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1. WO2020113222 - PETITES CELLULES MODULANT LE PDI NEUROPROTECTEUR ET LEURS MÉTHODES D'UTILISATION

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

What is claimed is:

1. A compound having the formula (I):

wherein a dashed line indicates the presence of an optional double bond, wherein X, Y and Z are independently selected from the group consisting of C, N, S and O,

wherein R1, R2, R3, and R4 are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl- heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

wherein R5, R6, R7, R8 and R10 are independently selected from the group consisting of no atom, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),– (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R9 and R11 are independently selected from the group consisting of H, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),

wherein R is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1- 6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1- 6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

with the proviso that the compound is not

,

,

,

,


, , ,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

2. A compound have the formula (II):

wherein a dashed line indicates the presence of an optional double bond, wherein R1 is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1- 6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

wherein R3, R4, R5, R6 and R8 are independently selected from the group consisting of no atom, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),– (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R7 and R9 are independently selected from the group consisting of H, NR, N(R)2, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),

wherein R is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1- 6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl- heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1- 6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, which is selected from the group consisting of:


, ,


, and combinations thereof,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2, which is selected from the group consisting of:

, , combinations thereof,

or an N-oxide, crystalline form, hydrate thereof, or
pharmaceutically acceptable salt thereof.

5. A compound selected from the group consisting of:

, , and combinations thereof,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

6. A composition comprising a compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

7. A pharmaceutically acceptable salt of a compound according to any one of claims 1-5.

8. A composition comprising a pharmaceutically acceptable salt of a compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

9. A kit comprising:

(i) a compound according to any one of claims 1-5 or a composition according to claim 6; and

(ii) instructions for use.

10. The kit according to claim 9, wherein the instructions for use are instructions for treating or ameliorating the effects of a neurodegenerative disease in a subject.

11. The kit according to claim 9, wherein the instructions for use are instructions for treating or ameliorating the effects of a condition associated with increased protein disulfide isomerase (PDI) activity in a subject.

12. The kit according to claim 9, wherein the instructions for use are instructions for modulating PDI activity in a cell.

13. A method for treating or ameliorating the effects of a neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective amount of a compound selected from the group consisting of formula (I)

wherein a dashed line indicates the presence of an optional double bond, wherein X, Y and Z are independently selected from the group consisting of C, N, S and O,

wherein R1, R2, R3, and R4 are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl- heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

wherein R5, R6, R7, R8 and R10 are independently selected from the group consisting of no atom, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),– (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R9 and R11 are independently selected from the group consisting of H, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),

wherein R is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1- 6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1- 6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

with the proviso that the compound is not

,


, , ,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof;

formula (II)

wherein a dashed line indicates the presence of an optional double bond, wherein R1 is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1- 6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

wherein R3, R4, R5, R6 and R8 are independently selected from the group consisting of no atom, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),– (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R7 and R9 are independently selected from the group consisting of H, NR, N(R)2, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),

wherein R is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1- 6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl- heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1- 6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof;

a compound selected from the group consisting of:

, , and combinations thereof,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein the compound is selected from the group consisting of:

, , , ,


or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

15. A method for treating or ameliorating the effects of a neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective amount of a composition of claim 6 or claim 8.

16. The method of claim 13 or claim 15, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia, multiple sclerosis, Huntington’s disease, transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and hereditary spastic paraparesis.

17. The method of claim 13 or claim 15, wherein the neurodegenerative disease is Huntington’s disease.

18. The method of claim 13 or claim 15, wherein the neurodegenerative disease is Alzheimer’s disease.

19. The method of claim 13 or claim 15, wherein the subject is a mammal.

20. The method of claim 8 wherein the mammal is selected from the group consisting of humans, veterinary animals, and agricultural animals.

21. The method of claim 13 or claim 15, wherein the subject is a human.

22. The method of claim 13 or claim 15, further comprising co-administering to the subject an effective amount of one or more additional therapeutic agents.

