IP Library › Granted Patent US 11,746,103

Granted Patent B2

US 11,746,103 · App. 17/733,650 · Granted Sep 5, 2023

ALK-5 inhibitors and uses thereof

Inventors: Bettina Franz (South Jordan, UT); Adam Siddiqui-Jain (South Jordan, UT); Steven L. Warner (Sandy, UT); Siva Reddy Basireddy (Telangana, IN); Srinivas Padakanti (Telangana, IN); Naresh Kumar (Telangana, IN)

Assignee: Sumitomo Pharma Oncology, Inc.

C07D403/14 A61P35/00 C07D401/14 C07D403/12 C07D405/14 C07D413/14 C07D471/08

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 11,746,103
App. No.: 17/733,650
Granted: Sep 5, 2023
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Provided herein are compounds (e.g., compounds of Formulae (I), (II), (III) and (IV), or of Table 1 or Table 4), and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and kits comprising the same. The compounds provided herein are activin receptor-like kinase (e.g., ALK-5) inhibitors and are, therefore, useful, for example, for treating and/or preventing diseases (e.g., proliferative diseases, such as cancer) in a subject, inhibiting tumor growth in a subject, or inhibiting the activity of an activin receptor-like kinase (e.g., ALK-5) in vitro or in vivo. Also provided herein are methods and synthetic intermediates useful in the preparation of compounds described herein.

Claims (87)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a C 1 -C 5 alkyl, C 3 -C 5 carbocycle, or a halogen;

R 2 is an aryl of at least 6 carbon atoms or nitrogen-containing heteroaryl of at least 6 atoms, optionally substituted with one or more of:

(i) one or more halogens;

(ii) a C 1 -C 6 alkyl optionally substituted with a hydroxyl or one or more halogen wherein, when selected to be an alkyl larger than C 3 , the alkyl is present at a position on the aryl or heteroaryl of R 2 which is meta- or para- to the amino bond to the aryl or heteroaryl of R 2 ;

(iii) a sulfonamide;

(iv) a monocyclic, bicyclic, or spirocyclic carbocycle which is optionally substituted with a hydroxyl, one or more halogen, or one or more linear, branched, or cyclic alkyl moieties of up to 6 carbon atoms which are optionally substituted with hydroxy or one or more halogen, wherein said carbocycle is attached to the aryl or heteroaryl of R 2 by a single bond or a methylene or ethylene linker and wherein, when present and selected to be a carbocycle larger than cyclopropyl, the carbocycle is at a position on the aryl or heteroaryl of R 2 which is meta- or para- to the amino bond to the aryl or heteroaryl of R 2 ; or

(v) a monocyclic, bicyclic or spirocyclic heterocycle which may contain up to 3 heteroatoms which are selected independently from N and O, and which is optionally and independently substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen, wherein said heterocycle is attached to the aryl or heteroaryl of R 2 by a single bond or a methylene or ethylene linker and wherein, when present, said heterocycle is at a position on the aryl of R 2 which is meta- or para- to the amino bond to said aryl;

R 3 is —H, —F, or —Cl;

R 4 is —H, a halogen, or a C 1 -C 3 alkyl or cyclopropyl optionally substituted with one or more —F; and

R 5 is —H, —F, or a C 1 -C 3 alkyl or cyclopropyl optionally substituted with one or more —F.

2. The compound of claim 1 , wherein R 1 is a C 1 -C 5 alkyl or C 3 -C 5 carbocycle.

3. The compound of claim 1 , wherein R 1 is —CH 3 , cyclopropyl, —Cl, or —F.

4. The compound of claim 1 , wherein R 2 is a phenyl or pyridinyl substituted with one or more of:

(i) one or more halogens;

(iii) a sulfonamide;

5. The compound of claim 1 , wherein R 2 is:

wherein:

R 6 is —H, —F, —Cl, or a C 1 -C 3 alkyl or cyclopropyl which is optionally and independently substituted with one or more halogen;

one of R 7A and R 7B is —H, and the other is:

(i) a halogen;

(ii) —SO 2 NR 7F 2 , wherein each R 7F is independently —H or a linear or branched alkyl of up to 4 carbon atoms;

(iii) a C 1 -C 6 alkyl which is optionally substituted with one or more halogen; or

wherein:

A is N or C(H);

E is O, N(R 8 ), or C(H)(R 13 );

R 8 is —H or a C 1 -C 6 alkyl or C 3 -C 6 carbocycle which is optionally substituted with hydroxyl or one or more halogen;

R 13 is —H or a C 1 -C 6 alkyl or C 3 -C 6 carbocycle which is optionally substituted with hydroxy or one or more halogen; and

n is 0, 1, or 2, and

when E is N(R 8 ), X, Y, and Z are defined as follows:

Z is C(H) 2 and X and Y are independently C(H) 2 or C(CH 3 ) 2 , or both X and Y are CH) and are bonded together through a methylene or ethylene bridge; or

Y is C(H) 2 or C(CH 3 ) 2 , and X and Z are both C(H) and are bonded together through a methylene or ethylene bridge, and

when E is O or C(H)(R 13 ), X, Y, and Z are C(H) 2 .

6. The compound of claim 5 , wherein R 6 is —H, —F, —Cl, —CH 3 , or —CF 3 .

7. The compound of claim 5 , wherein one of R 7A and R 7B is —H, and the other is:

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

9. The compound of claim 1 , wherein R 4 is-CF 3 ,-CH 3 , —H, —Cl, or —F.

10. The compound of claim 6 , wherein R 4 is-H.

11. The compound of claim 1 , wherein R 5 is —H,-CH 3 ,—CF 3 or —F.

12. The compound of claim 11 , wherein R 5 is-H.

13. The compound of claim 1 of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is-CH 3 or —Cl;

R 2 is:

wherein:

one of R 6A and R 6B is —H, and the other is —H, —F, —Cl,-CH 3 , or CF 3 ;

one of R 7C and R 7D is —H, and the other is:

(i) —F;

(ii) —Cl;

(iii) —SO 2 NH 2 ;

(iv) cyclohexyl;

(v) t-butyl; or

(vi)

R 4 is —H or -CH 3 ; and

R 5 is —H or —F.

14. The compound of claim 1 of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R 1A is-CH 3 or cyclopropyl;

R 6B is —H, —F, or —Cl; and

one of R 7D and R 7E is —H, and the other is a heterocycle of the formula:

15. The compound of claim 1 having the following structure:

or a pharmaceutically acceptable salt thereof, wherein R′ is H or F; and R″ is at a position meta or para to the amino bond, and is morpholino or piperazinyl optionally N-substituted with-CH 3 ,-CH 2 CF 3 , or -CH 2 CH 2 OH.

16. A compound, or a pharmaceutically acceptable salt thereof, selected from:

17. The compound of claim 16 , wherein the compound is of the following formula: