(br s,3H)1.62(br d,J=7.00Hz,3H).LC-MS,[MH]+507.2
实施例15的合成
步骤1:4-(2,4-二甲氧基苄基)氨基)-N-乙基-1,3-二甲基-N-(5-(三氟甲基)吡啶-2-基甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(3)
将4-((2,4-二甲氧基苄基)氨基)-1,3-二甲基咪唑并[1,5-a]喹喔啉-8-羧酸(h)(100毫克,246.0微摩尔,1当量)溶解在N,N-二甲基甲酰胺(2.5毫升)中,加N-(5-(三氟甲基)吡啶-2-基甲基)乙胺(60.3毫克,295.2微摩尔,1.2当量),N,N,N,N-四甲基氯甲脒六氟磷酸盐(138毫克,492.1微摩尔,2当量)和N-甲基咪唑(101毫克,1.23毫摩尔,98.1微升,5当量),反应液50摄氏度反应16小时。LCMS原料消耗完全,目标产物生成。反应液减压浓缩至干通过柱层析色谱纯化(4克硅胶柱,0~2.3%甲醇/二氯甲烷体系,流速20毫升/分钟)得黄色油状物4-(2,4-二甲氧基苄基)氨基)-N-乙基-1,3-二甲基-N-(5-(三氟甲基)吡啶-2-基甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(3)(150毫克,233.45微摩尔,94.88%产率,92.23%纯度)。LCMS:ES19974-409-P1B1,(ESI)m/z=593.2[M+1]+;RT=0.82min,purity:92.23%
步骤2:4-氨基-N-乙基-1,3-二甲基-N-((5-三氟甲基)吡啶-2-基甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例15)
将4-(2,4-二甲氧基苄基)氨基)-N-乙基-1,3-二甲基-N-(5-(三氟甲基)吡啶-2-基甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(3)(140毫克,236.2微摩尔,1当量)溶解在二氯甲烷中
(0.5毫升)加三氟乙酸(2.5毫升),反应液50摄氏度反应16小时,LC-MS检测到原料消耗完全,目标产物生成。反应液减压浓缩至干,加10%碳酸钠(10毫升),用二氯甲烷萃取(10毫升*3),合并有机相用饱和食盐水洗涤(10毫升),硫酸镁干燥,过滤,浓缩至干,通过反相制备液相色谱纯化(Boston Prime C18柱子,150*30毫米*5微米;流动相:[水(氨水)-乙腈];B%梯度:30%-50%,9分钟)得到白色固体4-氨基-N-乙基-1,3-二甲基-N-((5-三氟甲基)吡啶-2-基甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例15)(30毫克,67.81微摩尔,28.70%产率)。LCMS:ES19974-414-P1B1,(ESI)m/z=443.1[M+1]+;RT=2.623min,purity:100.0%。HNMR:ES19974-414-P1A,1H NMR(400MHz,DMSO-d6)Shift=8.97(br s,1H),8.20(br d,J=6.9Hz,1H),7.97(br s,1H),7.61(br d,J=8.1Hz,1H),7.39(br s,2H),6.72(br s,2H),4.82(br s,2H),3.45(q,J=6.9Hz,2H),3.10-2.60(m,3H),2.56(br s,3H),1.14(t,J=7.0Hz,3H)
实施例86的合成
步骤1:7-氯-4-[(2,4-二甲氧基苯基)甲基氨基]-1-甲基-N-(1-甲基吡唑-4-基)-N-[[6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]甲基]咪唑并[1,5-a]喹喔啉-8-甲酰胺(3)
将7-氯-4-((2,4-二甲氧基苄基)氨基)-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(中间体A3)(145毫克,339微摩尔,1当量)加入1-甲基-N-[[6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]甲基]吡唑-4-胺(中间体B2)(100毫克,339微摩尔,1当量)的到乙腈(2毫升)溶液中,溶解后依次加入N,N,N,N-四甲基氯甲脒六氟磷酸盐(285毫克,1毫摩尔,3当量)和N-甲基咪唑(139毫克,1.7毫摩尔,135微升,5当量)。反应在50摄氏度下搅拌16小时。LC-MS检测到原料反应完全,目标产物生成。反应液过滤后减压浓缩得到粗产物。粗产物经柱层析分离纯化(二氧化硅,10%甲醇在二氯甲烷中)得到黄色油状7-氯-4-[(2,4-二甲氧基苯基)甲基氨基]-1-甲基-N-(1-甲基吡唑-4-基)-N-[[6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]甲基]咪唑并[1,5-a]喹喔啉-8-甲酰胺(3)(130毫克,185微摩尔,54.5%产率)。
步骤2:4-氨基-7-氯-1-甲基-N-(1-甲基-1氢-吡唑-4-基)-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基])甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例86)
7-氯-4-[(2,4-二甲氧基苯基)甲基氨基]-1-甲基-N-(1-甲基吡唑-4-基)-N-[[6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]甲基]咪唑并[1,5-a]喹喔啉-8-甲酰胺(3)(120毫克,170微摩尔,1当量)加入到三氟乙酸(0.4毫升)和二氯甲烷(1毫升)的混合溶液中并溶解。反应在50摄氏度下搅拌16小时。LC-MS显示原料反应完全有目标产物生成。反应经减压浓缩至干。通过反相制备液相色谱纯化(Boston Prime C18柱子,5微米二氧化硅30毫米直径,150毫米长度,使用水和乙腈的极性递减的混合物作为洗脱液)得到白色4-氨基-7-氯-1-甲基-N-(1-甲基-1氢-吡唑-4-基)-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基])甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例86)(30毫克,53微摩尔,31%
产率,98.%纯度).H NMR:1H NMR(400MHz,DMSO-d6)δ9.15-9.31(m,1H),8.33(s,1H),8.07-8.16(m,1H),7.92-8.03(m,1H),7.76-7.86(m,1H),7.58-7.75(m,2H),7.41-7.55(m,3H),7.18-7.33(m,1H),4.71-5.17(m,2H),3.53-3.83(m,3H),2.80-2.97(m,3H).LCMS:(ESI)m/z=554.2(M+1)+,RT=1.544min,purity of 98.7%.