23. The method of claim 22, wherein the one or more additional therapeutic agents are selected from the group consisting of 5-hydroxytryptophan, Activase, AFQ056 (Novartis), Aggrastat, Albendazole, alpha-lipoic acid/L- acetyl carnitine, Alteplase, Amantadine (Symmetrel), amlodipine, Ancrod, Apomorphine (Apokyn), Arimoclomol, Arixtra, Armodafinil, Ascorbic acid, Ascriptin, Aspirin, atenolol, Avonex, baclofen (Lioresal), Banzel, Benztropine (Cogentin), Betaseron, BGG492 (Novartis Corp.), Botulinum toxin, Bufferin, Carbatrol®, Carbidopa/levodopa immediate-release (Sinemet), Carbidopa/levodopa oral disintegrating (Parcopa), Carbidopa/levodopa/Entacapone (Stalevo), CERE-110: Adeno-Associated Virus Delivery of NGF (Ceregene), cerebrolysin, CinnoVex, citalopram, citicoline, Clobazam, Clonazepam, Clopidogrel, clozapine (Clozaril), Coenzyme Q, Creatine, dabigatran, dalteparin, Dapsone, Davunetide, Deferiprone, Depakene®, Depakote ER®, Depakote®, Desmoteplase, Diastat, Diazepam, Digoxin, Dilantin®, Dimebon, dipyridamole, divalproex (Depakote), Donepezil (Aricept), EGb 761, Eldepryl, ELND002 (Elan Pharmaceuticals), Enalapril, enoxaparin, Entacapone (Comtan), epoetin alfa, Eptifibatide, Erythropoietin, Escitalopram, Eslicarbazepine acetate, Esmolol, Ethosuximide, Ethyl-EPA (Miraxion™), Exenatide, Extavia, Ezogabine, Felbamate, Felbatol®, Fingolimod (Gilenya), fluoxetine (Prozac), fondaparinux, Fragmin, Frisium, Gabapentin, Gabitril®, Galantamine, Glatiramer (Copaxone), haloperidol (Haldol), Heparin, human chorionic gonadotropin (hCG), Idebenone, Inovelon®, insulin, Interferon beta 1a, Interferon beta 1b, ioflupane 123I (DATSCAN®), IPX066 (Impax Laboratories Inc.), JNJ-26489112 (Johnson and Johnson), Keppra®, Klonopin, Lacosamide, L-Alpha glycerylphosphorylcholine, Lamictal®, Lamotrigine, Levetiracetam, liraglutide, Lisinopril, Lithium carbonate, Lopressor, Lorazepam, losartan, Lovenox, Lu AA24493, Luminal, LY450139 (Eli Lilly), Lyrica, Masitinib, Mecobalamin, Memantine, methylprednisolone, metoprolol tartrate, Minitran, Minocycline, mirtazapine, Mitoxantrone (Novantrone), Mysoline®, Natalizumab (Tysabri), Neurontin®, Niacinamide, Nitro-Bid, Nitro- Dur, nitroglycerin, Nitrolingual, Nitromist, Nitrostat, Nitro-Time, Norepinephrine (NOR), Carbamazepine, octreotide, Onfi®, Oxcarbazepine, Oxybutinin chloride, PF-04360365 (Pfizer), Phenobarbital, Phenytek®, Phenytoin,

piclozotan, Pioglitazone, Plavix, Potiga, Pramipexole (Mirapex), pramlintide, Prednisone, Primidone, Prinivil, probenecid, Propranolol, PRX-00023 (EPIX Pharmaceuticals Inc.), PXT3003, Quinacrine, Ramelteon, Rasagiline (Azilect), Rebif, ReciGen, remacemide, Resveratrol, Retavase, reteplase, riluzole (Rilutek), Rivastigmine (Exelon), Ropinirole (Requip), Rotigotine (Neupro), Rufinamide, Sabril, safinamide (EMD Serono), Salagen, Sarafem, Selegiline (l-deprenyl, Eldepryl), SEN0014196 (Siena Biotech), sertraline (Zoloft), Simvastatin, Sodium Nitroprussiate (NPS), sodium phenylbutyrate, Stanback Headache Powder, Tacrine (Cognex), Tamoxifen, tauroursodeoxycholic acid (TUDCA), Tegretol®, Tenecteplase, Tenormin, Tetrabenazine (Xenazine), THR-18 (Thrombotech Ltd.), Tiagabine, Tideglusib, tirofiban, tissue plasminogen activator (tPA), tizanidine (Zanaflex), TNKase, Tolcapone (Tasmar), Tolterodine, Topamax®, Topiramate, Trihexyphenidyl (formerly Artane), Trileptal®, ursodiol, Valproic Acid, valsartan, Varenicline (Pfizer), Vimpat, Vitamin E, Warfarin, Zarontin®, Zestril, Zonegran®, Zonisamide, Zydis selegiline HCL Oral disintegrating (Zelapar), and combinations thereof.

