WO2022063094A1 - 四氢异喹啉衍生物及其应用 - Google Patents
四氢异喹啉衍生物及其应用 Download PDFInfo
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- WO2022063094A1 WO2022063094A1 PCT/CN2021/119445 CN2021119445W WO2022063094A1 WO 2022063094 A1 WO2022063094 A1 WO 2022063094A1 CN 2021119445 W CN2021119445 W CN 2021119445W WO 2022063094 A1 WO2022063094 A1 WO 2022063094A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to a series of tetrahydroisoquinoline derivatives and crystal forms thereof, in particular to a compound represented by formula (VII), crystal forms and pharmaceutically acceptable salts thereof.
- Epigenetic regulation of gene expression is an important factor in protein production and cell differentiation and plays an important role in many diseases.
- Epigenetic regulation is the heritable change in gene expression without changes in the nucleotide sequence.
- the conformational transition between the transcriptionally active state and the inactive state of chromatin is controlled by selectively reversible modifications (such as methylation, etc.) to DNA and proteins (histones, etc.).
- modifications can be carried out by, for example, methyltransferases (eg, the family of protein arginine methyltransferases).
- methyltransferases eg, the family of protein arginine methyltransferases.
- PRMTs protein arginine methyltransferases
- the protein arginine methyltransferases (PRMTs) family involved in arginine methylation is a widespread post-translational modification in the nucleus and cytoplasm, which uses S-adenosyl-methionine as the methyl group. Donor, methylation modifies the nitrogen atom of the protein arginine side chain to generate S-adenosylhomocysteine and methylarginine.
- the substrates of PRMTs are proteins rich in glycine and arginine domains. A total of 10 PRMTs have been found in mammals, 8 of which are biologically active.
- type I PRMT catalyzes the formation of monomethylarginine and asymmetric dimethylarginine
- type II PRMT catalyzes the formation of symmetric dimethylarginine
- Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT.
- PRMT5 can methylate different proteins involved in regulating physiological processes. For example, PRMT5 can affect gene transcription by methylating histones and transcription elongation factors; it can also methylate the tumor suppressor gene p53 to change the activation state of p53.
- PRMT5 and its molecular chaperone MEP50 can form macromolecular complexes with a variety of proteins, catalyzing the synthesis of various substrate proteins in the cytoplasm and nucleus such as Sm protein, nucleolar protein, p53, histone H2A, H3 and H4, SPT5 and MBD2. Methylation plays a key role in RNA processing, chromatin remodeling, and gene regulation in expression.
- PRMT5 can regulate MAPK/ERK signaling pathway by methylating RAF protein, regulate ribosome biosynthesis by methylating ribosomal protein S10, and play an important role in apoptosis by regulating the expression of eIF4E and the translation of p53. In embryonic stem cells, differentiation genes are inhibited by methylating H2A in the cytoplasm.
- PRMT5 is highly expressed in mantle cell lymphoma and diffuse large B-cell lymphoma, and is directly related to the proliferation and survival of malignant B cells. Therefore, PRMT5 is a very promising tumor therapeutic target.
- the PRMT5 inhibitor GSK3326595 disclosed in patent WO2014100719 has now entered the second clinical phase, and its clinical indications include non-Hodgkin's lymphoma, acute lymphoblastic leukemia, myelodysplastic syndrome, adenoid cystic carcinoma and breast cancer.
- the present invention provides a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof,
- T 1 , T 2 and T 3 are each independently selected from CH and N;
- each R 1 is independently selected from H, F, Cl, Br, I, OCH 3 and CH 3 , said OCH 3 and CH 3 being optionally substituted with 1, 2 or 3 F;
- R 4 ' is selected from H and C 1-3 alkyl
- R 5 is selected from H, F, Cl and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F;
- R 6 and R 8 are each independently selected from H, F, Cl, C 3-6 cycloalkyl and C 1-3 alkyl, said C 3-6 cycloalkyl and C 1-3 alkyl optionally being 1, 2 or 3 F substitutions;
- R 7 and R 9 are each independently selected from H, F, Cl and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F;
- R6 and R7 together with the atoms to which they are commonly attached form C3-6 cycloalkyl or 4-6 membered heterocycloalkyl, said C3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 F;
- R8 and R9 together with the atoms to which they are commonly attached form C3-6 cycloalkyl or 4-6 membered heterocycloalkyl, said C3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 F;
- Ring B is selected from C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
- R 2 is selected from H, OH, C 1-3 alkyl, C 1-3 alkoxy, -NH - C 3-6 cycloalkyl, C 3-6 cycloalkyl and phenyl, the C 1-3 alkyl, C 1-3 Alkoxy, -NH-C 3-6 cycloalkyl, C 3-6 cycloalkyl and phenyl are optionally substituted with 1, 2 or 3 R a ;
- R 3 is selected from C 3-6 cycloalkyl
- Ring A is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally surrounded by 1, 2 or 3 R b replace;
- n is selected from 0 and 1;
- n is selected from 0, 1, 2 and 3;
- R a and R c are each independently selected from H, F, Cl, Br, I, OH, -OCH 3 and NH 2 ;
- the 4-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from -NH-, -O-, -S- and N.
- each of the above R 1 is independently selected from H, F, Cl, Br, I and CH 3 , and other variables are as defined in the present invention.
- each of the above R 1 is independently selected from H, F, OCH 3 and CH 3 , and other variables are as defined in the present invention.
- each of the above R 1 is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
- R 2 is selected from H, OH, C 1-3 alkyl, C 1-3 alkoxy, phenyl, cyclobutyl, -NH-cyclobutyl and -NH-cyclopropyl, the C 1-3 alkyl, C 1-3 alkane Oxy, phenyl, cyclobutyl, -NH-cyclobutyl and -NH-cyclopropyl are optionally substituted with 1, 2 or 3 R a , other variables are as defined herein.
- R 2 is selected from H, OH, CH3 , Other variables are as defined in the present invention.
- R 3 is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- the above-mentioned structural units Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, other variables are as defined in the present invention.
- the above-mentioned ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxanyl, azetidinyl, Azacyclohexyl and thietanyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl , azacyclohexyl and thietanyl are optionally substituted with 1, 2 or 3 R b and other variables are as defined herein.
- the above-mentioned ring A is selected from Other variables are as defined in the present invention.
- R 5 is selected from H and CH 3 , and other variables are as defined in the present invention.
- R 6 is selected from H, and other variables are as defined in the present invention.
- R 7 is selected from H, and other variables are as defined in the present invention.
- R 6 is selected from H
- R 7 is selected from H
- other variables are as defined in the present invention.
- R 6 is selected from H and CH 3
- R 7 is selected from H and CH 3
- other variables are as defined in the present invention.
- R 8 is selected from H and CH 3
- R 9 is selected from H and CH 3
- other variables are as defined in the present invention.
- the above R 6 and R 7 are linked together to form cyclopropyl, cyclobutyl, cyclopentyl and oxetanyl, and the cyclopropyl, cyclobutyl, cyclopentyl and oxetyl groups are Heterocyclobutyl is optionally substituted with 1, 2 or 3 F, other variables are as defined herein.
- the above-mentioned ring B is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally 3 R c substitutions, other variables are as defined in the present invention.
- the above-mentioned ring B is selected from Other variables are as defined in the present invention.
- the above-L 1 -(R 3 ) m -L 2 -R 2 is selected from H, OH, CH3 , Other variables are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- T 1 , T 2 , T 3 , R 1 , R 4 , R 4 ′, X and n are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- T 1 , T 2 , T 3 , R 1 , R 4 , R 4 ′, R 5 , R 6 , R 7 , X and n are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- T 1 , T 2 , T 3 , R 1 , R 4 , R 4 ′, R 5 , X and n are as defined in the present invention
- R 6 is selected from F, Cl, C 3-6 cycloalkyl and C 1-3 alkyl, said C 3-6 cycloalkyl and C 1-3 alkyl are optionally substituted with 1, 2 or 3 F ;
- R 8 is selected from F, Cl, C 3-6 cycloalkyl and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F ;
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- T 1 , T 2 , T 3 , R 1 , R 4 , R 4 ′, R 5 , R 6 , X and n are as defined in the present invention
- the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- T 1 , T 2 , T 3 , R 1 , R 4 , R 4 ′, X and n are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
- T 1 , T 2 , T 3 , R 1 , R 2 , R 3 , R 4 , R 4 ′, L 1 , L 2 , X, ring A, m and n are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of,
- Ring A, Ring B, R 1 , R 2 , R 3 , R 4 ′, L 1 and L 2 are as defined in the present invention.
- the present invention provides a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof,
- T 1 , T 2 and T 3 are each independently selected from CH and N;
- each R 1 is independently selected from H, F, Cl, Br, I and CH 3 ;
- R 4 ' is selected from H and C 1-3 alkyl
- R 5 is selected from H, F, Cl and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F;
- R 6 and R 8 are each independently selected from H, F, Cl, C 3-6 cycloalkyl and C 1-3 alkyl, said C 3-6 cycloalkyl and C 1-3 alkyl optionally being 1, 2 or 3 F substitutions;
- R 7 and R 9 are each independently selected from H, F, Cl and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F;
- R6 and R7 together with the atoms to which they are commonly attached form C3-6 cycloalkyl or 4-6 membered heterocycloalkyl, said C3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 F;
- R8 and R9 together with the atoms to which they are commonly attached form C3-6 cycloalkyl or 4-6 membered heterocycloalkyl, said C3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 F;
- Ring B is selected from C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
- R 2 is selected from H, OH, C 1-3 alkyl, C 1-3 alkoxy, -NH - C 3-6 cycloalkyl, C 3-6 cycloalkyl and phenyl, the C 1-3 alkyl, C 1-3 Alkoxy, -NH-C 3-6 cycloalkyl, C 3-6 cycloalkyl and phenyl are optionally substituted with 1, 2 or 3 R a ;
- R 3 is selected from C 3-6 cycloalkyl
- Ring A is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally surrounded by 1, 2 or 3 R b replace;
- n is selected from 0 and 1;
- n is selected from 0, 1, 2 and 3;
- R a and R c are each independently selected from H, F, Cl, Br, I, OH, -OCH 3 and NH 2 ;
- the 4-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from -NH-, -O-, -S- and N.
- the present invention also provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
- T 1 , T 2 and T 3 are each independently selected from CH and N;
- each R 1 is independently selected from H, F, Cl, Br, I and CH 3 ;
- R 4 ' is selected from H and C 1-3 alkyl
- R 5 is selected from H, F, Cl and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F;
- R 6 is selected from H, F, Cl, C 3-6 cycloalkyl and C 1-3 alkyl, the C 3-6 cycloalkyl and C 1-3 alkyl are optionally separated by 1, 2 or 3 Replaced by F;
- R 7 is selected from H, F, Cl and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F;
- R 6 and R 7 are joined together to form a C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 F;
- X is selected from a single bond, CH2 and O, and R4 and R4 ' together with the atoms to which they are commonly attached form a fragment
- X and R are linked together to form ring B ;
- Ring B is selected from C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
- R 2 is selected from H, OH, C 1-3 alkyl, C 1-3 alkoxy, -NH - C 3-6 cycloalkyl, C 3-6 cycloalkyl and phenyl, the C 1-3 alkyl, C 1-3 Alkoxy, -NH-C 3-6 cycloalkyl, C 3-6 cycloalkyl and phenyl are optionally substituted with 1, 2 or 3 R a ;
- R 3 is selected from C 3-6 cycloalkyl
- Ring A is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally surrounded by 1, 2 or 3 R b replace;
- n is selected from 0 and 1;
- n is selected from 0, 1, 2 and 3;
- R a and R c are each independently selected from H, F, Cl, Br, I, OH, -OCH 3 and NH 2 ;
- the 4-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from -NH-, -O-, -S- and N.
- the present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
- T 1 , T 2 and T 3 are each independently selected from CH and N;
- each R 1 is independently selected from H, F, Cl, Br, I and CH 3 ;
- R 4 ' is selected from H and C 1-3 alkyl
- X is selected from a single bond, CH2 and O, and R4 and R4 ' together with the atoms to which they are commonly attached form a fragment
- X and R are linked together to form ring B ;
- Ring B is selected from C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R c ;
- R 2 is selected from H, OH, C 1-3 alkyl, C 1-3 alkoxy, -NH-C 3-6 cycloalkyl, C 3-6 cycloalkyl and phenyl, the C 1-3 alkyl, C 1-3 Alkoxy, -NH-C 3-6 cycloalkyl, C 3-6 cycloalkyl and phenyl are optionally substituted with 1, 2 or 3 R a ;
- R 3 is selected from C 3-6 cycloalkyl
- Ring A is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally surrounded by 1, 2 or 3 R b replace;
- n is selected from 0 and 1;
- n is selected from 0, 1, 2 and 3;
- R a and R c are each independently selected from H, F, Cl, Br, I, OH, -OCH 3 and NH 2 ;
- the 4-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from -NH-, -O-, -S- and N.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- each R 1 is independently selected from H, F, Cl, Br, I and CH 3 ;
- n is selected from 0 and 1;
- n is selected from 0, 1, 2 and 3;
- R 2 is selected from H, OH, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl-NH-, C 3-6 cycloalkyl and phenyl, the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl-NH-, C 3-6 cycloalkyl and phenyl are optionally substituted with 1, 2 or 3 R a ;
- R 3 is selected from C 3-6 cycloalkyl
- Ring A is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally surrounded by 1, 2 or 3 R b replace;
- T 1 , T 2 and T 3 are selected from CH and N, respectively;
- Ra is selected from H, F, Cl, Br, I, OH, -OCH 3 and NH 2 ;
- the 4-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from -NH-, -O-, -S- and N.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- each R is independently selected from H, F , Cl, Br, I;
- n is selected from 0 and 1;
- n is selected from 0, 1, 2 and 3;
- R 2 is selected from H, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl-NH-, C 3-6 cycloalkyl and phenyl, the C 1-3 alkoxy base, C 1-3 alkoxy, C 3-6 cycloalkyl-NH-, C 3-6 cycloalkyl and phenyl are optionally substituted with 1, 2 or 3 R a ;
- R 3 is selected from C 3-6 cycloalkyl
- Ring A is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally surrounded by 1, 2 or 3 R b Substituted; T 1 , T 2 and T 3 are respectively selected from CH and N;
- Ra is selected from H, F, Cl, Br, I, OH, NH2 ;
- R b is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy;
- the 4-6 membered heterocycloalkyl groups each independently contain 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from -NH-, -O-, -S- and N.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- each R is independently selected from H, F , Cl, Br, I;
- n is selected from 0 and 1;
- n is selected from 0, 1, 2 and 3;
- R 2 is selected from H, C 1-3 alkoxy, C 3-6 cycloalkyl-NH-, C 3-6 cycloalkyl and phenyl, the C 1-3 alkoxy, C 3-6 Cycloalkyl-NH-, C3-6cycloalkyl and phenyl are optionally substituted with 1, 2 or 3 R a ;
- R 3 is selected from C 3-6 cycloalkyl
- Ring A is selected from C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl optionally surrounded by 1, 2 or 3 R b replace;
- T 1 , T 2 and T 3 are selected from CH and N, respectively;
- Ra is selected from H, F, Cl, Br, I, OH, NH2 ;
- R b is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy;
- the 4-6 membered heterocycloalkyl groups each independently contain 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from -NH-, -O-, -S- and N.
- the above R 2 is selected from H, C 1-3 alkyl, C 1-3 alkoxy, phenyl, cyclobutyl, cyclobutyl-NH- and cyclopropyl-NH-,
- the C 1-3 alkyl, C 1-3 alkoxy, phenyl, cyclobutyl, cyclobutyl-NH- and cyclopropyl-NH- are optionally substituted with 1, 2 or 3 R a , Ra and other variables are as defined in the present invention.
- the above R 2 is selected from H, C 1-3 alkoxy, phenyl, cyclobutyl, cyclobutyl-NH- and cyclopropyl-NH-, the C 1-3 alkane Oxy, phenyl, cyclobutyl, cyclobutyl-NH- and cyclopropyl-NH- are optionally substituted with 1, 2 or 3 R a , R a and other variables as defined herein.
- R 2 is selected from H, OH, CH3 , Other variables are as defined in the present invention.
- R 2 is selected from H, CH 3 , Other variables are as defined in the present invention.
- R 2 is selected from H, Other variables are as defined in the present invention.
- R b is selected from H, F, Cl, Br, I, OH and NH2 , and other variables are as defined in the present invention.
- the above-mentioned ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, thietanyl, azetidinyl, oxolane and oxanyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, thietanyl, azetidinyl , oxolane and oxhexyl are optionally substituted with 1, 2 or 3 R b , R b and other variables as defined herein.
- the above ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, thietanyl, azetidinyl and Oxanyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, thietanyl, azetidinyl and oxetyl groups are any is optionally substituted with 1, 2 or 3 R b , R b and other variables as defined herein.
- the above-mentioned ring A is selected from said Optionally substituted with 1, 2 or 3 R b , R b and other variables as defined herein.
- the above-mentioned ring A is selected from said Optionally substituted with 1, 2 or 3 R b , other variables are as defined in the present invention.
- Rings A , R1 and n are as defined in the present invention.
- Rings A , R1 and n are as defined in the present invention.
- the above-mentioned structural units selected from Rings A , R1 and n are as defined in the present invention.
- R 2 -L 2 -(R 3 ) m -L 1 - is selected from H, OH, CH3 ,
- Other variables are as defined in the present invention.
- R 2 -L 2 -(R 3 ) m -L 1 - is selected from H,
- Other variables are as defined in the present invention.
- R 2 -L 2 -(R 3 ) m -L 1 - is selected from Other variables are as defined in the present invention.
- the above-mentioned structural units selected from T 1 , T 2 , T 3 , R 1 and n are as defined in the present invention.
- the above-mentioned structural units selected from T 1 , T 2 , T 3 , R 1 and n are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- L 1 , L 2 , R 2 , R 3 and ring A are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- L 1 , R 2 and ring A are as defined in the present invention.
- the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:
- the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:
- the present invention also provides the A crystal form of compound 46a, the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 4.70 ⁇ 0.20°, 11.32 ⁇ 0.20°, 13.35 ⁇ 0.20 °, 16.25 ⁇ 0.20°, 17.36 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.70 ⁇ 0.20°, 8.68 ⁇ 0.20°, 9.35 ⁇ 0.20°, 11.32 ⁇ 0.20° , 13.35 ⁇ 0.20°, 16.25 ⁇ 0.20°, 17.36 ⁇ 0.20°, 23.22 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.70 ⁇ 0.20°, 8.68 ⁇ 0.20°, 9.35 ⁇ 0.20°, 9.99 ⁇ 0.20° , 11.32 ⁇ 0.20°, 13.35 ⁇ 0.20°, 14.05 ⁇ 0.20°, 16.25 ⁇ 0.20°, 17.36 ⁇ 0.20°, 20.08 ⁇ 0.20°, 23.22 ⁇ 0.20°, 25.65 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of Form A above has characteristic diffraction peaks at the following 2 ⁇ angles: 4.70 ⁇ 0.20°, 8.68 ⁇ 0.20°, and also 9.35 ⁇ 0.20°, and/ or 9.99 ⁇ 0.20°, and/or 11.32 ⁇ 0.20°, and/or 13.35 ⁇ 0.20°, and/or 14.05 ⁇ 0.20°, and/or 16.25 ⁇ 0.20°, and/or 17.36 ⁇ 0.20°, and/or 20.08 Characteristic diffraction peaks at ⁇ 0.20°, and/or 23.22 ⁇ 0.20°, and/or 25.65 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.70°, 8.68°, 9.35°, 9.99°, 11.32°, 13.35°, 14.05° °, 16.25°, 17.36°, 17.65°, 20.08°, 23.22°, 23.80°, 24.13°, 25.65°, 28.34°, 30.32°, 33.54°.
- the XRPD pattern of the above-mentioned A crystal form is shown in FIG. 3 .
- the differential scanning calorimetry (DSC) curve of the above-mentioned Form A shows a peak with an endothermic peak at 241.2°C ⁇ 3°C.
- the DSC spectrum of the above-mentioned A crystal form is shown in FIG. 4 .
- thermogravimetric analysis (TGA) curve of the above-mentioned crystal form A has a weight loss of 2.55% at 200.0°C ⁇ 3°C.
- the TGA spectrum of the above-mentioned A crystal form is shown in FIG. 5 .
- the dynamic moisture adsorption analysis (DVS) of the above-mentioned Form A shows slight hygroscopicity.
- the DVS spectrum of the above-mentioned A crystal form is shown in FIG. 6 .
- the present invention also provides a method for preparing the above-mentioned A crystal form, the method comprising the following steps:
- the solvent X is selected from ethyl acetate, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, acetone, dichloromethane, 1,4-dioxane and isopropanol;
- the solvent Y is selected from n-heptane, n-hexane, cyclohexane, water and methyl tert-butyl ether, and the volume ratio of the solvent X and the solvent Y is 1:1-1:10.
- the present invention also provides a method for preparing the above-mentioned A crystal form, the method comprising the following steps:
- the solvent P is selected from tetrahydrofuran, chloroform, dimethylacetamide and dimethyl sulfoxide;
- the solvent Q is selected from toluene, n-heptane, water and methyl isobutyl ketone.
- the present invention also provides the B crystal form of compound 46a, the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 10.69 ⁇ 0.20°, 12.74 ⁇ 0.20 °, 14.28 ⁇ 0.20°, 15.18 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 7.12 ⁇ 0.20°, 10.15 ⁇ 0.20°, 10.69 ⁇ 0.20°, 12.74 ⁇ 0.20° , 14.28 ⁇ 0.20°, 15.18 ⁇ 0.20°, 17.87 ⁇ 0.20°, 25.12 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 3.61 ⁇ 0.20°, 7.12 ⁇ 0.20°, 10.15 ⁇ 0.20°, 10.69 ⁇ 0.20° , 12.74 ⁇ 0.20°, 14.28 ⁇ 0.20°, 15.18 ⁇ 0.20°, 17.87 ⁇ 0.20°, 20.39 ⁇ 0.20°, 21.09 ⁇ 0.20°, 23.86 ⁇ 0.20°, 25.12 ⁇ 0.20°.
- the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 3.61°, 7.12°, 10.16°, 10.69°, 10.95°, 12.08°, 12.74° °,14.28°,15.18°,17.07°,17.87°,20.08°,20.39°,21.09°,22.79°,23.29°,23.86°,24.77°,25.12°,26.37°,30.02°,30.68°,31.23°, 32.46°, 34.80°, 36.18°, 37.13°.
- the XRPD pattern of the above-mentioned B crystal form is shown in FIG. 7 .
- the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form B shows a peak with an endothermic peak at 241.4°C ⁇ 3°C.
- the DSC spectrum of the above-mentioned B crystal form is shown in FIG. 8 .
- thermogravimetric analysis (TGA) curve of the above crystal form B loses weight up to 2.98% at 140.0°C ⁇ 3°C.
- the TGA spectrum of the above-mentioned B crystal form is shown in FIG. 9 .
- the present invention also provides the application of the above compound or a pharmaceutically acceptable salt thereof in preparing a drug related to a therapeutic protein arginine methyltransferase 5 inhibitor.
- the present invention also provides the application of the above-mentioned crystal form A or crystal form B in preparing a drug related to a therapeutic protein arginine methyltransferase 5 inhibitor.
- the above-mentioned protein arginine methyltransferase 5 inhibitor-related drug is a drug for preventing and/or treating lymphoma and solid tumor-related diseases.
- the above-mentioned lymphoma is non-Hodgkin's lymphoma
- the above-mentioned solid tumor is breast cancer.
- the above-mentioned lymphoma is a non-Hodgkin's lymphoma, such as mantle cell lymphoma.
- the above solid tumor is breast cancer.
- the compounds of the present invention As a class of protein arginine methyltransferase 5 (PRMT5) inhibitors, the compounds of the present invention have good PRMT5 enzyme inhibitory activity, and can effectively inhibit the proliferation of non-Hodgkin's lymphoma cells and/or triple-negative breast cancer cells , with good plasma exposure and reasonable oral bioavailability.
- PRMT5 arginine methyltransferase 5
- the results of in vivo pharmacodynamics showed that the compounds of the present invention have significant antitumor effect.
- the compounds of the present invention as drug inhibitors for lymphoma and solid tumors, have great application prospects in the prevention and/or treatment of diseases related to lymphoma and solid tumors.
- the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
- the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
- the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
- the diastereoisomers were resolved and the pure enantiomers recovered.
- separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- the substituent can bond to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene.
- substituents do not specify through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine rings. The carbon atom is attached to the substituted group.
- the direction of attachment is arbitrary, for example,
- the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
- Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- any one or more sites in the group can be linked to other groups by chemical bonds.
- connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
- the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines Express.
- a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
- the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
- the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
- Indicates that any linkable site on the group can be connected to other groups through a chemical bond, including at least These 8 connection methods.
- C 1-3 alkyl is used by itself or in combination with other terms to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms, respectively.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
- Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 1-3 alkoxy by itself or in combination with other terms, respectively, refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C 3-6 cycloalkyl by itself or in combination with other terms means, respectively, a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, the C 3-6 cycloalkyl includes C3-5 , C4-5 , and C5-6 cycloalkyl, and the like; it may be monovalent, divalent, or polyvalent.
- Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like
- 4-6 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings.
- a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
- the 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
- 4-6 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
- Cn-n+m or Cn - Cn+m includes any one specific case of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-member
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
- hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
- Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
- alkyl groups such as methyl, ethyl and tert-butyl
- acyl groups such as alkanoyl (eg acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- the solvent used in the present invention is commercially available.
- N 2 represents nitrogen
- DMSO represents dimethyl sulfoxide
- HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate
- HOBt 1-hydroxybenzotriazole
- EDCI for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- TMSCN for trimethylnitrile Silane
- DAST for diethylaminosulfur trifluoride
- DPPF for 1,1'-bis(diphenylphosphino)ferrocene
- DMAP for 4-dimethylaminopyridine
- TBSCl for tert-butyldimethylsilyl chloride
- DIEA stands for N,N-diisopropylethylamine
- Pd/C stands for palladium carbon
- Pd(dppf)Cl 2 stands for [1,1'-bis
- Hygroscopic classification ⁇ W% deliquescence Absorbs enough water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% hygroscopic 15%> ⁇ W% ⁇ 2% slightly hygroscopic 2%> ⁇ W% ⁇ 0.2% No or almost no hygroscopicity ⁇ W% ⁇ 0.2%
- ⁇ W% represents the hygroscopic weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
- Figure 1 shows the tumor growth curve of human mantle cell lymphoma Z-138 cell subcutaneous xenograft tumor model in tumor-bearing mice after administration of compounds 1 and 4
- Figure 2 shows the tumor growth curve of human mantle cell lymphoma Z-138 cell subcutaneous xenograft tumor model in tumor-bearing mice after administration of compound 8
- Step 1 Synthesis of Compound BB-1-3
- reaction solution was added with ethyl acetate (100 mL), washed with water (30 mL ⁇ 3), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile], the retention time of the high performance liquid phase column is 11.5min) to obtain compound 1.
- reaction solution was cooled to 0-15°C, then dichloromethane (200 mL) was added, and the reaction solution was quenched with sodium bisulfite solution (10%, 200 mL), the mixture was stirred for 0.5 hours, and then extracted with dichloromethane (200 mL ⁇ 3 ), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-2.
- reaction solution was cooled to 0-15°C, then dichloromethane (200 mL) was added, and the reaction solution was quenched with sodium bisulfite solution (10%, 200 mL), the mixture was stirred for 0.5 hours, and then extracted with dichloromethane (200 mL ⁇ 3 ), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 4-2.
- Iron powder (2.55g) was added to a solution of compound 5-1 (1g, 4.57mmol, 1eq), ammonium chloride (2.44g, 45.66mmol, 10eq) in ethanol (20mL) and water (20mL) at 75°C , 45.66mmol, 10eq), the reaction solution continued to stir for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 5-2.
- reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the reaction solution was quenched by adding saturated citric acid solution (15 mL), extracted with ethyl acetate (15 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced pressure concentrate.
- the crude compound 5-6 was obtained.
- reaction solution was diluted with water (10 mL), diluted hydrochloric acid (1 M) was added to adjust the pH to 3, extracted with ethyl acetate (15 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL ⁇ 2), and anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain crude compound 5-9.
- reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 25%-55%, retention of high performance liquid phase column time is 10 min) to obtain compound 5.
- the reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (2 mL), the suspension was filtered through celite, the filter cake was washed with ethyl acetate (50 mL), the filtrates were combined and separated, and the aqueous phase was filtered with ethyl acetate (50 mL ⁇ 3 ) extraction, the combined organic phases were washed successively with water (50 mL ⁇ 3) and saturated brine (50 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound 6-4, which was directly used in the next step.
- Ammonium chloride (1.03 g, 19.24 mmol, 5 eq) was added to a mixed solution of compound 8-1 (1.14 g, 3.85 mmol, 1 eq) in ethanol (10.00 mL) and water (10.00 mL) at room temperature, and the temperature was raised to 80°C Reduced iron powder (1.07 g, 19.24 mmol, 5 eq) was slowly added, and the reaction solution was stirred at 80° C. for 3 hours.
- diluted hydrochloric acid (0.5M, 11.09mL, 1.5eq) was added to a solution of compound 9-2 (1g, 3.70mmol, 1eq) in ethyl acetate (10mL), and the reaction solution was stirred for 11 hours.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product Compound 9-3.
- HATU 41.24 mg, 108.46 ⁇ mol, 1.05 eq
- dimethicone dimethicone
- Isopropylethylamine (16.02mg, 123.96 ⁇ mol, 21.59 ⁇ L, 1.2eq) was stirred for 10 minutes, then compound BB-1 (21.31mg, 103.30 ⁇ mol, 1eq) was added to it, and the reaction solution was stirred for 30 minutes.
- reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- reaction solution was diluted with water (10 mL), diluted hydrochloric acid (1 M) was added to adjust the pH to 6, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL ⁇ 2), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain crude compound 10-2.
- reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- Preparative high performance liquid phase separation and purification chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (0.05% ammonia water)-acetonitrile, acetonitrile%: 13%-43%, the retention time of high performance liquid phase column is 10min ) to obtain compound 11.
- reaction solution was quenched by adding saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, the organic phase was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentration under reduced pressure gave crude compound 12-1.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 15%-45%, the The retention time is 10 min) to obtain compound 12.
- reaction solution was diluted with water (25 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product Compound 13-1.
- the reaction solution was diluted with water (15 mL), extracted with ethyl acetate (15 mL ⁇ 3), the organic phases were combined, washed with saturated brine (15 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 14%-47%, HPLC column The retention time was 9 min) to obtain compound 13.
- reaction solution was diluted with water (10 mL), extracted with dichloromethane (20 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product Compound 14-1.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 15%-49%, HPLC column The retention time is 10 min) to obtain compound 14.
- reaction solution was quenched by adding saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (15 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentration under reduced pressure gave crude compound 15-4.
- reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 mL) to quench, the layers were separated, the aqueous phase was extracted with dichloromethane (100 mL), the organic phases were combined, washed with saturated brine (100 mL ⁇ 2), and anhydrous sodium sulfate After drying, filtering, the filtrate was concentrated under reduced pressure, and the crude compound 17-2 was directly used in the next reaction.
- Reduced iron powder (1.75 g, 31.38 mmol, 6 eq) was added to a solution of compound 17-3 (2.00 g, 5.23 mmol, 1 eq) in glacial acetic acid (10 mL) at room temperature, and the reaction solution was stirred at 80° C. for 3.5 hours.
- the reaction solution was poured into saturated sodium bicarbonate (250 mL), then filtered through celite, and the layers were separated.
- the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 2), and the combined organic phases were washed with water (100 mL) and saturated brine (100 mL).
- the crude product was prepared by HPLC separation and purification (chromatographic column: Phenomenex Gemini-NX C18 75 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [water (0.05% ammonia water)-acetonitrile, acetonitrile: 12%-42%, retention time of high performance liquid phase column is 8min ], the obtained mixture was further purified by SFC chiral [chromatographic column: DAICEL CHIRALPAK IC (250mm ⁇ 30mm ⁇ 10 ⁇ m); mobile phase: mobile phase A was CO 2 , mobile phase B was ethanol (0.1% ammonia water); gradient: B% : 60%-60%] to give compounds 17 and 18.
- the crude product is prepared by High performance liquid phase separation and purification (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (0.05% ammonia water)-acetonitrile, acetonitrile: 26%-56%, the retention time of high performance liquid phase column is 10min], obtain The mixture was further chirally purified by SFC [chromatographic column: DAICEL CHIRALPAK IC (250mm ⁇ 30mm ⁇ 10 ⁇ m); mobile phase: mobile phase A was CO 2 , mobile phase B was isopropanol (0.1% ammonia water); isopropyl alcohol Alcohol (0.1% ammonia): 60%-60%] to give compounds 19 and 20.
