Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
SUBSTITUTED STILBENES AS INHIBITORS OF NF-KB AND ACTIVATORS OF NRF2
Document Type and Number:
WIPO Patent Application WO/2019/108773
Kind Code:
A1
Abstract:
The present invention relates to substituted stilbenes and dienones which exhibit unexpected dual activity, as inhibitors of NFκB and as agonists (activators) of Nrf2. In particular, these compounds show dual activity and makes them particularly useful in the treatment of inflammation, including chronic inflammation arid a number of related chronic disease states and conditions, including neurological diseases, including Alzheimer's, Alzheimer's prodrome and mild cognitive impairment, and other diseases and conditions, such as Parkinson's disease, depression, bipolar disorders and autism spectrum disorders. Compounds, pharmaceutical compositions and methods of treatment are described.

Inventors:
VANDER JAGT DAVID (US)
DECK LORRAINE (US)
ROYER ROBERT (US)
Application Number:
PCT/US2018/063028
Publication Date:
June 06, 2019
Filing Date:
November 29, 2018
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
STC UNM (US)
International Classes:
A61K31/04; A61K31/03; A61K31/085; A61K31/12; A61K31/122; A61P1/00; A61P3/00; A61P13/12; A61P17/00; A61P19/00; A61P25/00; A61P35/00; A61P37/08; C07C25/24; C07C39/21; C07C39/373; C07C43/215; C07C43/225; C07C49/235; C07C49/248; C07C49/255; C07C49/753; C07C205/06; C07C205/35
Foreign References:
CN102688493A2012-09-26
EP2774915A12014-09-10
Other References:
DECK L. M. ET AL.: "Activation of anti-oxidant Nrf2 signaling by substituted trans stilbenes", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 25, no. 4, 6 January 2017 (2017-01-06), pages 1423 - 1430, XP029911257
Attorney, Agent or Firm:
COLEMAN, Henry, D. (US)
Download PDF:
Claims:
Oates

1. A method of a treating a subject afflicted with a disease or condition which is modulated throug irpregulaiion of F-kB signaling and inhibition of Nr£2 signalling, the method comprising administering to the subject a composition comprising a therapeutically effective amount of at least one compound which exhibits dual activity as a MF~KB signaling inhibitor and a Nrf2 signaling agonist, optionally in combination with at least one additional bioactive agent.

2 The method of date 1 , wherein the composition further compri ses a pharmaceutically acceptable carrier.

3. The method of claim 1 or 2, wherein the compound is according to the chemical structure:

a pharmaceutically acceptable salt thereof, ora mixture thereof.

4. The method according to claim 3 wherein said compoundCs) is

or a pharmaceutically acceptable salt thereof or a mixture thereof'

5 The method according to any of claims 1 -4 wherein said compound is

a pharmaceutically acceptable salt thereof or mixture thereof.

6 The method according to any of claims 1-5 wherein said compound is administered in combination with at least one additional bioactive agent.

7. The method according to any of claims 1~6 wherein said disease or condition is

Alzheimer’s; A.LS; autism; bipolar disorder; brain injury; chronic pain; chronic inflammatory demyelinating polyneuropathy (CIPD); diabetic neuropathy; epilepsy; fibromyalgia;

Huntington’s; inflammatory myopathy; meningitis; migraine; multiple sclerosis (MS);

Parkinson’s; stroke; chronic kidney disease; Crohn’s; diabetes melliius type 1 and type 2; rheumatoid arthritis, osteoarthritis, psoriatic arthritis, lupus, gout; ulcerative colitis; acne; eczema; psoriasis; tendinitis; atherosclerosis; obesity; cancer; allergies or depression.

8. The method according to any of claims 1-6 wherein said di sease state or condition i a skin disease.

9. The method according to claim 8 wherein said skin disease or condition i

Acrodermatitis, Cellulite, Cryotherapy, Cutaneous skin tags. Dermatitis herpetiformis. Dry skin. Ectodermal dysplasia. Epidermolysis bullosa. Erythema multiforme, Erythema

nodosum. Erythema toxicura, Granuloma annulare, Benoeh-Schonlem purpura, Hyperelastic skin. Ichthyosis vulgaris. Idiopathic or primary livedo reticularis. Intertrigo, Keratosis pilaris, Lamellar ichthyosis. Lichen planus, Lichen simplex chronicus, Miiia, Nikolsky's sign.

Perioral dermatitis. Pityriasis rosea. Pityriasis rubra pilaris, Polymorphic light eruption, Preaurkuhtr tag or pi t, Purpura Pyogenic granuloma. Sebaceous cyst. Seborrheic dermatitis. Seborrheic keratosis. Skin and hair changes during pregnancy. Skin blushing/flushing, Skin discoloration - bluish. Skin graft, Skin lesion biopsy. Skin lumps, Skin turgor, Stasis dermatitis and ulcers, Striae, Subcutaneous emphysema. Vesicles, Wood's lamp examination. Xanthoma, Xeroderma pigmentosa, Xerosis, Eczema, Impetigo, itching, Psoriasis, Rashes, Scleroderma, Skin Aging, Skin Cancer. Skin Infections or a Ski Pigmentation Disorder.

10. The method according to claim 7 wherein said d sease state or condition is cancer.

1 1. The method according to claim 10 wherein said cancer is carcinoma (e.g., squaraous- cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas), particularly those of the bladder, bone, bowel, breast, cervix, colon (colorectal), esophagus, head, kidney, liver, lung, nasopharyngeal, neck, thyroid, ovary, pancreas, prostate, and stomach; leukemias, such as acute myelogenous leukemia, acute lymphocytic leukemia, acute promyeiocytie leukemia (APL), acute T-cell lymphoblastic leukemia, adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytk leukemia, micromyelabkstic leukemia, monocytic leukemia, neutrophilic leukemia and. stem cell leukemia; benign and malignant lymphomas, particularly Burkin's lymphoma, Non-Hodgkin's lymphoma and B-cell lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, particularly Ewing's sarcoma

hemangiosarconia, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral

neuroepithelioma, and synovial sarcoma; tumors of the central nervous system (e,g., gliomas, astrocytomas. oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas); germ-line tumors (e.g., bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer (e.g., small cell lung cancer, mixed small cell and non-small cell cancer, pleural mesothelioma, including metastatic pleural mesothelioma small ceil lung cancer and non-small ceil lung cancer), ovarian cancer, testicular· cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed types of neoplasias, particularly carcinosarcoma and Hodgkin’s disease; and tumors of mixed origin, such as Wilms' tumor and teratocarcinomas, medulloblastoma and B-cell lymphoma.

12. The method according to claim 10 or 1 1 wherein said compound is co-administered with an additional anti-cancer agent.

13. The method according to claim 12 wherein said additional anti-cancer agent is evero!imus, trabectedin, abraxane. TLK 286, AY-299, EtN-!Oi , pazopamb, GSK690693. RTA 744, ON OAiO.Na, AZD 6244 (ARRY- 142886), AMN-107, TK1-258, GSK461364, AZD 1 152, enxastaurm, vandeta b, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhib tor, a P.IK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARE inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a P13 kinase inhibitors, an ART inhibitor, a JAK/STAT inhibitor, a checkpoint- 1 or 2 inhibi tor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a V.EGF trap antibody, pe etrexed, erioiinib, dasatanib, niiotinib, decatanih, panitumumab,

ammbicin, oregovoraab, Lep-etu, uolatrexed, a,id23?l, hatabulin, ofatumumab,

zanoiiniunutb, edoiecari , tetrandrine, rubitecan tesmilifene, ob!imersen, ticilinmmab, ipi!imumab, gossypol, Bio i II , 13! -I~TM-6(B , ALT-1 10, BIO 140, CC 8490, cilengitide, gimatecan, ILI 3-PE38QQR, INC) 1001 , IPdRi KRX-04O2, lueanihonfi, LY 317615, nenradiab, vitespan, Rta 744, Sdx 102, talampand, atrasentan, Xt 311 , ramidepsin, A.DS- 100380, simitmib, .5-fiuorouracii, vorinostat, etoposide, ge citabine, doxorubicin, irinotecan, liposomal doxorubicin, 5’-deoxy-S-fiuorouridine, vincristine, temozolooride, ZK-304709, seiiciciib; RD0325 01 , AZD-6244, capecitahine, L-Glutamic acid, M -{4 f 2-(2-amino-4,?- dihydro-4-oxo-l H - pyrrolo|2,3- d Spyrimidin-5-yl)elhyi benzoyl]~, disodium salt, heptahydrate, eamptothecin, FEG-lsbeled irmotecan, tamoxifen, toremifene citrate, anast zole, exemestane, leirozole, DESCdiethylsiilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, 1MC-ICI 1 , CHIR-258,); 3-[5~(melhy1sulfonylpiperadinemethyl)- indolyij-quinotone, vatalanib, A.G-013736, A.VE-0005, the acetate salt of [D- Ser(Bu t } 6 ,Azg!y i 0 \ (pyro-Glu-His-Trp-Ser-Tyr-D-SeiCBis t )-Leu-Arg-Pro- Axgly-NH 2 acetate IC^HMNJSOU -(CjlLOa v; where x ~ 1 to 2.4], gosere!in acetate, leuprolide acetate, triptoreiin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestroi acetate, raloxifene, bicalutamide, ftuiamide, miutamide, megestroi acetate, CP-724714; ΪAK-

165, HR 1-272, erlounib, lapatanib, canertinib, ABX-EGF antibody, erbitnx, EKB-569, RKΪ-

166, GW-S72016, lonafattub, B.MS-214662 tipifamih; amifostine, NVP-LAQ824, suberoyl aaalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SUl 1248, sorafenib,

KRN951 , aminogiutethimide, arnsacrine, anagreltde, L-asparagmase, Bacillus Calmette- Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, earhoplalin, e&rmustme,

chlorambucil, cisplatin, ciadribine, clodronate, cyproterone, cytarabme, dacarbazme, dact omycra, daunorubicia, dieiliylstilbestroL epirubicin fludarabine, fludrocortisone, fiuoxymesterone, tlulamide, gem tabine, gleevac (imitinib), hydroxyurea, idarubicin, ifosfamide, imatmib. !eupro!ide, ievamisole, lomnstine, mech!orethamine, melphalan, 6- metcaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, lutamide, octreotide, oxalipiatin, pamidronate, pentostatio, plicamycin porfimer, procarbazine, raltitrexed, ri ximab, streptozo n, teniposide, testosterone, thalidomide, tbiognanine, thiotepa, tretinoin, vindesine, i 3-cis-retinoic acid, phenylalanine mustard, uracil mnstard, estramustine, altreta ine, ftoxuridine, 5-deooxyuridine, cytosine arabinoside, 6- meeaptopurine, deoxyeoforrnycin, calciltioi, vslrubiein, nrithra ycin, vinblastine vinorelbine, topotecan, raxoxin, marimastat, COL-3, neovasiai, BM$-2'·5291 . squalamine, endostatin, SU541 , SIJ6668, EMD121974, mtefieukin-12, IM862, angiostaitn, vitaxin, droloxifeae, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, deniieulrin diilitox.gefitinib, bortezinrib, paclitaxel, trinotecan, topotecan, doxorubicin, docetaxel. vinorelbine, bevacmitnab (monoclonal antibody) and erbitux, cremophor-free paditaxel, epithiSone B, BMS- 247550, BMS-310705, droloxifene, 4~hydr0xytamoxii%n, pipendoxiibne, ERA- 923, arzoxifene, fulvesirani, aeolbifene, ksoibxifene, idoxifene, TSE-424, HMR- 3339, Z 186619, PT 787/ZK 222584, VX-745, FD 184352, rapaniyein, 40-0(2- hydroxyethyl)-rapamyein, temsiroliraus, AP-23573, RAD001 , ABT-578, BC-210,

LY294002, LY292223, LY292696, LY293684, LY293646, wortroarmm, ZM336372, L-

779,450, PEG-filgrastim darhepoetin, erythropoietin granulocyte colony-stimulating factor, zoleodronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor. histrelm, pegylated interferon alfa~2a, interferon alfa 2a, pegylated interferon alfa~2b, interferon alfa-2b, azaeitidine, PEG-L-asparaginase, lenaiidomide, gemtuzumah,

hydrocortisone, interleukin- 1 1 , dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard,

methylpredmsolone, ibritgumomab tiuxetan, androgens, decitabine, he x a me i hy hue 1 amt ne . bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal ckunorubiein, E wina-asparaginase, strontium 89, casopitant, netupltant, an NK-1 receptor antagonists, pa!onosetron, aprepitant, diphenhydramine, hydroxyzine,

nietoclopramide, lorazepam, alprazolam, haloperidoL droperidol, dronabinol, dexamethasone. methylpredmsolone, prochlorperazine, gntniseiron, ondansetron, dolasetron, tropisetron. pegfilgrastim, erythropoietin, epoetin alfa orarbepoetio alia, ipi!i umab. pembrelizumab, nivOlumab, alemtuzomab, breutoximab vedotin, blmatumomab, cetuximab or a mixture thereof.