24. A method for treating or ameliorating the effects of a condition associated with increased protein disulfide isomerase (PDI) activity in a subject in need thereof comprising administering to the subject an effective amount of a compound selected from the group consisting of formula (I)

wherein a dashed line indicates the presence of an optional double bond, wherein X, Y and Z are independently selected from the group consisting of C, N, S and O,

wherein R1, R2, R3, and R4 are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

wherein R5, R6, R7, R8 and R10 are independently selected from the group consisting of no atom, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),– (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R9 and R11 are independently selected from the group consisting of H, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),

wherein R is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1- 6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1- 6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

with the proviso that the compound is not

or an N-oxide, crystalline form, hydrate thereof, or
pharmaceutically acceptable salt thereof;

formula (II)

wherein a dashed line indicates the presence of an optional double bond, wherein R1 is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1- 6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

wherein R3, R4, R5, R6 and R8 are independently selected from the group consisting of no atom, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),– (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R7 and R9 are independently selected from the group consisting of H, NR, N(R)2, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),–(optionally substituted mono-or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),

wherein R is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1- 6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1- 6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally

substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof;

a compound selected from the group consisting of:


,

, , and combnatons t ereo ,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, wherein the compound is selected from the group consisting of:

, ,

, and combinations thereof, or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

26. A method for treating or ameliorating the effects of a condition associated with increased protein disulfide isomerase (PDI) activity in a subject in need thereof comprising administering to the subject an effective amount of a composition of claim 6 or claim 8.

27. The method of claim 24 or claim 26, wherein the subject is a mammal.

28. The method of claim 27, wherein the mammal is selected from the group consisting of humans, veterinary animals, and agricultural animals.

29. The method of claim 24 or claim 26, wherein the subject is a human.

30. The method of claim 24 or claim 26, wherein the condition is selected from the group consisting of a protein folding disorder, cancer, HIV, infection and a blood clot.

31. The method of claim 30, wherein the infection is influenza infection.

32. A method of modulating PDI activity in a cell comprising administering to the subject an effective amount of a compound selected from the group consisting of formula (I)

wherein a dashed line indicates the presence of an optional double bond, wherein X, Y and Z are independently selected from the group consisting of C, N, S and O,

wherein R1, R2, R3, and R4 are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

wherein R5, R6, R7, R8 and R10 are independently selected from the group consisting of no atom, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),– (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R9 and R11 are independently selected from the group consisting of H, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),

wherein R is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1- 6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1- 6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

with the proviso that the compound is not

or an N-oxide, crystalline form, hydrate thereof, or
pharmaceutically acceptable salt thereof;

formula (II)

wherein a dashed line indicates the presence of an optional double bond, wherein R1 is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1- 6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

wherein R3, R4, R5, R6 and R8 are independently selected from the group consisting of no atom, NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),– (optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R7 and R9 are independently selected from the group consisting of H, NR, N(R)2, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O); N(R)SO2, SO2N(R), S, SO, SO2,–(optionally substituted C1–6 alkyl),–(optionally substituted mono-or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),–C1–4 alkyl–(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S),

wherein R is selected from the group consisting of H, D, O, halo, C1-6alkyl, C1- 6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1- 6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally

substituted with an atom or a group selected from the group consisting of halo, C1-4alkyl, CF3, and combinations thereof,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof;

a compound selected from the group consisting of:


,

, , and combnatons t ereo ,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the compound is selected from the group consisting of:

, ,

, and combinations thereof, or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

34. A method of modulating PDI activity in a cell comprising administering to the subject an effective amount of a composition of claim 6 or claim 8.

