CN115887463A - Pharmaceutical composition containing cyclic amide compound - Google Patents

Pharmaceutical composition containing cyclic amide compound Download PDF

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CN115887463A
CN115887463A CN202211691223.8A CN202211691223A CN115887463A CN 115887463 A CN115887463 A CN 115887463A CN 202211691223 A CN202211691223 A CN 202211691223A CN 115887463 A CN115887463 A CN 115887463A
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pharmaceutical composition
radical
alkoxy
cycloalkyl
hydroxy
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王中利
郝欣
刘桑
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Ruishi Biomedical Co ltd
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Ruishi Biomedical Co ltd
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Abstract

The present disclosure relates to a pharmaceutical composition containing a cyclic amide compound. Specifically, the disclosure provides a pharmaceutical composition, which contains a compound shown as a formula I or pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, wherein the ring A, the ring B and the ring R 1 ～R 3 W, o, m are as defined herein.

Description

Pharmaceutical composition containing cyclic amide compound
Technical Field
The disclosure belongs to the field of medicine, and relates to a pharmaceutical composition containing a cyclic amide compound.
Background
Until now, phosphodiesterases (PDEs) have been identified as the 11 isofunctional enzymes including PDE1 to 11, and among them, PDE4 has a high specificity for cAMP and is considered to be effective for inflammatory allergic diseases such as conjunctivitis and asthma, and autoimmune diseases such as arthritis.
For example, roflumilast is approved for use in severe Chronic Obstructive Pulmonary Disease (COPD) to reduce the number of sudden episodes or to prevent exacerbations of COPD symptoms, and aplite is approved for the treatment of adults with active psoriatic arthritis. In addition, various heterocyclic structures such as oxazole compounds have been reported, such as WO03/072102, WO98/15274, WO2007058338, and the like.
Although PDE4 inhibitors show good pharmacological activity, there are problems with these PDE inhibitors, such as induction of gastrointestinal symptoms such as emesis and diarrhea, or cases where PDE4 inhibition is competitive, and there is still a need to develop new specific selective PDE4 inhibitors.
Disclosure of Invention
The disclosure provides a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient,
Figure BDA0004021401090000011
wherein ring a is selected from a 5-to 8-membered aromatic ring or a heteroaromatic ring containing a nitrogen atom;
R 1 selected from aryl or heteroaryl, said aryl or heteroaryl being optionally substituted by one or more groups selected from deuterium, halogen (e.g. fluorine, chlorine), hydroxy, alkyl (e.g. C) 1-6 Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy (e.g. C) 1-6 Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkoxy (e.g., C) 3-6 Cycloalkoxy, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkoxy (e.g., 3-12 membered heterocycloalkoxy), or cycloalkenyloxy (e.g., C) 5-8 Cycloalkenyloxy), said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkoxy, or cycloalkenyloxy being optionally substituted by one or more R 7 Substituted;
R 2 、R 3 each independently selected from hydrogen, deuterium, hydroxy, alkyl (e.g. C) 1-6 Alkyl including but not limited to methyl, ethyl, propyl or isopropyl), alkoxy (e.g. C) 1-6 Alkoxy, including but not limited to methoxy, ethoxy, propoxy, or isopropoxy), said alkyl groupOr alkoxy optionally substituted with one or more groups selected from deuterium, halogen, nitrile, nitro or hydroxy;
or, when o =1, R 2 And R 3 Together form a keto group (= O);
ring B is selected from 3-to 11-membered carbocyclic ring, C 6-10 An aromatic ring or a 5-to 8-membered heteroaromatic ring, said ring B being substituted by one or more R 4 Substituted;
R 4 selected from the group consisting of hydrogen, deuterium, halogen, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, -SR', -S (O) 2 R ', -NR ' (R "), -COR ', -COOR ' or-CONR ' (R"), said alkyl, alkenyl, alkynyl or alkoxy being optionally substituted with one or more groups selected from deuterium, halogen, nitrile, nitro or hydroxy;
r 'or R' are independently selected from hydrogen, deuterium, hydroxy, alkyl (e.g. C) 1-6 Alkyl, alkoxy (e.g. C) 1-6 Alkoxy), cycloalkyl (e.g. C) 3-6 Cycloalkyl), heterocycloalkyl (such as 3-to 6-membered heterocycloalkyl), aryl (such as phenyl or naphthyl) or heteroaryl (such as 5-to 8-membered heteroaryl, pyridine or piperidine), said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;
R 7 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;
o is selected from an integer between 1 and 3, such as1 or 2;
m is selected from integers between 1 and 3, such as1 or 2.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 1 Selected from phenyl, said phenyl being optionally substituted by 1-3 substituents selected from deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-8 Cycloalkoxy, 3-to 6-membered heterocyclyloxy or C 5-8 Cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclyloxy or cycloalkenyloxy being optionally substituted by one or more R 7 Substituted, R 7 As defined above.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 1 Selected from phenyl, said phenyl being optionally substituted by 1-3 substituents selected from deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more R 7 Substituted, R 7 As defined above.
In other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition 1 Selected from phenyl, said phenyl being optionally substituted by 1-3 substituents selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-8 Cycloalkoxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclyloxy or cycloalkenyloxy being optionally substituted with one or more R 7 Substituted, R 7 As defined above.
In some embodiments, the ring B in the pharmaceutical composition is selected from 3-to 6-membered carbocyclic ring, C 6-10 An aromatic or 5-to 6-membered heteroaromatic ring including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, phenyl, thienyl or pyridyl, said ring B optionally substituted with 1 to 3R 4 Substituted; r 4 As defined above.
In other embodiments, the ring B is selected from C in the compounds of formula I or pharmaceutically acceptable salts thereof in pharmaceutical compositions 6-10 An aromatic ring or a 5-to 6-membered heteroaromatic ring, preferably phenyl, thienyl or pyridyl, more preferably phenyl or pyridyl; said ring B is optionally substituted with 1 to 3R 4 Substituted, R 4 As defined above.
In another aspect, in some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 4 Selected from hydrogen, deuterium, halogen, nitrile group, nitro group, hydroxyl group, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, -SR', -S (O) 2 R ', -NR ' (R '), -COR ', -COOR ' or-CONR ' (R '), R ' and R ' being as defined above.
In other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 4 Selected from hydrogen, deuterium, halogen, nitro.
In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 4 Selected from hydroxyl, nitrile and C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, -SR', -S (O) 2 R ', -NR ' (R '), -COR ', -COOR ' or-CONR ' (R '), R ' and R ' being as previously defined.
In an alternative embodiment, the compound of formula I in the pharmaceutical composition is:
Figure BDA0004021401090000031
wherein R is 5 、R 6 Each independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-8 Cycloalkoxy, 3-to 8-membered heterocycloalkoxy or C 5-8 Cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heteroEpoxy or cycloalkenyloxy optionally substituted by one or more R 7 Substituted;
ring C is selected from:
Figure BDA0004021401090000032
ring D is selected from:
Figure BDA0004021401090000033
ring B, R 2 、R 3 、R 7 O and m are defined in the compounds shown in formula I.
In some embodiments, the ring B of a compound of formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition is selected from 3 to 6 membered carbocyclic cycloalkyl, C 6-10 Aryl or 5 to 6 membered heteroaryl including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, phenyl, thienyl or pyridyl; said ring B is optionally substituted with 1 to 3R 4 Substituted; r 4 As defined for the compounds of formula I.
In other embodiments, R in the compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 5 、R 6 Each independently selected from C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-8 Cycloalkoxy, 3-to 8-membered heterocycloalkoxy or C 5-8 Cycloalkenyloxy, said alkoxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted by one or more groups selected from halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In certain embodiments, R in a compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in a pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy or 3-to 6-membered heterocyclic alkoxy, said alkoxy, cycloalkoxy or heterocyclic alkoxy being optionally substituted by one or more groups selected from halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 CycloalkanesRadicals or halogen radicals C 3-6 Cycloalkyl is substituted; r 6 Is selected from C 1-6 Alkoxy optionally substituted with one or more substituents selected from halogen or hydroxy.
In some embodiments, R in the compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 5 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 5 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 6 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 6 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkylAlkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocyclooxy optionally substituted with 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 6 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In certain embodiments, R in a compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in a pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy or 3-to 6-membered heterocycloalkoxy, said alkoxy, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 substituents selected from halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl is substituted; r 6 Is selected from C 1-6 Alkoxy optionally substituted with 1 to 3 substituents selected from halogen or hydroxy.
In some embodiments, R in the compound of formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3 to 8 membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano; r 6 Is selected from C 1-6 Alkoxy optionally substituted with 1 to 3 substituents selected from fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano.
In some embodiments, the ring C of the compound of formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is selected from the group consisting of:
Figure BDA0004021401090000051
in some embodiments, the ring D of the compound of formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is selected from:
Figure BDA0004021401090000052
in another aspect, in some embodiments, o =1,R in a compound of formula I or formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition 2 And R 3 Together form a ketone group (= O).
In other embodiments, R in the compound of formula I or formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition 2 And R 3 Each independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with one or more groups selected from deuterium, halogen, nitrile, nitro or hydroxy.
Some embodiments provide pharmaceutical compositions of a compound of formula I or formula II-1 or formula II-2 or a pharmaceutically acceptable salt thereof, wherein R is 2 And R 3 Selected from hydrogen; o =1 or 2.
Further, some embodiments provide that the compound of formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is:
Figure BDA0004021401090000053
Figure BDA0004021401090000061
Figure BDA0004021401090000062
wherein n0, 1,2 or 3 5 、R 6 Each independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 1-6 Alkoxy radical, C 2-6 Alkene oxygenBase, C 2-6 Alkynyloxy, C 3-8 Cycloalkoxy, 3-to 8-membered heterocycloalkoxy or C 5-8 Cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy being optionally substituted by one or more R 7 Substituted;
ring C is selected from:
Figure BDA0004021401090000063
R 2 、R 3 、R 4 、R 7 o and m are defined in the compounds shown in formula I.
In other embodiments, R in the compounds of formulae III-1a through III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 4 Selected from hydrogen, deuterium, halogen, nitro.
In some embodiments, R in the compounds of formulae III-1a through III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 4 Selected from hydroxyl, nitrile and C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, -SR', -S (O) 2 R ', -NR ' (R '), -COR ', -COOR ' or-CONR ' (R '), R ' and R ' being as previously defined.
In some embodiments, R in the compounds of formulae III-1a to III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-1a through III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-1a through III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-1a to III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-1a to III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-1a to III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-1a to III-1k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 fluoro, chloro, deuterium,Hydroxy, oxo, nitro, cyano; r 6 Is selected from C 1-6 Alkoxy, said alkoxy being optionally substituted with 1 to 3 substituents selected from fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano.
Other embodiments provide a pharmaceutical composition wherein the compound of formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, is:
Figure BDA0004021401090000071
Figure BDA0004021401090000072
wherein n =0, 1,2 or 3,R 5 、R 6 Each independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-8 Cycloalkoxy, 3-to 8-membered heterocycloalkoxy or C 5-8 Cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy being optionally substituted by one or more R 7 Substituted;
ring D is selected from:
Figure BDA0004021401090000081
R 2 、R 3 、R 4 、R 7 o and m are defined in the compounds shown in formula I.
In other embodiments, R in the compounds of formulae III-2a through III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 4 Selected from hydrogen, deuterium, halogen, nitrile group and nitro group.
In some embodiments, R in the compounds of formulae III-2a to III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 4 Selected from hydroxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, -SR', -S(O) 2 R ', -NR ' (R '), -COR ', -COOR ' or-CONR ' (R '), R ' and R ' being as previously defined.
In some embodiments, R in the compounds of formulae III-2a through III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-2a to III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3 to 8 membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-2a to III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-2a to III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-2a to III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxyOr heterocyclyloxy optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-2a to III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae III-2a to III-2k or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3 to 8 membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano; r 6 Is selected from C 1-6 Alkoxy, said alkoxy being optionally substituted with 1 to 3 substituents selected from fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano.