14. The method according to any of claims 1-13 wherein said compound is

coadministered with resveratroL

15. A method of reducing tire likelihood of a disease or condition in a patient at risk wherein the disease or condition is modulated through upregitlaiion of NF-KB signal ng and inhibition of Nrf2 signalling, the method comprising administering to the patient at risk composi tion comprisin a therapeutically effective amoun t of at least one compound which exhibits dual activity as a MF-kB signaling inhibitor and a Nrf2 signalling agonist, optionally in combination with at least one additional bioactive agent.

16. The method of claim 15, wherein the composition further comprises a pharmaceutically acceptable carrier. 57

17. The method of claim 15 or 16, wherein di compound is according to the chemical structure:

a pharmaceutically acceptable salt thereof, ora mixture thereof.

18, The method according to any of claims 15-17 wherein said compoundfs) is according to the chemical structure:

or a pharmaceutically acceptable salt thereof or a mixture thereo f

1 The method according to any of claims i 5- 17 wherein said compound is

a phar aceutically acceptable salt thereof of mixture thereof.

20. The method according to any of claims 15-19 wherein said compound(s)

is a mixture of compounds.

21. The method according to any of claims 15-20 wherem said compound is administered in combination with at least one additional hioactive agent.

22. The method according to any of claims 15 - 1 wherem said disease or condition is Alzheimer's; Alzheimer's prodrome, ild cognitive impairment, A.LS; autism; bipolar disorder; brain injury; chronic pain; chronic inflammatory demy inating polyneuropathy (QPD); diabetic neuropathy; epilepsy; fibromyalgia; Huniragton’s; infl mmatory myopathy; meningitis; migraine; multiple sclerosis (MS); Parkinson's; stroke; chronic kidney disease; Crohn's; diabetes mellitus type 1 and type 2; rheumatoid arthritis, osteoarthritis, psoriatic arthritis, lupus, gout, ulcerative colitis; acne; eczema; psoriasis; tendinitis; atherosclerosis; obesity; cancer; allergies; depression.

23. The method according to any of claims 15 2 i wherein said disease state or condition is a skin disease.

24. The method according to claim 23 wherein said skin disease or condition is

Acrodermatitis, Cellulite, Cryotherapy, Cutaneous skin tags. Dermatitis herpetiformis. Dr skin, Ectodermal dysplasia. Epidermolysis bullosa. Erythema multi fomie. Erythema

nodosum. Erythema toxicu . Granuloma annulare, Heooch-Schonieio purpura, Hyperelastic skin. Ichthyosis vulgaris. Idiopathic or primary livedo reticularis. Intertrigo, Keratosis pilaris. Lamellar ichthyosis. Lichen planus. Lichen simplex chronicus, Milia, Nikolsky's sign.

Perioral dermatitis. Pityriasis rosea. Pityriasis rubra pilaris, Polymorphic light eruption, Preauricular tag or pit, Purpura Pyogenic granuloma, Sebaceous cyst, Seborrheic dermatitis, Seborrheic keratosis, Skin and hair changes during pregnancy, Skin blushing/flushing, Skin discoloration ~ bluish, Skin graft. Skin lesion biopsy. Skin lumps, Skin turgor, Stasis dermatitis an ulcers, Striae, Subcutaneous emphysema, Vesicles, Wood’s lamp examination. Xanthoma, Xeroderma pigmentosa, Xerosis, Eczema, Impetigo, Itching, Psoriasis, Rashes, Scleroderma, Skin Aging, Skin Cancer, Skin Infections or a Skin Pigmentation Disorder.

25. The method according to claim 22 wherein said disease state or condition is cancer.

26. The method according to claim 25 wherein said cancer is carcinoma (e.g., squamous- cell carcinomas, adenocarcino as, hepatocellular carcinomas, and renal cell carcinomas), particularly those of the bladder, bone, bowel, breast, cervix, colon (colorectal), esophagus, head, kidney, liver, lung, nasopharyngeal, neck thyroid ovary, pancreas, prostate, and stomach; leukemias, such as acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cdi lymphoblastic leukemia, adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytic leukemia, microraye!o Elastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia; benign and malignant lymphomas, particularly Burkitt’s lymphoma, Non-Hodgkin's lymphoma and B-cell lymphoma; benign arid malignant melanomas; myeloproliferative diseases; sarcomas, particularly Ewing's sarcoma, hemaiigiosarcoma, Kaposi’s sarcoma, liposareoma, myosarcomas, peripheral

neuroepithelioma, an synovial sarcoma; tumors of the central nervous system (e.g , gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,

ganglioneuromas., gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas); germ-line tumors (e.g., bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer (e.g., small cell lung cancer, mixed small cel! and non-small cell cancer, pleural mesothelioma, including metastatic pleural mesotheliom small cell lung cancer and non-small cell lung cancer), ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed types of

neoplasias, particularly carcinosarcoma and Hodgkin’s disease; and tumors of mixed origin, such as Wilms' tumor and teratocarcinoraas, medulloblastoma and B-cell lymphoma.

27. The method according to claim 25 or 26 wherein said compound is co-admin stered with an additional anti-cancer agent

28. The method according to claim 27 wherein said additional anti-cancer agent is everoiinius, traheetedm, ahraxane, TLK 286, AV-299, DN-101 , paxopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-!42886), AMN-107, TKI-258, GSK46J364, AZD 1 152, enzastauriu, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-i modulator, a Bel-2 inhibitor, an HDAC InhbHor, a c-MET inhibitor, aPAR? inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, a !GFR~TK inhibitor, an anii-HGF antibody, a PI kinase inhibitors, an LKT inhibitor, a JAK/STAY inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetre ed, erlotinib, dasatanib, rn!otinib, decatanib, panitumuu b, amrubic , oregovomsb, Lep-eiu, nolatrexed, azd217l, batabulm, ofatumtanab,

anolinrnmab, edotecarin, tetrandvine, rubitecaa. t smiiifene. oblirnet er». itcilimuraah, n.niimnmab, gossypo1, Bio 1 1 1 i 31 -i-TM ftOJ , ALT-1 0, BIO 1 -KF CC 849 . cilenghide, gimatecan, 1L13-PE38QQR, 1NO 1001 , lFdR{ KRX-0402, kcanthone, LY 317615, neuradiab, vilespan, Rta 744, Sdx 102, talarapanel, atrase an, Xr 3 ! ! , romidepsin, ADS- 100380, sunitinib, 5-0uoronraeil, vorinostat, etoposk!e, ge citabine, doxorubicin, irinotecan, liposomal doxorubicin, o’-deoxy-S-lluoroitridine, viucn sling, iemozo!omide, CK1-3Q4709, selieidib: PD0325901 , AZD-6244, capecltabirse, L-Gk-uuiuc acid, N ~|4~j 2-{2-amaio-4,7- dihydro-4~oxo- 1 H ~ pyrrolo 2,3~ d ]pyrir dm~5-yi}ethyi|benxoy!K disodm sail, heptahydrate, caraptothecin, PEG-iabeled irinotecan, tamoxifen, toremifene citrate, anasiraxole, exemestane, letrozo!e, DES(dieihylsti!hesiio!), estradiol estrogen, con ugated estrogen, fcevacizumab, IMCMCI I , CHiR 258,)» 3- S ( eihylsuifony1piperadinetnethyl)« indofylj-quinolone, vatalanib, AG-013736, AYE-0005, the acetate salt of [13- SeifBu t ) 6 ,Azgly 10 } {pyro-Glu-Mis-Trp-Ser-Tyr-D-SeriBu t )-Len-Arg Pro- Azgly-NH 2 acetate

[CssB^NigOu (CAL.Oslx where x ::: ! to 2 4], goserelin acetate, leeprolide acetate, iriptorefin pamoate, medroxyprogesterone acetate, hydros yprogesterone caproaie, megestrol acetate, raloxifene, bicalntamide, flutami e, nilutamide, megestrol acetate, CP-724714; TAK-

165, H I-272, erlotinib, lapaianib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKJ-

166, GW-572016, lonafamib, BMS-214662, iipifamib; amifostine, VP-LAQ824, suberoyl analide hydroxamic add, valproic acid, trichostatin A, FK~228, SOI 1248, somfenib,

KRN951 , aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmeite- Guerin (BCG) vaccine, bleomycin, bnserelin, busuffan, carbopiairn, camiusiioe,

chlorambucil, cisplatin, cladribine, ciodronate, eyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbesirol, epirubicin, iludarabine, fludrocortisone, fluoxymesterone, llutamide, gemcitabme, gieevac (imitinib), hydroxyurea, idaru icin, rfbsianiide, imatinib, leuprolide, levannsole, lomusdne, mechlorethamme, melphalan, 6- mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plica ycin, porfnner procarbazine, rairitrexed, rituximab, streptoxodn, teniposide, testosterone, thalidomide, thioguanine, thioiepa, tretinoin, vindesine, O-cis-rei oio acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridme, 5-deooxyttridine, cytosine arabinoside, 6- mecaptopurine, deoxycofbrtnycin, caldtriol, valrubicin, itbramyeia, vinblastine, vinorelbine, topotecan, razoxin, marhnastai, COL-3, neovastat BMS-27S291 , squa!amine, endosiatin, SU5436, SU6668, EMD121974, inter!eukin-12, 1M862, angiostatin, vitaxin, droloxifene, idoxyffene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin iftitox;,gefitinib, bortezimib, paclitaxei, ir oieean, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxei, epithilone B, BMS- 247550, BMS -310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA- 923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, BMR- 3339, ZK 186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2- hydmxyethyi)-rapamyci», ie sirolimus, AP-23573, RADOOl , ABT-578, BC-2I0,

LY 94002, LY292223, LY292696, LY293684, LY293646, wor mannk, ZM336372, L- 779,450, PEG -filgrastim, darbepoefin, erythropoietin, granulocyte colony-stimulating factor zolendronate, prednisone, eetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon aifa-2b, interferon alfa-2b, azacitklme, PEG-L aspamginase, !enahdornide, gemtuz.urnab,

hydrocortisone, interleukin-1 1 , dexrazoxane, alemtuzumab, all-iransreiinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard,

meihy!prednisotone, ibritgumomab tluxetan, androgens, deekabine, hexamethyhnelamine, bexarotene, tositumomab arsenic trioxide, cortisone, editronats, mitotaue, cyclosporine, liposomal daunorubicin, Edwlna-asparaginase, strontium 89, casopitant, netupitant, an NK-I receptor antagonists, palonosetron, aprepitani, diphenhydramine, hydroxyzine,

metoclopramide, toraxepam, alprazolam, haSoperidoI, droperidol, dronabinol, dexamethasone, raethylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfslgrastim, erythropoietin, epoetin alia, arbepoettn alia, ipiliraumab, pembrolizumab, nivoSumab, alemiuzumab, brentuximab vedotin, blinatumo ab, eetuximab or a mixture thereof.

29 The method according to any of claims 15-28, wherein the compoun is

coadministered with resveratrel.

30 A compound according to the chemical structure:

or a pharmaceutically acceptable salt thereof

31. A pharmaceutical composition comprising no effective amount ofa compound according to claim 30 in combination with a pharmaceutically acceptable carrier, additive and/or excipient.

32 A pharmaceutical composition comprising an effective amount of a compound according to the chemical structure:

a pharmaceutically acceptable salt thereof, or a mixture thereof in combination with a pharmaceutically acceptable carrier, additive and/or excipient.

33. The composition according to claim 1 or 32 further comprising an additional bioactive agent.

34. The composition according to claim 33 wherein said bioactive agent is an additional anti-cancer agent.

35 , The composition according to claim 34 wherein said additional anticaaeer agent is everoiimus, trabectedin, abraxane, TLK. 286, AV-299, DN-IOL pa opa b, GSK690693, RTA 744, ON OPi O.Na, AZD 6244 (ARRY-l 42886), AMN-I07, TKI-25S, GSK46I364, AZD 1 152, en¾astaurin, vandetanib, AR -197, MK-0457, M1.N8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an BGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an !iDAC inhbltor, a e-MET inhibitor, a PAR? inhibitor, a Cdk inhibitor, an BGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a P13 kinase inhibitors, an ART inhibitor, a JAK/STAT inhibitor, a checkpoint- 1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a V1GF trap antibody, petnetrexed, etiotmib, dasatanib, nikttkib, deeaianib, panitumumab, amrubiein, oregovomab, Lep~etu, nolatrexed, azd2171 , batabulin, ofatumumab.

za dimimiab, edotecarin, tetrandrke, rubhecan, tesmilifette, oblimersen, ticilinrumab, ipiiimumab, gossypo!, Bio 111 , 131-I-TM-dOl , ALT-1 19, BIO 140, CC 8490, etiengttide, gimaiecan, iL13 PE38QQR, INO 1001 , IPdRj KRX-0402, iucanthone, LY 317615, ueuradiab, vtiespan, Rta 744, Sdx 102, tai&mpane!, atrasentaa, Xr 31 1 , romidepsin, ADS- 100380, sunitinib, 5-iiuorouraeil, vormostat, etoposide, gemciiabine, doxorubicin, irinotecan, liposomal doxorubicin, 5*~deoxy-5 1nOTOuridke, vincristine, iemozoloniide, ZK-304709, sebciebb: FD0325901 , AZD-6244, capeebabine, L-Glutamk acid, ~B~|2~(2-aovtuo-4,7- dihydro~4~oxo~ 1 H - pyrrolo[2,3~ d 3pyri:nhdm~5-yi}ethy!JbenxoYi disod m salt, heptabydrate, caiaptolbecia, PEG-laheled irinolecan, tamoxifen, torennfene citrate, aru raxole, exemestaua, letrozo!e, DES{dieihy1stilbesirol), estradiol, estrogen, conjugated estrogen, hevacixumab, IMC-1C11 , CHlR-258,); 3 [5 ( eibyls«lfony1piperadin neiby1)~ indolyij -quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of |D- SerfBu t ) 6 ,AzgIy 10 } (pyro-Glu-His-Trp-Ser-Tyr-D-SeriBu t )-Len-Arg-Fro- Azgly-NB ¾ acetate CssEi^NjsOL -(€2.H4q2)c where x ::: 1 to 2.4], goserelk acetate, ietiprobde acetate, tripiorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalotaraide, ilntamide, mlutamide, megestrol acetate, CP-724714; TAK-

165, MKi-272, etiotmib, lapaianib, canertmih, ABX-EGF antibody, erbitux, EKB-569, PKI-

166, GW-572016, lonalamib, SMS-214662, tipifamib; amifostke, VP-LAQ824, suberoyi aaai de hydroxamic acid, valproic acid, trichostatk A, FK-228, SO! 1248, sorafenib,

KRN951 , aminoglnteihimkle, amsacrine, anagrelids, L-asparaginase Bacillus Calmette- Guerin (BCG) vaccine, bleomycin, bnserelin, busu!ian, carbop!atin, carmusdne,

chlorambucil, dsplatk, cladrib e, cfodronate, eyproterone, cytarabke, dacarbaxke, dactkomycm, datmorubick, dlethylstiibesiroi epirubtem, f!udarabme, fludrocortisone, fTuoxymesterone, flutamkle, gerucltabine, gieevac (imitinib), hydroxyurea, idarubicia, ifosfamide, imat ib, leuprolide, ievarnisole, lomustine, mecblorethamine, melpha!an, 6- raercaptopurine, mesna, methotrexate, mitomycin, mitotane, r itoxantrone, mlutamide, octreotide, oxaliplat , pstoMronate, peotostaiin, pbcamyeiu. poriimer. procarbazine, raltitrexed, tituximab, stTeptoxochi, teoiposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-ret oic acid, phenylalanine mustard, uracil mustard, estramustke, altretamioe, tloxuridine, 5-deooxynridine, cytosine arabmoside, 6- mecaptopnrine, deoxyeolbr ydn, caldiriol, valrubieux, m itlirarnye hi, vinblastine. vinorefbine, iopoieean, raxoxin, marimastat, COL-3, aeovaslat, BMS-27529! , squalamine, endostatin, SU5416, SU6668, EMD121 74, imerieukin- 2, JM862, aagiostaiin, vitaxin, droloxifene, idoxyfeue, spironolactone, finasteride, dmilidine, t iuzumab. denileukin di ffitox,gefitinib, bortezimib, paclitaxe!, irinotecan, topotecan, doxorubicin, docetaxel, vinoreibine, bevacizumab (monoclonal antibody) and erbitux, cremopbor-free paciitaxel, eplthiione B, BMS« 247550, BMS-310705, droioxifene, 4-hydroxytaraoxifen, pipendoxifene, ERA- 923. arzoxifene, fiiivestrant, acoibifene, lasofoxifene, idoxifene, TSE-424, HMR- 3339, ZK186619, FTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2- hydroxyethyl)-raparaycin, iemsiro!imus, AP-23573, RAD001 , ABT-578, BC-210,

LY294002, LY292223, LY292696, LY293684, LY293646, worimannin, ZM336372, L- 779,450, PEG-filgrastira, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, eetuximab, granulocyte macrophage colony-stimulating factor, hisfrelin, pegylated mterferon alfa-2a, interferon alfa~2a, pegylated interferon alia- 2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, leoalidomide, gemiuzumab,

hydrocortisone, interleukin- 1 1 , dextazoxane, afemhmanab, alMransrel ok acid, ketoconazole, interleukin-2, megestroi, immune globulin, nitrogen mustard,

methylprednisolone, ibritgumomab tiuxetan, androgens decitabine, bexametbylmelaraine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daimombicin, Edwina-asparaginase, strontium 89, casopitani, netupitant, an NK-I receptor antagonists, palonosetron, aprepitant diphenhydramine, hydroxyzine,

metoclopramide, lorazepam, alprazolam, ha!operidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, graivisetron, ondansetron, dolasetron, tropisetroo, pegfilgrasti , erythropoietin, epoetin alia, arbepoetm aifa, ipilimumab, pembrolizumab, mvohraiab, alemtuzumab, brenluximab vedotin, blinatu omab. cetuximab or a mixture thereof.

Description:
Substituted Stiibeiies as Inhibitors of 1NF-KB and Activators of Nrf2

Related Applications

This application claims the benefit of priority of pro visional application serial nu ber US62/591 ,912, of identical title, filed 29 November 2017, the entire contents of which is incorporated by reference herein.

Field of the Invention

The present Invention relates to substituted siiibenes and dtenones which exhibit unexpecte acti vity, as inhibitors of proirifTaromatoty NFKB signaling and as agonists (activators) of anti-oxidani Nrf2 signaling. In particular, these compounds show dual anti- inflammatory acti vity and anti-oxidant activity, which makes them particularly useful in the treatment of inflammation and its associated oxidative stress, including chronic inflammation and a number of related chronic disease states and conditions, including neurological diseases, including Alzheimer’s, Alzheimer’$ prodrome and mild cognitive impairment, and other diseases and conditions, such as Parkinson’s disease, depression, bipolar disorders and autism spectrum disorders . Compounds, pharmaceutical composition and methods of treatment are described.

Background and Overview of the Invention

The nuclear factor KB (NF-KBa) family of transcription factors in mammals consists of homo- and heterodimerie combination of five related proteins (p50, p52, p65/RelA, c-Rel, and RelB) that have a marked influence on the expression of numerous genes involved in immunity and inflammation, as well as cellular stress responses, growth, and apoptosis. Diverse pathways activate NF-kB, and control of these pa hways is increasingly viewed as an approach to chemotherapy in the many diseases: that have an associated inflammatory component, including cancer, stroke, Alzheimer's disease, and diabetes. Activation of NF~KB occurs through multiple pathways. The classical pathway is triggered by binding of proinflammatory cytokines (TNFa and IL-1 ) and of a number of pathogens to several different receptors in the TNF-receptor and Toli-Iike/IL-l receptor siiperfaniilies. This leads to recruitment to the plasma membrane and activation of the IkB-kinas complex (IKK) consisting of ΪKKa and 1K |3 kinases, and the scaffold protein NEMO/ ΪKKg, as well as a number of IKK-assoeiated proteins. The main NF-ieB that is activated in the classical pathway is the p50/p65 heterodimer that exists in the cytoplasm as a complex with inhibitory' protein IkBa. Activation of IKK primarily through IKKb resuits in phosphorylation of IkBa on Ser32 and Ser36, followed by polyubiquitination and degradation of IkBa by the 26S proteasome, allowing p50/ p65 to translocate to the nucleus.

Release of p5G/p65 from ΐ Ba also can be achieved by IKK-independent pathways triggered by DNA damage or oxidative stress that result in phosphorylation oPkBa on Ser residues other than Ser32 or Ser36, again leading to proteosomal degradation of IkBa This signaling pathway involves a number of kinases including the MAP kinase p38 and casein kinase 2, There is also an oxidative stress pathway that phosphorylates J Ba on Tyr residues, leading to release of p50/p65 without proteosomal degradation of ϊkBa. Superimposed on the complex activation of p50/p65 is additional downstream regulation of the DNA-bindmg properties of p50/p65 through phosphorylation, acetylation, and peptidyl -prolyl

isomerization. Mostly this occurs in p65 and provides multiple points tor control ofNF-kB activation in a celt-specific and environment-specific manner. A wide range of kinases can phosphorylate p50/p65 which appears essentia! for the transactivation potential of p50/p65. This includes phosphorylation at many different sites, especially in p65, which adds to the complex regulation of NF-KB.

Transcription factor nuclear factor erythroid 2 related factor 2 (Nrf2), which is a member of the eap’n’eollar family of transcription factors, is the master regulator of art inducible cellular system of cytoprotective genes. These genes code for a broad range of proteins, including phase land 11 detoxification enzymes, anti-oxidant proteins, as well as anti-inflammator and neuroprotective factors, growt factors and receptors, and other transcription factors. Interest has emerged in Nr£2 as a therapeutic target, especially for treatment of chronic inflammatory diseases and the associated oxidative stress. '6 In the absence of stress, Nrf2 forms a cytosolic complex with Keich-like ECU associated protein I (Keapl) and Cul3; Cul3 is an adaptor to link Nrf2 to an E3 ubiquitin ligase complex. Newly synthesized NrI2 to unstressed cells is degraded by ubiquitinalion and proteosomal degradation, which limits the cytosolic concentration of Nr!2. In response to oxidative and electrophilic stresses, cysteine residues of Keapl are modified, which alters the interaction between Nrf2 and Kea l and locks Keapl in the Nr£2 complex. This allows newly synthesized Nr£2 to accumulate and translocate to the nucleus where Nrf2 interacts with small Maf proteins and then hinds to promoters with anti-oxidant response element (ARB) sequences. !

Numerous r£2 -activating chemicals have been identified, including some natural product phenols, such as the enone curcumin and the bans stilbene resveratrol, that can acti vate Nrl2 after oxidation to electrophile quinones, which can modify select cysteine residues in Keapl by Michael addition. Keapl cysteine residues 273, 288 and 151 appear to be especially important, Peptide inhibitors of the Keapl -Nr£2 protein-protein interaction have been developed as well as a variety of small molecules that inhibit the Keapl -Nr£2 interaction. These studies have been aided by the availability of several crystal structures ofNrfS 20 -”

Natural product phenols such as curcumin and resveratrol exhibits numerous biological activities including ability to induce the expression of Nrl2-dependent phase II and anti-oxidant enzymes such as glutathione S-transferase, aldose reductase and heme

oxygenase- 1. i > Curcumin appeals to utilize more than a single mechanism for activation of

Nrfit, including covalent modification of Keap ΐ 5 L> and activation of upstream kinases/ 5 ^ Curcumin has bee examined in a number of clinical studies with limite success, ^ mainly owing to limited bioayailability and rapid metabolism. Atempts to improve curcumin as a therapeutic agent include development of new formulations that may enhance bioavailabi!ily.

There is considerable interest in the development of analogues and derivati ves of natural product phenols with improved therapeutic potent ial/ ^ There also is interest in the development of analogues that activate anti-oxidant Nri2 but simultaneously inhibit pro-

inflammatory NF-kB signaling, which is consistent with the ability of curcumin and resveratrol to target bo th of these pathways *’ 31 In the present application is a description and evaluation of the Nr 12 -activating potential and NF-KB inhibiting potential of brans stilbene analogues of resveratrol as well as dieaone analogues of curcumin. NF-kB is a major pro-inilammatory transcription factor. Nrf2 is a major anti-oxidant transcription factor, which also controls anii-inilanimaiory and neuroproiecti ve genes. The importance of inflammation and oxidative stress in many chronic diseases supports the concept that simultaneous inhibition of NF-JCB signaling and activation of anti-oxidant Nrf2 signaling may have therapeutic potential. A number of Nrf2 activators have entered into clinical trials. One concern with the design of Nrf2 activators that are electrophilic covalent modifiers of Keapl is the issue of selectivity. In the present report, substituted trims sii!benes were identified as activators of Nrf2 These activators of Nri2 are not highly electrophilic and therefore are unlikely to activate Nrf2 through covalent modification of Keapl . Dose- response studies demonstrated that a range of substituents on either ring of the tram stilbenes, especially fluorine and methoxy substituents, influenced not only the sensitivity to activation, reflected in E€ values but also the extent of activation, which suggests that multiple mechanisms are involved in the activation ofNrfi. The stilbene backbone appears to be a privileged scaffold for development of a new class of rf2 activators. In addition, many of these trans stilbenes analogues of resveratrol are also inhibitors of the activation of NFKB, Moreover, a number of dienone analogues of cutcurain are described that also exhibit this dual activity

Summary of the Invention

Inasmuch as inflammation and oxidative stress are often inseparable in a large number of disease states, compounds which affec t both of these physiological manifestations simultaneously represent particularly effective compounds for use in treating an disease state or condition which would benefit from the simultaneous inhibition of the NF-kB pathway and activation of the Nr£2 pathway. Accordingly, compounds according to the present invention may function as particularly effective therapy in disease states and/or conditions where the NFKB pathway is upregu!aied and/or stimulated and the Nri2 pathway is down regulated or inhibited. hi one embodiment, the present invention is directed to a compound according to the chemical structure which appears below. All of these compounds exhibit dual activity as inhibitors (down regulators) of tire NF-kB pathway and agonists (up-regulators) of the Nr £2

a pharmaceutically acceptable salt thereof.

Preferred compounds according to the present in vention include die following compounds:

or a pharmaceutically acceptable sail thereof.

in alternative embodiments, preferred compounds include the following compounds:

a pharmaceutically acceptable salt thereof. in another embodiment, the present invention relates to pharmaceutical compositions comprising an effective amount of at least one compound according to the chemical structure set forth above in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with an additional bioactive agent. In certain embodiments, pharmaceutical compositions comprise at leasttwo of the above-described compounds. in additional embodiments, the present invention is directed to pharmaceutical compositions comprising an effective amount of at least one compound according to the chemical structure;

or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with an additional bioactive agent i certain embodiments, pharmaceutical compositions comprise at least two of the above-described compounds in a single composition, optionally in combination with an additional bioactive agent.

In additional embodiments, the present invention is directed to pharmaceutical compositions comprising an effective amount of at least one compound according to the chemical structure:

a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with an additional bioaetive agent. In certain embodiments, pharmaceutical compositions comprise at least two of the above- described compounds in a single composition. i still another embodiment, the present invention is directed to a method lor treating or reducing the likelihoo of a disease state or condition which is modulated through NF-rB (b up regulation) and Nri2 (by down regulation) such that compounds which inhibit NF-KB signaling and increase Nrl2 signaling find particularuse m the treat ent of these disease states and/or conditions. These disease states and/or conditions include for example,

Alzheimer’s; ALS; autism; bipolar disorder; brain injiiry; chronic pain; chronic inflammatory demyelinating polyneuropathy (CIPD); diabetic neuropathy; epilepsy; fibromyalgia;

Huntington’s; inflammatory myopathy; meningitis; migraine; multiple sclerosis (MS);

Parkinson’s; spoke; chronic kidney disease; Crohn's disease; diabetes mellitas type 1. and type 2; rheumatoid arthritis, osteoarthritis, psoriatic arthritis, lupus, gout, ulcerative colitis; acne; eczema; psoriasis; tendinitis; atherosclerosis; obesity; cancer; allergies; depression, among others, including skin diseases or conditions as described herein in a particular embodiment of the present invention, an effective amount of at least one compound set forth above, optionally in combination with an additiona bioaciive agent is administered to a patient in need to treat one or more of these disease states . In additional embodiments, one or more compounds or compositions disclosed herein may be used in inhibit the NF-kB pathway and enhancing (up-regulate) the Nrf2 signaling pathway to provide particularly effective therapy.

It should be understood that the method of the in vention is generally useful for treating any disease state or condition that can be ameliorated by both inhibiting (do n- reguiatiog) the NF-kB pathway and enhancing (up-regulating) the Nr£2 signaling pathway to provide particularly effective therapy.

Brief Descrip tion of the Figures

Figure 1 shows scheme 1, which is directed to the chemical synthesis of compounds according to the present invention. In scheme I, a substituted phosphonate ester is reacte with a substituted aldehyde under reaction conditions a to produce the substituted stiibene compound. The reaction conditions employed are: (a ) R } substituted phosphonate ester (1 5 equiv), NaH (2 equiv), dry THF, OX', 30 min, R ;> substituted aldehyde (1.0 equiv), 0"C to rt, 20 h, then H20/HC1; see Figure 2, Table 1.

Figure 2 shows a number o f the compounds according to the present invention and references for their synthesis.

Figures 3-S show a number of compounds according to the present invention and their Nir2 activation activity.

Figure 6 shows a number of compounds according to the present invention and their NF-kB inhibition activity.

Detailed Description of the In vention

Unless otherwise specified, "a," "an," "the," and "at least one" are used

interchangeably and mean one or more than one, depending on the context of use. The following terras shall be used to describe the present invention in instances where a term is not defined herein, such: teen is given its common meaning by those of ordinary skill in the art.

The term“patient” or“subject” refers to a mammal, preferably a human, including a domesticated mammal (including a dog, cat, sheep, horse, cow. pig, goat or other domesticated mammal in need of treatment or therapy to which compounds according to the present invention are administered in order to treat a condition or disease state otherwise described herein.

The terra“compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes within context, tautomers, regioisomers, geometric isomers, and where applicable, optical isomers thereof where applicable, as well as pharmaceutically acceptable salts, solvates and polymorphs thereof. Within its use in context, the ter compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and'or optica! isomers (including in some instances, racemic mixtures) as well as specific enantiomers or enamiomerical!y enriched mixtures of disclosed compounds. The compounds of this invention include all pharmaceutically acceptable salt forms, solvates, polymorphs and prodrug forms of the present compounds, where applicable. The present invention relates to both the cis- and traos-stilbene structures, preferably, trans structures as generally presented herein and their methods of use.

The term“modulate” means, with respect to disease states or conditions, modulated through (e.g, by binding) or having an effect on KP-tcB and/or r£2 signaling pathways to produce, either directly or indirectly, an improvement or lessening of a condition or disease state which was, prior to administration of a compound according to the present invention, sub-optimal and in many eases, debilitating and even life threatening. Modulation occurs by virtue of antagonist/inhibitor activity for NF-kB and agonist activity for NrO signalling pathway activity. In most/many instances, the term modulate shall mean direct or indirect inhibition or enhancement/up-regidation of F-KB/ rf2 signalling pathways alone or within the context of treating a disease or condition associated with same. The term“independently” is used herein to indicate that the variable, which is independently applied, varies independently from application to application.

The term“disease or condition” is used to describe disease states or conditions which are modulated through NF-kB signaling pathways (via up regulation) and Nrf2 signaling pathways (via down regulation) such that compounds which both inhibit NF K8 signaling and increase Nrf2 signaling may be used to treat these disease states and/or conditions. T hese disease states and/or conditions include for example, Alzheimer’s; ALS; autism; bipolar disorder; brain injury; chronic pain; chronic inflammatory demye!inatmg polyneuropathy (CIPD); diabetic neuropathy; epilepsy; fibromyalgia; Huntington’ s; inflammatory myopathy; meningitis; migraine; multiple sclerosis (MS); Parkinson’s; stroke; chronic kidney disease; Crohn's; diabetes meiiitus type 1 and type 2; rheumatoid arthritis, osteoarthritis, psoriatic arthritis, lupus, gout, ulcerative colitis; acne; eczema; psoriasis; tendinitis; atherosclerosis; obesity; cancer; allergies; depression, among others.

The term“coadmimstration” or“combination therapy” is used to describe a therapy in which at least two active compounds in effective amounts are used to treat cancer or another disease state or condition as otherwise described herein at the same time. Although the term coadmimstration preferably includes the administration of two active compounds to the patient at the same time, it is not necessary' that the compounds be administered to the patient at the same time, although effective amounts of the individual compounds will be present in the patient at the same time to effect a» intended result in cancer aspects of the invention, one or more compounds according to the present invention may be administere with one or more anti-cancer agents, including antimetaboli es, alkylating agents, topolsomerase I an topoisomerase 11 inhibitors as well as microtubule inhibitors, among others. Anticancer compounds for use in the present invention include those described herein below, and mixtures thereof, among others. Preferred anticancer agents for use in the present invention in coadministration with one or more of the compounds disclosed herein include for example, fluorouraeiS, iniiquimod, vismodegib, aldesleukin daearbazine. ipilitmmiab, vemurafenib or mixtures thereof

Coadministration of one of the present compounds with another antieancer agent as otherwise described herein will often result in a synergistic enhancement of the anticancer activity of the other anticancer agent, an unexpected result. One or more of the present compounds may also be coadministered with another bioactive agent which treat the diseases or conditions as otherwise described herein), depending upon the desired therapeutic outcome and the disease state or condition treated.

“Treat",“treating", an “treatment”, etc,, as used herein, refer to any action providing a benefit to a patient at risk for or afflicted with a disease, including improvement in the condition through lessening or suppression of at least one symptom, delay in progression of the disease, prevention, inhibition or delay in the onset or progression of the disease, etc.

Treatment, as used herein, encompasses both prophylactic (reducing the likelihood of the occurrence of the disease) and therapeutic treatment, dependi ng on the context of use. Compounds according to the invention cart, for example, be administered prophylactic-ally to a mammal in advance of the occurrence of disease. Prophylactic administration is effective to decrease the likelihood of the subsequent occurrence of disease in the mammal or decrease the severity of disease that has not yet occurred but that subsequently occurs. Alternatively, compounds according to the invention can, for example, h administered therapeutically to a mammal that is already afflicted by disease. In one embodiment of therapeutic

administration, administration of the compounds according to the invention is effective to eliminate the disease; in another embodiment, administration of the compounds of the present invention is effective to inhibit the disease state or condition treated, including decrease the severity of the disease or lengthen the lifespan of the mammal so afflicted.

“Pharmaceutically acceptable" as used herein means that the compound or

composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment

‘Inhibit" as used herein refers io the partial or complete elimination of a potential effect, while inhibitors are compounds that have the ability to inhibit.

The present invention includes the compositions comprising the pharmaceutically acceptable salt i.e., the acid or base addition salts of compounds of the present invention and their derivatives, where applicable. The acids which may be used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds useful in ibis invention are those which farm non-toxic acid addition salts, Le , salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisuliate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleaie, fumarate, gluconate, saecharate, benzoate,

methanesulibnate, ethanesu!fonate, benxenesulfonate, p-toiuenesnifo«aie and pamoate [i.e., i,r-methyiene-bi$-(2-hydroxy-3 naphthoate)|salt$, among others.

Pharmaceutically acceptable base addition salts ma also be used to produce

pharmaceutically acceptable salt forms of the compounds according to the present invention. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (eg., potassium and sodium) and alkaline earth metal cations (e, calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meghimme), and the lower alkanoiamnioniuin and other base salts of pharmaceutically aceeptable organic amines, among others.

The term '‘cancer” shall refer to a proliferation of tumor cells having the unique trait of loss of normal controls, resulting in unregulated growth, lack of differentiation, local tissue invasion, and/or metastasis. As used herein, neoplasms include, without limitation,

morphological irregularities in cells in tissue of a subject or host, as well as pathologic proliferation of cells in tissue of a subject, as compared with normal proliferation in the same type of tissue. Additionally, neoplasms include benign tumors and malignant tumors (e.g., colon tumors) that are either invasive or «©«invasive. Malignant neoplasms are distinguished from benign neoplasms in that the former show a greater degree of anaplasia, or loss of differentiation and orientation of cells, and have the properties of invasion and metastasis.