35. A compound selected from the group consisting of:


,

, ,


, ,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

36. A composition comprising a compound according to claim 35 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

37. A compound having the structure of:

,

or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

38. A composition comprising a compound according to claim 37 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

39. A method for identifying a compound that targets a disease-related reactive oxygen species (ROS) regulator, comprising:

(a) providing siRNA, gRNA, and/or cDNA libraries that target a plurality of ROS regulators;

(b) screening the libraries assembled in (a) for candidate ROS regulators that are associated with a disease;

(c) identifying desired ROS regulator(s) by validating candidate ROS regulators in cell assays specific for the disease;

(d) assembling a compound library based on a plurality of redox regulating scaffolds;

(e) screening the library assembled in (d) for candidate scaffolds that modulate the ROS regulator(s) identified in (c);

(f) identifying the desired scaffold(s) by evaluating safety and selectivity of the candidate scaffolds; and

(g) identifying a candidate compound that targets the disease-related ROS regulator based on the compound’s ability to bind to the desired scaffold identified in (f).

40. The method of claim 39, wherein the ROS regulator is selected from the group consisting of glutathione peroxidases (GPX), glutathione (GSH), NF- E2-related factor 2 (Nrf2), superoxide dismutases (SOD), peroxiredoxins, catalases, glutaredoxins, thioredoxins, protein disulfide isomerases (PDI), and combinations thereof.

41. The method of claim 39, wherein the ROS regulator is a thiol-containing protein.

42. The method of claim 39, wherein the ROS regulator is a protein from the thioredoxin superfamily.

43. The method of claim 39, wherein the ROS regulator is a protein disulfide isomerase (PDI).

44. The method of claim 39, wherein the disease is a neurodegenerative disease. 45. The method of claim 44, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia, multiple sclerosis, Huntington’s disease, transmissible spongiform encephalopathy, Charcot- Marie-Tooth disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and hereditary spastic paraparesis.

46. The method of claim 44, wherein the neurodegenerative disease is Huntington’s disease.

47. The method of claim 44, wherein the neurodegenerative disease is Alzheimer’s disease.

48. A method for treating or ameliorating the effects of a disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound identified by the method according to claim 39.

49. The method of claim 48, wherein the disease is a neurodegenerative disease. 50. The method of claim 49, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia, multiple sclerosis, Huntington’s disease, transmissible spongiform encephalopathy, Charcot- Marie-Tooth disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and hereditary spastic paraparesis.

51. The method of claim 49, wherein the neurodegenerative disease is Huntington’s disease.

52. The method of claim 49, wherein the neurodegenerative diseas is Alzheimer’s disease.

53. The method of claim 48, wherein the subject is a mammal.

54. The method of claim 53, wherein the mammal is selected from the group consisting of humans, veterinary animals, and agricultural animals.

55. The method of claim 48, wherein the subject is a human.

56. The method of claim 48, further comprising co-administering to the subject an effective amount of one or more additional therapeutic agents.