Further, some embodiments provide pharmaceutical compositions wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is:
Figure BDA0004021401090000091
Figure BDA0004021401090000092
wherein n =0, 1,2 or 3,R 5 、R 6 Each independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-8 Cycloalkoxy, 3-to 8-membered heterocycloalkoxy or C 5-8 Cycloalkenyloxy, said alkyl, alkoxyAlkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy optionally substituted with one or more R 7 Substituted, R 2 、R 3 、R 4 、R 7 O and m are defined in the compounds shown in formula I.
In other embodiments, R in the compounds of formulae V-1 through V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 4 Selected from hydrogen, deuterium, halogen, nitrile group and nitro group.
In some embodiments, R in the compounds of formulae V-1 through V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 4 Selected from hydroxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, -SR', -S (O) 2 R ', -NR ' (R '), -COR ', -COOR ' or-CONR ' (R '), R ' and R ' being as previously defined.
In some embodiments, R in the compounds of formulae V-1 through V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-1 through V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-1 through V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some implementationsIn the scheme, R in the compounds shown in formulas V-1 to V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-1 through V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-1 through V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-1 through V-11 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3 to 8 membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano; r 6 Is selected from C 1-6 Alkoxy optionally substituted with 1 to 3 substituents selected from fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano.
Other embodiments provide pharmaceutical compositions wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is:
Figure BDA0004021401090000101
/>
Figure BDA0004021401090000111
Figure BDA0004021401090000112
wherein n =0, 1,2 or 3,R 5 、R 6 Each independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-8 Cycloalkoxy, 3-to 8-membered heterocycloalkoxy or C 5-8 Cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy or cycloalkenyloxy being optionally substituted by one or more R 7 Substituted, R 2 、R 3 、R 4 、R 7 O and m are defined in the compounds shown in formula I.
In other embodiments, R in the compounds of formulae V-12 through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 4 Selected from hydrogen, deuterium, halogen, nitrile group and nitro group.
In some embodiments, R in the compounds of formulae V-12 through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 4 Selected from hydroxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, -SR', -S (O) 2 R ', -NR ' (R '), -COR ', -COOR ' or-CONR ' (R '), R ' and R ' being as previously defined.
In some embodiments, R in the compounds of formulae V-12 through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-12 through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-12 through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 5 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-12 through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-12 through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, R in the compounds of formulae V-12 through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition 6 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
In some embodiments, in a pharmaceutical compositionR in the compounds of formulae V-12 to V-19 or pharmaceutically acceptable salts thereof 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3 to 8 membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano; r 6 Is selected from C 1-6 Alkoxy, said alkoxy being optionally substituted with 1 to 3 substituents selected from fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano. In some embodiments, R 'or R' in the compounds of formulae I through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition is independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 6-8 Aryl or 5 to 6 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
In some embodiments, R 'or R' in the compounds of formulae I through V-19 or pharmaceutically acceptable salts thereof in the pharmaceutical composition is independently selected from hydrogen, C 1-6 Alkyl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
Typical compounds of formula I, or pharmaceutically acceptable salts thereof, include, but are not limited to:
Figure BDA0004021401090000121
/>
Figure BDA0004021401090000131
in some embodiments, the unit dose of the pharmaceutical composition is from 0.001mg to 1000mg.
In certain embodiments, the pharmaceutical composition comprises from 0.01 to 99.99% of the aforementioned 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 aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the compound or a pharmaceutically acceptable salt thereof.
In certain embodiments, the pharmaceutical composition comprises from 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.
In some embodiments, the disclosed medicaments are useful as phosphodiesterase inhibitors, preferably phosphodiesterase 4 inhibitors, and/or tumor necrosis factor- α inhibitors.
The present disclosure also provides a method for preventing and/or treating a patient having a PDE-related disorder by administering to the patient a therapeutically effective amount of a compound of formula I or formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, as described above, or a compound prepared by the foregoing method, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing.
In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.
The present disclosure also provides a method for preventing and/or treating a patient suffering from asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism by administering to the patient a therapeutically effective amount of a compound represented by the foregoing formula I or formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, or a compound prepared by the foregoing method, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The present disclosure also provides the use of a compound of formula I or formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of a PDE-related disorder. In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.
The present disclosure also provides the use of a compound of formula I or formula II-1 or formula II-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.
The disclosure also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and/or treatment of a PDE-related condition,
Figure BDA0004021401090000141
wherein, ring A, ring B, R 1 ～R 3 O, m are as defined above.
The present disclosure also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and/or treatment of asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism,
Figure BDA0004021401090000151
wherein, ring A, ring B, R 1 ～R 3 O, m are as defined above. The disclosure also provides compounds of formula I or pharmaceutically acceptable salts thereof
Figure BDA0004021401090000152
Figure BDA0004021401090000161
In another aspect, the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts, and the compounds described in this disclosure are reacted with an acid, such as hydrochloric acid, to form the corresponding salts.
In another aspect, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
In addition, 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 present 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 referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. An example of a lactam-lactam equilibrium is between A and B as shown below.
Figure BDA0004021401090000162
All compounds of the present invention can be drawn as form a or form B. All tautomeric forms are within the scope of the invention. The naming of the compounds does not exclude any tautomers. "
The disclosed compounds may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is 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), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The disclosure also includes some isotopically-labeled compounds of the present disclosure that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the 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 stated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compound of examples can have a natural abundance of deuterium greater than that of deuterium of at least 1000 times the abundance of deuterium, deuterium of at least 2000 times the abundance of deuterium, deuterium of at least 3000 times the abundance of deuterium, deuterium of at least 4000 times the abundance of deuterium, deuterium of at least 5000 times the abundance of deuterium, deuterium of at least 6000 times the abundance of deuterium, or deuterium of greater abundance. The 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 by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like.
"optionally" or "optionally" means 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 "optionally halogen-or cyano-substituted C 1-6 Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.
In the chemical structure of the compound of the present invention, a bond
Figure BDA0004021401090000171
Denotes an unspecified configuration, i.e. if a chiral isomer is present in the chemical structure, the bond->
Figure BDA0004021401090000172
Can be based on->
Figure BDA0004021401090000173
Or>
Figure BDA0004021401090000174
Or both>
Figure BDA0004021401090000175
And &>
Figure BDA0004021401090000176
Two configurations. Although all of the above structural formulae are drawn as certain isomeric forms for the sake of simplicity, the present invention may include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.
Interpretation of terms:
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock animals.