实施例143的合成
合成方法:
步骤1:2-甲基-N-(5-三氟甲基)吡啶-2-基甲基)吡啶-3-胺(3)
5-(三氟甲基)吡啶甲醛(2)(300毫克,1.71毫摩尔,1.0当量),2-甲基吡啶-3-胺(1)(216毫克,2.00毫摩尔,1.17当量)和醋酸(123毫克,2.05毫摩尔,117.25微升,1.2当量)溶解在二氯甲烷中(10毫升),室温搅拌4小时,加三乙酰氧基硼氢化钠(1.09g,5.15毫摩尔,3.01当量),室温搅拌12小时。LCMS检测到原料消耗完全,产物生成。反应液加水和二氯甲烷稀释,用2摩尔碳酸钾水溶液调节pH到12左右,分液,水相用二氯甲烷萃取(10毫升*3),合并有机相用硫酸钠干燥,过滤,减压浓缩至干经柱层析色谱纯化(12克硅胶柱,0~25%乙酸乙酯/石油醚体系,流速,30毫升/分钟)得黄色浆状物2-甲基-N-(5-三氟甲基)吡啶-2-基甲基)吡啶-3-胺(3)(205毫克,44.7%产率)。LCMS ES15882-1182-P1A:(ESI)m/z=268.1[M+1]+;RT=0.65min
步骤2:4-氨基-7-氟-1-甲基-N-(2-甲基吡啶-3-基)-N-(5-(三氟甲基)吡啶-2-基甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例143)
将2-甲基-N-(5-三氟甲基)吡啶-2-基甲基)吡啶-3-胺(3)(60毫克,224.51微摩尔,1.0当量),4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(60毫克,230.57微摩尔,1.03当量)和N-乙基-N-异丙基-2-丙胺(119毫克,925.11微摩尔,161.13微升,4.12当量)溶解在1-甲基吡咯烷-2-酮(1.0毫升)中,加2-氯-1,3-二甲基-4,5-二氢咪唑-1-氯化物(DMC)(57.82毫克,342.02微摩尔,1.52当量),反应液80摄氏度反应16小时。LCMS检测到目标产物生成。反应液通过反相制备液相色谱纯化(甲酸条件;Boston Prime C18柱子,150*30毫米*5微米;流动相:[水(甲酸)-乙腈];梯度:15%-35%B,10分钟)得到黄色固体4-氨基-7-氟-1-甲基-N-(2-甲基吡啶-3-基)-N-(5-(三氟甲基)吡啶-2-基甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例143)(8毫克,6.29%产率)。LCMS ES15882-1205-P1B1:(ESI)m/z=510.1[M+1]+;RT=0.996min.1H NMR(400MHz,DMSO-d6)Shift 8.84-8.98(m,1H),8.17-8.27(m,2H),7.72-7.87(m,4H),7.50(s,2H),7.13(dd,J=4.64,7.91Hz,1H),7.01(d,J=11.29Hz,1H),5.44(d,J=15.81Hz,1H),5.01(d,J=15.81Hz,1H),2.82(s,3H),2.37(s,3H)
19F NMR(376.5MHz,DMSO-d6)Shift-60.71,-60.85,-116.51,-119.18
实施例145的合成
合成方法:
步骤1:2-甲氧基-N-(5-三氟甲基)吡啶-2-基甲基)吡啶-3-胺(3)
5-(三氟甲基)吡啶甲醛(2)(300毫克,1.71毫摩尔,1.0当量),2-甲氧基吡啶-3-胺(1)(248毫克,2.00毫摩尔,1.17当量)和醋酸(123毫克,2.05毫摩尔,1.2当量)溶解在二氯甲烷中(10毫升)室温搅拌4小时。加三乙酰氧基硼氢化钠(1.09g,5.15毫摩尔,3.01当量)室温搅拌12小时,LCMS检测到原料消耗完全,产物生成。反应液加水和二氯甲烷稀释,用2摩尔碳酸钾水溶液调节pH到12左右,分液,水相用二氯甲烷萃取(10毫升*3),合并有机相用硫酸钠干燥,过滤,减压浓缩至干经柱层析色谱纯化(12克硅胶柱,0~15%乙酸乙酯/石油醚体系,流速,30毫升/min)得黄色浆状物2-甲氧基-N-(5-三氟甲基)吡啶-2-基甲基)吡啶-3-胺(3)(430毫克,1.52毫摩尔,88.61%产率)。
LCMS ES15882-1189-P1A:(ESI)m/z=284.0[M+1]+;RT=0.82min
步骤2:4-氨基-7-氟-N-(2-甲氧基吡啶-3-基)-1-甲基-N-(5-三氟甲基)吡啶-2-甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例145)
将2-甲氧基-N-(5-三氟甲基)吡啶-2-基甲基)吡啶-3-胺(3)(64毫克,226微摩尔,1.0当量.),4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(61毫克,234微摩尔,1.04当量.)和N-乙基-N-异丙基-2-丙胺(119毫克,919微摩尔,4.07当量.)溶解在1-甲基吡咯烷-2-酮中(1.0毫升)加2-氯-1,3-二甲基-4,5-二氢咪唑-1-氯化物(DMC)(58毫克,344微摩尔,1.52当量.),反应液80摄氏度反应16小时。LCMS检测到目标产物生成。反应液通过反相制备液相色谱纯化(甲酸条件;Boston Prime C18柱子,150*30毫米*5微米;流动相:[水(甲酸)-乙腈];梯度:23%-43%B,10分钟)得到黄色固体4-氨基-7-氟-N-(2-甲氧基吡啶-3-基)-1-甲基-N-(5-三氟甲基)吡啶-2-甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例145)(12毫克,8.79%产率,87%纯度)LCMS ES15882-1206-P1B1:(ESI)m/z=526.1[M+1]+;RT=1.140min
