CN111471037B - Allylamine compound and application thereof - Google Patents
Allylamine compound and application thereof Download PDFInfo
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- CN111471037B CN111471037B CN202010043158.2A CN202010043158A CN111471037B CN 111471037 B CN111471037 B CN 111471037B CN 202010043158 A CN202010043158 A CN 202010043158A CN 111471037 B CN111471037 B CN 111471037B
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an allylamine compound shown as a formula I or pharmaceutically acceptable salt, ester, stereoisomer and tautomer thereof, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、L 1 、C y1 As defined in the specification; the invention also relates to pharmaceutical preparations, pharmaceutical compositions comprising these compounds and their use in the prevention and/or treatment of diseases related to or mediated by SSAO/VAP-1 protein.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to allylamine compounds or pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof, pharmaceutical preparations and pharmaceutical compositions containing the allylamine compounds, and applications of the allylamine compounds or pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof in preventing and/or treating diseases related to SSAO/VAP-1 protein or mediated by SSAO/VAP-1 protein.
Background
Semicarbazide-sensitive amine oxidases (SSAO) are a class of amine oxidases that are particularly sensitive to semicarbazides, and are widely distributed in the body, both on cell membranes and in plasma. In endothelial cells, SSAO exists in the form of vascular adhesion protein-1 (VAP-1, vascular adhesion protein-1). At present, the physiological function in the body is considered to be mainly involved in the metabolism of amine, and the short-chain primary amine such as methylamine and aminoacetone is catalyzed to be oxidized and deaminated to generate corresponding aldehyde, hydrogen peroxide and ammonia. The SSAO structure contains 1 bivalent copper ion and takes quinone group as coenzyme. SSAO has no specific substrate, being predominantly aliphatic and aromatic primary amines.
At present, no SSAO/VAP-1 inhibitor is on the market, and the SSAO/VAP-1 inhibitor can be used for effectively relieving symptoms and pathological changes under various disease states and related disorder states such as SSAO/VAP-1 overexpression, and the like, so that the SSAO/VAP-1 inhibitor has a huge application prospect.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel SSAO/VAP-1 inhibitor, which has strong inhibitory activity on SSAO/VAP-1 protein and can be used for preventing and/or treating diseases related to the SSAO/VAP-1 protein or mediated by the SSAO/VAP-1 protein. Furthermore, the allylamine compounds of the present invention exhibit excellent selectivity for SSAO/VAP-1 protein, thereby preventing and/or treating diseases associated with or mediated by SSAO/VAP-1 protein while avoiding other side effects.
Specifically, the present invention provides the following technical solutions.
In one embodiment of the present invention, there is provided a compound represented by the following formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof (hereinafter, sometimes also referred to as "the present compound"):
wherein R is 1 And R 2 Each independently selected from hydrogen, halogen, and R 1 And R 2 Not hydrogen at the same time;
R 3 and R 4 Each independently selected from hydrogen or C 1-6 Alkyl, or together with the N atom to which it is attached, forms an optionally substituted nitrogen-containing 5-10 membered heterocyclic ring;
R 5 and R 6 Each independently selected from hydrogen or C 1-6 An alkyl group;
L 1 is a bond, or is-CR 'R' -, -N-, -O-, -S-, -SO 2 -、S(O)、-SONR’-、-SO 2 NR ' -or-NR ' CONR ', R ' and R ' are each independently selected from hydrogen or C 1-6 An alkyl group;
C y1 is unsubstituted or substituted by one or more R a A substituted group represented by the following formula (a):
m and n are integers of 0-3, X 1 、X 2 、X 3 Each independently selected from CH 2 、CH、N、O、S、NH、C＝O，X 4 、X 5 、X 6 Each independently selected from CH or N, X 7 、X 8 Each independently selected from CH or C, when m and n > 0, each X 3 Or X 4 May be the same or different;
each R a Independently selected from: hydroxy, amino, carboxy, cyano, nitro, halogen atoms, aminosulfonyl, or unsubstituted or substituted by one or more R b Substituted C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Alkylthio radical C 1-6 Alkyl radical, C 1-6 Alkylamino radical, (C) 1-6 Alkyl radical) 2 Amino group, C 1-6 Alkylamino radical C 1-6 Alkyl radical, C 1-6 Alkylaminocarbonyl, (C) 1-6 Alkyl radical) 2 Aminocarbonyl group, C 1 - 6 Alkylaminocarbonyl radical C 1-6 Alkyl radical, C 1-6 Alkylcarbonylamino, C 1-6 Alkylcarbonylamino group C 1-6 Alkyl, (C) 1-6 Alkyl radical) 2 Amino group C 1-6 Alkyl radical, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl radical C 1-6 Alkyl radical, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylsulfonyl radical C 1-6 Alkyl radical, C 1-6 Alkylaminosulfonyl radical, C 1-6 Alkylaminosulfonyl radical C 1-6 Alkyl radical, C 1-6 Alkylsulfonylamino, C 1 - 6 Alkylsulphonamido C 1-6 Alkyl, cy 2 -、Cy 2 -C 1-6 Alkyl, cy 2 -C 1-6 Alkoxy, cy 2 -O-、Cy 2 -C(O)-、Cy 2 -NH-C(O)-，Cy 2 Is 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, aryl, 5-14 membered heteroaryl;
each R b Independently selected from: hydroxy, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 Alkyl, halo C 1 - 6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1 - 6 Alkoxy radical C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, (C) 1-6 Alkyl radical) 2 Amino group, C 1-6 Alkylaminocarbonyl radical, C 1-6 Alkylcarbonylamino, C 1-6 Alkylcarbonyl group, C 1-6 Alkylaminosulfonyl radical, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylsulfonyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, aryl, 5-14 membered heteroaryl;
provided that when Cy is used 1 Is that
When R is a Is other than C 1-6 Alkylaminocarbonyl and (C) 1-6 Alkyl radical) 2 An aminocarbonyl group.
In one embodiment, the compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, wherein, R is 1 And R 2 Each independently selected from hydrogen, halogen, and R 1 And R 2 Not hydrogen at the same time;
R 3 and R 4 Each independently selected from hydrogen or C 1-6 An alkyl group;
R 5 and R 6 Each independently selected from hydrogen or C 1-6 An alkyl group;
L 1 is a bond, or is-CR 'R' -, -N-, -O-, -S-, R 'and R' are each independently selected from hydrogen or C 1-6 An alkyl group;
C y1 is unsubstituted or substituted by one or more R a A substituted group represented by the following formula (a-1):
m and n are integers of 0-3, X 1 、X 2 、X 3 Each independently selected from CH 2 、CH、N、O、NH、C＝O，X 4 、X 5 、X 6 Each independently selected from CH or N, when m and N > 0, each X 3 Or X 4 May be the same or different;
each R a Independently selected from: hydroxy, amino, carboxy, cyano, nitro, halogen atoms, aminosulfonyl, or unsubstituted or substituted by one or more R b C substituted by substituents 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1 - 6 Alkoxy radical C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Alkylthio radical C 1-6 Alkyl radical, C 1-6 Alkylamino radical, (C) 1-6 Alkyl radical) 2 Amino group, C 1-6 Alkylamino radical C 1-6 Alkyl radical, C 1-6 Alkylaminocarbonyl, (C) 1-6 Alkyl radical) 2 Aminocarbonyl group, C 1-6 Alkylaminocarbonyl radical C 1-6 Alkyl radical, C 1-6 Alkylcarbonylamino, C 1-6 Alkylcarbonylamino group C 1-6 Alkyl radical, C 1-6 Alkylcarbonyl group, C 1-6 Alkyl carbonyl group C 1-6 Alkyl radical, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylsulfonyl radical C 1-6 Alkyl radical, C 1-6 Alkylaminosulfonyl radical, C 1 - 6 Alkylaminosulfonyl radical C 1-6 Alkyl radical, C 1-6 Alkylsulfonylamino, cy 2 -、Cy 2 -C 1-6 Alkyl, cy 2 -C 1-6 Alkoxy, cy 2 -O-、Cy 2 -C(O)-、Cy 2 -NH-C(O)-，Cy 2 Is 3-8 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl;
each R b Independently selected from: hydroxy, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 Alkyl, halo C 1 - 6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 1 - 6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Alkylaminocarbonyl radical, C 1-6 Alkylcarbonylamino, C 1-6 Alkylcarbonyl, 3-8 membered cycloalkyl, 5-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl;
provided that when Cy 1 Is that
When R is a Is other than C 1-6 Alkylaminocarbonyl and (C) 1-6 Alkyl radical) 2 An aminocarbonyl group.
In one embodiment, the compounds of formula I, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
C y1 is unsubstituted or substituted by one or more R a A substituted group represented by the following formula (a-1):
m and n are integers of 1-2, X 1 、X 2 、X 3 Each independently selected from CH 2 、CH、N、O、NH，X 4 、X 5 、X 6 Each independently selected from CH or N, when m and N > 0, each X 3 Or X 4 May be the same or different;
In one embodiment, the compounds of formula I, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
wherein, C y1 Is unsubstituted or substituted by one or more R a Substituted groups represented by the following formulae (a-11), (a-12):
m and n are integers of 1-2, X 1 、X 2 、X 3 Each independently selected from CH 2 、CH、N、O、NH，X 4 、X 5 、X 6 Each independently selected from CH or N, when m > 0, each X 3 May be the same or different;
In one embodiment, the compounds of formula I, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
wherein, C y1 Is unsubstituted or substituted by one or more R a Substituted with the following groups:
In one embodiment, the compounds of formula I, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
wherein, C y1 Is unsubstituted or substituted by one or more R a Substituted with the following groups:
each R a Independently selected from: hydroxy, amino, carboxy, cyano, nitro, halogen atoms, aminosulfonyl, or unsubstituted or substituted by one or more R b C substituted by substituents 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1 - 6 Alkoxy radical C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Alkylaminocarbonyl, (C) 1-6 Alkyl radical) 2 Aminocarbonyl group, C 1-6 Alkylcarbonylamino, C 1-6 Alkyl carbonyl, C 1-6 Alkyl carbonyl radical C 1-6 Alkyl radical, C 1-6 Alkylsulfonyl radical, C 1 - 6 Alkylsulfonyl radical C 1-6 Alkyl radical, C 1-6 Alkylaminosulfonyl radical, C 1-6 Alkylaminosulfonyl radical C 1-6 Alkyl radical, C 1-6 Alkylsulfonylamino, C 1-6 Alkylsulphonamido C 1-6 Alkyl, cy 2 -、Cy 2 -C 1-6 Alkyl, cy 2 -C 1-6 Alkoxy radical, cy 2 -O-、Cy 2 -C(O)-、Cy 2 -NH-C(O)-，Cy 2 Is 3-8 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl;
each R b Independently selected from: hydroxy, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 Alkyl, halo C 1 - 6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 1 - 6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Alkylaminocarbonyl radical, C 1-6 Alkylcarbonylamino, C 1-6 Alkylcarbonyl, 3-8 membered cycloalkyl, 5-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl;
provided that when Cy is used 1 Is that
When R is a Is other than C 1-6 Alkylaminocarbonyl and (C) 1-6 Alkyl radical) 2 An aminocarbonyl group.
In one embodiment, the compounds of formula I, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
wherein, C y1 Is unsubstituted or substituted by one or more R a Substituted with the following groups:
each R a Independently selected from: hydroxy, amino, carboxy, cyano, nitro, halogen atoms, aminosulfonyl, or unsubstituted or substituted by one or more R b C substituted by substituents 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Alkylcarbonylamino, C 1-6 Alkylcarbonyl group, (C) 1-6 Alkyl radical) 2 Aminocarbonyl group, C 1-6 Alkyl carbonyl radical C 1-6 Alkyl radical, C 1 - 6 Alkylsulfonyl radical, C 1-6 Alkylaminosulfonyl radical, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylsulphonamido C 1-6 Alkyl, cy 2 -、Cy 2 -C 1-6 Alkyl, cy 2 -C 1-6 Alkoxy radical, cy 2 -O-、Cy 2 -C(O)-、Cy 2 -NH-C(O)-，Cy 2 Is 3-8 membered cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl;
each R b Independently selected from: hydroxy, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 Alkyl, halo C 1 - 6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Alkylaminocarbonyl radical, C 1-6 Alkylcarbonylamino, C 1-6 Alkylcarbonyl, 3-8 membered cycloalkyl, 5-10 membered heterocyclyl, phenyl, 5-10 membered heteroaryl.
In one embodiment, the compounds of formula I, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
wherein, C y1 Is unsubstituted or substituted by one or more R a Substituted with the following groups:
each R a Independently selected from: hydroxy, amino, halogen atoms, aminosulfonyl, or unsubstituted or substituted by one or more R b C substituted by substituents 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylcarbonylamino, C 1-6 Alkylcarbonyl group, C 1-6 Alkylsulfonyl radical, C 1-6 Alkylaminosulfonyl, (C) 1-6 Alkyl radical) 2 Aminocarbonyl group, C 1-6 Alkyl carbonyl group C 1-6 Alkyl radical, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylsulphonamido C 1-6 Alkyl, cy 2 -、Cy 2 -C 1-6 Alkyl radical、Cy 2 -C(O)-、Cy 2 -NH-C(O)-，Cy 2 Is 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-10 membered heteroaryl;
each R b Independently selected from: hydroxy, amino, halogen atom, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl, 4-6 membered heterocyclyl.
In another embodiment of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, wherein:
in another embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, optionally with one or more pharmaceutically acceptable carriers.
In another embodiment of the present invention, the pharmaceutical composition can be administered to a patient or subject in need of prevention and/or treatment by any suitable administration means known in the art, for example, by oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal administration, and the like.
In another technical scheme of the invention, the pharmaceutical composition can be prepared into conventional solid preparations, such as tablets, capsules, pills, granules and the like; can also be made into oral liquid preparation, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, the pharmaceutical composition can be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as a suppository or the like. For pulmonary administration, the pharmaceutical composition can be made into inhalant or spray.
In another embodiment of the present invention, there is provided a use of a compound represented by formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof for the manufacture of a medicament for the prevention and/or treatment of a disease associated with or mediated by SSAO/VAP-1 protein.
In another aspect of the present invention, there is provided a method for preventing and/or treating a disease associated with or mediated by SSAO/VAP-1 protein, comprising administering to a subject a compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof.
In another embodiment of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof for use in the prevention and/or treatment of diseases associated with or mediated by SSAO/VAP-1 protein.
In another embodiment of the present invention, there is provided a use of the above pharmaceutical composition for preventing and/or treating a disease associated with or mediated by SSAO/VAP-1 protein.
Effects of the invention
The present invention provides novel allylamine compounds that are useful in the treatment and/or prevention of diseases associated with or mediated by SSAO/VAP-1 protein. Specifically, the compound shown in the formula I, pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof show strong inhibitory activity on SSAO/VAP-1 protein. Also, the compounds of the present invention show excellent selectivity for SSAO/VAP-1 proteins relative to rhAOC1 protein (DAO).
Thus, the present invention may provide a medicament for the prevention and/or treatment of diseases associated with or mediated by SSAO/VAP-1 protein.
Detailed Description
Embodiments of the present invention will be described in more detail below with reference to specific embodiments, but those skilled in the art will appreciate that the specific embodiments described below are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Unless otherwise specified, the embodiments of the present invention may be combined in any manner, and the changes, modifications, and alterations of the technical solutions obtained thereby are also included in the scope of the present invention.
Definition of
In the present invention, "C a-b The expression "radical" (a and b denote integers of 1 or more, a < b) denotes that the "radical" has a to b carbon atoms, e.g. C 1-6 Alkyl, i.e. representing an alkyl group having 1 to 6 carbon atoms, C 1-6 Alkoxy, i.e. alkoxy having 1 to 6 carbon atoms, C 3-8 Cycloalkyl, i.e. cycloalkyl having 3 to 8 carbon atoms, C 1-6 Alkoxy radical C 1-6 The alkyl group means a group in which an alkoxy group having 1 to 6 carbon atoms and an alkyl group having 1 to 6 carbon atoms are bonded.
The "halogen" or "halogen atom" as used herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom. Preferably a fluorine atom, a chlorine atom.
"C" according to the invention 1-6 Alkyl "refers to a straight or branched chain alkyl group derived from an alkane moiety containing 1 to 6 carbon atoms by the removal of one hydrogen atom, including straight chain C 1-6 Alkyl and branched C 1-6 An alkyl group. In fact, C is well known to those skilled in the art 1-6 The alkyl group having a branch (branch C) 1-6 Alkyl) having at least 3 carbon atoms. As "C 1-6 Examples of the alkyl group "include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and 1-methyl-2-methylpropyl. Said "C 1-4 Alkyl "refers to the above examples containing 1 to 4 carbon atoms.
"C" according to the invention 2-6 The alkenyl group "means a straight-chain or branched alkenyl group derived by removing one hydrogen atom from an olefin moiety of 2 to 6 carbon atoms having at least one carbon-carbon double bond, and examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butan-1-yl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-2-yl, 1, 3-pentadien-1-yl, 1, 4-pentadien-3-yl, 1-hexen-3-yl, 1, 4-hexadien-1-yl and the like. Preferably, "C" is 2-6 Alkenyl "contains one carbon-carbon double bond.
"C" according to the invention 2-6 Alkynyl "means a straight-chain or branched alkynyl group derived by removing one hydrogen atom from an alkynyl moiety of 2 to 6 carbon atoms having at least one carbon-carbon triple bond, and examples thereof include ethynyl, propynyl, 2-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-methyl-2-pentyn-1-yl, 2-hexyn-1-yl, 3-hexyn-2-yl, 3-hexyn-1-yl, 3-hexyn-2-yl and the like. Preferably, "C" is 2-6 Alkynyl "contains a carbon-carbon triple bond.
"C" according to the invention 1-6 Alkoxy "means" C "as defined hereinbefore 1-6 The alkyl group "is a group attached to the parent molecular moiety through an oxygen atom, i.e." C 1-6 Examples of the alkyl-O- "group include the above-mentioned" C 1-6 The group bonded to-O-of the groups listed under "alkyl" includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexoxy and the like. Said "C 1-4 Alkoxy "refers to the above examples containing 1 to 4 carbon atoms, i.e." C 1-4 An alkyl-O- "group.
Said "C 1-6 Alkoxy C 1-6 Alkoxy "means C 1-6 Alkoxy substituted C 1-6 A group formed by one or more hydrogen atoms on the alkoxy group.
Said "C 1-6 Alkylamino groups "," (C) 1-6 Alkyl radical) 2 Amino group and C 1-6 Alkylcarbonylamino group and C 1-6 Alkylaminocarbonyl group and C 1-6 Alkylcarbonyl group and C 1-6 Alkylaminosulfonyl group and "C 1-6 Alkylsulfonylamino group "," C 1-6 Alkylsulfonyl group "," C 1-6 Alkylthio "means C 1-6 Alkyl is each independently substituted with-NH 2 、-CO-NH 2 -、-NH 2 -CO-、-CO-、-NH 2 SO 2 -、-SO 2 NH 2 -、-SO 2 -, -S-are linked to form a group.
Said "C 1-6 Alkoxy C 1-6 Alkyl group "," C 1-6 Alkylthio group C 1-6 Alkyl group "," C 1-6 Alkylamino radical C 1-6 Alkyl group "," C 1-6 Alkylamino carbonyl radical C 1-6 Alkyl group "," C 1-6 Alkylcarbonylamino group C 1-6 Alkyl group "," C 1-6 Alkyl carbonyl radical C 1-6 Alkyl group "," C 1-6 Alkylaminosulfonyl radical C 1-6 Alkyl group "," C 1-6 Alkylsulphonamido C 1-6 Alkyl group "," C 1-6 Alkylsulfonyl radical C 1-6 Alkyl "means C 1 - 6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Alkylamino radical, C 1-6 Alkylamino carbonyl, C 1-6 Alkylcarbonylamino group, C 1-6 Alkylcarbonyl group, C 1 - 6 Alkylaminosulfonyl radical, C 1-6 Alkylsulfonylamino group, C 1-6 Alkylsulfonyl substitutionC 1-6 A group formed by one or more hydrogen atoms on an alkyl group.
The "condensed ring" in the present invention means a polycyclic structure formed by connecting two or more cyclic structures in a parallel, spiro or bridged manner. The fused ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (i.e., sharing a bond). The bridged ring refers to a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other. The spiro ring refers to a fused ring structure formed by two or more cyclic structures sharing one ring atom with each other.
"cycloalkyl" as used herein refers to a monovalent or (if desired) divalent group derived from a cycloalkane, including a monocyclic or fused ring cycloalkane, and may have 3,4, 5,6, 7, 8, 9, 10, 11, or 12 carbon atoms. Unless otherwise specified, a certain cycloalkyl group includes all monocyclic, fused rings (including fused rings in the form of a parallel, spiro, or bridge) which may be formed. The cycloalkyl group may be a 3-to 12-membered monovalent group or (as necessary) a divalent or more group, and may be a 3-to 10-membered monovalent group or (as necessary) a divalent or more group, a 3-to 8-membered monovalent group or (as necessary) a divalent or more group, a 3-to 6-membered monovalent group or (as necessary) a divalent or more group, a 4-to 6-membered monovalent group or (as necessary) a divalent or more group, a 5-to 7-membered monovalent group or (as necessary) a divalent or more group.
The monocyclic cycloalkyl group (monovalent or divalent or more) may be a 3-12 membered cycloalkyl group, a 3-10 membered cycloalkyl group, a 3-8 membered cycloalkyl group, a 3-6 membered cycloalkyl group, a 4-6 membered cycloalkyl group, a 5-7 membered cycloalkyl group, and examples thereof include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentane-1, 3-diyl, cyclohexane-1, 4-diyl, cycloheptane-1, 4-diyl, etc.
The (monovalent or divalent or more) fused ring cycloalkyl group includes a fused ring cycloalkyl group, a bridged ring cycloalkyl group, and a spiro cycloalkyl group.