The "effective amount" or "therapeutically effective amount" as referred to in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow 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 method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
"alkyl" refers to a saturated aliphatic hydrocarbon group comprising 1 to 20Straight and branched chain groups of 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, various branched isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. E.g. "C 2-6 Alkenyl "denotes alkenyl having 2, 3,4, 5 or 6 carbon atoms or other C having 1-3 double bonds 2-6 Straight or branched alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if the specified number of carbon atoms is specified, that particular number is intended. For example "C 2-6 Alkynyl "denotes alkynyl having 2, 3,4, 5 or 6 carbon atoms or other C with 1-3 double bonds 2-6 Straight-chain or branched alkynyl, ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl. Alkynyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "cycloalkyl" or "carbocyclic ring" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. Cycloalkenylalkynyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "heterocycloalkyl" or "heterocycle" 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 is selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 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 include pyrrolidinyl, imidylOxazolidinyl, 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:
Figure BDA0004021401090000191
/>
Figure BDA0004021401090000201
Figure BDA0004021401090000202
and so on.
The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from, for example, halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "aryl" or "aromatic ring" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-or 6-membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,
Figure BDA0004021401090000203
and so on.
Examples of nitrogen atom-containing heteroaryl groups include, but are not limited to, pyrrolyl, piperazinyl, pyrimidinyl, imidazolyl, pyridazinyl, pyrazinyl, tetrazolyl, triazolyl, pyridyl, pyrazolyl, oxazolyl, thiazolyl, or the like.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
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, cyclopentyloxy, cyclohexyloxy. Similarly, "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", "cycloalkenyloxy" are as defined above for "alkoxy".
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 "nitro" means-NO 2 。
The term "oxo" refers to the = O substituent.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
Detailed Description
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) at 10 -6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated Methanol (Methanol-d) 4 ) Internal standard is Tetramethylsilane (TMS).
The HPLC assay used an Agilent1100 high pressure liquid chromatograph, GAS15B DAD uv detector, water Vbridge C18 x 4.6mm 5um column.
MS was measured using an Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, waters Xbridge C18.6 x 50mm,5um chromatography column, scanning in positive/negative ion mode with a mass scan range of 80-1200.
The silica gel plate for thin layer chromatography is HSGF254 silica gel plate of cigarette platform yellow sea, and the silica gel plate for Thin Layer Chromatography (TLC) is 0.2mm + -0.03 mm, and the specification of the product for thin layer chromatography separation and purification is 0.4mm-0.5mm.
The flash column purification system used either Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
The forward column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel of Taiwan yellow sea as carrier, or uses the ultra-pure forward phase silica gel column (40-63 μm,60g,24g,40g,120g or other specifications) pre-filled by Santai in Changzhou.
Known starting materials in this disclosure can be synthesized by or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan science, ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoshi Chemical technology (Accela ChemBio Inc), biddy medicine, and the like.
In the examples, the reactions were all carried out under a nitrogen atmosphere without specific indication.
The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The hydrogen is prepared by QPH-1L type hydrogen generator of Shanghai Quanpu scientific instruments company.
The nitrogen atmosphere or the hydrogenation atmosphere is usually vacuumized, and filled with nitrogen or hydrogen, and the operation is repeated for 3 times.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the reaction progress in the examples employs Thin Layer Chromatography (TLC), a developing agent used for the reaction, an eluent system for column chromatography used for purifying a compound, and a developing agent system for thin layer chromatography, and the volume ratio of a solvent is adjusted according to the polarity of the compound, and may also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
Example 1
Figure BDA0004021401090000221
Synthesis of Compound 1b
Pyridine tribromide (23.12g, 72.28mmol) was added to a 250 ml single-neck flask at room temperature, methylene chloride (100 ml) was added thereto and stirred until dissolved, and compound 1a (10g, 65.71mmol) was dissolved in methylene chloride (60 ml) and slowly added dropwise to the single-neck flask. After addition was complete the reaction was stirred overnight. After completion of the TLC detection reaction, it was then quenched by addition of 1M hydrochloric acid (50 ml), extracted with ethyl acetate (150ml X3), and the extracts were combined. The extract was washed with water (150 ml) and saturated sodium chloride (150 ml) in this order. The organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give the objective compound 1b (12.1 g).
1 H NMR：(400MHz,CDCl 3 )δ6.96(dd,J＝7.4,1.9Hz,2H),6.82–6.76(m,1H),5.66(s,1H),4.55(dq,J＝12.0,6.0Hz,1H),1.38(s,3H),1.36(s,3H).
Synthesis of Compound 1c
To a 250 ml single neck flask was added compound 1b (10.1g, 9.79mmol) and acetonitrile/water (16954 ml) at room temperature, stirred until dissolved, followed by the addition of potassium hydroxide (49.06g, 4.76mmol) and diethyl bromofluoromethylphosphonate (23.34g, 4.76mmol) in portions. The reaction was stirred overnight at room temperature. After completion of the TLC detection reaction, extraction was performed with ethyl acetate (150ml X3), and the extracts were combined. The extract was washed with water (150 ml) and saturated sodium chloride (150 ml) in this order. The organic phase was concentrated under reduced pressure and subjected to column chromatography (petroleum ether) to give the objective compound 1c (7.3 g).
1 H NMR：(400MHz,DMSO-d 6 )δ7.37(s,1H),7.22–6.82(m,3H),4.77–4.62(m,1H),1.28(s,3H),1.27(s,3H).
Synthesis of Compound 1d
Compound 1c (5.1g, 18.4mmol) was added to a 250 ml single-neck flask at room temperature under nitrogen blanket and dioxane (80 ml) was added with stirring until dissolved, followed by the sequential addition of pinacol diborate (6.91g, 27.21mmol), potassium acetate (3.56g, 36.29mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (664mg, 0.91mmol). The reaction was heated to 80 ℃ and stirred overnight. After completion of the TLC detection reaction, it was cooled and filtered. The filtrate was concentrated under reduced pressure and subjected to column chromatography (ethyl acetate/petroleum ether) to give the objective compound 1d (3.7 g).
