CN114621190B - Allylamine derivative and application thereof - Google Patents

Allylamine derivative and application thereof Download PDF

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CN114621190B
CN114621190B CN202111527773.1A CN202111527773A CN114621190B CN 114621190 B CN114621190 B CN 114621190B CN 202111527773 A CN202111527773 A CN 202111527773A CN 114621190 B CN114621190 B CN 114621190B
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李云飞
钟志雄
莫明广
谭亮
张芳
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Shanghai Tuojie Biomedical Technology Co ltd
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Abstract

The present disclosure relates to allylamine derivatives and uses thereof. Specifically, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein X 1 ～X 4 、R 1 ～R 8 、Z 1 ～Z 4 L is as defined herein.

Description

Allylamine derivative and application thereof
Technical Field
The present disclosure belongs to the field of medicine, and relates to allylamine derivatives and uses thereof.
Background
Semicarbazide-sensitive amine oxidase (SSAO) is a class of amine oxidases containing a dopamine quinone group, and belongs to a family of semicarbazide-sensitive amine oxidases, also known as vascular adhesion protein-1, vap-1 (vascular adhesion protein 1). Numerous studies have demonstrated that SSAO and its metabolites are closely related to inflammatory-related diseases such as atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, retinopathy, chronic Obstructive Pulmonary Disease (COPD), autoimmune diseases, multiple sclerosis, rheumatoid arthritis, alzheimer's disease, and the like.
Several known MAO inhibitors such as Morfejine have been synthesized, studies have shown that Morfejine inhibits experimental autoimmune encephalomyelitis (US 20060025438),
WO2009066152 describes 3-substituted 3-haloallylamine SSAO/VAP-1 inhibitors and claims them as treatment of inflammatory diseases,
WO2013163675 on the basis of this develops a new class of 3-haloallylamine SSAO/VAP-1 inhibitors, exemplified by the following compounds:
in addition, other 3-haloallylamine SSAO/VAP-1 inhibitors have also been reported successively, such as CN109251166, CN109810041, CN110938059, CN108778278, CN109988093, CN109988106, CN109988109, WO2018027892, WO2018149226, WO2020233583, WO2007120528, WO2018196677, WO2020063854, WO2020089025, WO2020089026, WO2020125776, etc., however SSAO/VAP-1 inhibitors have not been marketed yet, while the compounds of the present disclosure are not disclosed in any literature, and such compounds exhibit specific VAP-1 inhibitory effects.
Disclosure of Invention
The disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof
Wherein R is 1 And R is 2 Independently selected from hydrogen, deuterium, chlorine, and fluorine;
R 3 and R is 4 Independently selected from hydrogen, deuterium, C 1-6 Alkyl, said alkyl optionally being substituted with one or more R A1 Each independently substituted, R A1 Selected from halogen, deuterium, hydroxy, nitro, cyano or amino;
R 5 and R is 6 Independently selected from hydrogen, deuterium, C 1-6 Alkyl, said alkyl optionally being substituted with one or more R A2 Each independently substituted, R A2 Selected from halogen, deuterium, hydroxy, nitro, cyano or amino;
R 7 and R is 8 Independently selected from hydrogen, deuterium, C 1-6 Alkyl, said alkyl optionally being substituted with one or more R A3 Each independently substituted with，R A3 Selected from halogen, deuterium, hydroxy, nitro, cyano or amino;
R 9 and R is 10 Independently selected from hydrogen, deuterium, C 1-6 Alkyl, said alkyl optionally being substituted with one or more R A4 Each independently substituted, R A4 Selected from halogen, deuterium, hydroxy, nitro, cyano or amino;
l is selected from-CR 1a R 1b -、-C(O)-、-SO 2 -、-CR 1a R 1b CR 1c R 1d -or-N (R) 1a )-；
Z 1 Selected from a bond or-CR 2a R 2b -、-CR 2a R 2b CR 2c R 2d -；
Z 2 Selected from a bond or-CR 3a R 3b -、-CR 3a R 3b CR 3c R 3d -；
Z 3 Selected from a bond or-CR 4a R 4b -、-CR 4a R 4b CR 4c R 4d -、-N(R 1a )-、-C(O)NH-、-O-、-C(O)-、-SO n -、-C(O)O-、-CR 4a R 4b -N(R 1a )-、-OCR 4a R 4b -、-C(O)-CR 4a R 4b -、-SO n -CR 4a R 4b -、-C(O)O-CR 4a R 4b -、-OC(O)O-CR 4a R 4b -、-C(O)NH-CR 4a R 4b -or-NHC (O) -CR 4a R 4b -；
Z 4 Selected from a bond or-CR 5a R 5b -；
R 1a 、R 1b 、R 1c And R is 1d Each independently selected from hydrogen, deuterium, halogen or C 1-6 An alkyl group;
alternatively, R 1a 、R 1b 、R 1c And R is 1d Any two of which together with the adjacent carbon atoms form a 3 to 7 membered cycloalkyl or heterocycloalkyl, optionally substituted with one or more R A5 Substituted, R A5 Each independently selected from deuterium, halogen, nitro, cyano, and C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen, nitro, cyano or C 1-6 Alkoxy substituted;
R 2a 、R 2b 、R 2c and R is 2d Each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen, nitro, cyano or C 1-6 Alkoxy substituted;
