CN109384793B - Thiol compound with HDAC6 inhibitory activity and application thereof - Google Patents
Thiol compound with HDAC6 inhibitory activity and application thereof Download PDFInfo
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- CN109384793B CN109384793B CN201811402951.6A CN201811402951A CN109384793B CN 109384793 B CN109384793 B CN 109384793B CN 201811402951 A CN201811402951 A CN 201811402951A CN 109384793 B CN109384793 B CN 109384793B
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- Prior art keywords
- carboxamide
- indazole
- tetrahydropyrazolo
- acetylthiohexyl
- mercaptohexyl
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- -1 Thiol compound Chemical class 0.000 title claims abstract description 164
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- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- DITBWPUMEUDVLU-UHFFFAOYSA-N 1h-indazole-3-carboxamide Chemical group C1=CC=C2C(C(=O)N)=NNC2=C1 DITBWPUMEUDVLU-UHFFFAOYSA-N 0.000 claims abstract description 24
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- 125000003545 alkoxy group Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 25
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
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- 201000005202 lung cancer Diseases 0.000 description 1
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
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- ZBCGBIZQNMVMPC-UHFFFAOYSA-N methyl isoquinoline-3-carboxylate Chemical compound C1=CC=C2C=NC(C(=O)OC)=CC2=C1 ZBCGBIZQNMVMPC-UHFFFAOYSA-N 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
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- SUTRDULVNIPNLW-SFHVURJKSA-N tert-butyl n-[(2s)-6-acetamido-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxohexan-2-yl]carbamate Chemical compound CC1=CC(=O)OC2=CC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCNC(=O)C)=CC=C21 SUTRDULVNIPNLW-SFHVURJKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, relates to a thiol compound with antitumor activity, and particularly relates to a thiol compound containing 6(7) -substituted-N- (6-mercaptohexyl) -pyrazolo [3,4-e]Thiol compounds of indazole-3-formamide fragments and pyrazoloquinoline/isoquinoline fragments, pharmaceutically acceptable salts and hydrates thereof, pharmaceutical compositions containing the compounds and the pharmaceutically acceptable salts and hydrates thereof as active ingredients, and application of the compounds and the pharmaceutically acceptable salts and hydrates thereof in preparing histone deacetylase inhibitors and preparing medicines for treating and/or preventing cancers. The structure of the compound is shown as a formula I: wherein A, X, R is as described in the claims and specification.
Description
The technical field is as follows:
the invention belongs to the technical field of medicines, and relates to a thiol compound with antitumor activity, in particular to a thiol compound containing a 6(7) -substituted-N- (6-mercaptohexyl) -pyrazolo [3,4-e ] indazole-3-formamide fragment and a pyrazoloquinoline/isoquinoline fragment, pharmaceutically acceptable salts and hydrates thereof, a pharmaceutical composition containing the compound and the pharmaceutically acceptable salts and hydrates thereof as active ingredients, and application of the compound and the pharmaceutically acceptable salts and hydrates thereof in preparation of histone deacetylase inhibitors and preparation of medicines for treating and/or preventing cancers.
Background art:
epigenetic studies are becoming promising candidates for human tumor eradication. Epigenetic changes occur in the early stages of tumorigenesis, and at the moment, tumor cells do not cause substantial damage to the human body, and intervention is carried out, so that the tumor cells are probably killed in the cradle. In addition, the epigenetic modification abnormality can be reversed, as compared to the genetic modification being almost irreversible, and the tumor cells are restored toAnd (4) a normal state. Therefore, the epigenetic research has wider application prospect. Histone modification is an important mode of epigenetic modification, and most of human tumor cells have histone modification abnormalities which can cause cancer suppressor gene silencing to cause tumor formation. Histone Deacetylases (HDACs) are a family of enzymes comprising multiple members, and 18 subtypes are currently known, and are classified into the following four classes according to their germline and homology to yeast: class i homologous to yeast Rpd3, HoS1, HoSt2, including HDAC1, HDAC2, HDAC3, HDAC 8; class IIa, including HDAC4, HDAC5, HDAC7, HDAC9, class IIb, including HDAC6, HDAC10, homologous to yeast Hda1, HoS 3; class III homologous to yeast Sir2, including SIRT 1-SIRT 7; there is partial homology to both class I and II HDACs, but a different class IV from the family, including HDAC 11. Wherein the I, II and IV are classical Zn2+HDACs dependent, while class III belongs to the Sirtuin family and is NAD+Dependent HDACs. Research shows that class I and II HDACs can inhibit tumor cell differentiation and apoptosis, promote tumor cell proliferation, and the like, are closely related to the occurrence and development of tumors, and the research of inhibitors taking the HDACs as targets becomes one of the hot spots of the research of antitumor drugs.