1H NMR(400MHz,DMSO-d6)Shift 8.91(s,1H),8.23-8.30(m,1H),8.20(s,0.2H,HCOOH),7.91-7.95(m,1H),7.86(d,J=6.53Hz,1H),7.77-7.83(m,2H),7.72-7.76(m,1H),7.50(br s,2H),7.03(d,J=11.29Hz,1H),6.89(dd,J=5.02,7.53Hz,1H),5.34(d,J=16.06Hz,1H),5.04(d,J=15.81Hz,1H),3.74(s,3H),2.80(s,3H)
19F NMR(376.5MHz,DMSO-d6)Shift-60.72,-117.24
实施例188的合成
合成方法:
步骤1:1,3-二甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)-1H-吡唑-4-胺(2)
将5-(三氟甲基)吡啶甲醛(1)(300毫克,1.71毫摩尔,1当量)溶解在二氯甲烷(8毫升)中,加入1,3-二甲基-1H-吡唑-4-胺(247毫克,2.22毫摩尔,1.3当量)和冰醋酸(134毫克,2.23毫摩尔,127.74微升,1.3当量),反应在15~20摄氏度下搅拌4小时。再加入醋酸硼氢化钠(1.09克,5.15毫摩尔,3.01当量),15~20摄氏度下搅拌12小时。LC-MS检测到原料反应完全,目标产物生成。向反应液中加入10毫升水和10毫升二氯甲烷,用2摩尔每升的碳酸钾水溶液碱化至pH等于12,分液,用二氯甲烷(10毫升*3)萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩至干,经柱层析色谱纯化(12克硅胶柱,洗脱液0~40%(乙酸乙酯:乙醇=3:1)/石油醚,流速@30毫升/分钟),减压浓缩得到黄色固体1,3-二甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)-1H-吡唑-4-胺(3)(311毫克,1.15毫摩尔,67.17%产率)。
LCMS ES15882-1166-P1A:(ESI)m/z=228.2[M+1]+;RT=0.601min
步骤2:4-氨基-N-(1,3-二甲基-1H-吡唑-4-基)-1,7-二甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例188)
向反应液4-氨基-1,7-二甲基咪唑并[1,5-a]喹喔啉-8-羧酸(c)(42毫克,163.90微摩尔,1当量),1,3-二甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)-1H-吡唑-4-胺(b)(45.18毫克,167.17微摩尔,1.02当量)和N,N-二异丙基乙胺(84.73毫克,655.59微摩尔,114.19微升,4当量)溶解在1-甲基-2-吡咯烷酮(1毫升)中,加入2-氯-1,3-二甲基-4,5-二氢咪唑-1-氯化物(41.56毫克,245.84微摩尔,1.5当量)。反应在50摄氏度下搅拌3小时。LC-MS检测有原料反应完全,目标产物生成。通过反相制备液相色谱纯化(Boston Prime C18柱子,5微米二氧化硅30毫米直径,150毫米长度,使用水(含有0.05%甲酸)和乙腈(20%-40%)的极性递减的混合物作为洗脱液)得到黄色固体。粗品再通过反相制备液相色谱纯化(Boston Prime C18柱子,5微米二氧化硅30毫米直径,150毫米长度,使用水(含有0.05%甲酸)和乙腈(18%-38%)的极性递减的混合物作为洗脱液)得到白色固体4-氨基-N-(1,3-二甲基-1H-吡唑-4-基)-1,7-二甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例188)(10毫克,19.67微摩尔,12.00%产率)。LCMS:ES13685-1063-P1D,(ESI)m/z=509.1[M+1]+;RT=1.066minNMR:ES13685-1063-P1A,1H NMR(400MHz,DMSO-d6)8.95(s,1H),8.25(br d,J=8.60Hz,1H),8.15(s,1H),7.75(s,2H),7.56-7.72(m,2H),7.23(br d,J=4.84Hz,3H),5.14(s,2H),3.51-3.70(m,3H),2.79(s,3H),2.38-2.44(m,3H),1.83(s,3H),19F NMR(376MHz,DMSO-d6)-60.68(br s,3F)
实施例210的合成
合成方法:
步骤1:1,4-二甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)-1H-咪唑-2-胺(2)
