Amide derivatives as C-KIT modulators
The invention provides methods and compositions for treating conditions mediated by c-kit wherein derivatives of amide 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 method of modulating c-kit kinase, said method comprising administering an effective amount of a compound corresponding to Formula (IA):
wherein:
M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl;
N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl; and
K is
Y is O or S;
each R k is independently H, halogen, substituted or unsubstituted alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R 2 , —NO 2 , —N(R 2 ) 2 , —SR 2 , —C(O)R 2 , —C(O) 2 R 2 , —C(O)N(R 2 ) 2 , or —N(R 2 )C(O)R 2 ,
each R 2 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R 2 groups are linked together by an optionally substituted alkylene; and
each n is independently 0, 1, 2, 3 or 4;
or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.
2 . The method of claim 1 , wherein said compound corresponds to Formula (IB):
wherein:
each Z is independently C, CR 3 , N, NR 3 , O, or S, provided that no more than two Z's are heteroatoms and wherein no two adjacent Z's are O or S, where R 3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl; and
each R 1 is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR c —OH, —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 ; or two adjacent R 1 's, are taken together to form a substituted or unsubstituted aryl or heteroaryl,
each R c is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
3 . The method of claim 2 , wherein said compound corresponds to Formula (I):
wherein K is
each R k is independently H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
4 . The method of claim 3 , wherein said compound corresponds to Formula (II):
5 . The method of claim 4 , wherein said compound corresponds to Formula (III):
wherein Z 1 is CR 3 or N; and Z 2 is O or S.
6 . The method of claim 5 , wherein said compound corresponds to Formula (IV):
wherein:
each R 1 is independently H, halogen, substituted or unsubstituted alkyl, —O(substituted or unsubstituted alkyl), —O(substituted or unsubstituted alkenyl), —NR c C(O)O(substituted or unsubstituted alkyl), —NR c C(O) (substituted or unsubstituted alkyl), —NR c C(O)(substituted or unsubstituted alkenyl), —C(O)NR(substituted or unsubstituted alkyl), —C(O)NR c (substituted or unsubstituted alkenyl), —NO 2 , —S(═O)R c , —SR c , C(O) 2 R c , or —C(O)R c ; and
two adjacent R 1 's, taken together, form a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and
each R 2 is independently H or substituted or unsubstituted alkyl.
7 . The method of claim 6 , wherein the compound is:
8 . The method of claim 5 , wherein said compound corresponds to Formula (V):
9 . The method of claim 8 , wherein said compound is selected from the group consisting of:
10 . The method of claim 4 , wherein said compound corresponds to Formula (VI):
wherein Z 1 is O or S; and Z 2 is CR 3 or N.
11 . The method of claim 10 , wherein said compound corresponds to Formula (VII):
wherein:
each R 1 is independently H, halogen, substituted or unsubstituted alkyl , —O(substituted or unsubstituted alkyl) , —O(substituted or unsubstituted alkenyl), —NR c C(O)O(substituted or unsubstituted alkyl), —NR c C(O) (substituted or unsubstituted alkyl), —NR c C(O)(substituted or unsubstituted alkenyl), —C(O)NR c (substituted or unsubstituted alkyl), —C(O)NR c (substituted or unsubstituted alkenyl), —NO 2 , —S(═O)R c , —SR c , C(O) 2 R c , or —C(O)R c ; and
each R 2 is independently H or substituted or unsubstituted alkyl.
12 . The method of claim 10 , wherein said compound corresponds to Formula (VIII):
13 . The method of claim 12 , wherein said compound is selected from the group consisting of:
14 . The method of claim 5 , wherein said compound corresponds to Formula (IX):
wherein:
L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substituted or unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkenylene)-, —NHC(O)(substituted or unsubstituted alkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-, —C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—; and
T is a mono-, bi-, or tricyclic, substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.
15 . The method of claim 14 , wherein T of said compound corresponds to Formula (X):
wherein A is a substituted or unsubstituted five or six-membered heterocyclyl, aryl, or heteroaryl; and B is a substituted or unsubstituted five or six-membered heterocyclene, arylene, or heteroarylene, wherein A and B together form a fused two ring moiety.