alternatively, R 2a 、R 2b 、R 2c And R is 2d Any two of which together with the adjacent carbon atoms form a 3 to 7 membered cycloalkyl or heterocycloalkyl, optionally substituted with one or more R A6 Substituted, R A6 Each independently selected from deuterium, halogen, nitro, cyano, and C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen, nitro, cyano or C 1-6 Alkoxy substituted;
R 3a 、R 3b 、R 3c and R is 3d Each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen, nitro, cyano or C 1-6 Alkoxy substituted;
alternatively, R 3a 、R 3b 、R 3c And R is 3d Any two of which together with the adjacent carbon atoms form a 3 to 7 membered cycloalkyl or heterocycloalkyl, optionally substituted with one or more R A7 Substituted, R A7 Each independently selected from deuterium, halogen, nitro, cyano, and C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen, nitro, cyano or C 1-6 Alkoxy substituted;
R 4a 、R 4b 、R 4c and R is 4d Each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -SR 6a 、-S(O)R 6a 、-S(O) 2 R 6a 、-NR 6a (R 6b )、-(CH 2 ) p COR 6a 、-(CH 2 ) p NHCOR 6a 、-(CH 2 ) p CONR 6a (R 6b )、-(CH 2 ) p OCONR 6a (R 6b )、-N(CH 2 ) p CONR 6a (R 6b )、-N(CH 2 ) p COR 6a The alkyl or alkoxy groups being optionally substituted by halogen, nitro, cyano or C 1-6 Alkoxy substituted;
R 6a or R is 6b Each independently selected from hydrogen, deuterium, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano or amino;
alternatively, R 4a 、R 4b 、R 4c And R is 4d Any two of which together with the adjacent carbon atoms form a 3 to 7 membered cycloalkyl or heterocycloalkyl, optionally substituted with one or more R A8 Substituted, R A8 Each independently selected from deuterium, halogen, nitro, cyano, and C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen, nitro, cyano or C 1-6 Alkoxy substituted;
R 5a and R is 5b Each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -SR 7a 、-S(O)R 7a 、-S(O) 2 R 7a 、-NR 7a (R 7b )、-(CH 2 ) p COR 7a 、-(CH 2 ) p NHCOR 7a 、-(CH 2 ) p CONR 7a (R 7b )、-(CH 2 ) p OCONR 7a (R 7b )、-N(CH 2 ) p CONR 7a (R 7b )、-N(CH 2 ) p COR 7a ；
R 7a Or R is 7b Each independently selected from hydrogen, deuterium, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano or amino;
X 1 、X 2 、X 3 and X 4 Each independently selected from-CH-or-N-, and not simultaneously-N-;
o, p are each selected from integers between 0 and 3.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, R 2 Selected from fluorine.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from fluorine, R 2 Selected from hydrogen.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, R 2 Selected from chlorine.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from chlorine, R 2 Selected from hydrogen.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 7 And R is 8 Independently selected from C 1-6 Alkyl, said alkyl optionally being substituted with one or more R A3 Substituted, R A3 Each independently selected from halogen, deuterium, hydroxy, nitro, cyano or amino.
In other embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 7 And R is 8 Independently selected from methyl, ethyl or propyl, further optionally substituted with one or more R A3 Substituted, R A3 Each independently selected from halogen, deuterium, hydroxy, nitro, cyano or amino.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 5 And R is 6 Independently selected from hydrogen or deuterium.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 5 、R 6 、R 7 And R is 8 Selected from hydrogen.
On the other hand, in some embodiments, X in a compound of formula I or a pharmaceutically acceptable salt thereof 2 Selected from-N-, X 1 、X 3 、X 4 Selected from-CH-; or X 3 Selected from-N-, X 1 、X 2 、X 4 Selected from-CH-. In some embodiments, X in a compound of formula I or a pharmaceutically acceptable salt thereof 1 、X 2 、X 3 、X 4 Selected from-CH-. In some embodiments, X in a compound of formula I or a pharmaceutically acceptable salt thereof 1 、X 4 Selected from-N-, X 2 、X 3 Selected from-CH-.
Some embodiments provide that the compound of formula I or a pharmaceutically acceptable salt thereof is
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from hydrogen or C 1-6 An alkyl group. In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from hydrogen, methyl or ethyl.
In other embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from C 1-6 Alkyl, preferably methyl, ethyl or propyl, said alkyl optionally being substituted with one or more R A1 Substituted, R A1 Each independently selected from halogen (e.g., fluorine or chlorine), deuterium, hydroxy, nitro, cyano, or amino.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 1a 、R 1b 、R 1c And R is 1d Independently selected from hydrogen, deuterium, C 1-6 An alkyl group. In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 1a 、R 1b 、R 1c And R is 1d Independently selected from hydrogen, deuterium, methyl, ethyl.
