Substituted 3-carboxamido isoxazoles as kinase modulators
View Patent ↗The invention provides methods and compositions for treating conditions mediated by various kinases wherein substituted 3-carboxamido isoxazoles compounds are employed. The invention also provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.
1. A compound of formula (IV):
wherein:
Z 1 is N;
Z 2 is O;
R 4 , is H, alkyl, cycloalkyl, heteroaryl or aryl;
K is
such that K can attach to the isoxazole moiety through either the right side or left side of K;
Y is O or S, n is independently 0 or 1; and each R 2 is independently H or alkyl;
each R 1 is independently H, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR c , —OC(O)R c , —NO 2 , —N(R c ) 2 , —SR c , S(O) j R c where j is 1 or 2, —NR c C(O)R c , —C(O)N(R c ) 2 , —C(O) 2 R c , or —C(O)R c ; where each R c is independently H, alkyl, cycloalkyl, aryl or heteroaryl;
L is —C(O)NH—; and
T is a bi-, or tricyclic, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
2. The compound of claim 1 , wherein T corresponds to formula (V):
wherein A is a five or six-membered aryl or heteroaryl; and B is a five or six-membered arylene or heteroarylene, wherein A and B together form a fused two-ring moiety.
3. The compound of claim 2 , corresponding to formula (VI):
4. The compound of claim 3 , wherein B is phenylene, pyridinylene, pyrimidinylene, pyridazinylene, thiophenylene, imidazolylene, or pyrrolylene.
5. The compound of claim 4 , selected from the group consisting of:
6. A compound of formula (IX):
wherein:
L is —C(O)NH—; each of X 1 , X 2 , X 4 , and X 5 is independently CR or N;
where each R is independently H, halogen, alkyl, —OH, alkoxy, —OC(O)R c , —NO 2 , —N(R c ) 2 , —SR c , —NR c C(O)R c , or —C(O)R c ; where each R c is independently H, alkyl, cycloalkyl, aryl, or heteroaryl;
X 3 is independently CR 8 or N, wherein no more than two of X 1 , X 2 , X 3 , X 4 , and X 5 are N, and when X 3 is N, at least one of X 1 , X 2 , X 4 , or X 5 is not CH,
where R 8 is selected from the group consisting of H, halogen, alkyl, —OR c , alkoxy, —C(O)R c , —OC(O)R c , —NO 2 , —N(R c ) 2 , and —SR c , where each R c is independently H, alkyl, cycloalkyl, aryl, or heteroaryl,
Z 1 is N;
Z 2 is O;
R 4 is H, alkyl, cycloalkyl, heteroaryl or aryl;
K is
such that K can attach to the isoxazole moiety through either the right side or left side of K;
Y is O or S, each n is independently 0 or 1; each R 2 is independently H or alkyl; and
each R 1 is independently H, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR c , —OC(O)R c , —NO 2 , —N(R c ) 2 , —SR c , S(O) j R c where j is 1 or 2, —NR c C(O)R c , —C(O)N(R c ) 2 , —C(O) 2 R c , or —C(O)R c ; where each R c is independently H, alkyl, cycloalkyl, aryl or heteroaryl.
7. The compound of claim 6 , corresponding to formula (X):
8. The compound of claim 7 , corresponding to formula (XI):
9. The compound of claim 8 , selected from the group consisting of:
10. The compound of claim 7 , corresponding to formula (XII):
11. The compound of claim 10 , corresponding to:
12. The compound of claim 7 , corresponding to formula (XIV):
13. The compound of claim 12 , selected from the group consisting of:
14. The compound of claim 7 , corresponding to formula (XV):
15. The compound of claim 14 , corresponding to:
16. The compound of claim 7 , corresponding to formula (XVI):
17. The compound of claim 16 , selected from the group consisting of:
18. A compound having formula (XIX),
wherein
L 1 is a bond; and L is —C(O)NH—
K is
such that K can attach to the isoxazole moiety through either the right side or left side of K;
Y is O or S, each n is independently 0 or 1; and each R 2 is independently H or alkyl;
U is phenyl, or thiazolyl; and V is piperidinylene, thiazolylene, imidazolylene, or thiophenylene.
19. A compound corresponding to formula (XX):
wherein
L 1 is a bond, —CH 2 O—, —N(CH 3 )— or —O—; and L is —CH 2 O— or —NHC(O)—,
K is
such that K can attach to the isoxazole moiety through either the right side or left side of K;
Y is O or S, each n is independently 0 or 1; each R 2 , is independently H or alkyl; and
U is phenyl, C 3 -C 6 cycloalkyl, pyrimidine or pyridine.
20. The compound of claim 19 , wherein L 1 is a bond, —CH 2 O—, or —O—.
21. A compound corresponding to formula (XXI):
wherein
L 1 is a bond, —CH 2 O—, —N(CH 3 )— or —O—; and L is —CH 2 O— or —NHC(O)—,
K is
or
such that K can attach to the isoxazole moiety through either the right side or left side of K;
Y is O or S, each n is independently 0 or 1; each R 2 is independently H or alkyl; and
U is phenyl, C 3 -C 6 cycloalkyl, pyrimidine or pyridine.
22. The compound of claim 21 , wherein L 1 is —O—.
23. A compound selected from
24. A compound selected from: