Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors

Patent metadata

Field	Value
Publication number	US-9809579-B2
Application number	US-201615381295-A
Country	US
Kind code	B2
Filing date	Dec 16, 2016
Priority date	Dec 29, 2015
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

Provided herein are substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

First claim

The invention claimed is:

1. A compound of Formula I

or a pharmaceutically salt thereof, wherein
Y is N or C—CN;
Z is N or CH;
X is N or CR 3 ;
provided that at least one of Y, Z, or X is N;
R 1 is C 3-7 cycloalkyl or a 4- to 7-membered heterocyclic moiety, wherein the heterocyclic moiety contains 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and wherein the cycloalkyl or heterocyclic moiety has 0 to 3 substitutuents independently selected from —C 1-3 alkyl, and —OH, provided that there is no more than one —OH substituent; or
N(C 1-3 alkyl) 2 , NH(C 1-3 alkyl), or NH(C 3-4 cycloalkyl), wherein each C 1-3 alkyl is substituted with 0 to 1 OH;
R 2 is -(L) m -CON(R N ) 2 , -(L) m -SO 2 R s , -L-(CH 2 ) n SO 2 R s , -L-(CH 2 ) n CO 2 H, -L -(CH 2 ) n C(O)R c , -L-(CH 2 ) n CONHSO 2 R s , -L-(CH 2 ) n SO 2 NHCOR s , -L-(CH 2 ) n SO 2 NHCONH 2 , or -L-(CH 2 ) n tetrazol-5-yl;
m is 0 or 1;
n is 0 or 1;
R N is H or —C 1-3 alkyl;
R s is H or —C 1-3 alkyl;
L is CH 2 , CHF, or CF 2 ;
R c is —C 1-4 alkyloxy, —C 1-4 alkyloxycarbonyloxy-C 1-4 alkyloxy, or —C 1-4 alkylcarbonyloxy-C 1-4 alkyloxy;
R 3 is H, halogen, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl substituted with 1 to 3 halogen atoms, or —C 3-4 cycloalkyl; and
R 4 is cyclopropyl, cyclobutyl, or —C 1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Y is N or C—CN;
Z is N or CH;
X is CR 3 ;
provided that at least one of Y or Z is N;
R 1 is C 3-7 cycloalkyl or a 4- to 7-membered heterocyclic moiety, wherein the heterocyclic moiety contains 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and wherein the cycloalkyl or heterocyclic moiety has 0 to 3 substitutuents independently selected from —C 1-3 alkyl, and —OH, provided that there is no more than one —OH substituent; or
N(C 1-3 alkyl) 2 , NH(C 1-3 alkyl), or NH(C 3-4 cycloalkyl), wherein each C 1-3 alkyl is substituted with 0 to 1 OH;
R 2 is -(L) m -CON(R N ) 2 , -(L) m -SO 2 R s , -L-(CH 2 ) n SO 2 R s , -L-(CH 2 ) n CO 2 H, -L -(CH 2 ) n C(O)R c , -L-(CH 2 ) n CONHSO 2 R s , -L-(CH 2 ) n SO 2 NHCOR s , -L-(CH 2 ) n SO 2 NHCONH 2 , or -L-(CH 2 ) n tetrazol-5-yl;
m is 0 or 1;
n is 0 or 1;
R N is H or _ 13 C 1-3 alkyl;
R s is H or —C 1-3 alkyl;
L is CH 2 , CHF, or CF 2 ;
R c is —C 1-4 alkyloxy, —C 1-4 alkyloxycarbonyloxy-C 1-4 alkyloxy, or —C 1-4 alkylcarbonyloxy-C 1-4 alkyloxy;
R 3 is H, halogen, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl substituted with 1 to 3 halogen atoms, or —C 3-4 cycloalkyl; and
R 4 is —C 1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

