Quinazoline compounds as modulators of Ras signaling

Patent metadata

Field	Value
Publication number	US-11318137-B2
Application number	US-201716500369-A
Country	US
Kind code	B2
Filing date	May 17, 2017
Priority date	May 17, 2017
Publication date	May 3, 2022
Grant date	May 3, 2022

Abstract

The present invention relates to quinazoline compounds and compositions that modulate Ras signaling. Compounds and compositions of the present invention are useful in the treatment of cancers and other disease states associated with Ras dysfunction (e.g., Ras-associated autoimmune leukoproliferative disorder, or certain types of mitochondrial dysfunction) in a subject, for example a mammal or a human.

First claim

We claim:

1. A compound of the following formula:

wherein
X 1 is selected from C 1-6 —R A ;
X 2 is selected from C 1-6 —R B ;
R A is optionally substituted and selected from

C 1 -C 6 alkylamino, piperazinyl, pyridinyl, C 1 -C 6 alkylalcohol, cycloamino, cycloalkylamino, H, cycloalkenylamino, —NH 2 , -alkylNH 2 , -alkyl-NH-alkyl, —NHMe, —NMe 2 , —OH, —NH-alkyl-NH 2 , —NH-alkyl-NHMe, —NH-alkyl-NMe 2 , —NH-alkyl-OH, bromine, CN;
R B is optionally substituted with one or more Z and selected from H, alkyl, aminoalkyl, cycloalkyl, alkoxy, halogen, cycloheteroalkyl, aryl, heteroaryl;
provided that R A and R B are not both H;
R 1 is optionally substituted with one or more Z and selected from alkyl, benzyl, phenyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl-cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkenyl-cycloalkyl;
R 2 is (i) optionally substituted with one or more Z, and selected from phenyl, aryl, heteroaryl, alkyl-heteroalkyl, alkyl-heteroaryl, alkyl-cycloalkyl, biaryl, heterobiaryl, alkyl-biaryl, alkenyl, furanyl, thiophenyl, triazolyl, imidazolyl, pyrrolidinyl, thiazolyl, or forms a heteroalkyl ring with itself; or (ii) benzyl substituted with one or more Z;
Z is independently H, alkyl, halogen, CF 3 , alkoxy, alkyl-alkoxy, OH, O—CF 3 , O-Me, acetonitrile, Cl, F, Br, cyano, CF 3 , or alkyl, including methyl, ethyl, vinyl, cyclopropyl, or more than one Z joins together to form a 5 or six membered ring;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof; provided that when X 1 is C—H, X 2 is CH, and R 1 is furan, R 2 is not phenyl and where X 1 is C—H, X 2 is CH, and R 1 is benzyl, R 2 is not phenyl.

2. A compound of claim 1 wherein:
R 1 is selected from —(CH m ) n -cycloalkyl, —(CH m ) n -heterocycloalkenyl, —(CH m ) n -heteroaryl, or —(CH m ) n -alkyl and optionally substituted with cycloalkyl, methyl, or ethyl;
R 2 is selected from —(CH 2 ) n -cycloalkyl, —(CH 2 ) n -alkenyl, or (CH 2 ) n -aryl, and optionally independently substituted with alkyl, cycloalkyl, CF 3 , one or more halogen such as Cl, F, Br; methyl, or cyano, provided that when R 2 is benzyl it is substituted by one or more Z;
m is 1 or 2;
n is 0-3;
X 2 is selected from H or ethylaminyl;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

3. A compound of claim 1 wherein R 1 is optionally substituted and selected from

4. A compound of claim 1 wherein R 2 is optionally substituted and selected from

provided that when R 2 is benzyl it is substituted by one or more Z;
Z is independently H, Cl, F, Br, cyano, CF 3 , methoxy, or alkyl, including methyl, ethyl, vinyl, cyclopropyl; or more than one Z joins together to form a 5 or six membered ring;
n is 0-3;
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof.

5. A compound of claim 1 , wherein R 2 and more than one Z together form:

6. A compound of claim 1 wherein R A is amino.

7. A compound of claim 1 wherein R A is

8. A compound of claim 1 wherein R A is

9. A compound of claim 1 wherein R 1 is

10. A compound of claim 1 wherein R 1 is

11. A compound of claim 1 wherein R 1 is

12. A compound of claim 1 wherein R 1 is

13. A compound of claim 1 wherein R 1 is

14. A compound of claim 1 wherein R 2 is

15. A compound of claim 1 wherein R 2 is

16. A compound of claim 1 wherein R 2 is

17. A method of activating nucleotide exchange on Ras in a patient in need thereof, comprising administering to the patient a Ras nucleotide exchange effective amount of a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

18. The method of claim 17 , wherein the compound binds to SOS.

19. The method of claim 17 , wherein the nucleotide exchange on Ras is in a tumor cell.

20. A method of modulating Ras activity in a patient in need thereof, comprising administering to the patient an effective Ras activity modulating amount of a compound of claim 1 or a pharmaceutically acceptable carrier.

21. A method of inhibiting Ras pathway activity in a tumor cell, the method comprising contacting the cell with a compound of claim 1 .

22. A method of affecting levels of phosphoERK in a tumor cell, the method comprising contacting the cell with an effective amount of a compound of claim 1 .

23. A method of affecting levels of phosphoAkt in a tumor cell, the method comprising contacting the cell with an effective amount of a compound of claim 1 .

24. A method of inhibiting the proliferation of cells associated with a malignant or non-malignant disease or pathological state, the method comprising: administering to a patient in need thereof an effective Ras-inhibiting amount of a compound of claim 1 .

25. A method of inhibiting proliferation of cells associated with a malignant or non-malignant disease or pathological state, with a compound that affects nucleotide exchange on Ras, the method comprising: administering to a patient in need thereof an effective Ras-modulating amount of a compound of claim 1 .

26. A method of modulating angiogenesis, tumor progression, and/or metastasis comprising the step of administering to a tissue or a subject associated with a disease condition a therapeutically effective amount of a compound of claim 1 .

27. The method of claim 20 , wherein said modulating inhibits angiogenesis, tumor progression, and/or metastasis.

28. The method of claim 24 , wherein said inhibition involves inhibiting Ras pathway activity.

29. The method of claim 17 , further comprising co-administration with a known anti-cancer medication.

30. A method of inhibiting cell prolife

Assignees

• Univ Vanderbilt

Inventors

• Waterson Alex G
• Abbott Jason R
• Kennedy J Phillip
• Fesik Stephen W
• Sun Qi
• Phan Jason
• Burns Michael C
• Patel Pratiq

Classifications

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/5377

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

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/14 Primary

  containing three or more hetero rings · CPC title