将2-溴-1,4-二甲基-1H-咪唑(210毫克,1.20毫摩尔,1当量)溶解在四氢呋喃(12毫升)中,在氮气保护下加入(5-(三氟甲基)吡啶-2-基)甲胺(1)(211毫克,1.20毫摩尔,1当量),三甲基(氧化)硅烷钠(267毫克,1.44毫摩尔,1.2当量)和溴代[二环己基[3-(1,1-二甲基乙氧基)-6-甲氧基-2′,6′-双(1-甲基乙基)[1,1′-联苯基]-2-基-κC1′]膦-κP][4-[[2-(三甲基硅基)乙氧基]羰基]苯基]-,(SP-4-2)-钯(GPhos-Pd-G6)(50毫克,59.99微摩尔,0.05当量),反应在80摄氏度下搅拌16小时。LC-MS检测到原料反应完全,目标产物生成。降至室温,向反应液中加入10毫升水,用乙酸乙酯萃取(10毫升*3),有机相用无水硫酸镁干燥,过滤滤液减压浓缩至干,经柱层析色谱纯化(4克+4克硅胶柱,洗脱液0~40%乙酸乙酯/石油醚,流速20毫升/分钟)得到黄色液体1,4-二甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)-1H-咪唑-2-胺(2)(50毫克,185.01微摩尔,15.42%产率)。
LCMS:ES13685-1155-P1C,(ESI)m/z=271.1[M+1]+;RT=0.926min
步骤2:4-氨基-N-(1,4-二甲基-1H-咪唑-2-基)-7-氟-1-甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)咪唑[1,5-a]喹喔啉-8-甲酰胺(实施例210)
向反应液4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(40毫克,153.71微摩尔,1当量),1,4-二甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)-1H-咪唑-2-胺(2)(41.54毫克,153.71微摩尔,1当量)和N,N-二异丙基乙胺(79.46毫克,614.86微摩尔,107.09微升,4当量)溶解在1-甲基-2-吡咯烷酮(1毫升)中,加入2-氯-1,3-二甲基-4,5-二氢咪唑-1-氯化物(38.98毫克,230.5微摩尔,1.5当量)。反应在60摄氏度下搅拌16小时。LC-MS检测有少量原料剩余,目标产物生成。通过反相制备液相色谱纯化(Boston Prime C18柱子,5微米二氧化硅30毫米直径,150毫米长度,使用水(含有0.05%甲酸)和乙腈(10%-30%)的极性递减的混合物作为洗脱液)得到黄色固体。粗品再通过反相制备液相色谱纯化(Boston Prime C18柱子,5微米二氧化硅30毫米直径,150毫米长度,使用水(含有0.05%氨水)和乙腈(28%-48%)的极性递减的混合物作为洗脱液)得到白色固体4-氨基-N-(1,4-二甲基-1H-咪唑-2-基)-7-氟-1-甲基-N-((5-(三氟甲基)吡啶-2-基)甲基)咪唑[1,5-a]喹喔啉-8-甲酰胺(实施例210)(3毫克,5.56微摩尔,3.62%产率)。LCMS:ES13685-1158-P1C1,(ESI)m/z=513.3[M+1]+;RT=0.759min
NMR:ES13685-1158-P1A,1H NMR(400MHz,DMSO-d6)8.91(br s,1H),8.23(br d,J=8.13Hz,1H),7.97(br d,J=6.75Hz,1H),7.89(br s,1H),7.81(s,1H),7.34(br s,2H),7.13(br d,J=11.26Hz,1H),6.50(s,1H),5.17(br s,2H),3.23-3.28(m,3H),2.87(s,3H),1.96(br s,3H).NMR:ES13685-1158-P1A,19F NMR(376MHz,DMSO-d6)-60.85(s,3F),-118.24(br s,1F)
实施例213的合成
合成方法:
步骤1:1-甲基-N-(1-三氟甲基)吡唑-4-基甲基)-1H-吡唑-5-胺(3)
1-甲基吡唑-5-胺(133毫克,1.37毫摩尔,1.5当量)和1-三氟甲基吡唑-4-甲醛(1)(150毫克,914.16微摩尔,1当量)溶解在甲醇中(5毫升)加醋酸(164毫克,2.74毫摩尔,156.99微升,3当量),反应液室温搅拌半小时。加氰基硼氢化钠(172.34毫克,2.74毫摩尔,3当量),室温搅拌15.5小时。LCMS检测反应完成,目标产物生成。减压浓缩至干,加碳酸氢钠(10毫升),用乙酸乙酯萃取(10毫升*3),合并有机相用无水硫酸钠干燥,过滤,减压浓缩至干,通过柱层析色谱纯化(12g 硅胶柱,0~60%乙酸乙酯:乙醇(3:1)/石油醚体系,流速,35毫升/分钟)。得到无色油状物1-甲基-N-(1-三氟甲基)吡唑-4-基甲基)-1H-吡唑-5-胺(3)(220毫克,897.21微摩尔,86.86%产率)。LCMS:ES13683-1961-P1C,(ESI)m/z=246.1(M+1)+,RT=0.786min
步骤2:4-氨基-7-氟-1-甲基-1-甲基吡唑-5-基)-N-(1-三氟甲基-1H-吡唑-4-基)甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例213)