The (monovalent or divalent or more) acyclic cycloalkyl group may be a 6-12 membered acyclic cycloalkyl group, a 7-10 membered acyclic cycloalkyl group, examples of which include, but are not limited to: bicyclo [3.1.1] heptanyl, bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, bicyclo [3.2.2] nonanyl, bicyclo [3.3.1] nonanyl, and bicyclo [4.2.1] nonanyl.
The "cycloalkenyl group" in the present invention means a group having at least one carbon-carbon double bond in the group of the cycloalkyl group. Preferably with one carbon-carbon double bond.
"cycloalkyl" and "cycloalkenyl" can also be monovalent radicals obtained by removing one hydrogen atom from a 6-12 membered spirocyclic ring, a 7-11 membered spirocyclic ring, or divalent radicals obtained by removing one hydrogen atom from each of two different carbon atoms, as desired. Examples of spiro rings include, but are not limited to:
"cycloalkyl" and "cycloalkenyl" can also be monovalent radicals obtained by removing one hydrogen atom from a 6-12 membered bridged ring, a 7-11 membered bridged ring, or divalent radicals obtained by removing one hydrogen atom from each of two different carbon atoms, as desired. Examples of such bridge rings include, but are not limited to:
thus, the term "3-12 membered cycloalkenyl" as used herein, unless otherwise specified, includes all monocyclic, fused rings (including fused rings in a parallel, spiro, or bridged form) that may be formed. Which is a group having at least one carbon-carbon double bond in the above-exemplified 3-to 12-membered monovalent group or (as required) a cycloalkyl group of a divalent or more group. For example, monovalent or divalent groups derived from 3-to 8-membered cycloalkenes, 7-to 11-membered spirocycloalkenes, 7-to 11-membered benzocycloalkenes, 6-to 11-membered bridged cycloalkenes, and the like. Examples thereof include cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl and 1, 5-cyclooctadienyl.
The "heterocyclic group" in the present invention means a non-aromatic monovalent or divalent cyclic group in which at least one ring carbon atom of the above cycloalkyl group is replaced with a hetero atom selected from O, S and N. Preferably without a carbon-carbon double bond or with one carbon-carbon double bond. Preferably by 1 to 3 heteroatoms selected from O, S, N. The heterocyclic group of the present invention also includes the case where a carbon atom, a sulfur atom, or a nitrogen atom is substituted by oxo or aza as a ring-forming atom, for example, the case where a carbon atom is substituted by C (= O), S (= O) 2 S (= O) (= NH) substitution.
Specifically, the "heterocyclic group" may be a group having 3,4, 5,6, 7, 8, 9, 10, 11 or 12 ring-constituting atoms. It may be a 3-14-membered heterocyclic group, a 3-12-membered heterocyclic group, a 3-10-membered heterocyclic group, a 4-10-membered heterocyclic group, a 3-8-membered heterocyclic group, a 4-12-membered heterocyclic group, a 4-8-membered heterocyclic group, a 4-6-membered heterocyclic group, a 5-10-membered heterocyclic group.
In addition, "heterocyclic group" includes monovalent or (as necessary) divalent or more monocyclic heterocyclic group systems or monovalent or (as necessary) divalent or more polycyclic heterocyclic group systems (also referred to as condensed ring systems), including saturated, partially saturated heterocyclic groups, but excluding aromatic rings. All monocyclic, fused ring (including fused in the form of a parallel, spiro, bridge), saturated, partially saturated situations are included, where possible, unless otherwise specified.
The monovalent or (if necessary) divalent or more monocyclic heterocyclic group may be a 3-14-membered heterocyclic group, a 3-12-membered heterocyclic group, a 3-10-membered heterocyclic group, a 4-10-membered heterocyclic group, a 3-8-membered heterocyclic group, a 4-12-membered heterocyclic group, a 4-8-membered heterocyclic group, a 4-6-membered heterocyclic group, a 5-10-membered heterocyclic group, a 3-8-membered saturated heterocyclic group, a 3-6-membered heterocyclic group, a 4-12-membered heterocyclic group, a 4-7-membered heterocyclic group, a 4-6-membered heterocyclic group, a 5-10-membered heterocyclic group, a 5-7-membered heterocyclic group, a 5-6-membered oxygen-containing heterocyclic group, a 5-6-membered nitrogen-containing heterocyclic group, a 5-6-membered saturated heterocyclic group, a 5-7-membered saturated heterocyclic group or the like, which may be saturated, partially saturated or unsaturated, but is not aromatic. Examples include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidyl, hexahydropyridazinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 2H-1, 2-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl, 1-dioxothienyl, 1-tetrahydrothiofuranyl, 1, 5-tetrahydrothiofuranyl, etc.
Monovalent or (as desired) divalent or higher fused heterocyclic rings include heterocyclic, spiro heterocyclic, bridged heterocyclic, which may be saturated, partially saturated or unsaturated, but are not aromatic.
The said heterocyclic group may be 6-12 membered heterocyclic group, 7-10 membered heterocyclic group, 6-12 membered saturated heterocyclic group, 7-8 membered saturated heterocyclic group, examples of which include but are not limited to: 3-azabicyclo [3.10 ] hexanyl, 3, 6-diazabicyclo [3.2.0] heptanyl, 3, 8-diazabicyclo [4.2.0] octanyl, 3, 7-diazabicyclo [4.2.0] octanyl, octahydropyrrolo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-b ] [1,4] oxazinyl, octahydro-1H-pyrrolo [3,4-c ] pyridyl, 2, 3-dihydrobenzofuran-2-yl, 2, 3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3 dihydrobenzothien-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl, octahydrocyclopenta [ c ] pyrrolyl, hexahydrocyclopenta [ c ] furanyl, 2-dioxohexahydrocyclopenta [ c ] furanyl, 2-oxocyclopenta [ c ] thiophenyl.
The spiro heterocyclic group can be removed from 6-12 membered spiro heterocyclic ring, 7-11 membered spiro heterocyclic ring, 6-12 membered saturated spiro heterocyclic ring, 7 membered saturated spiro heterocyclic ringA monovalent group obtained by removing one hydrogen atom from each of two different carbon atoms, or a divalent group obtained by removing one hydrogen atom from each of two different carbon atoms, as required, and examples of the spiroheterocycle include, but are not limited to:
the bridged heterocyclic group may be a monovalent group obtained by removing one hydrogen atom from a 6-12-membered bridged heterocyclic ring, a 7-11-membered bridged heterocyclic ring, a 6-12-membered saturated bridged ring, a 7-8-membered saturated bridged ring, or a divalent group obtained by removing one hydrogen atom from each of two different carbon atoms as required, and examples of the bridged heterocyclic group include, but are not limited to:
the term "aryl" as used herein refers to a monovalent group or groups of greater than two valencies as desired derived from aromatic carbocyclic hydrocarbons, including 6-to 8-membered monocyclic aromatic hydrocarbons and 8-to 14-membered fused ring aromatic hydrocarbons. A6-8 membered monocyclic aryl group is for example phenyl. Examples of the 8-to 14-membered fused ring aryl group include naphthyl, phenanthryl, anthryl and the like. When it is a divalent group, phenylene, naphthylene and the like are exemplified.
The "heteroaryl" in the present invention may be a 5-14 membered heteroaryl, a 5-10 membered heteroaryl, or a 5-6 membered heteroaryl, and refers to a monovalent or divalent cyclic group having aromaticity with the number of ring atoms of 5,6, 7, 8, 9, 10, 11, 12, 13, or 14 having at least one heteroatom selected from O, S, and N. Preferably with 1-3 heteroatoms. The heteroaryl group also includes a ring-forming atom containing a carbon atom, a sulfur atom, an oxo group, and a nitrogeno group, and examples thereof include a ring-forming atom containing a carbon atom represented by C (= O), S (= O) 2 S (= O) (= NH) substitution. The heteroaromatic ring of the present invention may be a monocyclic ring system or a fused ring system (fused in the form of a parallel, spiro or bridge)) Heteroaryl includes both mono-and fused heteroaryl, where a single heteroaryl includes all monocyclic, fused, wholly aromatic, and partially aromatic moieties that may be formed, unless otherwise specified. The monoheteroaryl group may be a 5-7 membered heteroaryl group, a 5-6 membered heteroaryl group, and examples thereof include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. The fused heteroaryl group may be an 8-12 membered and heteroaryl group, a 9-10 membered and heteroaryl group, examples of which include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzothiophenyl, benzooxadiazolyl, benzothiazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, naphthyridinyl, purinyl, quinolyl. The heteroaryl group may also be a divalent group derived from the above groups.
The term "3-6-membered ring", 3-8-membered ring "," 4-6-membered ring "or" 4-7-membered ring "as used herein refers to a chemically feasible cyclic structure of 3-6 ring atoms, 3-8 ring atoms, 4-6 ring atoms or 4-7 ring atoms, wherein the ring atoms may be optionally selected from C, N, O, S, C (= O), S (= O) 2 S (= O) (= NH), the cyclic structure formed may be a monocyclic ring, may be a fused polycyclic ring, may be saturated, may be partially saturated, or may be aromatic. Specifically, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups are exemplified.
The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable acid or base addition salt of a compound of formula I or a solvate thereof. When acidic functional groups (e.g., -COOH, -OH, -SO) are present in the compound 3 H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases. When a basic functional group (e.g., -NH) is present in the compound 2 Etc.) with a suitable inorganic or organic anion (acid), including salts with inorganic acid salts, organic acids.Such "pharmaceutically acceptable salts" include, but are not limited to, salts of acids such as: hydrochloric acid, trifluoroacetic acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acids (e.g., acetic acid, HOOC- (CH) 2 ) n -COOH (wherein n is 0 to 4)) and the like; salts of bases: sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt, etc.
In the present invention, the N atom of the amino group may be optionally protected with an amino protecting group at the time of reaction. "amino protecting group" refers to a chemical group attached to an amino group and readily removable under certain conditions, including but not limited to, alkoxycarbonyl, acyl, alkyl; for example, t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, p-methoxybenzyl, trityl and the like. Those skilled in the art can refer to the commonly used textbook Greene's Protective Groups in Organic Synthesis (4) th edition) to make appropriate selections and operations.
The term "optionally substituted" or "optionally substituted" means that any moiety known to those skilled in the art to be available for substitution can be unsubstituted or substituted with a substituent as described herein, wherein if more than one substituent is present, each substituent can be independently selected.
The phrase "pharmaceutically acceptable" means that the substance or composition must be pharmaceutically and/or toxicologically compatible with the other ingredients included in the formulation and/or pharmaceutical composition.
The "isomers" of the present invention include stereoisomers and tautomers.
Stereoisomers refer to compounds that when asymmetric carbon atoms are present, enantiomers are produced; when a compound has a carbon-carbon double bond or a cyclic structure, cis-trans isomers are produced.
"tautomer" refers to a functional isomer arising from the rapid movement of an atom in a molecule at two positions, and a tautomer is a particular functional isomer. Such as carbonyl containing alpha-HTautomerism of the base compounds, e.g. in particular
T、T 1 、T 2 Each independently is any group which conforms to the bonding law of the compounds.
Such as other proton-transport tautomers, in particular phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers.
All enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers, tautomers and mixtures thereof of the compounds of formula I are included within the scope of the present invention.
The pharmaceutical composition comprises at least one compound shown in formula I or pharmaceutically acceptable salt, ester, stereoisomer and tautomer thereof and one or more optional pharmaceutical carriers.
The pharmaceutical compositions of the present invention may be administered to a patient or subject in need of prophylaxis and/or treatment by any suitable mode of administration known in the art, for example, by oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal modes of administration and the like.
The pharmaceutical composition can be prepared into conventional solid preparations, such as tablets, capsules, pills, granules and the like; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When formulated for oral administration, one or more substances selected from suitable excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrating agents, stabilizers, preservatives and encapsulating materials may be added. For parenteral administration, the pharmaceutical composition can be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding suitable additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition can be made into inhalant or spray. In the present invention, suitable solid carriers include, but are not limited to, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, acacia, sodium alginate, parabens, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, cocoa butter, and the like. Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, glycerides, and mixtures thereof.
Methods of preparing the pharmaceutical compositions of the present invention are generally known. The preparation of the pharmaceutical compositions of the invention in known manner includes conventional mixing, granulating, tabletting, coating, dissolving or lyophilizing processes.
The pharmaceutical formulation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage forms may be packaged in a pack containing discrete quantities of preparation, such as packeted tablets, capsules, or powders in vials or ampoules.
The dose of the drug to be administered depends on various factors including the age, weight and condition of the patient and the route of administration. The precise dose to be administered is determined at the discretion of the attendant physician. Typical dosages for administering the active compounds may be, for example: about 0.01 to about 100mg per day, about 0.05 to about 75mg per day, about 0.1 to about 50mg per day, or about 5 to about 10mg per day. The desired dosage will also depend on the particular compound employed, the severity of the disease, the route of administration, the weight and health of the patient and the judgment of the treating physician.
The compound of the present invention may further contain a compound in which one or more of a hydrogen atom, a fluorine atom, a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom is replaced with a radioisotope or a stable isotope. These labeled compounds are useful for metabolic or pharmacokinetic studies, biological analyses as ligands for receptors, and the like.
The compounds of the invention may be used for the treatment and/or prevention of diseases associated with or mediated by SSAO/VAP-1 protein, comprising administering a compound of the invention to a subject.
Pharmaceutical compositions comprising a compound of the invention may be used for the treatment and/or prevention of diseases associated with or mediated by the SSAO/VAP-1 protein comprising administering to a subject a compound of the invention.
The invention relates to a method for preparing a compound of general formula (I)
The compounds of the present invention can be prepared by a variety of methods, including standard chemical methods. Any previously defined variables will continue to have the previously defined meanings unless otherwise indicated. Exemplary general synthetic methods are set forth in the schemes below and can be readily modified to prepare other compounds of the invention. Those skilled in the art can routinely practice (e.g., organic Synthesis 2) in accordance with the teachings of the art nd edition, michael b. Smith etc.) the following reaction was carried out. Specific compounds of the invention are specifically prepared in the examples section.
In one embodiment of the invention, the compounds of the general formula (I), obtained by reacting a compound of the formula (SM 1) with a compound of the formula (SM 2),
wherein, cy 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、L 1 As described hereinbefore; x 1 Is a leaving group including, but not limited to, halogen or sulfonate.
Further, when R is 3 And R 4 When hydrogen is used, the preparation process needs to be carried out
Protection of hydrogen atoms on N in the structure to form
Wherein, G 1 And G 2 Respectively an amino protecting group.
The "amino-protecting group" is a protecting group commonly used by those skilled in the art, for example: t-butoxycarbonyl, benzyloxycarbonyl, t-butyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trifluoroacetyl, chloroacetyl, triphenylmethyl, tetrahydropyranyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, o-nitrobenzenesulfonyl, phthaloyl. Furthermore, the protection and deprotection of the amino group can be carried out by methods known to those skilled in the art, for example, refer to Protective Groups in Organic Synthesis,3 rd The procedure described in edition.
In one embodiment of the present invention, the compound represented by the general formula (I') is prepared by the following steps:
wherein, cy 1 、G 1 、G 2 、X 1 As defined above.
(1) Dissolving the formula (SM 1) in an organic solvent 1 Adding a suitable base to react with the formula (SM 2-a) to obtain a formula (II-a);
(2) Dissolving the formula (II-a) in an organic solvent 2 And adding a suitable deprotection reagent for deprotection to obtain the formula (I').
In one embodiment of the present invention, the compound represented by the general formula (I') is prepared by the following steps:
wherein, cy 1 、X 1 As defined above;
G 2 selected from: t-butyloxycarbonyl, benzyloxycarbonyl, t-butyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trisFluoroacetyl, chloroacetyl, triphenylmethyl, tetrahydropyranyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, o-nitrobenzenesulfonyl; wherein, the first and the second end of the pipe are connected with each other,
(1) Dissolving the formula (SM 1) in an organic solvent 1 Adding a compound of formula (SM 2-c) and a base to obtain a compound of formula (II-c);
(2) Dissolving the formula (II-c) in an organic solvent 2 Adding a deprotection agent for deprotection to obtain the formula (I').
In one embodiment of the present invention, the compound represented by the general formula (I') is prepared by the following steps:
wherein, cy 1 、X 1 As defined above, wherein,
(1) Dissolving the formula (SM 1) in an organic solvent 1 Adding a suitable alkali to react with the compound shown in the formula (SM 2-b) to obtain a compound shown in the formula (II-b);
(2) Dissolving the formula (II-b) in an organic solvent 2 And adding hydrazine hydrate to perform a hydrazinolysis reaction to obtain the formula (I').
In one embodiment of the present invention, the organic solvent is 1 DMF, DMA, ACN, methanol, ethanol, isopropanol, THF.
In one embodiment of the present invention, the organic solvent is 2 Methanol, ethanol, and isopropanol.
In one embodiment of the invention, the base is sodium hydride, cesium carbonate, potassium carbonate, lithium bis (trimethylsilyl) amide.
In one embodiment of the present invention, the deprotecting agent is hydrochloric acid, trifluoroacetic acid, hydrobromic acid, trimethyliodosilane, or the like.
In one embodiment of the present invention, a phase-transfer catalyst, which may be a catalyst commonly used in the art, including, but not limited to, copper acetate, copper chloride, palladium on charcoal, ferric chloride, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, and the like, may be added during the reaction to obtain the target compound.
By "suitable deprotecting agent" is meant the amino protecting group G in the chemical structure of a person skilled in the art 1 And G 2 The kind of (B) is different, and corresponding acid, alkali or oxidizing agent is selected to carry out the reagent used for deprotection reaction. It can use Protective Groups in Organic Synthesis,3 rd Those described in edition.
In the present invention, the "acid" may be an acid commonly used in the art, and includes organic acids and inorganic acids. Examples of the organic acid include formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, and ethanesulfonic acid; examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, and hydroiodic acid. Hydrochloric acid is preferred.
In the present invention, the "base" may be a base commonly used in the art, and includes organic bases and inorganic bases. Examples of the organic base include methylamine, ethylamine, propylamine, N-diisopropylethylamine, trimethylamine, triethylamine, N-methylmorpholine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, and quinoline; as the inorganic base, there may be mentioned hydroxides, carbonates, bicarbonates, lithium bis (trimethylsilyl) amide of alkali metals (for example, lithium, sodium, potassium, cesium); hydroxides, carbonates, bicarbonates of alkaline earth metals (magnesium, calcium, strontium, barium); sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, etc.
In the present invention, the "oxidizing agent" may be any oxidizing agent commonly used in the art, including, but not limited to, cerium ammonium nitrate, 2, 3-dichloro-5, 6-dicyan-p-benzoquinone, copper chloride, manganese dioxide, permanganate, dichromate, peracetic acid, perbenzoic acid, etc.
In the present invention, the "organic solvent" is 1 "refers to a single or mixed organic solvent commonly used in the art, including but not limited to ethers, alkanes, haloalkanes, aromatic hydrocarbons, alcohols, and the like. Specific examples thereof include N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene, trimethylbenzene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1, 2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1, 2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, isopropanol, t-butanol, etc.), water and a mixed solvent thereof.
In the present invention, the "organic solvent" is 2 "refers to a single or mixed organic solvent commonly used in the art, including but not limited to ethers, alkanes, haloalkanes, aromatics, alcohols, and the like. Specific examples thereof include N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene, trimethylbenzene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1, 2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1, 2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, isopropanol, t-butanol, etc.), water and a mixed solvent thereof.
In the present invention, in the above-mentioned reaction process, the reaction temperature may be adjusted as necessary, for example, high temperature, room temperature, low temperature, etc. High temperature is usually higher than 30 ℃ and if necessary, heating treatment can be carried out, room temperature is usually 15-30 ℃, low temperature is usually lower than 15 ℃, and if necessary, cooling treatment can be carried out.
Examples
The reaction conditions are not specified in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
In the present invention, unless otherwise specified, wherein: (i) The temperature is expressed in degrees centigrade (DEG C), and the operation is carried out in a room temperature environment; (ii) The progress of the reaction is followed by Thin Layer Chromatography (TLC) or LC-MS; (iii) The final product has a clear proton NMR spectrum ( 1 H-NMR) data and Mass Spectrometry (MS) data.
The abbreviations and English expressions used in the present invention have the following meanings:
DAST: diethylaminosulfur trifluoride
DCM: methylene dichloride
DIPEA: n, N-diisopropylethylamine
-Boc: tert-butyloxycarbonyl radical
(Boc) 2 O: di-tert-butyl dicarbonate
t-BuONa: sodium tert-butoxide
NaBH 3 CN: sodium cyanoborohydride
NaH: sodium hydride
LiHMDS: lithium bis (trimethylsilyl) amide
EtOH: ethanol
TFA: trifluoroacetic acid
DMF: n, N-dimethylformamide
Pd 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium
AcOH: acetic acid
THF: tetrahydrofuran (THF)
DMAC: dimethylacetamide
A dioxane: dioxane (dioxane)
Pd(dPPf)Cl 2 :1,1' -bis (diphenylphosphino) ferrocenyl palladium chloride
EA: acetic acid ethyl ester
PE: petroleum ether
HATU:2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate
MeOH: methanol
MTBE: methyl tert-butyl ether
Xphos: 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl
Intermediate product
Namely: (E) 2- (2- (bromomethyl) -3-fluoroallyl) isoindole-1, 3-dione, prepared with reference to Ian A. McDonald, philipe bey. A general preparation of fluoroallylamine enzyme inhibitors in hydrogenation beta. Substitated hydroterotoms tetrahedron, vo1.26, no.32, pp 3807-3810, 1985.