The term cancer also within context, includes drag resistant cancers, including multiple drug resistant cancers. Examples of neoplasms or neoplasias from which the target cell of the present invention may be derived include, without limitation, carcinomas (e.g., squamous-cell carcinomas, adenocarcinomas, hepatocellular carcinomas, and renal cell carcinomas), particularly those of the bladder, bone, bowel, breast , cervix, col on (colorectal), esoph agus, head, kidney, liver, lung, nasopharyngeal, neck, thyroid, ovary, pancreas, prostate, and stomach; leukemias, siseh as acute myelogenous leukemia, acute lymphocytic- leukemia, acute promyelooylic leukemia (APL), acute T-cell lymphoblastic leukemia, adult T-eell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytic leukemia, micromyeioblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia; benign and malignant lymphomas, particularly Burkiit's lymphoma, Non-Hodgkin’s lymphoma and B-celi lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, particularly Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral

neuroepithelioma, and synovial sarcoma; tumors of the central nervous system (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastoraas, neuroblastomas, ganglioneuromas, ganglioglioraas, medulloblastomas, pineal cel! tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas); germ-line tumors (e.g., bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer (e.g., small ceil lung cancer, mixed small cell and non-small cell cancer, pleural mesothelioma, including metastatic pleural mesothelioma small cell lung cancer and non-small cell lung cancer), ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, and melanoma); mixed types of neoplasias, particularly carcinosarcoma and Hodgkin’s disease; and tumors of mixed origin, such as Wilms * tumor and teratoearehiom s, among others.

The terra“additional anti-cancer agent’ * is used to describe an additional compound which may be coadministered with one or more compounds of the present invention in the treatment of cancer. Such agents include, for example, antirnetabolrtes, alkylating agents, topoisomerase I an topoisomerase II inhibitors as well as microtubule inhibitors, among others. Specific anti-cancer agents for use in the present invention include, for example, evero!imus, trabectedin, abraxane, TI.JC 286, AV-299, DN-101 , pa panib, GSK690693, RTA 744, ON 09I0,Na, AZB 6244 CARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1 152, emtastaurin, vandetaaib, ARQ-197, MK-0457, MLN8054, PHA-7393S8, R-763, LT-9263. a FLT-3 inhibitor, a VEGFR inhibitor, an ECiFR TK inhibitor, an aurora kinase inhibitor a P1 -1 modulator, a Bel-2 inhibitor, an FIDAC inhibitor, a c- ET inhibitor, a PAJRP inhibitor, a Cdk inhibitor, an EGFR TK. inhibitor, an KIFR-TK inhibitor, an ami-HGF antibody, & PI3 kinase inhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint-·! or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemeirexed, erlotinib, dasatanib, nilotinib, decatanib, paniiumuraab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd217! : batabuiin, oi tu umah,

zanol mnmab, edotecarin, tetmndrine, rubitecan, tesmilifene, obiimetsen, ticilmiumab, ipilimumab, gossypol, Bio 1 11 , 13! -l-TM-601 , ALT-! !0, BIO 140, CC 8490, citengi ide, gimatecaa IL13-PE38QQR * INO 1001 , IPdRj KRX-0402, lucanthone, LY 3 ! 7615, nearadiab, vitespan, Rta 744, Sdx 102, ialampanei, atrasentan, Xr 31 1 , romidepsln, ADS 100380, sunitinib, 5-fluorouraeil, vorinostat, eioposide, gemcitabine, doxorubicin, irinoiecsn, liposomal doxorubicin, S’-deoxv-S-fTuorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD032590I , AZD-6244, ca eckabme, L-Glutamk add, N ~[4~[2-{2-amino * 4,7- dihydro-4-oxo-! H - pyrrolo 2,3~ d JpyTimidin 5-yl)eihy13beuzoylK disodium salt, heptahydrate, eamptothecin, PBG-labeled Ir oteean, tamoxifen, toremifene citrate, aaastraxole, exemestane, letrozole, DESfdkthy!stilbestrol), estradiol, estrogen, conjugated estrogen * hevacizumab, 1MCMCS.1 , CHIR-258,}; 3-f methylsulfonylpipemdine eihyl)- indoiylj-quinolone, vata!anib, AG-013736, AVB-0005, the acetate salt of [D- SerfBe t ) 6 ,A gIy 10 ] (pyro-Glu His-Ttp-Ser Tyr-D Ser(Bu t )-Leu- Arg-Pro- Azgly-NB acetate

[CsdbuNigOu (CJ¾OJ)X where x ::: 1 to 2,4], goserelin acetate, leuptolide acetate, iriptoreUu pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestro! acetate, raloxifene, bicalutamide, fiutami e, nilutamide, megestro! acetate, CP-724714; TA -

165, HKI-272, er!otinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-

166, GW~5720bS, fenafaniib, BMS-214662, lipllarnib; amiibstine, NVP-LAQ824, suberoyl analide bydroxaraic acid, valproic acid, trichostatin A, FK-228, SOI 1248, sorafenib,

KRN951 , aminoglntethimide, arasaerme, anagrelide, L-asparagina$e, Bacillus Calmette- Guerin (BCG) vaccine, bleomycin, bnserelin, husuifan, carfeopfatin, carmustine,

chlorambucil, cisplatin, adribine, ciodronate, cyprote ne, cytarabine, dacarbaxine, dactinomydn, daunorubicin, diethy!stilbestrol, epirubicin, l!udarabine, fludrocortisone, iluoxymesternne, fiutamide, gemcitabine, gieevac (imitinib), hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, ievumisole, !omustine mechloretham e * melpba!sn, 6- mercaptopurine, esna, methotrexate, mitomycin, mitotane, iioxamrone, nilutamide, octreotide, oxa!iplatm, patnidronaie, pentostatin, plica ycin, porfrmer, procarbazine, raltitrexed, ritusriraab, sireptozoem, teniposide, testosterone, thalidomide, thiognaoine, ihioiepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabkoside, 6

mecaptopunne, deoxyeoformyein, caicitrioi, vaimbicin, mithramycin, vinblastine, vinorelbme, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291 , sqnafat ine. endostal , SIJ54I6, Bϋ6668, EMDI2I9 /4, iaiex eukm-12, IM862, angiostaim, vitaxin foloxifene, idoxyfene, spironolactone, finasteride, eimiiidios, traxtuzumab denileukin diltitox, gefMnib, bortezimib, paclitaxel irinotecan, topoiecan doxorubicin, docetaxeL vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithilone B, BMS- 247550, BMS-310705, droioxifene, 4-hydroxytamoxifea, pipendoxifene, ERA 923, arzoxifene, fulvestrant, acoSb fene, lasofoxifene, idoxifene, TSE * 424, HMR

3339, ZK186619, FTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-CH2- hydn>xyethyl)-rapamycin, iemsirolinius, AP-23573, RAD001 , ABT-578, BC * 210,

LY294992, LY292223, LY292696, LY293684, LY293646, wortmaanm, ZM336372, L- 779,450, PEG -filgrastim, darbepcietin, erythropoietin, granulocyte colony-stimulating factor zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon aifa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidme, PEG-L-asparaginase, lena!idomide, gemtuzumab,

hydrocortisone, interleukin- 1 I , dexrazoxane, a!emtozumab, all-transreiinoic acid,

ketoconazole, interleukin-2, raegestrol immune globulin, nitrogen mustard,

melhylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, bexamethyhnek ine, bexarotene, tositumoroab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal dannorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine,

metoclopramide, torazepam, alprazolam, ha!operidol, droperido!, dronabinol, dexa eihasone, methylpred solone, prochlorperazine, granisetron, ondansetron, dolasetroa, tropisetroa, pegfilgrastim, erythropoietin, epoetin alia and darbepoelin alia, among others, including for example immunotherapies, such as ipilimumab, pembro!izumab, nivolumab, aienmtzumab, brentuximab vedotin, blinatumomab and eetuximab, among others.

Because of the dual activity exhibite by compounds according to the present invention, these compounds ma be used to treat numerous disease states or conditions in patients or subjects who suffer from those conditions or disease states or are at risk for those conditions in this method at least one compound, alone or in further combination with at least one additional bioactive agent i an effective amount is administered to a patient in need of therapy to treat or reduce the likelihood of the occurrence of the condition·; -n ot disease state(s). The compounds and methods of the invention are useful for treating or reducing the likelihood of arty the following diseases: These disease states and/or conditions include for example, Alzheimer’s; ALS; autism; bipolar disorder; brain injury; chronic pain; chronic inflammatory demyelinating polyneuropathy (CIPD); diabetic neuropathy; epilepsy;

fibromyalgia; Huntmgtojrfls; inflammatory myopathy; meningitis; migraine; multiple sclerosis (MS); Parkinson’s; stroke; chronic kidney disease; Crohn’s; diabetes mellitus type 1 and type 2; rheumatoid arthritis; osteoarthritis; psoriatic arthritis; lupus; gout; ulcerative colitis; acne; eczema; psoriasis; tendinitis; atherosclerosis; obesity; cancer; allergies; depression, among others. Compounds also are useful in treating skin diseases and/or conditions including, for example. Acrodermatitis, Cellulite, Cryotherapy, Cutaneous skin tags. Dermatitis

herpetiformis. Dry skin, Ectodermal dysplasia, Epidermolysis bullosa. Erythema multiforme, Erythema nodosum. Erythema toxicum, Granuloma annulare, Henoeh-Sehoulein purpura, Hyperelastic skin, Ichthyosis vulgaris. Idiopathic or primary livedo reticularis, Intertrigo, Keratosis pilaris. Lamellar ichthyosis, Lichen planus, Lichen simplex chronictts, Milky Nikolsky's sign. Perioral dermatitis, Pityriasis rosea, Pityriasis rubra pilaris, Polymorphic light eruption, Preauricuiar tag or pit. Purpura Pyogenic granuloma, Sebaceous cyst, Seborrheic dermatitis. Seborrheic keratosis. Skin an hair changes during pregnancy. Skin blushing/flushing. Skin discoloration bluish, Skin graft. Skin lesion biopsy, Skin lumps. Skin turgor. Stasis dermatitis and ulcers, Striae, Subcutaneous emphysema, Vesicles, Wood's lamp examination. Xanthoma, Xeroderma pigmentosa. Xerosis, Eczema, Impetigo, Itching, Psoriasis, Rashes, Scleroderma, Skin Aging, Skin Cancer, Skin infections and Skin

Pigmentation Disorders, among others.

Compositions according to the present invention may he administered by any conventional means known in the art. Pharmaceutical formulations include those suitable for oral, recta!, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration, but compositions which are administered by topical and/or iransdersm! route of administration directly at tire site in the skin of tire disease state or condition to be treated are preferred. Compositions according to the present invention may also be presented as a bolus, electuary or paste. TableLs and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disiotegranis, or wetting agents. The tablets may be coated according to methods well known in tire art. Oral liquid preparations may be in the form of for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives. When desired, the above described formulations may be adapted to provide sustained release characteristics of the active ingredient(s) in the composition using standard methods well- known in the art. la t e pharmaceutical aspect according to the present invention, the compound(s) according io the present in vention is formulated preferably in admixture with a

pharmaceutically acceptable carrier. In general it is preferable to administer the

pharmaceutical composition orally, but certain formulations may be preferably administered parenteraiSy and in particular in intravenous, intramuscular or intraperitoneal dosage form, as well as via other parenteral routes such as transdermal, buccal, subcutaneous, suppository or other route, including via inhalation or intranasaliy Topical routes of administration may be preferred when treating skin disease states and/or conditions. Oral dosage forms are

preferably administered in tablet or capsule (preferably, hard or soft gelatin) form.

Intravenous and intramuscular formulations are preferably administered in sterile saline. Of course, one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.

Compositions suitable for parenteral injection may comprise physiologically

acceptable sterile aqueous or nouaqueous solutions, dispersions:, suspensions, or emulsions, or may comprise sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nouaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, triglycerides, including vegetable oils such as olive oil, or injectable organic esters such as ethyl oieate. Proper fluidity can be maintained, for example, by the use of a coating such as leci thin, by the maintenance of the required particle size in the case of d ispersions, and/or by the use of surfactants.

These composi tions may also contain adjuvants such as preserving, wetting, emulsifying, and/or dispersing agents. Prevention of microorganism contamination of the compositions can be accomplished by the addition of various antibacterial an antifungal agents, for example, para bens, chlorobutanot, phenol, sorbic acid, and th like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents capable o f delaying absorption for example, aluminum monostearaie and/or gelatin.