- the crude product was prepared by HPLC separation and purification (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: [water (0.05% ammonia water)-acetonitrile], acetonitrile %: 25%-55%, retention time of HPLC column 7min), the obtained mixture was further purified by chiral SFC (chromatographic column: DAICEL CHIRALCEL OJ (250mm*30mm, 10 ⁇ m); mobile phase: mobile phase A was CO 2 , mobile phase B: [0.1% ammonia water-methanol]; mobile phase: Phase B %: 30%-30%) to give compounds 21 and 22.
- Dess-Martin reagent (676.70 mg, 1.60 mmol, 493.94 ⁇ L, 1.2 eq) was added to a solution of compound 17-5 (0.350 g, 1.33 mmol, 1 eq) in dichloromethane (10 mL) at 25°C, and the reaction solution Continue stirring for 2 hours.
- the reaction solution was quenched with saturated sodium sulfite (10 mL) and saturated sodium bicarbonate solution (10 mL), then extracted with dichloromethane (15 mL ⁇ 3), the organic phases were combined, and the organic phases were washed with saturated brine (15 mL ⁇ 2), no Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
- reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- Preparative high performance liquid phase separation and purification chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 18%-48%, the retention time of high performance liquid phase column is 9 min) to obtain compound 27.
- Lithium hydroxide monohydrate (22.22 mg, 529.61 ⁇ mol, 5 eq) was added to a solution of compound 28-1 (0.030 g, 105.92 ⁇ mol, 1 eq) in methanol (2 mL) and water (0.5 mL) at 25 °C, and the reaction was carried out at 25 °C. The temperature of the liquid was raised to 40°C and stirred for 12 hours.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 25%-55%, retention of high performance liquid phase column time 9 min) to give compound 28.
- reaction solution was adjusted to pH 10 with saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced Concentration under pressure gave crude compound 29-2.
- the reaction solution was diluted with water (15 mL), extracted with ethyl acetate (15 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (15 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 18%-51%, retention of high performance liquid phase column time 9 min) to give compound 29.
- the reaction solution was diluted with water, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Phenomenex Gemini-NX C18 75 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 24%-54%, high performance liquid phase The retention time of the column was 8 min) to give compound 30.
- reaction solution was quenched by adding saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (15 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrate under reduced pressure.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 26%-56%, retention of high performance liquid phase column time 10 min) to obtain compound 32.
- reaction solution was quenched with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (5 mL ⁇ 3), the organic phases were combined, the organic phases were washed with water (5 mL), saturated brine (5 mL), dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure to obtain crude compound 33-2.
- reaction solution was added with water (10mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (30mL), spin-dried, and the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water] (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 30%-60%, the retention time of the high performance liquid phase column is 10min) to obtain compound 33.
- chromatographic column Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water] (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 30%-60%, the retention time of the high performance liquid phase column is 10min
- HATU (438.44 mg, 1.15 mmol, 1.2 eq) and DIEA were added to a solution of compound 34-5 (0.226 g, 960.91 ⁇ mol, 1 eq) in N,N-dimethylformamide (5 mL) at 25°C, respectively. (186.28 mg, 1.44 mmol, 251.06 ⁇ L, 1.5 eq), the reaction solution was stirred for 10 minutes, then compound BB-1 (198.22 mg, 960.91 ⁇ mol, 1 eq) was added thereto, and the reaction solution was stirred for 30 minutes.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (15 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 25%-55%, retention of high performance liquid phase column time 10 min) to give compound 34.
- reaction solution was diluted with water (10 mL), extracted with ethyl acetate (15 mL ⁇ 3), the organic phases were combined, washed with saturated brine (15 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 17%-50%, the The retention time is 9min), and then separated and purified by SFC (chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 10 ⁇ m); mobile phase B: [0.1% ammonia water isopropanol]; B%: 60%-60%) to obtain the compound 35 and 36.
- SFC chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 10 ⁇ m)
- mobile phase B [0.1% ammonia water
- reaction solution was quenched with saturated sodium sulfite (10 mL) solution, extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, and the organic phases were washed with saturated sodium bicarbonate solution (10 mL ⁇ 5) and saturated brine (10 mL ⁇ 2), Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude compound 37-3.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 1150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 15%-48%, retention of high performance liquid phase column time 9 min) to give compound 37.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile: 29%-59%, retention of high performance liquid phase column time 10 min) to give compound 38.
- reaction solution was stirred at 20°C for 4.5 hours, water (50 mL) was added to the reaction solution and extracted three times with ethyl acetate (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 39-4 .
- reaction solution was poured into water (50mL), extracted twice with ethyl acetate (50mL*2), the combined organic phase was washed twice with saturated brine (50mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced.
- the filtrate was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge BEH C18 250*50mm*10 ⁇ m; mobile phase: [water (0.05% ammonium hydroxide (v/v))-acetonitrile]; acetonitrile%: 5%- 35%), separated and purified by SFC (chromatographic column: DAICEL CHIRALCEL OJ (250mm*30mm, 10 ⁇ m); mobile phase 0.1% ammonia water methanol: 55%-55%) to obtain compounds 40 and 41.
- reaction solution was poured into water (150mL), extracted with ethyl acetate (100mL*3), the organic phase was separated and washed with saturated brine (100mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the obtained
- reaction solution was cooled to 80°C, filtered, the filter cake was washed with methanol (10 mL), saturated aqueous sodium bicarbonate solution (50 mL) was added to the filtrate, extracted with ethyl acetate (50 mL*6), the organic phases were combined with water and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure to obtain compound 42-4.
- reaction solution was quenched with water (15 mL), extracted with ethyl acetate (15 mL), the organic phase was washed with 1N hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure to obtain compound 42-5.
- reaction solution was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL ⁇ 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative high performance liquid phase (chromatographic column). : Phenomenex Gemini-NX C18 75 ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; acetonitrile%: 10%-40%, the retention time of high performance liquid phase column is 7min) to obtain the compound 42.
- reaction solution was poured into ice water (100 mL), extracted with dichloromethane (100 mL ⁇ 3), the organic phases were combined, washed with saturated brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the reaction solution was added with saturated sodium bicarbonate solution to adjust the pH to 10, filtered through celite, the filtrate was extracted with dichloromethane (50 mL ⁇ 3), the organic phases were combined, and the organic phases were washed with saturated brine (50 mL ⁇ 2), anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
- Lithium hydroxide monohydrate (75.67 mg, 1.80 mmol, 5 eq) was added to a solution of compound 43-9 (0.1 g, 360.66 ⁇ mol, 1 eq) in methanol (5 mL) and water (1 mL) at 25 °C, and the reaction solution The temperature was raised to 45°C and stirred for 12 hours.
- the reaction solution was added with dilute hydrochloric acid (1M) to adjust the pH to 5, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced Concentration under pressure gave crude compound 43-10.
- the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- the crude product was separated and purified by preparative high performance liquid phase (chromatographic column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 16%-46%, the retention time 10 min) to give compounds 43 and 44.
Abstract
一系列四氢异喹啉衍生物及其晶型,具体公开了式(VII)所示化合物、其晶型及其药学上可接受的盐。
Description
本发明主张如下优先权:
CN202011000192.8,申请日2020年09月22日;
CN202110187630.4,申请日2021年02月08日;
CN202110251658.X,申请日2021年03月08日;
CN202110529022.7,申请日2021年05月14日;
CN202110802850.3,申请日2021年07月15日。
本发明涉及一系列四氢异喹啉衍生物及其晶型,具体涉及式(VII)所示化合物、其晶型及其药学上可接受的盐。
基因表达的表观遗传调节是蛋白质产生和细胞分化的一个重要的因素,在许多疾病中发挥重要的作用。
表观遗传调节是在核苷酸序列不发生改变的情况下,基因表达发生可遗传的变化。例如,通过对DNA和蛋白质(组蛋白等)进行选择性的可逆的修饰(如甲基化等)控制染色质的转录活性态和非活性态之间的构象转变。这些修饰可以通过诸如甲基转移酶(如蛋白精氨酸甲基转移酶家族)等进行。因此,这些酶与引起人类疾病的特定遗传改变是相关联的。
蛋白精氨酸甲基转移酶(PRMTs)家族参与的精氨酸甲基化是一种在细胞核和细胞质中广泛存在的翻译后修饰方式,它以S-腺苷-甲硫氨酸为甲基供体,甲基化修饰蛋白精氨酸侧链的氮原子,生成S-腺苷同型半胱氨酸和甲基精氨酸。PRMTs的底物是富含甘氨酸和精氨酸结构域的蛋白质。目前在哺乳动物上共发现10种PRMTs,其中8种具有生物学活性。根据甲基化产物的不同分为I型和II型:I型PRMT催化形成单甲基精氨酸和非对称的二甲基精氨酸,II型PRMT催化形成对称的二甲基精氨酸。蛋白精氨酸甲基转移酶5(PRMT5)属于II型PRMT。
PRMT5可甲基化不同的蛋白参与调节生理过程,例如PRMT5可以通过甲基化组蛋白和转录延长因子影响基因转录过程;也能甲基化抑癌基因p53改变p53的激活状态。PRMT5与其分子伴侣蛋白MEP50能够和多种蛋白形成大分子复合物,催化Sm蛋白,核仁蛋白,p53,组蛋白H2A,H3和H4,SPT5和MBD2等细胞质和细胞核中的多种底物蛋白的甲基化,在RNA加工、染色质重塑以及基因调控表达过程中发挥关键作用。PRMT5可以通过甲基化RAF蛋白调节MAPK/ERK信号通路,通过甲基化核糖体蛋白S10调节核糖体的生物合成,通过调控eIF4E的表达和p53的翻译从而在细胞凋亡中起重要作用。在胚胎干细胞中,通过甲基化包浆中H2A来抑制分化基因。
目前已有研究发现PRMT5在套细胞淋巴瘤和弥漫性大B细胞淋巴瘤中高表达,与恶性肿瘤B细胞的增殖和存活有直接的关联。因此,PRMT5是一个非常有前景的肿瘤治疗靶点。专利WO2014100719公开的PRMT5抑制剂GSK3326595,现已进入临床二期,临床适应症包括非霍奇金淋巴瘤、急性淋巴白血病、骨髓增生异常综合征、腺样囊性癌和乳腺癌等。
综上所述,本领域迫切需要开发新型蛋白精氨酸甲基转移酶5抑制剂。
发明内容
本发明提供了式(VII)所示化合物或其药学上可接受的盐,
其中,
T
1、T
2和T
3各自独立地选自CH和N;
各R
1分别独立地选自H、F、Cl、Br、I、OCH
3和CH
3,所述OCH
3和CH
3任选被1、2或3个F取代;
R
4’选自H和C
1-3烷基;
R
5选自H、F、Cl和C
1-3烷基,所述C
1-3烷基任选被1、2或3个F取代;
R
6和R
8分别独立地选自H、F、Cl、C
3-6环烷基和C
1-3烷基,所述C
3-6环烷基和C
1-3烷基任选被1、2或3个F取代;
R
7和R
9分别独立地选自H、F、Cl和C
1-3烷基,所述C
1-3烷基任选被1、2或3个F取代;
或者,R
6与R
7与它们共同连接的原子一起形成C
3-6环烷基或4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个F取代;
或者,R
8与R
9与它们共同连接的原子一起形成C
3-6环烷基或4-6元杂环烷基,所述C
3-6环烷基和4-6元杂 环烷基任选被1、2或3个F取代;
环B选自C
3-6环烷基,所述C
3-6环烷基任选被1、2或3个R
c取代;
L
1和L
2各自独立地选自单键和-C(=O)-;
R
2选自H、OH、
C
1-3烷基、C
1-3烷氧基、-NH-C
3-6环烷基、C
3-6环烷基和苯基,所述C
1-3烷基、C
1-
3烷氧基、-NH-C
3-6环烷基、C
3-6环烷基和苯基任选被1、2或3个R
a取代;
R
3选自C
3-6环烷基;
环A选自C
3-6环烷基和4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个R
b取代;
m选自0和1;
n选自0、1、2和3;
R
a和R
c各自独立地选自H、F、Cl、Br、I、OH、-OCH
3和NH
2;
各R
b分别独立地选自H、F、Cl、Br、I、=O、OH、NH
2、C
1-3烷基和C
1-3烷氧基;
所述4-6元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明的一些方案中,上述各R
1分别独立地选自H、F、Cl、Br、I和CH
3,其他变量如本发明所定义。
本发明的一些方案中,上述各R
1独立地选自H、F、OCH
3和CH
3,其他变量如本发明所定义。
本发明的一些方案中,上述各R
1独立地选自H、F和CH
3,其他变量如本发明所定义。
本发明的一些方案中,上述R
2选自H、OH、
C
1-3烷基、C
1-3烷氧基、苯基、环丁基、-NH-环丁基和-NH-环丙基,所述C
1-3烷基、C
1-3烷氧基、苯基、环丁基、-NH-环丁基和-NH-环丙基任选被1、2或3个R
a取代,其他变量如本发明所定义。
本发明的一些方案中,上述R
3选自环丙基、环丁基、环戊基和环己基,其他变量如本发明所定义。
本发明的一些方案中,上述环A选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环己基和硫杂环丁基,所述环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环己基和硫杂环丁基任选被1、2或3个R
b取代,其他变量如本发明所定义。
本发明的一些方案中,上述R
5选自H和CH
3,其他变量如本发明所定义。
本发明的一些方案中,上述R
6选自H,其他变量如本发明所定义。
本发明的一些方案中,上述R
7选自H,其他变量如本发明所定义。
本发明的一些方案中,上述R
6选自H,R
7选自H,其他变量如本发明所定义。
本发明的一些方案中,上述R
6选自H和CH
3,R
7选自H和CH
3,其他变量如本发明所定义。
本发明的一些方案中,上述R
8选自H和CH
3,R
9选自H和CH
3,其他变量如本发明所定义。
本发明的一些方案中,上述R
6与R
7连接在一起形成环丙基、环丁基、环戊基和氧杂环丁基,所述环丙基、环丁基、环戊基和氧杂环丁基任选被1、2或3个F取代,其他变量如本发明所定义。
本发明的一些方案中,上述环B选自环丙基、环丁基、环戊基和环己基,所述环丙基、环丁基、环戊基和环己基任选被1、2或3个R
c取代,其他变量如本发明所定义。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自,
其中,T
1、T
2、T
3、R
1、R
4、R
4’、X和n如本发明所定义。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自,
其中,T
1、T
2、T
3、R
1、R
4、R
4’、R
5、R
6、R
7、X和n如本发明所定义。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自,
其中,
T
1、T
2、T
3、R
1、R
4、R
4’、R
5、X和n如本发明所定义;
R
6选自F、Cl、C
3-6环烷基和C
1-3烷基,所述C
3-6环烷基和C
1-3烷基任选被1、2或3个F取代;
R
8选自F、Cl、C
3-6环烷基和C
1-3烷基,所述C
3-6环烷基和C
1-3烷基任选被1、2或3个F取代;
带“*”碳原子为手性碳原子,以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自,
其中,
T
1、T
2、T
3、R
1、R
4、R
4’、R
5、R
6、X和n如本发明所定义;
带“*”碳原子为手性碳原子,以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自,
其中,
T
1、T
2、T
3、R
1、R
4、R
4’、X和n如本发明所定义。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其选自,
其中,T
1、T
2、T
3、R
1、R
2、R
3、R
4、R
4’、L
1、L
2、X、环A、m和n如本发明所定义。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其化合物选自,
其中,环A、环B、R
1、R
2、R
3、R
4’、L
1和L
2如本发明所定义。
本发明提供了式(VII)所示化合物或其药学上可接受的盐,
其中,
T
1、T
2和T
3各自独立地选自CH和N;
各R
1分别独立地选自H、F、Cl、Br、I和CH
3;
R
4’选自H和C
1-3烷基;
R
5选自H、F、Cl和C
1-3烷基,所述C
1-3烷基任选被1、2或3个F取代;
R
6和R
8分别独立地选自H、F、Cl、C
3-6环烷基和C
1-3烷基,所述C
3-6环烷基和C
1-3烷基任选被1、2或3个F取代;
R
7和R
9分别独立地选自H、F、Cl和C
1-3烷基,所述C
1-3烷基任选被1、2或3个F取代;
或者,R
6与R
7与它们共同连接的原子一起形成C
3-6环烷基或4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个F取代;
或者,R
8与R
9与它们共同连接的原子一起形成C
3-6环烷基或4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个F取代;
环B选自C
3-6环烷基,所述C
3-6环烷基任选被1、2或3个R
c取代;
L
1和L
2各自独立地选自单键和-C(=O)-;
R
2选自H、OH、
C
1-3烷基、C
1-3烷氧基、-NH-C
3-6环烷基、C
3-6环烷基和苯基,所述C
1-3烷基、C
1-
3烷氧基、-NH-C
3-6环烷基、C
3-6环烷基和苯基任选被1、2或3个R
a取代;
R
3选自C
3-6环烷基;
环A选自C
3-6环烷基和4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个R
b取代;
m选自0和1;
n选自0、1、2和3;
R
a和R
c各自独立地选自H、F、Cl、Br、I、OH、-OCH
3和NH
2;
各R
b分别独立地选自H、F、Cl、Br、I、=O、OH、NH
2、C
1-3烷基和C
1-3烷氧基;
所述4-6元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明还提供了式(V)所示化合物或其药学上可接受的盐,
其中,
T
1、T
2和T
3各自独立地选自CH和N;
各R
1分别独立地选自H、F、Cl、Br、I和CH
3;
R
4’选自H和C
1-3烷基;
R
5选自H、F、Cl和C
1-3烷基,所述C
1-3烷基任选被1、2或3个F取代;
R
6选自H、F、Cl、C
3-6环烷基和C
1-3烷基,所述C
3-6环烷基和C
1-3烷基任选被1、2或3个F取代;
R
7选自H、F、Cl和C
1-3烷基,所述C
1-3烷基任选被1、2或3个F取代;
或者,R
6与R
7连接在一起形成C
3-6环烷基,所述C
3-6环烷基任选被1、2或3个F取代;
或者,X与R
4连接在一起形成环B;
环B选自C
3-6环烷基,所述C
3-6环烷基任选被1、2或3个R
c取代;
L
1和L
2各自独立地选自单键和-C(=O)-;
R
2选自H、OH、
C
1-3烷基、C
1-3烷氧基、-NH-C
3-6环烷基、C
3-6环烷基和苯基,所述C
1-3烷基、C
1-
3烷氧基、-NH-C
3-6环烷基、C
3-6环烷基和苯基任选被1、2或3个R
a取代;
R
3选自C
3-6环烷基;
环A选自C
3-6环烷基和4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个R
b取代;
m选自0和1;
n选自0、1、2和3;
R
a和R
c各自独立地选自H、F、Cl、Br、I、OH、-OCH
3和NH
2;
各R
b分别独立地选自H、F、Cl、Br、I、=O、OH、NH
2、C
1-3烷基和C
1-3烷氧基;
所述4-6元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明提供了式(IV)所示化合物或其药学上可接受的盐,
其中,
T
1、T
2和T
3各自独立地选自CH和N;
各R
1分别独立地选自H、F、Cl、Br、I和CH
3;
R
4’选自H和C
1-3烷基;
或者,X与R
4连接在一起形成环B;
环B选自C
3-6环烷基,所述C
3-6环烷基任选被1、2或3个R
c取代;
L
1和L
2各自独立地选自单键和-C(=O)-;
R
2选自H、OH、
C
1-3烷基、C
1-3烷氧基、-NH-C
3-6环烷基、C
3-6环烷基和苯基,所述C
1-3烷基、C
1-3烷氧基、-NH-C
3-6环烷基、C
3-6环烷基和苯基任选被1、2或3个R
a取代;
R
3选自C
3-6环烷基;
环A选自C
3-6环烷基和4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个R
b取代;
m选自0和1;
n选自0、1、2和3;
R
a和R
c各自独立地选自H、F、Cl、Br、I、OH、-OCH
3和NH
2;
R
b选自H、F、Cl、Br、I、=O、OH、NH
2、C
1-3烷基和C
1-3烷氧基;
所述4-6元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明提供了式(I)所示化合物或其药学上可接受的盐,
其中,
L
1和L
2各自独立地选自单键和-C(=O)-;
各R
1独立地选自H、F、Cl、Br、I和CH
3;
m选自0和1;
n选自0、1、2和3;
R
2选自H、OH、
C
1-3烷基、C
1-3烷氧基、C
3-6环烷基-NH-、C
3-6环烷基和苯基,所述C
1-3烷基、C
1-3烷氧基、C
3-6环烷基-NH-、C
3-6环烷基和苯基任选被1、2或3个R
a取代;
R
3选自C
3-6环烷基;
环A选自C
3-6环烷基和4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个R
b取代;
T
1、T
2和T
3分别选自CH和N;
R
a选自H、F、Cl、Br、I、OH、-OCH
3和NH
2;
R
b选自H、F、Cl、Br、I、=O、OH、NH
2、C
1-3烷基和C
1-3烷氧基;
所述4-6元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明提供了式(I)所示化合物或其药学上可接受的盐,
其中,
L
1、L
2各独立地选自单键和-C(=O)-;
各R
1独立地选自H、F、Cl、Br、I;
m选自0和1;
n选自0、1、2和3;
R
2选自H、C
1-3烷基、C
1-3烷氧基、C
3-6环烷基-NH-、C
3-6环烷基和苯基,所述C
1-3烷基、C
1-3烷氧基、C
3-6环烷基-NH-、C
3-6环烷基和苯基任选被1、2或3个R
a取代;
R
3选自C
3-6环烷基;
环A选自C
3-6环烷基和4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个R
b取代;T
1、T
2和T
3分别选自CH和N;
R
a选自H、F、Cl、Br、I、OH、NH
2;
R
b选自H、F、Cl、Br、I、OH、NH
2、C
1-3烷基和C
1-3烷氧基;
所述4-6元杂环烷基分别独立包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明提供了式(I)所示化合物或其药学上可接受的盐,
其中,
L
1、L
2各独立地选自单键和-C(=O)-;
各R
1独立地选自H、F、Cl、Br、I;
m选自0和1;
n选自0、1、2和3;
R
2选自H、C
1-3烷氧基、C
3-6环烷基-NH-、C
3-6环烷基和苯基,所述C
1-3烷氧基、C
3-6环烷基-NH-、C
3-6环烷基和苯基任选被1、2或3个R
a取代;
R
3选自C
3-6环烷基;
环A选自C
3-6环烷基和4-6元杂环烷基,所述C
3-6环烷基和4-6元杂环烷基任选被1、2或3个R
b取代;
T
1、T
2和T
3分别选自CH和N;
R
a选自H、F、Cl、Br、I、OH、NH
2;
R
b选自H、F、Cl、Br、I、OH、NH
2、C
1-3烷基和C
1-3烷氧基;
所述4-6元杂环烷基分别独立包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明的一些方案中,上述R
2选自H、C
1-3烷基、C
1-3烷氧基、苯基、环丁基、环丁基-NH-和环丙基-NH-,所述C
1-3烷基、C
1-3烷氧基、苯基、环丁基、环丁基-NH-和环丙基-NH-任选被1、2或3个R
a取代,R
a及其他变量如本发明所定义。
本发明的一些方案中,上述R
2选自H、C
1-3烷氧基、苯基、环丁基、环丁基-NH-和环丙基-NH-,所述C
1-3烷氧基、苯基、环丁基、环丁基-NH-和环丙基-NH-任选被1、2或3个R
a取代,R
a及其他变量如本发明所定义。
本发明的一些方案中,上述R
b选自H、F、Cl、Br、I、=O、OH和NH
2,其他变量如本发明所定义。
本发明的一些方案中,上述R
b选自H、F、Cl、Br、I、OH和NH
2,其他变量如本发明所定义。
本发明的一些方案中,上述环A选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、硫杂环丁基、氮杂环己基、氧杂环戊基和氧杂环己基,所述环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、硫杂环丁基、氮杂环己基、氧杂环戊基和氧杂环己基任选被1、2或3个R
b取代,R
b及其他变量如本发明所定义。
本发明的一些方案中,上述环A选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、 硫杂环丁基、氮杂环己基和氧杂环己基,所述环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、硫杂环丁基、氮杂环己基和氧杂环己基任选被1、2或3个R
b取代,R
b及其他变量如本发明所定义。
环A、R
1和n如本发明所定义。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其化合物选自
其中,L
1、L
2、R
2、R
3和环A如本发明所定义。
本发明的一些方案中,上述化合物或其药学上可接受的盐,其化合物选自
其中,L
1、R
2和环A如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明还提供了下式所示化合物或其药学上可接受的盐:
本发明还提供了下式所示化合物或其药学上可接受的盐:
本发明还提供了化合物46a的A晶型,所述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.70±0.20°,11.32±0.20°,13.35±0.20°,16.25±0.20°,17.36±0.20°。
本发明的一些方案中,上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.70±0.20°,8.68±0.20°,9.35±0.20°,11.32±0.20°,13.35±0.20°,16.25±0.20°,17.36±0.20°,23.22±0.20°。
本发明的一些方案中,上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.70±0.20°,8.68±0.20°,9.35±0.20°,9.99±0.20°,11.32±0.20°,13.35±0.20°,14.05±0.20°,16.25±0.20°,17.36±0.20°,20.08±0.20°,23.22±0.20°,25.65±0.20°。
本发明的一些方案中,上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.70±0.20°,8.68±0.20°,还在9.35±0.20°,和/或9.99±0.20°,和/或11.32±0.20°,和/或13.35±0.20°,和/或14.05±0.20°,和/或16.25±0.20°,和/或17.36±0.20°,和/或20.08±0.20°,和/或23.22±0.20°,和/或25.65±0.20°处具有特征衍射峰。
本发明的一些方案中,上述A晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.70°,8.68°,9.35°,9.99°,11.32°,13.35°,14.05°,16.25°,17.36°,17.65°,20.08°,23.22°,23.80°,24.13°,25.65°,28.34°,30.32°,33.54°。
本发明的一些方案中,上述A晶型的XRPD图谱如图3所示。
本发明的一些方案中,上述A晶型的Cu Kα辐射的XRPD图谱中,衍射峰的峰位置及相对强度如下表所示:
表1化合物46a的A晶型的XRPD衍射数据
本发明的一些方案中,上述A晶型的差示扫描量热(DSC)曲线显示在241.2℃±3℃处具有吸热峰的峰值。
本发明的一些方案中,上述A晶型的DSC图谱如图4所示。
本发明的一些方案中,上述A晶型的热重分析(TGA)曲线在200.0℃±3℃时失重达2.55%。
本发明的一些方案中,上述A晶型的TGA图谱如图5所示。
本发明的一些方案中,上述A晶型的动态水分吸附分析(DVS)显示略有引湿性。
本发明的一些方案中,上述A晶型的DVS图谱如图6所示。
本发明还提供了上述A晶型的制备方法,所述方法包括如下步骤:
(a)将化合物46a加入溶剂X和溶剂Y的混合溶剂中;
(b)悬浮液在25~80℃下搅拌3~6天;
(c)室温下过滤,收集固体;
其中,
所述溶剂X选自乙酸乙酯、乙腈、2-甲基四氢呋喃、四氢呋喃、丙酮、二氯甲烷、1,4-二氧六环和异丙醇;
所述溶剂Y不存在;
或者,溶剂Y选自正庚烷、正己烷、环己烷、水和甲基叔丁基醚,溶剂X和溶剂Y的体积比为1:1~1:10。
本发明还提供了上述A晶型的制备方法,所述方法包括如下步骤:
(a)将化合物46a加入溶剂P中,充分溶解;
(b)5~25℃搅拌下滴加溶剂Q至有固体析出;
(c)离心,收集固体;
其中,
所述溶剂P选自四氢呋喃、氯仿、二甲基乙酰胺和二甲基亚砜;
所述溶剂Q选自甲苯、正庚烷、水和甲基异丁基甲酮。
本发明还提供了化合物46a的B晶型,所述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.12±0.20°,10.69±0.20°,12.74±0.20°,14.28±0.20°,15.18±0.20°。
本发明的一些方案中,上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.12±0.20°,10.15±0.20°,10.69±0.20°,12.74±0.20°,14.28±0.20°,15.18±0.20°,17.87±0.20°,25.12±0.20°。
本发明的一些方案中,上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:3.61±0.20°,7.12±0.20°,10.15±0.20°,10.69±0.20°,12.74±0.20°,14.28±0.20°,15.18±0.20°,17.87±0.20°,20.39±0.20°,21.09±0.20°,23.86±0.20°,25.12±0.20°。
本发明的一些方案中,上述B晶型的Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:3.61°,7.12°,10.16°,10.69°,10.95°,12.08°,12.74°,14.28°,15.18°,17.07°,17.87°,20.08°,20.39°,21.09°,22.79°,23.29°,23.86°,24.77°,25.12°,26.37°,30.02°,30.68°,31.23°,32.46°,34.80°,36.18°,37.13°。
本发明的一些方案中,上述B晶型的XRPD图谱如图7所示。
本发明的一些方案中,上述B晶型的Cu Kα辐射的XRPD图谱中,衍射峰的峰位置及相对强度如下表所示:
表2化合物46a的B晶型的XRPD衍射数据
本发明的一些方案中,上述B晶型的差示扫描量热(DSC)曲线显示在241.4℃±3℃处具有吸热峰的峰值。
本发明的一些方案中,上述B晶型的DSC图谱如图8所示。
本发明的一些方案中,上述B晶型的热重分析(TGA)曲线在140.0℃±3℃时失重达2.98%。
本发明的一些方案中,上述B晶型的TGA图谱如图9所示。
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗蛋白精氨酸甲基转移酶5抑制剂相关药物上的应用。
本发明还提供了上述A晶型或B晶型在制备治疗蛋白精氨酸甲基转移酶5抑制剂相关药物上的应用。
本发明的一些方案中,上述蛋白精氨酸甲基转移酶5抑制剂相关药物是用于预防和/或治疗淋巴瘤和实体瘤相关疾病的药物。
本发明的一些方案中,上述淋巴瘤为非霍奇金淋巴瘤,上述实体瘤为乳腺癌。
本发明的一些方案中,上述淋巴瘤为非霍奇金淋巴瘤,例如套细胞淋巴瘤。
本发明的一些方案中,上述实体瘤为乳腺癌。
技术效果
本发明化合物作为一类蛋白精氨酸甲基转移酶5(PRMT5)的抑制剂,具有良好的PRMT5酶抑制活性,能有效抑制非霍奇金淋巴瘤细胞和/或三阴性乳腺癌细胞的增殖,具有很好的血浆暴露量和合理的口服生物利用度。体内药效结果显示,本发明化合物具有显著的抑瘤作用。本发明化合物作为淋巴瘤和实体瘤的药物抑制剂,在预防和/或治疗淋巴瘤和实体瘤相关疾病方面具有较大的应用前景。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无 机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
除非另有说明,术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明,术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像的关系的立体异构体。
除非另有说明,“(+)”表示右旋,“(-)”表示左旋,“(±)”表示外消旋。
除非另有说明,用楔形实线键
和楔形虚线键
表示一个立体中心的绝对构型,用直形实线键
和直形虚线键
表示立体中心的相对构型,用波浪线
表示楔形实线键
或楔形虚线键
或用波浪线
表示直形实线键
或直形虚线键
除非另有说明,当化合物中存在双键结构,如碳碳双键、碳氮双键和氮氮双键,且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中,氮原子上的一对孤对电子视为其连接的一个取代基),如果该化合物中双键上的原子与其取代基之间用
表示,则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。
除非另有说明,术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100%,并且,该异构体或对映体的含量大于等于60%,或者大于等于70%, 或者大于等于80%,或者大于等于90%,或者大于等于95%,或者大于等于96%,或者大于等于97%,或者大于等于98%,或者大于等于99%,或者大于等于99.5%,或者大于等于99.6%,或者大于等于99.7%,或者大于等于99.8%,或者大于等于99.9%。
除非另有说明,术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如,其中一种异构体或对映体的含量为90%,另一种异构体或对映体的含量为10%,则异构体或对映体过量(ee值)为80%。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(
3H),碘-125(
125I)或C-14(
14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,取代基可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)
0-,表示该连接基团为单键。
当一个取代基数量为0时,表示该取代基是不存在的,比如-A-(R)
0表示该结构实际上是-A。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时,这种取代基可以与这个环上的任意原子相键合,例如,结构单元
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时,这种取代基可以通过其任何原子相键合,例如,吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向,其连接方向是任意的,例如,
中连接基团L为-M-W-,此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定,当某一基团具有一个或多个可连接位点时,该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的,且可连接位点存在H原子时,则连接化学键时,该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
直形虚线键
或波浪线
表示。例如-OCH
3中的直形实线键表示通过该基团中的氧原子与其他基团相连;
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连;
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连;
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连,至少包括
这4种连接方式,即使-N-上画出了H原子,但是
仍包括
这种连接方式的基团,只是在连接1个化学键时,该位点的H会对应减少1个变成相应的一价 哌啶基;
表示该基团上的任意可连接位点可以通过1个化学键与其他基团相连,至少包括
这8种连接方式。
除非另有规定,术语“C
1-3烷基”本身或者与其他术语联合分别用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C
1-3烷基包括C
1-2和C
2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定,术语“C
1-3烷氧基”本身或者与其他术语联合分别表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C
1-3烷氧基包括C
1-2、C
2-3、C
3和C
2烷氧基等。C
1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定,“C
3-6环烷基”本身或者与其他术语联合分别表示由3至6个碳原子组成的饱和环状碳氢基团,其为单环和双环体系,所述C
3-6环烷基包括C
3-5、C
4-5和C
5-6环烷基等;其可以是一价、二价或者多价。C
3-6环烷基的实例包括,但不限于,环丙基、环丁基、环戊基、环己基等
除非另有规定,术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和环状基团,其1、2、3或4个环原子为独立选自O、S和N的杂原子,其余为碳原子,其中氮原子任选地被季铵化,氮和硫杂原子可任选被氧化(即NO和S(O)
p,p是1或2)。其包括单环和双环体系,其中双环体系包括螺环、并环和桥环。此外,就该“4-6元杂环烷基”而言,杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基或六氢哒嗪基。
除非另有规定,C
n-n+m或C
n-C
n+m包括n至n+m个碳的任何一种具体情况,例如C
1-12包括C
1、C
2、 C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
11、和C
12,也包括n至n+m中的任何一个范围,例如C
1-12包括C
1-
3、C
1-6、C
1-9、C
3-6、C
3-9、C
3-12、C
6-9、C
6-12、和C
9-12等;同理,n元至n+m元表示环上原子数为n至n+m个,例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环,也包括n至n+m中的任何一个范围,例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基,如甲基、乙基和叔丁基;酰基,例如链烷酰基(如乙酰基);芳基甲基,如苄基(Bn),对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基,DPM);甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:
扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词:N
2代表氮气;DMSO代表二甲基亚砜;HATU代表2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯;HOBt代表1-羟基苯并三氮唑;EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;TMSCN代表三甲基腈硅烷;DAST代表二乙胺基三氟化硫;DPPF代表1,1'-双(二苯基膦)二茂铁;DMAP代表4-二甲氨基吡啶;TBSCl代表叔丁基二甲基氯硅烷;DIEA代表N,N-二异丙基乙胺;Pd/C代表钯碳;Pd(dppf)Cl
2代表[1,1'-双(二苯基膦)二茂铁]二氯化钯;Pd(dppf)Cl
2·CH
2Cl
2代表[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物;TBAF代表四丁基氟化铵;TosCl代表对甲苯磺酰氯;DEA代表二乙胺;ACN代表乙腈;CO
2代表二氧化碳;MPa代表压力单位兆帕;psi代表磅力/平方英寸;PDA代表二级阵列管检测器;RCF代表相对离心力;RLU代表相对光单位;AUC代表曲线下面积;PO代表口服; PEG400:聚乙二醇400;RH代表相对湿度;lux代表勒克斯;μw/cm
2代表微瓦每平方厘米;rpm代表转速;XRPD代表X射线粉末衍射;DSC代表差示扫描量热分析;DVS代表动态水分吸附分析;TGA代表热重分析;
1H NMR代表核磁共振氢谱。
本发明仪器及分析方法
(1)本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法
详细的XRPD仪器信息和参数如下表所示:
表3 XRPD仪器信息及测试参数
(2)本发明差热分析(Differential Scanning Calorimeter,DSC)方法和热重分析(Thermal Gravimetric Analyzer,TGA)方法
详细的TGA和DSC仪器信息和参数如下表所示:
表4 TGA和DSC仪器信息及测试参数
TGA | DSC | |
仪器型号 | TA Q5000/5500热重分析仪 | TA Q2500差示扫描量热仪 |
方法 | 线性升温 | 线性升温 |
样品盘 | 铝盘,敞开 | 铝盘,压盖/不压盖 |
温度范围 | 室温-设置终点温度 | 25℃-设置终点温度 |
扫描速率(℃/分钟) | 10 | 10 |
保护气体 | 氮气 | 氮气 |
(3)动态水分吸附分析(Dynamic Vapor Sorption,DVS)方法
详细的DVS仪器信息和参数如表5所示,引湿性评价分类如表6所示:
表5 DVS仪器信息及测试参数
表6引湿性评价分类
吸湿性分类 | ΔW% |
潮解 | 吸收足量水分形成液体 |
极具吸湿性 | ΔW%≥15% |
有吸湿性 | 15%>ΔW%≥2% |
略有吸湿性 | 2%>ΔW%≥0.2% |
无或几乎无吸湿性 | ΔW%<0.2% |
注:ΔW%表示受试品在25±1℃和80±2%RH下的吸湿增重。
图1表示人套细胞淋巴瘤Z-138细胞皮下异种移植瘤模型荷瘤鼠在给予化合物1和4后的肿瘤生长曲线
图2表示人套细胞淋巴瘤Z-138细胞皮下异种移植瘤模型荷瘤鼠在给予化合物8后的肿瘤生长曲线
图3化合物46a晶型A的XRPD谱图
图4化合物46a晶型A的DSC谱图
图5化合物46a晶型A的TGA谱图
图6化合物46a晶型A的DVS谱图
图7化合物46a晶型B的XRPD谱图
图8化合物46a晶型B的DSC谱图
图9化合物46a晶型B的TGA谱图
图10化合物46a二水合物的立体结构椭球图
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1:片段BB-1
步骤1:化合物BB-1-3的合成
在0℃合下向化合物BB-1-1(50.00g,375.40mmol,47.17mL,1.00eq)的四氢呋喃(500.00mL)溶液中加入氟化钾(87.24g,1.50mol,35.18mL,4.00eq),反应液在0℃,下搅拌1小时,然后加入化合物BB-1-2(107.05g,412.94mmol,1.10eq),反应液在20℃反下搅拌16小时。反应液通过硅藻土过滤,滤液减压浓缩,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=10:1~6:1),得到化合物BB-1-3。MS(ESI)m/z:190.2[M+H]
+。
步骤2:化合物BB-1的合成
在-70℃下向乙醇(1000.00mL)中通入氨气50分钟,然后将化合物BB-1-3(20.00g,105.68mmol,1.00eq)加入到上述溶液,反应液转移到高压釜中,加热到40℃,压力(0.5MPa)条件下,搅拌48小时。反应液减压浓缩得到粗品化合物BB-1。MS(ESI)m/z:207.3[M+H]
+。
实施例1:化合物1的制备
步骤1:化合物1-3的合成
在冰浴下向化合物1-2(1.10g,6.14mmol,1.00eq)二氯甲烷(3.00mL)溶液中加入N,N-二甲基甲酰胺(22.40mg,307.24μmol,0.05eq),缓慢滴加氯化亚砜(877.20mg,7.37mmol,1.20eq),反应液升温至40℃反搅拌6小时,然后降温到0℃时,将上述反应液缓慢滴入化合物1-1(1.03g,6.14mmol,1.00eq)和N-甲基***啉(1.55g,15.36mmol,2.5eq)的二氯甲烷(3.00mL)溶液中,反应液升温至室温下搅拌0.5小时。反应液加水(100mL)淬灭,使用乙酸乙酯(100mL×2)萃取,合并有机相,有机相使用无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物1-3。MS(ESI)m/z:327.8[M+H]
+。
步骤2:化合物1-4的合成
向化合物1-3(1.60g,4.88mmol,1.00eq)的N,N-二甲基甲酰胺(10.00mL)溶液中加入碳酸钾(3.37g,24.38mmol,5.00eq),反应液升温到80℃反搅拌16小时,然后降至室温,加水(100mL)淬灭,使用乙酸乙酯(100mL×3)萃取,合并有机相,有机相使用水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物1-4。MS(ESI)m/z:248.1[M+H]
+。
步骤3:化合物1-5的合成
向化合物1-4(400.00mg,1.62mmol,1.00eq)的四氢呋喃(4.00mL)、甲醇(2.00mL)和水(1.00mL)溶液中加入一水合氢氧化锂(203.60mg,4.85mmol,3.00eq),反应液升温至60℃反搅拌5小时,然后加入水(20mL),使用乙酸乙酯(20mL)洗涤,水相用稀盐酸调节pH=6,过滤,得到粗品化合物1-5直接用于下步反应。MS(ESI)m/z:234.0[M+H]
+。
步骤4:化合物1的合成
在冰浴下向化合物1-5(380.00mg,1.63mmol,1.00eq)的N,N-二甲基甲酰胺(6.00mL)的溶液中加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(619.50mg,1.63mmol,1.00eq)和N,N-二异丙基乙胺(421.17mg,3.26mmol,2.00eq),反应液在冰浴条件下搅拌10分钟,然后加入化合物BB-1(336.11mg,1.63mmol,1.00eq),搅拌20分钟。反应液加入乙酸乙酯(100mL),用水(30mL×3)洗涤,有机相使用无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈],高效液相柱的保留时间为11.5min),得到化合物1。
1H NMR(400MHz,CDCl
3):δ9.07(m,1H),7.68(d,J=2.0Hz,1H),7.31(br t,J=5.6Hz,1H),7.24-7.13(m,4H),7.03-7.01(m,1H),6.88(d,J=8.4Hz,1H),4.13-4.05(m,1H),3.85(d,J=14.8Hz,1H),3.80-3.72(m,1H),3.71-3.60(m,2H),3.00-2.90(m,3H),2.82-2.62(m,5H),2.40-2.29(m,2H),2.08-1.91(m,3H)。MS(ESI)m/z:422.4[M+H]
+。
实施例2:化合物2的制备
步骤1:化合物2-2的合成
向化合物2-1(20g,175.22mmol,19.05mL,1eq)中加入三溴化磷(7.59g,28.04mmol,0.16eq),反应液在100℃下搅拌1小时,然后将液溴(70.00g,438.05mmol,22.58mL,2.5eq)加入到反应液中,反应液继续在100℃下搅拌12小时。反应液冷却0-15℃,然后加入二氯甲烷(200mL),再用亚硫酸氢钠溶液(10%,200mL)淬灭反应液,混合物搅拌0.5小时,然后用二氯甲烷萃取(200mL×3),合并有机相,饱和食盐水洗涤(200mL),无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物2-2。
1H NMR(400MHz,CDCl
3):δ10.70(br s,1H),2.36-2.13(m,4H),2.00-1.84(m,2H),1.82-1.64(m,2H)。
步骤2:化合物2-3的合成
将化合物2-2(1.73g,8.97mmol,1.5eq)溶于二氯甲烷(20mL),然后加入1-1(1g,5.98mmol,1eq),N,N-二 异丙基乙胺(2.55g,19.74mmol,3.44mL,3.3eq)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(3.41g,8.97mmol,1.5eq),反应液在25℃搅拌1小时。然后加入水(20mL),用二氯甲烷萃取(30mL×3),合并有机相,饱和食盐水洗涤(30mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Phenomenex luna C18 250×80mm×10μm;流动相:[水(0.05%盐酸)-乙腈];乙腈%:28%-58%,高效液相柱的保留时间为28min)得到化合物2-3。MS(ESI)m/z:342.1[M+1]
+。
步骤3:化合物2-4的合成
将化合物2-3(0.64g,1.87mmol,1eq)溶于N,N-二甲基甲酰胺(10mL),然后加入碳酸钾(1.29g,9.35mmol,5eq),反应液在80℃搅拌8小时。然后向反应液中加入水(50mL),用乙酸乙酯萃取(50mL×3),合并有机相,饱和食盐水洗涤(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩。得到粗品化合物2-4。MS(ESI)m/z:262.1[M+1]
+。
步骤4:化合物2-5的合成
将化合物2-4(2.2g,8.42mmol,1eq)溶于四氢呋喃(12mL)和甲醇(6mL)溶液中,然后加入一水合氢氧化锂(1.41g,33.68mmol,4eq)溶于水(3mL)的溶液。反应液在60℃搅拌5小时。反应液减压浓缩。然后用盐酸(2M)调节pH到2-3,反应液在25℃下搅拌1小时,混合物过滤,收集滤饼在减压下干燥。得到化合物2-5。MS(ESI)m/z:248.2[M+1]
+。
步骤5:化合物2的合成
在0℃下将化合物2-5(0.1g,404.46μmol,1eq)溶于N,N-二甲基甲酰胺(6mL),然后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(153.79mg,404.46μmol,1eq)和N,N-二异丙基乙胺(104.55mg,808.91μmol,140.90μL,2eq),反应液搅拌10分钟,向反应液中加入化合物BB-1(83.43mg,404.46μmol,1eq),反应液在0℃下继续搅拌20分钟。向反应液中加水(20mL),乙酸乙酯萃取(20mL×3),合并有机相,饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:25%-55%,高效液相柱的保留时间为10min),得到化合物2。
1H NMR(400MHz,CDCl
3):δ8.00(br s,1H),7.38(d,J=2.0Hz,1H),7.33(dd,J=2.0,8.0Hz,1H),7.25-7.08(m,4H),7.04(d,J=6.8Hz,1H),6.91(d,J=8.0Hz,1H),4.07(m,1H),3.89-3.83(m,1H),3.79-3.64(m,2H),3.53(m,1H),3.01-2.90(m,3H),2.83-2.58(m,3H),2.26-2.15(m,2H),2.05-1.77(m,6H)。MS(ESI)m/z:436.3[M+1]
+。
实施例3:化合物3的制备
步骤1:化合物3-2的合成
向化合物3-1(20g,156.04mmol,19.42mL,1eq)中加入三溴化膦(8.45g,31.21mmol,0.2eq),反应液在100℃下搅拌1小时,然后将液溴(62.34g,390.11mmol,20.11mL,2.5eq)加入到反应液中,反应液继续在100℃下搅拌48小时。反应液冷却0-15℃,然后加入二氯甲烷(200mL),再用亚硫酸氢钠溶液(10%,200mL)淬灭反应液,混合物搅拌0.5小时,然后用二氯甲烷萃取(200mL×3),合并有机相,饱和食盐水洗涤(200mL),无水硫酸钠干燥,过滤,滤液减压浓缩。得到化合物3-2。
1H NMR(400MHz,CDCl
3):δ12.11(br s,1H),2.16-2.01(m,3H),1.91-1.80(m,1H),1.74-1.61(m,2H),1.59-1.30(m,4H)。
步骤2:化合物3-3的合成
将化合物3-2(1.86g,8.97mmol,1.5eq)溶于二氯甲烷(20mL),然后加入1-1(1g,5.98mmol,1eq),N,N-二异丙基乙胺(2.55g,19.73mmol,3.44mL,3.3eq)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(3.41g,8.97mmol,1.5eq),反应液在25℃搅拌1小时。然后加入水(20mL),用二氯甲烷萃取(30mL×3),合并有机相,饱和食盐水洗涤(30mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Phenomenex luna C18 150×25mm×10μm;流动相:[水(0.05%盐酸)-乙腈];乙腈%:45%-75%,高效液相柱的保留时间为10min)得到化合物3-3。MS(ESI)m/z:356.1[M+1]
+。
步骤3:化合物3-4的合成
将化合物3-3(0.24g,673.76μmol,1eq)溶于N,N-二甲基甲酰胺(10mL),然后加入碳酸钾(465.60mg,3.37mmol,5eq),反应液在80℃搅拌2小时。然后向反应液中加入水(50mL),用乙酸乙酯萃取(50mL×3),合并有机相,饱和食盐水洗涤(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩。得到粗品化合物3-4。MS(ESI)m/z:276.1[M+1]
+。
步骤4:化合物3-5的合成
将化合物3-4(0.2g,726.48μmol,1eq)溶于四氢呋喃(12mL)和甲醇(6mL)溶液中,然后加入一水合氢氧化锂(121.93mg,2.91mmol,4eq)的水(3mL)溶液。反应液在60℃搅拌6小时。反应液减压浓缩。然后用HCl(2M)调节pH到2-3,反应液在25℃下搅拌1小时,混合物过滤,收集滤饼在减压下干燥。得到粗品化合物3-5。MS(ESI)m/z:262.0[M+1]
+。
步骤5:化合物3的合成
在0℃下将化合物3-5(0.15g,574.11μmol,1eq)溶于N,N-二甲基甲酰胺(6mL),然后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(218.29mg,574.11μmol,1eq)和N,N-二异丙基乙胺(148.40mg,1.15mmol,200.00μL,2eq),反应液搅拌10分钟,向反应液中加入化合物BB-1(118.43mg,574.11μmol,1eq),反应液在0℃下继续搅拌20分钟。向反应液中加水(20mL),乙酸乙酯萃取(20mL×3),合并有机相,饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge C18 150×50mm×10μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:33%-63%,高效液相柱的保留时间为11.5min),得到化合物3。
1H NMR(400MHz,CDCl
3):δ8.01(br s,1H),7.43(d,J=2.0Hz,1H),7.36(dd,J=1.6,8.4Hz,1H),7.24-7.13(m,4H),7.07-7.01(m,1H),6.99(d,J=8.4Hz,1H),4.10(br dd,J=4.8,8.6Hz,1H),3.97-3.85(m,1H),3.81-3.69(m,2H),3.64-3.49(m,1H),3.07-2.92(m,3H),2.91-2.60(m,4H),1.96-1.72(m,10H)。MS(ESI)m/z:450.3[M+1]
+。
实施例4:化合物4的制备
步骤1:化合物4-2的合成
将化合物4-1(10g,76.84mmol,19.42mL,1eq)溶于入1,2-二氯乙烷(100mL),然后加入三溴化磷(4.16g,15.37mmol,0.2eq),反应液在100℃下搅拌1小时,然后将液溴(30.70g,192.10mmol,9.90mL,2.5eq)加入到反应液中,反应液继续在100℃下搅拌48小时。反应液冷却0-15℃,然后加入二氯甲烷(200mL),再用亚硫酸氢钠溶液(10%,200mL)淬灭反应液,混合物搅拌0.5小时,然后用二氯甲烷萃取(200mL×3),合并有机相,饱和食盐水洗涤(200mL),无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物4-2。
1H NMR(400MHz,CDCl
3):δ11.18(br s,1H),4.00-3.69(m,4H),2.26-2.07(m,3H),1.86-1.72(m,1H)。
步骤2:化合物4-3的合成
将化合物4-2(2.5g,11.96mmol,1eq)溶于N,N-二甲基甲酰胺(20mL),然后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(4.55g,11.96mmol,1eq),化合物1-1(2.00g,11.96mmol,1eq)和N,N-二异丙基乙胺(3.09g,23.92mmol,4.17mL,2eq),反应液在25℃搅拌2小时。然后加入水(50mL),用乙酸乙酯萃取(50mL×3),合并有机相,饱和食盐水洗涤(50mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Phenomenex luna C18 250×50mm×15μm;流动相:[水(0.05%盐酸)-乙腈];乙腈%:20%-50%,高效液相柱的保留时间为25min)得到化合物4-3。MS(ESI)m/z:358.1[M+1]
+。
步骤3:化合物4-4的合成
将化合物4-3(1.2g,3.35mmol,1eq)溶于N,N-二甲基甲酰胺(24mL),然后加入碳酸钾(2.32g,16.75mmol,5eq),反应液在80℃搅拌2小时。然后向反应液中加入水(50mL),用乙酸乙酯萃取(50mL×3),合并有机相,饱和食盐水洗涤(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩。得到化合物4-4。MS(ESI)m/z:278.1[M+1]
+。
步骤4:化合物4-5的合成
将化合物4-4(0.6g,2.16mmol,1eq)溶于四氢呋喃(12mL)和甲醇(6mL)溶液中,然后加入一水合氢氧化锂(363.20mg,8.66mmol,4eq)溶于水(3mL)的溶液。反应液在60℃搅拌3小时。反应液减压浓缩。然后用盐酸(2M)调节pH到2-3,反应液在25℃下搅拌1小时,混合物过滤,收集滤饼在减压下干燥。得到粗品化合物4-5。MS(ESI)m/z:264.2[M+1]
+。
步骤5:化合物4的合成
在0℃下将化合物4-5(0.1g,379.87μmol,1eq)溶于N,N-二甲基甲酰胺(3mL),然后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(144.44mg,379.87μmol,1eq)和N,N-二异丙基乙胺(98.19mg,759.75μmol,132.33μL,2eq),反应液搅拌10分钟,向反应液中加入化合物BB-1(78.36mg,379.87μmol,1eq),反应液在0℃下继续搅拌20分钟。向反应液中加水(20mL),乙酸乙酯萃取(20mL×3),合并有机相,饱和食盐水洗涤(20mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱: Waters Xbridge C18 150×50mm×10μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:17%-47%,高效液相柱的保留时间为10min),得到化合物4。
1H NMR(400MHz,CDCl3):δ8.71(br s,1H),7.60(d,J=2.0Hz,1H),7.34-7.29(m,1H),7.25-7.12(m,4H),7.03(d,J=7.4Hz,1H),6.97(d,J=8.4Hz,1H),4.09(m,1H),3.95-3.81(m,5H),3.77(m,1H),3.72-3.53(m,2H),3.03-2.89(m,3H),2.87-2.59(m,3H),2.25(m,2H),1.79(br d,J=12.0Hz,3H)。MS(ESI)m/z:452.3[M+1]
+。
实施例5:化合物5的制备
步骤1:化合物5-2的合成
在75℃条件下,向化合物5-1(1g,4.57mmol,1eq),氯化铵(2.44g,45.66mmol,10eq)的乙醇(20mL)和水(20mL)溶液中加入铁粉(2.55g,45.66mmol,10eq),反应液继续搅拌2小时。反应液冷却至室温,过滤,滤液减压浓缩,得到粗品化合物5-2。
步骤2:化合物5-4的合成
在25℃条件下,向化合物5-2(691.38mg,3.86mmol,1eq)的N,N-二甲基甲酰胺(10mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.76g,4.63mmol,1.2eq)和二异丙基乙胺(748.73mg,5.79mmol,1.01mL,1.5eq),搅拌10分钟,向其中加入化合物5-3(0.730g,3.86mmol,1eq),反应液继续搅拌12小时。反应液加水稀释(10mL),乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=3:1)得到化合物5-4。
步骤3:化合物5-5的合成
在25℃条件下,向化合物5-4(0.7g,2.00mmol,1eq)的N,N-二甲基甲酰胺(2mL)溶液中加入碳酸钾(414.61mg,3.00mmol,1.5eq),反应液升温至80℃,搅拌2小时。反应液加水稀释(10mL),乙酸乙酯(10 mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物5-5。
步骤4:化合物5-6的合成
在25℃条件下,向化合物5-5(0.3g,1.11mmol,1eq)和二碳酸二叔丁酯(364.97mg,1.67mmol,384.18μL,1.5eq)的四氢呋喃(10mL)溶液中加入4-二甲氨基吡啶(13.62mg,111.49μmol,0.1eq),反应液继续搅拌1小时。反应液加饱和柠檬酸溶液(15mL)淬灭,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。得到粗品化合物5-6。
步骤5:化合物5-7的合成
在一氧化碳(50psi)氛围下,将化合物5-6(0.4g,1.08mmol,1eq),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(237.82mg,325.02μmol,0.3eq)和三乙胺(328.88mg,3.25mmol,452.38μL,3eq)的甲醇(20mL)溶液置于80℃搅拌反应12小时。反应液冷却至室温,过滤,滤液减压浓缩。粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=3:1~1:1),得到化合物5-7。
步骤6:化合物5-8的合成
在25℃条件下,向化合物5-7(0.2g,574.14μmol,1eq)的乙酸乙酯(5mL)溶液中加入盐酸/乙酸乙酯(4M,5mL,34.84eq),反应液继续搅拌12小时。反应液减压浓缩,粗品加饱和碳酸氢钠溶液(10mL)调节pH至9,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=3:1~0:1)得到化合物5-8。
步骤7:化合物5-9的合成
在25℃条件下,向化合物5-8(0.055g,221.57μmol,1eq)的甲醇(5mL),四氢呋喃(3mL)和水(1mL)溶液中加入一水合氢氧化锂(27.89mg,664.70μmol,3eq),反应液继续搅拌2小时。反应液加水稀释(10mL),加稀盐酸(1M)调节pH至3,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干躁,过滤,滤液减压浓缩得到粗品化合物5-9。
步骤8:化合物5的合成
在25℃条件下,向化合物5-9(0.038g,162.25μmol,1eq)的N,N-二甲基甲酰胺(2mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(74.03mg,194.70μmol,1.2eq)和N,N-二异丙基乙胺(31.45mg,243.37μmol,42.39μL,1.5eq),搅拌10分钟,再向其中加入化合物BB-1(33.47mg,162.25μmol,1eq),反应液继续搅拌1小时。反应液加水稀释(10mL),乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:25%-55%,高效液相柱的保留时间为10min)得到化合物5。
1H NMR(400MHz,DMSO-d
6):δ11.38(s,1H),8.10(br s,1H),7.65(d,J=8.2Hz,1H),7.55(d,J=8.2Hz,1H),7.22-6.99(m,4H),5.05(br s,1H),4.25-3.41(m,3H),3.01-2.73(m,4H),2.63-2.52(m,4H),2.44-2.17(m,4H),2.01-1.90(m,1H),1.90-1.74(m,1H)。MS(ESI)m/z:423.4[M+H]
+。
实施例6:化合物6的制备
步骤1:化合物6-3的合成
向化合物6-2(332.8mg,1.54mmol,1eq)的二氧六环(5.00mL)溶液中加入钠氢(92.2mg,2.31mmol,60%纯度,1.5eq)和化合物6-1(200.0mg,1.54mmol,1eq),继续在20℃续下搅拌16小时。然后加水溶液(50mL)淬灭,乙酸乙酯(50mL×4)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经薄层制备板(石油醚:乙酸乙酯=5:1)分离纯化得到化合物6-3。MS(ESI)m/z:311.0[M+H]
+。
步骤2:化合物6-4的合成
在室温下向化合物6-3(194.0mg,625.28μmol,1eq)的冰醋酸(2.00mL)溶液中加入还原铁粉(139.6mg,2.50mmol,4eq),反应液70℃液搅拌2小时。反应液加饱和碳酸氢钠水溶液(2mL)淬灭,悬浊液通过硅藻土过滤,滤饼用乙酸乙酯(50mL)洗涤,合并滤液,分液,水相用乙酸乙酯(50mL×3)萃取,合并有机相依次用水(50mL×3)和饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物6-4,直接用于下步反应。
1H NMR(400MHz,CDCl
3):δ8.60(d,J=2.0Hz,1H),8.50-8.40(m,1H),7.76-7.73(m,1H),3.95(s,3H),2.83-2.70(m,2H),2.59-2.48(m,2H),2.17-1.95(m,2H)。MS(ESI)m/z:249.0[M+H]
+。
步骤3:化合物6-5的合成
在室温下向化合物6-4(86.0mg,346.45μmol,1eq)的四氢呋喃(1.00mL)和水(0.20mL)混合溶液中加入一水合氢氧化锂(43.6mg,1.04mmol,3eq),反应液20℃应搅拌3小时。反应液使用稀盐酸调节pH=4, 用乙酸乙酯(20mL×3)萃取,合并有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物6-5直接用于下步反应。MS(ESI)m/z:235.0[M+H]
+。
步骤4:化合物6的合成
在0℃下向化合物6-5(79.0mg,337.31μmol,1eq)的N,N-二甲基甲酰胺(1.00mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(153.9mg,404.77μmol,1.2eq)和N,N-二异丙基乙胺(87.2mg,674.61μmol,117.51μL,2eq),反应液搅拌0.5小时,然后再加入化合物BB-1(69.6mg,337.31μmol,1eq)的N,N-二甲基甲酰胺(0.50mL)溶液,继续在0℃液下搅拌0.5小时。然后加水稀释(20mL),用乙酸乙酯(20mL×3)萃取,合并有机相用水(20mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(0.05%氨水)-乙腈,乙腈:18%-48%,高效液相柱的保留时间为10min]得到化合物6。
1H NMR(400MHz,CDCl
3):δ8.29(d,J=2.4Hz,1H),7.72(d,J=2.0Hz,1H),7.23-7.09(m,4H),7.05-7.01(m,1H),4.12-4.04(m,1H),3.87(d,J=15.2Hz,1H),3.81-3.74(m,1H),3.67(d,J=14.8Hz,1H),3.52(dt,J=5.8,13.6Hz,1H),3.01-2.90(m,3H),2.83-2.67(m,4H),2.65-2.58(m,1H),2.56-2.45(m,2H),2.14-1.95(m,2H);MS(ESI)m/z:423.2[M+H]
+。
实施例7:化合物7的制备
步骤1:化合物7-3的合成:
0℃下向化合物7-1(300mg,2.58mmol,1eq)的N,N-二甲基甲酰胺(3.00mL)溶液中加入钠氢(206.69mg,5.17mmol,60%纯度,2eq),反应液在0℃下搅拌10分钟,然后再滴加化合物7-2(514.50mg,2.58mmol,1eq),继续在10℃下搅拌2小时。然后加饱和氯化铵水溶液淬灭(50mL),乙酸乙酯萃取(50mL×3),合并有 机相,有机相使用水洗涤(50mL),饱和食盐水洗涤(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品化合物7-3直接用于下一步反应。MS(ESI)m/z:296.0[M+1]
+。
步骤2:化合物7-4的合成:
在室温下向化合物7-3(660mg,2.24mmol,1eq)的冰醋酸(6.00mL)溶液中加入还原铁粉(624.19mg,11.18mmol,5eq),反应液80℃搅拌1小时。反应液加饱和碳酸氢钠水溶液淬灭(50mL),悬浊液通过硅藻土过滤,滤饼用乙酸乙酯洗涤(50mL),合并滤液,分液,有机相使用水洗涤(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物7-4直接用于下步反应。MS(ESI)m/z:234.0[M+1]
+。
步骤3:化合物7-5的合成:
在室温下向化合物7-4(469mg,2.01mmol,1eq)的四氢呋喃(4.00mL),甲醇(2.00mL)和水(1.00mL)混合溶液中加入一水合氢氧化锂(253.16mg,6.03mmol,3eq),反应液17℃搅拌16小时。反应液使用稀盐酸调节pH=4,用乙酸乙酯萃取(50mL×2),合并有机相用水洗涤(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物7-5直接用于下步反应。MS(ESI)m/z:220.0[M+1]
+。
步骤4:化合物7的合成:
在0℃下向化合物7-5(130mg,593.08μmol,1eq)的N,N-二甲基甲酰胺(2.00mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(248.06mg,652.39μmol,1.1eq)和N,N-二异丙基乙胺(229.96mg,1.78mmol,309.91μL,3eq),反应液搅拌0.5小时,然后再加入化合物BB-1(122.34mg,593.08μmol,1eq),继续在0℃下搅拌0.5小时。然后加水稀释(10mL),悬浊液搅拌10分钟,过滤,滤饼用水洗涤(30mL),减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(0.05%氨水)-乙腈,乙腈%:25%-55%,高效液相柱的保留时间为10min]。得到化合物7。
1H NMR(400MHz,CDCl
3):δ9.54(s,1H),7.75(s,1H),7.47-7.39(m,1H),7.21-7.10(m,4H),7.02-6.97(m,1H),6.69(d,J=8.4Hz,1H),4.12-4.03(m,1H),3.82(d,J=14.8Hz,1H),3.77-3.69(m,1H),3.69-3.58(m,2H),2.97-2.88(m,3H),2.83-2.75(m,1H),2.71(dd,J=12.4,4.8Hz,1H),2.65(dd,J=12.4,8.4Hz,1H),1.48-1.43(m,2H),1.25-1.19(m,2H)。MS(ESI)m/z:408.3[M+1]
+。
实施例8:化合物8的制备
步骤1:化合物8-1的合成:
20℃下向6-2(1.60g,13.78mmol,1eq)和化合物7-2(2.98g,13.78mmol,1eq)的四氢呋喃(30.00mL)溶液中加入三乙烯二胺(3.09g,27.56mmol,3.03mL,2eq),反应液在20℃下搅拌16小时,反应液加水(100mL),乙酸乙酯萃取(100mL×2),合并有机相,有机相使用水洗涤(100mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品用硅胶柱层析(石油醚:乙酸乙酯=10:1)分离纯化得到化合物8-1。
步骤2:化合物8-2的合成:
在室温下向化合物8-1(1.14g,3.85mmol,1eq)的乙醇(10.00mL)和水(10.00mL)的混合溶液中加入氯化铵(1.03g,19.24mmol,5eq)升温至80℃缓慢加入还原铁粉(1.07g,19.24mmol,5eq),反应液80℃搅拌3小时。反应液趁热通过硅藻土过滤加,滤液减压浓缩掉有机溶剂,用乙酸乙酯萃取(50mL×3),合并有机相用水洗涤(20mL),无水硫酸钠干燥,过滤,滤液减压浓缩,到粗品化合物8-2直接用于下一步反应。MS(ESI)m/z:267.0[M+1]
+。
步骤3:化合物8-3的合成:
向化合物8-2(657.0mg,2.47mmol,1eq)的甲醇(7.00mL)混合物中加入一水合对甲苯磺酸(234.69mg,1.23mmol,0.5eq),反应液在70℃下搅拌3小时,减压浓缩,加入饱和碳酸氢钠溶液(5mL),过滤,滤饼用水洗涤(10mL),减压浓缩得到粗品化合物8-3直接用于下一步反应。MS(ESI)m/z:235.1[M+1]。
步骤4:化合物8-4的合成:
在室温下向化合物8-3(533.0mg,2.28mmol,1eq)的四氢呋喃(8.00mL),甲醇(4.00mL)和水(3.00mL)混合溶液中加入一水合氢氧化锂(286.5mg,6.83mmol,3eq),反应液50℃搅拌5小时。反应液减压浓缩掉有机溶剂,水相使用稀盐酸调节pH≈6,过滤,滤饼减压浓缩得到粗品化合物8-4直接用于下步反应。
1H NMR(400MHz,DMSO-d
6):δ11.10(s,1H),8.31(d,J=2.0Hz,1H),7.71(d,J=2.4Hz,1H),1.40-1.33(m,2H),1.33-1.27(m,2H)。MS(ESI)m/z:221.1[M+1]
+。
步骤5:化合物8的合成:
在0℃下向化合物8-4(497.0mg,2.26mmol,1eq)的N,N-二甲基甲酰胺(10.00mL)溶液中分别加入2-(7-氮 杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(944.09mg,2.48mmol,1.1eq)和二异丙基乙胺(583.46mg,4.51mmol,786.34μL,2eq),反应液搅拌1小时,然后再加入化合物BB-1(512.19mg,2.48mmol,1.1eq),继续在0℃下搅拌1小时。然后加水稀释(30mL),用乙酸乙酯萃取(30mL×3),合并有机相用水洗涤(30mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(0.05%氨水)-乙腈,乙腈%:15%-45%,高效液相柱的保留时间为10min]。得到化合物8。
1H NMR(400MHz,CDCl
3):δ8.25(d,J=2.0Hz,1H),7.81(d,J=2.0Hz,1H),7.26-7.23(m,1H),7.21-7.10(m,3H),7.03-6.99(m,1H),4.12-4.03(m,1H),3.84(d,J=14.8Hz,1H),3.80-3.72(m,1H),3.65(br d,J=14.8Hz,1H),3.50(td,J=6.0,13.6Hz,1H),3.00-2.88(m,3H),2.81-2.73(m,1H),2.69(dd,J=4.4,12.4Hz,1H),2.61(dd,J=9.2,12.4Hz,1H),1.58-1.52(m,2H),1.43-1.37(m,2H)。MS(ESI)m/z:409.3[M+1]
+。
实施例9:化合物9的制备
步骤1:化合物9-2的合成
在25℃条件下,向化合物9-1(2g,11.68mmol,1eq)和三甲基腈硅烷(1.62g,16.36mmol,2.05mL,1.4eq)的四氢呋喃溶液(30mL)中加入碘化锌(745.82mg,2.34mmol,0.2eq),反应液继续搅拌12小时。反应液减压浓缩,粗品加乙酸乙酯(25mL)稀释,再分别经饱和碳酸氢钠溶液(15mL),饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物9-2。
1H NMR(400MHz,CDCl
3):δ4.70(s,4H),1.49(s,9H),0.32-0.11(m,9H)。
步骤2:化合物9-3的合成
在0℃条件下,向化合物9-2(1g,3.70mmol,1eq)的乙酸乙酯溶液(10mL)中加入稀盐酸(0.5M,11.09mL,1.5eq),反应液搅拌11小时。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相, 有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物9-3。
1H NMR(400MHz,CDCl
3):δ4.38(dd,J=1.0,9.6Hz,2H),4.08(dd,J=1.0,9.8Hz,2H),1.46(s,9H)。
步骤3:化合物9-4的合成
在0℃条件下,向化合物9-3(0.1g,504.49μmol,1eq)的N,N-二甲基甲酰胺溶液(2mL)中加入钠氢(30.27mg,756.74μmol,60%纯度,1.5eq),搅拌30分钟,然后向其中加入化合物7-1(100.46mg,504.49μmol,1eq),反应液在25℃搅拌12小时。反应液加入饱和氯化铵溶液(10mL)淬灭,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=5:1~1:1)得到化合物9-4。
步骤4:化合物9-5的合成
在75℃条件下,向化合物9-4(0.05g,132.50μmol,1eq)和氯化铵(35.44mg,662.52μmol,5eq)的乙醇(2mL)和水溶液(2mL)中加入铁粉(37.00mg,662.52μmol,5eq),反应液继续搅拌2小时。反应液过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=3:1~1:1),得到化合物9-5。
步骤5:化合物9-6的合成
在25℃条件下,向化合物9-5(0.040g,114.83μmol,1eq)的乙酸乙酯溶液(2mL)中加入盐酸/乙酸乙酯(4M,4mL,138.55eq),反应液搅拌2小时。反应液减压浓缩,得到粗品化合物9-6盐酸盐。
步骤6:化合物9-7的合成
在25℃条件下,向化合物9-6(0.035g,盐酸盐粗品)和丙酮(10.71mg,184.41μmol,13.56μL,1.5eq)的甲醇(5mL),醋酸溶液(0.5mL)中加入醋酸硼氢化钠(52.11mg,245.88μmol,2.0eq),反应液继续搅拌2小时。反应液加饱和碳酸氢钠溶液调节pH至9,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干躁,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=3:1~0:1),得到化合物9-7。
步骤7:化合物9-8的合成
在25℃条件下,向化合物9-7(0.030g,103.34μmol,1eq)的甲醇(5mL),水(1mL)和四氢呋喃(1.5mL)溶液中加入一水合氢氧化锂(21.68mg,516.68μmol,5eq),反应液搅拌1小时,然后升温至45℃搅拌12小时。反应液加水(10mL)稀释,加稀盐酸(1M)调节pH至6,乙酸乙酯(10mL×3)萃取,检测表明产品在水相,水相减压浓缩旋干,得到粗品化合物9-8。
步骤8:化合物9的合成
在25℃条件下,向化合物9-8(0.028g,103.30μmol,1eq)的N,N-二甲基甲酰胺溶液(2mL)中分别加入HATU(41.24mg,108.46μmol,1.05eq)和二异丙基乙胺(16.02mg,123.96μmol,21.59μL,1.2eq),搅拌10分钟,然后向其中加入化合物BB-1(21.31mg,103.30μmol,1eq),反应液继续搅拌30分钟,反应液加水 (10mL)稀释,乙酸乙酯/四氢呋喃(4:1,V/V,10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge C18 150×50mm×10μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:25%-55%,高效液相柱的保留时间为10min)得到化合物9。
1H NMR(400MHz,CD
3OD):δ7.40-7.38(m,1H),7.36(s,1H),7.17-7.09(m,3H),7.06–7.00(m,1H),7.01-6.97(m,1H),4.17–4.05(m,1H),3.82-3.68(m,4H),3.55-3.40(m,4H),2.99-2.85(m,4H),2.78-2.65(m,2H),2.60–2.48(m,1H),0.98(d,J=6.0Hz,6H)。MS(ESI)m/z:465.4[M+H]
+。
实施例10:化合物10的制备
步骤1:化合物10-1的合成:
在25℃条件下向化合物9-6(0.120g,483.41μmol,1eq,粗品盐酸盐)的N,N-二甲基甲酰胺(5mL)溶液中加N,N-二异丙基乙胺(374.86mg,2.90mmol,505.20μL,6eq)和三氟甲磺酸三氟乙酯(145.86mg,628.44μmol,1.3eq),反应液继续搅拌2小时。反应液加水稀释(10mL),乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经柱层析分离纯化(石油醚:乙酸乙酯=3:1-1:1),得到化合物10-1。
步骤2:化合物10-2的合成
在25℃条件下向化合物10-1(110mg,333.07μmol,1eq)的甲醇(5mL),水(1mL)和四氢呋喃(1.5mL)溶液中加入一水合氢氧化锂(69.88mg,1.67mmol,5eq),反应液升温至50℃搅拌12小时。反应液加水稀释(10mL),加稀盐酸(1M)调节pH至6,乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物10-2。
步骤3:化合物10的合成
在25℃条件下向化合物10-2(0.100g,316.22μmol,1eq)的N,N-二甲基甲酰胺(5mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(126.25mg,332.03μmol,1.05eq)和DIEA(49.04mg,379.47μmol,66.09μL,1.2eq),反应液搅拌10分钟,然后向反应液中加入化合物BB-1(65.23mg,316.22μmol,1eq),反应液在继续搅拌30分钟。反应液加水稀释(10mL),乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色 谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(0.05%氨水v/v)-乙腈];乙腈%:28%-58%,高效液相柱的保留时间为10min),再经柱层析分离纯化(石油醚:乙酸乙酯=1.5:1,然后二氯甲烷:甲醇=10:1),最后经制备型高效液相分离纯化(色谱柱:Phenomenex Gemini NX-C18(75×30mm×3μm);流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:24%-54%,高效液相柱的保留时间为8min),得到化合物10。
1H NMR(400MHz,DMSO-d
6):δ10.96(br s,1H),8.56–8.31(m,1H),7.53-7.27(m,2H),7.17-6.93(m,5H),4.82(d,J=4.4Hz,1H),3.96-3.75(m,3H),3.67-3.53(m,4H),3.32-3.27(m,5H),3.27-3.17(m,1H),2.85-2.63(m,4H)。MS(ESI)m/z:505.4[M+1]
+。
实施例11:化合物11的制备
步骤1:化合物11-1的合成
在25成条件下向化合物9-6(150mg,粗品盐酸盐)的二氯甲烷(5.00mL)溶液中加入三乙胺(91.72mg,906.40μmol,126.16μL,1.5eq)和乙酸酐(74.03mg,725.12μmol,67.91μL,1.2eq),反应液在25℃搅拌1hr。反应液加水(10mL)稀释,二氯甲烷萃取(20mL×3),合并有机相,饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚:乙酸乙酯=1:0-0:1)得到化合物11-1。MS(ESI)m/z:291.1[M+1]
+。
步骤2:化合物11-2的合成
在25℃条件下,向化合物11-1(139mg,478.86μmol,1eq)的四氢呋喃(2mL),甲醇(2mL),和水(2mL)溶液中加入一水合氢氧化锂(60.28mg,1.44mmol,3eq),反应液在25℃继续搅拌48小时。反应液用稀盐酸(1mol/L)调节pH至5,乙酸乙酯(20mL×3)萃取,合并有机相,有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物11-2。MS(ESI)m/z:277.0[M+1]
+。
步骤3:化合物11的合成
在25℃条件下,向化合物11-2(112mg,405.44μmol,1eq)的N,N二甲基甲酰胺(3.00mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(200.41mg,527.07μmol,1.3eq)和N,N-二异丙基乙胺(78.60mg,608.16μmol,105.93μL,1.5eq),反应液搅拌0.5小时,然后向反应液中加入化合物BB-1(83.64mg,405.44μmol,1eq),反应液继续搅拌0.5小时。反应液加水(10mL)稀释,乙酸乙酯萃取(20mL×3),合并有机相,有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗 品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(0.05%氨水)-乙腈,乙腈%:13%-43%,高效液相柱的保留时间为10min),得到化合物11。
1H NMR(400MHz,DMSO-d
6):δ8.47-8.33(s,1H),7.44-7.37(m,2H),7.15-7.06(m,4H),7.06-6.98(m,2H),4.85-4.78(m,1H),4.60-4.53(m,1H),4.31-4.22(m,2H),4.04-3.76(m,2H),3.64-3.60(m,2H),3.25-3.16(m,2H),2.83-2.68(m,6H),1.82-1.81(s,3H)。MS(ESI)m/z:465.3[M+1]
+。
实施例12:化合物12的制备
步骤1:化合物12-1的合成:
在25℃条件下,向化合物9-6(0.070g,245.88μmol,1eq,粗品盐酸盐)和甲醛水溶液(59.87mg,737.63μmol,54.92μL,37%纯度,3eq)的二氯甲烷(5mL)溶液中加入醋酸硼氢化钠(312.67mg,1.48mmol,6eq),反应液继续搅拌2小时。反应液加饱和碳酸氢钠溶液(10mL)淬灭,乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物12-1。
步骤2:化合物12-2的合成:
在25℃条件下,向化合物12-1(0.095g,362.23μmol,1eq)的甲醇(2mL),四氢呋喃(2mL)和水(1mL)溶液中加入一水合氢氧化锂(76.00mg,1.81mmol,5eq),反应液升温至45℃搅拌12小时。反应液加稀盐酸调节pH至3,乙酸乙酯萃取(10mL×2),水相减压浓缩,得到粗品化合物12-2。
步骤3:化合物12的合成:
在25℃条件下,向化合物12-2(0.020g,80.57μmol,1eq)的N,N-二甲基甲酰胺(2mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(45.95mg,120.85μmol,1.5eq)和N,N-二异丙基乙胺(20.83mg,161.14μmol,28.07μL,2.0eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(21.61mg,104.74μmol,1.3eq)和4-二甲氨基吡啶(1.97mg,16.11μmol,0.2eq),反应液搅拌12小时。反应液加水稀释(10mL),乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:15%-45%,高效液相柱的保留时间为10min)得到化合物12。
1H NMR(400MHz,CD
3OD):δ7.41-7.33(m,2H),7.15-7.03(m,4H),7.01-6.90(m,1H),4.12–4.05(m,1H), 3.81-3.70(m,4H),3.58-3.40(m,4H),2.93-2.90(m,2H),2.88-2.83(m,2H),2.70-2.62(m,2H),2.43(s,3H)。MS(ESI)m/z:437.5[M+1]
+。
实施例13:化合物13的制备
步骤1:化合物13-1的合成:
在25℃条件下,向化合物9-6(0.170g,粗品盐酸盐)的N,N-二甲基甲酰胺(5mL)溶液加入N,N-二异丙基乙胺(531.05mg,4.11mmol,715.70μL,6eq)和2-溴乙基甲基醚(123.74mg,890.29μmol,83.61μL,1.3eq),反应液继续搅拌1小时。反应液加水(25mL)稀释,乙酸乙酯萃取(20mL×3),合并有机相,有机相经饱和食盐水洗涤(20mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物13-1。
1H NMR(400MHz,DMSO-d
6):δ10.94(br s,1H),7.56(dd,J=2.0,8.4Hz,1H),7.50(d,J=1.6Hz,1H),7.20-7.13(m,1H),3.95(d,J=9.8Hz,2H),3.85-3.79(m,3H),3.62(d,J=9.8Hz,2H),3.55(d,J=9.8Hz,2H),3.33-3.26(m,3H),2.61(t,J=5.6Hz,2H)。
步骤2:化合物13-2的合成:
在25℃条件下,向化合物13-1(0.250g,816.16μmol,1eq)的甲醇(4mL)、四氢呋喃(4mL)和水(2mL)溶液中加入一水合氢氧化锂(171.24mg,4.08mmol,5eq),搅拌1小时,然后反应液升温至40℃搅拌12小时。反应液加稀盐酸(1M)调节pH至5,乙酸乙酯萃取(15mL×3),水相减压浓缩,粗品经柱层析分离纯化(二氯甲烷:甲醇=10:1),再经制备型高效液相分离纯化(色谱柱:Phenomenex Synergi C18 150×25mm×10μm;流动相:[水(0.1%三氟乙酸)-乙腈];乙腈%:1%-25%,高效液相柱的保留时间为40min)得到化合物13-2。
步骤3:化合物13的合成:
在25℃条件下,向化合物13-2(0.030g,102.64μmol,1eq)的N,N-二甲基甲酰胺(2mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(46.83mg,123.17μmol,1.2eq)和N,N-二异丙基乙胺(19.90mg,153.96μmol,26.82μL,1.5eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(21.17mg,102.64μmol,1eq),反应液搅拌30分钟。反应液加水稀释(15mL),乙酸乙酯萃取(15mL×3),合并有机相,有机相经饱和食盐水洗涤(15mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:14%-47%,高效液相柱的保留时间为9min)得到化合物13。
1H NMR(400MHz,CDCl
3):δ8.06(br s,1H),7.64(s,1H),7.42(dd,J=1.8,8.4Hz,1H),7.25-7.12(m,3H),7.06 (d,J=7.2Hz,1H),6.94(d,J=8.4Hz,1H),4.46-4.34(m,1H),4.33-4.17(m,2H),3.95–3.80(m,2H),3.71-3.53(m,4H),3.48-3.43(m,2H),3.37(br s,2H),3.31(s,3H),3.22-3.15(m,2H),3.14-3.05(m,4H),2.88–2.81(m,2H)。MS(ESI)m/z:481.4[M+1]
+。
实施例14:化合物14的制备
步骤1:化合物14-1的合成:
向化合物9-6(100mg,盐酸盐粗品)和甲烷磺酸酐(70.17mg,402.85μmol,1eq)的二氯甲烷(5mL)溶液中加入DMAP(24.61mg,201.42μmol,0.5eq)和三乙胺(61.15mg,604.27μmol,84.11μL,1.5eq),反应液在25℃搅拌1小时。反应液加水稀释(10mL),二氯甲烷萃取(20mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物14-1。
步骤2:化合物14-2的合成:
在25℃条件下,向化合物14-1(0.079g,242.09μmol,1eq)的甲醇(6mL),四氢呋喃(6mL)和水(3mL)溶液中加入一水合氢氧化锂(101.59mg,2.42mmol,10eq),反应液在45℃搅拌8小时。反应液加稀盐酸(1M)调节pH至5,乙酸乙酯萃取(10mL×2),合并有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物14-2。
步骤3:化合物14的合成:
在25℃条件下,向化合物14-2(0.050g,160.10μmol,1eq)的N,N-二甲基甲酰胺(5mL)溶液中分别加入HATU(73.05mg,192.12μmol,1.2eq)和DIEA(31.04mg,240.16μmol,41.83μL,1.5eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(33.03mg,160.10μmol,1eq),反应液搅拌1小时。反应液加水稀释(10mL),乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:15%-49%,高效液相柱的保留时间为10min)得到化合物14。
1H NMR(400MHz,DMSO-d
6):δ11.16(br s,1H),8.44(t,J=5.4Hz,1H),7.47-7.37(m,2H),7.13-6.99(m,5H),4.86–4.77(m,1H),4.40(d,J=10.4Hz,2H),4.04(d,J=10.4Hz,2H),3.96–3.84(m,1H),3.62(d,J=4.4Hz,2H),3.47-3.39(m,1H),3.32-3.27(m,2H),3.26-3.16(m,1H),3.10(s,3H),2.85–2.77(m,2H),2.75-2.64(m,2H)。MS(ESI)m/z:501.4[M+1]
+。
实施例15:化合物15的制备
步骤1:化合物15-2的合成
在0℃条件下,向化合物15-1(2g,11.36mmol,1eq)的氯仿(22mL)溶液中加入尿素过氧化氢(1.07g,11.36mmol,1eq)和三氟乙酸酐(4.77g,22.73mmol,3.16mL,2eq),反应液在20℃搅拌15小时。反应液在冰浴条件下加饱和亚硫酸钠溶液(10mL)淬灭,然后向其中加入饱和碳酸氢钠溶液(10mL),氯仿萃合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物15-2。
1H NMR(400MHz,CDCl
3):δ8.36–8.33(m,1H),7.70-7.60(m,1H),7.01–6.96(m,1H)。
步骤2:化合物15-3的合成
在0℃条件下,向化合物15-2(2.67g,13.91mmol,1eq)的浓硫酸(20mL)中加入发烟硝酸(90%~97.5%,3.5g,55.54mmol,5.8mL,3.99eq),反应液升温至120℃继续搅拌8小时。反应液倒入冰水中,乙酸乙酯(20mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:0-5:1),得到化合物15-3。
1H NMR(400MHz,CDCl
3):δ9.17(d,J=6.8Hz,1H),8.79(d,J=8.8Hz,1H)。
步骤3:化合物15-4的合成
在冰浴0℃条件下向化合物15-3(0.112g,506.82μmol,1eq)和1-羟基环丙烷-1-羧酸甲酯(58.85mg,506.82μmol,1eq)的四氢呋喃(5mL)溶液中加入钠氢(40.55mg,1.01mmol,60%纯度,2.0eq),反应液升温至25℃继续搅拌15分钟。反应液加饱和氯化铵溶液(10mL)淬灭,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物15-4。
步骤4:化合物15-5的合成
在70℃条件下向化合物15-4(0.490g,1.55mmol,1eq)和氯化铵(413.30mg,7.73mmol,5eq)的乙醇(10mL)和水溶液(2mL)中加入铁粉(431.48mg,7.73mmol,5eq),反应液继续搅拌30分钟。反应液过滤, 滤液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物15-5。
1H NMR(400MHz,CDCl
3):δ8.78(br s,1H),7.95(s,1H),7.09(s,1H),1.56-1.49(m,2H),1.38-1.32(m,2H)。
步骤5:化合物15-6的合成
在一氧化碳氛围下,将化合物15-5(0.260g,1.02mmol,1eq)、三乙胺(206.29mg,2.04mmol,283.76μL,2.0eq)和1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(166.49mg,203.87μmol,0.2eq)的甲醇(5mL)溶液置于80℃条件下搅拌反应12小时。反应液过滤,滤液减压浓缩旋干。粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1-1:1)得到化合物15-6。
步骤6:化合物15-7的合成
在25℃条件下向化合物15-6(0.050g,213.49μmol,1eq)的四氢呋喃(2mL)和水(0.5mL)溶液中加入一水合氢氧化锂(26.88mg,640.46μmol,3eq),反应液继续搅拌1小时。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,水相加稀盐酸(1M)调节pH至5,减压浓缩,加水(2mL)搅拌2min,过滤,滤饼减压干燥得到化合物15-7。
步骤7:化合物15的合成
在25℃条件下向化合物15-7(0.010g,45.42μmol,1eq)的N,N-二甲基甲酰胺(1mL)溶液中分别加入HATU(20.72mg,54.50μmol,1.2eq)和DIEA(8.80mg,68.13μmol,11.87μL,1.5eq),反应液搅拌10分钟,然后向反应液中加入化合物BB-1(9.37mg,45.42μmol,1eq),反应液搅拌30分钟。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:W Phenomenex Gemini-NX C18 75×30mm×3μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:22%-52%,高效液相柱的保留时间为8min)得到化合物15。
1H NMR(400MHz,CDCl
3):δ9.81(br s,1H),8.47(br t,J=6.1Hz,1H),7.99(s,2H),7.26-7.14(m,3H),7.10-7.03(m,1H),4.57–4.44(m,1H),4.38-4.17(m,2H),3.85-3.64(m,1H),3.55-3.45(m,1H),3.44-3.33(m,2H),3.29-3.02(m,4H),1.55-1.31(m,4H);MS(ESI)m/z:409.3[M+H]
+。
实施例16:化合物16的制备
步骤1:化合物16-2的合成
在室温下向化合物1-羟基环丙烷-1-羧酸甲酯(3.00g,29.39mmol,1eq)的二氯甲烷(20mL)和N,N-二甲基甲酰胺(10.74mg,146.93μmol,11.30μL,0.005eq)溶液中加入二氯亚砜(10mL),反应液在80应下搅拌1小时。反应完全后减压浓缩得到酰氯。向化合物16-1(2.86g,17.42mmol,0.6eq)和二异丙基乙胺(18.76g,145.19mmol,25.29mL,5eq)的二氯甲烷(35mL)溶液中加入上述酰氯,反应液在20℃下搅拌0.5小时。反应液加水(100mL),用二氯甲烷(100mL×2)萃取,合并有机相用水(100mL×2)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗产品用硅胶柱层析(石油醚:乙酸乙酯=4:1)分离得到化合物16-2。
步骤2:化合物16-3的合成
向化合物16-2(2.00g,8.06mmol,1eq)的N,N-二甲基甲酰胺(10.00mL)溶液中加入氢氧化钠(644.94mg,16.12mmol,2eq),反应液在85℃下搅拌2小时,反应液加水(50mL),用乙酸乙酯(50mL×3)萃取,合并有机相用水(50mL×3)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品,用(石油醚:乙酸乙酯=1:2)25℃下搅拌2分钟,过滤,得到化合物16-3。MS(ESI)m/z:212.0[M+H]
+。
步骤3:化合物16-4的合成
向化合物16-3(620.0mg,2.93mmol,1eq)的N,N-二甲基甲酰胺(5mL),甲醇(5mL)和三乙胺(0.5mL)的混合溶液中加入醋酸钯(131.56mg,586.00μmol,0.2eq)和1,1'-双(二苯膦基)二茂铁(324.86mg,586.00μmol,0.2eq),反应瓶用一氧化碳置换3次,升温至80℃,在一氧化碳(50psi)氛围下搅拌16小时。反应液通过硅藻土过滤,滤液减压浓缩,加水(50mL),用乙酸乙酯(50mL×3)萃取,合并有机相,用水(50mL)洗涤,无水硫酸钠干燥,过滤滤液减压浓缩,粗产品用(石油醚:乙酸乙酯=1:1)在20下打浆5分钟,再经制备高效液相分离纯化(色谱柱:Phenomenex Luna C18 75×30mm×3μm;流动相:[水(0.05%盐酸)-乙腈,乙腈:4%-24%,高效液相柱的保留时间为7min)得到化合物16-4。
1H NMR(400MHz,DMSO-d
6):δ11.67(s,1H),7.53(s,1H),3.92(s,3H),1.50-1.39(m,4H)。MS(ESI)m/z:236.0[M+H]
+。
步骤4:化合物16-5的合成