In other embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 1a 、R 1b 、R 1c And R is 1d Any two of which are phase-connectedTogether the adjacent carbon atoms form a 3 to 5 membered cycloalkyl or heterocycloalkyl, optionally substituted with one or more R A5 Substituted, R A5 As defined above.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of-CH 2 -、-CH(CH 3 )-、-C(CH 3 ) 2 -、-C(O)-、-NH-、-N(CH 3 )-、-CH 2 CH 2 -or. In other embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of-CH 2 -or-NH-.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from-CR 2a R 2b -or-CR 2a R 2b CR 2c R 2d -，R 2a 、R 2b 、R 2c And R is 2d Each independently selected from hydrogen, deuterium, halogen, hydroxy.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from-CR 2a R 2b -or-CR 2a R 2b CR 2c R 2d -，R 2a 、R 2b 、R 2c And R is 2d Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy being optionally fluorine or chlorine.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from-CR 2a R 2b -or-CR 2a R 2b CR 2c R 2d -，R 2a 、R 2b 、R 2c And R is 2d Any two of which together with the adjacent carbon atoms form a 3 to 5 membered cycloalkyl or heterocycloalkyl, optionally substituted with one or more R A6 Substituted, R A6 As defined above.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from the group consisting of bonds.
In one placeIn some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof A5 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by halogen, such as fluorine or chlorine.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof A6 Each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by halogen, such as fluorine or chlorine.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 2 Selected from-CR 3a R 3b -、-CR 3a R 3b CR 3c R 3d -，R 3a 、R 3b 、R 3c And R is 3d Each independently selected from hydrogen, deuterium, halogen, hydroxy.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 2 Selected from-CR 3a R 3b -、-CR 3a R 3b CR 3c R 3d -，R 3a 、R 3b 、R 3c And R is 3d Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by fluorine or chlorine.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 2 Selected from-CR 3a R 3b -、-CR 3a R 3b CR 3c R 3d -，R 3a 、R 3b 、R 3c And R is 3d Any two of which together with the adjacent carbon atoms form a 3 to 5 membered cycloalkyl or heterocycloalkyl, optionally substituted with one or more R A7 Substituted, R A7 As defined above.
In other embodiments, Z in the compound of formula I or a pharmaceutically acceptable salt thereof 2 Selected from the group consisting of bonds.
On the other hand, in some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof A7 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen-substitutedSubstitution, for example fluorine or chlorine.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from the group consisting of a bond; z is Z 2 Selected from-CR 3a R 3b -，R 3a And R is 3b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by fluorine or chlorine.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from-CR 2a R 2b -，R 2a And R is 2b Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with fluorine or chlorine; z is Z 2 Selected from the group consisting of bonds.
In other embodiments, Z in the compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from the group consisting of a bond; z is Z 2 Selected from-CR 3a R 3b CR 3c R 3d -，R 3a 、R 3b 、R 3c And R is 3d Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by fluorine or chlorine.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 1 Selected from-CR 2a R 2b CR 2c R 2d -，R 2a 、R 2b 、R 2c And R is 2d Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with fluorine or chlorine; z is Z 2 Selected from the group consisting of bonds.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 9 Selected from hydrogen or deuterium.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 9 Selected from C 1-6 An alkyl group. In other embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 9 Selected from methyl, ethyl or fluoromethyl.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 9 Selected from hydrogen;R 10 selected from hydrogen.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 10 Selected from C 1-6 An alkyl group. In other embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 10 Selected from methyl, ethyl or fluoromethyl.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from-CR 4a R 4b -or-CR 4a R 4b CR 4c R 4d -. In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 4a 、R 4b 、R 4c And R is 4d Each independently selected from hydrogen, deuterium, halogen, hydroxy, -NR 6a (R 6b )、-(CH 2 ) p COR 6a 、-(CH 2 ) p NHCOR 6a 、-(CH 2 ) p CONR 6a (R 6b )、-(CH 2 ) p OCONR 6a (R 6b )，p、R 6a Or R is 6b As defined above.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from-CR 4a R 4b -or-CR 4a R 4b CR 4c R 4d -. In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 4a 、R 4b 、R 4c And R is 4d Each independently selected from hydrogen, deuterium, halogen, hydroxy, -SR 6a 、-S(O)R 6a 、-S(O) 2 R 6a 、-N(CH 2 ) p CONR 6a (R 6b )、-N(CH 2 ) p COR 6a ，p、R 6a Or R is 6b As defined above.
In another aspect, embodiments provide a compound of formula I or a pharmaceutically acceptable salt thereof wherein Z 3 Selected from-C (O) NH-; z is Z 4 Selected from a bond or-CR 5a R 5b -，R 5a And R is 5b Each independently selected from hydrogen, deuterium, halogen, hydroxy.
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from-OCR 4a R 4b -；Z 4 Selected from-CR 5a R 5b -。
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from the group consisting of-OC (O) O-CR 4a R 4b -；Z 4 Selected from-CR 5a R 5b -。
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from-NHC (O) -CR 4a R 4b -；Z 4 Selected from-CR 5a R 5b -。
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from-C (O) NH-CR 4a R 4b -；Z 4 Selected from-CR 5a R 5b -。
In some embodiments, Z in a compound of formula I or a pharmaceutically acceptable salt thereof 3 Selected from-CR 4a R 4b -；Z 4 Selected from the group consisting of bonds.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 4a 、R 4b 、R 4c And R is 4d Each independently selected from hydrogen, hydroxy, C 1-3 Alkyl, -COOH, -COC 1-3 Alkoxy, -CONHC 1-3 An alkoxy group.
