Substituted benzoazepines as toll-like receptor modulators
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.
1. A compound having the formula I:
or a tautomer, enantiomer or salt thereof, wherein:
Y is heteroaryl;
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.
2. A compound having the formula III:
or a tautomer, enantiomer or salt thereof, wherein
T is CH, CZ, or N;
U is CH, CZ, or N;
V is CH, CZ, or N;
X is CH, CZ, or N;
W is CH, CZ, or N;
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,
R 12 , R 13 and R 14 are each independently selected from H and alkyl, wherein said alkyl is optionally substituted with —OH;
Z is selected from halogen, —CN, —CONR 16 R 17 , —COOR 18 , —CH═CHCOOR 18 , and —OR 19 ; and
R 16 , R 17 , R 18 , and a R 19 are each independently selected from H, alkyl, and —CH 2 O(alkyl).
3. The compound according to claim 1 , having the formula IV:
or a tautomer, enantiomer or salt thereof.
4. A compound selected from the Group consisting of:
132
133
134
135
141
142
143
144
and tautomers, enantiomers and salts thereof.
5. The compound according to claim 1 , wherein the salt is a pharmaceutically acceptable salt.
6. A kit comprising:
a) a container comprising a pharmaceutical composition comprising a compound of claim 1 or a tautomer, enantiomer or salt thereof; and
b) optionally instructions for use.
7. 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.
8. 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.
9. 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.
10. The method of claim 9 , 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.
11. The compound of claim 4 , selected from
141
142
143
144
133
134
135
and tautomers, enantiomers and salts thereof.
12. The compound of claim 4 , selected from
141
143
144
133
135
and tautomers, enantiomers and salts thereof.
13. A pharmaceutical composition, which comprises a compound of claim 4 or a tautomer, enantiomer or salt thereof together with a pharmaceutically acceptable diluent or carrier.
14. A method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of claim 4 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.
15. A method of treating allergy, comprising administering to a patient in need thereof an effective amount of a compound of claim 4 or a tautomer, enantiomer or salt thereof such that said allergy is treated.
16. The method of claim 15 , 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.
17. A pharmaceutical composition, which comprises a compound of claim 3 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 3 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 3 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.