The invention designs and synthesizes a series of thiol compounds containing 6(7) -substituted-N- (6-mercaptohexyl) -pyrazolo [3,4-e ] indazole-3-formamide fragment and pyrazoloquinoline/isoquinoline fragment, and pharmaceutically acceptable salts and hydrates thereof on the basis of reference documents, and in vitro antitumor activity test results show that the thiol compounds have good antitumor activity and show excellent HDAC inhibition effect.
The invention content is as follows:
the invention aims to provide a thiol compound with HDAC6 inhibitory activity and good anti-tumor activity, a preparation method thereof and application of the compound as a histone deacetylase inhibitor in preventing and/or treating tumors. The compounds specifically comprise the following fragments: 6(7) -substituted-N- (6-mercaptohexyl) -pyrazolo [3,4-e ] indazole-3-carboxamide fragments and pyrazoloquinoline/isoquinoline fragments.
The invention relates to a compound shown as a formula I, and pharmaceutically acceptable salts and hydrates thereof:
wherein,
ring a is a 5-6 membered aromatic or heteroaromatic ring containing 1-3 heteroatoms of N, O or S; the A ring may be substituted with a substituent selected from the group consisting of H, halogen and (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C4) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C6) Alkyl substituted phenyl, (C)1-C6) Alkoxy-substituted phenyl or benzyl, halo (C)6-C10) Aryl group, (C)6-C10) A phenolic aryl group;
"- - -" represents a single bond or a double bond;
x is NH or O;
r is selected from one or more of the following substituents: H. (C)2-C4) Acyl, (C)1-C6) Alkyl, (C)6-C10) An aryl-substituted ester group; (C)6-C10) An aryl group; (C)1-C6) Alkoxy (C)1-C6) An alkyl group; the aryl group may be substituted by halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, nitro, amino, hydroxy substitution;
the present invention preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:
wherein,
ring a is selected from one or more of the following ring systems:
R1selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) Alkyl, (C)3-C4) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkyl substituted phenyl, (C)1-C4) Alkoxy-substituted phenyl or benzyl, halo (C)6-C10) Aryl group, (C)6-C10) A phenolic aryl group;
R2selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) Alkyl, (C)3-C4) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkyl substituted phenyl, (C)1-C4) Alkoxy-substituted phenyl or benzyl, halo (C)6-C10) Aryl group, (C)6-C10) A phenolic aryl group;
R3selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) Alkyl, (C)3-C4) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkyl substituted phenyl, (C)1-C4) Alkoxy-substituted phenyl or benzyl, halo (C)6-C10) Aryl group, (C)6-C10) A phenolic aryl group;
r is selected from one or more of the following substituents: H. (C)2-C4) Acyl, (C)1-C6) Alkyl, (C)6-C10) An aryl-substituted ester group; (C)6-C10) An aryl group; (C)1-C6) Alkoxy (C)1-C6) An alkyl group; the aryl group may be substituted by halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, nitro, amino, hydroxy substitution;
"- - -" represents a single bond or a double bond;
x is NH or O.
The present invention preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:
wherein,
the A ring is preferably:
R1selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) Alkyl, (C)3-C4) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkyl substituted phenyl, (C)1-C4) Alkoxy-substituted phenyl or benzyl, halo (C)6-C10) Aryl group, (C)6-C10) A phenolic aryl group;
R2selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) Alkyl, (C)3-C4) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkyl substituted phenyl, (C)1-C4) Alkoxy-substituted phenyl or benzyl, halo (C)6-C10) Aryl group, (C)6-C10) A phenolic aryl group;
r is selected from one or more of the following substituents: H. (C)2-C4) Acyl, (C)1-C4) Alkyl, (C)6-C10) An aryl-substituted ester group; (C)6-C10) An aryl group; (C)1-C4) Alkoxy (C)1-C4) An alkyl group; the aryl group may be substituted by halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, nitro, amino, hydroxy substitution;
"- - -" represents a single bond or a double bond;
x is NH or O.
The invention also preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:
wherein,
the A ring is preferably
R1Selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) An alkyl group;
R2selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) An alkyl group;
r is selected from one or more of the following substituents: H. (C)2-C4) Acyl, (C)1-C4) Alkyl, (C)6-C10) An aryl-substituted ester group; a phenyl group; a benzyl group; (C)1-C4) Alkoxy (C)1-C4) An alkyl group; the phenyl or benzyl group may be substituted by halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, nitro, amino or hydroxy substitution;
"- - -" represents a single bond or a double bond;
x is NH or O.
The invention also preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:
wherein,
the A ring is preferably
R1、R2The following substituents are used: H. methyl, ethyl, methoxyethyl, ethoxyethyl, cyclopropylmethyl, benzyl, p-fluorobenzyl, p-methoxybenzyl, p-hydroxybenzyl;
r is selected from one or more of the following substituents: H. (C)2-C4) Acyl, (C)1-C6) Alkyl, (C)6-C10) An aryl-substituted ester group; a phenyl group; a benzyl group; (C)1-C6) Alkoxy (C)1-C6) An alkyl group; the phenyl or benzyl group may be substituted by halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, nitro, amino or hydroxy substitution;
"- - -" represents a single bond or a double bond;
x is NH or O.