在室温下向化合物16-4(45.0mg,191.33μmol,1eq)的四氢呋喃(1mL)、甲醇(1mL)和水(0.5mL)的混合溶液中加入一水合氢氧化锂(16.06mg,382.66μmol,2eq),反应液在25℃下搅拌1小时。减压浓缩掉有机溶剂,水相用乙酸乙酯(10mL)萃取,再用盐酸调节pH至6,减压浓缩,加水(1mL),搅拌5分钟,过滤,得粗品化合物16-5直接用于下一步反应。
步骤5:化合物16的合成
在0℃下向化合物16-5(42.0mg,189.90μmol,1eq)的N,N-二甲基甲酰胺(1mL)溶液中分别加入化合物BB-1(77.37mg,375.08μmol,1eq),1-羟基苯并***(30.79mg,227.88μmol,1.2eq),二异丙基乙胺(73.63mg,569.70μmol,99.23μL,3eq)和1-乙基-3(3-二甲基丙胺)碳二亚胺(43.68mg,227.88μmol,1.2eq),反应液25℃下搅拌16小时。然后加水(10mL)稀释,用乙酸乙酯(10mL×2)萃取,合并有机相用水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈,乙腈:18%-48%,高效液相柱的保留时间为10min]得到化合物16。
1H NMR(400MHz,CDCl
3):δ8.53(br t,J=5.8Hz,1H),8.08(s,1H),7.19-7.09(m,3H),7.04-6.99(m,1H),4.19-4.11(m,1H),3.90(d,J=15.2Hz,1H),3.81-3.68(m,2H),3.61-3.51(m,1H),3.05-2.89(m,3H),2.89-2.80(m,1H),2.76-2.61(m,2H),1.65-1.59(m,2H),1.58-1.51(m,2H);MS(ESI)m/z:410.4[M+H]
+。
实施例17:化合物17和18的制备
步骤1:化合物17-2的合成
0℃下向化合物17-1(5.00g,28.38mmol,1eq)的二氯甲烷(50mL)溶液中加入三甲基腈硅烷(4.22g,42.56mmol,5.32mL,1.5eq),然后滴加三氟化硼***溶液(4.03g,28.38mmol,3.50mL,1eq),继续在0℃下搅拌0.5小时。然后将反应液倒入饱和碳酸氢钠水溶液(100mL)淬灭,分液,水相用二氯甲烷(100mL) 萃取,合并有机相,用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品化合物17-2直接用于下一步反应。
1H NMR(400MHz,CDCl
3):δ7.38-7.31(m,6H),4.46(s,2H),4.00(q,J=7.0Hz,1H),3.05-2.98(m,2H),2.41-2.33(m,2H)。
步骤2:化合物17-3的合成
在-10℃下向化合物17-2(5.24g,25.78mmol,2.1eq)和化合物7-1(2.44g,12.28mmol,1eq)的四氢呋喃(60.00mL)溶液中加入氢化钠(638.37mg,15.96mmol,60%纯度,1.3eq),反应液缓慢升温至15℃搅拌16小时。反应液倒入饱和氯化铵水溶液(100mL)淬灭,用乙酸乙酯(100mL×3)萃取,合并有机相用水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品化合物用硅胶柱层析(石油醚:乙酸乙酯=10:1)分离纯化得到化合物17-3。
1H NMR(400MHz,CDCl
3):δ8.50-8.42(m,1H),8.21-8.12(m,1H),7.31-7.27(m,5H),7.04(d,J=8.8Hz,1H),4.42(s,2H),3.88(s,3H),3.23-3.15(m,2H),2.65-2.57(m,2H),2.35-2.24(m,1H)。
步骤3:化合物17-4的合成
在室温下向化合物17-3(2.00g,5.23mmol,1eq)的冰醋酸(10mL)溶液中加入还原铁粉(1.75g,31.38mmol,6eq),反应液80℃搅拌3.5小时。反应液倒入饱和碳酸氢钠(250mL),然后通过硅藻土过滤,分液,水相用乙酸乙酯(50mL×2)萃取,合并有机相用水(100mL)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品用硅胶柱层析(石油醚:乙酸乙酯=9:1至2:1)分离纯化得到化合物17-4。
1H NMR(400MHz,CDCl
3):δ8.07(br s,1H),7.78-7.68(m,1H),7.55-7.50(m,1H),7.43-7.31(m,5H),7.10-7.02(m,1H),4.52-4.47(m,2H),4.16-4.07(m,1H),3.93(s,3H),3.09-2.96(m,2H),2.51-2.38(m,2H);MS(ESI)m/z:354.1[M+H]
+。
步骤4:化合物17-5的合成
在室温下向化合物17-4(1.00g,2.83mmol,1eq)的甲醇溶液中加入Pd/C(50.0mg,10%纯度)和浓盐酸(14.3mg,141.50μmol,14.05μL,36-38%纯度,0.05eq),反应瓶用氢气置换3次,在氢气(15psi)氛围下,升温至70℃,搅拌2小时。反应液通过硅藻土过滤,滤液减压浓缩得到粗品化合物17-5直接用于下一步反应。MS(ESI)m/z:263.9[M+H]
+。
步骤5:化合物17-6的合成
在室温下向化合物17-5(200.0mg,759.75μmol,1eq)的四氢呋喃(4mL),甲醇(2mL)和水(2mL)的混合溶液中加入一水合氢氧化锂(95.65mg,2.28mmol,3eq),反应液在60℃下搅拌3小时。减压浓缩掉有机溶剂,水相用盐酸调节pH至4,用乙酸乙酯(10mL×2)萃取合并有机相用无水硫酸钠干燥,过滤,滤 液减压浓缩得到粗品化合物17-6直接用于下一步反应。
步骤6:化合物17和18的合成
在0℃下向化合物17-6(165.0mg,662.07μmol,1eq)的N,N-二甲基甲酰胺(2.00mL)溶液中分别加入HATU(251.74mg,662.07μmol,1eq)和二异丙基乙胺(256.70mg,1.99mmol,345.96μL,3eq),反应液搅拌1小时,然后再加入化合物BB-1(136.57mg,662.07μmol,1eq),继续在0℃下搅拌10分钟。然后加水稀释(20mL),用乙酸乙酯(30mL×3)萃取,合并有机相用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75×30mm×3μm;流动相:[水(0.05%氨水)-乙腈,乙腈:12%-42%,高效液相柱的保留时间为8min],得到的混合物进一步SFC手性纯化[色谱柱:DAICEL CHIRALPAK IC(250mm×30mm×10μm);流动相:流动相A为CO
2,流动相B为乙醇(0.1%氨水);梯度:B%:60%-60%]得到化合物17和18。
化合物17:SFC分析条件:色谱柱:Chiralpak IC-3 50×4.6mm I.D,3μm,流动相:流动相A为CO
2,流动相B为乙醇(0.05%二乙胺);梯度:B%:40%-40%;流速:3mL/min;检测器:PDA;保留时间为1.896min,手性纯度=100%。
1H NMR(400MHz,CD
3OD):δ7.37-7.32(m,2H),7.15-7.06(m,3H),7.05-7.00(m,1H),6.91(d,J=8.8Hz,1H),4.19-4.12(m,1H),4.12-4.06(m,1H),3.74(s,2H),3.54-3.48(m,1H),3.48-3.42(m,1H),2.95-2.84(m,6H),2.72-2.61(m,2H),2.31-2.22(m,2H);MS(ESI)m/z:438.3[M+H]
+;
化合物18:SFC分析条件:色谱柱:Chiralpak IC-3 50×4.6mm I.D,3μm,流动相:流动相A为CO
2,流动相B为乙醇(0.05%二乙胺);梯度:B%:40%-40%;流速:3mL/min;检测器:PDA;保留时间为2.762min,手性纯度=96.25%。
1H NMR(400MHz,CD
3OD):δ7.36(dd,J=2.0,8.4Hz,1H),7.33(d,J=2.0Hz,1H),7.14-7.07(m,3H),7.05-7.00(m,1H),6.93(d,J=8.0Hz,1H),4.60-4.51(m,1H),4.13-4.06(m,1H),3.75(s,2H),3.54-3.48(m,1H),3.48-3.42(m,1H),2.95-2.84(m,5H),2.73-2.62(m,2H),2.54(d,J=7.2Hz,4H).MS(ESI)m/z:438.3[M+H]
+。
实施例18:化合物19和20的制备
步骤1:化合物19-2的合成
在室温下向化合物17-5(200.0mg,759.75μmol,1eq)的二氯甲烷(30mL)溶液中加入化合物19-1,反应液在20℃下搅拌16小时。反应完全后缓慢倒入饱和碳酸氢钠溶液中(50mL),用乙酸乙酯(50mL×2)萃取,合并有机相用水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗产品用薄层层析硅胶板(石油醚:乙酸乙酯=3:1)分离得到化合物19-2。
1H NMR(400MHz,CDCl
3):δ7.95(br s,1H),7.71(dd,J=2.0,8.8Hz,1H),7.51(d,J=2.0Hz,1H),7.04(d,J=8.4Hz,1H),3.91(s,3H),3.30(s,3H),3.04-2.97(m,2H),2.39-2.33(m,2H);MS(ESI)m/z:278.0[M+H]
+。
步骤2:化合物19-3的合成
在室温下向化合物19-2(75.0mg,270.49μmol,1eq)的四氢呋喃(2mL)、甲醇(2mL)和水(2mL)的混合溶液中加入一水合氢氧化锂(34.0mg,811.48μmol,3eq),反应液在50℃下搅拌3小时。减压浓缩掉有机溶剂,水相用盐酸调节pH至4,用乙酸乙酯(30mL×3)萃取,合并有机相用水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物19-3直接用于下一步反应。
步骤3:化合物19和20的合成
在0℃下向化合物19-3(74.0mg,281.11μmol,1eq)的N,N-二甲基甲酰胺(2.00mL)溶液中依次加入HATU(106.89mg,281.11μmol,1eq)和二异丙基乙胺(108.99mg,843.32μmol,146.89μL,3eq),反应液搅拌1小时,然后再加入化合物BB-1(57.99mg,281.11μmol,1eq),继续在0℃下搅拌5分钟。然后加水(30mL)稀释,用乙酸乙酯(30mL×2)萃取,合并有机相用水(30mL)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(0.05%氨水)-乙腈,乙腈:26%-56%,高效液相柱的保留时间为10min],得到的混合物进一步手性进一步手性纯化SFC[色谱柱:DAICEL CHIRALPAK IC(250mm×30mm×10μm);流动相:流动相A为CO
2,流动相B为异丙醇(0.1%氨水);异丙醇(0.1%氨水):60%-60%]得到化合物19和20。
化合物19:SFC分析条件:色谱柱:Chiralpak IC-3 50×4.6mm I.D,3μm,流动相:流动相A为CO
2,流动相B为异丙醇+乙腈(0.05%乙二胺);流动相B:40%-40%;流速:3mL/min;检测器:PDA;保留时间为1.338min,手性纯度=100%。
1H NMR(400MHz,CDCl
3):δ8.44(s,1H),7.54(d,J=2.0Hz,1H),7.25(dd,J=2.0, 8.0Hz,1H),7.23-7.12(m,4H),7.02(d,J=7.6Hz,1H),6.91(d,J=8.4Hz,1H),4.12-4.02(m,1H),3.93-3.83(m,2H),3.78-3.72(m,1H),3.71-3.65(m,1H),3.59(dt,J=6.0,13.6Hz,1H),3.29(s,3H),3.02-2.91(m,5H),2.84-2.77(m,1H),2.75-2.62(m,2H),2.38-2.27(m,2H).MS(ESI)m/z:452.3[M+H]
+。
化合物20:SFC分析条件:色谱柱:Chiralpak IC-3 50×4.6mm I.D,3μm,流动相:流动相A为CO
2,流动相B为异丙醇+乙腈(0.05%乙二胺);流动相B:40%-40%;流速:3mL/min;检测器:PDA;保留时间为1.843min,手性纯度=94.29%。
1H NMR(400MHz,CDCl
3):δ8.65(s,1H),7.55(d,J=2.0Hz,1H),7.27(dd,J=2.0,8.0Hz,1H),7.24-7.11(m,4H),7.04-7.00(m,1H),6.91(d,J=8.4Hz,1H),4.26(q,J=7.2Hz,1H),4.12-4.04(m,1H),3.86(d,J=14.8Hz,1H),3.78-3.71(m,1H),3.68(d,J=14.8Hz,1H),3.58(dt,J=5.6,14.0Hz,1H),3.28(s,3H),3.02-2.90(m,3H),2.84-2.76(m,1H),2.75-2.70(m,1H),2.69-2.61(m,3H),2.60-2.51(m,3H);MS(ESI)m/z:452.3[M+H]
+。
实施例19:化合物21和22的制备
步骤1:化合物21-2的合成:
在室温下向化合物17-5(491.0mg,1.87mmol,1eq)的二氯甲烷(10.00mL)溶液中加入化合物21-1(531.54mg,2.80mmol,399.65μL,1.5eq),反应液在25℃下搅拌24小时。反应完全后缓慢倒入饱和碳酸氢钠溶液中(20mL),用乙酸乙酯(20mL×2)萃取,合并有机相用水(50mL)洗涤无水硫酸钠干燥,过滤,滤液减压浓缩,粗产品用制备板(石油醚:乙酸乙酯=1:1)分离得到化合物21-2。
MS(ESI)m/z:292.2[M+1]
+。
步骤2:化合物21-3的合成:
在室温下向化合物21-2(98.0mg,336.42μmol,1eq)的四氢呋喃(2.00mL),甲醇(2.00mL)和水(1.00mL)的混合溶液中加入一水合氢氧化锂(42.35mg,1.01mmol,3eq),反应液在50℃下搅拌18小时。减压浓缩 掉有机溶剂,水相用盐酸调节pH至6,用乙酸乙酯(30mL×3)萃取,合并有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物21-3直接用于下一步反应。
步骤3:化合物21和22的合成:
在0℃下向化合物21-3(104.0mg,375.08μmol,1eq)的N,N-二甲基甲酰胺(2.00mL)溶液中分别加入HATU(156.88mg,412.59μmol,1.1eq)和二异丙基乙胺(96.95mg,750.17μmol,130.67μL,2eq),反应液搅拌0.5小时,然后再加入化合物BB-1(77.37mg,375.08μmol,1eq),继续在0℃下搅拌0.2小时。然后加水稀释(50mL),用乙酸乙酯萃取(50mL×3),合并有机相用水(50mL)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.05%氨水)-乙腈],乙腈%:25%-55%,高效液相柱的保留时间为7min),得到的混合物进一步手性纯化SFC(色谱柱:DAICEL CHIRALCEL OJ(250mm*30mm,10μm);流动相:流动相A为CO
2,流动相B:[0.1%氨水-甲醇];流动相B%:30%-30%)得到化合物21和22。
化合物21:SFC分析条件:色谱柱:Chiralcel OJ-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);流动相B:40%-40%;流速:3mL/min;检测器:PDA;保留时间为1.536min,手性纯度=100%。
1H NMR(400MHz,CDCl
3):δ8.82(s,1H),7.60-7.51(m,2H),7.39(dd,J=1.6,8.4Hz,1H),7.25-7.12(m,3H),7.07-7.02(m,1H),6.94(d,J=8.4Hz,1H),4.39-4.29(m,1H),4.24-4.16(m,1H),4.03(d,J=15.2Hz,1H),3.91(d,J=14.4Hz,1H),3.76-3.70(m,1H),3.63-3.54(m,1H),3.44(q,J=7.2Hz,2H),3.18-2.96(m,4H),2.94-2.80(m,2H),2.69-2.59(m,2H),2.58-2.49(m,2H),1.28-1.18(m,4H)。MS(ESI)m/z:466.5[M+1]
+。化合物22:SFC分析条件:色谱柱:Chiralcel OJ-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);流动相B:40%-40%;流速:3mL/min;检测器:PDA;保留时间为1.722min,手性纯度=99.19%。
1H NMR(400MHz,CDCl
3):δ8.88(s,1H),7.61(d,J=2.0Hz,1H),7.57-7.49(m,1H),7.34(dd,J=2.0,8.4Hz,1H),7.25-7.13(m,3H),7.05-7.01(m,1H),6.91(d,J=8.0Hz,1H),4.23-4.15(m,1H),4.02(d,J=15.2Hz,1H),3.97-3.92(m,1H),3.89(d,J=14.8Hz,1H),3.78-3.69(m,1H),3.65-3.56(m,1H),3.44(q,J=6.8Hz,2H),3.17-3.07(m,1H),3.06-2.98(m,3H),2.96-2.89(m,2H),2.89-2.79(m,2H),2.37-2.30(m,2H),1.21(t,J=7.0Hz,4H);MS(ESI)m/z:466.5[M+1]
+。
实施例20:化合物23和24的制备
步骤1:化合物23-1的合成:
在室温下向化合物17-5(440mg,1.67mmol,1eq)的N,N-二甲基甲酰胺(4.00mL)溶液中加入碳酸铯(653.51mg,2.01mmol,1.2eq),搅拌0.5小时后加入对甲氧基苄氯(274.85mg,1.76mmol,239.00μL,1.05eq),反应液在25℃搅拌16小时。反应完全后加水(50mL),用乙酸乙酯(50mL×2)萃取,合并有机相用水(50mL)洗涤无水硫酸钠干燥,过滤,滤液减压浓缩,粗产品用制备板(石油醚:乙酸乙酯=3:1)分离得到化合物23-1。
MS(ESI)m/z:384.2[M+1]
+。
步骤2:化合物23-3的合成:
0℃下,向化合物23-1(495.0mg,1.29mmol,1eq)的N,N-二甲基甲酰胺(5.00mL)混合液中加入氢化钠(103.28mg,2.58mmol,60%纯度,2eq),反应液搅拌0.2小时;向反应液中滴加化合物23-2(3.59g,25.82mmol,2.43mL,20eq),27℃搅拌1小时。反应液用饱和氯化铵溶液(50mL)淬灭,用乙酸乙酯(50mL乙酸)萃取,有机相用水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1)得到化合物23-3。
步骤3:化合物23-4的合成:
将化合物23-3(190.0mg,430.38μmol,1eq)溶解于三氟乙酸(6.00mL)中,加热至100热搅拌3小时。将反应液倒入饱和碳酸氢钠(50mL)中淬灭,用乙酸乙酯(50mL×2)萃取,合并有机相用水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:1)得到化合物23-4。
步骤4:化合物23-5的合成:
在室温下向化合物23-4(108.0mg,336.11μmol,1eq)的四氢呋喃(2.00mL),甲醇(2.00mL)和水(1.00mL)的混合溶液中加入一水合氢氧化锂(42.31mg,1.01mmol,3eq),反应液在80应下搅拌3小时。减压浓缩掉有机溶剂,水相用盐酸调节pH至6,用乙酸乙酯(50mL×3)萃取,合并有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物23-5直接用于下一步反应。MS(ESI)m/z:308.1[M+1]
+。
步骤5:化合物23和24的合成:
在0℃下向化合物23-5(138.0mg,449.08μmol,1eq)的N,N-二甲基甲酰胺(3.00mL)溶液中分别加入 HATU(187.83mg,493.98μmol,1.1eq)和二异丙基乙胺(116.08mg,898.15μmol,156.44μL,2eq),反应液27℃搅拌0.5小时,然后再加入化合物BB-1(138.96mg,673.61μmol,1.5eq),继续在27续下搅拌0.5小时。然后加水稀释(50mL),用乙酸乙酯萃取(50mL×3),合并有机相用水(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.05%氨水)-乙腈,乙腈%:20%-48%,高效液相柱的保留时间为7min],得到的混合物进一步手性纯化SFC(色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm);流动相B:[0.1%氨水-甲醇];B%:60%-60%)得到化合物23和24。
化合物23:SFC分析条件:色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);甲醇(0.05%二乙胺):40%-40%;流速:3mL/min;检测器:PDA;保留时间为3.349min,手性纯度=100%。
1H NMR(400MHz,CDCl
3):δ9.40(s,1H),7.69(s,1H),7.65-7.58(m,1H),7.30-7.27(m,1H),7.23-7.11(m,3H),7.04-6.99(m,1H),6.84(d,J=8.4Hz,1H),4.21-4.12(m,1H),4.01-3.91(m,2H),3.83(d,J=14.8Hz,1H),3.77-3.67(m,1H),3.64-3.58(m,1H),3.54(s,4H),3.39(s,3H),3.08-3.04(m,1H),3.01-2.94(m,4H),2.93-2.89(m,2H),2.88-2.83(m,1H),2.83-2.76(m,1H),2.42-2.32(m,2H)。MS(ESI)m/z:496.5[M+1]
+。
化合物24:SFC分析条件:色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);甲醇(0.05%二乙胺):40%-40%;流速:3mL/min;检测器:PDA;保留时间为4.942min,手性纯度=100%。
1H NMR(400MHz,CDCl
3):δ9.48(s,1H),7.67(d,J=1.2Hz,1H),7.56(br t,J=5.2Hz,1H),7.30-7.26(m,1H),7.21-7.10(m,3H),7.03-6.98(m,1H),6.86(d,J=8.4Hz,1H),4.38(quin,J=7.2Hz,1H),4.16-4.08(m,1H),3.87(d,J=15.2Hz,1H),3.76-3.68(m,2H),3.62-3.56(m,1H),3.54(s,4H),3.38(s,3H),3.02-2.90(m,4H),2.87-2.82(m,1H),2.80-2.74(m,1H),2.73-2.63(m,3H),2.57-2.49(m,2H);MS(ESI)m/z:496.5[M+1]
+。
实施例21:化合物25和26的制备
步骤1:化合物25-1的合成:
-5℃下,向化合物23-1(495.0mg,1.29mmol,1eq)和碘代异丙烷(4.39g,25.82mmol,2.58mL,20eq)的N,N-二甲基甲酰胺(4.00mL)混合液中加入氢化钠(103.29mg,2.58mmol,60%纯度,2eq),反应液-5℃搅拌1小时。用饱和氯化铵溶液(50mL)淬灭,用乙酸乙酯(50mL×2)萃取,有机相用水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=15:1至3:1)得到25-1。
步骤2:化合物25-2的合成:
将化合物25-1溶解于三氟乙酸(5.00mL)中,加热至100℃搅拌3小时,将反应液倒入饱和碳酸氢钠(30mL)中淬灭,用乙酸乙酯(30mL×2)萃取,合并有机相用水(30mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物25-2直接用于下一步反应。
1H NMR(400MHz,CDCl
3):δ7.73-7.69(m,1H),7.68-7.66(m,1H),7.49-7.47(m,1H),7.05(d,J=8.8Hz,1H),4.48-4.39(m,1H),4.07-3.98(m,1H),3.92-3.90(m,3H),,2.73-2.64(m,2H),2.62-2.55(m,2H),,1.18(s,3H),1.16(s,3H)。
步骤3:化合物25-3的合成:
在室温下向化合物25-2(151.0mg,494.55μmol,1eq)的四氢呋喃(2.00mL)、甲醇(2.00mL)和水(0.50mL)的混合溶液中加入一水合氢氧化锂(62.26mg,1.48mmol,3eq),反应液在60应下搅拌2小时。减压浓缩掉有机溶剂,水相用盐酸调节pH至6,用乙酸乙酯(50mL×2)萃取,合并有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物25-3接用于下一步反应。MS(ESI)m/z:292.1[M+1]
+。
步骤4:化合物25和化合物26的合成:
在0℃下向化合物25-3(65mg,223.14μmol,1eq)的N,N-二甲基甲酰胺(1.00mL)溶液中分别加入HATU(93.33mg,245.45μmol,1.1eq)和二异丙基乙胺(57.68mg,446.28μmol,77.73μL,2eq),反应液0℃搅拌0.5小时,然后再加入化合物BB-1(50.63mg,245.45μmol,1.1eq),继续在0继下搅拌0.5小时。然后加水稀释(30mL),用乙酸乙酯萃取(30mL×2),合并有机相用水(30mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.05%氨水)-乙腈,乙腈%:26%-56%,高效液相柱的保留时间为8min],得到的混合物进一步手性 纯化SFC(色谱柱:DAICEL CHIRALCEL OJ(250mm*30mm,10μm);流动相B:[0.1%氨水-甲醇];B%:30%-30%)得到化合物25和26。
化合物25:SFC分析条件:色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);甲醇(0.05%二乙胺):40%-40%;流速:3mL/min;检测器:PDA;保留时间为0.727min,手性纯度=100%。
1H NMR(400MHz,CDCl
3):δ9.28(s,1H),7.96(br s,1H),7.66(s,1H),7.47(br d,J=8.4Hz,1H),7.25-7.13(m,3H),7.09-7.05(m,1H),6.94(d,J=8.4Hz,1H),4.43-4.36(m,1H),4.28-4.13(m,2H),3.79-3.69(m,1H),3.66-3.57(m,2H),3.36-3.28(m,2H),3.18-3.01(m,4H),2.63-2.47(m,5H),1.16(s,3H),1.15(s,3H)。MS(ESI)m/z:480.4[M+1]
+。
化合物26:SFC分析条件:色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);甲醇(0.05%二乙胺):40%-40%;流速:3mL/min;检测器:PDA;保留时间为0.616min,手性纯度=94.36%。
1H NMR(400MHz,CDCl
3):δ9.83(s,1H),8.43(s,1H),7.75(s,1H),7.57-7.50(m,1H),7.26-7.14(m,3H),7.13-7.06(m,1H),6.91-6.85(m,1H),4.82-4.68(m,1H),4.64-4.51(m,1H),4.37-4.23(m,1H),3.92-3.80(m,2H),3.78-3.64(m,2H),3.62-3.54(m,1H),3.50-3.29(m,4H),3.17-3.00(m,1H),2.88-2.74(m,2H),2.31-2.20(m,2H),1.15(s,3H),1.13(s,3H);MS(ESI)m/z:480.4[M+1]
+。
实施例22:化合物27的制备
步骤1:化合物27-2的合成
在25℃条件下向化合物17-5(0.350g,1.33mmol,1eq)的二氯甲烷(10mL)溶液中加入戴斯-马丁试剂(676.70mg,1.60mmol,493.94μL,1.2eq),反应液继续搅拌2小时。反应液用饱和亚硫酸钠(10mL)和饱和碳酸氢钠溶液(10mL)淬灭,然后用二氯甲烷(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:1),得到化合物27-2。
1H NMR(400MHz,CDCl
3):δ8.15(br s,1H),7.76(dd,J=2.0,8.4Hz,1H),7.59(d,J=2.0Hz,1H),7.10(d,J=8.4Hz,1H),3.93(s,3H),3.90-3.79(m,2H),3.46-3.30(m,2H)。
步骤2:化合物27-3的合成
将化合物27-2(0.050g,191.40μmol,1eq)的醋酸(2mL)和浓盐酸溶液(1mL)置于100℃搅拌反应1小 时。反应液加水(15mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物27-3。
步骤3:化合物27的合成
在25℃条件下,向化合物27-3(0.040g,161.81μmol,1eq)的N,N-二甲基甲酰胺(4mL)溶液中分别加入HATU(92.29mg,242.72μmol,1.5eq)和DIEA(41.83mg,323.62μmol,56.37μL,2.0eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(33.38mg,161.81μmol,1eq),反应液继续搅拌20分钟。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:18%-48%,高效液相柱的保留时间为9min)得到化合物27。
1H NMR(400MHz,CDCl
3):δ7.61(br s,1H),7.24-7.10(m,5H),7.08-6.88(m,2H),4.08(br s,1H),3.93-3.75(m,4H),3.70-3.54(m,2H),3.43-3.26(m,2H),3.07–2.87(m,4H),2.82-2.48(m,3H);MS(ESI)m/z:436.4[M+H]
+。
实施例23:化合物28的制备
步骤1:化合物28-1的合成
在冰浴0℃条件下向化合物27-2(0.1g,382.80μmol,1eq)的二氯甲烷(5mL)溶液中加入二乙胺基三氟化硫(308.52mg,1.91mmol,252.88μL,5eq),反应液升温至25℃继续搅拌反应12小时。反应液倒入饱和碳酸氢钠(10mL)溶液中,二氯甲烷(10mL×3)萃取,合并有机相,饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=5:1),得到化合物28-1。
1H NMR(400MHz,CDCl
3):δ8.02(br s,1H),7.78-7.72(m,1H),7.56(d,J=1.8Hz,1H),7.12(d,J=8.4Hz,1H),3.95-3.91(m,3H),3.47-3.30(m,2H),3.01-2.84(m,1H)。
步骤2:化合物28-2的合成
在25℃条件下,向化合物28-1(0.030g,105.92μmol,1eq)的甲醇(2mL)和水(0.5mL)溶液中加入一水合氢氧化锂(22.22mg,529.61μmol,5eq),反应液升温至40℃搅拌12小时。反应液加稀盐酸(1M)调节pH至3,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物28-2。
步骤3:化合物28的合成
在25℃条件下,向化合物28-2(0.030g,111.44μmol,1eq)的N,N-二甲基甲酰胺(4mL)溶液中分别加入HATU(63.56mg,167.16μmol,1.5eq)和DIEA(28.81mg,222.88μmol,38.82μL,2.0eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(22.99mg,111.44μmol,1eq),反应液继续搅拌20分钟。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:25%-55%,高效液相柱的保留时间为9min)得到化合物28。
1H NMR(400MHz,CDCl
3):δ7.66(s,1H),7.44–7.34(m,1H),7.33-7.28(m,1H),7.24-7.12(m,3H),7.07–6.99(m,1H),6.96(d,J=8.4Hz,1H),4.19–4.05(m,1H),3.99-3.86(m,1H),3.82-3.68(m,2H),3.65-3.53(m,1H),3.44-3.26(m,2H),3.08-2.65(m,8H)。MS(ESI)m/z:458.3[M+H]
+。
实施例24:化合物29的制备
步骤1:化合物29-2的合成
在0℃条件下,向化合物29-1(0.1g,942.76μmol,1eq)的二氯甲烷(5mL)溶液中加入三甲基腈硅烷(112.23mg,1.13mmol,141.53μL,1.2eq),然后再加入三氟化硼***(133.81mg,942.76μmol,116.35μL,1eq),反应液搅拌1小时。反应液用饱和碳酸氢钠溶液调节pH至10,二氯甲烷(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物29-2。
1H NMR(400MHz,CDCl
3):δ4.21-3.92(m,1H),3.38-3.20(m,2H),3.07-2.91(m,2H)。
步骤2:化合物29-3的合成
在25℃条件下,向化合物29-2(25.81mg,193.93μmol,1.2eq)和6-氯-5-硝基烟酸甲酯(0.035g,161.60μmol,1eq)的四氢呋喃(4mL)溶液中加入1,4-二氮杂二环[2.2.2]辛烷(36.25mg,323.21μmol,35.54μL, 2.0eq),反应液升温至60℃搅拌12小时。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经薄层层析分离纯化(石油醚:乙酸乙酯=2:1),得到化合物29-3。
步骤3:化合物29-4的合成
在80℃条件下向化合物29-3(0.090g,287.34μmol,1eq)和氯化铵(76.85mg,1.44mmol,5eq)的乙醇(10mL)和水溶液(2mL)中加入铁粉(80.24mg,1.44mmol,5eq),反应液搅拌1小时。反应液经硅藻土过滤,滤液加水(15mL)稀释,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水洗涤(15mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品化合物29-4。
步骤4:化合物29-5的合成
在25℃条件下,向化合物29-4(0.090g,317.76μmol,1eq)的四氢呋喃(2mL)溶液中加入稀盐酸(2M,794.41μL,5eq),然后升温至70℃搅拌12小时。反应液加水(15mL)稀释,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物29-5。
步骤5:化合物29-6的合成
在25℃条件下,向化合物29-5(0.080g,281.48μmol,1eq)的甲醇(8mL),四氢呋喃(8mL)和水(2mL)溶液中加入一水合氢氧化锂(118.12mg,2.81mmol,10eq),反应液升温至45℃搅拌1小时。反应液加稀盐酸(1M)调节pH至3,乙酸乙酯(15mL×2)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物29-6。
步骤6:化合物29的合成
在25℃条件下,向化合物29-6(0.050g,185.06μmol,1eq)的N,N-二甲基甲酰胺(4mL)溶液中分别加入HATU(84.44mg,222.07μmol,1.2eq)和DIEA(35.87mg,277.58μmol,48.35μL,1.5eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(38.17mg,185.06μmol,1eq),反应液搅拌30分钟。反应液加水(15mL)稀释,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:18%-51%,高效液相柱的保留时间为9min)得到化合物29。
1H NMR(400MHz,CD
3OD):δ8.35(d,J=2.0Hz,1H),7.75(d,J=2.0Hz,1H),7.29-7.18(m,3H),7.13(br d,J=7.2Hz,1H),4.33-4.19(m,3H),3.62-3.51(m,1H),3.49-3.35(m,5H),3.18-2.95(m,6H)。
MS(ESI)m/z:459.3[M+H]
+。
实施例25:化合物30的制备
步骤1:化合物30-1的合成
在-70℃条件下向化合物17-5(70mg,265.91μmol,1eq)的二氯甲烷(5mL)溶液中加入二乙胺基三氟化硫(50.15mg,311.12μmol,41.11μL,1.17eq),反应液在20℃搅拌反应12小时。反应液用饱和碳酸氢钠溶液(3mL)淬灭,二氯甲烷(20mL×3)萃取,合并有机相,饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:0-0:1),得到化合物30-1。
步骤2:化合物30-2的合成
向化合物30-1(303mg,1.14mmol,1eq)的四氢呋喃(4mL),甲醇(4mL)和水(2mL)溶液中加入一水合氢氧化锂(22.22mg,529.61μmol,5eq),反应液在17℃搅拌16小时。反应液加稀盐酸(1M)调节pH至4,乙酸乙酯萃取(50mL×2),合并有机相,有机相经水洗涤(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物30-2。
步骤3:化合物30的合成
在0℃条件下,向化合物30-2(171mg,680.71μmol,1eq)的N,N-二甲基甲酰胺(3mL)溶液中分别加入HATU(310.59mg,816.85μmol,1.2eq)和二异丙基乙基胺(131.96mg,1.02mmol,177.85μL,1.5eq),反应液搅拌30分钟,然后向其中加入化合物BB-1(140.42mg,680.71μmol,1eq),反应液继续搅拌30分钟。反应液加水稀释,乙酸乙酯(20mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75×30mm×3μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:24%-54%,高效液相柱的保留时间为8min)得到化合物30。
1H NMR(400MHz,CDCl