1 H NMR(400MHz,CDCl 3 )δ7.28(dd,J＝27.6,26.4Hz,2H),7.07(d,J＝7.8Hz,1H),6.53(t,J＝75.5Hz,1H),4.57(dq,J＝12.6,6.3Hz,1H),1.28(d,J＝6.1Hz,6H),1.26(d,J＝3.4Hz,12H).
Synthesis of Compound 1f
Compound 1e (1.50g, 6.02mmol) was added to a 50ml single-neck flask at room temperature, and N, N-dimethylformamide (10 ml) was added and stirred to dissolve, followed by the addition of 1, 3-dioxoisoindoline-2-potassium (2.23g, 12.04mmol). The reaction was warmed to 70 ℃ and stirring was continued for 2 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (20 ml), and washed with saturated brine (25 ml). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give the objective compound 1f (1.76 g).
LCMS:m/z 316.99(M+2H) + 。
Synthesis of Compound 1
To a 10ml single-necked flask, compound 1f (200mg, 0.63mmol), compound 1d (208mg, 0.63mmol), 1' -bisdiphenylphosphinoferrocene palladium dichloride (37.1mg, 0.06mmol), sodium carbonate (134mg, 1.27mmol), 1, 4-dioxane (5 ml) and water (0.5 ml) were added at room temperature. The reaction was heated to 100 ℃ under nitrogen for 3 hours, monitored by LCMS for completion, cooled to room temperature, and filtered. The filtrate was concentrated and purified by preparative thin layer chromatography (ethyl acetate/petroleum ether) to give example 1 (144 mg).
LCMS:m/z 455.2(M+H+NH 3 ) + 。
1 H NMR(400MHz,CD 3 OD)δ7.86–7.84(m,2H),7.80–7.75(m,2H),7.59(s,1H),7.51–7.47(m,1H),7.41–7.33(m,2H),7.24(d,J＝1.9Hz,1H),7.19-7.12(m,2H),6.73(t,J＝75.0Hz,1H),4.87(s,2H),4.72–4.64(m,1H),1.35(d,J＝6.0Hz,6H).
Example 2
Figure BDA0004021401090000241
Compound 2 was prepared according to the procedure described in example 1.
LCMS:m/z 439.5(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ8.10-8.05(m,2H),7.96–7.90(m,2H),7.82–7.80(m,2H),7.43(d,J＝7.7Hz,1H),7.37-7.36(m,1H),7.28(d,J＝8.4Hz,1H),6.68(t,J＝75.0Hz,1H),5.73(s,2H),5.02-4.92(m,1H),1.42(d,J＝4.3Hz,6H).
Example 3
Figure BDA0004021401090000242
Compound 3 was prepared according to the procedure described in example 1.
LCMS:m/z:439.2(M+H) + ， 1 H NMR(400MHz,CDCl 3 )δ8.70(s,2H),7.89(s,1H),7.86(dd,J＝5.3,3.1Hz,2H),7.73(dd,J＝5.3,3.0Hz,2H),7.24(d,J＝8.1Hz,1H),7.12(s,1H),7.09(d,J＝8.2Hz,1H),6.60(t,J＝75.3Hz,1H),4.92(s,2H),4.67-4.61(m,1H),1.40(s,3H),1.38(s,3H).
Example 4
Figure BDA0004021401090000243
Synthesis of Compound 2b
Compound 2a (10.0 g,55.5 mmol) was added to a 250-ml single-neck flask at room temperature, N-dimethylformamide (40 ml) was added thereto, the mixture was stirred until dissolved, and isopropyl bromide (8.50g, 69.1 mmol) and potassium carbonate (9.55g, 69.2mmol) were added. The reaction was warmed to 80 ℃ and stirring was continued for 2 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (200ml X2), and washed with saturated brine (100 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 2b (12 g crude).
LCMS:m/z 231.1(M+H) + 。
Synthesis of Compound 2c
Under an ice-water bath, compound 2b (12.0 g,52.2 mmol) was added to a 250-ml single-neck flask, and ethyl acetate (80 ml) was added and stirred to dissolve, followed by addition of sulfamic acid (5.68g, 58.5 mmol) and water (10 ml). A25% aqueous solution of sodium chlorite (21.2g, 58.5 mmol) was added dropwise while controlling the reaction temperature to 20 ℃ or lower, and the reaction was stirred after completion of the addition. TLC detection, complete conversion of the raw material. Subsequently, 25% aqueous sodium hydroxide (10 ml) and 10% aqueous sodium sulfite (80.4g, 63.8mmol) were added in this order, and stirring was continued for 15 to 30 minutes, concentrated hydrochloric acid (2 ml) was added to the reaction system, and the organic phase was separated and concentrated under reduced pressure. Methanol (40 ml), water (80 ml) and a 25% aqueous solution (10 ml) of sodium hydroxide were added to the concentrated residue, dissolved with stirring, and concentrated hydrochloric acid (5 ml) was added dropwise with stirring for 1 hour. Filtration and vacuum drying of the filter cake gave compound 2c (6.4 g).
LCMS:m/z 245.0(M-H) - 。
Synthesis of Compound 2d
To a 250 ml single-neck flask, compound 2c (4.9g, 19.9mmol) was added at room temperature, acetonitrile (80 ml) was added and stirred until dissolved, followed by carbonyldiimidazole (3.9g, 23.9mmol). The reaction mixture was stirred at room temperature for 3 hours, followed by addition of 28% concentrated aqueous ammonia (20 ml), and a large amount of white precipitate was formed. Filtration and washing of the filter cake gave compound 2d (4.8 g).
LCMS:m/z 246.1(M+H) + 。
Synthesis of Compound 2e
Compound 2c (4.8g, 19.6mmol) was charged into a 250-ml single-neck flask at room temperature, and toluene (80 ml) was added and stirred to dissolve, followed by addition of 1, 3-dichloropropan-2-one (3.8g, 58.8mmol) and heating of the reaction system to 120 ℃ for 16 to 24 hours. The reaction solution was cooled to room temperature, concentrated and purified by column chromatography (ethyl acetate/petroleum ether) to give compound 2e (4.5 g).