The invention also particularly preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:
wherein,
the A ring is preferably
R1、R2Preferred are the following substituents: H. methyl, ethyl, methoxyethyl, ethoxyethyl, cyclopropylmethyl, benzyl, p-fluorobenzyl, p-methoxybenzyl, p-hydroxybenzyl;
r is preferably H or acetyl;
"- - -" represents a single bond or a double bond;
x is NH or O.
The invention also particularly preferably defines compounds of formula i, and pharmaceutically acceptable salts, hydrates thereof:
wherein,
the A ring is preferably
R1、R2Preferred are the following substituents: H. methyl, ethyl, methoxyethyl, ethoxyethyl, cyclopropylmethyl, benzyl, p-fluorobenzyl, p-methoxybenzyl, p-hydroxybenzyl;
r is preferably H or acetyl;
y is preferably-CH2-CH2-or-CH ═ CH-;
x is NH or O.
Specifically, the following compounds are preferred in the present invention:
n- (6-mercaptohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -5, 6-dihydro-4H-isoxazolo [5,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -5, 6-dihydro-4H-isoxazolo [5,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7-methyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-methyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6-methyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-methyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7-benzyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-benzyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6-benzyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-benzyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7- (4-fluorobenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7- (4-fluorobenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6- (4-fluorobenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6- (4-fluorobenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7- (4-methoxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7- (4-methoxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6- (4-methoxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6- (4-methoxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7- (4-hydroxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7- (4-hydroxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6- (4-hydroxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6- (4-hydroxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6(7) H-isoxazolo [5,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6(7) H-isoxazolo [5,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-methyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-methyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-methyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-methyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-Ethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-Ethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-Ethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-Ethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-methoxyethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-methoxyethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-methoxyethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-methoxyethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-cyclopropylmethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-cyclopropylmethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-cyclopropylmethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-cyclopropylmethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-mercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
N- (6-mercaptohexyl) -1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-mercaptohexyl) -1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
N- (6-mercaptohexyl) -7-ethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-ethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -6-ethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-ethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -7-methoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-methoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -6-methoxyethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-methoxyethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -7-ethoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-ethoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -6-ethoxyethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-ethoxyethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -7-cyclopropylmethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-cyclopropylmethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-Thiohexyl) -6-cyclopropylmethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-cyclopropylmethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
Or hydrates, solvates, metabolites and pharmaceutically acceptable salts thereof or prodrugs thereof.
In addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs, according to the present invention, are compounds of formula i which may themselves be less active or even inactive, but which, upon administration, are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise).
The invention includes pharmaceutical compositions comprising a thiol compound of a fragment encompassed by formula i above and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The compounds of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field, for example, oral preparations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are immediately ready for use by addition of water for injection prior to injection); topical formulations (e.g. ointments or solutions).
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binders, lubricants, disintegrating agents, solubilizing agents, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers and the like for injectable preparations; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
Through screening of an in vitro enzyme inhibiting test, the compound can inhibit the activity of histone deacetylase, so that the compound can be used for preparing medicines for treating diseases related to abnormal expression of the histone deacetylase activity, such as various cancers.
Through in vitro activity screening and in vivo pharmacodynamic research, the compound of the invention is found to have antitumor activity, so the compound of the invention can be used for preparing medicaments for treating and/or preventing various cancers, such as breast, lung, colon, rectum, stomach, prostate, bladder, uterus, pancreas and ovary cancer.
The active compounds of the present invention may be used as sole anticancer agents or in combination with one or more other antitumor agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes describe the preparation of the compounds of formula I of this invention, all starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these routes are as defined below or in the claims.
According to the compounds of formula i according to the invention, when ring a is a (substituted) pyrazole ring and "- - -" is a double bond, the target compound is prepared according to the method of scheme one, the substituents being as defined in the summary of the invention.
The reagent and the condition are (a) DMF-DMA, neat, reflux,1 h; (b) NH (NH)2NH2.HCl,MeOH,reflux.2h；(c)RX,K2CO3or KOH,MeCN,reflux,2h；(d)dimethyl oxalate,LiHMDs,THF,r.t.,4h；(e)NH2NH2.H2O,AcOH,80℃,2h；(f)NaOH,H2O,50℃,2h；(g)6-bromohexan-1-amine,EDCI,HOBt,DMF,r.t.,24h；(h)KSAc,EtOH,reflux,4h；(i)DDQ,dioxane,reflux,4h；(j)LiOH,MeOH,r.t.,1h.
When ring A is a (substituted) pyrazole ring and "- - -" is a single bond, the target compound is prepared according to the method of scheme II. The other substituents are as defined in the summary of the invention.