In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof 4a 、R 4b 、R 4c And R is 4d Each independently selected from hydrogen, hydroxy, -SC 1-3 Alkoxy, -SO 2 C 1-3 An alkoxy group.
Some embodiments provide compounds of formula I or pharmaceutically acceptable salts thereof as
In some embodiments of the present invention, in some embodiments,r in the compound shown in the formula I or the formula Ia or the formula Ib or pharmaceutically acceptable salt thereof 5a 、R 5b 、R 5c And R is 5d Each independently selected from hydrogen, hydroxy, C 1-3 Alkyl, -COOH, -COC 1-3 Alkoxy, -CONHC 1-3 An alkoxy group.
In some embodiments, R in a compound of formula I or formula Ia or formula Ib, or a pharmaceutically acceptable salt thereof 5a 、R 5b 、R 5c And R is 5d Each independently selected from hydrogen, hydroxy, -SC 1-3 Alkoxy, -SO 2 C 1-3 An alkoxy group.
In some embodiments, R in a compound of formula I or formula Ia or formula Ib, or a pharmaceutically acceptable salt thereof 6a Or R is 6b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally substituted with one or more substituents selected from halogen (e.g. fluorine or chlorine).
In some embodiments, R in a compound of formula I or formula Ia or formula Ib, or a pharmaceutically acceptable salt thereof 6a Or R is 6b Each independently selected from hydrogen, hydroxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl optionally being substituted by one or more substituents selected from halogen (e.g. fluoro or chloro).
In some embodiments, R in a compound of formula I or formula Ia or formula Ib, or a pharmaceutically acceptable salt thereof 7a Or R is 7b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally substituted with one or more substituents selected from halogen (e.g. fluorine or chlorine).
In some embodiments, R in a compound of formula I or formula Ia or formula Ib, or a pharmaceutically acceptable salt thereof 7a Or R is 7b Each independently selected from hydrogen, hydroxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, said cycloalkyl or heterocycloalkyl optionally being substituted by one or more substituents selected from halogen (e.g. fluoro or chloro).
In some embodiments, o, p in a compound of formula I or formula Ia or formula Ib or a pharmaceutically acceptable salt thereof are each independently selected from 0, 1 or 2.
Typical compounds of formula I or pharmaceutically acceptable salts thereof include, but are not limited to:
wherein->Including the E or Z configuration.
In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof
Also provided in the present disclosure is a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula I, formula Ia, or formula Ib, or a pharmaceutically acceptable salt thereof, as described above, and a pharmaceutically acceptable excipient.
In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.
In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the foregoing compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the foregoing compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical compositions comprise 1% to 99% of the foregoing compounds, or pharmaceutically acceptable salts thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the foregoing compound or a pharmaceutically acceptable salt thereof.
In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.
The present disclosure also provides a method of preventing and/or treating a patient suffering from a SSAO or SSAO/VAP-1 related disorder comprising administering to the patient a therapeutically effective amount of a compound of formula I or formula Ia or formula Ib, or a pharmaceutically acceptable salt thereof, as described above, or a pharmaceutical composition as described above.
In some embodiments, the disorder associated with SSAO or SSAO/VAP-1 is selected from inflammation, diabetes, an ocular disease, fibrosis, a neuroinflammatory disease, or cancer.
The present disclosure also provides a method of preventing and/or treating a patient suffering from inflammation, diabetes, an ocular disease, fibrosis, a neuroinflammatory disease, or cancer comprising administering to the patient a therapeutically effective amount of a compound of formula I or formula Ia or formula Ib, as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
The present disclosure also provides the use of a compound of formula I, formula Ia, formula Ib, or a pharmaceutically acceptable salt thereof, as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of a condition associated with SSAO or SSAO/VAP-1. In some embodiments, the PDE-related disorder is preferably inflammation, diabetes, an ocular disease, fibrosis, a neuroinflammatory disease, or cancer.
The present disclosure also provides the use of a compound of formula I, formula Ia, or formula Ib, or a pharmaceutically acceptable salt thereof, as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of inflammation, diabetes, an ocular disease, fibrosis, a neuroinflammatory disease, or cancer.
Pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.
The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time comprise->And->Two configurations. Key with a keyIndicating unspecified configurations including cis (E) or trans (Z) configurations. Or +.>Refers to a double bond, in which the structure bonded may be "cis isomer" or "trans isomer" or "a mixture of cis and trans isomers in any ratio", e.g., formula E represents E-1, formula E-2, or a mixture of both in any ratio:
the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of lactam-lactam balances are between a and B as shown below.
All compounds in the present disclosure may be drawn as form a or form B. All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.
The present disclosure also includes some isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium. The present disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound of formula (I) or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.
"optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano 1-6 Alkyl "means that halogen or cyano may be, but need not be, present, and this description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.
Term interpretation:
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
"pharmaceutically acceptable excipients" include, but are not limited to, any auxiliary agent, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.
An "effective amount" or "therapeutically effective amount" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the route of administration and the dosage and severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.
"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from deuterium, halogen, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 An alkoxy group.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from deuterium, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen, nitro, cyano or C 1-6 Alkoxy groups are substituted.
The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms.
The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ringsAn atom wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:
etc.
