US2021284645A1PendingUtilityA1
Compositions useful for treating disorders related to kit
Est. expiryOct 17, 2033(~7.3 yrs left)· nominal 20-yr term from priority
A61K 31/53C07D 403/14A61K 31/496A61K 45/06A61P 35/00C07D 487/04A61K 31/5377C07D 413/14C07D 417/14C07D 403/04A61P 1/04C07D 401/14A61P 43/00A61K 31/497A61P 35/02A61P 3/04
74
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Claims
Abstract
Compounds and compositions useful for treating disorders related to mutant KIT are described herein.
Claims
exact text as granted — not AI-modified1 . A method of treating melanoma in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
W is selected from hydrogen and
wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, cycloalkyl and heterocyclyl;
each X and Y is independently selected from CR 1 and N;
Z is selected from C 1 -C 6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclic heterocyclylalkyl; wherein each of C 1 -C 6 alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl, monocyclic and bicyclic heterocyclylalkyl is independently substituted with 0-5 occurrences of R C ;
L is selected from a bond, —(C(R 2 )(R 2 )) m —, —(C 2 -C 6 alkynylene)-, —(C 2 -C 6 alkenylene)-, —(C 1 -C 6 haloalkylene)-, —(C 1 -C 6 heteroalkylene)-, —(C 1 -C 6 hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —S(O) 2 —, —N(R 2 )—, —O—(C 1 -C 6 alkylene)-, —(C 1 -C 6 alkylene)-O—, —N(R 2 )—C(O)—, —C(O)—N(R 2 )—, —(C 1 -C 6 alkylene)-N(R 2 )—, —N(R 2 )—(C 1 -C 6 alkylene)-, —N(R 2 )—C(O)—(C 1 -C 6 alkylene)-, —C(O)—N(R 2 )—(C 1 -C 6 alkylene)-, —N(R 2 )—S(O) 2 —, —S(O) 2 —N(R 2 )—, —N(R 2 )—S(O) 2 —(C 1 -C 6 alkylene)-, and —S(O) 2 —N(R 2 )—(C 1 -C 6 alkylene)-;
each R A and R B is independently selected from C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 heterocyclyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, monocyclic or bicyclic aralkyl, —N(R 2 )(R 2 ), cyano, and —OR 2 ;
each R C is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkynyl, halo, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano, —C(O)R 2 , —OC(O)R 2 , —C(O)OR 2 , —SR 2 , —S(O) 2 R 2 , —S(O) 2 —N(R 2 )(R 2 ), —(C 1 -C 6 alkylene)-S(O) 2 —N(R 2 )(R 2 ), —N(R 2 )(R 2 ), —C(O)—N(R 2 )(R 2 ), —N(R 2 )(R 2 )—C(O)R 2 , —(C 1 -C 6 alkylene)-N(R 2 )—C(O)R 2 , —NR 2 S(O) 2 R 2 , —P(O)(R 2 )(R 2 ), and —OR 2 ; wherein each of heteroalkyl, haloalkyl, haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl is independently substituted with 0-5 occurrences of R a ; or 2 R C together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring substituted with 0-5 occurrences of R a ;
each of R D and R F is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, hydroxyl, halo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, —N(R 2 )(R 2 ), and cyano;
each R 1 is independently selected from hydrogen, C 1 -C 6 alkyl, monocyclic aralkyl, C 1 -C 6 hydroxyalkyl, halo, C 1 -C 6 haloalkyl, —N(R 2 )(R 2 ), and —OR 2 ;
each R 2 is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6 thioalkyl, —NR″R″, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of C 1 -C 6 alkyl, cycloalkyl and heterocyclyl is independently substituted with 0-5 occurrences of R b , or 2 R 2 together with the atoms to which they are attached form a cycloalkyl or heterocyclyl ring;
each R a and R b is independently selected from hydrogen, halo, cyano, hydroxyl, C 1 -C 6 alkoxyl, —C(O)R′, C(O)OR′, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxyalkyl, —NR′R′, and cycloalkyl, wherein cycloalkyl is substituted with 0-5 occurrences of R′;
each R′ is hydrogen, hydroxyl, or C 1 -C 6 alkyl;
each R″ is hydrogen, C 1 -C 6 alkyl, —C(O)—C 1 -C 6 alkyl, —C(O)—NR′R′; or —C(S)—NR′R′; and
m, p, and q are each independently 0, 1, 2, 3, or 4.
2 . The method of claim 1 , wherein the compound is a compound of Formula II:
or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein the compound is a compound of Formula III:
or a pharmaceutically acceptable salt thereof.
4 . The method of claim 1 , wherein at least one of X and Y is N.
5 . (canceled)
6 . The method of claim 1 , wherein L is —(C(R 2 )(R 2 )) m —.
7 . The method of claim 1 , wherein A is monocyclic or bicyclic aryl.
8 . The method of claim 1 , wherein Z is monocyclic or bicyclic aryl.
9 . The method of claim 1 , wherein Z is monocyclic or bicyclic heteroaryl.
10 . The method of claim 1 , wherein Z is monocyclic heteroaryl.
11 . The method of claim 1 , wherein Z is selected from pyrazolyl, isoxazolyl, thiophenyl, thiazolyl, and pyridyl.
12 . The method of claim 1 , wherein Z is phenyl.
13 . The method of claim 1 , wherein Z is monocyclic or bicyclic heterocyclyl.
14 . The method of claim 1 , wherein R A is fluoro and q is 1.
15 . A method of treating melanoma in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a compound selected from the group consisting of the compounds below, or a pharmaceutically acceptable salt thereof:
Compound
Number
Structure
1
2
4
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
95
96
97
94
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
16 .- 19 . (canceled)
20 . The method of claim 1 , wherein the patient has a mutation in Exon 17 in KIT.
21 . The method of claim 20 , wherein the patient has a D816 mutation in KIT in Exon 17.
22 . The method of claim 21 , wherein the D816 mutation is D816V.
23 .- 24 . (canceled)
25 . A method of treating systemic mastocytosis in a patient in need thereof, wherein the systemic mastocytosis is selected from aggressive systemic mastocytosis (ASM), SM with associated hematologic non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia, wherein the method comprises administering to the patient once daily
i) 200-300 mg of a compound which is:
or a pharmaceutically acceptable salt thereof, or
ii) a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 200-300 mg of the compound or a pharmaceutically acceptable salt thereof.
26 .- 31 . (canceled)
32 . The method of claim 25 , wherein the patient is administered once daily
i) 200 mg of the compound or a pharmaceutically acceptable salt thereof; or ii) a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 200 mg of the compound or a pharmaceutically acceptable salt thereof.Cited by (0)
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