57. The method of claim 56, wherein the one or more additional therapeutic agents are selected from the group consisting of 5-hydroxytryptophan, Activase, AFQ056 (Novartis), Aggrastat, Albendazole, alpha-lipoic acid/L- acetyl carnitine, Alteplase, Amantadine (Symmetrel), amlodipine, Ancrod, Apomorphine (Apokyn), Arimoclomol, Arixtra, Armodafinil, Ascorbic acid, Ascriptin, Aspirin, atenolol, Avonex, baclofen (Lioresal), Banzel, Benztropine (Cogentin), Betaseron, BGG492 (Novartis Corp.), Botulinum toxin, Bufferin, Carbatrol®, Carbidopa/levodopa immediate-release (Sinemet), Carbidopa/levodopa oral disintegrating (Parcopa), Carbidopa/levodopa/Entacapone (Stalevo), CERE-110: Adeno-Associated Virus Delivery of NGF (Ceregene), cerebrolysin, CinnoVex, citalopram, citicoline, Clobazam, Clonazepam, Clopidogrel, clozapine (Clozaril), Coenzyme Q, Creatine, dabigatran, dalteparin, Dapsone, Davunetide, Deferiprone, Depakene®, Depakote ER®, Depakote®, Desmoteplase, Diastat, Diazepam, Digoxin, Dilantin®, Dimebon, dipyridamole, divalproex (Depakote), Donepezil (Aricept), EGb 761, Eldepryl, ELND002 (Elan Pharmaceuticals), Enalapril, enoxaparin, Entacapone (Comtan), epoetin alfa, Eptifibatide, Erythropoietin, Escitalopram, Eslicarbazepine acetate, Esmolol, Ethosuximide, Ethyl-EPA (Miraxion™), Exenatide, Extavia, Ezogabine, Felbamate, Felbatol®, Fingolimod (Gilenya), fluoxetine (Prozac), fondaparinux, Fragmin, Frisium, Gabapentin, Gabitril®, Galantamine, Glatiramer (Copaxone), haloperidol (Haldol), Heparin, human chorionic gonadotropin (hCG), Idebenone, Inovelon®, insulin, Interferon beta 1a, Interferon beta 1b, ioflupane 123I (DATSCAN®), IPX066 (Impax Laboratories Inc.), JNJ-26489112 (Johnson and Johnson), Keppra®, Klonopin, Lacosamide, L-Alpha glycerylphosphorylcholine, Lamictal®, Lamotrigine, Levetiracetam, liraglutide, Lisinopril, Lithium carbonate, Lopressor, Lorazepam, losartan, Lovenox, Lu AA24493, Luminal, LY450139 (Eli Lilly), Lyrica, Masitinib, Mecobalamin, Memantine, methylprednisolone, metoprolol tartrate, Minitran, Minocycline, mirtazapine, Mitoxantrone (Novantrone), Mysoline®, Natalizumab (Tysabri), Neurontin®, Niacinamide, Nitro-Bid, Nitro-Dur, nitroglycerin, Nitrolingual, Nitromist, Nitrostat, Nitro-Time, Norepinephrine (NOR), Carbamazepine, octreotide, Onfi®, Oxcarbazepine, Oxybutinin chloride, PF-04360365 (Pfizer), Phenobarbital, Phenytek®, Phenytoin, piclozotan, Pioglitazone, Plavix, Potiga, Pramipexole (Mirapex), pramlintide, Prednisone, Primidone, Prinivil, probenecid, Propranolol, PRX-00023 (EPIX Pharmaceuticals Inc.), PXT3003, Quinacrine, Ramelteon, Rasagiline (Azilect), Rebif, ReciGen, remacemide, Resveratrol, Retavase, reteplase, riluzole (Rilutek), Rivastigmine (Exelon), Ropinirole (Requip), Rotigotine (Neupro), Rufinamide, Sabril, safinamide (EMD Serono), Salagen, Sarafem, Selegiline (l-deprenyl, Eldepryl), SEN0014196 (Siena Biotech), sertraline (Zoloft),

Simvastatin, Sodium Nitroprussiate (NPS), sodium phenylbutyrate, Stanback Headache Powder, Tacrine (Cognex), Tamoxifen, tauroursodeoxycholic acid (TUDCA), Tegretol®, Tenecteplase, Tenormin, Tetrabenazine (Xenazine), THR-18 (Thrombotech Ltd.), Tiagabine, Tideglusib, tirofiban, tissue plasminogen activator (tPA), tizanidine (Zanaflex), TNKase, Tolcapone (Tasmar), Tolterodine, Topamax®, Topiramate, Trihexyphenidyl (formerly Artane), Trileptal®, ursodiol, Valproic Acid, valsartan, Varenicline (Pfizer), Vimpat, Vitamin E, Warfarin, Zarontin®, Zestril, Zonegran®, Zonisamide, Zydis selegiline HCL Oral disintegrating (Zelapar), and combinations thereof. 58. A compound identified by the method according to claim 39.

59. The compound of claim 58, wherein the desired scaffold comprises one of the following pharmacophores:

, , wherein R indicates a functional group.

60. A composition comprising the compound according to claim 58 or claim 59, individually or in combination, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

61. A detectable probe for measuring protein disulfide isomerase (PDI) abundance and target engagement in vitro and in vivo, comprising:

(a) a probe portion that targets a protein disulfide isomerase (PDI); and (b) a detectable label portion.

62. The detectable probe of claim 61, wherein the probe portion comprises one selected from the group consisting of LOC14, thiomuscimol, 16F16, securinine, and combinations thereof.

63. The detectable probe of claim 61, wherein the probe portion comprises LOC14.

64. The detectable probe of claim 61, wherein the detectable label portion comprises one selected from the group consisting of radiolabels, fluorescent labels, an enzyme, a hapten, a phosphorescent molecule, a chemiluminescent molecule, a chromophore, a luminescent molecule, a photoaffinity molecule, a color particle or a ligand.

