IRE-1α inhibitors

A compound, or a pharmaceutically acceptable salt or prodrug thereof, where the compound directly inhibits IRE-1αactivity in vitro and is represented by structural formula (A-1):

• wherein
• R3 is halogen;
• 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;
• R4 is hydrogen;
• halogen;
• alkyl, alkoxyl, or alkylamino, each optionally substituted with (1) a C1-C6 ydrocarbon 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;
• R5 is 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;
• R6is R21;
• alkenyl, alkynyl, or phenyl, each optionally substituted with 1 , 2, or 3substituents 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;
• or R5 and R6, together with the carbon atoms to which they are attached, form a 5-membered cycloalkyl;
• R9 and R10 are independently hydrogen;
• alkyl;
• alkoxylalkyl;
• perfluoroalkoxylalkyl;
• aryl, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from members of 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 members of R11;
• R11 is hydrogen;
• alkyl;
• aryl;
• heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S;
• arylalkyl;
• heteroarylalkyl in which the heteroaryl contains 1 or 2 heteroatoms selected from N, O, and S;
• R12 is amino;
• alkoxy;
• aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from members of R11;
• 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 substitutents selected independently from members of R11;
• or a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3;
• substitutents selected independently from members of R11;
• R13 is alkyl;
• alkoxylalkyl;
• perfluoroalkoxylalkyl;
• aryl, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• or
• wherein n is 0, 1, 2, or 3;
• and R14 is hydrogen or R13;
• or
• R13 and R14, together with the nitrogen to which they are attached, form a heterocycle containing 1, 2, or 3 heteroatoms selected independently from N, O, and S, optionally substituted with 1, 2, or 3 substitutents selected independently from R16;
• R15 is amino;
• alkoxy;
• aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from members of R21;
• 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 substitutents selected from members of R21;
• or a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substitutents selected from members of R21;
• R16 is hydrogen;
• alkyl;
• aryl;
• heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S;
• arylalkyl;
• heteroarylalkyl in which the heteroaryl contains 1 or 2 heteroatoms selected from N, O, and S;
• amino, or
• R17 is alkyl;
• alkoxylalkyl;
• perfluoroalkoxylalkyl;
• aryl, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from members of or R21;
• or
• wherein n is 0, 1, 2, or 3;
• and R18 is hydrogen or R17;
• or
• R17 and R18, together with the nitrogen to which they are attached, form a heterocycle containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, and S, optionally substituted with 1, 2, or 3 substituents selected independently from members of R20;
• R19 is alkoxy;
• aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from members of R21;
• a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• or a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from members of R21;
• R20 is a 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1, 2, or 3 substituents selected independently from members of R21;
• a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents selected independently from members of R21;
• or R21;
• and
• R21 is perfluoroalkyl, perfluoroalkoxy, —CN, —CONH2, —CON(CH3)2, alkyl, hydroxylalkyl, or alkoxylalkyl.