The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl group, non-limiting examples of which include:
etc.
The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, said alkyl or alkoxy optionally being halogen, nitro, cyano or C 1-6 Alkoxy groups are substituted.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. Alkoxy groupMay be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 An alkoxy group.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "cyano" refers to-CN.
The term "amino" refers to-NH 2 。
The term "nitro" refers to-NO 2 。
The term "oxo" refers to an =o substituent.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort.
Detailed Description
The present disclosure is further described below in connection with examples, which are not intended to limit the scope of the disclosure.
Experimental methods for which specific conditions are not noted in the examples in this disclosure are generally in accordance with conventional conditions, or in accordance with conditions recommended by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated Methanol (Methanol-d) 4 ) The internal standard is Tetramethylsilane (TMS).
HPLC was determined using an Agilent1100 high pressure liquid chromatograph, GAS15B DAD ultraviolet detector, water Vbridge C18 150 x 4.6mm 5um column.
The mass of the sample is measured by an Agilent6120 triple quadrupole mass spectrometer, a G1315D DAD detector, a Waters Xbridge C18.6 x 50mm, a 5um chromatographic column, and the sample is scanned in a positive/negative ion mode, and the mass scanning range is 80-1200.
The thin layer chromatography silica gel plate is a smoke table yellow sea HSGF254 silica gel plate, the Thin Layer Chromatography (TLC) adopts a silica gel plate with the specification of 0.2mm plus or minus 0.03mm, and the thin layer chromatography separation and purification product adopts a specification of 0.4mm-0.5mm.
Flash column purification systems used Combiflash Rf150 (teldyne ISCO) or isolaraone (Biotage).
The forward column chromatography generally uses the yellow sea silica gel of the smoke table with 200-300 meshes or 300-400 meshes as a carrier, or uses the Santai prefill of Changzhou to prefill the ultra-pure phase silica gel column (40-63 mu m,60g,24g,40g,120g or other specifications).
Known starting materials in the present disclosure may be synthesized using or following methods known in the art, or may be purchased from Shanghai taitant technology, ABCR GmbH & Co.KG, acros Organics, aldrich Chemical Company, shaoshan chemical technology (Accela ChemBio Inc), pichia medicine, and the like.
The examples are not particularly described, and the reactions can all be carried out under nitrogen atmosphere.
The nitrogen atmosphere is defined as the reaction flask being connected to a nitrogen balloon of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.
The hydrogen is prepared by a QPH-1L type hydrogen generator of Shanghai full-pump scientific instrument company.
The nitrogen atmosphere or the hydrogenation atmosphere is usually vacuumized, filled with nitrogen or hydrogen, and repeatedly operated for 3 times.
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The reaction progress in the examples was monitored by Thin Layer Chromatography (TLC), a developing agent used in the reaction, a system of column chromatography eluent used for purifying the compound and a developing agent system of thin layer chromatography, and the volume ratio of the solvent was adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine and acetic acid.
Example 1
2- [6- [ (E) -2- (aminomethyl) -3-fluoroallyloxy ] pyridin-3-yl) sulfonyl ] -2-azabicyclo [2.2.1] heptane (1)
And 2- [6- [ (Z) -2- (aminomethyl) -3-fluoroallyloxy ] pyridin-3-yl) sulfonyl ] -2-azabicyclo [2.2.1] heptane (2) synthesis
Step 1: synthesis of 2- [ 6-chloropyridin-3-yl) sulfonyl ] -2-azabicyclo [2.2.1] heptane (1 b)
2-azabicyclo [2.2.1]Heptane (458 mg,4.7 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (1.43 g,14.1 mmol) and 6-chloropyridine-3-sulfonyl chloride (1.00 g,4.71 mmol) were added and the reaction was allowed to react at room temperature until completion as monitored by LC-MS. Filtration using a flash chromatography apparatus1b (500 mg, yield 38.9%) was isolated.
MS(ESI)m/z(ESI):273.3[M+H] + 。 1 H NMR(400MHz,CHLOROFORM-d)δ8.84(d,J＝2.4Hz,1H),8.07(dd,J＝2.4,8.3Hz,1H),7.63-7.39(m,1H),4.25(s,1H),3.22-3.02(m,2H),2.58(br s,1H),1.85-1.61(m,3H),1.49-1.41(m,1H),1.34(d,J＝10.1Hz,1H),1.16(td,J＝1.9,10.1Hz,1H)
Step 2: synthesis of 2- [ [ -2- (((tert-butoxycarbonyl) amino) methyl) -3-fluoroallyloxy ] pyridin-3-yl) sulfonyl ] -2-azabicyclo [2.2.1] heptane (1 c)
Compound 1b (53.2 mg,0.20 mmol) was dissolved in N-methylpyrrolidone (1 mL) and triethylamine (30 mg,0.29 mmol) was added and cooled to 0deg.C with an ice-water bath. A solution of BB-1 (40 mg,0.20 mmol) in tetrahydrofuran (2 mL) and a solution of sodium tert-butoxide (28 mg,0.29 mmol) in dimethyl sulfoxide (0.5 mL) were added. The reaction was completed at room temperature until LC-MS was monitored, water (10 mL) was added, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to give crude 1c (50 mg, yield 58%).