16 . The method of claim 15 , wherein said compound corresponds to Formula (XI):
17 . The method of claim 16 , wherein L of said compound is a covalent bond, —C(O)NH(substituted or unsubstituted alkylene), —O(substituted or unsubstituted alkylene)-, —C(O)NH—, or —NHC(O)(alkylene)-.
18 . The method of claim 17 , wherein B of said compound is a substituted or unsubstituted five-membered heteroarylene.
19 . The method of claim 18 , wherein said compound is selected from the group consisting of:
20 . The method of claim 17 , wherein B of said compound is a substituted or unsubstituted 6-membered arylene or heteroarylene.
21 . The method of claim 20 , wherein said compound is selected from the group consisting of:
22 . The method of claim 20 , wherein said compound is selected from the group consisting of:
23 . The method of claim 14 , wherein T of said compound is a tricyclic, substituted or unsubstituted aryl, heterocyclyl, or heteroaryl.
24 . The method of claim 23 , wherein said compound is selected from the group consisting of:
25 . The method of claim 5 , wherein said compound corresponds to Formula (XII):
wherein:
L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substituted or unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkenylene)-, —NHC(O)(substituted or unsubstituted alkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-, —C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—; and
each of X 1 -X 5 is independently C, CR, N, NR, S, or O, wherein no more than three of X 1 -X 5 is a heteroatom, and no two adjacent ring atoms are O or S; where
each R is independently H, halogen, substituted or unsubstituted alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R d , —NO 2 , —N(R d ) 2 , —SR d , —S(O) j R d where j is 1 or 2, —NR d C(O)R d , —C(O) 2 R d , —C(O)N(R d ) 2 or —C(O)R d , or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where
each R d is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
26 . The method of claim 25 , wherein said compound corresponds to Formula (XIII):
27 . The method of claim 26 , wherein L of said compound is a covalent bond, —C(O)NH—, or —O(substituted or unsubstituted alkylene)-.
28 . The method of claim 27 , wherein
of said compound is selected from the group consisting of:
29 . The method of claim 28 , wherein said compound is selected from the group consisting of:
30 . The method of claim 5 , wherein said compound corresponds to Formula (XIV):
L is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substituted or unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkenylene)-, —NHC(O)(substituted or unsubstituted alkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-, —C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—; and
each of X 1 -X 5 is independently C, CR, N, NR, S, or O, wherein no more than three of X 1 -X 5 is a heteroatom, and no two adjacent ring atoms are O or S; where
each R is independently H, halogen, substituted or unsubstituted alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R d , —NO 2 , —N(R d ) 2 , —SR d , —S(O) j R d where j is 1 or 2, —NR d C(O)R d , —C(O) 2 R d , —C(O)N(R d ) 2 or —C(O)R d , or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where
each R d is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
31 . The method of claim 30 , wherein said compound corresponds to Formula (XV):
32 . The method of claim 31 , wherein said compound is selected from the group consisting of:
33 . The method of claim 31 , wherein said compound corresponds to Formula (XVI):
34 . The method of claim 33 , wherein said compound is selected from the group consisting of:
35 . The method of claim 31 , wherein said compound corresponds to Formula (XVII):
36 . The method of claim 35 , wherein said compound is selected from the group consisting of:
37 . The method of claim 31 , wherein said compound corresponds to Formula (XVIII):
38 . The method of claim 37 , wherein said compound is selected from the group consisting of:
39 . The method of claim 31 , wherein said compound corresponds to Formula (XIX):
40 . The method of claim 39 , wherein said compound is selected from the group consisting of:
41 . The method of claim 31 , wherein said compound corresponds to Formula (XX):
42 . The method of claim 41 , wherein said compound is selected from the group consisting of:
43 . The method of claim 31 , wherein said compound corresponds to Formula (XXI):
44 . The method of claim 43 , wherein L of said compound is —NHC(O)—, —NHC(O)(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkylene), —C(O)NH(substituted or unsubstituted alkenylene), or —NHC(O)(substituted or unsubstituted alkenylene)-.
