Tyrosine kinase inhibitor compositions, methods of making and methods of use
The present disclosure relates to new compounds or pharmaceutically acceptable salts or stereoisomers thereof of formula I as inhibitors of receptor tyrosine kinases (RTK), in particular extracellular mutants of ErbB-receptors. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the treatment of cancer in mammals (e.g. humans).
1. A compound of formula II:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y 2 is —O—;
L is a covalent bond or straight chain or branched C 1-4 alkyl;
Z is —(NR 4 R 5 ), wherein R 4 and R 5 each independently are C 1-6 alkyl or 3-6-membered heterocycloalkyl; or Z is —(NR 6 R 7 ) or —(CHR 6 R 7 ), wherein R 6 and R 7 , together with the atom to which they are attached, form 3-9-membered heterocycloalkyl, wherein the 3-9-membered heterocycloalkyl contains at least one nitrogen atom wherein the 3-9-membered heterocycloalkyl is unsubstituted or substituted with one or more C 1-4 alkyl or —OR′, wherein R′ is C 1-4 alkyl;
R a and R b each is H; and
X is
wherein Ar 1 is 6 membered aryl which is unsubstituted or substituted with one or more hal; X 1 is —O—; L 1 is straight or branched C 1-3 alkyl; and Ar 2 is 6-membered N-heteroaryl.
2. The compound of claim 1 , wherein -X 1 -L 1 - is —O—CH 2 —.
3. The compound of claim 1 , wherein X is
wherein:
R 2 and R 2 ′ each independently are H or hal;
R 3 and R 3 ′ each are H; and
n is 1.
4. The compound of claim 3 , wherein R 2 and R 2 ′ each independently are H or Cl.
5. The compound of claim 4 , wherein X is
6. The compound of claim 1 , wherein L is a covalent bond.
7. The compound of claim 1 , wherein L is straight chain or branched C 1-4 alkyl.
8. The compound of claim 7 , wherein L is —(CH 2 ) 2 — or —(CH 2 ) 3 —.
9. The compound of claim 1 , wherein Z is —(NR 4 R 5 ).
10. The compound of claim 1 , wherein Z is —(NR 6 R 7 ) or —(CHR 6 R 7 ).
11. The compound of claim 10 , wherein Z is —(NR 6 R 7 ).
12. The compound of claim 11 , wherein —(NR 6 R 7 ) is
wherein:
X 6 is —CH 3 or —OCH 3 ; and
X 7 is —O—, —NH—, or —N(CH 3 )—.
13. The compound of claim 12 , wherein —(NR 6 R 7 ) is
14. The compound of claim 10 , wherein Z is —(CHR 6 R 7 ).
15. The compound of claim 14 , wherein —(CHR 6 R 7 ) is
wherein R c is H or C 1-4 alkyl.
16. The compound of claim 15 , wherein —(CHR 6 R 7 ) is
17. A compound of formula II:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y 2 is —O—;
L is straight chain or branched C 1-4 alkyl;
Z is —(NR 6 R 7 ), wherein R 6 and R 7 , together with the atom to which they are attached, form 3-9-membered heterocycloalkyl, wherein the 3-9-membered heterocycloalkyl is unsubstituted or substituted with one or more C 1-4 alkyl or —OR′, wherein R′ is C 1-4 alkyl;
R a and R b each is H; and
X is
wherein Ar 1 is 6 membered aryl which is unsubstituted or substituted with one or more hal; X 1 is —O—; L 1 is straight or branched C 1-3 alkyl; and Ar 2 is 6-membered N-heteroaryl.
18. The compound of claim 17 , wherein X is
wherein:
R 2 and R 2 ′ each independently are H or hal;
R 3 and R 3 ′ each are H; and
n is 1.
19. The compound of claim 18 , wherein R 2 and R 2 ′ each independently are H or Cl.
20. The compound of claim 19 , wherein X is
21. The compound of claim 17 , wherein L is —(CH 2 ) 2 — or —(CH 2 ) 3 —.
22. The compound of claim 17 , wherein —(NR 6 R 7 ) is
wherein:
X 6 is —CH 3 or —OCH 3 ; and
X 7 is —O—, —NH—, or —N(CH 3 )—.
23. The compound of claim 22 , wherein —(NR 6 R 7 ) is
24. A compound of formula II:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Y 2 is —O—;
L is —(CH 2 ) 2 — or —(CH 2 ) 3 —;
Z is —(NR 6 R 7 ), wherein R 6 and R 7 , together with the atom to which they are attached, form 3-9-membered heterocycloalkyl, wherein the 3-9-membered heterocycloalkyl is unsubstituted or substituted with one or more C 1-4 alkyl or —OR′, wherein R′ is C 1-4 alkyl;
R a and R b each is H; and
wherein R 2 and R 2 ′ each independently are H or Cl; R 3 and R 3 ′ each are H; and n is 1.
25. A compound being selected from
Compound
No.
8
17
20
21
36
40
41
51
69
120
167
177
and pharmaceutically acceptable salts thereof.
26. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
27. A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof a therapeutically effective amount of the compound of claim 1 .
28. A pharmaceutical composition comprising the compound of claim 25 and one or more pharmaceutically acceptable carriers or excipients.
29. A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof a therapeutically effective amount of the compound of claim 25 .