65. The detectable probe of claim 61, wherein the detectable label portion comporises a radiolabel.

66. A method of patient selection, comprising:

(a) administering to a subject with a neurodegenerative disease a detectable probe according to claim 61;

(b) determining the distribution of the protein disulfide isomerase (PDI) in the subject;

(c) comparing the distribution determined in step (b) with a reference distribution determined in a healthy subject; and

(d) selecting the subject for appropriate treatment based on the comparison result obtained in step (c).

67. A method for measuring protein disulfide isomerase (PDI) target engagement of a compound in a subject, comprising:

(a) administering the compound to the subject;

(b) administering to the subject a detectable probe according to claim 61; and

(c) measuring the PDI target engagement of the compound.

68. A method for determining efficacy of a compound in treating a neurodegenerative disease in a subject, comprising:

(a) obtaining a biological sample from the subject;

(b) contacting the sample with a detectable probe according to claim 61; (c) determining the abundance of the PDI in the subject;

(d) administering the compound to the subject;

(e) after a certain period of time, repeating steps (a) to (c) to obtain an updated abundance of the PDI in the subject;

(f) if the abundance of the PDI determined in step (e) is significantly higher than the abundance of the PDI determined in step (c), the disease in the subject is progressing and the compound is not effective; and

(g) adjusting the treatment protocol for the subject diagnosed with progressing disease.

69. The method of any one of claims 66-68, wherein the neurodegenerative disease is Alzheimer’s disease or Huntington’s disease.

70. A method for diagnosing a disease in a subject in need thereof, comprising: (a) administering to the subject a detectable probe that targets a reactive oxygen species (ROS) regulator, which is associated with the disease; (b) determining the distribution of the ROS regulator in the subject; and (c) if the distribution determined in step (b) is significantly different from a reference distribution determined in a healthy subject, the subject is diagnosed with the disease.

71. The method of claim 70, wherein the ROS regulator is selected from the group consisting of glutathione peroxidases (GPX), glutathione (GSH), NF- E2-related factor 2 (Nrf2), superoxide dismutases (SOD), peroxiredoxins, catalases, glutaredoxins, thioredoxins, protein disulfide isomerases (PDI), and combinations thereof.

72. The method of claim 70, wherein the ROS regulator is a thiol-containing protein.

73. The method of claim 70, wherein the ROS regulator is a protein from the thioredoxin superfamily.

74. The method of claim 70, wherein the ROS regulator is a protein disulfide isomerase (PDI).

75. The method of claim 70, wherein the disease is a neurodegenerative disease. 76. The method of claim 75, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia, multiple sclerosis, Huntington’s disease, transmissible spongiform encephalopathy, Charcot- Marie-Tooth disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and hereditary spastic paraparesis.

77. The method of claim 75, wherein the neurodegenerative disease is Alzheimer’s disease.

78. The method of claim 75, wherein the neurodegenerative disease is Huntington’s disease.

79. The method of claim 70, wherein the subject is a mammal.

80. The method of claim 79, wherein the mammal is selected from the group consisting of humans, veterinary animals, and agricultural animals.

81. The method of claim 70, wherein the subject is a human.

82. The method of claim 70, wherein the detectable probe comprises a probe portion and a detectable label portion.

83. The method of claim 82, wherein the detectable label portion comprises one selected from the group consisting of radiolabels, fluorescent labels, an enzyme, a hapten, a phosphorescent molecule, a chemiluminescent molecule, a chromophore, a luminescent molecule, a photoaffinity molecule, a color particle or a ligand.

84. The method of claim 82, wherein the detectable probe is radiolabeled.

85. The method of claim 82, wherein the probe portion comprises one selected from the group consisting of LOC14, thiomuscimol, 16F16, securinine, and combinations thereof.

86. The method of claim 82, wherein the probe portion comprises LOC14.

87. The method of claim 70, wherein the determination in step (b) is carried out by positron emission tomography (PET).

88. A method for monitoring the progress of a disease in a subject in need thereof, comprising:

(a) obtaining a biological sample from the subject;

(b) contacting the sample with a detectable probe that targets a reactive oxygen species (ROS) regulator, which is associated with the disease; (c) determining the abundance of the ROS regulator in the subject;

(d) after a certain period of time, repeating steps (a) to (c) to obtain an updated abundance of the ROS regulator in the subject;

(e) if the abundance of the ROS regulator determined in step (d) is significantly higher than the abundance of the ROS regulator determined in step (c), the disease in the subject is progressing; and (f) initiating a treatment protocol for the subject diagnosed with a progressing disease.