LCMS:m/z 318.0(M+H) + 。
Synthesis of Compound 4
To a 10ml single-necked flask, compound 2e (50mg, 0.169mol), 5H-pyrrolo [3,4-b ] pyridine-5, 7 (6H) -dione (28mg, 0.19mmol), potassium iodide (27mg, 0.169mol), potassium carbonate (44mg, 0.32mmol) and N, N-dimethylformamide (3 ml) were added at room temperature. The reaction was heated to 60 ℃ and stirred for 3 hours, LCMS monitored for completion, cooled to room temperature and filtered. The filtrate was purified by preparative liquid chromatography (formic acid/acetonitrile/water system) to give compound 4 (22.22 mg).
LCMS:m/z 430.1(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ8.99(d,J＝3.8Hz,1H),8.20(dd,J＝7.7,1.3Hz,1H),7.73(s,1H),7.63(dd,J＝7.6,5.0Hz,1H),7.60(d,J＝1.7Hz,1H),7.54(dd,J＝8.4,1.9Hz,1H),7.18(d,J＝8.4Hz,1H),6.60(t,J＝75.2Hz,1H),4.92(s,2H),4.67(dt,J＝12.1,6.1Hz,1H),1.38(s,3H),1.36(s,3H).
Example 5
Figure BDA0004021401090000261
Compound 5 was prepared according to the procedure described in example 4.
LCMS:m/z 430.1(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ9.20(s,1H),9.11(d,J＝4.6Hz,1H),7.89(d,J＝4.4Hz,1H),7.75(s,1H),7.59(d,J＝1.8Hz,1H),7.54(dd,J＝8.4,1.9Hz,1H),7.20(d,J＝8.3Hz,1H),6.61(t,J＝75.0Hz,1H),4.92(s,2H),4.67(dt,J＝12.0,6.0Hz,1H),1.38(d,J＝6.1Hz,6H).
Example 6
Figure BDA0004021401090000262
Compound 6 was prepared according to the procedure described in example 4.
LCMS:m/z 459.2(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝8.3Hz,1H),7.66(s,1H),7.63(s,1H),7.56(dd,J＝8.4,1.8Hz,1H),7.36(d,J＝2.2Hz,1H),7.20–7.14(m,2H),6.60(t,J＝75.2Hz,1H),4.84(s,2H),4.72-4.66(m,1H),3.93(s,3H),1.39(d,J＝6.1Hz,6H).
Example 7
Figure BDA0004021401090000263
Compound 7 was prepared according to the procedure described in example 4.
LC-MS:m/z 454.1(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),8.06–7.98(m,2H),7.72(s,1H),7.59(s,1H),7.55(dd,J＝8.4,1.9Hz,1H),7.19(d,J＝8.4Hz,1H),6.60(t,J＝75.1Hz,1H),4.89(s,2H),4.67(dt,J＝12.0,6.1Hz,1H),1.38(d,J＝6.1Hz,6H).
Example 8
Figure BDA0004021401090000271
Compound 8 was prepared according to the procedure described in example 4.
LCMS:m/z 407.1(M+H) + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.12(s,1H),7.57(s,1H),7.55–7.48(m,1H),7.18(dd,J＝106.3,41.4Hz,2H),4.77–4.64(m,1H),4.59(s,2H),2.58(dd,J＝11.0,6.5Hz,2H),2.05(d,J＝3.5Hz,2H),1.31(d,J＝6.0Hz,6H).
Example 9
Figure BDA0004021401090000272
Compound 9 was prepared according to the procedure described in example 4.
LCMS:m/z 433.1(M+H) + 。
1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝1.7Hz,1H),7.56–7.51(m,2H),7.19(d,J＝8.3Hz,1H),6.61(t,J＝75.2Hz,1H),5.96–5.85(m,2H),4.72–4.65(m,1H),4.64(s,2H),3.19–3.07(m,2H),2.71–2.57(m,2H),2.32–2.16(m,2H),1.38(d,J＝6.1Hz,6H).
Example 10
Figure BDA0004021401090000273
Compound 10 was prepared according to the procedure described in example 4.
LCMS:m/z 415.1(M-H) - 。
1 H NMR(400MHz,CD 3 OD)δ7.97(s,1H),7.80(d,J＝7.6Hz,1H),7.71(d,J＝2.0Hz,1H),7.63–7.54(m,3H),7.50(t,J＝7.4Hz,1H),7.23(d,J＝8.4Hz,1H),6.79(t,J＝74.8Hz,1H),4.80(s,2H),4.74-4.68(m,1H),4.57(s,2H),1.36(d,J＝6.0Hz,6H).
Example 11
Figure BDA0004021401090000274
Compound 11 was prepared according to the procedure described in example 4.
LCMS:m/z 429.2(M+H) + 。
1 H NMR(400MHz,CD 3 OD)：δ8.01–7.91(m,2H),7.72(d,J＝1.6Hz,1H),7.59(dd,J＝8.4,1.6Hz,1H),7.48(t,J＝7.4Hz,1H),7.36(t,J＝7.6Hz,1H),7.25(dd,J＝11.6,8.0Hz,2H),6.80(t,J＝74.9Hz,1H),4.75(s,2H),4.71(dd,J＝12.1,6.1Hz,1H),3.72(t,J＝6.7Hz,2H),3.04(t,J＝6.6Hz,2H),1.37(d,J＝6.0Hz,6H)。
Example 12
Figure BDA0004021401090000281
Compound 12 was prepared according to the procedure described in example 4.
LCMS:m/z 393.1(M+H) + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.08(s,1H),7.56(d,J＝1.9Hz,1H),7.52(dd,J＝8.4,1.9Hz,1H),7.35–6.94(m,2H),4.73(dt,J＝12.1,6.1Hz,1H),4.38(d,J＝0.8Hz,2H),2.64(dd,J＝7.8,3.8Hz,2H),1.65–1.47(m,2H),1.32(d,J＝6.0Hz,6H).
Biological evaluation
The following further description explains the present disclosure in conjunction with test examples, but these test examples are not meant to limit the scope of the present disclosure.
