US2016228437A1PendingUtilityA1
Mixed lineage kinase inhibitors and method of treatments
Est. expiryMar 7, 2033(~6.6 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 9/04A61P 9/00A61P 9/12A61P 7/10A61P 43/00A61P 3/06A61P 3/10A61P 9/10A61P 3/04A61P 27/02A61P 29/00A61P 25/28A61P 25/16A61P 31/18A61K 31/5025A61K 31/536A61K 31/513A61P 1/16A61K 45/06A61P 13/12C07D 513/04A61K 31/427A61P 19/06A61P 15/00A61P 1/18C07D 487/04C07D 519/00A61K 31/4402A61P 25/00A61P 1/04Y02A50/30
32
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Provided herein are imidazopyridine compounds having an inhibitory effect on mixed lineage kinases (MLKs), methods of their synthesis, and methods of their therapeutic. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and pharmaceutical compositions.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for treating a MLK-mediated disease comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a compound having the structure of Formula I
or a pharmaceutically acceptable isomer, isotope, enantiomer, salt, ester, prodrug, hydrate or solvate thereof, wherein
J has a structure of
where J is optionally substituted with up to four R 10 , each R 10 is independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, —OH, and —OCOR 6 ;
X is NR 12 or S;
each X 1 , X 2 , X 3 , and X 4 is independently CH or N and wherein no more than one of X 1 , X 2 , X 3 , and X 4 is N;
Y is —W—(CH 2 ) n —R 1 ,
W is null, phenylene, or —NR 6 -phenylene, where the NR 6 is attached to the imidazopyridazine core structure of Formula I;
R 1 is —NR 2 R 3 , or piperazinyl, where the nitrogen atom of the piperazinyl is optionally substituted with alkyl or alkoxy;
R 2 is H or alkyl;
R 3 is selected from the group consisting of C 2 -C 10 alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, where any atom of R 3 is optionally substituted with one or more R 7 ; or R 2 and R 3 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclic ring optionally substituted with R 8 ;
R 4 is H or alkyl;
R 5 is H, alkyl, or NHR 9 ;
R 6 is H or alkyl;
each R 7 is independently alkyl, cycloalkyl, alkoxy, cycloalkoxy, cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR 11 , or —O—(CH 2 ) m —OH;
R 8 is alkoxy, hydroxyalkyl, or COOR 11 ;
R 9 is H, alkyl, or cycloalkyl;
R 11 is H, or alkyl;
R 12 is H, or alkyl;
n is 0 or 1;
m is 1, 2, or 3; and
p is 1, 2, or 3;
with the proviso that if J is an unsubstituted benzothiophene, then R 3 is either aryl or heteroaryl, where any atom of R 3 is optionally substituted with one or more R 7 ;
and together with at least one pharmaceutically acceptable carrier, diluent or excipient.
2 . The method of claim 1 wherein J is selected from the group consisting of
3 . The method of claim 1 wherein J is
wherein each R 10 is independently selected from the group consisting of F, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH 3 ; and k is 0, 1, 2, or 3.
4 . The method of claim 1 wherein J is
wherein each R 10 is independently selected from the group consisting of F, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH 3 ; and k is 0, 1, 2, or 3.
5 . The method of claim 4 wherein each of X 1 , X 2 , X 3 , and X 4 is CH.
6 . The method of claim 4 wherein X 1 is N, and each of X 2 , X 3 , and X 4 is CH.
7 . The method of claim 4 wherein X 2 is N, and each of X 1 , X 3 , and X 4 is CH.
8 . The method of claim 4 wherein X 3 is N, and each of X 1 , X 2 , and X 4 is CH.
9 . The method of claim 4 wherein X 4 is N, and each of X 1 , X 2 , and X 3 is CH.
10 . The method of claim 1 wherein Y is —W—(CH 2 ) n —R 1 .
11 . The method of claim 10 wherein R 1 is —NR 2 R 3 .
