# US 9,040,714 B2 · IRE-1α inhibitors

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- Number: US 9,040,714 B2
- Document ID: US9040714B2
- Status: Granted
- Kind: B2
- Application number: 13/639,734
- Filed: 2011-04-05
- Published: 2013-05-09
- Granted: 2015-05-26
- Earliest claimed: 2010-04-05
- Assignees: MannKind Corporation
- Applicants: Qingping Zeng; Andras Toro; John Bruce Patterson; Warren Stanfield Wade; Zoltan Zubovics; Yun Yang; Zhipeng Wu
- Inventors: Qingping Zeng; Andras Toro; John Bruce Patterson; Warren Stanfield Wade; Zoltan Zubovics; Yun Yang; Zhipeng Wu
- Web page: https://patentgrep.com/patent/US9040714B2

## CPC

- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61K 31/37: Coumarins, e.g. psoralen
- A61K 31/381: having five-membered rings
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/415: 1,2-Diazoles
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/4172: Imidazole-alkanecarboxylic acids, e.g. histidine
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4433: containing a six-membered ring with oxygen as a ring hetero atom
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/452: Piperidinium derivatives (pancuronium A61K31/58)
- A61K 31/453: containing a six-membered ring with oxygen as a ring hetero atom
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/06: Antianaemics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D 217/08: with a hetero atom directly attached to the ring nitrogen atom
- C07D 311/12: substituted in position 3 and unsubstituted in position 7
- C07D 311/16: substituted in position 7
- C07D 311/20: hydrogenated in the hetero ring
- C07D 311/22: with oxygen or sulfur atoms directly attached in position 4
- C07D 311/94: condensed with rings other than six-membered or with ring systems containing such rings
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Compounds which directly inhibit IRE-1α activity in vitro, prodrugs, and pharmaceutically acceptable salts there-of. 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

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