MS(ESI)m/z(ESI):442.4[M+H] +
Wherein BB-1 is prepared by taking commercial BB-1a as a raw material:
compound BB-1a (6.62 g,21.80 mmol) was dissolved in tetrahydrofuran (300 mL), compound BB-1b (10.0 g,21.60 mmol) was added, cooled to-60℃and NaHMDS (32.7 mL,32.7mmol, 1.0M) was then slowly added, reacted at-50-60℃for 1 hour, saturated aqueous ammonium chloride solution (500 mL) was added, extracted with ethyl acetate (500 mL. Times.2), saturated aqueous salt was washed with water, dried over anhydrous magnesium sulfate, and the mixture was purified by a flash chromatography apparatusBB-1c (1.50 g, yield 21%) was isolated.
MS(ESI):m/z 220.2[M+H] + 。 1 H NMR(400MHz,CDCl 3 )δ6.78-6.16(m,1H),4.34-3.96(m,2H),3.85-3.44(m,2H),1.34(d,J＝2.1Hz,9H),0.83-0.80(m,9H),0.01(d,J＝5.5Hz,6H).
Compound BB-1c (1.50 g,0.46 mmol) was dissolved in tetrahydrofuran (30 mL), TBAF (7.0 mL,7.0mmol, 1.0M) was added, reacted at room temperature until the TLC detection was complete, saturated aqueous ammonium chloride solution (100 mL) was added, extracted with ethyl acetate (100 mL. Times.2), saturated brine, dried over anhydrous magnesium sulfate, and purified using a flash chromatography apparatusBB-1 (0.61 g, yield 63%) was isolated.
Step 3: synthesis of 2- [6- [ (E) -2- (aminomethyl) -3-fluoroallyloxy ] pyridin-3-yl) sulfonyl ] -2-azabicyclo [2.2.1] heptane (1) and example 2.2- [6- [ (Z) -2- (aminomethyl) -3-fluoroallyloxy ] pyridin-3-yl) sulfonyl ] -2-azabicyclo [2.2.1] heptane (2)
Compound 1c (50 mg,0.11 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature until the reaction was complete by LC-MS monitoring, and the reaction solution was concentrated to give a crude product. The crude product was directly separated by preparative high performance liquid chromatography to give compound 1 (19 mg, yield 49%) and compound 2 (4 mg, yield 10%).
Compound 1: MS (ESI) m/z (ESI): 342.4[ M+H ]] + .
1 H NMR:(400MHz,METHANOL-d4)δ8.63(d,J＝2.3Hz,1H),8.12(dd,J＝2.5,8.7Hz,1H),7.44-7.12(m,1H),7.04(d,J＝8.7Hz,1H),5.01(d,J＝3.4Hz,2H),4.21(s,1H),3.81(d,J＝1.8Hz,2H),3.19-3.09(m,1H),3.08-3.00(m,1H),2.54(br s,1H),1.84-1.61(m,3H),1.51-1.38(m,1H),1.33(br d,J＝9.9Hz,1H),1.07(br d,J＝10.0Hz,1H).
Compound 2: MS (ESI) m/z (ESI): 342.4[ M+H ]] + 。
1 H NMR:(400MHz,METHANOL-d4)δ8.64(d,J＝2.2Hz,1H),8.13(dd,J＝2.5,8.7Hz,1H),7.35-6.94(m,2H),5.17(d,J＝2.4Hz,2H),4.22(br s,1H),3.69(d,J＝2.7Hz,2H),3.19-3.01(m,2H),2.54(br s,1H),1.79-1.62(m,3H),1.51-1.40(m,1H),1.33(br d,J＝10.1Hz,1H),1.07(br d,J＝10.1Hz,1H).
Example 2
3- [6- [ (E) -2- (aminomethyl) -3-fluoroallyloxy ] pyridin-3-yl) sulfonyl ] -3, 8-diazabicyclo [3.2.1] octane trifluoroacetate (3) and
3- [6- [ (Z) -2- (aminomethyl) -3-fluoroallyloxy]Pyridin-3-yl) sulfonyl]-3, 8-diazabicyclo [3.2.1]The synthesis of octane trifluoroacetate (4) was carried out in analogy to example 1, using 38-diazabicyclo [3.2.1]Octane instead of 2-azabicyclo [2.2.1]The corresponding procedure was followed with heptane to give compound 3 (116 mg, yield 50%), MS (ESI): m/z 357.1[ M+H ]] + ， 1 H NMR (400 mhz, metanol-d 4) delta 8.62 (d, j=2.3 hz, 1H), 8.07 (dd, j=2.5, 8.8hz, 1H), 7.47-7.13 (m, 1H), 7.07 (d, j=8.8 hz, 1H), 5.03 (d, j=3.8 hz, 2H), 4.16 (br s, 2H), 3.84 (d, j=1.8 hz, 2H), 3.73 (dd, j=1.8, 12.5hz, 2H), 2.97 (d, j=12.0 hz, 2H), 2.13 (s, 4H) and compound 4 (43 mg, 14% yield), MS (ESI): m/z 357.1[ m+h ]] + ， 1 H NMR(400MHz,METHANOL-d4)δ8.63(d,J＝2.5Hz,1H),8.08(dd,J＝2.5,8.8Hz,1H),7.29-6.95(m,2H),5.18(d,J＝2.5Hz,2H),4.16(br s,2H),3.89-3.61(m,4H),2.96(d,J＝12.3Hz,2H),2.13(s,4H).