Example 1 Synthesis of (E) - (1- (2- (aminomethyl) -3-fluoroallyl) indolin-5-yl) (pyrrolidin-1-yl) methanone (Compound 3) hydrochloride
Step 1: synthesis of (1H-indol-5-yl) (pyrrolidin-1-yl) methanone
Indole-5-carboxylic acid (5.00g, 0.03mol, 1.0eq) as a raw material was dissolved in DMF (35 mL), cooled to 0 ℃, HATU (18.10 g,0.05mol, 1.5eq), tetrahydropyrrole (2.60g, 0.04mol, 1.2eq) and DIPEA (12.00g, 0.09mol, 3.0eq) were sequentially added under stirring, and the reaction was stirred overnight under nitrogen protection, and TLC was used to monitor completion of the reaction. Adding H to the reaction solution 2 Diluting with O (70 mL), separating out solid, filtering, rinsing the filter cake with water, and drying to obtain the product (5.20 g, yield: 79.0%).
And 2, step: synthesis of indolin-5-yl (pyrrolidin-1-yl) methanone
Intermediate (1H-indol-5-yl) (pyrrolidin-1-yl) methanone (3.00g, 14mmol, 1eq) was dissolved in AcOH (30 mL), cooled to 0 deg.C and NaBH was added slowly with stirring 3 CN (2.20g, 35mmol, 2.5eq), reacted at room temperature overnight, and TLC monitored the completion of the reaction. Saturated Na was added to the reaction mixture 2 CO 3 Aqueous solution, adjusting the pH of the reaction solution to =7, using CH 2 Cl 2 The organic phase is dried over anhydrous sodium sulfate and concentrated to give the crude product (theoretical amount 3.03 g) which is directly fed to the next reaction.
And 3, step 3: synthesis of (Z) -2- (3-fluoro-2- ((5- (pyrrolidine-1-carbonyl) indolin-1-yl) methyl) allyl) isoindoline-1, 3-dione
Dissolving intermediate indolin-5-yl (pyrrolidin-1-yl) methanone (0.44g, 2.01mmol, 1eq) in THF (5 mL), cooling to-20 deg.C, under nitrogen protection, slowly adding LiHMDS (0.37g, 2.21mmol, 1.1eq) dropwise, stirring for 10min after addition, adding (E) -2- (2- (bromomethyl) -3-fluoroallyl) isoindole-1, 3-dione (0.72g, 2.41mmol, 1.2eq) in THF (4 mL), reacting overnight at room temperature, monitoring completion of reaction by TLC, adding NH to the reaction solution 4 Aqueous Cl solution (8 mL), CH 2 Cl 2 Extraction (10 mL × 3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification of the crude product by silica gel column chromatography (DCM: meOH = 150.
And 4, step 4: (E) Synthesis of (1- (2- (aminomethyl) -3-fluoroallyl) indolin-5-yl) (pyrrolidin-1-yl) methanone hydrochloride
Intermediate (Z) -2- (3-fluoro-2- ((5- (pyrrolidine-1-carbonyl) indolin-1-yl) methyl) allyl) isoindoline-1, 3-dione (0.61g, 1.41mmol, 1eq) was dissolved in EtOH (15 mL), 85% hydrazine hydrate (0.29g, 4.94mmol, 3.5eq) was added, and the reaction was refluxed for 5 hours. TLC monitoring the reaction was complete, suction filtered, concentrated, the crude was purified by preparative thin layer chromatography (DCM: meOH =15 1), redissolved in a small amount of ethanol, added hydrogen chloride in ethanol until solution pH =4, stirred for 1h, added acetonitrile, concentrated at 30 ℃, the solid was washed with a small amount of absolute ethanol slurry, and suction filtered to give the product (33 mg, yield: 6.9%) 1 HNMR(400 MHz,DMSO-d 6 )δ(ppm):8.36(s,3H),7.25-7.27(d,2H),7.03-7.24(d,1H),6.71-6.73(d,1H),3.83(s,2H),3.43-3.50(d,6H),3.28-3.32(t,2H),2.90-2.94(t,2H),1.81(s,4H).
Molecular formula C 17 H 22 FN 3 O molecular weight 303.38 LC-MS (Pos, m/z) =304.23[ 2[ M + H ]] + .
Example 2 Synthesis of (E) - (1- (2- (aminomethyl) -3-fluoroallyl) indolin-5-yl) (morpholino) methanone (Compound 7)
Step 1: synthesis of (1H-indol-5-yl) (morpholino) methanone
Indole-5-carboxylic acid (5.00g, 31.02mmol, 1.0eq) as a raw material was dissolved in DMF (30 mL), cooled to 0 ℃, and under stirring, HATU (17.68g, 46.54mmol, 1.5eq) was added first, then a mixture of morpholine (3.24g, 37.23mmol, 1.2eq) and DIPEA (12.02g, 93.07mmol, 3.0eq) was slowly added dropwise, and after the addition, the reaction was carried out at room temperature for 16 hours, and the completion of the reaction was monitored by TLC. The reaction mixture was diluted with water, EA extracted, the organic phase was backwashed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the product (3.60 g, yield: 50.4%).
Step 2: synthesis of indolin-5-yl (morpholino) methanones
Intermediate (1H-indol-5-yl) (morpholino) methanone (1.09g, 4.73mmol,1.0 eq) was dissolved in AcOH (10 mL), cooled to 0 deg.C and NaBH was slowly added 3 CN (0.74g, 11.83mmol,2.5 eq), and the reaction was completed at room temperature for 1 hour, and the completion of the reaction was monitored by TLC. Adding water into the reaction solution for dilution, adding NaOH solution at 0 ℃, adjusting the pH =8 of the reaction solution,extracting with EA, drying the organic phase with anhydrous sodium sulfate, concentrating to obtain the product, and directly carrying out the next reaction.
And step 3: synthesis of (Z) -2- (3-fluoro-2- ((5- (morpholine-4-carbonyl) indolin-1-yl) methyl) allyl) isoindole-1, 3-dione
The crude intermediate indolin-5-yl (morpholino) methanone (1.10 g,4.73mmol, 1eq) was dissolved in DMF (11 mL), cooled to 0 ℃ N 2 After adding 60% NaH (0.21g, 5.21mmol, 1.1eq) under protection, stirring for 30min, (E) -2- (2- (bromomethyl) -3-fluoroallyl) isoindole-1, 3-dione (1.69g, 5.68mmol, 1.2eq) in DMF (11 mL) was added dropwise, reacted overnight at room temperature, TLC monitored for reaction completion, water (60 mL) was added, EA (80 mL × 3) was extracted, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was chromatographed on silica gel column (DCM: meOH = 150) to give the product (0.80 g, yield: 37.6%).
And 4, step 4: (E) Synthesis of (1- (2- (aminomethyl) -3-fluoroallyl) indolin-5-yl) (morpholino) methanone
Intermediate (Z) -2- (3-fluoro-2- ((5- (morpholine-4-carbonyl) indolin-1-yl) methyl) allyl) isoindole-1, 3-dione (0.80g, 1.78mmol, 1eq) was dissolved in EtOH (20 mL), and 85% hydrazine hydrate (0.37g, 6.23mmol,3.5 eq) was added and the reaction was refluxed for 2 hours. TLC monitored the reaction was complete, filtered with suction, concentrated, and the crude product was purified by preparative thin layer chromatography (DCM: meOH = 10.
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):7.10-7.12(m,2H),6.89-7.10(d,1H),6.67-6.69(t,1H),6.15-6.20(m,2H),3.78(d,2H),3.57-3.59(t,4H),3.47-3.49(t,4H),3.37-3.38(d,2H),3.30-3.34(t,2H),2.90-2.95(t,2H).
Molecular formula C 17 H 22 FN 3 O 2 Molecular weight 319.38 LC-MS (Pos, m/z) =320.24[ M + H ],] + .
EXAMPLE 3 Synthesis of (E) -3-fluoro-2- ((5-Morpholinoindol-1-yl) methyl) prop-2-en-1-amine (Compound 11)
Step 1: synthesis of 5-bromoindoline
The starting material, 5-bromoindole (50.00g, 0.26mol, 1.0eq), was dissolved in AcOH (500 mL), cooled to 0 deg.C, and NaBH was slowly added with stirring 3 CN (40.00g, 0.64mol, 2.5eq), at room temperature for 1 hour, and the completion of the reaction was monitored by TLC. Adding water into the reaction liquid for dilution, adding NaOH aqueous solution at 0 ℃, adjusting the pH value to 8, extracting with EA, drying organic phase anhydrous sodium sulfate, concentrating to obtain a crude product (the theoretical yield is 50.50 g), and directly putting the crude product into the next step for reaction.
Step 2: synthesis of 5-bromoindoline-1-carboxylic acid tert-butyl ester
Intermediate 5-bromoindoline (0.26mol, 1eq, based on 50.50 g) was dissolved in THF (500 mL) and slowly added dropwise (Boc) 2 O (61.20g, 0.28mol, 1.1eq), after the addition was completed, the mixture was stirred at room temperature overnight, and the completion of the reaction was monitored by TLC. Concentrating the reaction solution, filtering, heating and dissolving the filter cake with EA, adding 5% of activated carbon, refluxing for 10min, filtering while hot, concentrating the filtrate, filtering, and drying the filter cake at 50 ℃ to obtain the product (62.00 g, yield: 81.6%).
And 3, step 3: synthesis of 5-morpholinoindoline-1-carboxylic acid tert-butyl ester
Under the protection of nitrogen, intermediate 5-bromoindoline-1-carboxylic acid tert-butyl ester (5.00g, 16.76mmol, 1eq), morpholine (7.30g, 83.84mmol, 5eq), t-BuONa (12.60g, 130.79mmol, 7.8eq), xphos (0.60g, 1.34mmol, 0.08eq) and Pd 2 (dba) 3 (0.60g, 0.69mmol, 0.04eq) 1, 4-dioxane (100 mL) was added with H 2 The reaction was performed in a mixed solvent of O (20 mL) at 110 ℃ under reflux for 105min, and the completion of the reaction was monitored by TLC. To the reaction solution was added water (300 mL), EA (400 mL × 2) was extracted, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EA = 10) to obtain a product (3.60 g, yield: 70.6%).
And 4, step 4: synthesis of 4- (indolin-5-yl) morpholine
Intermediate 5-morpholinoindoline-1-carboxylic acid tert-butyl ester (2.00g, 6.57mmol, 1eq) was dissolved in CH 2 Cl 2 To (10 mL) was added TFA (15.00g, 131.41mmol, 20eq) dropwise at room temperature, and the reaction was stirred at 40 ℃ for 1 hour. TLC to monitor the reaction completion, saturated NaHCO was added 3 Aqueous solution, pH =7,CH adjusted 2 Cl 2 Extraction, drying of the organic phase over anhydrous sodium sulfate, suction filtration, concentration, column chromatography separation to give 4- (indolin-5-yl) morpholine as a brown solid (1.40 g, yield: 94.8%).
And 5: synthesis of (Z) -2- (3-fluoro-2- ((5-morpholinoindolin-1-yl) methyl) allyl) isoindoline-1, 3-dione
Intermediate 4- (indolin-5-yl) morpholine (1.10g, 5.38mmol, 1eq) was dissolved in DMF (11 mL), cooled to 0 ℃, under nitrogen protection, naH (0.24g, 5.92mmol, 1.1eq) at a content of 60% was added, after stirring for 30min, (E) -2- (2- (bromomethyl) -3-fluoroallyl) isoindole-1, 3-dione (1.93g, 6.46mmol, 1.2eq) in DMF (11 mL) was added dropwise, the reaction was carried out at room temperature for 3 hours, TLC monitored for completion of the reaction, water (50 mL) was added, EA (80 mL × 3) was extracted, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (DCM: meOH = 50) to give product (2.00 g, yield: 88.1%).
Step 6: (E) Synthesis of (E) -3-fluoro-2- ((5-morpholinoindolin-1-yl) methyl) prop-2-en-1-amine
Intermediate (Z) -2- (3-fluoro-2- ((5-morpholinoindolin-1-yl) methyl) allyl) isoindoline-1, 3-dione (2.00g, 4.75mmol, 1eq) was dissolved in EtOH (50 mL), 85% hydrazine hydrate (0.98g, 16.62mmol, 3.5eq) was added, and the reaction was refluxed for 3 hours. TLC monitored the reaction was complete, filtered with suction, the filtrate was concentrated, and the crude product was purified by preparative thin layer chromatography (DCM: meOH = 10).
1 HNMR(400MHz,DMSO-d 6 )δ(ppm):7.78-7.90(m,2H),6.97-7.18(d,1H),6.79(s,1H),6.64-6.67(t,2H),3.69-3.72(t,4H),3.63(d,2H),3.49(d,2H),3.09-3.13(t,2H),2.90-2.93(t,4H),2.80-2.84(t,2H).
Molecular formula C 16 H 22 FN 3 O molecular weight of 291.37 LC-MS (Pos, m/z) =292.24[ 2[ M ] +H] + .
Example 4: (E) Synthesis of hydrochloride salt of- (1- (2- (aminomethyl) -3-fluoroallyl) indolin-5-yl) (piperidin-1-yl) methanone (Compound 8)
Step 1: synthesis of (1H-indol-5-yl) (piperidin-1-yl) methanone
Dissolving 1H-indole-5-carboxylic acid (5.00g, 31.02mmol and 1eq) in DMF (35 mL), cooling to 0 ℃, adding HATU (18.16g, 46.54mmol), piperidine (3.17g, 37.23mmol and 1.2eq) and DIPEA (12.03g, 0.0931mol and 3eq) for reaction under the protection of nitrogen gas overnight, detecting the completion of the reaction by LC-MS, adding water (70 mL), precipitating a large amount of solid, performing suction filtration, washing a filter cake with water, and drying to obtain a product (4.94 g, yield: 70.7%).
Step 2: synthesis of indolin-5-yl (piperidin-1-yl) methanone
(1H-indol-5-yl) (piperidin-1-yl) methanone (3.00g, 14.00mmol, 1.0eq) was dissolved in glacial acetic acid (30 mL), and sodium cyanoborohydride (2.06g, 32.87mmol, 2.5eq) was added under ice bath, stirred for 20 minutes, warmed to room temperature, and reacted overnight. LC-MS detection showed complete reaction, saturated aqueous sodium carbonate solution was added to adjust the pH to 7, dichloromethane (100 mL. Times.2) was extracted, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (3.5 g crude, 3.02g theoretical).
And step 3: synthesis of (Z) -2- (3-fluoro-2- ((5- (piperidine-1-carbonyl) indolin-1-yl) methyl) allyl) isoindoline-1, 3-dione
Indolin-5-yl (piperidin-1-yl) methanone (610mg, 2.65mmol, 1eq) was dissolved in tetrahydrofuran, cooled to-20 ℃, liHMDS (1 mol/L,3ml,2.92mmol, 1.1eq) was added, stirred for 30 minutes, (E) -2- (2- (bromomethyl) -3-fluoroallyl) isoindoline-1, 3-dione (1.24g, 4.15mmol, 1.2eq) in tetrahydrofuran was added dropwise, the reaction was monitored at room temperature for 4.5 hours, LC-MS monitored for completion, saturated aqueous ammonium chloride (13 mL) was added, DCM was extracted (15 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (DCM: meOH = 150) to give a product (1 g, yield: 84%).
And 4, step 4: (E) Synthesis of (1- (2- (aminomethyl) -3-fluoroallyl) indolin-5-yl) (piperidin-1-yl) methanone hydrochloride
(Z) -2- (3-fluoro-2- ((5- (piperidine-1-carbonyl) indolin-1-yl) methyl) allyl) isoindoline-1, 3-dione (1g, 2.24mmol,1.0 eq) was dissolved in EtOH (25 mL), hydrazine hydrate (80%, 0.46g,7.83mmol,3.5 eq) was added, and the reaction was refluxed overnight. The reaction was monitored by LC-MS for completion, suction filtration, concentration of the filtrate under reduced pressure, addition of EA (20 mL), reflux, filtration while hot, concentration of the filtrate under reduced pressure, addition of ethanol, addition of an ethanol solution of hydrogen chloride to pH 3, addition of acetonitrile (10 mL), concentration under reduced pressure, addition of a mixed solvent of ethanol and ethyl acetate (1, 10 mL) for beating, and suction filtration gave the product (311 mg, yield: 43.8%).
1 HNMR(400MHz,DMSO-d 6 )δ(ppm):8.37(brs,1H),7.07-7.09(m,2H),7.03-7.24(d,J＝83Hz,1H),6.73-6.75(d,1H),3.82-3.83(d,2H),3.49-3.50(d,2H),3.43-3.47(m,4H),3.30-3.32(t,2H),2.90-2.95(t,2H),1.58-1.60(m,2H),1.48-1.49(m,4H).
Molecular formula C 18 H 24 FN 3 O molecular weight: 317.41 LC-MS (Pos, m/z) =318.23[ M + H ]] + .
Example 5 Synthesis of (E) - (1- (2- (aminomethyl) -3-fluoroallyl) indolin-5-yl) (4-hydroxypiperidin-1-yl) methanone (Compound 9)
Step 1: (E) Synthesis of tert-butyl- (3-fluoro-2- ((5- (4-hydroxypiperidine-1-carbonyl) indolin-1-yl) methyl) allyl) carbamate
DMF (3.5 mL) was added to (E) -1- (2- (((tert-butoxycarbonyl) amino) methyl) -3-fluoroallyl) indoline-5-carboxylic acid (412.0mg, 1.17mmol, 1.0eq.), DIPEA (453.3mg, 3.51mmol, 3.0eq.) and HATU (670.6mg, 1.76mmol, 1.5eq.) were added under ice bath, stirred for 2 hours, piperidine-4-ol (165.6mg, 1.63mmol, 1.4eq.) was added thereto, gradually increased to room temperature and stirred for 12 hours, TLC monitored for completion of the reaction, concentrated under reduced pressure, EA (50 mL) and water (80 mL) were added, liquid separation, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM: meOH = 100.
Step 2: (E) Synthesis of (1- (2- (aminomethyl) -3-fluoroallyl) indolin-5-yl) (4-hydroxypiperidin-1-yl) methanone
Tert-butyl (E) - (3-fluoro-2- ((5- (4-hydroxypiperidine-1-carbonyl) indolin-1-yl) methyl) allyl) carbamate (217.6 mg,0.50mmol,1.0 eq.) was added to EtOH (4 mL), and a hydrogen chloride ethanol solution (4 mL) was added dropwise under ice bath, gradually warmed to room temperature and stirred for 2 hours, TLC monitored for completion of the reaction, concentrated under reduced pressure, DCM (20 mL) and a saturated aqueous sodium carbonate solution (40 mL) were added, liquid was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (DCM: meOH = 10) to give a product (25.1 mg, yield: 15.1%).
1 HNMR(400MHz,DMSO-d 6 )δ(ppm):7.06-7.07(m,2H),6.97(s,0.4H),6.76(s,0.5H),6.60-6.62(m,1H),4.76(s,1H),3.79(s,2H),3.71-3.72(s,3H),3.29(s,4H),3.27(s,2H),3.10-3.15(m,2H),2.90-2.94(m,2H),1.71-1.74(d,2H),1.30-1.34(m,2H).
Molecular formula C 18 H 24 FN 3 O 2 Molecular weight 333.41 LC-MS (Pos, m/z) =334.23[ 2[ M ] +H] + .
Example 6: (E) Synthesis of (E) -2- ((5-cyclopropylindolin-1-yl) methyl) -3-fluoroprop-2-en-1-amine (Compound 10)
The method comprises the following steps:
step 1: synthesis of 5-cyclopropylindoline-1-carboxylic acid tert-butyl ester
Tert-butyl 5-bromoindoline-1-carboxylate (5 g,16.8mmol, 1.0eq), potassium phosphate (11.7g, 55.3mmol, 3.3eq), tricyclohexylphosphine (0.47g, 1.68mmol, 0.1eq), cyclopropylboronic acid (2.02g, 23.5mmol, 1.4eq), and palladium acetate (0.38g, 1.68mmol, 0.1eq) were charged into a reaction flask, toluene (50 mL) and water (5 mL) were added, nitrogen gas was substituted 3 times, and the reaction was refluxed for 5 hours. LC-MS detection showed complete reaction, dissolution in water, dilution with ethyl acetate, suction filtration, liquid separation of the filtrate, drying of the organic phase over anhydrous sodium sulfate, and purification of the crude product by silica gel column chromatography (PE: EA =5: 1) to give the product (3.6 g, yield: 82.6%).
And 2, step: synthesis of 5-cyclopropylindoline
Tert-butyl 5-cyclopropylindoline-1-carboxylate (3 g) was mixed with trifluoroacetic acid (21 mL) and stirred at room temperature overnight. TLC showed complete reaction, saturated aqueous sodium carbonate solution was added, pH was adjusted to 7-8, dichloromethane (20 mL. Times.2) was extracted, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (2.2 g crude) which was used directly in the next reaction.
And step 3: synthesis of (Z) -2- (2- ((5-cyclopropylindolin-1-yl) methyl) -3-fluoroallyl) isoindoline-1, 3-dione
5-Cyclopropylindoline (1.3 g crude) was dissolved in DMF (26 mL), sodium hydride (60%, 0.22g, 8.98mmol) was added under ice bath, stirred for 30min, a solution of (E) -2- (2- (bromomethyl) -3-fluoroallyl) isoindoline-1, 3-dione (2.92g, 9.79mmol) in DMF (26 mL) was added dropwise, reacted overnight at room temperature, LC-MS monitored for completion of reaction, water (50 mL) was added, DCM was extracted (70 mL. Times.3), the organic phase was backwashed with water (50 mL. Times.5), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product (3.8 g crude) which was used directly in the next step.
And 4, step 4: (E) Synthesis of (E) -2- ((5-cyclopropylindolin-1-yl) methyl) -3-fluoroprop-2-en-1-amine
(Z) -2- (2- ((5-Cyclopropylindolin-1-yl) methyl) -3-fluoroallyl) isoindoline-1, 3-dione (1.00 g crude) was dissolved in ethanol (25 mL), hydrazine hydrate (0.547g, 9.30mmol, 3.5eq) was added, and the reaction was refluxed for 2 hours. The reaction was monitored by LC-MS to completion, suction filtered, the filtrate was concentrated under reduced pressure, and the crude product was isolated by preparative thin layer chromatography (DCM: meOH =10: 1) to give the product (38 mg, three-step yield: 5.8%).