The reagent and the condition are (a) DMF-DMA, neat, reflux,1 h; (b) NH (NH)2NH2.HCl,MeOH,reflux.2h；(c)RX,K2CO3or KOH,MeCN,reflux,2h；(d)dimethyl oxalate,LiHMDs,THF,r.t.,4h；(e)NH2NH2.H2O,AcOH,80℃,2h；(f)NaOH,H2O,50℃,2h；(g)6-bromohexan-1-amine,EDCI,HOBt,DMF,r.t.,24h；(h)KSAc,EtOH,reflux,4h；(i)LiOH,MeOH,r.t.,1h.
When the ring A is a pyridine ring and the "- - -" is a single bond or a double bond, the target compound is prepared according to the method of the third route. The other substituents are as defined in the summary of the invention.
Reagents and conditions (a) KMnO4,CH3COOH,r.t.；(b)dimethyl oxalate,LiHMDs,THF,r.t.,4h；(c)NH2NH2.H2O,CH3COOH,80℃,0.5h；(d)NaOH(aq),50℃,1h；(e)6-bromohexan-1-amine,EDCI,HOBt,DMF,r.t.,overnight；(f)KSAc,C2H5OH,reflux,1h；(g)LiOH(aq),CH3OH,r.t.,4h；(h)DDQ,1,4-dioxane,reflux,2h.
The preparation method is simple to operate and mild in condition, and the obtained compounds have histone deacetylase inhibitory activity and remarkable anti-tumor effect.
The specific implementation mode is as follows:
the present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
Example 1: preparation of N- (6-mercaptohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
Step A: preparation of 2- (dimethylamino) methylene-1, 3-cyclohexanedione
1, 3-cyclohexanedione (50mmol) and N, N-dimethylformamide dimethyl acetal (DMF-DMA) (100mmol) were added to a 250mL Erica flask and heated at 95 ℃ under reflux for 1 h. Then, unreacted DMF-DMA was recovered by distillation under reduced pressure to give a brown solid, which was subjected to the next reaction without purification. The yield thereof was found to be 100%. LC-MS M/z 168.2[ M + H ]]+。
And B: preparation of 2,5,6, 7-tetrahydro-4H-indazol-4-one
2- (dimethylamino) methylene-1, 3-cyclohexanedione (50mmol) was dissolved in methanol (100mL) and hydrazine hydrochloride (55mmol) was added and heated to 60 ℃ for 2 h. Then, insoluble matter in the reaction was removed, and the filtrate was evaporated to dryness to obtain a brown solid, which was subjected to the next reaction without purification. The yield thereof was found to be 100%. LC-MS M/z 137.2[ M + H ]]+.
And C: preparation of 2-triphenylmethyl-6, 7-dihydro-2H-indazol-4 (5H) -one
2,5,6, 7-tetrahydro-4H-indazol-4-one (10mmol)) Dissolved in dichloromethane (50mL), followed by addition of triethylamine (20mmol), triphenylmethyl chloride (11mmol), and heating to 80 ℃ for 4 h. The reaction solvent was then removed and petroleum ether recrystallized to give a white solid. The yield thereof was found to be 88%. LC-MS M/z 179.3[ M + H ]]+.
Step D: preparation of methyl 1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxylate
2-Triphenylmethyl-6, 7-dihydro-2H-indazol-4 (5H) -one (10mmol) was dissolved in tetrahydrofuran (50mL), followed by addition of dimethyl oxalate (12mmol), dropwise addition of LiHMDS (1M in THF,12mmol) and reaction at room temperature for 4H. The reaction solution was removed, redissolved in acetic acid (50mL), added hydrazine hydrate (80%, 12mmol) and heated to 80 ℃ for 4 h. And (3) cooling the reaction liquid to room temperature, pouring the reaction liquid into water (100mL), precipitating a large amount of solid, performing suction filtration, and collecting a filter cake to obtain a white solid. The yield thereof was found to be 62%. LC-MS M/z 219.1[ M + H ]]+.
Step E: preparation of N- (6-acetylthiohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
1,4,5, 6-tetrahydropyrazolo [3,4-e]Indazole-3-carboxylic acid methyl ester (8mmol) was dissolved in methanol (10mmol), and an aqueous solution of sodium hydroxide (10mmol) was added thereto, followed by heating at 50 ℃ for 4 hours to react. Cooling the reaction liquid to room temperature, adjusting the pH value to 2 by using 0.5M hydrochloric acid, separating out a large amount of solid, performing suction filtration, collecting a filter cake, and performing vacuum drying. Subsequently, the mixture was dissolved in DMF (50mL), and HOBt (10mmol), 6-bromo-1-hexylamine (10mmol) and EDCI (10mmol) were added in this order under ice bath to react at room temperature for 24 hours. The reaction solution was then poured into water (100mL), extracted with ethyl acetate (60 mL. times.3), the organic layers were combined, back-washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Then, the mixture was redissolved in ethanol (50mL), potassium thioacetate (10mmol) was added, and the mixture was heated at 60 ℃ for reaction for 4 hours. Removing solvent, separating with silica gel column chromatography to obtain white solid. The yield thereof was found to be 42%. LC-MS M/z 362.3[ M + H ]]+.