Test example 1In vitro PDE4B enzyme Activity detection assay
1. Experimental Material
Name (R) Brand Goods number/model
PDE4B1 BPS 60041
Trequinsin T℃RIS 2337/10
IMAP FP IPP Explorer Kit Molecular Device R8124
FAM-cAMP Molecular Device R7506
OptiPlate TM -384 F black assay plate PerkinElmer 6007279
384 well Echo plate Labcyte PP-0200
2. Experimental procedure
For compound testing, compound stock solutions at a concentration of 10mM were first prepared in tubes with 100% DMSO and used to prepare serial dilutions with a dilution gradient of 1. For enzyme assay, 0.2ul of compound solution was transferred to 384 well reaction plates, and both negative and positive controls were transferred to 0.2ul of 100% DMSO. 10ul of a 2-fold concentration of PDE4B1 enzyme solution (final concentration of 0.04 nM) was then added to the wells, and 10ul of a 1-fold reaction buffer was substituted for the enzyme solution for the enzyme-free control wells. Centrifuge at 1000rpm for 1min and incubate at room temperature for 15 min. Then, 10ul of a 2-fold FAM-cAMP substrate solution (final substrate concentration: 0.1 uM) was added to each well of the 384-well reaction plate, centrifuged at 1000rpm for 1min, and reacted at 25 ℃ for 30 minutes. After the reaction, 60ul of the reaction stop solution was added to each well of the 384-well reaction plate to terminate the reaction, and the plate was incubated at room temperature for 60 minutes while shaking at 600rpm in a dark place. Reading RLU data after the incubation is finished, calculating the inhibition rate, and calculating an IC50 value according to a curve fitted by the concentration and the inhibition rate, wherein the maximum value is the reading value of a DMSO control, and the minimum value is the reading value of a control without enzyme activity.
Inhibition of PDE4B1 enzyme Activity in vitro by the examples of the present disclosure IC determined by the above assays 50 The values are shown in Table 1.
TABLE 1
Figure BDA0004021401090000291
Note: N/A was not detected.

Claims (41)

1. A pharmaceutical composition comprises at least one compound shown in formula I or pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients,
Figure FDA0004021401080000011
wherein ring a is selected from a 5-to 8-membered aromatic ring or a heteroaromatic ring containing a nitrogen atom;
R 1 selected from aryl or heteroaryl, said aryl or heteroaryl being optionally substituted by one or more groups selected from deuterium, halogen, hydroxy, alkyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkoxy, heterocycloalkoxy or cycloalkenoxy, said alkyl, alkoxy, alkenoxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclooxy or cycloalkenoxy being optionally substituted by one or more R 7 Substituted;
R 2 、R 3 each independently selected from hydrogen, deuterium, hydroxy, alkylAn alkoxy group, said alkyl or alkoxy group being optionally substituted with one or more groups selected from deuterium, halogen, nitrile, nitro or hydroxy;
or, when o =1, R 2 And R 3 Together form a keto group (= O);
ring B is selected from 3-to 11-membered carbocyclic ring, C 6-10 An aromatic ring or a 5-to 8-membered heteroaromatic ring, said ring B being substituted by one or more R 4 Substituted;
R 4 selected from the group consisting of hydrogen, deuterium, halogen, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, -SR', -S (O) 2 R ', -NR ' (R "), -COR ', -COOR ' or-CONR ' (R"), said alkyl, alkenyl, alkynyl or alkoxy being optionally substituted with one or more groups selected from deuterium, halogen, nitrile, nitro or hydroxy;
r 'or R' are independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;
R 7 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano;
o is selected from an integer between 1 and 3, such as1 or 2;
m is selected from integers between 1 and 3, such as1 or 2.
2. The pharmaceutical composition of claim 1, wherein R 1 Selected from phenyl, said phenyl being optionally substituted by 1-3 substituents selected from deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-8 Cycloalkoxy, 3-to 6-membered heterocyclyloxy or C 5-8 Cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclyloxy or cycloalkenyloxy being optionally substituted with one or more R 7 Substituted, R 7 As defined in claim 1.
3. The pharmaceutical composition of claim 1 or 2, wherein R 1 Selected from phenyl, said phenyl being optionally substituted by 1-3 substituents selected from deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more R 7 Substituted, R 7 As defined in claim 1.
4. The pharmaceutical composition of claim 1 or 2, wherein R 1 Selected from phenyl, said phenyl being optionally substituted by 1-3 substituents selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 3-8 Cycloalkoxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkoxy, heterocyclyloxy or cycloalkenyloxy being optionally substituted by one or more R 7 Substituted, R 7 As defined in claim 1.
5. The pharmaceutical composition of claim 1 or 2, wherein ring B is selected from a 3-to 6-membered carbocyclic ring, a C6-10 aromatic ring, or a 5-to 6-membered heteroaromatic ring, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, phenyl, thienyl, or pyridyl; said ring B is optionally substituted with 1 to 3R 4 Substituted, R 4 Such as rightAs defined in claim 1.
6. The pharmaceutical composition of claim 1 or 2, wherein ring B is selected from C 6-10 An aromatic ring or a 5 to 6 membered heteroaromatic ring, preferably phenyl, thienyl or pyridyl, more preferably phenyl or pyridyl; said ring B is optionally substituted with 1 to 3R 4 Substituted, R 4 As defined in claim 1.
7. The pharmaceutical composition of any one of claims 1-6, wherein R 4 Selected from hydrogen, deuterium, halogen, nitrile group, nitro group, hydroxyl group, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, -SR', -S (O) 2 R ', -NR ' (R '), -COR ', -COOR ' or-CONR ' (R '), R ' and R ' being as defined in claim 1.
8. The pharmaceutical composition of any one of claims 1-7, wherein R 4 Selected from hydrogen, deuterium, halogen, nitro.
9. The pharmaceutical composition of any one of claims 1-7, wherein R 4 Selected from hydroxyl, nitrile and C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkoxy, -SR', -S (O) 2 R ', -NR' (R "), -COR ', -COOR' or-CONR '(R"), R' and R "are as defined in claim 1.
10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is:
Figure FDA0004021401080000031
wherein R is 5 、R 6 Each independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-8 Cycloalkoxy, 3-to 8-membered heterocycloalkoxy or C 5-8 Cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocyclyloxy or cycloalkenyloxy being optionally substituted by one or more R 7 Substituted;
ring C is selected from:
Figure FDA0004021401080000032
ring D is selected from:
Figure FDA0004021401080000033
ring B, R 2 、R 3 、R 7 O, m are as defined in claim 1.
