Aminoamide compounds

Patent metadata

Field	Value
Publication number	US-10905684-B2
Application number	US-201916438185-A
Country	US
Kind code	B2
Filing date	Jun 11, 2019
Priority date	Jun 13, 2018
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

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 compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
n is 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;
X 1 and X 2 are each 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 —;
R 3a , R 3b , R 3c , R 3d , R 4a , and R 4b are each independently H, deuterium, or C 1 -C 6 alkyl;
R 5a , R 5b , R 6a , R 6b , R 7a , and R 7b are each 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 an 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, hydroxy, 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, 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, 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 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, optionally substituted amino, halogen, or cyano; or two geminal R 9 form oxo (═O); and
m1, m2, and m3 are each independently 1, 2, 3, 4, or 5.

2. The compound of claim 1 , wherein the compound is a compound of also represented by Formula (Ia), (Ib), (Ic), (Id), (Ie) (If), (Ig), (Ih), or (Ii):

or a pharmaceutically acceptable salt thereof; wherein the phenyl moiety in Formula (Ig), (Ih) or (Ii) is optionally substituted with one or more R A .

3. The compound of claim 1 , wherein R 1 is H.

4. The compound of claim 3 , wherein n is 1.

5. The compound of claim 4 , wherein Q is CH 2 .

6. The compound of claim 4 , wherein Q is C(═O).

7. The compound of claim 1 , wherein R 2 is H, deuterium, fluoro, or methyl.

8. The compound of claim 1 , wherein L is

9. The compound of claim 8 , wherein X 1 is O, and R 3a and R 3b are each H.

10. The compound of claim 8 , wherein Z 1 and Z 3 are each a bond.

11. The compound of claim 8 , wherein Z 1 is (CR 8a R 8b ) m1 — and Z 3 is —(CR 8e R 8f ) m3 —, or Z 1 is —(CR 8a R 8b ) m1 — and Z 3 is a bond, or Z 1 is a bond and Z 3 is —(CR 8e R 8f ) m3 —.

12. The compound of claim 11 , wherein each R 8a and R 8b is H; and each R 8c , R 8d , R 8e and R 8f is independently H, deuterium, halogen or C 1 to C 6 alkyl.

13. The compound of claim 12 , wherein each of R 8c , R 8d , R 8e and R 8f is H.

14. The compound of claim 12 , wherein each of R 8e and R 8f is H, and at least one of R 8c and R 8d is halogen or C 1 -C 6 alkyl.

15. The compound of claim 11 , wherein m1, m2 and m3 are each independently 1 or 2.

16. The compound 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, 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 .

17. The compound of claim 16 , wherein ring-B is phenyl or pyridyl, each substituted with one, two, or three R B .

18. The compound of claim 17 , 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 .

19. The compound of claim 18 , 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

20. The compound of claim 17 , 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 )—

Assignees

• Biotheryx Inc

Inventors

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

Classifications

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title