Step F: preparation of N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e]Indazole-3-carboxamide (5mmol) was dissolved in dioxane (50mL), dichlorodicyanobenzoquinone (DDQ,10mmol) was added, and the mixture was heated at 100 ℃ for reaction for 2 hours. And (3) cooling the reaction liquid to room temperature, adding saturated sodium bicarbonate to quench the reaction, pouring the reaction liquid into water (100mL), extracting with ethyl acetate (60mL multiplied by 3), combining organic layers, backwashing with saturated sodium chloride, drying with anhydrous sodium sulfate, and separating by silica gel column chromatography to obtain a white solid. The yield thereof was found to be 58%. LC-MS M/z 360.2[ M + H ]]+.
Step G: preparation of N- (6-mercaptohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e]Indazole-3-carboxamide (3mmol) was dissolved in methanol (10mL), and a lithium hydroxide solution (1.2M,3.3mmol) was added to react at room temperature for 4 h. Then, the reaction solution was poured into a large amount of water (100mL) and extracted with ethyl acetate (60mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography, with the pH being adjusted to 2 with 0.5M hydrochloric acid. A white solid was obtained. The yield thereof was found to be 61%. LC-MS M/z 320.0[ M + H ]]+.
The compounds of examples 2-60 were prepared by the preparation of example 1, selecting the appropriate starting materials.
Example 2: preparation of N- (6-acetylthiohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:362.3[M+H]+.
Example 3: preparation of N- (6-mercaptohexyl) -5, 6-dihydro-4H-isoxazolo [5,4-e ] indazole-3-carboxamide
LC-MS m/z:320.1[M+H]+.
Example 4: preparation of N- (6-acetylthiohexyl) -5, 6-dihydro-4H-isoxazolo [5,4-e ] indazole-3-carboxamide
LC-MS m/z:363.2[M+H]+.
Example 5: preparation of N- (6-mercaptohexyl) -7-methyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:333.2[M+H]+.
Example 6: preparation of N- (6-acetylthiohexyl) -7-methyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:376.3[M+H]+.
Example 7: preparation of N- (6-mercaptohexyl) -6-methyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:333.2[M+H]+.
Example 8: preparation of N- (6-acetylthiohexyl) -6-methyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:376.3[M+H]+.
Example 9: preparation of N- (6-mercaptohexyl) -7-benzyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:409.2[M+H]+.
Example 10: preparation of N- (6-acetylthiohexyl) -7-benzyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:452.3[M+H]+.
Example 11: preparation of N- (6-mercaptohexyl) -6-benzyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:409.2[M+H]+.
Example 12: preparation of N- (6-acetylthiohexyl) -6-benzyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:452.3[M+H]+.
Example 13: preparation of N- (6-mercaptohexyl) -7- (4-fluorobenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:427.2[M+H]+.
Example 14: preparation of N- (6-acetylthiohexyl) -7- (4-fluorobenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:470.3[M+H]+.
Example 15: preparation of N- (6-mercaptohexyl) -6- (4-fluorobenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:427.2[M+H]+.
Example 16: preparation of N- (6-acetylthiohexyl) -6- (4-fluorobenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:470.3[M+H]+.
Example 17: preparation of N- (6-mercaptohexyl) -7- (4-methoxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:439.1[M+H]+.
Example 18: preparation of N- (6-acetylthiohexyl) -7- (4-methoxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:482.2[M+H]+.
Example 19: preparation of N- (6-mercaptohexyl) -6- (4-methoxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:439.1[M+H]+.
Example 20: preparation of N- (6-acetylthiohexyl) -6- (4-methoxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:482.2[M+H]+.
Example 21: preparation of N- (6-mercaptohexyl) -7- (4-hydroxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:425.1[M+H]+.
Example 22: preparation of N- (6-acetylthiohexyl) -7- (4-hydroxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:468.2[M+H]+.
Example 23: preparation of N- (6-mercaptohexyl) -6- (4-hydroxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:425.1[M+H]+.
Example 24: preparation of N- (6-acetylthiohexyl) -6- (4-hydroxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:468.2[M+H]+.
Example 25: preparation of N- (6-mercaptohexyl) -7-ethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:346.0[M-H]+.
Example 26: preparation of N- (6-acetylthiohexyl) -7-ethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:389.1[M+H]+.
Example 27: preparation of N- (6-thiohexyl) -6-ethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:346.0[M+H]+.
Example 28: preparation of N- (6-acetylthiohexyl) -6-ethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:389.1[M+H]+.
Example 29: preparation of N- (6-thiohexyl) -7-methoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:376.0[M-H]+.