1 HNMR(400MHz,DMSO-d 6 )δ(ppm):6.91-7.12(d,J＝84Hz,1H),6.76-6.78(m,2H),6.58-6.60(d,1H),4.70(s,2H),3.63-3.64(d,2H),3.42-3.43(d,2H),3.12-3.17(m,2H),2.80-2.84(t,2H),1.76-1.82(m,1H),0.83-0.84(m,2H),0.45-0.55(m,2H).
Molecular formula C 15 H 19 FN 2 Molecular weight 246.33 LC-MS (Pos, m/z) =247.21[ 2[ M ] +H] + .
EXAMPLE 7 Synthesis of (E) -3-fluoro-2- ((5- (thiazol-2-yl) indolin-1-yl) methyl) prop-2-en-1-amine (Compound 32)
The method comprises the following steps:
step 1: synthesis of tert-butyl 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline-1-carboxylate
5-Bromoindoline-1-carboxylic acid tert-butyl ester (5.0g, 16.8mmol, 1eq), potassium acetate (4.9g, 50.4mmol, 3eq), pinacol diboron (8.5g, 33.5mmol, 2eq) and Pd (dppf) Cl 2 (1.5g, 1.68mmol, 0.1eq) was added to a reaction flask, DMAC (25 mL) was added, reaction was carried out at 90 ℃ for 5 hours, LC-MS detection showed completion of the reaction, dilution with water was added, extraction with ethyl acetate (100 mL × 2), organic phase combination, water backwashing (50 mL × 4), concentration under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EA = 5) to obtain a product (4.8 g, yield: 82.8%).
Step 2: synthesis of 5- (thiazol-2-yl) indoline-1-carboxylic acid tert-butyl ester
Tert-butyl 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline-1-carboxylate (3.6 g,10.427mmol, 1.0eq), cesium carbonate (6.79g, 20.854mmol, 2.0eq), 2-bromothiazole (1.71g, 10.427mmol, 1.0eq) and Pd (dppf) Cl 2 (0.95g, 1.043mmol, 0.1eq) was charged in a reaction flask, 1, 4-dioxane (36 mL) and water (3.6 mL) were added, and the mixture was replaced with nitrogen gas 3 times, followed by reflux reaction for 5 days. Water was added for dilution, ethyl acetate was extracted (80 mL × 3), the organic phase was backwashed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EA =5: 1) to obtain a product (1.1 g, yield: 34.9%). And step 3: synthesis of 2- (indolin-5-yl) thiazole
Tert-butyl 5- (thiazol-2-yl) indoline-1-carboxylate (1g, 3.31mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (7 mL) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium carbonate solution was added, the pH was adjusted to 8, methylene chloride (20 mL. Times.2) was extracted, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily product (650 mg, yield: 97.2%).
And 4, step 4: synthesis of (Z) -2- (3-fluoro-2- ((5- (thiazol-2-yl) indolin-1-yl) methyl) allyl) isoindoline-1, 3-dione
Dissolving 2- (indolin-5-yl) thiazole (700mg, 3.46mmol, 1.0eq) in THF (10 mL), cooling to-20 ℃, adding LiHMDS (1 mol/L,3.8mL,3.81mmol, 1.1eq), stirring for 30 minutes, dropwise adding a THF (4 mL) solution of (E) -2- (2- (bromomethyl) -3-fluoroallyl) isoindoline-1, 3-dione (1.24g, 4.15mmol, 1.2eq) at 10 ℃, reacting for 3 hours, LC-MS monitoring reaction completion, adding glacial acetic acid, adjusting pH to 7, adding dichloromethane (20 mL) for dilution, washing, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, purifying the crude product by silica gel column chromatography to obtain the product (1.00 g, yield: 68.96%)
And 5: (E) -3-fluoro-2- ((5- (thiazol-2-yl) indolin-1-yl) methyl) prop-2-en-1-amine
(Z) -2- (3-fluoro-2- ((5- (thiazol-2-yl) indolin-1-yl) methyl) allyl) isoindoline-1, 3-dione (1g, 2.38mmol, 1.0eq) was dissolved in EtOH (30 mL), and hydrazine hydrate (0.49g, 8.34mmol, 3.5eq) was added and reacted for 2h under reflux. The reaction was monitored by LC-MS, filtered with suction, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (DCM: meOH =10: 1), followed by addition of a small amount of MTBE, stirring, and suction filtration to give the product (81 mg, yield: 11.75%).
1 HNMR(400MHz,DMSO-d 6 )δ(ppm):8.26(brs,2H),7.77(s,1H),7.63-7.66(d,2H),7.04-7.25(d,J＝83Hz,1H),6.80-6.82(d,1H),3.88(s,2H),3.50(s,2H),2.97-2.99(s,2H).
Molecular formula C 15 H 16 FN 3 S molecular weight of 289.37 LC-MS (Pos, m/z) =290.12[ M + H ],] + .
other compounds of the invention may be prepared by reference to the above methods.
Biological example 1: determination of enzymatic Activity
Test article: compounds of the invention shown in Table 1, prepared according to the methods of the examples
1. Inhibitory Activity of Compounds on rhVAP-1 enzyme
(1) Instrument consumable and reagent
Multifunctional microplate reader (MD, flexStation 3), black impermeable bottom 96-well plate (Corning), rhVAP-1 (PeproTech)
(2) Preparation of compound concentration gradient solution
An appropriate amount of test compound was dissolved in DMSO to 10mM and stored. Before the experiment, a proper amount of 10mM stock solution of the compound to be tested is diluted to 1mM solution by DMSO, then diluted by 3-fold gradient by DMSO for 10 concentration gradients, and then diluted by 100-fold by PBS to prepare 10X series concentration compound solutions.
(3) Preparation of enzyme solution
An appropriate amount of protein diluent was added to the rhVAP-1 powder to give 1mg/mL of mother liquor for storage. The enzyme solution was diluted with PBS before the experiment to give a 4 Xconcentration.
(4) Preparation of 2 Xconcentration substrate mixture
Weighing a proper amount of benzylamine, adding PBS to dissolve the benzylamine to obtain a 200mM benzylamine solution, adding 2mM Amplex Red mother liquor and 500U/mL HRP mother liquor, and diluting the mixture with the PBS to obtain a substrate mixed liquor with the concentration of 2 multiplied by the concentration.
(5) Test method
First, 10. Mu.L of compound solutions of different concentrations, 25. Mu.L of 4 XrhVAP-1 enzyme solution and 15. Mu.L of LPBS were added to a 96-well plate, mixed by shaking, and incubated at 37 ℃ for 30min. Then adding 50 μ L of 2 × substrate mixed solution into each well, immediately detecting by using a microplate reader, exciting light at 565nm, emitting light at 590nm, detecting the fluorescence intensity of each well for 5 min/time, detecting for 25min, and calculating the inhibition rate according to the following formula:
V(RFU/min)＝(F t (RFU)-F 0 (RFU))/(time (min))
Inhibition (%) =100% -V cmpd (RFU/min)/V max (RFU/min)×100％
V: the rate of change of fluorescence; f t : fluorescence readings at time t; f 0 : an initial fluorescence reading; time: a duration t; v cmpd : the rate of change of fluorescence of the test compound; v max : max pore fluorescence change rate.
(6) Fitting dose-effect curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and the log (inhibitor) v.response-Variable slope of GraphPad Prism 5 of analysis software is adopted to fit a dose-effect curve, so that the IC of each compound to the enzyme activity is obtained 50 The value is obtained.
2. Selectivity of compounds for rhAOC1 enzyme
(1) Instrument consumable and reagent
Microplate reader (Perkin Elmer, nivo 5S), black, bottom-impermeable 96-well plate (Corning), and rhAOC1 (R & D)
(2) Compound concentration gradient solution preparation
Taking a proper amount of a test compound, dissolving the test compound in DMSO (dimethylsulfoxide) to 10mM, storing the test compound, and taking a proper amount of 10mM test compound mother liquor to perform 3-time gradient dilution on the test compound mother liquor before an experiment to obtain 10 concentration gradients. Each concentration gradient was then diluted 10-fold with 0.1M PBS.
(3) Preparation of enzyme solution
Taking an appropriate amount of rhAOC1 mother liquor with the concentration of 0.441mg/mL, adding an appropriate amount of 50mM HEPES buffer solution, and diluting to obtain a 4X-concentration enzyme solution.
(4) Preparation of 2 Xconcentration substrate mixture
An appropriate amount of histamine was weighed, and 50mM HEPES buffer solution was added to dissolve the histamine solution of 20mM, 2mM Amplex Red mother solution and 500U/mL HRP mother solution were added, and the mixture was diluted with 50mM HEPES buffer solution to obtain a substrate mixture of 2X concentration.
(5) Test method
First, 10. Mu.L of compound solutions of different concentrations, 25. Mu.L of 4 × rhAOC1 enzyme solution and 15. Mu.L of 50mM HEPES buffer solution were added to a 96-well plate, mixed by shaking, and incubated at 37 ℃ for 30min. Then, 50. Mu.L of 2 Xsubstrate mixed solution is added into each well, the detection is carried out immediately by using a microplate reader, the excitation light is 580nm (20 nm), the emission light is 620nm (10 nm), the fluorescence intensity of each well is detected for 5 min/time for 30min, and the inhibition rate is calculated according to the following formula:
V(RFU/min)＝(F t (RFU)-F 0 (RFU))/(time (min))
Inhibition (%) =100% -V cmpd (RFU/min)/V max (RFU/min)×100％
V: the rate of change of fluorescence; f t : fluorescence readings at time t; f 0 : an initial fluorescence reading; time: a time period t; v cmpd : the rate of change of fluorescence of the test compound; v max : max pore fluorescence change rate.
(6) Fitting dose-effect curve
The log value of the concentration is taken as an X axis, the percent inhibition is taken as a Y axis, and the analysis software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope is adopted to fit a dose-effect curve, so as to obtain the IC of each compound on the enzyme activity 50 The value is obtained.
3. The test results are shown in Table 1
TABLE 1
"-" indicates not tested.
As can be seen from the above table, the compounds of the present invention have good inhibitory activity against rhVAP-1 enzyme, and show excellent selective inhibitory activity against VAP-1 enzyme relative to rhAOC1 enzyme. This indicates that the compounds of the present invention are useful for the prevention and/or treatment of diseases associated with elevated expression or increased activity of VAP-1 enzyme.
Biological example 2: determination of enzymatic Activity
Test article: compounds of the invention shown in Table 2, prepared according to the methods of the examples
1. Inhibitory Activity of Compounds on rhVAP-1 enzyme
(1) Instrument consumable and reagent
Enzyme-linked immunosorbent assay (Perkin Elmer, nivo 5S), black impermeable bottom 96-well plate (Corning), rhVAP-1 (PeproTech)
(2) Preparation of compound concentration gradient solution
An appropriate amount of the test compound was dissolved in DMSO to 10mM and stored. A suitable amount of 10mM stock solution of the test compound is diluted in DMSO in 3-fold gradient for a total of 10 concentration gradients before the experiment. Each concentration gradient was then diluted 100-fold with 0.1M PBS.
