Ire-1alpha inhibitors

A compound or pharmaceutically acceptable salt thereof, where the compound is represented by a structural formula selected from the group consisting of structural formula (A-3), structural formula (A-9a), and structural formula (A-9b):

• wherein:
• R3 and R4 independently are hydrogen;
• halogen;
• alkyl, alkoxyl, or alkylamino, each optionally substituted with (1) a C1-C6 hydrocarbon chain containing an N or O atom and optionally substituted with a C1-C3 perfluoroalkyl, or (2) a cycloalkyl which optionally contains 1 or 2 heteroatoms selected from N, O, and S, and which is optionally substituted with a C1-C3 perfluoroalkyl,
• R6 is hydrogen;
• R21;
• alkenyl, alkynyl, or phenyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
• a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxyl,
• wherein n is 0, 1, or 2;
• R7 is H or methyl;
• and
• R9 and R10 are independently hydrogen;
• alkyl;
• alkoxylalkyl;
• perfluoroalkoxylalkyl;
• a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
• or
• wherein n is 0, 1, 2, or 3;
• or,
• R9 and R10, together with the nitrogen atom to which they are attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from R11;
• R11 is hydrogen or alkyl;
• R12 is amino;
• alkoxy;
• or a 5- or 6-membered heterocycle having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substituents selected independently from R11;
• and
• R21 is halogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH2, —CON(CH3)2, alkyl, alkoxy, hydroxylalkyl, or alkoxylalkyl;
• with the exception of compounds of structural formula (A3) in which:
• i. R3 and R4 are hydrogen and R6 is optionally substituted phenyl;
• ii. R3 and R4 are hydrogen, R6 is methoxy, and R7 is methyl;
• iii. R3 is ethyl, R4 is hydrogen, R6 is fluorophenyl, and R7 is methyl;
• iv. R3 is halogen and R4 and R7 are hydrogen, and R6 is bromophenyl;
• or
• v. R6 and R7 are both methyl and either:
• i. R3 is halogen and R4 is hydrogen;
• or
• ii. one of R3 and R4 is methyl and the other is hydrogen;
• wherein:
• R3 and R4 independently are hydrogen;
• halogen;
• alkyl, alkoxyl, or alkylamino, each optionally substituted with (1) a C1-C6 hydrocarbon chain containing an N or O atom and optionally substituted with a C1-C3 perfluoroalkyl, or (2) a cycloalkyl which optionally contains 1 or 2 heteroatoms selected from N, O, and S, and which is optionally substituted with a C1-C3 perfluoroalkyl;
• R6 is R21;
• alkynyl, or phenyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
• a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxyl alkyl, alkoxylalkyl, perfluoroalkoxyl,
• wherein n is 0, 1, or 2;
• R9 and R10 are independently hydrogen;
• alkyl;
• alkoxylalkyl;
• perfluoroalkoxylalkyl;
• a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
• or
• wherein n is 0, 1, 2, or 3;
• or,
• R9 and R10, together with the nitrogen atom to which they are attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from R11;
• R11 is hydrogen or alkyl;
• R12 is amino;
• alkoxy;
• or a 5- or 6-membered heterocycle having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substituents selected independently from R11;
• and
• R21 is halogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH2, —CON(CH3)2, alkyl, alkoxy, hydroxylalkyl, or alkoxylalkyl;
• wherein
• R3 and R4 independently are hydrogen;
• halogen;
• alkyl, alkoxyl, or alkylamino, each optionally substituted with (1) a C1-C6 hydrocarbon chain containing an N or O atom and optionally substituted with a C1-C3 perfluoroalkyl, or (2) a cycloalkyl which may contain 1 or 2 heteroatoms selected from N, O, and S, and which is optionally substituted with a C1-C3 perfluoroalkyl;
• and
• R6 is hydrogen;
• R21;
• alkenyl, alkynyl, or phenyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
• a 5- or 6-membered heteroaryl that is substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxyl,
• wherein n is 0, 1, or 2;
• R9 and R10 are independently hydrogen;
• alkyl;
• alkoxylalkyl;
• perfluoroalkoxylalkyl;
• a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
• or
• wherein n is 0, 1, 2, or 3;
• or,
• R9 and R10, together with the nitrogen atom to which they are attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from R11;
• R11 is hydrogen or alkyl;
• R12 is amino;
• alkoxy;
• or a 5- or 6-membered heterocycle having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substituents selected independently from R11;
• and
• R21 is halogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH2, —CON(CH3)2, alkoxy, hydroxylalkyl, or alkoxylalkyl.