Aryl aminopyrimidines as dual MerTK and TYRO3 inhibitors and methods thereof

Patent metadata

Field	Value
Publication number	US-12448365-B2
Application number	US-202017755908-A
Country	US
Kind code	B2
Filing date	Nov 13, 2020
Priority date	Nov 15, 2019
Publication date	Oct 21, 2025
Grant date	Oct 21, 2025

Abstract

Aminopyrimidine containing compounds that inhibit both Mer tyrosine kinase (MerTK) activity and Tyro3 kinase activity are disclosed herein. Additionally disclosed are methods of synthesis and use of the aminopyrimidine containing compounds as anti-cancer agents, immunostimulatory and immunomodulatory agents, anti-platelet agents, anti-infective agents, and as adjunctive agents.

First claim

What is claimed is:

1. A compound of Formula I:

wherein,
“a” and “b” designate carbons that are at specific opposite positions in the cyclohexyl ring;
U and U 2 are each independently N or CX, provided that only one of U or U 2 can be N;
wherein,
X is H or C1-C8 alkyl;
R 1 is selected from the group consisting of C1-C4 alkoxy, halogen, C1-C8 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkylamino, nitrile, C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, —C(O)R 10 , and (C1-C4) (C1-C4) dialkylamino; wherein said cycloalkyl or heterocycloalkyl is independently substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy;
wherein,
R 10 is —NH 2 , hydrogen, or C1-C4 alkyl;
G is —OH or —NR e R f , wherein,
R e and R f are each independently hydrogen, C1-C4 alkyl, or —C(O)R 50 ; wherein,
R 50 is C1-C4 alkyl or hydrogen;
m is 0 or 1;
and,
R 2 is selected from the group consisting of hydrogen, C1-C10 alkyl, C1-C4 haloalkyl, —C(O)R 20 , and —(CH 2 ) n Cy 3 ; wherein,
n is 0, 1, 2, 3, or 4;
Cy 3 is selected from the group consisting of C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, aryl, and C3-C5 heteroaryl, each independently substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, C3-C8 cycloalkyl, and (C1-C4) (C1-C4) dialkylamino;
R 20 is selected from the group consisting of C1-C4 alkyl, —(CH 2 ) q OR30, and —(CH 2 ) w Cy 4 ;
wherein,
q is 0, 1, 2, 3, or 4;
w is 0, 1, 2, 3, or 4;
R 30 is hydrogen or C1-C8 alkyl; and
Cy 4 is selected from the group consisting of C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, aryl, and C3-C5 heteroaryl, each independently substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of halogen, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —C(O)—(C1-C4 alkyl), C1-C4 hydroxyalkyl, C1-C4 alkylamino, and (C1-C4) (C1-C4) dialkylamino;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein m is 1.

3. The compound of claim 2 , wherein G is —OH.

4. The compound of claim 3 , wherein U is N and U 2 is CH.

5. The compound of claim 3 , wherein U is CH and U 2 is CH.

6. The compound of claim 3 , wherein U is N and U 2 is —C—CH 3 .

7. The compound of claim 1 , wherein R 1 is selected from the group consisting of methoxy, chloro, methyl, cyclopropyl, ethyl, —C(O) NH 2 , difluoroethyl, difluoromethyl, fluoromethyl, and trifluoromethyl.

8. The compound of claim 7 , wherein R 1 is trifluoromethyl or chloro.

9. The compound of claim 7 , wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, and neopentyl.

10. The compound of claim 7 , wherein R 2 is —C(O)R 20 , wherein R 20 is —(CH 2 ) q OR 30 , wherein q is 0 and R 30 is C1-C4 alkyl.

11. The compound of claim 7 , wherein R 2 is —C(O)R 20 , wherein R 20 is —(CH 2 ) w Cy 4 , wherein w is 0 and Cy 4 is cyclopentyl or cyclohexyl each independently substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl.

12. The compound of claim 7 , wherein R 2 is —(CH 2 ) n Cy 3 , wherein n is 0 or 1, and Cy 3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, cycloheptyl, phenyl, oxetanyl, isoxazolyl, piperidinyl, and tetrahydropyranyl, each independently substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of methyl, fluoro, cyclopropyl, chloro, n-propyl, and isopropyl.

13. The compound of claim 12 , wherein Cy 3 is cyclopentyl.

14. The compound of claim 1 , wherein G is —NR e R f .

15. The compound of claim 14 , wherein G is —NH 2 , —NHCH 3 , —N(CH 3 ) 2 or —NHC(O)CH 3 .

16. The compound of claim 15 , wherein U is N and U 2 is CH.

17. The compound of claim 16 , wherein R 1 is methoxy.

18. The compound of claim 17 , wherein R 2 is hydrogen or —C(O)R 20 , wherein R 20 is —(CH 2 ) w Cy 4 , wherein w is 0 and Cy 4 is cyclopentyl.

19. The compound of claim 1 , wherein the substituents on the carbons marked “a” and “b” are in a trans configuration.

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

Structure

1

2

3

4

5

6

7

8

9

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Wang Xiaodong
• Zhou Yubai
• Ding Ransheng
• Kong Deyu
• Frye Stephen

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/04

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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title