(3) Preparation of enzyme solution
An appropriate amount of protein diluent was added to the rhVAP-1 powder to give 1mg/mL of mother liquor for storage. The enzyme solution was diluted with PBS before the experiment to give a 4 Xconcentration.
(4) Preparation of 2 Xconcentration substrate mixture
Weighing a proper amount of benzylamine, adding PBS to dissolve the benzylamine to obtain a 200mM benzylamine solution, adding 2mM Amplex Red mother liquor and 500U/mL HRP mother liquor, and diluting the mixture with the PBS to obtain a substrate mixed liquor with the concentration of 2 multiplied by the concentration.
(5) Test method
First, 10. Mu.L of compound solutions of different concentrations, 25. Mu.L of 4 XrhVAP-1 enzyme solution and 15. Mu.L of LPBS were added to a 96-well plate, mixed by shaking, and incubated at 37 ℃ for 30min. Then, 50. Mu.L of 2 Xsubstrate mixture was added to each well, and immediately detected by a microplate reader, excitation light was 580nm (20 nm), emission light was 620nm (10 nm), 5 min/time, and detection was carried out for 30min, and the inhibition ratio was calculated according to the following formula:
V(RFU/min)＝(F t (RFU)-F 0 (RFU))/(time (min))
Inhibition (%) =100% -V cmpd (RFU/min)/V max (RFU/min)×100％
V: the rate of change of fluorescence; f t : fluorescence readings at time t; f 0 : an initial fluorescence reading; time: a time period t; v cmpd : the rate of change of fluorescence of the test compound; v max : max pore fluorescence change rate.
(6) Fitted dose-effect curve
The log value of the concentration is taken as an X axis, the percentage inhibition rate is taken as a Y axis, and the log (inhibitor) v.s.response-Variable slope of GraphPad Prism 5 of analysis software is adopted to fit a dose-effect curve, so that each compound is obtainedIC of substrate to enzyme activity 50 The value is obtained.
2. Selectivity of compounds for rhAOC1 enzyme
(1) Instrument consumable and reagent
Microplate reader (Perkin Elmer, nivo 5S), black, bottom-impermeable 96-well plate (Corning), and rhAOC1 (R & D)
(2) Preparation of compound concentration gradient solution
Taking a proper amount of a test compound, dissolving the test compound in DMSO (dimethylsulfoxide) to 10mM, storing the test compound, and taking a proper amount of 10mM test compound mother liquor to perform 3-time gradient dilution on the test compound mother liquor before an experiment to obtain 10 concentration gradients. Each concentration gradient was then diluted 10-fold with 0.1M PBS.
(3) Preparation of enzyme solution
Taking a proper amount of rhAOC1 mother liquor with the concentration of 0.441mg/mL, adding a proper amount of 50mM HEPES buffer solution, and diluting to obtain a 4X-concentration enzyme solution.
(4) Preparation of 2 Xconcentration substrate mixture
An appropriate amount of histamine was weighed, and 50mM HEPES buffer solution was added to dissolve the histamine solution of 20mM, 2mM Amplex Red mother solution and 500U/mL HRP mother solution were added, and the mixture was diluted with 50mM HEPES buffer solution to obtain a substrate mixture of 2X concentration.
(5) Test method
First, 10. Mu.L of compound solutions of different concentrations, 25. Mu.L of 4 XRhAOC 1 enzyme solution and 15. Mu.L of 50mM HEPES buffer solution were added to a 96-well plate, mixed by shaking, and incubated at 37 ℃ for 30min. Then, 50. Mu.L of 2 Xsubstrate mixed solution is added into each well, the detection is carried out immediately by using a microplate reader, the excitation light is 580nm (20 nm), the emission light is 620nm (10 nm), the fluorescence intensity of each well is detected for 5 min/time for 30min, and the inhibition rate is calculated according to the following formula:
V(RFU/min)＝(F t (RFU)-F 0 (RFU))/(time (min))
Inhibition (%) =100% -V cmpd (RFU/min)/V max (RFU/min)×100％
V: the rate of change of fluorescence; f t : fluorescence readings at time t; f 0 : an initial fluorescence reading; time: a duration t; v cmpd : the rate of change of fluorescence of the test compound; v max : max holeThe rate of change of fluorescence.
(6) Fitted dose-effect curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and the log (inhibitor) v.response-Variable slope of GraphPad Prism 5 of analysis software is adopted to fit a dose-effect curve, so that the IC of each compound to the enzyme activity is obtained 50 The value is obtained.
3. The test results are shown in Table 2
TABLE 2
"-" indicates not tested.
As can be seen from the above table, the compounds of the present invention have good inhibitory activity against rhVAP-1 enzyme, and show excellent selective inhibitory effect against SSAO/VAP-1 enzyme compared to rhAOC1 enzyme. This indicates that the compounds of the present invention are useful for the prevention and/or treatment of diseases associated with elevated expression or increased activity of VAP-1 enzyme.
Biological Experimental example 3 selectivity of the Compound of the present invention for MAO-A/B enzyme
(1) Instrument consumable and reagent
Microplate reader (Perkin Elmer, enVision), 384 well plates (Perkin Elmer), centrifuge (Eppendorf), MAO-Glo TM (PromegA), MAO-A (Active Motif) and MAO-B (Active Motif).
(2) Compound concentration gradient solution preparation
The appropriate amount of test compound was dissolved in DMSO to 10mM and stored, followed by 4-fold gradient dilution in DMSO for a total of 6 concentration gradients.
(3) Preparation of enzyme solution
The MAO-A/B stock was diluted to A2 Xconcentration of enzyme solution with MAO-A/B assay buffer.
(4) Preparation of 2 Xconcentration substrate mixture
The MAO-A/B substrate mixture mother liquor was diluted to 2 Xconcentration with MAO-A/B assay buffer.
(5) Test method
200 n of compound solutions or solvents of different concentrations, 10. Mu. of 2 XMAO-A/B enzyme solution, centrifugation at 1000rpm for 60s, shaking and mixing, and incubation at room temperature for 15min. The reaction was then initiated by adding 10. Mu.L of 2 Xsubstrate mix per well. The 384 well plate was centrifuged at 1000rpm for 60s, shaken well and incubated at room temperature for 60min. . The reaction was stopped by adding 20. Mu.L of a termination detection solution, centrifuging at 1000rpm for 60 seconds, and shaking and mixing. Standing for 30min, and reading with a microplate reader.
The inhibition rate was calculated according to the following formula:
suppression ratio (%) = (Signal _ Max-Signal _ sample)/(Signal _ Max-Signal _ min) × 100
(6) Fitted dose-effect curve
The log value of the concentration is taken as an X axis, the percent inhibition is taken as a Y axis, and the analysis software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope is adopted to fit a dose-effect curve, so as to obtain the IC of each compound on the enzyme activity 50 The value is obtained.
3. Test results
TABLE 3
As is clear from Table 3 above, the compounds of the present invention exhibit excellent selective inhibitory activity against SSAO/VAP-1 enzyme as compared to monoamine oxidase (MAO).
Industrial applicability
The allylamine compounds of the invention are useful for the prevention and/or treatment of diseases associated with or mediated by SSAO/VAP-1 protein, and show excellent selectivity for SSAO/VAP-1 enzyme.
Claims (5)
1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof:
wherein R is 1 And R 2 Each independently selected from hydrogen, halogen, and R 1 And R 2 Not hydrogen at the same time;
R 3 and R 4 Each independently selected from hydrogen or C 1-6 An alkyl group;
R 5 and R 6 Each independently selected from hydrogen or C 1-6 An alkyl group;
L 1 is a bond;
C y1 is one to more than one R a Substituted groups shown below:
Cy 1 x of (A) to 4 、X 4 ’ 、X 5 Or X 6 Is represented by one to a plurality of R a Substitution;
m is 1;
X 1 is selected from CH 2 ，X 2 Is selected from CH 2 ，X 3 Selected from N, X 4 、X 4 ’ 、X 5 、X 6 Each independently is selected from CH;
each R a Independently selected from: hydroxy, halogen atom, or unsubstituted or substituted by one or more R b Substituted C 1-6 Alkyl radical, C 1-6 Alkoxy radical, cy 2 -、Cy 2 -C(O)-，Cy 2 Is 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, 5 membered heteroaryl;
each R b Independently selected from: hydroxy, halogen atom, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 An alkoxy group;
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,
wherein, C y1 Is divided into one or more R a Substituted with the following groups:
each R a Independently selected from: hydroxy, halogen atom, or unsubstituted or substituted by one or more R b C substituted by substituent 1-6 Alkyl, cy 2 -、Cy 2 -C(O)-，Cy 2 Is 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, 5 membered heteroaryl;
each R b Independently selected from: hydroxy, halogen atom, C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 An alkoxy group.
3. A compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein said compound is selected from the group consisting of:
4. a pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, characterized in that it optionally comprises one or more pharmaceutically acceptable carriers.
5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof or pharmaceutical composition according to claim 4, for the preparation of a medicament for the prophylaxis and/or treatment of diseases which are related to or mediated by SSAO/VAP-1 protein.
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| WO2007120528A2 (en) * | 2006-03-31 | 2007-10-25 | La Jolla Pharmaceutical Company | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases |
| WO2009055002A1 (en) * | 2007-10-24 | 2009-04-30 | La Jolla Pharmaceutical Company | Combined inhibitors of cyclooxygenase and semicarbazide-sensitive amine oxidase (ssao) (vascular adhesion protein, vap-1) |
| WO2018151985A1 (en) * | 2017-02-14 | 2018-08-23 | Eli Lilly And Company | Amino pyrimidine compounds useful as ssao inhibitors |
| WO2018196677A1 (en) * | 2017-04-28 | 2018-11-01 | 四川科伦博泰生物医药股份有限公司 | Fluoroallylamine derivative and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007120528A2 (en) * | 2006-03-31 | 2007-10-25 | La Jolla Pharmaceutical Company | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment and prevention of diseases |
| WO2009055002A1 (en) * | 2007-10-24 | 2009-04-30 | La Jolla Pharmaceutical Company | Combined inhibitors of cyclooxygenase and semicarbazide-sensitive amine oxidase (ssao) (vascular adhesion protein, vap-1) |
| WO2018151985A1 (en) * | 2017-02-14 | 2018-08-23 | Eli Lilly And Company | Amino pyrimidine compounds useful as ssao inhibitors |
| WO2018196677A1 (en) * | 2017-04-28 | 2018-11-01 | 四川科伦博泰生物医药股份有限公司 | Fluoroallylamine derivative and use thereof |
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Address after: 3 / F, building 9, phase II of biomedical Valley accelerator, Jiangbei new district, Nanjing, Jiangsu Province, 210032 Applicant after: Yaojie Ankang (Nanjing) Technology Co.,Ltd. Address before: 3 / F, building 9, phase II of biomedical Valley accelerator, Jiangbei new district, Nanjing, Jiangsu Province, 210032 Applicant before: NANJING TRANSTHERA BIOSCIENCES Co.,Ltd. |
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| GR01 | Patent grant | ||
| GR01 | Patent grant |