Aminoamide compounds

Patent metadata

Field	Value
Publication number	US-11400084-B2
Application number	US-202117163802-A
Country	US
Kind code	B2
Filing date	Feb 1, 2021
Priority date	Jun 13, 2018
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

Compounds with amino amide linkers and pharmaceutical compositions and medicaments comprising such compounds are disclosed. In addition, methods of making such compounds and their uses for treating or ameliorating diseases, disorders, or conditions associated with protein malfunction, such as cancer, are provided.

First claim

What is claimed is:

1. A method of treating or ameliorating leukemia in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
n is an integer of 0, 1, or 2;
R 1 is H, deuterium, C 1 -C 6 alkyl,

R 2 is H, deuterium, fluoro, or C 1 -C 6 alkyl;
Q is C═O or CR 4a R 4b ;
Ring A is

wherein Ring A is optionally substituted with one or more R A ;
Ring B is C 6 -C 10 aryl, 5 to 10 membered heteroaryl, C 3 to C 8 carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more R B ;
L is

wherein the asterisk * indicates the point of connection to ring B;
each X 1 and X 2 is independently O, S, or NH;
each Z 1 is independently a bond or —(CR 8a R 8b ) m1 —;
each Z 2 is independently —(CR 8c R 8d ) m2 —;
each Z 3 is independently a bond or —(CR 8e R 8f ) m3 —;
each R 3a , R 3b , R 3c , R 3d , R 4a , and R 4b is independently H, deuterium, or C 1 -C 6 alkyl;
each R 5a , R 5b , R 6a , R 6b , R 7a , and R 7b is independently H, optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form optionally substituted 5 or 6 membered heterocyclyl;
each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is independently H, deuterium, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or optionally substituted C 3 -C 6 cycloalkyl;
each R A is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, C 1 -C 6 alkylamino, amino(C 1 -C 6 alkyl), —(C═O)NR 10a R 10b , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, or optionally substituted C 3 -C 7 cycloalkyl;
each R B is independently halogen, hydroxyl, cyano, nitro, acyl, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, amino(C 1 -C 6 alkyl), —(C═O)NR 10a R 10b , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkyl(C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl(C 1 -C 6 alkyl), optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heteroaryl(C 1 -C 6 alkyl), optionally substituted heterocyclyl, or optionally substituted heterocyclyl(C 1 -C 6 alkyl);
each R 10a and R 10b is independently H or C 1 -C 6 alkyl, or R 10a and R 10b together with the nitrogen atom to which they are attached form an optionally substituted 5 or 6 membered heterocyclyl optionally substituted with one or more R 9 ;
each R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted amino, halogen, or cyano; or two geminal R 9 form oxo (═O); and
each of m1, m2, and m3 is independently an integer of 1, 2, 3, 4, or 5.

2. The method of claim 1 , wherein Ring A is

each optionally substituted with one R A .

3. The method of claim 2 , wherein the compound is a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), or (If):

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein Ring A is

optionally substituted with one or more R A .

5. The method of claim 4 , wherein the compound is a compound of Formula (Ig), (Ih), or (Ii):

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein R 1 is H.

7. The method of claim 1 , wherein n is an integer of 1 or 2.

8. The method of claim 1 , wherein Q is C═O or CH 2 .

9. The method of claim 1 , wherein R 2 is H.

10. The method of claim 1 , wherein Ring B is phenyl, naphthyl, C 4 -C 6 cycloalkyl, 4 to 6 membered heterocyclyl, or 5 to 6 membered heteroaryl, each optionally substituted with one, two, three, or four R B , and wherein each R B is independently halogen, hydroxyl, cyano, nitro, acyl, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, amino(C 1 -C 6 alkyl), —(C═O)NR 10a R 10b , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl optionally substituted with one or more R 9 , C 3 -C 7 cycloalkyl(C 1 -C 6 alkyl) optionally substituted with one or more R 9 , C 6 -C 10 aryl optionally substituted with one or more R 9 , C 6 -C 10 aryl(C 1 -C 6 alkyl) optionally substituted with one or more R 9 , 5 or 6 membered heteroaryl optionally substituted with one or more R 9 , 5 or 6 membered heteroaryl(C 1 -C 6 alkyl) optionally substituted with one or more R 9 , heterocyclyl optionally substituted with one or more R 9 , or heterocyclyl(C 1 -C 6 alkyl) optionally substituted with one or more R 9 .

11. The method of claim 10 , wherein Ring B is phenyl or pyridyl, each independently substituted with one, two, or three R B .

12. The method of claim 11 , wherein each R B is independently chloro, fluoro, —NH 2 , (C 1 -C 6 alkyl)amino, amino(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, acyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 alkyl), 4 to 6 membered heterocyclyl, N—(C 1 -C 6 alkyl)heterocyclyl, or heterocyclyl(C 1 -C 6 alkyl), wherein each of C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 alkyl), 4 to 6 membered heterocyclyl, and heterocyclyl(C 1 -C 6 alkyl) is optionally substituted with one or more R 9 .

13. The method of claim 11 , wherein each R B is independently fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethoxy, —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —(CH 2 ) 1-3 —NH(C 1 -C 4 alkyl), —(CH 2 ) 1-3 —N(C 1 -C 4 alkyl) 2 ,

14. The method of claim 11 , wherein Ring B is substituted with two R B , and wherein one R B is C 1 -C 6 alkyl or halogen, and the other R B is halogen, —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —(CH 2 )—NH(C 1 -C 4 alkyl), —(CH 2 )—N(C 1 -C 4 alkyl) 2 ,

15. The method of claim 1 , wherein the compound is selected from the group consisting of:

Assignees

• Biotheryx Inc

Inventors

• Chan Kyle W H
• Chourasia Aparajita Hoskote
• Erdman Paul E
• Fung Leah M
• Mercurio Frank
• Sullivan Robert W

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title