Solid dosage forms for oral administration include capsules, tablets, powders, and granules, in such soli dosage forms, the ac tive compound is admixe with at least one inert customary excipient (or carrier) such as sodium citrate or diealeium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, or silicic acid; (b) binders, as for example, earboxymethylcelhdose, alginates, gelatin, polyvinylpyrrolidone, sucrose, or acacia; (c) humectants, as for example, glycerol; ( ) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, or sodium carbonate; (e) solution retarders, as for example, paraffin; (f) absorption

accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol or glycerol raonostearate; (h) adsorbents, as for example, kaolin or bentonite; and/or (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules mid. tablets, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be used as idlers in soft or bas d filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, and granules can be prepared with coatings or shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonl used in the art, such as water or other solvents, solubilizing agents and emulsifiers as for example, ethyl alcohol isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyilbrmamide, oils, in particular, cottonseed oil, groundnut ail, corn germ oil, olive oil, castor oil, sesame seed oil, glycerol, tetrabydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying aid suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compound, may contai suspending agents, as for example, ethoxyiated isosteary! alcohols, polyoxyethylene sorbitol or sofbitan esters, microcrystalline cellulose, aluminu metahydroxide, bentonite, agar-agar, or tragaeanfk, or mixtures of these substances, and the like.

Compositions for rectal or vaginal administration, where applicable, can he prepared by mixing an active agent and any additional compounds with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active.

Dosage forms for topical administration include ointments, powders, sprays and inhalants. The eoropound(s) are admixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, and/or propellants that may be required. Opthaimic formulations * eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

Generally, dosages and routes of administration of the pharmaceutical compositions and therapeutic compounds described herein are determined according to the size and condition of the subject, according to standard pharmaceutical practices. Dose levels employed can vary widely, and can readily be determined by those of skill in the art. Typically amounts in the milligram up to gram quantities are employed. The dosage administered pursuant to the present invention is an effecti ve amount for producing an intended result and will vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment and the effect desired. Usually a daily dosage of active compound can be about 0.01 to 500 milligrams per kilogram of body weight or more, often 0, 1 milligrams to 250 milligrams per kilogram of body weight. Ordinarily, 0.5 to 50, and often 1 to 25 milligrams per kilogram per day given in divide doses I to 6 times a day or in sustained release form is effective to obtain desired results.

The active compounds may be used at a concentration of 0.01. to 99.9 weight percent of the formulation, or in some cases a concentration of 0.001 to 99.9 weight percent of the formulation. Preferably the pharmaceutical formulation is in unit dosage form. The unit dosage form can be a. capsule or tablet itsel f, or the appropri a te number of any of these. The quantity of active compound in a unit dose of composition may e varied or adjusted from about 0.05 to several grams, often 0.1 to about 1000 milligrams or more or about 1 milligram to 500 milligrams according to the particular treatment involved. Compositions (dosage forms) suitable for internal administration contain from about 1 milligram to about 1000 milligrams of active compound per unit. In these pharmaceutical compositions the active compound will ordinarily be present in an amount of about 0 5-95% by weight based on the total weight of the composition.

Disease Treatment using The Present Compounds

Treatment, as defined herein, is the amelioration of the symptoms associated with disease. Symptoms may be reduce either by decreasing the level of the disease itself, or by decreasing tire symptoms associated with the disease. The subject of the treatment is preferably a mammal, such as a domesticated farm animal (e.g., cow, horse, pig. or a domesticated pet (e.g., dog, cat). More preferably, the subject is a human.

As noted herein, and without being bound by any particular theory, one mechanism by which admini stration of the compounds according to the present in vention may treat disease is through inhibition of the activity ofNF-tcB and up-regulatiou (increasing* the activity of Nr£2., nhibition of MF-tcB results in a decrease in HF-kB activity, an includes direct inhibition and indirect inhibition. Direc t inhibi tion is the direct effect of a compound on NF-KB and its activity. For example, one type of direct inhibition of NF-kB is a block of NF-kB DNA interactions. Indirect inhibition, on the other hand, involves the effect of a compound involve in the regulation of NF-&B that leads to a decrease in NF-KB activity. For example, as phosphorylation of the F-icB regulator IKB by IKB kinases (IKK) or Src fami ly kinases (SFK) results in a dysregulation of F-kB, and an according increase in NF- KB activity, inhibition of IKK or SFK by the present compounds provides an example of indirect inhibition.

Increase in Nrl2 results in an increase or up-regulatkm of ' Nir2 activity, and includes direct agonist activity and indirect agonist activity. Direct enhancement is the direct effect of a compound on Nr£2 (or its subunits) and its activity. Indirect inhibition, on the other hand, involves the effect of a compound according to the present invention in the regulation of Nr£2 that leads to an increase in Nrf2 activity.

Examples

Chemical synthesis

The synthesis of 56 substituted tram (E)-stilbenes (Figure 2, Table 1) was accomplished using Horaer-Wadsworth-Emmons (HWE) olefination chemistry " 4 The starred compounds in Table 1 are new to the literature, and their synthesis is described in Figure 1 , Scheme 1 / Synthesis of the other compounds in Table 1 was accomplished using a method reported previously." 1 HWE chemistry was used to avoid formation of a mixture of £ and Z isomers and formation of triphenyiphosphine oxide, which complicates the purification process.

The required phosphonate ester starting materials were prepared in high yields by the classical solvent free Michae!is- Arbuzov reaction of substituted benzyl chlorides or bromides with triethylphosphite at 130 o C, 2<s Removal of excess niethylphosphite and chloroethane or bromoethane product was carried out by vacuum distillation. Further purification using a short silica gel column and eluting wit ethyl acetate/hexane provided pure phosphonate esters as oils/’ Reaction of the appropriately substituted diethyl benzy!phosphonate ester wi th a corresponding freshly distilled substituted henzaldehyde in dry tetrahydmfuran using sodium hydride as the base (Figure 1, Scheme 1) afforded the 20 new substituted stilhenes (Figure 2, Table 1) exclusively in the E conformation. There was no detectable Z isomer, and the (ram geometry of the substi tuted sti!benes was confirmed by the coupling constants of

approximately 16.5 Hz for the olefmic protons in the proton NMR spectra. The reaction conditions allowed for a straightforward workup since the diethylphosphoric acid byproducts are water-soluble and were easily removed by extraction. Purification of the benzaldehydes and phosphonate esters was found to be critical for obtaining good yields and pure products.

In the case of enons compounds according to the present in vention, these are synthesized by methods which are well-known in the art and which are alternatively

presented in Deck, et al. Bur. J Med Chem 2018 Jan 1; 143:854-865, which is incorporated by reference herein.

Experimental Reporter Assays:

A Nrf2-ARE reporte.r~HepG2 stable cell line (BPS Bioscien.ee, San Diego CA) is grown in a humidified atmosphere at 7 in 5% CC¾/95% air. The cells are maintained in MEM medium with Earles balanced salts and L-g!uiaarine supplemented with 10% feta! bovine serum {FBS), 1 mM sodium pyruvate, 1% non-essential amino acids, 100 n is/ml penicillin, 100 pg/ml streptomycin, and 400 pg/mf Geneticin One day prior to treatment, the NrO-ARE ceils are plated into 24-well cell culture plates at approximately 30% confluency in the above media without Geneticin The following day. fresh media with or without substituted irons stilbene or snlfonvphane is applied to the cells. DMSO concentrations are kept at 0J The cells are again placed in a humidified atmosphere at 37 * 0 in 5% C<¾/ S% air lor 5 hours. Plate wells are gently washed with phosphate buffered saline (PBS) pH 7.4 and lysed with lx passive lysis buffer (Promega, Madison, WI, USA). The subsequent lysates are analyzed with the Luciferase Assay System (Promega) utilizing a GloMax 20/20 luminoraeter (Promega, Sunnyvale, CA, USA). The firefly luciferase relative light units are normalized to protein (rng/ral) with BCATM Protein Assay Kit protein (Pierce, Rockford, 1L, USA) 77

An NFkB reporter stable cell line from human 293Tembryome kidney cells

(293T FkB-liic) (Panomics, Inc., Redwood City, CA) was grown In a humidified

atmosphere at 37 0C in 5%€02/95% air. The cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM— high glucose containing 4 mM glutamine)

supplemented with 10% fetal bovine serum (FBS), i mM sodium pyruvate, 100 U/rnl penicillin, 100 ug/ml streptomycin, and 100 ug/ml hygromycin (Gibco/ihvitrogen, Carlsbad, CA) to maintain celt selection. One day prior to treatment, the 293T/NFkB-luc cells were plated into 24-well ceil culture plates {Costar, Cambridge. MA) at approximately 70*14 confluency in the above media without hygromycin. The following day cells were fed fresh media 1 h prior to treatment. Media with or without recombinant tumor necrosis factor alpha. (TNFa) (R&D Biosciences/C iontech, Palo Alto, CA) were then applied to the cells at 20 ug/ml followed by immediate treatments with inhibitor. The cells were placed again in a humidified atmosphere at 37 0C i 5%€02/95% air for 7 h. Plate wells were gently washed with phosphate-buffered saline, pH 7.4, and lysed with lx passive lysis buffer (Promega, Madison, W!), The subsequent lysates were analyzed with the Lnciferase Assay System

(Promega) utilizing a TD-20/20 lummomeier (Turner Designs, Sunnyvale, CA). The firefly lueiferase relative light units were normalized to protein ( g/ml) with BCATM Protein Assay Kit (Pierce, Rockford, IL) and standardized to percent of control (TNFa control). For assays of cell viability, cells were treated similarly as above and with 15 uM inhibitor. After washing, cells were treated with 100 ul media and 20 ui CellTiter 96 AQueous One Solution reagent for 1 h and then read at 490 nm with a Spectromax plate reader.

Synthesis

Reagents were purchased from commercial sources (Aldrich, Acres, etc.).

Tetrahydrofuran was distilled from lithium aluminum hydride. Thin layer chromatography was carried out on silica gel 60F254 plates. All compounds were shown to be > 98% pure by ¾ NMR and or € NMR unless otherwise noted. Column chromatographic separations were performed by using EM type 60 silica gel (230-400 mesh). Melting points were taken on a Thomas-Hoover Uni-Melt capillary eUiug point apparatus and reported uncorrected. Unless otherwise noted, f H spectra were recorded by using CIX¾ solutions at 300 MHz; C NMR spectra were recorded in CJX¾ at 75 MHz; i:5 F were recorded in CD(¾ at 282 MHz.

Chemical shifts are reported in ppm relative to CDCij at 7.24 ppm for T-i NMR and 77.0 ppm for ! NMR and the external standard hexafluotohenzene for 1 F NMR at - 164.9 ppm. Peak assignments were made with the aid of DEPT spectra. NMR data are reported as follows: chemical shift, mul tiplicity (s— singlet, d ~ doublet, t— triplet, q ~ quartet, dd ~ doublet of doublets, tel = triplet of doublets, m = muStiplet), coupling constant O in Hz) and integration. High resolution mass spectra (HRMS) were obtained at the UNM Mass Spectrometry Facility, Albuquerque, New Mexico.

General Procedure for Synthesis of Phosphorate Esters

Benzyl chloride or benzyl bromide derivatives (leq) were adde to trieihylphosphite (1.5 eq) and heated to 13C C for 20 h. After cooling, the resulting crude product was distilled in vacuo to remove excess triethylphosphlte and ethyl chloride or ethyl bromide. Purification by fil tration through a pad of silica get (70% ethyl acetate/30% hexanes) gave the phosphorate ester products as colorless oils.

General Procedure for Synthesis of Stilbenes

The appropriately substituted phosph rate ester (10 mmol) was dissolved in dry tetrahydroluran (20 ml) and stirred at 0~5°C, Sodium hydride (25 mmol) was added to the solution slowly and after thirty minutes the appropriate freshly distilled aldehyde (10 mmol) in tetrahydroluran (30 ml) was added dropwise. The mixture was allowed to stir at room temperature overnight. In order to increase the yield, compounds 35, 37 and 40 were heated under reflux for 3-4 hours. The mixture was cooled and quenched with ice water (10 ml) and poured onto ice. Dilute hydrochloric acid (IM) was added until acidic and the solution was extracted with ethyl acetate (4 s 50 ml). The combined organic layer were washed with saturated salt and dried over magnesium sulfate. Fil tration and evaporation of the ethyl acetate afforded crude stilhene products as oils or solids. The solids were crystallized from 95% ethanol to afford crystalline stilbenes, The oils were chromatographed on silica gel using methylene chloride to give pure products

(E}~l~FIu&m-2-(2-merh®xysfyfyi)bemene 10; 98% yield, white crystals; mp 34-35 °C; J H NMR (CDCi . 300 MHz .} : o7.66 kh, /- 7.8, 1.6 Hz, IH), 7.62 (dd, ,/ = 7 1.5 Hz, ! H), 7.54 (d, /= 16.6 Hx, 1H), 7.27 (d, J— !6 6 Bz, IH), 7.22 (m, 2H), 7.13 (dt, /= 7.5, 1.3 Hz, ffl), 7.05 (dt, 8.0, 1.3 Hz, IH), 6.98 (t, J = 7.4 Hz, IH), 6.91 (d, J = 8.3 Hz, IH), 3.88 (s, 3H). ¾ NMR (CDCl , 75 MHz): d 160.5 (d, J- 247.7 Hz), 157.2 (s), 129.2 (s), 128.6 (d, J - 8.4 Hz), 127.0 (d, /- 3.4 Hz), 126.7 (s), 126.5 (s), 126.0 (4, ,/- 12.1 Hz), 125,7 (4, 7 = 3.6 Hz), 124.2 (d, :::: 3.1 Hz), !2U (d, 7 = 4.0 Hz), 120.9 (s), 115.5 (d, ./- 22,2 Hz), 1 10.8 (s), 55.7 (s). !9 F (CDCb, 282 MHz): S -116.9 (s, IF). HRMS (El) calcd for C IJ H U FO [Mf: 228.0950; found, 228,0950.