Example 30: preparation of N- (6-acetylthiohexyl) -7-methoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:420.1[M+H]+.
Example 31: preparation of N- (6-thiohexyl) -6-methoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:376.0[M-H]+.
Example 32: preparation of N- (6-acetylthiohexyl) -6-methoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:420.1[M+H]+.
Example 33: preparation of N- (6-thiohexyl) -7-ethoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:390.1[M-H]+.
Example 34: preparation of N- (6-acetylthiohexyl) -7-ethoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:434.2[M+H]+.
Example 35: preparation of N- (6-thiohexyl) -6-ethoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:390.1[M-H]+.
Example 36: preparation of N- (6-acetylthiohexyl) -6-ethoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:434.2[M+H]+.
Example 37: preparation of N- (6-thiohexyl) -7-cyclopropylmethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:372.0[M-H]+.
Example 38: preparation of N- (6-acetylthiohexyl) -7-cyclopropylmethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:416.3[M+H]+.
Example 39: preparation of N- (6-thiohexyl) -6-cyclopropylmethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:372.0[M-H]+.
Example 40: preparation of N- (6-acetylthiohexyl) -6-cyclopropylmethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:416.3[M+H]+.
Example 41: preparation of N- (6-mercaptohexyl) -6(7) H-isoxazolo [5,4-e ] indazole-3-carboxamide
LC-MS m/z:319.0[M+H]+.
Example 42: preparation of N- (6-acetylthiohexyl) -6(7) H-isoxazolo [5,4-e ] indazole-3-carboxamide
LC-MS m/z:361.2[M+H]+.
Example 43: preparation of N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:318.1[M+H]+.
Example 44: preparation of N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:360.2[M+H]+.
Example 45: preparation of 7-methyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:332.0[M+H]+.
Example 46: preparation of 7-methyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:374.3[M+H]+.
Example 47: preparation of 6-methyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:332.1[M+H]+.
Example 48: preparation of 6-methyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:374.3[M+H]+.
Example 49: preparation of 7-ethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:346.3[M+H]+.
Example 50: preparation of 7-ethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:388.2[M+H]+.
Example 51: preparation of 6-ethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:346.2[M+H]+.
Example 52: preparation of 6-ethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:388.3[M+H]+.
Example 53: preparation of 7-methoxyethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:376.0[M+H]+.
Example 54: preparation of 7-methoxyethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:418.2[M+H]+.
Example 55: preparation of 6-methoxyethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:376.1[M+H]+.
Example 56: preparation of 6-methoxyethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:418.3[M+H]+.
Example 57: preparation of 7-cyclopropylmethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:372.3[M+H]+.
Example 58: preparation of 7-cyclopropylmethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:414.2[M+H]+.
Example 59: preparation of 6-cyclopropylmethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:372.2[M+H]+.
Example 60: preparation of 6-cyclopropylmethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
LC-MS m/z:414.3[M+H]+.
Example 61: preparation of N- (6-mercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
Step A: preparation of 6, 7-dihydroisoquinoline-8 (5H) -one
Dissolving 5,6,7, 8-tetrahydroisoquinoline in acetic acid, adding 1.2 equivalent of potassium permanganate, stirring at room temperature for 8h, adding water into the reaction solution, extracting with a large amount of dichloromethane, and separating and purifying the prepared liquid phase at a high speed and medium pressure to obtain colorless viscous oily substance with a yield of 15%. LC-MS M/z 148.1[ M + H ]]+。
And B: preparation of methyl 4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxylate
6, 7-dihydroisoquinoline-8 (5H) -one (10mmol) was dissolved in tetrahydrofuran (50mL), followed by addition of dimethyl oxalate (12mmol), dropwise addition of LiHMDS (1M in THF,12mmol) slowly, and reaction at room temperature for 4H. The reaction solution was removed, redissolved in acetic acid (50mL), added hydrazine hydrate (80%, 12mmol) and heated at 80 ℃ for 1 h. And (3) cooling the reaction liquid to room temperature, pouring the reaction liquid into water (100mL), precipitating a large amount of solid, performing suction filtration, collecting a filter cake to obtain a crude product, and performing rapid medium-pressure preparation liquid phase separation and purification to obtain a light yellow solid with the yield of 60%. LC-MS M/z 230.2[ M + H ]]+。
And C: preparation of N- (6-bromohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
