IRE-1α inhibitors

1. A compound, wherein the compound directly inhibits IRE-1α activity in vitro and is represented by structural formula (A-1):

or a pharmaceutically acceptable salt thereof,

wherein

R3 is hydrogen, halogen; alkoxyl or alkylamino, wherein the alkoxyl and alkylamino is each optionally substituted with (1) a C 1 -C 6 hydrocarbon chain containing an N or O atom and optionally substituted with a C 1 -C 3 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 C 1 -C 3 perfluoroalkyl;

R4 is hydrogen; halogen; alkyl, alkoxyl, or alkylamino, wherein the alkyl, alkoxyl and alkylamino is each optionally substituted with (1) a C 1 -C 6 hydrocarbon chain containing an N or O atom and optionally substituted with a C 1 -C 3 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 C 1 -C 3 perfluoroalkyl;

R5 is hydrogen; halogen; —CN; an optionally substituted alkyl; or an optionally substituted alkoxyl and optional substituents for the alkyl and for the alkoxyl are (1) a C 1 -C 6 hydrocarbon chain containing an N or O atom and optionally substituted with a C 1 -C 3 perfluoroalkyl, and (2) a cycloalkyl which optionally contains 1 or 2 heteroatoms selected from N, O, and S, and which is optionally substituted with a C 1 -C 3 perfluoroalkyl;

R6 is

wherein n is 0, 1, or 2;

or alkyl, which is substituted with 1, 2 or 3 substituents independently selected from the group consisting of

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 substituents 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 substituents 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 substituents 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 substituents selected independently from R16;

R15 is amino; alkoxy; aryl, optionally substituted with 1, 2, or 3 substituents 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 substituents 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 substituents 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 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 substituents 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, —CONH 2 , —CON(CH 3 ) 2 , alkyl, hydroxylalkyl, or alkoxylalkyl.

2. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein R3 is hydrogen; or alkoxyl, optionally substituted with (1) a C 1 -C 6 hydrocarbon chain containing an N or O atom, or (2) a cycloalkyl which optionally contains 1 or 2 heteroatoms selected from N, and O.

3. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein R4 is hydrogen; or alkoxyl, optionally substituted with a C 1 -C 6 hydrocarbon chain containing an N or O atom.

4. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein R5 is optionally substituted alkyl and optional substituents for the alkyl is a C 1 -C 6 hydrocarbon chain containing an N or O atom.

5. The compound or the pharmaceutically acceptable salt thereof of claim 4 , wherein the alkyl is methyl.

6. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein R6 is

wherein n is 0, 1, or 2;

or

alkyl independently substituted with 1, 2 or 3 of

R9 and R10 are independently hydrogen; alkyl; 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 6-membered heterocycle containing 1 or 2 heteroatoms selected from N and O, optionally substituted with 1, 2, or 3 substituents selected independently from alkyl; and

R12 is alkoxy; or a 6-membered heterocycle having 1 or 2 heteroatoms selected from N and O, and optionally substituted with 1, 2, or 3 substituents selected independently from alkyl.

7. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable vehicle.

9. A method for the treatment of a disorder associated with the unfolded protein response or a disorder associated with a target of regulated IRE-1α-dependent decay (RIDD) in a subject in need thereof, comprising administering to the subject the compound or the pharmaceutically acceptable salt thereof of claim 1 .

10. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with the compound or the pharmaceutically acceptable salt thereof of claim 1 .

11. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of claim 7 and a pharmaceutically acceptable vehicle.

12. A method for the treatment of a disorder associated with the unfolded protein response or a disorder associated with a target of regulated IRE-1α-dependent decay (RIDD) in a subject in need thereof, comprising administering to the subject the compound or the pharmaceutically acceptable salt thereof of claim 7 .

13. A method of inhibiting IRE-1α activity, comprising contacting IRE-1α with the compound or the pharmaceutically acceptable salt thereof of claim 7 .