(E}-i-(3 FhtorQ$tyryl)~2,3~ imeikoxyhmzem 16: 8% yield, oil; 'H NMR (CDCI 3 , 300 MHz):

§ 7.45 (4, J= 16.5 Hz, IH), 7.27 (m, 3H), 7.23 (dd, ./- 7.9, 1.3 Hz, IH), 7.08 (d, J = 16.5 Hz, IH), 7.06 (t, 7 = 8.1 Hz, IH), 6.96 (m, I H), 6.86 (¾ ./ - 8/1, 1.4 Hz, IH), 3.88 (s, 3H), 3.87 (s, 3H) °C NMR (CDClj, 75 MHz): 5 163.2 (<L = 245.1 Hz), 153.3 (s), 147.3 (s), 140.1 (d, 7 = 7.6 Hz), 131.0 (s), 130.1 (d, 7= 8.4 Hz), 128.7 (s), 124.3 (s), 124.2 (s), 122 6 (s), 1 17.9 (s), 1 14.4 (d, 7= 21.5 Hz), 1 12.9 (d, 7= 21.8 Hz), 1 1 1 ,8 (s), 61,2 (s), 56.0 (s). t9 ¥ (CDCfo 282 MHz): 6 -I N .9 (s, IF). HRMS (El) calcd for C t ftsFCE [Mf: 258.1056; found, 258.105 .

(E)-l-(4~Flwroslyryl)-2,3-dmethox bemene 17: 87% yield, white crystals; mp 50-51 °C; NM.R. (CDCb, 300 MHz): 6 7.50 (dd, 7* 8.4, 5.6 Hz, 2H), 7.36 (d, J - 16.5 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.07 (d, J = Ϊ .4 Hz, 1H), 7.04 (m, 3H), 6.83 id, J = 7,6 Hz, IH), 3,87 ($, 3H), 3.85 (s, 3H), l3 C NMR <CDC1 3 , 75 MHz): ø 162,4 (d, J- 247.1 Hz), 153,2 (s), 147.0 (s), 133.9 (d, 2.9 Hz), 131.4 (s), 128.7 (s), 128.2 (d, J- 7.9 Hz), 124.2 (s), 122.8 (s), 1 17.8 (s),

1 15.6 (d, 21.6 Hz), 111.5 (s), 61.1 (s), 55.8 (s). ¥ (CDC1 3 , 282 MHz): d -1 12.7 (s, IF). HRMS (El) calcd for CuflssFOs (Mf: 258.1056; found, 258, 1060.

(E)-2J4-Fiuora ^yl)~l,4-Jme(h<m' emene 18: 74° \ teld, while crystals; mp 58-59 °C;

! H NMR (CDC¾, 300 MHz): 5 7.49 (44, J- 8.7, 5.5 Hz, 2H), 7.37 (d,/- 16.4 Hz, IH), 7.13 (d, 7 = 2.6 Hz, IH), 7.05 (d, - 16.4 Hz, IH), 7.03 (t, 7= 8.7 Hz, 2H), 6.80 (ra, 2H), 3.83 (s, 3H), 3.81 (s, 3H). U C NMR(CDC¾, 75 MHz): 6 162.3 (d, .7- 247,0 Hz), 153.8 (s), 151.4 (s), 134.0 (d, 3.1 Hz), 128.1 (s), 128.0 (d, J = 7.7 Hz), 123.1 (s), 115.6 (d, 7= 21.6 Hz), 113.7 (s), 1 12.2 (s), 111.7 (s), 56.2 (s), 55.7 (s). 19 f (CDC¾, 282 MHz): d -112.9 (s, IF), FIRMS (El) calcd for C ½ Hi 5 F0 2 [M f: 258.1 56; found, 258.1057.

(B)~J2-Difimro-4-(4-methylsiyryl)benzene 22: 97% yield, white crystals; mp 90-9:

NMR (CDCI j , 300 MHz): S 7.38 (d, 7= 8.1 Hz, 2H), 7.29 (m, IH), 7.16 (d, /- 8.1 Hz, 2H), 7.13 (m, 2H), 6.99 (d, ,/- 16.4 Hz, 1 H), 6.92 (d, ,/- 16.4 Hz, 1 H), 2.36 (s, 3H). C NMR CEX¾, 75 MHz): 5151 " (dd. /= 69.7, 13.3 Hz), 148.5 (dd, 3 - 70.7, 13.3 Hz), 138.0 (s),

134.9 (t,,/- 5.0 Hz), 133.9 (s), 129.7 is), 129.5 (s), 126,5 {s), 125.5 (s), 122.6 (dd,./- 6.1,

2.9 Hz), 117.3 (d, < 7~ 17.5 Hz), 114.5 (d < /- 17.6 Hz), 21.3 (s). i9 F (CDCb, 282 MHz):S- 136.3 (d, ,/= 20.9 Hz, IF), -Ϊ37.7 (d,,/ = 20.9 Hz, IF), HRMS (El) calcd forCi 5 Hj 2 F 2 [Mf: 230,0907; found, 230,0911.

(E)-J4~l}ifiuoro-2-(4-meihoxp$tytyl)benzeM 23: 60% yield, pale yellow crystals; mp Ϊ 09- 110 "C; ! H NMR (€DC¾, 300 MHz); 67.46 (d, .7= ,6 Hz, 2H), 7.25 (m, 1H), 7,06 ($, 2H), 6.98 (m, 1 H), 6.89 (d, = 8.6 Hz, 2H), 6.86 (m, 1H), 3.81 (s, 3H). !3 C NMR (CDCIj, 75 MHz); d 159.8 (s), 159.2 (d,./- 2002 Hz), 156.0 (d, ,7-201.6 Hz), 131.5 (d,/- 3.9 Hz), 129.5 (s), 128.1 (s), 127.0 (dd, = 14.5, 8.2 Hz), 117.6 (s), 116.7 (dd, « 7 = 25.4, 8.7 Hz), 114.5 (dd,,/= 24.5, 9.0 Hz), 114.2 (s), 112.4 (dd = 24.6, 3,8 Hz), 55.3 (s). (CDCl ¾ 282 MHz): 5-117.7 (d, J= 17.2 Hz, IF), -122.9 (d, 17.2 Hz, IF). HRMS (El) cakd for

C 15 H i2 F 2 0 [Mf : 246.0856; tend, 246.0852.

(E)-l,2-Difluoro-4-(2-fluorostytyl)bmzme 24; 8:2% yield, white crystals; mp 85-86 °C; ! F1 NMR (CDC , 300 MHz); 67.56 (dt, J - 7.7, 1.6 Hz, 1H), 7,33 (dt, J - 7,7, 18 Hz, 1H), 7,23 (m, 2H), 7,17 (d, J~ 3 .4 Hz, 1H), 7.10 (m, 3H), 7.05 (d,./ = 16.3 Hz, 1H). 53 C NMR

(CDClj, 75 MHz): d 160.7 (d,./ - 247.9 Hz), 152,1 (dd,/=44,2, 12.0 Hz), 148.8 (dd,./- 46.6, 12.0 Hz), 134.7 (t,7=6.2 Hz), 129.4(d, ,/- 8.4 Hz), 128.9 (s), 127.3 (d,./ - 3.2 Hz), 124.7 (d, * 7 = 11.9 Hz), 124.4 (d, « 7= 2.7 Hz), 123.1 (dd,./- 53, 3.0 Hz), 122.3 (s), 117.6 (d, J = 17.5 Hz), 116,1 (d, « 7=22.1 Hz), 115.0 (d, < 7 = 17.6 Hz), 1:) F (CDC¾, 282 MHz): d -116.0 (s, IF), -1360 (d, J= 20.8 Hz, IF), -136.8 (d,7= 21.1 Hz, IF). HRMS (El) calcd for C 14 H 9 F 3 |MG: 2340656; found 234.0652.

{£)-},2-Diftuoro-4-(4-meth{>i 8tytyl)benMm 26: 66% yield, white crystals; m 73-7 “C 'H NMR (CDCU, 300 MHz); S 7.41 (d,J- 8.6 Hz, 2H), 7.27 (m, 1H),7.11 (m, 2H), 6.94 (d, J- 16.5 Hz, 1 H), 6.88 (d,./- 8.7 Hz, 2H), 6.83 (d,d- 16.5 Hz, 1H), 3.81 (s, 3H). °C NMR (CDCls, 75 MHz): 5159.8 (s), 151.8 (dd, J = 79.6, 12.7 Hz), 148.6 (dd, J - 81.0, 13.2 Hz), 135.2 (t,,/- 4.9 Hz), 129.6 (d,/- 13.0 Hz), 129.5 (s), 128,0 (s), 124.5 (s), 122.5 (dd,,/ - 5.4, 2.8 Hz), 117,5 (d, J - 17.4 Hz), 114.5 (d ,/= 16.0 Hz), 114.4 isj, 55.5 is). '*F (CDCl·,, 282 MHz): 5 -136.4 (d, ./- 20.9 Hz, IF), -138.1 (d, - 20.8 Hz, IF). HRMS (El) calcdfor

CI 5 H 12 F 2 0 |Mf: 246.0856; found, 246.0860. (E}-i,4-Biftmw-2~(2-fluow$tyryl)betiZ0ne 29: 88 yield, white crystals; rap 79-81 °C;

NMR (CDCb, 3(H) MHz); d 7.60 (dt, 7 = 7.7, 1.6 Hz, If-I), 7.27 {s, 2H), 7.26 (m, 211), 7.13 (dd, J ~ 7.6, 1.1 Hz, 111), 7.08 (m, 1H), 7.00 (m, 1H), 6,90 (m, 1H). *’C NMR (CDCI 3 , 75 MHz); § 160.6 (d, = 250.4 Hz), 159,3 (d, 7= 185.2 Hz), 156.1 (d, J= 189,0 Hz), 129.6 (d, J - 8.5 Hz), 127.2 (d,,/- 2.9 Hz), 126.5 (dd,./- 14.4, 7.9 Hz), 124.6 (d, J - 12.0 Hz), 124.3 (d,,/ - 3.3 Hz), 124.1 (s), 122.0 (s), 116.8 ( ,7-25.3,8.9 Hz), 115.9 (d,7-22.2 Hz),

115.5 (dd, J = 24.5, 8,8 Hz), 112.8 (dd, J- 24.7, 3.5). I9 F (CDCI 3 , 282 MHz): 8 -115.9 (s, IF), -117,3 (d, 7 = 17.2 Hz, IF), -122.4 (d, J = 17,2 Hz, IF). HRMS (El) ealed for Ci 4 ¾F 3 [M | ' ; 234,0656; found, 234.0654.