45 . The method of claim 44 , wherein said compound is selected from the group consisting of:
46 . The method of claim 43 , wherein L of said compound is —O— or —O(substituted or unsubstituted alkylene)-.
47 . The method of claim 46 , wherein said compound is selected from the group consisting of:
48 . The method of claim 43 , wherein L of said compound is -(substituted or unsubstituted alkylene)- or —NHC(O)(alkylene)S(alkylene)C(O)NH—.
49 . The method of claim 48 , wherein said compound is selected from the group consisting of:
50 . The method of claim 14 , wherein said compound corresponds to Formula (XXII):
wherein:
L 1 is a linker selected from the group consisting of a covalent bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substituted or unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted alkenylene)-, —NHC(O)(substituted or unsubstituted alkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-, —C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substituted or unsubstituted alkylene)S(substituted or unsubstituted alkylene)C(O)NH—;
U is a substituted or unsubstituted cycloalkyl, hetrocycloalkyl, aryl, or heteroaryl; and
V is a substituted or unsubstituted cycloalkylene, heterocyclene, arylene, or heteroarylene;
51 . The method of claim 50 , wherein said compound corresponds to Formula (XXIII):
52 . The method of claim 51 , wherein L 1 of said compound is a bond, —O(substituted or unsubstituted alkylene)-, -(substituted or unsubstituted alkylene)-, or —S—; and L of said compound is a covalent bond, —C(O)NH—, —C(O)NH(substituted or unsubstituted alkylene), or —NHC(O)(substituted or unsubstituted alkylene)-.
53 . The method of claim 52 , wherein V of said compound is substituted or unsubstituted 5-membered heteroarylene.
54 . The method of claim 53 , wherein said compound is selected from the group consisting of:
55 . The method of claim 51 , wherein said compound corresponds to Formula (XXIV):
wherein:
each of X 1 -X 4 is independently C, CR, or N, wherein no more than two of X 1 -X 5 is N; where
each R is independently H, halogen, substituted or unsubstituted alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R d , —NO 2 , —N(R d ) 2 , —SR d , —S(O) j R d where j is 1 or 2, —NR d C(O)R d , —C(O) 2 R d , —C(O)N(R d ) 2 or —C(O)R d , or two adjacent R's are taken together to form a substituted or unsubstituted aryl or hetroaryl, where
each R d is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
56 . The method of claim 55 , wherein U of said compound is substituted or unsubstituted pyrimidinyl or pyridinyl.
57 . The method of claim 56 , wherein said compound is selected from the group consisting of:
58 . The method of claim 55 , wherein U of said compound is substituted or unsubstituted phenyl.
59 . The method of claim 58 , wherein said compound is selected from the group consisting of:
60 . The method of claim 51 , wherein said compound is selected from the group consisting of:
61 . The method of claim 14 , wherein said compound corresponds to Formula (XXV):
wherein T is substituted or unsubstituted cycloalkyl or heterocylyl.
62 . The method of claim 61 , wherein said compound is selected from the group consisting of:
63 . The method of claim 1 , wherein said compound is
64 . The method of claim 1 , wherein said compound is selected from the group consisting of:
65 . A method of treating a c-kit mediated disease, said method comprising administering a therapeutically effective amount of a compound corresponding to Formula (IA):
wherein:
M is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl;
N is a substituted or unsubstituted aryl, or substituted or unsubstituted hetroaryl; and
K is
Y is O or S;
each R k is independently H, halogen, substituted or unsubstituted alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R 2 , —NO 2 , —N(R 2 ) 2 , —SR 2 , —C(O)R 2 , —C(O) 2 R 2 , —C(O)N(R 2 ) 2 , or —N(R 2 )C(O)R 2 ,
each R 2 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or wherein two R 2 groups are linked together by an optionally substituted alkylene; and
each n is independently 0, 1, 2, 3 or 4;
or an active metabolite, or a pharmaceutically acceptable prodrug, isomer, pharmaceutically acceptable salt or solvate thereof.