3):δ8.22-8.17(m,1H),7.47(s,1H),7.29–7.27(m,1H),7.22-7.11(m,5H),7.05(d,J=8.0Hz,1H),6.92(d,J=8.0Hz,1H),5.11–4.95(m,1H),4.07-4.02(m,1H),3.87-3.83(m,1H),3.75-3.61(m, 2H),3.58-3.49(m,1H),3.11-3.05(m,2H),2.95–2.88(m,3H),2.80–2.78(m,1H),2.70–2.52(m,4H);MS(ESI)m/z:440.3[M+H]
+。
实施例26:化合物32的制备
步骤1:化合物32-2的合成
在冰浴条件下向化合物32-1(0.1g,460.56μmol,1eq)和1-羟基环丙烷-1-羧酸甲酯(53.48mg,460.56μmol,1eq)的四氢呋喃(5mL)溶液中加入钠氢(27.63mg,690.84μmol,60%纯度,1.5eq),反应液升温至25℃继续搅拌1小时。反应液加饱和氯化铵溶液(10mL)淬灭,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品薄层层析分离纯化(石油醚:乙酸乙酯=3:1),得到化合物32-2。
步骤2:化合物32-3的合成
在75℃条件下向化合物32-2(0.080g,255.40μmol,1eq)和氯化铵(68.31mg,1.28mmol,5eq)的乙醇(3mL)和水溶液(1mL)中加入铁粉(71.32mg,1.28mmol,5eq),反应液继续搅拌1小时。反应液过滤,滤液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经薄层层析分离纯化(石油醚:乙酸乙酯=2:1),得到化合物32-3。
1H NMR(400MHz,CDCl
3):δ8.02(br s,1H),7.39(d,J=6.6Hz,1H),6.66(d,J=10.8Hz,1H),3.98-3.91(m,3H),1.55-1.50(m,2H),1.32-1.28(m,2H)。
步骤3:化合物32-4的合成
在25℃条件下向化合物32-3(0.035g,139.33μmol,1eq)的甲醇(4mL)、四氢呋喃(2mL)和水(1mL)溶液中加入一水合氢氧化锂(29.23mg,696.63μmol,5eq),反应液搅拌1小时,然后升温至45℃搅拌12小时。反应液加稀盐酸(1M)调节pH至3,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐 水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物32-4。
步骤4:化合物32的合成
在25℃条件下向化合物32-4(0.030g,126.48μmol,1eq)的N,N-二甲基甲酰胺(4mL)溶液中分别加入HATU(72.14mg,189.73μmol,1.5eq)和二异丙基乙基胺(32.69mg,252.97μmol,44.06μL,2.0eq),反应液搅拌10分钟,然后向反应液中加入化合物BB-1(26.09mg,126.48μmol,1eq),反应液在继续搅拌30分钟。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:26%-56%,高效液相柱的保留时间为10min),得到化合物32。
1H NMR(400MHz,CDCl
3):δ8.81(br s,1H),7.84(d,J=7.6Hz,1H),7.42-7.30(m,1H),7.22-7.10(m,3H),7.06-6.97(m,1H),7.06-6.94(m,1H),7.42-7.30(d,J=12.0Hz,1H),4.15–3.99(m,1H),3.85-3.73(m,2H),3.68-3.49(m,2H),3.00-2.88(m,3H),2.80–2.71(m,1H),2.69-2.53(m,2H),1.53-1.49(m,2H),1.31-1.20(m,2H)。MS(ESI)m/z:426.3[M+H]
+。
实施例27:化合物33的制备
步骤1:化合物33-2的合成:
在0℃,氮气保护的条件下向化合物33-1(0.1g,469.12μmol,1eq)和1-羟基环丙基甲酸甲酯(55mg,473.67μmol,1.01eq)的四氢呋喃(2mL)溶液中加入钠氢(30mg,750.07μmol,60%纯度,1.60eq),反应液在20℃-25℃下搅拌1小时。反应液用饱和氯化铵溶液(5mL)淬灭,乙酸乙酯萃取(5mL×3),合并有机相,有机相经水(5mL),饱和食盐水洗涤(5mL),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物33-2。
步骤2:化合物33-3的合成
向化合物33-2(120mg,388.01μmol,1eq)的醋酸(3mL)溶液中加入铁粉(120.00mg,2.15mmol,5.54eq),反应液在80℃下搅拌1小时。反应液加入饱和碳酸氢钠(30mL),经硅藻土过滤,滤饼用乙酸乙酯洗涤(30mL),滤液静置分层,有机相经水(30mL)洗涤无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物33-3。
步骤3:化合物33-4的合成
向化合物33-3(0.1g,404.46μmol,1eq)的四氢呋喃(2mL),甲醇(1mL),水(0.5mL)溶液中加入一水和氢氧化锂(60.00mg,1.43mmol,3.54eq),反应液在20-25℃下搅拌12小时,反应液在60℃下搅拌3小时。反应液用盐酸(1mol/L)调节pH至4,在用乙酸乙酯萃取(10mL×2),合并有机相用水洗涤(10mL),无水硫酸钠干燥,过滤,减压浓缩,得到化合物33-4。
步骤4:化合物33的合成
在0℃下向化合物33-4(0.1g,428.78μmol,1eq)的N,N二甲基甲酰胺(3mL)溶液中加入HATU(180mg,473.40μmol,1.1eq)和DIEA(170.66mg,1.32mmol,230μL,3.08eq),反应液在0℃下搅拌0.5小时,再向反应液中加入化合物BB-1(90mg,436.29μmol,1.02eq),反应液0℃下搅拌0.5小时。反应液加水(10mL),搅拌10分钟,过滤,滤饼用水(30mL)洗涤,旋干,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150*25mm*5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:30%-60%,高效液相柱的保留时间为10min),得到化合物33。
1H NMR(400MHz,CDCl
3):δ8.93(br s,1H),7.19-7.07(m,3H),7.04-6.93(m,2H),6.71-6.64(m,2H),4.08-4.00(m,1H),3.82(d,J=14.9Hz,1H),3.70(ddd,J=3.7,5.9,13.8Hz,1H),3.63(d,J=14.9Hz,1H),3.39(td,J=6.0,13.8Hz,1H),2.97-2.84(m,3H),2.79-2.70(m,1H),2.66-2.53(m,2H),2.42-2.32(m,3H),1.48-1.34(m,2H),1.24-1.11(m,2H);MS(ESI)m/z:422.3[M+1]
+。
实施例28:化合物34的制备
步骤1:化合物34-2的合成
向化合物34-1(0.5g,2.54mmol,1eq)中加入3-氧杂环丁酮(182.77mg,2.54mmol,1eq)和苄基异腈(297.11mg,2.54mmol,308.85μL,1eq)中,混合物置于55℃搅拌12小时。反应液减压浓缩,得到粗品化合物34-2。
步骤2:化合物34-3的合成
在25℃条件下,向化合物34-2(0.980g,2.54mmol,1eq)的N,N-二甲基甲酰胺(10mL)溶液中加入叔丁醇钾(569.25mg,5.07mmol,2eq),反应液升温至100℃搅拌1小时。反应液加水(10mL)和稀盐酸(1M,5mL)淬灭,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1),得到化合物34-3。
步骤3:化合物34-4的合成
在25℃条件下向化合物34-3(0.536g,1.58mmol,1eq)的醋酸(10mL)溶液中加入钯碳(0.536g,1.58mmol,10%纯度,1.00eq),反应液在氢气氛围下于110℃搅拌反应12小时。反应液经硅藻土过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=5:1-1:1),得到化合物34-4。
1H NMR(400MHz,DMSO-d
6):δ11.07(br s,1H),7.57(dd,J=2.0,8.4Hz,1H),7.50(d,J=2.0Hz,1H),7.19(d,J=8.4Hz,1H),5.05-4.86(m,2H),4.78-4.58(m,2H),3.81(s,3H)。
步骤4:化合物34-5的合成
在25℃条件下,向化合物34-4(0.240g,963.01μmol,1eq)的甲醇(10mL)和水(2mL)溶液中加入一水合氢氧化锂(202.04mg,4.82mmol,5eq),反应液升温至45℃搅拌2小时。反应液加稀盐酸(1M)调节pH至3,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物34-5。
步骤5:化合物34的合成
在25℃条件下,向化合物34-5(0.226g,960.91μmol,1eq)的N,N-二甲基甲酰胺(5mL)溶液中分别加入HATU(438.44mg,1.15mmol,1.2eq)和DIEA(186.28mg,1.44mmol,251.06μL,1.5eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(198.22mg,960.91μmol,1eq),反应液搅拌30分钟。反应液加水(10mL)稀释,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:25%-55%,高效液相柱的保留时间为10min)得到化合物34。
1H NMR(400MHz,DMSO-d
6):δ11.01(br s,1H),8.41(t,J=5.6Hz,1H),7.46-7.34(m,2H),7.18-6.95(m,5H),5.03–4.88(m,2H),4.87-4.79(m,1H),4.68-4.51(m,2H),4.01–3.85(m,1H),3.64-3.59(m,2H),3.35-3.17(m,4H),2.85–2.76(m,2H),2.74-2.64(m,2H);MS(ESI)m/z:424.3[M+H]
+。
实施例29:化合物35和36的制备
步骤1:化合物35-1的合成:
向化合物34-1(0.5g,2.54mmol,1eq)中加入3-羰基四氢呋喃(218.67mg,2.54mmol,1eq)和苄基异腈(297.55mg,2.54mmol,309.31μL,1eq),混合物置于55℃搅拌12小时。反应液减压浓缩,得到粗品化合物35-1。
步骤2:化合物35-2的合成:
在25℃条件下,向化合物35-1(1g,2.50mmol,1eq)的N,N-二甲基甲酰胺(10mL)溶液中加入叔丁醇钾(560.53mg,5.00mmol,2eq),反应液升温至100℃搅拌1小时。反应液加水(10mL)和稀盐酸淬灭(1M,10mL),乙酸乙酯萃取(15mL×3),合并有机相,有机相经饱和食盐水洗涤(15mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚:乙酸乙酯=10:1-4:1),得到化合物35-2。
步骤3:化合物35-3的合成:
在25℃条件下向化合物35-2(0.262g,741.44μmol,1eq)的醋酸(10mL)溶液中加入钯碳(0.262g,10%纯度),反应液在氢气氛围下于115℃搅拌反应12小时。反应液经硅藻土过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚:乙酸乙酯=10:1-2:1),得到化合物35-3。
1H NMR(400MHz,DMSO-d
6):δ11.08(br s,1H),7.58(dd,J=2.0,8.4Hz,1H),7.54(d,J=2.0Hz,1H),7.10(d,J=8.4Hz,1H),4.02-3.84(m,4H),3.82(s,3H),2.43-2.35(m,1H),2.21-2.10(m,1H)。
步骤4:化合物35-4的合成:
在25℃条件下,向化合物35-3(0.110g,417.86μmol,1eq)的甲醇(10mL)和水(2mL)溶液中加入一水合氢氧化锂(87.67mg,2.09mmol,5eq),反应液升温至45℃搅拌12小时。反应液加稀盐酸(1M)调节pH至3,乙酸乙酯萃取(15mL×3),合并有机相,有机相经饱和食盐水洗涤(15mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物35-4。
步骤5:化合物35和36的合成:
在25℃条件下,向化合物35-4(0.090g,361.13μmol,1eq)的N,N-二甲基甲酰胺(5mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(164.77mg,433.35μmol,1.2eq)和N,N-二异丙基乙胺(70.01mg,541.69μmol,94.35μL,1.5eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(111.74mg,541.69μmol,1.5eq),反应液搅拌30分钟。反应液加水稀释(10mL),乙酸乙酯萃取(15mL×3),合并有机相,有机相经饱和食盐水洗涤(15mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150*25mm*5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:17%-50%,高效液相柱的保留时间为9min),再经SFC分离纯化(色谱柱:DAICEL CHIRALPAK IC(250mm*30mm,10μm);流动相B:[0.1%氨水异丙醇];B%:60%-60%)得到化合物35和36。
化合物35:SFC分析条件:色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为异丙醇(0.05%二乙胺);异丙醇(0.05%二乙胺):40%-40%;流速:3mL/min;检测器:PDA;保留时间为2.317min,手性纯度=100%。
1H NMR(400MHz,CDCl
3):δ9.35(br s,1H),7.81(br s,1H),7.73(s,1H),7.42(dd,J=2.0,8.4Hz,1H),7.26-7.12(m,3H),7.05(d,J=7.2Hz,1H),6.93(d,J=8.4Hz,1H),4.34–4.22(m,1H),4.19-4.08(m,3H),4.07-3.96(m,3H),3.82–3.70(m,1H),3.67-3.55(m,1H),3.29-3.13(m,2H),3.11-2.91(m,4H),2.59-2.47(m,1H),2.32–2.20(m,1H);MS(ESI)m/z:438.3[M+1]
+。
化合物36:SFC分析条件:色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为异丙醇(0.05%二乙胺);异丙醇(0.05%二乙胺):40%-40%;流速:3mL/min;检测器:PDA;保留时间为4.500min,手性纯度=99.46%。
1H NMR(400MHz,CDCl
3):δ9.58-8.91(m,1H),7.71(s,2H),7.38(dd,J=1.8,8.4Hz,1H),7.26-7.11(m,3H),7.08-7.01(m,1H),6.92(d,J=8.4Hz,1H),4.29–4.18(m,1H),4.17-4.07(m,2H),4.06-3.86(m,4H),3.82–3.71(m,1H),3.67-3.55(m,1H),3.22-3.07(m,2H),3.04-2.84(m,4H),2.59–2.46(m,1H),2.26-2.22(m,1H);MS(ESI)m/z:438.3[M+1]
+。
实施例30:化合物37的制备
步骤1:化合物37-1的合成
向化合物34-1(0.5g,2.54mmol,1eq)中加入硫杂环丁烷-3-酮(223.85mg,2.54mmol,1eq)和苄基异腈(297.55mg,2.54mmol,309.31μL,1eq),混合物置于55℃搅拌12小时。反应液减压浓缩,得到粗品化合物37-1。
步骤2:化合物37-2的合成
在25℃条件下,向化合物37-1(1g,2.48mmol,1eq)的N,N-二甲基甲酰胺(10mL)溶液中加入叔丁醇钾(557.68mg,4.97mmol,2eq),反应液升温至100℃搅拌1小时。反应液加水(10mL)和稀盐酸(1M,10mL)淬灭,乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=20:1-4:1),得到化合物37-2。
步骤3:化合物37-3的合成
在冰浴条件下,向化合物37-2(0.235g,661.21μmol,1eq)的二氯甲烷(10mL)溶液中加入间氯过氧苯甲酸(402.73mg,1.98mmol,85%纯度,3.0eq),反应液升温至25℃搅拌12小时。反应液加饱和亚硫酸钠(10mL)溶液淬灭,二氯甲烷萃取(10mL×3),合并有机相,有机相经饱和碳酸氢钠溶液(10mL×5)和饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物37-3。
步骤4:化合物37-4的合成
在25℃条件下向化合物37-3(0.240g,619.51μmol,1eq)的醋酸(5mL)溶液中加入钯碳(0.050g,10%纯度),反应液在氢气(15psi)氛围下于115℃搅拌反应12小时。反应液经硅藻土过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=5:1-1:1),得到化合物37-4。
1H NMR(400MHz,DMSO-d
6):δ11.44(s,1H),7.63(dd,J=2.0,8.4Hz,1H),7.56(d,J=2.0Hz,1H),7.22(d,J=8.4Hz,1H),4.97-4.80(m,2H),4.62-4.39(m,2H),3.87-3.77(m,3H)。
步骤5:化合物37-5的合成
将化合物37-4(0.040g,134.55μmol,1eq)的醋酸(4mL)和浓盐酸(4mL)溶液置于95℃搅拌4小时。反应液加水稀释(10mL),(乙酸乙酯:四氢呋喃=4:1v/v,10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物37-5。
步骤6:化合物37的合成
在25℃条件下,向化合物37-5(0.040g,141.21μmol,1eq)的N,N-二甲基甲酰胺溶液(5mL)中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(64.43mg,169.46μmol,1.2eq)和N,N-二异丙基乙胺(27.38mg,211.82μmol,36.89μL,1.5eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(29.13mg,141.21μmol,1eq),反应液搅拌30分钟。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 1150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:15%-48%,高效液相柱的保留时间为9min)得到化合物37。
1H NMR(400MHz,DMSO-d
6):δ11.38(br s,1H),8.47(t,J=5.6Hz,1H),7.54-7.44(m,2H),7.16-7.06(m,4H),7.05-6.98(m,1H),4.96-4.86(m,2H),4.83-4.77(m,1H),4.56-4.42(m,2H),3.96-3.81(m,1H),3.71-3.55(m,2H),3.47-3.44(m,2H),3.27-3.15(m,1H),2.84-2.77(m,2H),2.76-2.64(m,2H)。MS(ESI)m/z:472.2[M+H]
+。
实施例31:化合物38的制备
步骤1:化合物38-2的合成:
在25℃条件下,向化合物38-1(2g,22.20mmol,1eq)的N,N-二甲基甲酰胺(10mL)溶液中加入咪唑(7.56g,111.02mmol,5eq)和叔丁基二甲基氯硅烷(8.37g,55.51mmol,6.80mL,2.5eq),反应液搅拌12小时。反应液加水(20mL)稀释,乙酸乙酯萃取(15mL×3),合并有机相,有机相经饱和食盐水洗涤(15mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=20:1),得到化合物 38-2。
1H NMR(400MHz,CDCl
3):δ4.51-4.36(m,4H),0.98-0.92(m,18H),0.10-0.08(m,12H)。
步骤2:化合物38-3的合成
向化合物34-1(1g,5.07mmol,1eq)中加入化合物38-2(1.62g,5.07mmol,1.0eq)和苄基异腈(594.22mg,5.07mmol,617.69μL,1.0eq),混合物置于55℃搅拌12小时。反应液减压浓缩,得到粗品化合物38-3。
步骤3:化合物38-4的合成
在25℃条件下,向化合物38-3(3g,4.74mmol,1eq)的N,N-二甲基甲酰胺(40mL)溶液中加入叔丁醇钾(1.06g,9.48mmol,2.0eq),反应液升温至100℃搅拌1小时。反应液加稀盐酸淬灭(1M,10mL),乙酸乙酯(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物38-4。
步骤4:化合物38-5的合成
在25℃条件下,向化合物38-4(3g,5.12mmol,1eq)的四氢呋喃(20mL)溶液中加入四丁基氟化铵(1M,12.80mL,2.5eq),反应液继续搅拌1小时。反应液加水(20mL)稀释,乙酸乙酯(20mL×3)萃取,合并有机相,有机相经饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=10:1–0:1)得到化合物38-5。
步骤5:化合物38-6的合成
在25℃条件下,向化合物38-5(1g,2.80mmol,1eq)的二氯甲烷(20mL)溶液中加入三乙胺(1.13g,11.19mmol,1.56mL,4eq),4-二甲氨基吡啶(170.94mg,1.40mmol,0.5eq)和对甲苯磺酰氯(2.13g,11.19mmol,4.0eq),反应液搅拌24小时。反应液加水(15mL)稀释,二氯甲烷(15mL×3)萃取,合并有机相,有机相经饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=10:1–2:1)得到化合物38-6。
步骤6:化合物38-7的合成
在25℃条件下向化合物38-6(0.667g,1.00mmol,1eq)的醋酸(10mL)溶液中加入钯碳(0.667g,10%纯度),反应液在氢气氛围下于115℃搅拌反应12小时。反应液过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1-1:1),得到化合物38-7。
步骤7:化合物38-8的合成
在25℃条件下向化合物38-7(0.090g,156.36μmol,1eq)和四丁基碘化铵(11.55mg,31.27μmol,0.2eq)的N,N-二甲基甲酰胺(4mL)溶液中加入九水硫化钠(187.77mg,781.78μmol,131.31μL,5eq),反应液升温至100℃继续搅拌反应2小时。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化 (石油醚:乙酸乙酯=5:1)得到化合物38-8。
1H NMR(400MHz,CD
3OD):δ7.73-7.67(m,1H),7.56(d,J=2.0Hz,1H),7.17(d,J=8.4Hz,1H),3.88(s,3H),3.70(d,J=11.0Hz,2H),3.46(d,J=11.0Hz,2H)。
步骤8:化合物38-9的合成
在25℃条件下,向化合物38-8(0.010g,37.70μmol,1eq)的四氢呋喃(2mL)和水(0.5mL)溶液中加入一水合氢氧化锂(7.91mg,188.48μmol,5eq),反应液升温至45℃搅拌2小时。反应液加稀盐酸(1M)调节pH至5,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物38-9。
步骤9:化合物38的合成
在25℃条件下,向化合物38-9(0.010g,39.80μmol,1eq)的N,N-二甲基甲酰胺(5mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(18.16mg,47.76μmol,1.2eq)和N,N-二异丙基乙胺(7.72mg,59.70μmol,10.40μL,1.5eq),反应液搅拌10分钟,然后向其中加入化合物BB-1(8.21mg,39.80μmol,1eq),反应液搅拌30分钟。反应液加水(10mL)稀释,乙酸乙酯(10mL×3)萃取,合并有机相,有机相经饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈:29%-59%,高效液相柱的保留时间为10min)得到化合物38。
1H NMR(400MHz,CDCl
3):δ8.85-8.17(m,1H),7.54(s,1H),7.38–7.28(m,2H),7.26-7.09(m,4H),7.06–6.97(m,2H),4.17–4.02(m,1H),3.95–3.84(m,1H),3.81-3.67(m,4H),3.62-3.54(m,1H),3.49–3.40(m,2H),3.06-2.89(m,3H),2.87–2.80(m,1H),2.78-2.72(m,1H),2.71-2.58(m,1H)。MS(ESI)m/z:440.3[M+H]
+。
实施例32:化合物39的制备
步骤1:化合物39-2的合成:
将化合物6-2(2.7g,12.47mmol,1eq),化合物39-1(820.88mg,13.71mmol,1.1eq)和碳酸钾(5.17g,37.40mmol,3eq)溶于无水1,4-二氧六环(30mL)溶液中,氮气保护下,加入四三苯基膦钯(1.44g,1.25mmol,0.1eq),反应液120液4搅拌12小时。反应液过滤得滤液,滤液减压浓缩,经薄层色谱(硅胶,石油醚/乙酸乙酯=10/1至5/1)分离纯化得到化合物39-2。
1H NMR(400MHz,CDCl
3):δ9.29(d,J=1.6Hz,1H),8.83(d,J=2.0Hz,1H),4.01(s,3H),2.94(s,3H)。
步骤2:化合物39-3的合成:
将化合物39-2(1.67g,8.51mmol,1eq)溶于1,4-二氧六环(30mL)溶液中,加入二氧化硒(1.89g,17.03mmol,1.85mL,2eq),反应液在100℃搅拌反应20小时。将反应液过滤,滤液减压浓缩得到化合物39-3。
步骤3:化合物39-4的合成:
将化合物39-3(0.5g,2.38mmol,1eq)溶于无水四氢呋喃(40mL)溶液中,加入(2-乙氧基乙酰基)膦酸二乙酯(640.11mg,2.86mmol,566.47μL,1.2eq)和碳酸铯(930.28mg,2.86mmol,1.2eq)。反应液在20℃搅拌4.5小时,向反应液中加入水(50mL)用乙酸乙酯(50mL)萃取三次,合并的有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物39-4。
步骤4:化合物39-5的合成:
将化合物39-4(0.75g,2.68mmol,1eq)溶于无水乙醇(10mL)溶液中,氮气保护下,加入钯碳(0.5g,3.57mmol,10%纯度),反应液在氢气氛围中20℃温度下搅拌反应10小时。反应液过滤,滤液减压浓缩得到化合物39-5。
步骤5:化合物39-6的合成:
将化合物39-5(0.65g,2.58mmol,1eq)溶于无水四氢呋喃(20mL)溶液中,加入冰醋酸(773.66mg,12.88mmol,736.82μL,5eq),反应液在60℃搅拌反应1.5小时。将反应液减压浓缩除去溶剂得到粗品,向粗品中加入石油醚(20mL),过滤,收集滤饼并减压浓缩干燥得到化合物39-6。
步骤6:化合物39-7的合成:
将化合物39-6(0.25g,1.21mmol,1eq)溶于无水二氯甲烷(5mL),加入二碳酸二叔丁酯(291.07mg,1.33mmol,306.39μL,1.1eq)和4-二甲胺基吡啶(74.06mg,606.21μmol,0.5eq),反应液在20℃搅拌反应10 分钟。反应液依次用饱和柠檬酸水溶液(10mL)和饱和食盐水(10mL)洗涤一次,无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物39-7。
步骤7:化合物39-9的合成:
将化合物39-7(0.6g,1.96mmol,1eq)和化合物39-8(1.06g,2.94mmol,1.5eq)溶于无水N,N–二甲基甲酰胺(3mL)溶液中,加入1,8-二氮杂二环十一碳-7-烯(894.60mg,5.88mmol,885.74μL,3eq),反应液在20℃搅拌反应1小时。将反应液倒入水(10mL)中,用乙酸乙酯(10mL*3)萃取三次,合并的有机相用饱和食盐水(10mL*3)洗涤三次,无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶薄层色谱纯化(石油醚:乙酸乙酯=1:1)得到化合物39-9。
步骤8:化合物39-10盐酸盐的合成:
将化合物39-9(80mg,240.71μmol,1eq)溶于无水1,4-二氧六环(2mL),加入盐酸/1,4-二氧六环溶液(4M,4mL,66.47eq),反应液在20℃搅拌反应0.5小时。反应液减压浓缩得到化合物39-10盐酸盐。
步骤9:化合物39-11的合成:
将化合物39-10(50mg,盐酸盐)溶于无水四氢呋喃(1mL)和水(1mL)的混合溶液中,加入一水合氢氧化锂(10.84mg,258.36μmol,1.2eq),反应液在20℃搅拌反应10分钟。反应液用盐酸/1,4–二氧六环(4M)溶液调节pH至6-7,减压浓缩得到化合物39-11。
步骤10:化合物39的合成:
将化合物39-11(30mg,137.48μmol,1eq)溶于N,N-二甲基甲酰胺(1mL),加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(57.50mg,151.23μmol,1.1eq)和N,N-二异丙基乙胺(17.77mg,137.48μmol,23.95μL,1eq)。反应液在20℃搅拌0.5小时,再加入化合物BB-1(36.87mg,178.73μmol,1.3eq),反应液在20℃搅拌1小时。经制备型高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm;流动相:[水(0.05%氨水(v/v))-乙腈];乙腈%:12%-40%,高效液相柱的保留时间为7分钟)得到化合物39。
1H NMR(400MHz,CD
3OD):δ8.55(d,J=2.0Hz,1H),7.64(d,J=2.0Hz,1H),7.15-7.07(m,3H),7.06-7.00(m,1H),4.20-4.09(m,1H),3.79(s,2H),3.60(dd,J=5.0,13.6Hz,1H),3.45(dd,J=6.8,13.6Hz,1H),3.12(s,2H),2.97-2.87(m,4H),2.74-2.66(m,2H),1.31(q,J=3.6,2H),0.90(q,J=3.6,2H);MS(ESI)m/z:407.4[M+1]
+。
实施例33:化合物40和41的制备
步骤1:化合物40-2的合成:
将化合物40-1(5g,38.42mmol,1eq)和醋酸钠(6.30g,76.84mmol,2eq)溶于冰醋酸(25mL),称取液溴(7.37g,46.10mmol,2.38mL,1.2eq)溶于冰醋酸(10mL)中,在80℃温度下将液溴的冰醋酸溶液滴加到上述反应液中,油浴80℃搅拌反应3小时。向反应液中加入二氯甲烷(50mL),用水(50mL)洗涤一次,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=10:1)得到化合物40-2。
1H NMR(400MHz,CDCl
3):δ9.05-8.97(m,2H),8.62-8.59(m,1H),8.41(dd,J=1.2,8.2Hz,1H),7.68(dd,J=4.2,8.6Hz,1H)。
步骤2:化合物40-3的合成:
将化合物40-2(6.60g,31.57mmol,1eq)溶于无水二氯甲烷(75mL)中,在0℃温度下加入间氯过氧苯甲酸(7.69g,37.89mmol,85%纯度,1.2eq),在20℃温度下搅拌反应12小时。反应液过滤,滤液依次用饱和亚硫酸钠水溶液(50mL)和碳酸氢钠水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=1:1)得到化合物40-3。
1H NMR(400MHz,DMSO-d
6):δ9.17(d,J=2.4Hz,1H),9.05(d,J=2.0Hz,1H),8.70(d,J=6.0Hz,1H),8.02(d,J=8.4Hz,1H),7.76(dd,J=6.2,8.8Hz,1H)。
步骤3:化合物40-4的合成:
将化合物40-3(3.00g,13.33mmol,1eq)和碳酸钾(6.45g,46.66mmol,3.5eq)溶于氯仿(45mL)和水(15mL)中,加入对甲苯磺酰氯(3.05g,16.00mmol,1.2eq),反应液在20℃搅拌反应48小时。反应液减压浓缩除去氯仿,向反应液中加入水(50mL),过滤得滤饼,减压浓缩干燥得到化合物40-4。
1H NMR(400MHz,DMSO-d
6):δ11.96(br s,1H),8.55(d,J=2.0Hz,1H),7.92(d,J=10Hz,1H),7.85(d,J=1.6Hz,1H),6.78(d,J=9.6Hz,1H)。
步骤4:化合物40-5的合成:
将化合物40-4(1.5g,6.67mmol,1eq)溶于无水N,N-二甲基甲酰胺(10mL)溶液中,加入钠氢(279.92mg,7.00mmol,60%纯度,1.05eq),油浴40℃反应1小时。在40℃温度下,加入对甲氧基苄氯(1.30g,8.33mmol,1.13mL,1.25eq),加毕,油浴50℃反应2小时。反应液倒入水(50mL)中,用乙酸乙酯(50mL*3)萃取三次,合并的有机相用饱和食盐水(50mL*3)洗涤三次,无水硫酸钠干燥,过滤,滤液减压浓缩,柱层析纯化(硅胶,石油醚:乙酸乙酯=1:1)得到化合物40-5。
步骤5:化合物40-6的合成:
将钠氢(236.37mg,5.91mmol,60%纯度,2eq)溶于二甲基亚砜(15mL)溶液中,在20℃温度下加入三甲基碘化亚砜(1.30g,5.91mmol,2eq),反应液在60℃温度下搅拌反应1小时。加入化合物40-5(1.02g,2.95mmol,1eq),反应液在60℃温度下搅拌反应0.5小时。反应液倒入水(50mL)中,用乙酸乙酯(50mL*2)萃取两次,合并的有机相用饱和食盐水(50mL*2)洗涤两次,无水硫酸钠干燥,过滤,滤液减压浓缩,经硅胶柱层析(石油醚:乙酸乙酯=1:3至1:1)得到化合物40-6。
1H NMR(400MHz,CDCl
3):δ8.20(d,J=1.8Hz,1H),7.25(d,J=1.8Hz,1H),7.13-7.07(d,J=8.6Hz,2H),6.86(d,J=8.6Hz,2H),5.16(br d,J=15.8Hz,1H),4.90(br d,J=16.0Hz,1H),3.78(s,3H),2.86-2.79(m,1H),2.54(m,1H),1.80(m,1H),0.80(q,J=5.0Hz,1H)。
步骤6:化合物40-7的合成:
将化合物40-6(0.71g,1.98mmol,1eq)溶于无水N,N-二甲基甲酰胺(10mL)和无水甲醇(15mL)中,氩气保护下,加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(144.62mg,197.65μmol,0.1eq)和醋酸钠(486.40mg,5.93mmol,3eq)。用一氧化碳置换三次后,在2MPa压力下120℃反应18小时。反应液减压浓缩后经硅胶柱层析(石油醚:乙酸乙酯=1:3至1:1)得到化合物40-7。
步骤7:化合物40-8的合成:
将化合物40-7(0.82g,2.42mmol,1eq)溶于三氟乙酸(5mL)和无水二氯甲烷(5mL)中,冷却0℃至,加入三氟甲磺酸(1.82g,12.12mmol,1.07mL,5eq)。反应液在20℃温度下搅拌反应10小时。将反应液减压浓缩得到化合物40-8。
1H NMR(400MHz,CDCl
3):δ8.83(d,J=1.6Hz,1H),8.24(br s,1H),7.65(d,J=1.6Hz,1H),3.96(s,3H),2.90-2.86(m,1H),2.43-2.32(m,1H),1.89(dt,J=5.2,9.2Hz,1H),0.93(q,J=5.2Hz,1H)。
步骤8:化合物40-9的合成:
将化合物40-8(200mg,916.56μmol,1eq)溶于无水四氢呋喃(10mL)和水(1mL)中,加入一水合氢氧化锂(76.92mg,1.83mmol,2eq),反应液在20℃搅拌反应1小时。将反应液减压浓缩得到化合物40-9。
步骤9:化合物40和41的合成:
将化合物40-9(190mg,930.54μmol,1eq)溶于N,N-二甲基甲酰胺(3mL),加入HATU(389.20mg,1.02mmol, 1.1eq)和二异丙基乙胺(132.29mg,1.02mmol,178.29μL,1.1eq)。反应液在20℃搅拌10分钟,化合物BB-1(191.96mg,930.54μmol,1eq)加入到反应中,反应液在20℃搅拌0.5小时。将反应液过滤得滤液。滤液经制备型高效液相分离纯化(色谱柱:Waters Xbridge BEH C18 250*50mm*10μm;流动相:[水(0.05%氢氧化铵(v/v))-乙腈];乙腈%:5%-35%),经SFC分离纯化(色谱柱:DAICEL CHIRALCEL OJ(250mm*30mm,10μm);流动相0.1%氨水甲醇:55%-55%)得到化合物40和41。
化合物40:SFC分析条件:色谱柱:Chiralcel OJ-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);甲醇(0.05%二乙胺):55%-55%;流速:3mL/min;检测器:PDA;保留时间为2.216min,手性纯度=99.73%。
1H NMR(400MHz,CDCl
3):δ8.64(br s,1H),8.56(d,J=1.6Hz,1H),7.75(d,J=1.2Hz,1H),7.37(br s,1H),7.20-7.11(m,3H),7.00(d,J=7.2Hz,1H),4.16-4.11(m,1H),3.90(br d,J=14.8Hz,1H),3.79-3.71(m,2H),3.59-3.52(m,1H),3.06-2.98(m,1H),2.95(br d,J=5.6Hz,2H),2.89-2.65(m,5H),2.35-2.24(m,1H),1.84-1.78(m,1H),0.84(q,J=5.2Hz,1H);MS(ESI)m/z:393.3[M+1]
+。