4-氨基-7-氟-1-甲基咪唑并[1,5-a]喹喔啉-8-羧酸(63.6毫克,244.69微摩尔,1当量)和1-甲基-N-(1-三氟甲基)吡唑-4-基甲基)-1H-吡唑-5-胺(3)(60毫克,244.69微摩尔,1当量)溶解在1-甲基吡咯烷-2-酮中(1.5毫升)加N-乙基-N-异丙基-2-丙胺(158毫克,1.22毫摩尔,213.11微升,5当量)和2-氯-1,3-二甲基-4,5-二氢咪唑-1-氯化物(DMC)(62.0毫克,367.04微摩尔,1.5当量),反应液50摄氏度反应16小时。LCMS检测原料消耗完全,目标产物生成。反应液用乙腈(1毫升)和水(1毫升)稀释,过滤,滤液反相制备液相色谱纯化(Boston Prime C18柱子150*30毫米*5微米;流动相:[水(甲酸)-乙腈];梯度:18%-38%,10分钟)得白色固体4-氨基-7-氟-1-甲基-1-甲基吡唑-5-基)-N-(1-三氟甲基-1H-吡唑-4-基)甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例213)(50毫克,100.53微摩尔,41.08%产率,98%纯度)。LCMS:ES13683-1966-P1C,(ESI)m/z=488.3[M+1]+,RT=0.767min HNMR:ES13683-1966-P1A,1H NMR(400MHz,DMSO-d6)Shift 8.39(s,1H),8.17(s,0.2H),7.84-8.07(m,2H),7.80(s,1H),7.52(s,2H),7.23(br s,1H),7.06(br d,J=11.01Hz,1H),6.06(br s,1H),4.49-5.28(m,2H),3.48-3.74(m,3H),2.87(s,3H).FNMR:19F NMR(376MHz,DMSO-d6)Shift-59.21(s,3F),-118.10(br s,1F)
实施例220的合成
合成方法:
步骤1:4-氟-2-甲基-N-[[6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]甲基]吡唑-3-胺(3)将6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(1)(700毫克,3.27毫摩尔,1当量)溶解在甲醇(14毫升)中,加入4-氟-1-甲基-1H-吡唑-5-胺(2)(402.61毫克,3.50毫摩尔,1.07当量)和冰醋酸(255.18毫克,4.25毫摩尔,243.26微升,1.3当量),反应在25摄氏度下搅拌1小时。再加入氰基硼氢化钠(616.24毫克,9.81毫摩尔,3当量),25摄氏度下搅拌15小时。LC-MS检测到原料反应完全,目标产物生成。反应液浓缩旋干,加入14毫升2摩尔/升的碳酸钠水溶液和14毫升乙酸乙酯,分液,用乙酸乙酯萃取(14毫升*3),有机相用无水硫酸镁干燥,过滤,滤液减压浓缩至干,经柱层析色谱纯化(12克+4克硅胶柱,洗脱液0~30%乙酸乙酯:乙醇3:1/石油醚,流速30毫升/分钟),减压浓缩得到浅黄色固体4-氟-2-甲基-N-[[6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]甲基]吡唑-3-胺(3)(970毫克,3.10毫摩尔,94.73%产率)。LCMS:ES13685-1213-P1A,(ESI)m/z=314.0[M+1]+;RT=1.537min。NMR:ES13685-1213-R2A,1H NMR(400MHz,CHLOROFORM-d)7.11(d,J=4.38Hz,1H),3.57(s,3H),3.24(br s,2H)。HNMR:ES13685-1213-R2A,19F NMR(376MHz,CHLOROFORM-d)-185.48(s,1F)
步骤2:4-氨基-7-氟-N-(4-氟-1-甲基-1H-吡唑-5-基)-1-甲基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶)-2-基)甲基)咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例220)
向反应液4-氨基-7-氟-甲基-咪唑并[1,5-a]喹喔啉-8-羧酸(500毫克,1.92毫摩尔,1当量),4-氟-2-甲基-N-[[6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]甲基]吡唑-3-胺(3)(601.89毫克,1.92摩尔,1当量)和N,N-二异丙基乙胺(993.30毫克,7.69摩尔,1.34毫升,4当量)溶解在1-甲基-2-吡咯烷酮(10毫升)中,加入2-氯-1,3-二甲基-4,5-二氢咪唑-1-氯化物(487.23毫克,2.88毫摩尔,1.5当量)。反应在50摄氏度下搅拌16小时。LC-MS检测有47%原料剩余,36%目标产物生成。再加入2-氯-1,3-二甲基-4,5-二氢咪唑-1-氯化物(74.71毫克,441.93微摩尔,0.23当量)。反应在50摄氏度下搅拌16小时。LC-MS检测有49%原料剩余,38%目标产物生成。通过反相制备液相色谱纯化(Boston Prime C18柱子,5微米二氧化硅30毫米直径,150毫米长度,使用水(含有0.05%甲酸)和乙腈(20%-40%)的极性递减的混合物作为洗脱液)得到浅黄色固体。核磁检测有部分成甲酸盐,粗品再通过反相制备液相色谱纯化(Boston Prime C18柱子,5微米二氧化硅30毫米直径,150毫米长度,使用水(含有0.05%氨水)和乙腈(32%-52%)的极性递减的混合物作为洗脱液)得到白色固体4-氨基-7-氟-N-(4-氟-2-甲基-吡唑-3-基)-1-甲基-N-[[6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基]甲基]咪唑并[1,5-a]喹喔啉-8-甲酰胺(实施例220)(155毫克,276.26微摩尔,14.38%产率)