Example 3
6- [6- [ (E) -2- (aminomethyl) -3-fluoroallyloxy ] pyridin-3-yl) sulfonyl ] -2, 6-diazabicyclo [3.2.1] octan-3-one trifluoroacetate salt (5) and
6- [6- [ (Z) -2- (aminomethyl) -3-fluoroallyloxy)]Pyridin-3-yl) sulfonyl]-2, 6-diazabicyclo [3.2.1]The synthesis of the octan-3-one trifluoroacetate salt (6) was carried out analogously to example 1 using 2, 6-diazabicyclo [3.2.1]Octane-3-ketone substituted 2-azabicyclo [2.2.1]The corresponding procedure was followed with heptane to give compound 5 (134 mg, yield 34%), MS (ESI): m/z 371.1[ M+H ]] + ， 1 H NMR (400 mhz, metanol-d 4) delta 8.68 (d, j=2.3 hz, 1H), 8.15 (dd, j=2.6, 8.8hz, 1H), 7.46-7.11 (m, 1H), 7.05 (d, j=8.8 hz, 1H), 5.02 (d, j=3.3 hz, 2H), 4.46-4.33 (m, 1H), 3.95 (br s, 1H), 3.84 (d, j=1.8 hz, 2H), 3.57 (dd, j=1.0, 9.6hz, 1H), 3.29 (dd, j=3.1, 9.7hz, 1H), 2.57 (d, j=2.6 hz, 2H), 1.94 (d, j=12.0 hz, 1H), 1.96-1.64 (m, 1H) and compound 6 (11 mg, 3 m+1H) [ yield 1.1.m/m ]] + ，δ8.70(d,J＝2.1Hz,1H),8.17(dd,J＝2.5,8.7Hz,1H),7.28-6.92(m,2H),5.18(d,J＝2.3Hz,2H),4.47-4.31(m,1H),3.95(br s,1H),3.71(d,J＝2.3Hz,2H),3.64-3.57(m,1H),3.30(d,J＝3.2Hz,1H),2.56(d,J＝2.7Hz,2H),1.95(d,J＝11.9Hz,1H),1.76-1.60(m,1H)。
Example 4
6- [6- [ (E) -2- (aminomethyl) -3-fluoroallyloxy)]Pyridin-3-yl) sulfonyl]-3, 6-diazabicyclo [3.2.1]The synthesis of the octan-2-one trifluoroacetate salt (7) is analogous to example 1 using 3, 6-diazabicyclo [3.2.1]Octane-2-ketone substituted 2-azabicyclo [2.2.1]The corresponding procedure was followed with heptane to give compound 7 (59 mg, yield 34%), MS (ESI): m/z 371.1[ M+H ]] + ， 1 H NMR(400MHz,METHANOL-d4)δ8.64(d,J＝2.2Hz,1H),8.11(dd,J＝2.5,8.7Hz,1H),7.45-7.13(m,1H),7.03(d,J＝8.8Hz,1H),6.69(td,J＝4.2,9.9Hz,1H),5.84-5.76(m,1H),5.11-4.95(m,2H),3.84(d,J＝2.0Hz,2H),3.72-3.57(m,1H),3.38-3.34(m,1H),3.02(d,J＝6.5Hz,2H),2.63-2.45(m,1H),2.42-2.29(m,1H)。
Biological evaluation
The following further description explains the present disclosure in connection with test examples, which are not meant to limit the scope of the present disclosure.
Test example 1: assessment of inhibitory Activity of rhVAP-1 enzyme
(1) Instrument consumable and reagent
Multifunctional enzyme labelling instrument (MD, flexStation 3), black impermeable bottom 96-1L plate (Corning), rhVAP-1 (PeproTech)
(2) Self-preparation of compound concentration gradient solution
And taking a proper amount of the compound to be tested, dissolving the compound to 10mM in DMSO, and storing. Before the experiment, a proper amount of 10mM compound mother solution to be tested is diluted to 1mM solution by DMSO, then 3-time gradient dilution is carried out by DMSO, 10 concentration gradients are added, and 100-time dilution is carried out by PBS to prepare 10X series concentration compound solutions.
(3) Enzyme solution preparation
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 to give a 4X concentration prior to the experiment.
(4) 2x concentration substrate mixed solution preparation
An appropriate amount of benzylamine was weighed, dissolved in PBS to obtain 200mM benzylamine solution, added with 2mM of Amplex Red mother liquor and 500U/mL of HRP mother liquor, and diluted with PBS to obtain a substrate mixture with 2X concentration.
(5) Test method
First, 10. Mu.L of a compound solution of different concentrations, 25. Mu.L of 4 XrhVAP-1 enzyme solution and 15. Mu.L of PBS were added to a 96-well plate, and after shaking and mixing, incubated at 37℃for 30min. Then 50 mu L of 2x substrate mixed solution is added into each hole, the detection is immediately carried out by using an enzyme-labeling instrument, excitation light is 565nm, emission light is 590nm, the fluorescence intensity of each hole is detected for 5 min/time, the total detection is 25min, 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)x 100％
V: rate of fluorescence change F t Fluorescent reading F at time t 0 : initial fluorescence readings; time: duration t; v (V) cmpd Rate of change of fluorescence of test compound V max Max Kong Yingguang rate of change.
