Substituted Benzoazepines as Toll-Like Receptor Modulators
AssigneesArray BioPharma Inc., VentiRx Pharmaceuticals, Inc.
InventorsJames Jeffry Howbert, Gregory Dietsch, Robert Hershberg, Laurence E. Burgess, Joseph P. Lyssikatos, Brad Newhouse, Hong-Woon Yang
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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.
Claims20
A method of treating a TLR7- and/or TLR8-mediated condition, comprising administering to a subject in need thereof an effective amount of a compound having the formula I:
- or a tautomer, enantiomer or salt thereof, wherein:
- Y is —(O)x(CH2)yR11;
- x is selected from 0 and 1;
- y is selected from 0, 1, 2, and 3;
- R11 is selected from aryl, heteroaryl, and saturated or partially saturated heterocycle, wherein when x is 0, said aryl or heteroaryl is substituted with —C(O)NR1R2 or T;
- R1 and R2 are independently selected from hydrogen and alkyl, wherein said alkyl is optionally substituted with —C(O)O(CH2)tR12 or R1 and R2 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring;
- t is selected from 0, 1, 2, and 3;
- R12 is selected from cycloalkyl and aryl;
- T is selected from heterocycle, —(CHR7)zOR9, —(O)u(CH2)sC(O)R8, —OSO2R13, and —CH(OH)CH2OH;
- R7 is H or —OH;
- R8 is selected from —OR10 and alkyl;
- R9 is selected from alkyl and H;
- R10 is selected from alkyl, —(CH2)R12, and hydrogen, wherein said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine;
- R13 is selected from —OH, alkyl, CF3, cycloalkyl, heterocycle, aryl, and heteroaryl;
- u is selected from 0 and 1;
- z is selected from 1, 2, and 3;
- s is selected from 1 and 2;
- R5 is selected from —NR3R4 and —OR10;
- R3 and R4 are independently selected from H, alkyl, and —(O)q(CH2)rP;
- wherein said alkyl is optionally substituted with one or more —OH;
- q is selected from 0 and 1;
- r is selected from 0, 1, 2, and 3;
- P is selected from aryl, —SO2R6, and heterocycle;
- and
- R6 is selected from —NH2, —NH(alkyl), and —N(alkyl)2,
- provided that when R11 is aryl or heteroaryl, then
- a) x+y≧1;
- or
- b) R11 is substituted with T;
- or
- c) R5 is NR3R4 and at least one of R3 or R4 is [(O)q(CH2)rP] and q+r≧1;
- or
- d) at least one of R1 or R2 is alkyl substituted with —C(O)O(CH2)R12.
A method of treating a TLR7- and/or TLR8-mediated condition, comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of:
- and tautomers, enantiomers and salts thereof.
A method of modulating a patient's immune system, comprising administering to a subject in need thereof an effective amount of a compound having the formula I:
- or a tautomer, enantiomer or salt thereof, wherein:
- Y is —(O)x(CH2)yR11;
- x is selected from 0 and 1;
- y is selected from 0, 1, 2, and 3;
- R11 is selected from aryl, heteroaryl, and saturated or partially saturated heterocycle, wherein when x is 0, said aryl or heteroaryl is substituted with —C(O)NR1R2 or T;
- R1 and R2 are independently selected from hydrogen and alkyl, wherein said alkyl is optionally substituted with —C(O)O(CH2)tR12 or R1 and R2 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring;
- t is selected from 0, 1, 2, and 3;
- R12 is selected from cycloalkyl and aryl;
- T is selected from heterocycle, —(CHR7)zOR9, —(O)u(CH2)sC(O)R8, —OSO2R13, and —CH(OH)CH2OH;
- R7 is H or —OH;
- R8 is selected from —OR10 and alkyl;
- R9 is selected from alkyl and H;
- R10 is selected from alkyl, —(CH2)R12, and hydrogen, wherein said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine;
- R13 is selected from —OH, alkyl, CF3, cycloalkyl, heterocycle, aryl, and heteroaryl;
- u is selected from 0 and 1;
- z is selected from 1, 2, and 3;
- s is selected from 1 and 2;
- R5 is selected from —NR3R4 and —OR10;
- R3 and R4 are independently selected from H, alkyl, and —(O)q(CH2)rP;
- wherein said alkyl is optionally substituted with one or more —OH;
- q is selected from 0 and 1;
- r is selected from 0, 1, 2, and 3;
- P is selected from aryl, —SO2R6, and heterocycle;
- and
- R6 is selected from —NH2, —NH(alkyl), and —N(alkyl)2,
- provided that when R11 is aryl or heteroaryl, then
- a) x+y≧1;
- or
- b) R11 is substituted with T;
- or
- c) R5 is NR3R4 and at least one of R3 or R4 is [(O)q(CH2)rP] and q+r≧1;
- or
- d) at least one of R1 or R2 is alkyl substituted with —C(O)O(CH2)R12.
Dependencies are inferred from the claim text.