LCMS:ES13685-1217-P1D1,(ESI)m/z=556.1[M+1]+;RT=1.929minNMR:ES13685-1217-P1B,1H NMR(400MHz,DMSO-d6)9.28(br s,1H),8.10(br s,1H),7.92(br s,1H),7.82(s,1H),7.73(d,J=9.76Hz,1H),7.55(s,2H),7.47(br d,J=8.63Hz,1H),7.29(br s,1H),7.11(br d,J=10.38Hz,1H),5.19(br s,1H),5.04-5.14(m,1H),3.59(s,3H),2.86(br s,3H)。NMR:ES13685-1217-P1B,19F NMR(376MHz,DMSO-d6)-60.47(s,3F),-118.15(s,1F),-173.54(s,1F)
实施例287的合成
步骤1:(E)-4-(((二甲氨基)亚甲基)氨基)-7-氟-3-甲基咪唑并[1,5-a]喹喔啉-8-碳酰氯(中间体A7-1)
向4-氨基-7-氟-3-甲基咪唑并[1,5-a]喹喔啉-8-甲酸(中间体A7)(270mg,1.04mmol,1当量)在DCM(3.00mL)中的搅拌溶液中添加HCl/二恶烷(4M,778uL,3当量)。将混合物在25℃搅拌0.5小时。然后将反应混合物浓缩,用甲苯(10mL x 3)蒸并干燥,将粗物质溶解在DCM(3.00mL)中,并冷却至0℃,加入草酰二氯(790mg,6.23mmol,544uL,在0℃下滴加6当量)和DMF(75.8毫克,1.04毫摩尔,79.8uL,1当量)。将混合物在25℃搅拌12小时。LCMS表明起始材料已消耗并且检测到具有所需质量的一个主峰。将反应混合物浓缩,用正己烷(10mL×3)蒸煮并减压干燥,得到呈黄色固体状的(E)-4-(((二甲氨基)亚甲基)氨基)-7-氟-3-甲基咪唑并[1,5-a]喹喔啉-8-碳酰氯(中间体A7-1)(340mg,粗品)。LC-MS(ESI)m/z=330.0[M+H]+
步骤2:4-氨基-7-氟-N-(1-甲氧基丙-2-基)-3-甲基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)咪唑[1,5-a]喹喔啉-8-甲酰胺(实施例287)
向1-甲氧基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)丙-2-胺(50.0mg,174umol,1eq)和DIEA(89.9mg,696umol,121uL,4eq)的THF(1.00mL)溶液中添加Int.24_COCl(63.9mg,191umol,1.1eq))在0℃。将混合物在25℃搅拌3小时。在25℃下通过添加MeOH(1.00mL)猝灭反应混合物,并减压浓缩,得到残余物。将残余物溶解于MeOH(1mL)和NH3/MeOH(7M,1mL)中。将混合物在70℃搅拌2小时。LCMS表明起始材料已消耗并且检测到具有所需质量的一个主峰。将反应混合物减压浓缩。残余物通过制备型HPLC纯化(柱:Waters Xbridge BEH C18 100*30mm*10um;流动相:[水(NH4HCO3)-ACN];B%:30%-60%,8分钟,UV 220nm&254nm),得到黄色固体状的4-氨基-7-氟-N-(1-甲氧基丙-2-基)-3-甲基-N-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)咪唑[1,5-a]喹喔啉-8-甲酰胺(实施例287)(58.1mg,109umol,64.2%产率)。1H NMR(400MHz,DMSO-d6)δ9.29-8.54(m,2H),8.18-7.78(m,2H),7.66(br s,1H),7.38(br d,J=7.9Hz,1H),7.13(br s,1H),6.72(br s,2H),4.95-4.39(m,2H),4.22-3.82(m,1H),3.52(br s,2H),3.31-3.10(m,3H),2.63(s,3H),1.21(br s,3H)LC-MS(ESI)m/z=530.2[M+H]+
以下化合物基于通用方法合成,产物结构见表1、表2,产物表征如下:
表3
生物测试例2HCT116、HCT116-MTAP-KO细胞体外抑制增殖实验
实验材料
HCT116细胞系购自中国科学院细胞库,利用CRISPR/Cas9技术敲除MTAP基因,获得HCT116-MTAP-KO细胞株。
McCoy'5A培养基(Gibco,目录号16600082),胎牛血清(Gibco,目录号10099141C),盘尼西林-链霉素双抗(Gibco,目录号15140122),胰酶(Gibco,目录号25200056),CellTiter-Glo检测试剂盒(Promega,目录号G7572),384孔透明平底黑壁细胞培养板(Corning,目录号3764),超微量加样仪(Tecan,目录号D300e),多功能酶标仪(Biotek,目录号SynergyHTX)
实验方法
1.细胞培养:HCT116和HCT116-MTAP-KO细胞培养条件为McCoy'5A培养基+10%胎牛血清+1%盘尼西林-链霉素双抗;保证其始终处于对数生长期,细胞活率大于95%。
