US2016137608A1PendingUtilityA1
Substituted benzoazepines as toll-like receptor modulators
Est. expiryAug 18, 2029(~3.1 yrs left)· nominal 20-yr term from priority
Inventors:James Jeffry HowbertGregory DietschRobert HershbergLaurence E. BurgessGeorge A. DohertyC. Todd EaryRobert D. GronebergZachery Jones
A61P 9/00A61P 37/06A61P 37/02A61P 37/00A61P 37/08A61P 43/00A61P 31/00A61P 31/04A61P 35/00A61P 29/00C07D 403/04C07D 401/12C07D 403/06C07D 403/10A61P 11/06A61K 31/4025A61K 31/55C07D 223/16C07D 401/04C07D 403/14C07D 401/14
46
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Provided are compositions and methods useful for modulation of signaling through the Toll-like receptors TLR7 and/or TLR8. The compositions and methods have use in treating or preventing disease, including cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft-verses-host disease.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the formula I:
or a tautomer, enantiomer or salt thereof, wherein:
Y is substituted aryl or substituted heteroaryl, wherein said substituted aryl or substituted heteroaryl is substituted with one or more groups independently selected from CN, OH, —C(═O)R 9 , halogen, and —CH═CHC(═O)R 9 ;
R 9 is selected from alkyl, OR 15 , and NR 10 R 11 ;
R 15 is selected from H, alkyl, and —CH 2 O(alkyl),
R 10 and R 11 are each independently alkyl, wherein said alkyl is optionally substituted with —OH or R 10 and R 11 together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more —OH;
R 2 is selected from OR 14 and NR 6 R 7 ;
R 6 and R 7 are each independently selected from H, alkyl, cycloalkyl, heterocycle or benzyl, wherein said alkyl, cycloalkyl, or benzyl is optionally substituted with one or more groups independently selected from —F, —OR 8 , —NR 12 SO 2 R 13 , —C(═O)NR 12 R 13 or R 6 and R 7 together with the nitrogen atom to which they are attached form a heterocyclic ring, further wherein said heterocyclic ring is optionally substituted with one or more —OH;
R 8 is selected from hydrogen and alkyl, and
R 12 , R 13 and R 14 are each independently selected from H and alkyl, wherein said alkyl is optionally substituted with —OH;
provided that
a) when Y is aryl substituted with
or
then R 2 is not —OCH 2 CH 3 ,
or
b) when Y is aryl substituted with —C(═O)R 9 wherein R 9 is NR 10 R 11 and R 10 and R 11 together with the nitrogen atom to which they are attached form an unsubstituted pyrrolidine ring, then R 2 is not —OCH 2 CH 3 or —N(propyl) 2 .
2 . The compound of claim 1 , having the formula II:
or a tautomer, enantiomer or salt thereof, wherein W is H or —OH; Z is H or —OH; and n is 1 or 2.
3 . The compound of claim 1 , having the formula V:
or a tautomer, enantiomer or salt thereof, wherein U is N or CZ, and Z is halogen.
4 . The compound of claim 1 , having the formula VI:
or a tautomer, enantiomer or salt thereof, wherein
J is independently selected from halogen, —C(═O)R 9 and —CH═CHC(═O)R 9 ; and
p is selected from 1, 2, and 3.
5 . A compound of claim 1 having the formula VII:
or a tautomer, enantiomer or salt thereof, wherein:
Y is substituted aryl or substituted heteroaryl, wherein said aryl or heteroaryl is substituted with one or more groups independently selected from —C(═O)R 9 , halogen, and —CH═CHC(═O)R 9 ;
R 9 is selected from alkyl, OR 15 , and NR 10 R 11 ;
R 15 is selected from H, alkyl, and —CH 2 O(alkyl);
R 10 and R 11 are each independently alkyl, wherein said alkyl is optionally substituted with —OH or R 10 and R 11 together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more —OH; and
R 6 and R 7 are each independently selected from H, alkyl or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more groups independently selected from —F or —OH;
provided that when Y is aryl substituted with —C(═O)R 9 , R 9 is NR 10 R 11 , and R 10 and R 11 together with the nitrogen atom to which they are attached form an unsubstituted pyrrolidine ring, then R 6 and R 7 are not both propyl.
6 . The compound of claim 5 , wherein Y is substituted aryl, wherein said aryl is substituted with —C(═O)R 9 .
7 . The compound of claim 6 , wherein R 9 is NR 10 R 11 .
8 . The compound of claim 5 , having the formula VIIa:
or a tautomer, enantiomer or salt thereof, wherein:
v is 0, 1, or 2;
R 6 is selected from H, allyl, prop-1-enyl, and propyl, wherein said propyl is optionally substituted with one or more —OH;
R 7 is selected from allyl, prop-1-enyl, and propyl, wherein said propyl is optionally substituted with one or more —OH;
provided that when v is 0, then R 6 and R 7 are not both propyl.
9 . The compound of claim 8 , wherein v is 1.
10 . The compound of claim 1 , wherein Y is substituted is substituted with CN.
11 . The compound of claim 10 , wherein Y is phenyl.
12 . The compound of claim 1 , selected from the group consisting of:
101
102
103
104
105
106
107
112
109
110
115
117
119
120
121
122
136
124
125
126
127
128
129
130
137
138
139
154
145
146
147
220
155
156
174
176
186
178
211
182
187
188
194
190
195
202
203
204
206
207
208
209
212
210
227
228
230
232
233
234
235
236
237
238
239
and tautomers, enantiomers and salts thereof.
13 . The compound of claim 12 , selected from the group consisting of:
109
124
127
128
126
136
137
138
145
146
147
154
155
156
178
and tautomers, enantiomers and salts thereof.
14 . The compound of claim 13 , selected from the group consisting of:
109
127
128
and tautomers, enantiomers and salts thereof.
15 . The compound of claim 5 , selected from the group consisting of:
229
231
and tautomers, enantiomers and salts thereof.
16 . The compound of claim 1 , wherein the salt is a pharmaceutically acceptable salt.
17 . A pharmaceutical composition, which comprises a compound of claim 1 or a tautomer, enantiomer or salt thereof together with a pharmaceutically acceptable diluent or carrier.
18 . A method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or a tautomer, enantiomer or salt thereof such that said cancer is treated, wherein said cancer is selected from biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastomas, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, sarcomas, skin cancer, testicular cancer, thyroid cancer, other carcinomas and sarcomas.
19 . A method of treating allergy, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or a tautomer, enantiomer or salt thereof such that said allergy is treated.
20 . The method of claim 19 , wherein said allergy is acquired hypersensitivity to an allergen, eczema, allergic rhinitis or coryza, hay fever, asthma, urticaria (hives), food allergies, or other atopic conditions.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.