4, 5-dihydro-1H-pyrazolo [4, 3-H)]Methyl isoquinoline-3-carboxylate (8mmol) was dissolved in methanol (10mmol), and an aqueous solution of sodium hydroxide (0.1M,10mmol) was added and heated at 50 ℃ for 1 hour. Cooling the reaction liquid to room temperature, adjusting the pH value to 3 by using 0.5M hydrochloric acid, separating out a large amount of solid, performing suction filtration, collecting a filter cake, and performing vacuum drying. Then the mixture is dissolved in DMF (50mL), pH is adjusted to be alkalescent (7-8) by triethylamine, HOBt (10mmol), 6-bromo-1-hexylamine (10mmol) and EDCI (10mmol) are added in sequence under ice bath, and the mixture reacts for 24 hours at room temperature. The reaction was then poured into water (100mL), and BExtracting with ethyl acetate (60mL × 3), combining organic layers, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and separating and purifying by rapid medium-pressure preparative liquid phase to obtain a yellowish oily viscous substance with a yield of 55%. LC-MS M/z 377.1[ M + H ]]+。
Step D: preparation of N- (6-acetylmercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
Reacting N- (6-bromohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H]Isoquinoline-3-carboxamide is dissolved in ethanol, potassium thioacetate (10mmol) is added, and the mixture is heated to 60 ℃ for reaction for 1 h. Removing solvent, and separating and purifying by rapid medium-pressure preparation liquid phase to obtain yellowish oily viscous substance with yield of 91%. LC-MS M/z 373.4[ M + H ]]+。
Step E: preparation of N- (6-acetylmercaptohexyl) -1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H]Isoquinoline-3-carboxamide (5mmol) was dissolved in dioxane (50mL), dichlorodicyanobenzoquinone (DDQ,10mmol) was added, and the mixture was heated at 100 ℃ for reaction for 2 hours. Cooling the reaction liquid to room temperature, adding saturated sodium bicarbonate to quench the reaction, pouring the reaction liquid into water (100mL), extracting with ethyl acetate (60mL multiplied by 3), combining organic layers, backwashing with saturated sodium chloride, drying with anhydrous sodium sulfate, and separating by silica gel column chromatography to obtain a white solid; the yield thereof was found to be 75%. LC-MS M/z 371.1[ M + H ]]+。
Step F: preparation of N- (6-mercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
Reacting N- (6-acetyl)Mercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H]Isoquinoline-3-carboxamide (3mmol) was dissolved in ethanol (10mL), and a lithium hydroxide solution (1.2M,3.3mmol) was added to the solution to react at room temperature for 4 hours. Then, the reaction solution was poured into a large amount of water (100mL) and extracted with ethyl acetate (60mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and subjected to preparative liquid phase separation and purification at a medium pressure to give a pale yellow solid with a yield of 45%. LC-MS M/z 328.8[ M-H ]]-。
By following the procedure for the preparation of example 61, selecting the appropriate starting materials, the compounds of examples 62-68 were prepared.
Example 62: preparation of N- (6-acetylmercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
LC-MS m/z:373.2[M+H]+.
Example 63: preparation of N- (6-mercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
LC-MS m/z:329.4[M-H]-.
Example 64: preparation of N- (6-acetylmercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
LC-MS m/z:373.4[M+H]+.
Example 65: preparation of N- (6-mercaptohexyl) -1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
LC-MS m/z:327.0[M-H]-.
Example 66: preparation of N- (6-acetylmercaptohexyl) -1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
LC-MS m/z:371.1[M+H]+.
Example 67: preparation of N- (6-mercaptohexyl) -1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
LC-MS m/z:372.2[M-H]-.
Example 68: preparation of N- (6-acetylmercaptohexyl) -1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
LC-MS m/z:371.0[M+H]+.
EXAMPLE 69 study of the pharmacological Effect of the product of the present invention
Experiment positive control group (Vorinuo)He and ACY-1215). HeLa cell nuclear extract (Enzo Life Sciences, USA) is used as HDACs enzyme source, and recombinant rHDAC1, 2, 3 and rHDAC6 protein (BPS Bioscience, USA) are used as subtype enzyme source. All reactions were performed in 96-well plates. The reaction buffer contained 25mM Tris-HCl (pH 8.0), 137mM NaCl, 2.7mM KCl, 1mM MgCl2And 0.1mg/mL BSA. A gradient of compound solution (5. mu.L) and enzyme (5. mu.L) was preincubated at 25 ℃ for 15min, followed by addition of the fluorogenic substrate Boc-Lys (Ac) -AMC (5. mu.L) to initiate the reaction and incubation at 37 ℃ for 60 min. Finally, stop buffer (25. mu.L) containing Trypsin and SAHA was added to the system and incubated for another 10 min. Fluorescence intensity was measured at an excitation wavelength of 355nm and an emission wavelength of 460nm (Thermo Scientific Varioskan Flash Station). IC calculation with GraphPad50. The inhibitory activity of the target compounds on HDACs is shown in table 1.
TABLE A inhibitory Activity of target Compounds on HDAC enzymes
aND stands for no activity, no activity measured or no activity of the subtype tested.
bThe measured result is the average of at least two independent measurements, expressed as standard deviation, expressed as IC50±SD。
The above experimental results show that the compound of the general formula to be protected of the present invention has good antitumor activity and HDAC inhibitory action. The compound of the invention has good industrial application prospect.
Claims (9)
1. Thiol compounds having HDAC6 inhibitory activity and pharmaceutically acceptable salts thereof, represented by formula I:
wherein,
the A ring is:
"- - -" represents a single bond or a double bond;
x is NH or O;
r is selected from one or more of the following substituents: H. (C)2-C4) Acyl, (C)1-C6) Alkyl, (C)6-C10) An aryl-substituted ester group; (C)6-C10) An aryl group; (C)1-C6) Alkoxy (C)1-C6) An alkyl group; the aryl group may be substituted by halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, nitro, amino, hydroxy substitution;
R1selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) Alkyl, (C)3-C4) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkyl substituted phenyl, (C)1-C4) Alkoxy-substituted phenyl or benzyl, halo (C)6-C10) Aryl group, (C)6-C10) A phenolic aryl group;
R2selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) Alkyl, (C)3-C4) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkyl substituted phenyl, (C)1-C4) Alkoxy-substituted phenyl or benzyl, halo (C)6-C10) Aryl group, (C)6-C10) A phenol aryl group.
2. The thiol compound having HDAC6 inhibitory activity of claim 1 and pharmaceutically acceptable salts thereof:
wherein,
r is selected from one or more of the following substituents: H. (C)2-C4) Acyl, (C)1-C4) Alkyl, (C)6-C10) An aryl-substituted ester group; a phenyl group; a benzyl group; (C)1-C4) Alkoxy (C)1-C4) An alkyl group; the phenyl or benzyl group may be substituted by halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, nitro, amino or hydroxy.
3. The thiol compound having HDAC6 inhibitory activity of claim 1 or 2 and pharmaceutically acceptable salts thereof:
wherein,
R1selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) An alkyl group;
R2selected from one or more of the following substituents: H. halogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alkoxy (C)1-C4) An alkyl group.
4. A compound as described below, and pharmaceutically acceptable salts thereof: is selected from the group consisting of,
n- (6-mercaptohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -5, 6-dihydro-4H-isoxazolo [5,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -5, 6-dihydro-4H-isoxazolo [5,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7-methyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-methyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6-methyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-methyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7-benzyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-benzyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6-benzyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-benzyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7- (4-fluorobenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7- (4-fluorobenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6- (4-fluorobenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6- (4-fluorobenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7- (4-methoxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7- (4-methoxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6- (4-methoxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6- (4-methoxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -7- (4-hydroxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7- (4-hydroxybenzyl) -1,4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6- (4-hydroxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6- (4-hydroxybenzyl) -1,4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -6(7) H-isoxazolo [5,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6(7) H-isoxazolo [5,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-methyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-methyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-methyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-methyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-Ethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-Ethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-Ethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-Ethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-methoxyethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-methoxyethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-methoxyethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-methoxyethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-cyclopropylmethyl-N- (6-mercaptohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
7-cyclopropylmethyl-N- (6-acetylthiohexyl) -1, 7-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-cyclopropylmethyl-N- (6-mercaptohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
6-cyclopropylmethyl-N- (6-acetylthiohexyl) -1, 6-dihydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-mercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-mercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -4, 5-dihydro-1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
N- (6-mercaptohexyl) -1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -1H-pyrazolo [4,3-H ] isoquinoline-3-carboxamide
N- (6-mercaptohexyl) -1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
N- (6-acetylmercaptohexyl) -1H-pyrazolo [4,3-H ] quinoline-3-carboxamide
N- (6-mercaptohexyl) -7-ethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-ethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -6-ethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-ethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -7-methoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-methoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -6-methoxyethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-methoxyethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -7-ethoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-ethoxyethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -6-ethoxyethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-ethoxyethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-thiohexyl) -7-cyclopropylmethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -7-cyclopropylmethyl-1, 4,5, 7-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-Thiohexyl) -6-cyclopropylmethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide
N- (6-acetylthiohexyl) -6-cyclopropylmethyl-1, 4,5, 6-tetrahydropyrazolo [3,4-e ] indazole-3-carboxamide.
5. A pharmaceutical composition characterized by: comprising a compound of any one of claims 1-4, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
6. The process for preparing thiol compounds having HDAC6 inhibitory activity according to claim 1, wherein the thiol compounds are represented by formula I,
when the ring A is a substituted pyrazole ring and the < - - - > is a double bond, the synthetic route is as follows:
wherein R is R in claim 11Or R2；
When the ring A is a substituted pyrazole ring and the < - - - > is a single bond, the synthetic route is as follows:
wherein R is R in claim 11Or R2；
When ring A is
When the < - - - > is a single bond or a double bond, the synthetic route is as follows:
X1when is C, X2Is N; x1When is N, X2Is C.
7. Use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for the treatment of a disease associated with aberrant expression of histone deacetylase activity.
8. Use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 5, for the manufacture of an anti-neoplastic medicament.
9. Use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for the treatment and/or prophylaxis of prostate cancer, breast cancer, cervical cancer or leukaemia.
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