化合物41:SFC分析条件:色谱柱:Chiralcel OJ-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);甲醇(0.05%二乙胺):55%-55%%;流速:3mL/min;检测器:PDA;保留时间为2.508min,手性纯度=96.59%。
1H NMR(400MHz,CDCl
3):δ8.60(s,1H),8.42(br s,1H),7.71(s,1H),7.48(br s,1H),7.23-7.10(m,3H),7.02(d,J=7.6Hz,1H),4.19(br s,1H),4.01(d,J=15.2Hz,1H),3.89-3.72(m,2H),3.60-3.43(m,1H),3.09(br s,1H),3.03-2.91(m,3H),2.87-2.73(m,3H),2.32-2.24(m,1H),1.84–1.78(m,1H),0.83(br d,J=4.8Hz,1H);MS(ESI)m/z:393.3[M+1]
+。
实施例34:化合物42的制备
步骤1:化合物42-2的合成:
化合物6-2(5g,23.09mmol,1eq)溶于N,N-二甲基甲酰胺(50mL)中,向其中加入碳酸铯(11.28g,34.64mmol,1.5eq)并在20℃下搅拌30分钟,然后加入42-1(3.66g,27.71mmol,3.18mL,1.2eq),反应液在20℃下搅 拌10小时。反应液倒入水(150mL)中,用乙酸乙酯(100mL*3)萃取,分离有机相用饱和食盐水(100mL*3)洗,无水硫酸钠干燥,过滤,滤液减压浓缩得到得到的粗品经硅胶柱层析(石油醚:乙酸乙酯=1:0~10:1)纯化得到化合物42-2。
步骤2:化合物42-3的合成
化合物42-2(3g,9.61mmol,1eq)溶于二甲基亚砜(30mL)和水(3mL)中,然后加入氯化锂(1.02g,24.02mmol,491.90μL,2.5eq)。反应液在120~130℃搅拌2小时。反应液冷却到20℃,然后加入水(100mL)和乙酸乙酯(100mL),分离有机相并用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用硅胶柱层析(石油醚:乙酸乙酯=10:1~4:1)分离纯化得到化合物42-3。
步骤3:化合物42-4的合成
在氮气氛围下向化合物42-3(800mg,3.15mmol,1eq)的甲苯(15mL)和醋酸(0.3mL)溶液中加入Pd/C(500mg,10%纯度),用氢气置换3次,反应液在112应和氢气(15psi)氛围中搅拌10小时。反应液冷却到80,过滤,滤饼用甲醇(10mL)洗涤,向滤液中加饱和碳酸氢钠水溶液(50mL),乙酸乙酯(50mL*6)萃取,合并有机相用水,无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物42-4。
步骤4:化合物42-5的合成
将化合物42-4(210mg,1.09mmol,1eq)溶于四氢呋喃(5mL)中,加入二碳酸二叔丁酯(476.99mg,2.19mmol,502.09μL,2eq)和DMAP(66.75mg,546.39μmol,0.5eq),在25℃下搅拌30分钟。反应液加水(15mL)淬灭,乙酸乙酯(15mL)萃取,有机相用1N盐酸(10mL),饱和碳酸氢钠水溶液(10mL)和饱和食盐水(10mL)洗,用无水硫酸钠干燥,过滤,滤液减压浓缩得到化合物42-5。
步骤5:化合物42-6的合成
化合物42-5(500.00mg,2.30mmol,1eq)溶解于二甲基亚砜(5mL)中,加入化合物39-8(409.14mg,1.13mmol,1.1eq)和1,8-二氮杂二环十一碳-7-烯(468.76mg,3.08mmol,464.12μL,3eq),反应液在25应搅拌10分钟。反应液加入水(15mL)淬灭,乙酸乙酯(15mL)萃取,分离有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到的粗品经制备薄层色谱(石油醚:乙酸乙酯=3:1)分离纯化得到化合物42-6。
步骤6:化合物42-7盐酸盐的合成
化合物42-6(100mg,314.15μmol,1eq)溶于醋酸(1mL)和浓盐酸(1mL)中,反应液在100应搅拌10小时。反应液减压浓缩得到化合物42-7盐酸盐。
步骤7:化合物42的合成
化合物42-7(50mg,盐酸盐)溶于N,N-二甲基甲酰胺(2mL)中,加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(111.73mg,293.86μmol,1.2eq)并在25℃下搅拌10分钟,然后加入化合物BB-1(50.51mg,244.88μmol,1eq)和N,N-二异丙基乙胺(158.25mg,1.22mmol,213.27μL,5eq),反应液在25℃搅拌20分 钟。反应液加水(10mL)淬灭,乙酸乙酯(10mL×2)萃取,合并有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗产品,经制备型高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75×30mm×3μm;流动相:[水(0.05%氨水v/v)-乙腈];乙腈%:10%-40%,高效液相柱的保留时间为7min)得到化合物42。
1H NMR(400MHz,CD
3OD):δ8.51(d,J=1.6Hz,1H),7.63(d,J=2.0Hz,1H),7.03-7.14(m,3H),6.96-7.03(m,1H),4.07-4.18(m,1H),3.72(s,2H),3.57(dd,J=13.6,8.4Hz,1H),3.44(dd,J=13.6,6.8Hz,1H),2.83-2.94(m,4H),2.61-2.71(m,2H),1.86-1.91(m,2H),1.74-1.80(m,2H);MS(ESI)m/z:393.4[M+1]
+。
实施例35:化合物43和44的制备
步骤1:化合物43-2的合成:
在-78℃条件下向化合物43-1(20g,113.50mmol,1eq)的四氢呋喃(100mL)溶液中加入甲基溴化镁(3M,113.50mL,3eq),反应液升温至25℃继续搅拌2小时。在冰浴条件下向反应液缓慢加入饱和氯化铵溶液淬灭(100ml),乙酸乙酯萃取(50mL×3),合并有机相,有机相经饱和食盐水洗涤(50mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物43-2。
1H NMR(400MHz,DMSO-d
6):δ7.34-7.26(m,5H),4.44-4.27(m,2H),3.79-3.57(m,1H),3.02-2.76(m,1H),2.31-2.18(m,1H),2.09-1.84(m,2H),1.41-1.13(m,3H)。
步骤2:化合物43-3的合成
在0℃条件下向化合物43-2(22.45g,116.77mmol,1eq)和咪唑(23.85g,350.32mmol,3.0eq)的二氯甲烷(200mL)溶液中加入叔丁基二甲基氯硅烷(26.40g,175.16mmol,21.46mL,1.5eq),反应液在25℃继续搅拌12小时。反应液倒入冰水中(100mL),二氯甲烷萃取(100mL×3),合并有机相,有机相经饱和食盐水洗涤(100mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经柱层析分离纯化(石油醚:乙酸乙酯=1:0),得 到化合物43-3。
1H NMR(400MHz,CDCl
3):δ7.36-7.33(m,5H),4.76(s,2H),4.42(s,1H),1.55(s,2H),1.31-1.27(m,2H),0.99-0.94(m,9H),0.12-0.10(m,6H),0.09-0.07(m,3H)。
步骤3:化合物43-4的合成
化合物43-3(19g,61.99mmol,1eq)和钯碳(1.9g,10%纯度)甲醇(4mL)溶液在25℃氢气氛围下搅拌反应12小时。反应液经硅藻土过滤,滤液减压浓缩。粗品经柱层析分离纯化(石油醚:乙酸乙酯=3:1),得到化合物43-4。
步骤4:化合物43-5的合成
在25℃条件下向化合物43-4(4g,18.49mmol,1eq)的二氯甲烷(80mL)溶液中加入戴斯-马丁试剂(9.41g,22.18mmol,6.87mL,1.2eq),反应液在25℃继续搅拌12小时。反应液加饱和亚硫酸钠和饱和碳酸氢钠混合溶液淬灭(100mL,1:1),二氯甲烷萃取(40mL×3),合并有机相,有机相经饱和食盐水洗涤(40mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物43-5。
1H NMR(400MHz,CDCl
3):δ3.24-3.16(m,2H),3.04-2.95(m,2H),1.60(s,3H),0.91-0.89(m,9H),0.14-0.11(m,6H)。
步骤5:化合物43-6的合成
在0℃条件下向化合物43-5(4.35g,20.29mmol,1eq)的二氯甲烷(50mL)溶液中加入三甲基硅氰(2.42g,24.35mmol,3.05mL,1.2eq),然后再加入三氟化硼***(2.88g,20.29mmol,2.50mL,1eq),反应液搅拌1小时。反应液加饱和碳酸氢钠溶液调节pH至10,经硅藻土过滤,滤液用二氯甲烷萃取(50mL×3),合并有机相,有机相经饱和食盐水洗涤(50mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚:乙酸乙酯=1:0-10:1),得到化合物43-6。
1H NMR(400MHz,CDCl
3):δ2.88-2.72(m,2H),2.60-2.49(m,1H),2.47-2.35(m,1H),1.53(d,J=0.6Hz,3H),0.90-0.87(m,9H),0.11-0.08(m,6H)。
步骤6:化合物43-7的合成
在25℃条件下向化合物4-氟-3-硝基苯甲酸甲酯(0.22g,1.10mmol,1eq)和化合物43-6(733.41mg,3.04mmol,2.75eq)的四氢呋喃(20mL)溶液中加入碳酸铯(899.89mg,2.76mmol,55.23μL,2.5eq),反应液搅拌12小时,然后反应液升温至60℃,继续搅拌2小时。反应液加水稀释(20mL),乙酸乙酯萃取(20mL×3),合并有机相,有机相经饱和食盐水洗涤(20mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚:乙酸乙酯=10:1),得到化合物43-7。
1H NMR(400MHz,CDCl
3):δ8.57-8.52(m,1H),8.28-8.21(m,1H),7.13(d,J=8.8Hz,1H),3.96(s,3H),3.21(br d,J=8.6Hz,2H),3.00-2.97(m,2H),1.64(s,3H),0.87-0.85(m,9H),0.10-0.09(m,6H)。
步骤7:化合物43-8的合成
在80℃条件下向化合物43-7(0.550g,1.31mmol,1eq)和氯化铵(349.80mg,6.54mmol,5eq)的乙醇(20mL)和水(10mL)溶液中加入铁粉(365.19mg,6.54mmol,5eq),反应液继续搅拌12小时。反应液经硅藻土过滤,滤液减压浓缩,得到粗品化合物43-8。
步骤8:化合物43-9的合成
在25℃条件下向化合物43-8(0.320g,817.30μmol,1eq)的四氢呋喃(10mL)溶液中加入稀盐酸(2M,2.04mL,5eq),反应液搅拌12小时。反应液加水稀释(20mL),乙酸乙酯萃取(15mL×3),合并有机相,有机相经饱和食盐水洗涤(15mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚:乙酸乙酯=5:1-1.5:1),得到化合物43-9。
步骤9:化合物43-10的合成
在25℃条件下,向化合物43-9(0.1g,360.66μmol,1eq)的甲醇(5mL)和水(1mL)溶液中加入一水合氢氧化锂(75.67mg,1.80mmol,5eq),反应液升温至45℃搅拌12小时。反应液加稀盐酸(1M)调节pH至5,乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物43-10。
步骤10:化合物43和44的合成
在25℃条件下向化合物43-10(0.1g,379.87μmol,1eq)的N,N-二甲基甲酰胺(5mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(173.33mg,455.85μmol,1.2eq)和N,N-二异丙基乙胺(73.64mg,569.81μmol,99.25μL,1.5eq),反应液搅拌10分钟,然后向反应液中加入化合物BB-1(117.54mg,569.81μmol,1.5eq),反应液继续搅拌30分钟。反应液加水稀释(10mL),乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150*25mm*5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:16%-46%,高效液相柱的保留时间为10min),得到化合物43和44。
化合物43:SFC分析条件:色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇+乙腈(0.05%二乙胺);60%甲醇+乙腈(0.05%二乙胺);流速:3mL/min;检测器:PDA;保留时间为0.793min,手性纯度=100%。
1H NMR(400MHz,CD
3OD):δ7.37-7.32(m,2H),7.16-7.07(m,3H),7.05-7.00(m,1H),6.97-6.92(m,1H),4.12–4.06(m,1H),3.74(s,2H),3.55-3.42(m,2H),2.95–2.82(m,4H),2.78-2.72(m,2H),2.71-2.61(m,2H),2.45–2.38(m,2H),1.43(s,3H);MS(ESI)m/z:452.3[M+1]
+。
化合物44:SFC分析条件:色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm,流动相:流动相A为CO
2,流动相B为甲醇+乙腈(0.05%二乙胺);60%甲醇+乙腈(0.05%二乙胺);流速:3mL/min;检测器:PDA;保留时间为2.872min,手性纯度=98.43%。
1H NMR(400MHz,CD
3OD):δ7.43-7.33(m,2H),7.15-7.07(m, 3H),7.04-6.99(m,1H),6.93(d,J=8.0Hz,1H),4.12–4.06(m,1H),3.73(s,2H),3.56-3.39(m,2H),2.98-2.79(m,4H),2.76-2.58(m,4H),2.38-2.25(m,2H),1.56(s,3H);MS(ESI)m/z:452.3[M+1]
+。
实施例36:化合物45的制备
步骤1:化合物45-2的合成:
向化合物45-1(100.0mg,421.57μmol,1eq)的四氢呋喃(1mL)和水(0.2mL)混合溶液中加入一水合氢氧化锂(26.5mg,632.36μmol,1.5eq),反应液20℃搅拌1小时。加入二氯甲烷(5mL)和无水硫酸钠(5.00g),搅拌干燥20分钟,过滤,得到含有化合物45-2的粗品滤液,直接用于下一步反应。
步骤2:化合物45-3的合成:
向化合物45-2(粗品滤液)的二氯甲烷(5mL)溶液中加入三乙胺(84.9mg,839.91μmol,116.91μL,2eq),4-二甲氨基吡啶(513.0μg,4.20μmol,0.01eq)和3-硝基苯磺酰氯(93.0mg,419.95μmol,1eq),反应液在20℃下搅拌16小时。加入水(30mL)稀释,二氯甲烷萃取(30mL×2),合并有机相,有机相使用水洗涤(30mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗产品经制备薄层色谱法(硅胶,石油醚:乙酸乙酯=1:1)分离纯化得到化合物45-3。
步骤3:化合物45-4的合成
向四氢异喹啉(30.0mg,225.24μmol,28.30μL,1eq)和化合物45-3(67.7mg,247.77μmol,1.1eq)的四氢呋喃(3mL)溶液中加入氟化钾(52.3mg,900.97μmol,21.11μL,4eq),反应液在30℃下搅拌16小时。反应液过滤,滤液减压浓缩,粗产品经硅胶柱层析(石油醚:乙酸乙酯=5:1)分离纯化得到化合物45-4。
步骤4:化合物45-5的合成
-70℃下,向乙醇(10mL)中通入氨气15分钟,加入化合物45-4(40.0mg,196.77μmol,1eq),反应液在80℃搅拌2小时。反应液减压浓缩得到粗品45-5直接用于下一步反应。
步骤5:化合物45的合成
向化合物8-4(15.0mg,68.13μmol,1eq)的N,N-二甲基甲酰胺(1.00mL)溶液中加入HATU(28.4mg, 74.94μmol,1.1eq)和二异丙基乙胺(17.6mg,136.25μmol,23.73μL,2eq),反应液19℃搅拌0.2小时,然后加入化合物45-5(20.0mg,90.78μmol,1.33eq),反应液继续搅拌0.1小时。加入水(10mL)稀释,乙酸乙酯萃取(10mL×2),合并有机相,有机相使用水洗涤(10mL),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150*25mm*5μm;流动相:水(0.05%氨水)-乙腈,乙腈%:18%-48%)得到化合物45。
1H NMR(400MHz,CDCl
3)δ=8.27(d,J=2.0Hz,2H),7.32-7.28(m,1H),7.28-7.27(m,1H),7.23-7.17(m,2H),7.06-7.02(m,1H),4.16-4.07(m,1H),3.86(dd,J=6.4,13.6Hz,1H),3.78(br d,J=15.2Hz,1H),3.46-3.38(m,1H),3.12-3.04(m,1H),3.01-2.89(m,3H),2.80-2.71(m,2H),1.54-1.50(m,2H),1.41-1.35(m,2H),1.30(s,3H)。MS(ESI)m/z:423.3[M+1]
+。
实施例37:化合物46a和46b的制备
步骤1:化合物46-2的合成
在0℃温度下,向化合物46-1(20g,148.15mmol,15.27mL,1eq)的无水二氯甲烷(100mL)溶液中,加入间氯过氧苯甲酸(33.08g,162.96mmol,85%含量,1.1eq),反应液置于20℃搅拌12小时。反应液过滤,滤液经饱和亚硫酸钠(100mL)和碳酸氢钠(100mL×2)洗涤,减压浓缩大部分溶剂,得到化合物46-2的二氯甲烷溶液。
1H NMR(400MHz,CDCl
3)δ=3.41-3.35(m,1H),3.34-3.28(m,1H),2.97(dt,J=1.6,6.0Hz,1H),2.92(dq,J=1.6,5.2Hz,1H),1.32(d,J=5.2Hz,3H)。
步骤2:化合物46-3的合成
在0℃温度下,将氢氧化钠(3.00g,75.08mmol,2eq)溶于N,N–二甲基甲酰胺(20mL)溶液中,加入四氢异喹啉(5g,37.54mmol,4.72mL,1eq),在0℃温度下搅拌10分钟,加入化合物46-2(18.38g,45.05 mmol,37%的二氯甲烷溶液,1.2eq),在20℃温度下搅拌1小时。反应液倒入水(100mL)中,用乙酸乙酯(50mL×3)萃取,合并的有机相用水(50mL×3)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:1)得到化合物46-3。
步骤3:化合物46-4的合成
将化合物46-3(2.2g,10.82mmol,1eq)溶于无水乙醇(10mL)溶液中,加入氨水(27.30g,194.75mmol,30mL,25%纯度,17.99eq),反应液放入闷罐中,置于100℃搅拌10小时,反应液减压浓缩,经反相制备分离(色谱柱:Waters Xbridge BEH C18 250×50mm×10μm;流动相:[水(0.05%氢氧化铵(v/v))-乙腈];乙腈%:25%-55%,高效液相柱的保留时间为17分钟)得到化合物46-4粗品。
步骤4:化合物46a和46b的合成
将化合物8-4(0.1g,454.17μmol,1eq)溶于N,N-二甲基甲酰胺(1mL),加入HATU(189.96mg,499.59μmol,1.1eq)和二异丙基乙胺(70.44mg,545.01μmol,94.93μL,1.2eq)。反应液在20℃搅拌10分钟,然后向其中加入化合物46-4(150.09mg,681.26μmol,1.5eq),反应液在20℃搅拌0.5小时。粗品经制备型高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75×30mm×3μm;流动相:[水(0.05%氢氧化铵(v/v))-乙腈];乙腈%:12%-42%,高效液相柱的保留时间为10分钟),经第一次手性分离纯化(手性色谱柱:DAICEL CHIRALCEL OJ(250mm×30mm,10μm);流动相:流动相A为二氧化碳,流动性B为0.1%氨水的甲醇溶液;梯度:B%:30%-30%,循环时间2分钟,持续时间100分钟)得到化合物46a和46b的混合物(分析条件:手性色谱柱:CHIRALCEL OJ-3(50mm×4.6mm,3μm);流动相:流动相A为CO
2,流动性B为0.05%二乙胺的甲醇溶液;梯度:B%:5%-40%,经分析两个峰保留时间分别为1.784分钟和1.849分钟,相隔太近未完全分离);再经第二次手性分离纯化(手性色谱柱:DAICEL CHIRALPAK AD(250mm×30mm,10μm,流动相:流动相A为二氧化碳,流动性B为0.1%氨水乙醇溶液;梯度:B%:70%-70%,循环时间5.7分钟,持续时间60分钟)得到化合物46a和化合物46b。
化合物46b(手性分析条件:色谱柱:Chiralpak AD-3 50×4.6mm,3μm,流动相:流动相A为CO
2,流动相B为乙醇(0.05%二乙胺);梯度:B%:60%,保留时间为1.078分钟,手性纯度=100%):
1H NMR(400MHz,CDCl
3)δ=8.27(s,1H),7.84(s,1H),7.70(d,J=8.2Hz,1H),7.23-7.08(m,4H),7.03(br d,J=7.4Hz,1H),4.33-4.29(m,1H),4.17-4.12(m,1H),4.06(d,J=15.2Hz,1H),3.83(d,J=15.2Hz,1H),3.14-3.04(m,2H),3.01-2.95(m,2H),2.86-2.81(m,2H),1.50-1.46(m,2H),1.36-1.32(m,2H),1.28(d,J=6.8Hz,3H);MS(ESI)m/z:423.4[M+H]
+。
化合物46a(手性分析条件:色谱柱:Chiralpak AD-3 50×4.6mm,3μm,流动相:流动相A为CO
2,流动相B为乙醇(0.05%二乙胺);梯度:B%:60%,保留时间为2.380分钟,手性纯度=100%):
1H NMR(400MHz,CDCl
3)δ=8.35(s,1H),7.88(s,1H),7.82(brs,1H),7.25-7.14(m,3H),7.07(d,J=7.2Hz,1H),4.32-4.22 (m,3H),4.06(d,J=14.4Hz,1H),3.32–3.18(m,2H),3.10–2.96(m,4H),1.50-1.38(m,2H),1.34-1.24(m,5H);MS(ESI)m/z:423.4[M+H]
+。
实施例38:化合物47的制备
步骤1:化合物47-1的合成
在25℃条件下,向化合物32-1(0.5g,2.30mmol,1eq)和化合物7-2(267.39mg,2.30mmol,1eq)的四氢呋喃(10mL)溶液中加入碳酸铯(2.25g,6.91mmol,3.0eq),反应液升温至45℃搅拌2小时,然后向反应液中加入甲醇钠(373.22mg,6.91mmol,3.0eq),反应液升温至60℃搅拌24小时。反应液经硅藻土过滤,滤液减压浓缩,得到粗品化合物47-1。
步骤2:化合物47-2的合成
在80℃条件下,向化合物47-1(0.630g,1.94mmol,1eq)和氯化铵(518.02mg,9.68mmol,5eq)的乙醇(200mL),水(10mL)溶液中加入铁粉(540.82mg,9.68mmol,5eq),反应液搅拌反应12小时。反应液经硅藻土过滤,滤液加水稀释(15mL),乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚:乙酸乙酯=5/1-1/1),得到化合物47-2。
步骤3:化合物47-3的合成
在25℃条件下,向化合物47-2(0.5g,1.90mmol,1eq)的甲醇(20mL)和水(2mL)溶液中加入一水氢氧化锂(398.49mg,9.50mmol,5eq),反应液升温至45℃搅拌12小时。反应液加稀盐酸(1mol/L)调节pH至3,乙酸乙酯萃取(15mL×3),合并有机相,饱和食盐水洗涤(15mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物47-3。
1H NMR(400MHz,DMSO-d
6)δ=12.42(br s,1H),10.73(s,1H),7.34(s,1H),6.68(s,1H),3.74(s,3H),1.32-1.25(m,2H),1.21-1.15(m,2H).
步骤4:化合物47的合成
在25℃条件下,向化合物47-3(0.050g,200.63μmol,1eq)的N,N-二甲基甲酰胺(2mL)溶液中加入HATU(91.54mg,240.75μmol,1.2eq)和二异丙基乙基胺(38.89mg,300.94μmol,52.42μL,1.5eq),搅拌10分钟,然后向反应中加入化合物BB-1(62.08mg,300.94μmol,1.5eq),反应液继续搅拌12小时。反应液加水稀释(10mL),乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱:Phenomenex Gemini-NX C18 75×30mm×3μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:2%-52%),得到化合物47。
MS(ESI)m/z:438.0[M+H]
+;
1H NMR(400MHz,DMSO-d
6)δ=8.23(t,J=5.2Hz,1H),7.55(s,1H),7.13-7.07(m,3H),7.05-6.98(m,1H),6.72(s,1H),4.94(d,J=4.8Hz,1H),3.95-3.84(m,1H),3.79(s,3H),3.65-3.57(m,2H),3.55-3.46(m,1H),3.28-3.21(m,1H),2.86-2.76(m,3H),2.75-2.65(m,3H),1.34-1.27(m,2H),1.22-1.13(m,2H)。
实施例39:化合物48a和48b的制备
步骤1:化合物48-2的合成
在25℃条件下,向化合物32-1(0.5g,2.30mmol,1eq)和化合物48-1(390.24mg,3.45mmol,1.5eq)的四氢呋喃(10mL)溶液中加入碳酸铯(1.50g,4.60mmol,2.0eq),反应液搅拌12小时,然后反应液升温至45℃搅拌12小时,反应液加水稀释(10mL),乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩。粗品经柱层析分离纯化(石油醚/乙酸乙酯=3/1-1/1),得到化合物48-2。
1H NMR(400MHz,CDCl
3)δ=8.62(d,J=7.6Hz,1H),7.15(d,J=10.8Hz,1H),4.34(s,2H),4.13(dd,J=6.4,7.4Hz,2H),3.98(s,3H),2.77-2.70(m,2H)。
步骤2:化合物48-3的合成
在25℃条件下,向化合物48-2(0.166g,535.08μmol,1eq)的四氢呋喃(10mL)溶液中加入甲醇钠(144.53mg,2.68mmol,5eq),反应液升温至45℃搅拌12小时。反应液经硅藻土过滤,滤液减压浓缩。粗品经柱层析分离纯化(石油醚:乙酸乙酯=3:1-1:1),得到化合物48-3。
步骤3:化合物48-4的合成
在25℃条件下,向化合物48-3(0.158g,490.27μmol,1eq)的乙醇(5mL)和水(5mL)溶液中加入氯化铵(131.13mg,2.45mmol,5eq),反应液升温至80℃,然后向其中缓慢加入铁粉(136.90mg,2.45mmol,5eq),在80℃搅拌12小时。反应液经硅藻土过滤,滤液用乙酸乙酯萃取(10mL×3),合并有机相,有机相经饱和食盐水洗涤(10mL),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物48-4。
1H NMR(400MHz,DMSO-d
6)δ=10.86(s,1H),7.33(s,1H),6.83(s,1H),4.04-3.95(m,2H),3.94-3.85(m,2H),3.81(s,3H),3.75(s,3H),2.46-2.38(m,1H),2.26-2.09(m,1H)。
步骤4:化合物48-5的合成
在25℃条件下,向化合物48-4(0.107g,364.85μmol,1eq)的四氢呋喃(4mL),水(2mL)和甲醇(5mL)溶液中加入一水合氢氧化锂(45.93mg,1.09mmol,3eq),反应液升温至45℃搅拌12小时。反应液调节pH值至6,乙酸乙酯萃取(20mL×2),合并有机相,有机相经无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物48-5。
步骤5:化合物48a和48b的合成
在25℃条件下,向化合物48-5(0.045g,161.15μmol,1eq)的N,N-二甲基甲酰胺(2mL)溶液中加入HATU(91.54mg,240.75μmol,1.2eq)和二异丙基乙基胺(31.24mg,241.72μmol,42.10μL,1.5eq),搅拌10分钟,然后向反应中加入化合物BB-1(49.86mg,241.72μmol,1.5eq),反应液继续搅拌12小时。反应液加水稀释(10mL),乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤(10mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150×25mm×5μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:25%-55%),再经SFC分离纯化(色谱柱:DAICEL CHIRALCEL OJ(250mm×30mm,10μm);流动相:A相:二氧化碳,B相:[0.1%氨水-甲醇];梯度:B%:35%-35%,3.0min;130min),得到化合物48a和48b。
化合物48a:(手性分析条件:色谱柱:OJ-3 50×4.6mm,I.D.3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);梯度:B%:5%~40%,保留时间为2.075分钟,手性纯度=100%);MS(ESI)m/z:468.0[M+H]
+;
1H NMR(400MHz,CD
3OD)δ=7.59(s,1H),7.17-7.05(m,3H),7.03-6.98(m,1H),6.81(s,1H), 4.15-4.04(m,3H),4.02-3.96(m,2H),3.88(s,3H),3.72(s,2H),3.62(dd,J=4.8,13.6Hz,1H),3.43(dd,J=6.6,13.6Hz,1H),2.94-2.88(m,2H),2.87-2.81(m,2H),2.64(d,J=6.4Hz,2H),2.57-2.44(m,1H),2.32-2.19(m,1H)。
化合物48b:(手性分析条件:色谱柱:OJ-3 50×4.6mm,I.D.3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);梯度:B%:5%~40%,保留时间为2.185分钟,手性纯度=98.19%);MS(ESI)m/z:468.0[M+H]
+;
1H NMR(400MHz,CD
3OD)δ=7.59(s,1H),7.14-7.06(m,3H),7.01(br d,J=6.0Hz,1H),6.80(s,1H),4.15-4.04(m,3H),4.02-3.95(m,2H),3.88(s,3H),3.71(s,2H),3.63(dd,J=4.6,13.6Hz,1H),3.42(dd,J=6.8,13.6Hz,1H),2.93-2.80(m,4H),2.63(d,J=6.0Hz,2H),2.56-2.42(m,1H),2.31-2.21(m,1H)。
实施例40:化合物49a和49b的制备
步骤1:化合物49-2的合成
将化合物49-1(3.5g,14.43mmol,1eq)的盐酸(50mL,5mol/L)和二氧六环(5mL)溶液置于100℃搅拌12小时。反应液冷却至室温,过滤,滤饼加水洗涤,干燥,得到化合物49-2。
步骤2:化合物49-3的合成
在0℃条件,氮气氛围下,向化合物49-2(3g,13.39mmol,1eq)的N,N-二甲基甲酰胺(50mL)溶液中分批加入钠氢(803.30mg,20.08mmol,60%纯度,1.5eq)和对甲氧基苄氯(2.52g,16.07mmol,2.19mL,1.2eq),反应液升温至25℃继续搅拌12小时。反应液加饱和氯化铵溶液淬灭(30mL),乙酸乙酯萃取(20mL×3),合并有机相,饱和食盐水洗涤(20mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚/乙酸乙酯=5/1-1/1),得到化合物49-3。
1H NMR(400MHz,CDCl
3)δ=7.67(d,J=9.6Hz,1H),7.49(d,J=1.6Hz,1H),7.41(d,J=8.0Hz,1H),7.30(dd,J=1.8,8.0Hz,1H),7.23-7.15(m,2H),6.89-6.83(m,2H),6.79(d,J=9.6Hz,1H),5.44(br s,2H),3.78(s,3H)。
步骤3:化合物49-4的合成
在0℃条件下,向三甲基碘化亚砜(1.92g,8.72mmol,3eq)的四氢呋喃(10mL)溶液中加入正丁基锂(2.5M,3.49mL,3eq),搅拌30分钟后,向反应液中加入化合物49-3(1g,2.91mmol,1eq)的四氢呋喃(10mL)溶液,反应液升温至25℃搅拌12小时。反应液加饱和氯化铵溶液(40mL)淬灭,乙酸乙酯萃取(30mL×3),合并有机相,有机相经饱和食盐水洗涤(30mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚/乙酸乙酯=3/1-1/1),得到化合物49-4。
1H NMR(400MHz,CDCl
3)δ=7.21(d,J=8.0Hz,1H),7.13(d,J=8.8Hz,2H),7.09(dd,J=2.0,8.0Hz,1H),7.02(d,J=1.6Hz,1H),6.89-6.82(m,2H),5.29–5.12(m,1H),5.02-4.83(m,1H),3.79(s,3H),2.59-2.48(m,1H),2.46–2.36(m,1H),1.71–1.60(m,1H),0.67(q,J=5.2Hz,1H)。
步骤4:化合物49-5的合成
在氮气氛围下,向化合物49-4(1g,2.79mmol,1eq)和三乙胺(621.44mg,6.14mmol,854.79μL,2.2eq)的N,N-二甲基甲酰胺(10mL),甲醇(5mL)溶液的高压釜中加入Pd(dppf)Cl
2(306.38mg,418.73μmol,0.15eq),然后用一氧化碳置换,最后在100℃,一氧化碳氛围(2MPa)条件下继续搅拌反应24小时。反应液经硅藻土过滤,滤液加水稀释(20mL),乙酸乙酯萃取(20mL×3),合并有机相,有机相经饱和食盐水洗涤(20mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经柱层析分离纯化(石油醚/乙酸乙酯=3/1),得到化合物49-5。
步骤5:化合物49-6的合成
将化合物49-5(0.75g,2.22mmol,1eq)的三氟乙酸溶液(10mL)置于70℃搅拌反应12小时。反应液缓慢倒入饱和碳酸氢钠溶液(150mL),乙酸乙酯萃取(40mL×3),合并有机相,有机相经饱和食盐水洗涤(40mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物49-6。
1H NMR(400MHz,CDCl
3)δ=7.69(dd,J=1.6,8.0Hz,1H),7.53(br s,1H),7.44(d,J=8.0Hz,1H),7.37(d,J=1.6Hz,1H),3.92(s,3H),2.62-2.50(m,1H),2.31-2.20(m,1H),1.78–1.69(m,1H),0.79(q,J=4.8Hz,1H)。
步骤6:化合物49-7的合成
在25℃条件下,向化合物49-6(0.7g,3.22mmol,1eq)的甲醇(12mL),四氢呋喃(12mL)和水(3mL)溶液中加入一水合氢氧化锂(676.09mg,16.11mmol,5eq),反应液升温至45℃搅拌1小时。反应液用稀盐酸(1mol/L)调节pH值至5,乙酸乙酯萃取(25mL×3),合并有机相,有机相经饱和食盐水洗涤(25mL×2),无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品化合物49-7。
步骤7:化合物49a和49b的合成
在25℃条件下,向化合物49-7(0.7g,3.44mmol,1eq)的N,N-二甲基甲酰胺(10mL)溶液中加入HATU(1.57g,4.13mmol,1.2eq)和二异丙基乙基胺(667.86mg,5.17mmol,900.08μL,1.5eq),搅拌10分钟,然后向反应液中加入化合物BB-1(746.18mg,3.62mmol,1.05eq),反应液继续搅拌12小时。反应液减压 浓缩,粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge BEH C18 250×50mm×10μm;流动相:[水(10mM碳酸氢铵)-乙腈];乙腈%:20%-50%),再经SFC分离纯化(色谱柱:DAICEL CHIRALPAK AS(250mm×30mm,10μm);流动相:A相:二氧化碳,B相:[0.1%氨水-甲醇];梯度:B%:55%-55%,4.1min;80min),得到化合物49a和49b。
化合物49a:(手性分析条件:色谱柱:Chiralpak AS-3 50×4.6mm I.D 3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);梯度:B%:5%~40%,保留时间为1.785分钟,手性纯度=100%,
1H NMR(400MHz,CD
3OD)δ=7.35(d,J=1.0Hz,2H),7.28(s,1H),7.15-7.07(m,3H),7.05-7.00(m,1H),4.10(quin,J=6.0Hz,1H),3.74(s,2H),3.48(dq,J=6.0,13.6Hz,2H),2.94-2.83(m,4H),2.71-2.57(m,3H),2.20-2.08(m,1H),1.78-1.69(m,1H),0.59(q,J=4.8Hz,1H),MS(ESI)m/z:392.0[M+H]
+。
化合物49b:(手性分析条件:色谱柱:Chiralpak AS-3 50×4.6mm I.D 3μm,流动相:流动相A为CO
2,流动相B为甲醇(0.05%二乙胺);梯度:B%:5%~40%,保留时间为2.246分钟,手性纯度=99.78%,
1H NMR(400MHz,CD