11. The pharmaceutical composition of claim 10, wherein R 5 、R 6 Each independently selected from C 1-6 Alkoxy radical, C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy, C 3-8 Cycloalkoxy, 3-to 8-membered heterocycloalkoxy or C 5-8 Cycloalkenyloxy, said alkoxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted by one or more groups selected from halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
12. The pharmaceutical composition of claim 10, wherein R 5 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
13. The pharmaceutical composition of claim 10, wherein R 5 Is selected from C 1-6 Alkoxy radical, C 3-6 A cycloalkyl group, a,3 to 6 membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
14. The pharmaceutical composition of claim 10, wherein R 5 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
15. The pharmaceutical composition of any one of claims 10 or 12-14, wherein R 6 Selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl optionally substituted by 1 to 3 halogens, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
16. The pharmaceutical composition of any one of claims 10 or 12-14, wherein R 6 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3-to 8-membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
17. The pharmaceutical composition of any one of claims 10 or 12-14, wherein R 6 Is selected from C 2-6 Alkenyloxy radical, C 2-6 Alkynyloxy or C 5-8 Cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3 halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl groups are substituted.
18. The pharmaceutical composition of claim 10, wherein R 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkoxy or 3 to 6 membered heterocyclic alkoxy, optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C 1-6 Alkyl radical, C 3-6 Cycloalkyl or halo C 3-6 Cycloalkyl is substituted; r 6 Is selected from C 1-6 Alkoxy optionally substituted with 1 to 3 substituents selected from halogen or hydroxy.
19. The pharmaceutical composition of claim 10, wherein R 5 Is selected from C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 3-8 Cycloalkoxy or 3 to 8 membered heterocycloalkoxy, said alkoxy, cycloalkoxy, heterocycloalkyl, cycloalkoxy or heterocycloalkoxy being optionally substituted with 1 to 3 fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano; r 6 Is selected from C 1-6 Alkoxy optionally substituted with 1 to 3 substituents selected from fluoro, chloro, deuterium, hydroxy, oxo, nitro, cyano.
20. The pharmaceutical composition of any one of claims 10-19, wherein ring C is selected from:
Figure FDA0004021401080000041
21. the pharmaceutical composition of any one of claims 10-19, wherein ring D is selected from the group consisting of:
Figure FDA0004021401080000042
22. the pharmaceutical composition of any one of claims 1-21, wherein o =1,r 2 And R 3 Together form a keto group (= O).
23. The pharmaceutical composition of any one of claims 1-21, wherein R 2 And R 3 Each independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy, said alkyl or alkoxy being optionally substituted by one or more groups selected from deuterium, halogen, nitrile, nitro or hydroxy, preferably R 2 And R 3 Selected from hydrogen; o =1 or 2.
24. The pharmaceutical composition of any one of claims 1-23, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is:
Figure FDA0004021401080000051
Figure FDA0004021401080000052
wherein n =0, 1,2 or 3,R 2 、R 3 、R 4 O, m are as defined in claim 1, ring C, R 5 、R 6 As defined in claim 10.
25. The pharmaceutical composition according to any one of claims 1-23, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is:
Figure FDA0004021401080000053
Figure FDA0004021401080000061
/>
Figure FDA0004021401080000062
wherein n =0, 1,2 or 3,R 2 、R 3 、R 4 O, m are as defined in claim 1, ring D, R 5 、R 6 As defined in claim 10As defined above.
26. The pharmaceutical composition according to any one of claims 1-23, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is
Figure FDA0004021401080000063
Figure FDA0004021401080000071
Figure FDA0004021401080000072
Wherein n =0, 1,2 or 3,R 2 、R 3 、R 4 O, m are as defined in claim 1, R 5 、R 6 As defined in claim 10. />
27. The pharmaceutical composition of any one of claims 1-23, wherein the compound of formula I is:
Figure FDA0004021401080000073
Figure FDA0004021401080000074
n =0, 1,2 or 3,R 2 、R 3 、R 4 O, m are as defined in claim 1, R 5 、R 6 As defined in claim 10.
28. The pharmaceutical composition of any one of claims 1-27, wherein R' or R "is independently selected from hydrogen, deuterium, hydroxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 6-8 Aryl or 5 to 6 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitroSubstituted by cyano.
29. The pharmaceutical composition of claim 28, wherein R' or R "is independently selected from hydrogen, C 1-6 Alkyl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
30. The pharmaceutical composition according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is selected from the group consisting of
Figure FDA0004021401080000081
Figure FDA0004021401080000091
31. A pharmaceutical composition according to any one of claims 1 to 30, which comprises 0.01 to 99.99% of a compound of formula I or a pharmaceutically acceptable salt thereof.
32. The pharmaceutical composition of any one of claims 1-31, which is administered topically, gastrointestinal, parenterally.
33. The pharmaceutical composition of any one of claims 1-32, which is a tablet, capsule, or injection.
34. The pharmaceutical composition according to any one of claims 1 to 33 for use as a phosphodiesterase inhibitor, preferably a phosphodiesterase 4 inhibitor, and/or a tumor necrosis factor-a inhibitor.
35. A method of preventing and/or treating a phosphodiesterase-related disease by administering to the patient the pharmaceutical composition of any one of claims 1-33.
36. A method for preventing and/or treating a patient suffering from asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism, by administering to said patient a pharmaceutical composition according to any one of claims 1-33.
37. Use of a pharmaceutical composition according to claims 1-33 for the preparation of a medicament for the prevention and/or treatment of a PDE-related disorder.
38. Use of a pharmaceutical composition according to any one of claims 1 to 33 for the preparation of a medicament for the prevention and/or treatment of asthma, obstructive pulmonary disease, septicemia, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatic diseases.
39. The use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of a PDE-related condition,
Figure FDA0004021401080000101
wherein, ring A, ring B, R 1 ～R 3 O, m are as defined in claims 1 to 9.
40. The use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis or rheumatism,
Figure FDA0004021401080000102
wherein, ring A, ring B, R 1 ～R 3 O, m are as defined in claims 1 to 9.
41. A compound of formula I or a pharmaceutically acceptable salt thereof
Figure FDA0004021401080000103
Figure FDA0004021401080000111
/>
CN202211691223.8A 2022-12-27 2022-12-27 Pharmaceutical composition containing cyclic amide compound Pending CN115887463A (en)

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