(6) Fitting dose-response curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a log (inhibitor) vs. response-Variable slope fit quantitative effect curve of analysis software GraphPad Prism 5 is adopted, so that the IC of each compound on the enzyme activity is obtained 50 Values.
Examples of the present disclosure in vitro inhibition of VAP-1 enzyme activity was determined by the above assay, IC measured 50 The values are shown in Table 1.
TABLE 1
Remarks:
test example 2: selectivity of MAO-A/B enzyme
(1) Instrument consumable and reagent
Microplate reader (Perkin Elmer, enVision), 384 well plate (Perkin Elmer), centrifuge (Eppendorf), MAO-GloTM (Promega), MAO-A (Active Motif) and MAO-B (Active Motif).
(2) Self-preparation of compound concentration gradient solution
An appropriate amount of the test compound was taken, dissolved in DMSO to 10mM, and stored, and then subjected to 4-fold gradient dilution with DMSO for a total of 6 concentration gradients.
(3) Enzyme solution preparation
MAO-A/B stock was diluted with MAO-A/B assay buffer to 2X concentration enzyme solution.
(4) 2x concentration substrate mixed solution preparation
The MAO-A/B substrate mixture stock solution was diluted with MAO-A/B assay buffer to A2X concentration substrate mixture.
(5) Test method
200nL of compound solution or solvent with different concentrations and 10 mu L of 2xMAO-A/B enzyme solution are added into A384-well plate, the mixture is centrifuged at 1000rpm for 60s, and the mixture is stirred and mixed uniformly and then incubated for 15min at room temperature. Then 10. Mu.L of 2 Xsubstrate mixture was added to each well to initiate the reaction. The 384-well plate is centrifuged at 1000rpm for 60s, and the mixture is stirred and mixed uniformly and then incubated for 60min at room temperature. And adding 20 mu L of stop detection solution, stopping reaction, centrifuging at 1000rpm for 60s, and shaking and mixing uniformly. After standing for 30min, reading is carried out by an enzyme-labeled instrument.
The inhibition rate was calculated according to the following formula:
inhibition ratio (%) = (signal_max-signal_sample)/(signal_max-signal_min) x 100
(6) Fitting dose-response curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a log (inhibitor) vs. response-Variable slope fit quantitative effect curve of analysis software GraphPad Prism 5 is adopted, so that the IC of each compound on the enzyme activity is obtained 50 Values.
Embodiments of the present disclosureInhibition of MAO-A and MAO-B enzyme Activity in vitro was determined by the above assay, IC 50 The values are shown in Table 2.
TABLE 2
From tables 1 and 2 above, it can be seen that the compounds of the present disclosure have good inhibitory activity against rhVAP-1 enzyme, and that the compounds of the present disclosure exhibit excellent selective inhibitory effect against rhVAP-1 enzyme compared to monoamine oxidase (MAO). Taken together with tables 1 and 2 above, it can be seen that the compounds of the present disclosure do not have side effects due to inhibition of rhAOC1 and MAO enzymes while treating and/or preventing diseases associated with SSAO/VAP-1 enzymes.

Claims (3)

1. A compound which is
Or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention and/or treatment of a condition associated with SSAO or SSAO/VAP-1.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101917845A (en) * 2007-11-21 2010-12-15 法马克西斯制药公司 Haloallylamine inhibitors of SSAO/VAP-1 and uses therefor
CN107266332A (en) * 2012-05-02 2017-10-20 勃林格殷格翰国际有限公司 SSAO 3 substituted halogenated allyl amine inhibitors and application thereof
CN110938059A (en) * 2018-09-25 2020-03-31 上海轶诺药业有限公司 Preparation and application of aminourea sensitive amine oxidase inhibitor
WO2020089026A1 (en) * 2018-10-29 2020-05-07 Boehringer Ingelheim International Gmbh Pyridinyl sulfonamide derivatives, pharmaceutical compositions and uses thereof
WO2020089025A1 (en) * 2018-10-29 2020-05-07 Boehringer Ingelheim International Gmbh Pyridinyl sulfonamide derivatives, pharmaceutical compositions and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101917845A (en) * 2007-11-21 2010-12-15 法马克西斯制药公司 Haloallylamine inhibitors of SSAO/VAP-1 and uses therefor
CN107266332A (en) * 2012-05-02 2017-10-20 勃林格殷格翰国际有限公司 SSAO 3 substituted halogenated allyl amine inhibitors and application thereof
CN110938059A (en) * 2018-09-25 2020-03-31 上海轶诺药业有限公司 Preparation and application of aminourea sensitive amine oxidase inhibitor
WO2020089026A1 (en) * 2018-10-29 2020-05-07 Boehringer Ingelheim International Gmbh Pyridinyl sulfonamide derivatives, pharmaceutical compositions and uses thereof
WO2020089025A1 (en) * 2018-10-29 2020-05-07 Boehringer Ingelheim International Gmbh Pyridinyl sulfonamide derivatives, pharmaceutical compositions and uses thereof

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