3OD)δ=7.35(s,2H),7.28(s,1H),7.15-7.07(m,3H),7.05-6.98(m,1H),4.09(quin,J=6.0Hz,1H),3.73(s,2H),3.56-3.39(m,2H),3.00-2.80(m,4H),2.74-2.56(m,3H),2.19-2.09(m,1H),1.79-1.69(m,1H),0.59(q,J=4.8Hz,1H),MS(ESI)m/z:392.0[M+H]
+。
实施例41:化合物46a二水合物的单晶X射线衍射检测分析
在室温条件下,将化合物46a(16mg)溶解于二氯甲烷/甲苯/乙醇(1.2mL,1:2:1,v/v/v)中,溶液置于4mL半密封样品瓶中,在室温条件下缓慢挥发,第二天得到无色针状晶体。收集晶体,用XtaLAB Synergy-S衍射仪收集衍射强度数据。单晶数据显示,单晶为化合物46a的二水合物,可以确定化合物46a的绝对构型。化合物46a二水合物的立体结构椭球图见附图10。化合物46a二水合物的晶体结构数据和参数见表7、8、9、10、11和12。
表7化合物46a二水合物的晶体数据
Atom | x | y | z | U(eq) |
O(2) | 7182(3) | 2849.3(8) | 3030.7(6) | 27.5(3) |
O(1) | 1970(3) | 4587.4(7) | 3626.5(5) | 24.5(3) |
O(3) | 1232(3) | 18.6(7) | 3798.1(6) | 30.2(3) |
O(5) | -3350(3) | 2533.0(8) | 4714.5(6) | 29.2(3) |
O(4) | -4203(3) | 499.3(8) | 4719.6(6) | 31.9(3) |
N(3) | 4041(3) | 732.6(9) | 3316.8(6) | 23.6(3) |
N(1) | 7488(3) | 5566.0(9) | 3401.1(6) | 20.7(3) |
N(2) | 2872(3) | 3265.1(9) | 3020.2(6) | 22.0(3) |
O(6) | -994(4) | 3765.1(10) | 4360.4(6) | 52.3(5) |
N(4) | -1345(3) | 1235.6(9) | 4258.0(6) | 23.8(4) |
C(14) | 4741(4) | 2755.7(11) | 3122.0(7) | 21.0(4) |
C(21) | -937(4) | -76.2(11) | 4170.3(7) | 22.6(4) |
C(18) | 758(4) | 1322.6(11) | 3881.6(7) | 20.8(4) |
C(16) | 3724(4) | 2043.9(10) | 3338.9(7) | 20.6(4) |
C(17) | 1598(4) | 1999.7(10) | 3710.3(7) | 20.7(4) |
C(2) | 9985(4) | 6751.4(11) | 3493.1(8) | 23.6(4) |
C(19) | 2022(4) | 705.0(11) | 3662.5(7) | 20.9(4) |
C(10) | 5314(4) | 5238.4(10) | 3071.2(7) | 20.3(4) |
C(20) | -2305(4) | 575.9(11) | 4405.5(7) | 22.9(4) |
C(1) | 8183(4) | 6273.4(10) | 3152.4(8) | 23.3(4) |
C(9) | 6575(4) | 5689.4(11) | 3963.8(7) | 24.1(4) |
C(15) | 4889(4) | 1400.3(11) | 3163.3(7) | 22.0(4) |
C(6) | 11904(4) | 7103.6(11) | 4346.7(9) | 29.9(4) |
C(12) | 3588(4) | 3985.3(10) | 2807.4(7) | 21.2(4) |
C(11) | 4267(4) | 4504.7(10) | 3277.0(7) | 20.2(4) |
C(4) | 13004(4) | 7787.2(12) | 3550.3(10) | 34.6(5) |
C(7) | 10253(4) | 6633.9(11) | 4046.8(8) | 24.5(4) |
C(3) | 11349(4) | 7332.4(11) | 3250.4(9) | 28.4(4) |
C(5) | 13286(4) | 7668.6(12) | 4103.9(9) | 34.1(5) |
C(13) | 1329(4) | 4268.1(12) | 2448.8(8) | 28.5(4) |
C(8) | 8886(4) | 5989.6(12) | 4304.2(7) | 27.1(4) |
C(22) | -698(5) | -732.8(13) | 4526.7(9) | 38.6(5) |
C(23) | -2631(4) | -732.1(12) | 4070.4(10) | 36.7(5) |
表10化合物46a二水合物的键角(°)
Atom Atom | Angle/° | Atom Atom | Angle/° |
C(19)O(3)C(21) | 119.29(15) | O(3)C(19)C(18) | 121.47(16) |
C(19)N(3)C(15) | 117.05(16) | N(3)C(19)O(3) | 114.50(16) |
C(10)N(1)C(9) | 111.13(14) | N(3)C(19)C(18) | 124.03(17) |
C(1)N(1)C(10) | 107.15(14) | N(1)C(10)C(11) | 114.76(15) |
C(1)N(1)C(9) | 109.28(15) | O(4)C(20)N(4) | 122.93(18) |
C(14)N(2)C(12) | 121.93(15) | O(4)C(20)C(21) | 120.23(17) |
C(20)N(4)C(18) | 122.80(16) | N(4)C(20)C(21) | 116.84(16) |
O(2)C(14)N(2) | 122.83(18) | N(1)C(1)C(2) | 114.41(15) |
O(2)C(14)C(16) | 120.87(18) | N(1)C(9)C(8) | 110.33(15) |
N(2)C(14)C(16) | 116.27(16) | N(3)C(15)C(16) | 123.68(16) |
O(3)C(21)C(20) | 119.81(16) | C(5)C(6)C(7) | 121.3(2) |
O(3)C(21)C(22) | 114.87(17) | N(2)C(12)C(11) | 109.67(15) |
O(3)C(21)C(23) | 114.52(16) | N(2)C(12)C(13) | 109.87(15) |
C(20)C(21)C(22) | 116.62(16) | C(13)C(12)C(11) | 113.10(16) |
C(23)C(21)C(20) | 117.17(17) | O(1)C(11)C(10) | 112.14(15) |
C(23)C(21)C(22) | 59.56(16) | O(1)C(11)C(12) | 110.40(14) |
C(17)C(18)N(4) | 122.03(18) | C(10)C(11)C(12) | 111.37(15) |
C(17)C(18)C(19) | 118.23(16) | C(3)C(4)C(5) | 119.6(2) |
C(19)C(18)N(4) | 119.72(17) | C(2)C(7)C(6) | 118.87(19) |
C(17)C(16)C(14) | 122.61(17) | C(2)C(7)C(8) | 119.75(18) |
C(15)C(16)C(14) | 119.27(16) | C(6)C(7)C(8) | 121.31(18) |
C(15)C(16)C(17) | 118.12(17) | C(4)C(3)C(2) | 120.8(2) |
C(18)C(17)C(16) | 118.82(17) | C(6)C(5)C(4) | 119.7(2) |
C(7)C(2)C(1) | 121.16(18) | C(7)C(8)C(9) | 112.69(16) |
C(7)C(2)C(3) | 119.72(19) | C(23)C(22)C(21) | 59.84(14) |
C(3)C(2)C(1) | 119.10(18) | C(22)C(23)C(21) | 60.60(14) |
表11化合物46a二水合物的扭转角度(°)
A-B-C-D | Angle/° | A-B-C-D | Angle/° |
O(2)-C(14)-C(16)-C(17) | 143.69(19) | C(10)-N(1)-C(9)-C(8) | 177.03(16) |
O(2)-C(14)-C(16)-C(15) | -37.2(3) | C(20)-N(4)-C(18)-C(17) | 175.83(17) |
O(3)-C(21)-C(20)-O(4) | 178.80(17) | C(20)-N(4)-C(18)-C(19) | -2.9(3) |
O(3)-C(21)-C(20)-N(4) | -1.5(3) | C(20)-C(21)-C(22)-C(23) | 107.3(2) |
O(3)-C(21)-C(22)-C(23) | -104.96(19) | C(20)-C(21)-C(23)-C(22) | -106.41(19) |
O(3)-C(21)-C(23)-C(22) | 105.6(2) | C(1)-N(1)-C(10)-C(11) | -178.48(15) |
N(1)-C(10)-C(11)-O(1) | 92.81(18) | C(1)-N(1)-C(9)-C(8) | -64.9(2) |
N(1)-C(10)-C(11)-C(12) | -142.91(16) | C(1)-C(2)-C(7)-C(6) | -178.57(17) |
N(1)-C(9)-C(8)-C(7) | 50.4(2) | C(1)-C(2)-C(7)-C(8) | 4.4(3) |
N(2)-C(14)-C(16)-C(17) | -38.2(2) | C(1)-C(2)-C(3)-C(4) | 179.46(19) |
N(2)-C(14)-C(16)-C(15) | 140.91(18) | C(9)-N(1)-C(10)-C(11) | -59.2(2) |
N(2)-C(12)-C(11)-O(1) | -60.76(19) | C(9)-N(1)-C(1)-C(2) | 48.3(2) |
N(2)-C(12)-C(11)-C(10) | 173.98(14) | C(15)-N(3)-C(19)-O(3) | 179.26(16) |
N(4)-C(18)-C(17)-C(16) | 179.35(16) | C(15)-N(3)-C(19)-C(18) | -1.0(3) |
N(4)-C(18)-C(19)-O(3) | 1.2(3) | C(15)-C(16)-C(17)-C(18) | -0.3(3) |
N(4)-C(18)-C(19)-N(3) | -178.55(17) | C(6)-C(7)-C(8)-C(9) | 162.85(18) |
C(14)-N(2)-C(12)-C(11) | -87.1(2) | C(12)-N(2)-C(14)-O(2) | -2.0(3) |
C(14)-N(2)-C(12)-C(13) | 148.02(17) | C(12)-N(2)-C(14)-C(16) | 179.97(15) |
C(14)-C(16)-C(17)-C(18) | 178.87(16) | C(7)-C(2)-C(1)-N(1) | -18.7(3) |
C(14)-C(16)-C(15)-N(3) | -177.08(17) | C(7)-C(2)-C(3)-C(4) | 1.1(3) |
C(21)-O(3)-C(19)-N(3) | 179.92(15) | C(7)-C(6)-C(5)-C(4) | 1.3(3) |
C(21)-O(3)-C(19)-C(18) | 0.2(3) | C(3)-C(2)-C(1)-N(1) | 163.03(17) |
C(18)-N(4)-C(20)-O(4) | -177.38(17) | C(3)-C(2)-C(7)-C(6) | -0.3(3) |
C(18)-N(4)-C(20)-C(21) | 2.9(3) | C(3)-C(2)-C(7)-C(8) | -177.31(18) |
C(17)-C(18)-C(19)-O(3) | -177.57(17) | C(3)-C(4)-C(5)-C(6) | -0.4(3) |
C(17)-C(18)-C(19)-N(3) | 2.7(3) | C(5)-C(6)-C(7)-C(2) | -0.9(3) |
C(17)-C(16)-C(15)-N(3) | 2.1(3) | C(5)-C(6)-C(7)-C(8) | 176.05(19) |
C(2)-C(7)-C(8)-C(9) | -20.2(3) | C(5)-C(4)-C(3)-C(2) | -0.8(3) |
C(19)-O(3)-C(21)-C(20) | 0.0(3) | C(13)-C(12)-C(11)-O(1) | 62.2(2) |
C(19)-O(3)-C(21)-C(22) | -146.62(19) | C(13)-C(12)-C(11)-C(10) | -63.0(2) |
C(19)-O(3)-C(21)-C(23) | 147.10(18) | C(22)-C(21)-C(20)-O(4) | -35.2(3) |
C(19)-N(3)-C(15)-C(16) | -1.5(3) | C(22)-C(21)-C(20)-N(4) | 144.54(19) |
C(19)-C(18)-C(17)-C(16) | -1.9(3) | C(23)-C(21)-C(20)-O(4) | 32.5(3) |
C(10)-N(1)-C(1)-C(2) | 168.81(15) | C(23)-C(21)-C(20)-N(4) | -147.78(18) |
表12化合物46a二水合物的氢键
实施例42:化合物46a的A晶型和B晶型的制备
A晶型的制备:将化合物46a(5g)溶于乙酸乙酯(50mL)溶液中,加入正庚烷(150mL),在25℃下搅拌72小时。过滤,收集滤饼,真空干燥得到固体,经XRPD检测为化合物46a的A晶型。
B晶型的制备:将化合物46a(20.8mg)溶于四氢呋喃(3.0mL)中,在室温下缓慢挥发得到固体,经XRPD检测为化合物46a的B晶型。
实施例43:化合物46a的A晶型的吸湿性研究
仪器:SMS DVS intrinsic动态水分吸附仪。取化合物46a的A晶型(约10mg)置于DVS样品盘内进行测试。化合物46a的A晶型的DVS谱图如图6所示,化合物46a的A晶型在25℃/80%RH下的吸湿增重ΔW%=0.8%,2%>ΔW%≥0.2%,略有吸湿性。
生物测试数据:
实验例1:PRMT5酶抑制活性试验
实验目的:测试化合物对PRMT5酶活性的抑制作用
实验材料:PRMT5酶
实验操作:使用LABCYTE Echo 550将测试化合物以一定浓度(0.17nM-99010nM)加入白色透明底384孔板中,加入PRMT5,设置溶媒对照(加入DMSO,不含化合物)和空白对照(加入DMSO,不含PRMT5)。在25℃孵育30分钟,然后加入底物,在25℃反应90分钟。90分钟后采用PerkinElmer LANCE Ultra TR-FRET标准方法,将检测试剂加入384孔板中,使其与酶-底物反应产物相结合,在25℃下反应1小时后,在PerkinElmer EnVision 2105 Multimode Plate Reader读板器上检测信号。原始数据用下列公式来计算检测化合物的抑制率:
将抑制率分别导入Excel中计算不同浓度化合物的抑制率,然后用XLfit软件作抑制曲线图和计算相关参数,包括最小抑制率,最大抑制率及IC
50。结果见表13。
表13本发明化合物抑制PRMT5酶活性结果
受试化合物 | IC 50(nM) | 受试化合物 | IC 50(nM) |
化合物1 | 20 | 化合物35 | 11 |
化合物2 | 128 | 化合物36 | 7 |
化合物3 | 18 | 化合物37 | 8 |
化合物4 | 22 | 化合物39 | 34 |
化合物8 | 15 | 化合物40 | 34 |
化合物9 | 36 | 化合物46a | 58 |
化合物23 | 18 | 化合物47 | 42 |
化合物24 | 15 | 化合物48a | 46.2 |
化合物29 | 16 | 化合物48b | 34.2 |
化合物34 | 13 | 化合物49b | 26.2 |
结论:本发明化合物能有效抑制PRMT5酶活性。
实验例2:Z-138细胞体外抗增殖试验
实验目的:测试化合物对Z-138非霍奇金淋巴瘤细胞抗增殖作用
实验材料:Z-138非霍奇金淋巴瘤细胞(ATCC-CRL-3001)
实验操作:将Z-138细胞以800个细胞每孔的密度种入白色透明底384孔细胞培养板中,当天将测试化合物以一定浓度(2.5nM-50000nM)加入到细胞培养孔中,设置溶媒对照(加入DMSO,不含化合物)和空 白对照(加入DMSO,不含细胞)。培养板在37℃,CO
2及100%相对湿度培养6天。采用Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7571)标准方法处理样品,在TECAN
10M读板器上检测发光信号。原始数据用下列公式来计算检测化合物的抑制率:
将抑制率分别导入Excel中计算不同浓度化合物的抑制率,然后用XLfit软件作抑制曲线图和计算相关参数,包括最小抑制率,最大抑制率及IC
50。结果见表14。
表14本发明化合物体外Z-138肿瘤细胞抗增殖活性结果
受试化合物 | IC 50(nM) | 受试化合物 | IC 50(nM) |
化合物1 | 54 | 化合物26 | 22 |
化合物2 | 24 | 化合物27 | 4 |
化合物3 | 78 | 化合物28 | 10 |
化合物4 | 22 | 化合物29 | 6 |
化合物6 | 6 | 化合物32 | 19 |
化合物7 | 73 | 化合物34 | 27 |
化合物8 | 10 | 化合物35 | 22 |
化合物9 | 100 | 化合物36 | 7 |
化合物10 | 23 | 化合物37 | 8 |
化合物11 | 88 | 化合物38 | 18 |
化合物13 | 47 | 化合物39 | 12 |
化合物14 | 14 | 化合物40 | 4 |
化合物16 | 90 | 化合物41 | 124 |
化合物17 | 13 | 化合物42 | 53 |
化合物18 | 18 | 化合物43 | 17 |
化合物19 | 8 | 化合物44 | 18 |
化合物20 | 15 | 化合物46a | 11 |
化合物21 | 18 | 化合物47 | 66.8 |
化合物22 | 12 | 化合物48a | 29.3 |
化合物23 | 23 | 化合物48b | 11.5 |
受试化合物 | IC 50(nM) | 受试化合物 | IC 50(nM) |
化合物24 | 22 | 化合物49b | 13.1 |
化合物25 | 22 | - | - |
结论:本发明化合物能有效抑制非霍奇金淋巴瘤细胞的增殖。
实验例3:MDA-MB-468细胞抗增殖活性评价
实验目的:测试化合物对MDA-MB-468人乳腺癌细胞的抗增殖作用
实验材料:
细胞株MDA-MB-468(购自普诺赛)、盘尼西林/链霉素抗生素(购自维森特),胎牛血清(购自Gibco)。CellTiter-Glo(细胞活率化学发光检测试剂,购自Promega)。
实验操作:
将MDA-MB-468细胞种于白色384孔板中,40μL细胞悬液每孔,其中包含1000个MDA-MB-468细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进3倍稀释至第10个浓度,即从2000μM稀释至101.61nM,设置双复孔实验。向中间板中加入78μL培养基,再按照对应位置,转移2μL每孔的梯度稀释化合物至中间板,混匀后转移10μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.51nM。细胞板置于二氧化碳培养箱中培养7天。另准备一块细胞板,在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入10μL细胞活率化学发光检测试剂,室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。加入化合物的细胞板结束孵育后,向细胞板中加入每孔10μL的细胞活率化学发光检测试剂,室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
数据分析:
利用方程式(Sample-Min)/(Max-Min)*100%将原始数据换算成抑制率,IC
50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。结果见表15。
表15本发明化合物体外MDA-MB-468肿瘤细胞抗增殖活性结果
受试化合物 | IC 50(nM) | 受试化合物 | IC 50(nM) |
化合物8 | 12 | 化合物46a | 5 |
化合物39 | 12 | 化合物49b | 4.2 |
化合物40 | 3 | - | - |
结论:本发明化合物能有效抑制三阴性乳腺癌细胞的增殖。
实验例4:本发明化合物的药代动力学评价
实验目的:研究化合物在CD-1小鼠体内药代动力学
动物实验设计:雄性CD-1小鼠(28.08-29.01克,6-7周),购自上海市计划生育科学研究所,n=2/组,共4只,采血时间点(h):0.083(仅静脉推注)、0.25(仅灌胃)、0.5、1、2、4、8、10和24,通过尾静脉注射化合物剂量为1mg/kg,单次灌胃剂量为5mg/kg,静脉和灌胃给药溶媒20%N,N-二甲基乙酰胺水溶液、20%羟丙基-β-环糊***溶液、5%DMSO/50%PEG400/45%注射用水或10%的solutol/30%PEG400/60%的注射用水。所有动物实验期间自由饮水,给药前过夜禁食,给药后4小时恢复供食。整个动物实验符合Institutional Animal Care and Use Committee(IACUC)动物福利。
样品采集及储存:完成给药后,从小鼠的隐静脉每个时间点采集约0.03mL到预冷冻的商用EDTA-K2试管中,并放置在湿冰上直到离心。血液样本将在4℃,3200g条件下,离心10分钟,分别收集血浆,转移到预先标记的96孔板中,在干冰上快速冷冻,保存在-70±10℃,直到LC-MS/MS分析。
血浆样品前处理:取3μL未知、标准曲线、质控、稀释质控和单、双空白样品于1.5mL管,添加60μL内标溶液(内标:拉贝洛尔100ng/mL的乙腈溶液,双空白添加相同体积的纯乙腈),至少涡旋15秒,在12000g,4℃条件下离心15分钟。取出50μL上清于干净的96孔板,加入200μL 70%乙腈,在800rpm条件下涡旋10分钟,在3220g,4℃条件下离心5分钟,取2.0μL上清用LC-MS/MS分析。稀释10倍样品处理过程:取2μL样本加入18μL空白基质;稀释2倍样品处理过程:取2μL样本加入2μL空白基质。血浆处理方式与不稀释样品处理方式一致。线性范围为4.00-6000nM。将用Triple Quad 6500 Plus分析血药浓度,并用Phoenix WinNonlin 6.3计算药代参数。结果见表16:
表16本发明化合物的药代动力学测试结果
结论:本发明化合物表现出很好的血浆暴露量和合理的口服生物利用度。
实验例5:本发明化合物的体内药效学评价
实验目的:本试验使用人套细胞淋巴瘤Z-138细胞皮下异种移植肿瘤CB17SCID小鼠模型评价化合物的抗肿瘤作用。
实验材料:CB17SCID小鼠
实验方法与步骤
5.1细胞培养
细胞培养:人套细胞淋巴瘤Z-138细胞(ATCC-CRL-3001)体外悬浮培养,培养条件为Improved Minimum Essential Medium培养基中加10%胎牛血清,1%双抗,37℃5%CO
2孵箱培养。一周两次进行常规消化处理传代。当细胞饱和度为80%-90%,数量到达要求时,收取细胞,计数,接种。
5.2肿瘤细胞接种及分组给药
(1)细胞接种:将0.2mL(5×10
6个)Z-138细胞(加基质胶,体积比为1:1)皮下接种于每只小鼠的右后背,肿瘤平均体积达到163mm
3时,采用随机分组,开始分组给药,实验分组和给药方案见下表17和表18。
表17药效学实验动物分组及给药方案
组别 | 小鼠数目 | 化合物治疗 | 剂量(mg/kg) | 给药体积参数(μL/g) 2 | 给药途径 | 给药频次 |
1 | 6 | 溶媒 | -- | 10 | PO | QD×21 |
2 | 6 | 化合物1 | 200 | 10 | PO | QD×21 |
3 | 6 | 化合物4 | 200 | 10 | PO | QD×21 |
表18药效学实验动物分组及给药方案
组别 | 小鼠数目 | 化合物治疗 | 给药体积参数(μL/g) 2 | 给药途径 |
1 | 6 | 溶媒 | 10 | PO |
2 | 6 | 化合物8 | 10 | PO |
化合物8给药方式:第0天到第8天200mg/kg QD;第9天到第15天100mg/kg BID;第16天到第21天150mg/kg BID;溶媒组给药频次与化合物8保持一致。
(2)细胞接种:将0.2mL(5×10
6个)Z-138细胞(加基质胶,体积比为1:1)皮下接种于每只小鼠的右后背,肿瘤平均体积达到107mm
3时,采用随机分组,开始分组给药,实验分组和给药方案见下表19。
表19药效学实验动物分组及给药方案
组别 | 小鼠数目 | 化合物治疗 | 剂量(mg/kg) | 给药体积参数(μL/g) 2 | 给药途径 | 给药频次 |
1 | 6 | 溶媒 | -- | 10 | PO | BID×21 |
2 | 6 | 化合物39 | 80 | 10 | PO | BID×21 |
3 | 6 | 化合物40 | 80 | 10 | PO | BID×21 |
4 | 6 | 化合物46a | 80 | 10 | PO | BID×21 |
5.3肿瘤测量和实验指标
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b
2,a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(%)或相对肿瘤增殖率T/C(%)评价。相对肿瘤增殖率T/C(%)=TRTV/CRTV×100%(TRTV:治疗组RTV;CRTV:阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为RTV=Vt/V0,其中V0是分组给药时(即D0)测量所得平均肿瘤体积,Vt为某一次测量时的平均肿瘤体积,TRTV与CRTV取同一天数据。
TGI(%),反映肿瘤生长抑制率。TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%。
本实验评价了本发明化合物在人套细胞淋巴瘤Z-138细胞皮下异种移植模型中的药效,以溶剂对照组为参照。化合物1和化合物4的实验结果见附图1,化合物8的实验结果见附图2,图中每个数据点用肿瘤平均体积±标准误差(SEM)标示。化合物39、化合物40和化合物46a的实验结果见表20。
表20受试化合物对人套细胞淋巴瘤Z-138异种移植瘤模型的抑瘤效果
注*:平均值±SEM,n=6。
结论:本发明化合物表现出优秀的体内抗肿瘤药效。
实验例6:本发明化合物在人乳腺癌MDA-MB-468小鼠模型中的药效活性评价
实验目的:评价受试化合物在人乳腺癌MDA-MB-468细胞皮下异种移植肿瘤Balb/c小鼠模型中的抗肿瘤作用。
实验材料:6~8周龄的Balb/c雌性小鼠
实验方法与步骤
6.1细胞培养
细胞培养:人乳腺癌MDA-MB-468细胞(ATCC-HTB-132)体外单层培养,培养条件为McCoy’s 5a培养基中加10%胎牛血清,100U/mL青霉素和100μg/mL链霉素,37℃5%CO
2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80%-90%,数量到达要求时,收取细胞,计数,接种。6.2肿瘤细胞接种及分组给药
细胞接种:将0.2mL(10×10
6个)MDA-MB-468细胞(加基质胶,体积比为1:1)皮下接种于每只小鼠的右后背,肿瘤平均体积达到130mm
3时开始分组给药,实验分组和给药方案见下表21。
表21药效学实验动物分组及给药方案
组别 | 小鼠数目 | 化合物治疗 | 剂量(mg/kg) | 给药体积参数(μL/g) 2 | 给药途径 | 给药频次 |
1 | 6 | 溶媒 | -- | 10 | PO | BID x 4W |
2 | 6 | 化合物40 | 100 | 10 | PO | BID x 4W |
3 | 6 | 化合物46a | 100 | 10 | PO | BID x 4W |
6.3肿瘤测量和实验指标
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V=0.5a×b
2,a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(%)或相对肿瘤增殖率T/C(%)评价。相对肿瘤增殖率T/C(%)=TRTV/CRTV×100%(TRTV:治疗组RTV;CRTV:阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为RTV=Vt/V0,其中V0是分组给药时(即D0)测量所得 平均肿瘤体积,Vt为某一次测量时的平均肿瘤体积,TRTV与CRTV取同一天数据。
TGI(%),反映肿瘤生长抑制率。TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%。
实验结果:
本实验评价了本发明化合物在人乳腺癌细胞皮下异种移植模型中的药效,以溶剂对照组为参照。实验结果如表22所示。
表22受试化合物对乳腺癌MDA-MB-468细胞皮下异种移植瘤模型的抑瘤效果
注:a.平均值±SEM。
结论:本发明化合物表现出非常优秀的体内抗肿瘤药效。
Claims (39)
- 式(VII)所示化合物或其药学上可接受的盐,其中,T 1、T 2和T 3各自独立地选自CH和N;各R 1分别独立地选自H、F、Cl、Br、I、OCH 3和CH 3,所述OCH 3和CH 3任选被1、2或3个F取代;R 4’选自H和C 1-3烷基;R 5选自H、F、Cl和C 1-3烷基,所述C 1-3烷基任选被1、2或3个F取代;R 6和R 8分别独立地选自H、F、Cl、C 3-6环烷基和C 1-3烷基,所述C 3-6环烷基和C 1-3烷基任选被1、2或3个F取代;R 7和R 9分别独立地选自H、F、Cl和C 1-3烷基,所述C 1-3烷基任选被1、2或3个F取代;或者,R 6与R 7与它们共同连接的原子一起形成C 3-6环烷基或4-6元杂环烷基,所述C 3-6环烷基和4-6元杂环烷基任选被1、2或3个F取代;或者,R 8与R 9与它们共同连接的原子一起形成C 3-6环烷基或4-6元杂环烷基,所述C 3-6环烷基和4-6元杂环烷基任选被1、2或3个F取代;或者,X与R 4连接在一起形成环B;环B选自C 3-6环烷基,所述C 3-6环烷基任选被1、2或3个R c取代;L 1和L 2各自独立地选自单键和-C(=O)-;R 2选自H、OH、 C 1-3烷基、C 1-3烷氧基、-NH-C 3-6环烷基、C 3-6环烷基和苯基,所述C 1-3烷基、C 1- 3烷氧基、-NH-C 3-6环烷基、C 3-6环烷基和苯基任选被1、2或3个R a取代;R 3选自C 3-6环烷基;环A选自C 3-6环烷基和4-6元杂环烷基,所述C 3-6环烷基和4-6元杂环烷基任选被1、2或3个R b取代;m选自0和1;n选自0、1、2和3;R a和R c各自独立地选自H、F、Cl、Br、I、OH、-OCH 3和NH 2;各R b分别独立地选自H、F、Cl、Br、I、=O、OH、NH 2、C 1-3烷基和C 1-3烷氧基;所述4-6元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,各R 1独立地选自H、F、OCH 3和CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 3选自环丙基、环丁基、环戊基和环己基。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,环A选自环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环己基和硫杂环丁基,所述环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、氮杂环丁基、氮杂环己基和硫杂环丁基任选被1、2或3个R b取代。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 5选自H和CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 6选自H和CH 3,R 7选自H和CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,R 8选自H和CH 3,R 9选自H和CH 3。
- 根据权利要求1所述化合物或其药学上可接受的盐,其中,环B选自环丙基、环丁基、环戊基和环己基,所述环丙基、环丁基、环戊基和环己基任选被1、2或3个R c取代。
- [根据细则91更正 30.12.2021]根据权利要求27所述的A晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.70±0.20°,8.68±0.20°,9.35±0.20°,11.32±0.20°,13.35±0.20°,16.25±0.20°,17.36±0.20°,23.22±0.20°。
- [根据细则91更正 30.12.2021]根据权利要求28所述的A晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.70±0.20°,8.68±0.20°,9.35±0.20°,9.99±0.20°,11.32±0.20°,13.35±0.20°,14.05±0.20°,16.25±0.20°,17.36±0.20°,20.08±0.20°,23.22±0.20°,25.65±0.20°。
- [根据细则91更正 30.12.2021]根据权利要求29所述的A晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:4.70°,8.68°,9.35°,9.99°,11.32°,13.35°,14.05°,16.25°,17.36°,17.65°,20.08°,23.22°,23.80°,24.13°,25.65°,28.34°,30.32°,33.54°。
- [根据细则91更正 30.12.2021]根据权利要求30所述的A晶型,其XRPD图谱如图3所示。
- [根据细则91更正 30.12.2021]根据权利要求32所述的B晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.12±0.20°,10.15±0.20°,10.69±0.20°,12.74±0.20°,14.28±0.20°,15.18±0.20°,17.87±0.20°,25.12±0.20°。
- [根据细则91更正 30.12.2021]根据权利要求33所述的B晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:3.61±0.20°,7.12±0.20°,10.15±0.20°,10.69±0.20°,12.74±0.20°,14.28±0.20°,15.18±0.20°,17.87±0.20°,20.39±0.20°,21.09±0.20°,23.86±0.20°,25.12±0.20°。
- [根据细则91更正 30.12.2021]根据权利要求34所述的B晶型,其Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:3.61°,7.12°,10.16°,10.69°,10.95°,12.08°,12.74°,14.28°,15.18°,17.07°,17.87°,20.08°,20.39°,21.09°,22.79°,23.29°,23.86°,24.77°,25.12°,26.37°,30.02°,30.68°,31.23°,32.46°,34.80°,36.18°,37.13°。
- [根据细则91更正 30.12.2021]根据权利要求35所述的B晶型,其XRPD图谱如图7所示。
- [根据细则91更正 30.12.2021]根据权利要求1~25任意一项所述的化合物或其药学上可接受的盐在制备治疗蛋白精氨酸甲基转移酶5抑制剂相关药物上的应用。
- [根据细则91更正 30.12.2021]根据权利要求27~31任意一项所述的A晶型或权利要求31~35任意一项所述的B晶型在制备治疗蛋白精氨酸甲基转移酶5抑制剂相关药物上的应用。
- [根据细则91更正 30.12.2021]根据权利要求37或38所述的应用,其中,所述蛋白精氨酸甲基转移酶5抑制剂相关药物是用于预防和/或治疗淋巴瘤和/或实体瘤相关疾病的药物。
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US20040044031A1 (en) * | 2000-05-11 | 2004-03-04 | Koji Yamada | N-acyltetrahydroisoquinoline derivatives |
WO2014100719A2 (en) | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
WO2014100695A1 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
CN108570059A (zh) * | 2017-03-09 | 2018-09-25 | 中国科学院上海药物研究所 | 一种具有prmt5抑制活性的化合物及其制备和应用 |
CN111542523A (zh) * | 2017-11-24 | 2020-08-14 | 朱比连特埃皮斯科瑞有限责任公司 | 作为prmt5抑制剂的杂环化合物 |
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US20040044031A1 (en) * | 2000-05-11 | 2004-03-04 | Koji Yamada | N-acyltetrahydroisoquinoline derivatives |
WO2014100719A2 (en) | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
WO2014100695A1 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
CN105452226A (zh) * | 2012-12-21 | 2016-03-30 | Epizyme股份有限公司 | 四氢-和二氢-异喹啉prmt5抑制剂及其用途 |
CN108570059A (zh) * | 2017-03-09 | 2018-09-25 | 中国科学院上海药物研究所 | 一种具有prmt5抑制活性的化合物及其制备和应用 |
CN111542523A (zh) * | 2017-11-24 | 2020-08-14 | 朱比连特埃皮斯科瑞有限责任公司 | 作为prmt5抑制剂的杂环化合物 |
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