JPWO2021215765A5

JPWO2021215765A5 -

Info

Publication number: JPWO2021215765A5
Application number: JP2022564050A
Authority: JP
Publication date: 2024-04-26

Description

前記実験を通じて得られた実施例化合物のＫｉは下記の表１に示した。
The Ki values of the example compounds obtained through the above experiments are shown in Table 1 below.

Claims

A compound of the following formula 1, a pharma- ceutically acceptable salt or isomer thereof :
The compound, or a pharma- ceutically acceptable salt or isomer thereof, wherein said isomer is selected from the group consisting of E or Z isomers, R or S isomers, a racemate, a rearranged isomer mixture and an individual rearranged isomer .
In the above Chemical Formula 1,
R ₁ represents a C ₃ -C ₇ heterocycloalkyl containing 1 to 3 N atoms, which is unsubstituted or substituted with a C ₁ -C ₅ alkyl;
R ₂ and R ₃ each independently represent hydrogen, halogen, or C ₁ -C ₅ alkyl;
R ₄ represents —(CH ₂ ) _m CO ₂ H;
m, p and q each independently represent an integer from 0 to 2;
X represents N or C-CN;
Y represents _CH2 or O;
Z represents _CH2 .

2. The compound of claim 1 , selected from the group consisting of:
2-((1R,5S,6S)-3-(4-cyano-3-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)-3-azabicyclo[3.1.1]heptan-6-yl)acetic acid;
2-((1R,5S,6S)-3-(4-cyano-3-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroisoquinolin-1-yl)-3-azabicyclo[3.1.1]heptan-6-yl)acetic acid;
2-(3-(4-cyano-3-((S)-2-methylazetidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-1-yl)-3-azabicyclo[3.1.1]heptan-6-yl)acetic acid;
2-((1R,5S,6S)-3-(5-cyano-6-((S)-2-methylazetidin-1-yl)-3,4-dihydro-1H-pyrano[3,4-c]pyridin-8-yl)-3-azabicyclo[3.1.1]heptan-6-yl)acetic acid;
2-(3-(7,7-dimethyl-2-((S)-2-methylazetidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptan-6-yl)acetic acid;
2-((1R,5S,6S)-3-((S)-7-methyl-2-((S)-2-methylazetidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptan-6-yl)acetic acid ;
2 -((1R,5S,6S)-3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptan-6-yl)acetic acid ;
2 -((1R,5S,6S)-3-(8,8-difluoro-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-azabicyclo[3.1.1]heptan-6-yl) acetic acid.

3. The compound according to claim 1 or 2 , or a pharma- ceutically acceptable salt or isomer thereof, for use as a ketohexokinase (KHK) inhibitor.

3. A compound according to claim 1 or claim 2 , or a pharma- ceutically acceptable salt or isomer thereof, for use in the prophylaxis or treatment of a metabolic disease.

A pharmaceutical composition for inhibiting ketohexokinase (KHK), comprising the compound according to claim 1 or 2, a pharma- ceutical acceptable salt or isomer thereof, and a pharma- ceutical acceptable carrier.

A pharmaceutical composition for preventing or treating a ketohexokinase (KHK)-associated metabolic disease, comprising the compound according to claim 1 or 2, a pharma- ceutical acceptable salt or isomer thereof, and a pharma- ceutical acceptable carrier.

The pharmaceutical composition for preventing or treating a metabolic disease according to claim 6, wherein the metabolic disease is selected from the group consisting of diabetes, diabetic complications, obesity, non-alcoholic steatohepatitis, and steatohepatitis.

A method for producing a pharmaceutical composition for preventing or treating a ketohexokinase (KHK)-associated metabolic disease, comprising the step of mixing a compound described in claim 1 or claim 2, or a pharma- ceutical acceptable salt or isomer thereof, as an active ingredient, with a pharma- ceutical acceptable carrier.

The method for producing a pharmaceutical composition according to claim 8, wherein the metabolic disease is selected from the group consisting of diabetes, diabetic complications, obesity, non-alcoholic steatohepatitis, and steatohepatitis.