89. The method of claim 88, wherein the ROS regulator is selected from the group consisting of glutathione peroxidases (GPX), glutathione (GSH), NF- E2-related factor 2 (Nrf2), superoxide dismutases (SOD), peroxiredoxins, catalases, glutaredoxins, thioredoxins, protein disulfide isomerases (PDI), and combinations thereof.

90. The method of claim 88, wherein the ROS regulator is a thiol-containing protein.

91. The method of claim 88, wherein the ROS regulator is a protein from the thioredoxin superfamily.

92. The method of claim 88, wherein the ROS regulator is a protein disulfide isomerase (PDI).

93. The method of claim 88, wherein the disease is a neurodegenerative disease. 94. The method of claim 93, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia, multiple sclerosis, Huntington’s disease, transmissible spongiform encephalopathy, Charcot- Marie-Tooth disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and hereditary spastic paraparesis.

95. The method of claim 93, wherein the neurodegenerative disease is Alzheimer’s disease.

96. The method of claim 93, wherein the neurodegenerative disease is Huntington’s disease.

97. The method of claim 88, wherein the subject is a mammal.

98. The method of claim 97, wherein the mammal is selected from the group consisting of humans, veterinary animals, and agricultural animals.

99. The method of claim 88, wherein the subject is a human.

100. The method of claim 88, wherein the detectable probe comprises a probe portion and a detectable label portion.

101. The method of claim 100, wherein the detectable label portion comprises one selected from the group consisting of radiolabels, fluorescent labels, an enzyme, a hapten, a phosphorescent molecule, a chemiluminescent molecule, a chromophore, a luminescent molecule, a photoaffinity molecule, a color particle or a ligand.

102. The method of claim 100, wherein the detectable probe is radiolabeled.

103. The method of claim 100, wherein the probe portion comprises one selected from the group consisting of LOC14, thiomuscimol, 16F16, securinine, and combinations thereof.

104. The method of claim 100, wherein the probe portion comprises LOC14.

105. A method for diagnosing Alzheimer’s disease in a subject in need thereof, comprising:

(a) administering to the subject a detectable probe that targets a protein disulfide isomerase (PDI), which is associated with Alzheimer’s disease;

(b) determining the distribution of the PDI in the subject by positron emission tomography (PET); and

(c) if the distribution determined in step (b) is significantly different from a reference distribution determined in a healthy subject, the subject is diagnosed with Alzheimer’s disease.

106. A method for monitoring the progress of Alzheimer’s disease in a subject in need thereof, comprising:

(a) obtaining a biological sample from the subject;

(b) contacting the sample with a detectable probe that targets a protein disulfide isomerase (PDI), which is associated with Alzheimer’s disease;

(c) determining the abundance of the PDI in the subject;

(d) after a certain period of time, repeating steps (a) to (c) to obtain an updated abundance of the PDI in the subject;

(e) if the abundance of the PDI determined in step (d) is significantly higher than the abundance of the PDI determined in step (c), Alzheimer’s disease in the subject is progressing; and

(f) initiating a treatment protocol for the subject diagnosed with progressing Alzheimer’s disease.

107. A method for diagnosing Huntington’s disease in a subject in need thereof, comprising:

(a) administering to the subject a detectable probe that targets a protein disulfide isomerase (PDI), which is associated with Huntington’s disease;

(b) determining the distribution of the PDI in the subject by positron emission tomography (PET); and

(c) if the distribution determined in step (b) is significantly different from a reference distribution determined in a healthy subject, the subject is diagnosed with Huntington’s disease.

108. A method for monitoring the progress of Huntington’s disease in a subject in need thereof, comprising:

(a) obtaining a biological sample from the subject;

(b) contacting the sample with a detectable probe that targets a protein disulfide isomerase (PDI), which is associated with Huntington’s disease;

(c) determining the abundance of the PDI in the subject;

(d) after a certain period of time, repeating steps (a) to (c) to obtain an updated abundance of the PDI in the subject;

(e) if the abundance of the PDI determined in step (d) is significantly higher than the abundance of the PDI determined in step (c), Huntington’s disease in the subject is progressing; and

(f) initiating a treatment protocol for the subject diagnosed with progressing Huntington’s disease.