3. The compound of claim 1 , or a pharmaceutically salt thereof, wherein Y is C—CN;
Z is N;
X is CR 3 ;
R 1 is C 3-7 cycloalkyl or a 4- to 7-membered heterocyclic moiety, wherein the heterocyclic moiety contains 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and wherein the cycloalkyl or heterocyclic moiety has 0 to 3 substitutuents independently selected from —C 1-3 alkyl, and —OH, provided that there is no more than one —OH substituent;
R 2 is -(L) m -CON(R N ) 2 , -(L) m -SO 2 R s , -L-(CH 2 ) n SO 2 R s , -L-(CH 2 ) n CO 2 H, -L -(CH 2 ) n C(O)R c , -L-(CH 2 ) n CONHSO 2 R s , -L-(CH 2 ) n SO 2 NHCOR s , or -L-(CH 2 ) n tetrazol-5-yl;
m is 0 or 1;
n is 0 or 1;
R N is H or —C 1-3 alkyl;
R s is H or —C 1-3 alkyl;
L is CH 2 , CHF, or CF 2 ;
R c is —C 1-4 alkyloxy, —C 1-4 alkyloxycarbonyloxy-C 1-4 alkyloxy, or —C 1-4 alkylcarbonyloxy-C 1-4 alkyloxy;
R 3 is H, halogen, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl substituted with 1 to 3 halogen atoms, or —C 3-4 cycloalkyl; and
R 4 is —C 1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Y is N;
Z is N;
X is CR 3 ;
R 1 is C 3-7 cycloalkyl or a 4- to 7-membered heterocyclic moiety, wherein the heterocyclic moiety contains 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and wherein the cyclalkyl or heterocyclic moiety has 0 to 3 substitutuents independently selected from —C 1-3 alkyl, and —OH, provided that there is no more than one —OH substituent;
R 2 is -(L) m -CON(R N ) 2 , -(L) m -SO 2 R s , -L-(CH 2 ) n SO 2 R s , -L-(CH 2 ) n CO 2 H, -L-(CH 2 ) n C(O)R c , -L-(CH 2 ) n CONHSO 2 R s , -L-(CH 2 ) n SO 2 NHCOR s , or -L-(CH 2 ) n tetrazol-5-yl;
m is 0 or 1;
n is 0 or 1;
R N is H or —C 1-3 alkyl;
R s is H or —C 1-3 alkyl;
L is CH 2 , CHF, or CF 2 ;
R c is —C 1-4 alkyloxy, —C 1-4 alkyloxycarbonyloxy-C 1-4 alkyloxy, or —C 1-4 alkylcarbonyloxy-C 1-4 alkyloxy;
R 3 is H, halogen, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl substituted with 1 to 3 halogen atoms, or —C 3-4 cycloalkyl; and
R 4 is —C 1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R s is H or —CH 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , or —CH 2 CO 2 CH 2 CH 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, —Cl, —CH 3 , —CH 2 CH 3 , —O—CH 3 , cyclopropyl, or CN.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —CF 3 , —CHF 2 , or —CF 2 CH 3 .

9. The compound of claim 1 , or a pharmaceutically salt thereof, wherein R 1 is the 4- to 7-membered heterocyclic moiety selected from azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl having 0 to 3 substitutuents independently selected from —CH 3 and —OH, provided that there is no more than one —OH substituent.

10. The compound of claim 1 , or a pharmaceutically salt thereof, wherein R 1 is azetidin-1-yl, having 1 to 2 —CH 3 substituents and having 0 to 1 —OH substituent, and wherein Y is C—CN and Z is N, or Y and Z are each N.

11. The compound of claim 1 , or a pharmaceutically salt thereof, wherein R 1 is cyclobutyl having 0 to 3 substitutuents independently selected from —CH 3 and —OH, provided that there is no more than one —OH substituent.

12. The compound of claim 1 , or pharmacuetically acceptable salt thereof, wherein the compound is selected from [(1R,5S,6R)-3-{5-cyano-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;
[(1R,5S,6R)-3-{3-chloro-5-cyano-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;
Methyl [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetate;
[(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;
[(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;
[(1R,5S,6R)-3-{5-cyclopropyl-2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;
[(1R,5S,6R)-3-{5-ethyl-2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;
[(1R,5S,6R)-3-{3-chloro-2-(1,1-difluoroethyl)-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]pyridin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]ace

Assignees

• Pfizer

Inventors

• Dowling Matthew
• Fernando Dilinie
• Futatsugi Kentaro
• Huard Kim
• Magee Thomas Victor
• Raymer Brian
• Shavnya Andre
• Smith Aaron
• Thuma Benjamin
• Tsai Andy
• Tu Meihua

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title