2.化合物浓度梯度配制:待测化合物通过超微量加样仪加入384孔板中,从30μM(HCT116细胞)或3μM(HCT116-MTAP-KO细胞)开始,用DMSO进行3倍稀释,共9个浓度,设置三复孔。
3.化合物处理细胞:将胰酶消化的HCT116或HCT116-MTAP-KO细胞悬液加入点好待测化合物的384孔板中,每孔40μL,即每孔含100个细胞,DMSO终浓度为0.4%。将细胞培养板置于37摄氏度,5%二氧化碳培养箱中培养6天。
4.检测:向细胞培养板中加入每孔20μL的CellTiter-Glo试剂,室温振荡孵育30分钟。使用多功能酶标仪检测578nm的发光信号。
5.数据分析:
GraphPad Prism 8.0软件使用四参数抑制剂-反应的模型对数据进行拟合,得到测试化合物的IC50值(半数抑制浓度)。
经实验方法测得部分化合物生物活性,“A”表示IC50(nm)<100,“B”表示100<IC50(nm)<1000,“C”表示1000<IC50(nm)<10000,见表4:
其中,第一列为细胞增殖抑制率HCT116MTAP WT IC50(nm),第二列为细胞增殖抑制率HCT116-MTAP null IC50(nm)
所测试产物对应结构见表1、表2,活性测试结果如下:
表4
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (15)
- 一种如下式I或II所示的化合物,或其药学上可接受的立体异构体、盐或氘代产物:
其中,Ra为W为O或S;X1、X2各自独立地选自下组:CR、N;X3为N;所述的L1选自下组:化学键、-CHR-、-C(R)R-;A环选自下组:取代或未取代的7-12元的桥环(包括碳环或杂环)、取代或未取代的7-12元的螺环(包括碳环或杂环)、取代或未取代的8-12元的稠合二环杂环基(包括碳环或杂环,优选为五并六环)、取代或未取代的7-10元的稠合二环杂芳基(优选为五并六环)、或所述的A环为取代或未取代的3-7元碳环或杂环、取代或未取代的5-6元芳环或杂芳环;E环选自下组:取代或未取代的3-7元单杂环,取代或未取代的7-12元的桥杂环、取代或未取代的7-12元的螺杂环、取代或未取代的8-12元的稠合多环杂环基(如稠合二环);R8选自下组:H、氘、卤素、氰基、C2-C6炔基、-SF5、氨基、硝基、羟基、巯基、醛基、羧基、取代或未取代或卤代的C1-C6烷基、取代或未取代或卤代的C1-C6烷氧基、或R8为R8'选自下组:H、氘、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、未取代或卤代的C1-C6烷基、取代或未取代的苯环、取代或未取代的5-12元的杂芳环、取代或未取代的C3-C10碳环(包括饱和或部分不饱和的情况)、取代或未取代的3-12元的杂环(包括饱和或部分不饱和的情况)、或R8'为所述的L3选自下组:化学键、-O-、-CHR-、-C(R)R-、羰基、S、-NH-;B环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环(包括饱和或部分不饱和的情况)、取代或未取代的3-7元的杂环(包括饱和或部分不饱和的情况);R2和R2'各自独立地选自下组:R7、-L2R7;其中,所述的L2选自下组:-O-、-CHR-、 -C(R)R-;其中R7选自下组:氢或无、取代或未取代的C1-C6烷基、取代或未取代的C6-10的芳环、取代或未取代的5-12元(优选为5-6元或8-10元)的杂芳环、取代或未取代的C3-C10碳环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环)、取代或未取代的3-10元的杂环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环);n为0、1、2或3;R3选自下组:H、氘、卤素、氰基、取代或未取代的C1-C6烷基;R4和R5与相连的环原子共同形成5-12元饱和或不饱和环,且所述的环可以是取代或未取代的;R为H、氘、卤素、取代或未取代的C1-C4烷基,取代或未取代的C1-C4烷氧基、取代或未取代C3-C6环烷基;除非特别说明,上述各式中,所述的取代指对应基团上的氢原子被一个或多个选自下组的取代基所取代:氘、氚、卤素、羟基、羧基、巯基、苄基、C1-C12烷氧基羰基、C1-C6醛基、氨基、C1-C6酰胺基、硝基、氰基、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷基-O-C1-C6烷基-、未取代或卤代的C1-C6烷基-O-C1-C6烷基-O-、未取代或卤代的C1-C6亚烷基-OH、未取代或卤代的C3-C8环烷基、C2-C10烯基、未取代或卤代的C1-C6烷氧基、C1-C6烷基-胺基、C6-C10芳基、五元或六元杂芳基、五元或六元非芳香性杂环基、-O-(C6-C10芳基)、-O-(五元或六元杂芳基)、C1-C12烷氨基羰基、未取代或卤代的C2-C10酰基、磺酰基(-SO2-OH)、磷酰基(-PO3-OH)、未取代或卤代的C1-C4烷基-S(O)2-、未取代或卤代C1-C4烷基-SO-、-SF5。 - 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的Ra选自下组:
