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US 9,867,803 B2Granted
IRE-1α inhibitors
AssigneeShanghai Fosun Pharmaceutical Industrial Development Co., Ltd.
InventorsQingping Zeng, Andras Toro, John Bruce Patterson, Warren Stanfield Wade, Zoltan Zubovics, Yun Yang, Zhipeng Wu
Life of this patent
Estimating the term…
Abstract
Compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts thereof. Such compounds and prodrugs are useful for treating diseases associated with the unfolded protein response or with regulated IRE1-dependent decay (RIDD) and can be used as single agents or in combination therapies.
Claims28
A method of inhibiting IRE-1a activity, comprising contacting IRE-1a with a compound of formula (A-1k):
- or a prodrug or pharmaceutically acceptable salt thereof;
- wherein
- R3 is hydrogen, optionally substituted alkoxyl, or optionally substituted alkylamino;
- R4 is hydrogen or alkoxyl;
- R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF3, or, together with R6 and the carbon atoms to which they are attached, forms a five-membered cycloalkyl;
- R6 is
- (a) alkenyl, optionally substituted with 1-3 substituents selected from halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
- or
- (b) alkyl, substituted with 1-3 substituents selected from halogen, —CN, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
- or
- (c) phenyl, substituted with 1-3 substituents selected from halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
- R9 and R10 are independently hydrogen;
- alkyl;
- alkoxylalkyl;
- perfluoroalkoxylalkyl;
- aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heteroaryl, 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;
- 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 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 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 R11;
- R13 is alkyl;
- alkoxylalkyl;
- perfluoroalkoxylalkyl;
- aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from 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 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 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 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;
- R17 is alkyl;
- alkoxylalkyl;
- perfluoroalkoxylalkyl;
- aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from 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 R20;
- R19 is alkoxy;
- aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from R21;
- a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- or a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from 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 R21;
- a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents selected independently from R21;
- or R21;
- and
- R21 is halogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH2, —CON(CH3)2, alkyl, alkoxy, hydroxylalkyl, or alkoxylalkyl;
- wherein the compound directly inhibits IRE-1a activity in vitro.
73 more elements
A method of inhibiting IRE-1a activity, comprising contacting IRE-1a with a pharmaceutical composition comprising:
- 1) a compound of formula (A-1k):
- or a prodrug or pharmaceutically acceptable salt thereof;
- wherein
- R3 is hydrogen, optionally substituted alkoxyl, or optionally substituted alkylamino;
- R4 is hydrogen or alkoxyl;
- R5 is hydrogen, alkyl, alkoxyl, alkylamino, CF3, or, together with R6 and the carbon atoms to which they are attached, forms a five-membered cycloalkyl;
- R6 is
- (a) alkenyl, optionally substituted with 1-3 substituents selected from halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
- or
- (b) alkyl, substituted with 1-3 substituents selected from halogen, —CN, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
- or
- (c) phenyl, substituted with 1-3 substituents selected from halogen, —CN, alkyl, perfluoroalkyl, alkoxy, hydroxylalkyl, alkoxylalkyl, perfluoroalkoxy,
- R9 and R10 are independently hydrogen;
- alkyl;
- alkoxylalkyl;
- perfluoroalkoxylalkyl;
- aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heteroaryl, 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;
- 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 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 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 R11;
- R13 is alkyl;
- alkoxylalkyl;
- perfluoroalkoxylalkyl;
- aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from 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 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 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 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;
- R17 is alkyl;
- alkoxylalkyl;
- perfluoroalkoxylalkyl;
- aryl, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from 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 R20;
- R19 is alkoxy;
- aryl, optionally substituted with 1, 2, or 3 substitutents selected independently from R21;
- a 5- or 6-membered heterocycle, optionally substituted with 1, 2, or 3 substituents independently selected from R21;
- or a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents independently selected from 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 R21;
- a 5- or 6-membered heteroaryl, optionally substituted with 1, 2, or 3 substituents selected independently from R21;
- or R21;
- and
- R21 is halogen, perfluoroalkyl, perfluoroalkoxy, —CN, —CONH2, —CON(CH3)2, alkyl, alkoxy, hydroxylalkyl, or alkoxylalkyl;
- wherein the compound directly inhibits IRE-1a activity in vitro;
- and
- 2) a pharmaceutically acceptable vehicle.
76 more elements
Dependencies are inferred from the claim text.