12 . The method of claim 11 wherein R 3 is selected from the group consisting of C 2 -C 10 alkyl, aryl, and cycloalkyl.
13 . The method of claim 12 wherein R 3 is phenyl optionally substituted with one or more R 7 , wherein each R 7 is independently selected from the group consisting of hydroxyl, methoxy, —COOH, —O—(CH 2 ) m —OH, cyclopropylmethoxy, cyclopentylmethoxy, and isopropyl.
14 . The method of claim 13 wherein each R 7 is independently selected from the group consisting of methoxy, —COOH, and —O—(CH 2 ) 3 —OH.
15 . The method of claim 11 wherein R 3 is C 2 -C 10 alkyl, aryl, and cycloalkyl, where any atom of R 3 is optionally substituted with one or more R 7 .
16 . The method of claim 1 wherein the compound is selected from any of:
or any pharmaceutically acceptable salt, tautomer, stereoisomer, or isotope thereof.
17 . The method of claim 16 wherein the compound is selected from any of
or any pharmaceutically acceptable salt, tautomer, stereoisomer, or isotope thereof.
18 . A method of claim 1 , wherein the compound is selected from any of compounds shown below:
Compound #
Structure
3
4
5
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
83
85
86
87
92
93
118
166
167
168
169
170
171
172
173
174
175
176
177
178
179
181
182
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
218
219
220
221
19 . The method of claim 1 , wherein the subject is a human being.
20 . The method of claim 1 , wherein the MLK-mediated disease is selected from the group consisting of stroke, diabetes mellitus, hyperglycemia, retinopathy, nephropathy, neuropathy, ulcers, microangiopathies, macroangiopathies, gout, diabetic foot disease, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, atherosclerosis, peripheral inflammation, cancer, hepatitis, steatohepatitis, HIV associated neurocognitive disorder, HIV associated neuropathy, Alzheimer's disease, Parkinson's disease, multiple sclerosis, neurodegenerative disease, cirrhotic liver disease, and cirrhotic pancreatic disease.
21 . A method for treating a MLK-mediated disease comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a compound having the structure of Formula I
or a pharmaceutically acceptable isomer, isotope, enantiomer, or salt thereof, wherein J has a structure of
substituted with up to four R 10 ,
or J has a structure of
optionally substituted with up to four R 10 ,
each R 10 is independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, —OH, and —OCOR 6 ;
X is NR 12 or S;
one of X 1 , X 2 , X 3 , and X 4 is N and the other three of X 1 , X 2 , X 3 , and X 4 are CH;
Y is —W—(CH 2 ) n —R 1 ,
W is null, phenylene, or —NR 6 -phenylene, where the NR 6 is attached to the imidazopyridazine core structure of Formula I;
R 1 is —NR 2 R 3 , or piperazinyl, where the nitrogen atom of the piperazinyl is optionally substituted with alkyl or alkoxy;
R 2 is H or alkyl;
R 3 is selected from the group consisting of C 2 -C 10 alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, where any atom of R 3 is optionally substituted with one or more R 7 ; or R 2 and R 3 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclic ring optionally substituted with R 8 ;
R 4 is H or alkyl;
R 5 is H, alkyl, or NHR 9 ;
R 6 is H or alkyl;
each R 7 is independently alkyl, cycloalkyl, alkoxy, cycloalkoxy, cycloalkylalkyoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR 11 , or —O—(CH 2 ) m —OH;
R 8 is alkoxy, hydroxyalkyl, or COOR 11 ;
R 9 is H, alkyl, or cycloalkyl;
R 11 is H, or alkyl;
R 12 is H, or alkyl;
n is 0 or 1;
m is 1, 2, or 3; and
p is 1, 2, or 3;
with the proviso that if J is an unsubstituted benzothiophene, then R 3 is either aryl or heteroaryl, where any atom of R 3 is optionally substituted with one or more R 7 .Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.