其中,所述的R9选自下组:氘、氚、卤素、羟基、羧基、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或取代的C1-C6烷基-OH、-NH(未取代或卤代的C1-C6烷基)、-N(未取代或卤代的C1-C6烷基)2;m选自0、1、2或3;较佳地,所述 的R9选自下组:氘、氚、卤素、未取代或卤代的C1-C6烷基。 - 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的L1为-CHR-、-C(R)R-;A环选自下组:取代或未取代的8-12元的稠合二环杂环基、取代或未取代的7-10元的稠合二环杂芳基;R8选自下组:H、卤素、氰基、氨基、C2-C6炔基、SF5、羟基、巯基、醛基、羧基、未取代或卤代的C1-C6烷基、且B环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环、取代或未取代的3-6元的杂环;L3选自下组:化学键,-O-、-CHR-、羰基、S、或-NH-。
- 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的R2选自下组:R7、-L2R7;其中,所述的L2选自下组:-O-、-CHR-、羰基、S、-NH-;其中R7选自下组:取代或未取代的C1-C6烷基、取代或未取代的C6-10的芳环、取代或未取代的5-12元的杂芳环。
- 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的R2为邻位取代的5元或6元杂芳环,如下式:
其中,R10为位于连接位点邻位的取代基,其选自下组:氢、氘、卤素、卤代或未卤代的C1-C3烷基,卤代或未卤代的C1-C3烷氧基;D环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环,较佳地,D环选自下组:
- 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的L1为-CH2-、-CH(CH3)-;A环选自下组:
其中,C环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环(包括饱和或部分不饱和的情况)、取代或未取代的3-6元的杂环(包括饱和或部分不饱和的情况);或A环选自下组:
R8为卤代或未卤代的C1-C6烷基,或且B环选自下组:取代或未取代的苯环、取代或未取代的5-6元的杂芳环、取代或未取代的C3-C6碳环、取代或未取代的3-6元的杂环;L3选自下组:化学键,-O-、-CHR-、羰基、S、或-NH-。 - 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,R2选自下组:R7、-(CHR)R7;其中R7选自下组:氢或无、取代或未取代的C1-C6烷基、取代或未取代的C6-10的芳环、取代或未取代的5-12元的杂芳环、取代或未取代的C3-C8碳环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环)、取代或未取代的3-8元的杂环(包括饱和或部分不饱和的情况,包括单环、稠环、螺环或桥环)。
- 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的化合物具有如下式所示的结构:
其中,Q为O、NH、CH2,或化学键(即,为五元环);R8的定义如上文中所述;所述的R8a和R8b各自独立地选自下组:H;或所述的R8a和R8b及其相连的碳原子共同构成4-7元的碳环或杂环;且当所述的R8a和R8b各自独立地为H时,所述的R8a或R8b可以任选地被R8取代;当所述的R8a和R8b及其相连的碳原子共同构成4-7元的碳环或杂环时,所述的R8可以位于该碳环或杂环上。 - 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的R3选自下组:H、氘、卤素、氰基、取代或未取代的C1-C6烷基。
- 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的R2为取代或未取代的5-7元杂芳环;且所述的A环选自下组:取代或未取代的5-6元芳环或杂芳环、取代或未取代的7-10元的稠合二环杂芳基;所述的R8为CF3。
- 如权利要求1所述的化合物,或其药学上可接受的立体异构体、盐或氘代产物,其特征在于,所述的化合物选自下组:表1
- 一种选自下组的化合物,或其药学上可接受的立体异构体、盐或氘代产物:表2
- 一种药物组合物,其特征在于,所述的药物组合物含有治疗有效量的如权利要求1-12任一所述的化合物、其可药用的盐、外消旋体、光学异构体、立体异构体或互变异构体中的一种或多种,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
- 如权利要求1-12任一所述的化合物、其外消旋体、立体异构体或可药用盐在制备治疗或预防与PRMT5的基因水平异常或表达异常(如对应的核酸突变、缺失,或MTAP基因水平异常,或所述的甲基转移酶产生异位或融合或过高表达)相关的疾病的药物中的用途。
- 如权利要求14所述的用途,其特征在于,所述的疾病选自下组:所述疾病或病症卵巢癌、食管癌、肺癌、淋巴癌、胶质母细胞瘤、结肠癌、黑色素瘤、胃癌、胰腺癌或膀胱癌。
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