Autophagy inhibitors

Patent metadata

Field	Value
Publication number	US-10544100-B2
Application number	US-201816003990-A
Country	US
Kind code	B2
Filing date	Jun 8, 2018
Priority date	May 9, 2011
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

Abstract

The present invention relates to compounds of formulas III and V that are useful as pharmaceutical agents, particularly as autophagy inhibitors.

First claim

The invention claimed is:

1. A compound of formula III

or a pharmaceutically acceptable salt thereof, wherein:
Q is —CH;
R N is —H;
R 1 is —H, —F, —Cl, —Br, or —CF 3 ;
R 2 is —CH(R 2-1 )-(CH 2 ) n2 —X;
R 2-1 is —H, or —C 3 cycloalkyl;
n 2 is 3;
X is —NX 1-2 X 1-3 , wherein
X 1-2 is —H, linear or branched —C 1 -C 4 alkyl, -cyclopropyl, -cyclobutyl, or —SO 2 —X 1-4 , wherein X 1-4 is selected from the group consisting of: —H, —C 1 -C 3 alkyl, and —CO—X 1-4 , wherein X 1-4 is as defined above;
X 1-3 is linear or branched —C 1 -C 4 alkyl substituted with one cyclopropyl;
R 3 is —H, —CF 3 , —OR 3-1 , wherein R 3-1 is —H, —C 1 -C 6 alkyl, —CO—R 3-2 , wherein R 3-2 is —C 1 -C 3 alkyl or -phenyl, —N(R 3-1 ) 2 , wherein the R 3-1 are the same or different and are as defined above, —SR 3-1 , wherein R 3-1 is as defined above, —S(O)—R 3-1 wherein R 3-1 is as defined above, or —SO 2 —R 3-1 , wherein R 3-1 is as defined above;
R 4 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 , wherein R 4-1 is —H, C 1 -C 6 alkyl or —CO—R 4-2 , wherein R 4-2 is C 1 -C 3 alkyl or phenyl, —N(R 4-1 ) 2 , wherein the R 4-1 are the same or different and are as defined above, —SR 4-1 , wherein R 4-1 is as defined above, —S(O)—R 4-1 , wherein R 4-1 is as defined above, or —SO 2 —R 4-1 , wherein R 4-1 is as defined above; and
R 5 is —H, —F, —Cl, —Br, —CF 3 , —OR 5-1 , wherein R 5-1 is —H, —C 1 -C 6 alkyl or —CO—R 5-2 wherein R 5-2 is —C 1 -C 3 alkyl or -phenyl, —N(R 5-1 ) 2 , wherein the R 5-1 are the same or different and are as defined above, —SR 5-1 , wherein R 5-1 is as defined above, —S(O)—R 5-1 , wherein R 5-1 is as defined above, or —SO 2 —R 5-1 , wherein R 5-1 is as defined above;
with the proviso that one of R 1 , R 3 , R 4 and R 5 must be other than —H.

2. The compound of claim 1 , wherein:
X is

wherein X 1-2 is selected from the group consisting of: —H, linear or branched —C 1 -C 4 alkyl, -cyclopropyl, -cyclobutyl, and —SO 2 —X 1-4 , wherein X 1-4 is selected from the group consisting of: —H and —C 1 -C 3 alkyl; and X 1-3 is a linear or branched —C 1 -C 4 alkyl substituted with one cyclopropyl;
R 3 is —H, —CF 3 , —OR 3-1 , wherein R 3-1 is —H or —C 1 -C 6 alkyl, or —N(R 34 ) 2 , wherein the R 3-1 are the same or different and are as defined above, or —SR 3-1 wherein R 3-1 is as defined above;
R 4 is —H, —F, —Cl, —Br, —CF 3 , —OR 4-1 wherein R 4-1 is —H or —C 1 -C 6 alkyl, —N(R 4-1 ) 2 wherein the R 4-1 are the same or different and are as defined above, or —SR 4-1 , wherein R 4-1 is as defined above; and
R 5 is —H, —F, —Cl, —Br, —CF 3 , —OR 5-1 , wherein R 5-1 is —H or —C 1 -C 6 alkyl, —N(R 54 ) 2 , wherein the R 5-1 are the same or different and are as defined above, or —SR 5-1 , wherein R 5-1 is as defined above;
with the proviso that one of R 1 , R 3 , R 4 , and R 5 must be other than —H.

3. The compound of claim 2 , wherein R 2 is selected from the group consisting of:

4. The compound of claim 1 , further comprising a pharmaceutically acceptable carrier, excipient, or diluent.

5. A compound selected from the group consisting of:

Example
Structure
Name

10

N 1 -(6-Chloro-2- methoxyacridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine

12

N 1 -(6-Chloro-2- methoxyacridin-9-yl)-N 4 - cyclopropyl-N 4 -ethylbutane- 1,4-diamine

13

N 1 -(6-Chloro-2- methoxyacridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - ethylbutane-1,4-diamine

30

N 1 -(acridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine

31

N 1 -(cyclopropylmethyl)-N 4 - (2-fluoroacridin-9-yl)-N 1 - methylbutane-1,4-diamine

32

N 1 -(2-chloroacridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine

33

N 1 -(cyclopropylmethyl)-N 4 - (2-methoxyacridin-9-yl)-N 1 - methylbutane-1,4-diamine

34

N 1 -(6-bromo-2- methoxyacridin-9-yl)-N 4 - (cyclopropylmethyl)-N 4 - methylbutane-1,4-diamine

35

N 1 -(cyclopropyl-methyl)-N 4 - (6-fluoro-2-methoxyacridin-9- yl)-N 1 -methylbutane-1,4- diamine

36

N 1 -(6-chloro-2-fluoroacridin- 9-yl)-N 4 -(cyclopropylmethyl)- N 4 -methylbutane-

Assignees

• Translational Genomics Res Inst
• Van Andel Res Institute
• Translational Genomics Res Institute

Inventors

• Mackeigan Jeffrey Paul
• Martin Katie Renee
• Goodall Megan Lynne
• Gately Stephen T
• Wang Tong

Classifications

• C07D219/08

  Nitrogen atoms · CPC title

• C07D219/10 Primary

  attached in position 9 · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D219/12

  Amino-alkylamino radicals attached in position 9 · CPC title

• C07D221/16

  containing carbocyclic rings other than six-membered · CPC title