(£)-l,2-Diflmro-4-(3-fluor0$tytyl)benzme 30; 95% yield, white crystals; mp 48-49 °C; ! H NMR (CDCii, 300 MHz): d 7.30 (m, 2H), 7.16 (m, 4H), 6.98 (m, 1H), 6.96 (d,/- 16.5 Hz, 1H), 6.90 <d,7 = 16.5 Hz, 1H). C NMR (CDCb, 75 MHz); 6163.2 (d, 7 = 245.6 Hz), 152.0 (dd, 7 = 42.1, 1I.I Hz), 148.7 (dd, 7 = 44.7, 11.1 Hz), 139.1, (d,7=7.8 Hz), 134.2 (t, 7 = 5.9 Hz), 130.2 (d, 7- 8.4 Hz), 128.5 (s), 127.8 (s), 122.9 (dd, J - 6.2, 3.6 Hz), 122.6 (d,7= 2.3 Hz),117.5(4,7 = 17.5 Hz), 114.9 (d, - 5.3 Hz), 114.7 (s), 112.8 (d, 7- 21.9 Hz). ! *F (CDCb, 282 MHz): S -111.4 (s, IF), -135.8 (d,7 = 20.9 Hz, IF), -136.5 (d, 7 =20.8 Hz, IF), HRMS (El) ealed lor CJ 4 ¾F 3 [Mf: 234,0656; found, 234,0660,

(E}-J4~Difiwro2~(3~fiuorostyryl)benzem 34; 89% yield, white crystals; rap 73-74 y C; *H NMR (CDCU, 300 MH¾): d 727 (m, 4H), 7.18 (d, J = 16.5 Hz, 1H), 7.06 (d, 7= 16.6 Hz,

IE), 7.01 (m, 2H), 6.93 (m, 1H). C NMR (CDCF, 75 MHz); § 163.2 (d,7= 245,7 Hz), 159.3 (d, J··· 1794 Hz), 156.0 (d, 7 = 183.7 Hz), 139.0 (d, J = 7.7 Hz), 130.8 (s), 130.2 (d, J = 8.3 Hz).1261 |ra), 122,8 id, J- 2.0 Hz), .121.2 (s), 116,9 (dd,7= 25.3, 8.8 Hz), 115.5 (dd, 7=24,5, 8.7 Bz), 115.1 (d,7 = 216 Hz), 113.1 (d, 7= 21.9 Hz), 112.8 (dd, J- 24.6, 3J Hz), ! F (CDC¾, 282MHz): d -111.5 (s, IF), -117.3 (d,/- 17.2 Hz, IF), -122.0 (d, - 17.2 Hz,

IF). HRMS (El) calcd for C H ¾F 3 [Mf: 234.0656; found, 234.0659.

(E)-2 ' 4-Diftuoro-l-(3-ftuorostyryl)beRzene 35: 67% yield, white crystals: rap 60-61 "C; ! H NMR (CDClj, 300 MHz); S 7,50 (44, = 15.0, 8.3 Hz, 1H), 7.23 (m, 3H), 7.16 (4,7= 16.5 Hz, I H), 7.04 (4,7= 16,5 Hz, 1H)„ 6.88 (;n.3.H). i3 C NMR (CDC!j, 75 MHz): 5163.2 <4.7 = 245.5 Hz), 163.1 (dd,7= 143.9, 12.3 Hz), 159.8 (dd, 7= 5461, 12.2), 339.5 (d, 7= 7.6 Hz), 130.2 (4,7= 8.4 Hz), 129.4 (s), 128,0 (dd, 7= 9.4, 5.0 Hz), 122,5 (d,7= 2.2 Hz), 121,3 (s), 121.1 (d, 7 = 3.5 Hz), 114.8 (d, 7- 21.4 Hz), 112.9 (d, 7= 21.9 Hz), 11.7 (dd,7=22.0, 3.7 Hz), 104.2 (t, 7 = 25.8 Hz). 5S F (CDCls, 282 MHz); 6 -108,6 (d, 7= 6.1 Hz, IF), -111,6 (s, IF), -1 11.7 (d, 7 :: 3 Hz, I F). HRMS (El) calcd for C r4 H ? F 3 [Mf; 234,0656; farad, 234.0658.

{E}-2,4-Diflu0ro-l-(2-fluorostyiyl)bemene 36; 70% yield, white crystals; mp 84-85 °C; *H NMR (CDCls, 300 MHz); d 7.60 (t, /= 8.8 Hz, IH), 7.58 (0 J * 8.7 Hz, IH), 7.25 (s, 2H), 7.22 (m, IH), 7.13 (dt, 7 » 7.6, 1.3 Hz, IH), 7.06 (dt, 9.5, 1.3 Hz, !H), 6.83 (m, 2H), ,3 C NMR (CDCls, 75 MHz); o 162.6 (dd, J = 250.5, 13.9 Hz), 162.3 (i, ,/= 5.1 Hz), 158.9 (t , /= 10.2 Hz), 129.3 (d, ./ = 8.4 Hz), 128.1 (dd, 7 = 9.5, 5.2 Hz), 127.2 (d, ./ = 3.1 Hz), 125.1 (d, J - 1 1.9 Hz), 124.4 (d, 7= 3.2 Hz), 122.9 (s) 122.2 (s), 121.7 (dd, 7- 11.7, 3.6 Hz), 116.0 (d, 7 = 22.2 Hz), 111.8 (dd, = 21.6, 3.5 Hz), 104.3 (t, 7= 25.7 Hz). % (CDCI 3 , 282 MHz); 5 - 108.8 (s, IF), -1 12.2 (6, ,/ = 5.6 Hz, IF), -116.4 (s, IF). HRMS (El) calcd for CMH 3 (Mf: 234.0656; found, 234.0658.

(E)-2,4-Difiuoro-l-(4-methybtyryl)bemwe 37: 32% yield, white crystals; nip 72-73 T; Ή NMR (CDCls, 300 MHz); 5 7.55 (dd, 7= 15.0, 8.4 Hz, IH), 7.89 (d, ,/= 7.9 Hz, 2H), 7.47 id, J ~ 7.5 Hz, 2H), 7.16 (d, 7 = 16.5 Hz, IH), 7.07 (d, 7 = 16.5 Hz, IH), 6.85 (m, 2H), 2.35 (s, 3H). 13 C NMR (CDCls, 75 MHz); 5 162.9 (dd, 7= 131.0, 12.1 Hz), 159,5 (dd, 7 = 133.5, 12.0 Hz), 137.9 ( S ), 134.3 (s), 130,5 (s), 129.5 (s), 127.7 (dd, 7 = 9,2, 5.4 Hz), 126.5 (s), 121,8 (dd, ,/ = 12.5, 3.8 Hz), 118.9 (s), 1 1 1.5 (dd, = 21.5, 2 8 Hz), 104.1 (t, J = 25.7 Hz), 2 .4 (s). i9 P (CDCls, 282 MHz); d -109.7 (d, 7 = 5.3 Hz, IF), -112 4 (d, J = 4.4 Hz, IF). HRMS (El) calcd for C 55 H 12 F 2 [Mf: 230.0907; found, 230.0912.

(E)-i t 4~Bifluoro-2-(4~fimrostytyl)be em : 50% yield, buff crystals; rap 76-77 °C; ¾ NMR (CDCfi, 300 MHz): d 7.48 (dd, ./ = 8.5, 5.5 Hz, 2H), 7.25 (m, IH), 7.09 (s, 2H), 7.00 (m, 3E), 6.90 (ra, IH). n C NMR (CDCH, 75 MHz): 8 162.8 (d, 7 = 248.3 Hz), 159.2 (d, = 190.6 Hz), 156.0 (d, »/— 192.8 Hz), 132.9 (d,/- 3.0 Hz), 130.7 (d, 7 = 4.3 Hz), 128.3 (d, J = 8.0 Hz), 126.5 (m), 119.7 (s), 1 16.8 (dd, 7 = 25,3, 8.9 Hz), 115.7 (d, ,/- 21.8 Hz), 1 15.1 (dd, ./ = 24.6, 8.9 Hz), 112.7 (dd, 7= 24.7, 3.0 Hz). i9 F (C0C1 ¾ 282 MHz): S -111.5 (s, IF), - 1 17.4 (d. J = 17.0 Hz, ! F). - 122.5 (d, 7 = 16.9 Hz, F). FIRMS (El) calcd

234.0656; found, 234.0650.

(E)-I,2~Dif i neikoxy 3~(4~meihyl$tyryl)beHz0n4 48; 92% yield, while crystals; rap 38-40 U C l H NMR (CDCls, 300 MHz); d 7.43 (d,7= 7.7 Hz, 2H), 7.41 (d, 7 = 16.7 Hz, IH), 7,22 (d,7 - 7.8 Hz, 1H), 7.14 (d, /= 7.9 Hz, 2% 7.08 (d, ./- 16.6 Hz, IH), 7.02 (t » /= 8.2 Hz, 1H),6.79 (d, : J = 7.3 Hz, 1H), 3.83 (s, 6H), 2.34 (s, 3H). ¾ NMR (CDCIj, 75 MHz); § 153.1,

146.8, 137.5, 1:34.9, 131.7, 129.8, 129.3, 126.6, 124.1, 121.9, 117.8, 111. , 61.0, 55.7, 21.2. HRMS (El) calcd lor Ci 7 H {S 0 3 (Mf: 270.1256; found, 270.1258.

(E)-}-Methoxy~2 (3 m¹ho!xy$fyryl}benzetie 49: 86% yield, white crystals; mp 49-50 * C; * H NMR (CDC- ' h, 300 MHz): § 7.55 id. J = 7.6 Hz, Hi), 7.48 fd. J = 16.5 Hz, IH), 7:23 (t, J = 7.7 Hz, I H), 7.18 (t , J = 7.4 Hz, IH), 7.09 (d, J = 8,9 Hz, IH), 7.06 (d, J = 16.6 Hz, 1 H), 7.05 (s, IH), 6.92 (t, ./ :::: 7.4 Hz, IH), 6.83 (d, J :::: 8.2 Hz, IH), 6.76 (dd, J- 8.0, 1.9 Hz, IH), 3.80 (s, 3H), 3.76 (s, 3H). ¾ NMR (CDC!j, 75 MHz): § 159.8, 156.9, 139.4, 129.5, 128.9, 128.7, 126.4, 126.2, 123.8, 120.7, 1 19.3, 1 13,0, 1 11.7, 1. 0.9, 55.4, 55.1. HRMS (El) calcd for f t Hii s [M T: 240.1150; found, 240.1156.

{E)~ j,4~D eAmy-2-{3 meihtixysi ryl)he em SO: 96% yield, white crystals; ra 48-49“C; l H NMR (CDC¾ 300 Mil/ S. e 7.44 (d, J- 16.4 Hz, I H), 7.24 (t,J 7.9 Hz > IH), 7.10 (m, 3H), 7.05 (d, J- 16.4 Hz, IH), 6.78 (m, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H). U C NMR (CDC , 75 MHz): 6 159.9, 153.8, 151.5, 139.3, 129.5, 129.2, 127.1, 123.6, 119.4,

1 13.8, 113.2, 112.3, 111.8, 111.7, 56.2, 55.7, 55.2. HRMS (El) calcd for CJ ? H 18 <¼ [Mf 270.1256; found. 270.1258.

(E)-i,2-Di ethoxy-3-(4~(iriflmmmethyl)styryl)hemene 54: 84% yield, white crystals; rap 67-69 X; l H NMR (CDCfe, 300 MHz): 5 7.62 (d, J - 9,3 Hz, 2H), 7.59 (d,J= 9.7 Hz, 2H), 7.54 (d, ,/ - 16.7 Hz, IH), 7.24 (d, J = 7.8 Hz. j H), 7.13 (d, J = 16.6 Hz, IH), 7.07 (t, J = 8.0 Hz, 1 H), 6.87 (d, J - 8.0 Hz, 1 H), 3.88 (s. 3H>, 3,87 (s, 3H), C NMR (CDCH, 75 .MHz): § 153.1, 147.3, 141.2, 130.9, 128,3, 726.7, 125.6, 125,5, 124,2, 1 8.0, 112.0, 61.3, 56,0. i9 ¥ (CDCb, 282 MHz): 8 -60.9 (s, 3F). HRMS (El) calcd for€%¾ f¼0 2 |Mf: 308.3002; found, 308.3000.

(E)-i-(4-I$opropylstyry})-2 s 3-dimethoxybmzene 55: 96% yield, oil; ¾ H NMR <OX¾ 300 MHz); S 7.35 (4 < /-:8.2 Hz 2H), 7.26 ( , ,/- 16.5 HzJH), 7.24 (dd, < /- 63, 1.6 Hz, I B), 7.17 (d, ,/ 8.1 Hz » 2H), 7.14 (d, ,/- 16.5 .Hz » 1H} » 7.07 (i, J= 8.0 Hz, 1 H), 6.84 (dd, 8.1 , 1.2 Hz, IH), 3.89 (s, 3H), 3,8? (s, 3H), 2.94 (sept, /= 6.9 Hz, 1H), 1.30 (d, J= 6.9 Hz, 6H) l3 C NMR (CDCls, 75 MHz); d 153.1, 148.5, 146.8, 135,3, 131.8, 129.8, 126.7, 126.6, 124,1, 122.0, 117.8, 111.1, 61.0, 55.7, 33.9, 23,9. HRMS (HI) ca!cd for Cu>H 22 C |M]*: 282.1620; found, 282.1618.

Results and discussion

Activation of Nrf2 fey resveratrol, D5S and sulforaphaite

Resveratrol, LOSS and sulforaphane were compared in an Nrf2-ARE reporter-HepG2 stable cell line, which was designed for use as a luciferase reporter-based assay for activators ofNrf2. The abil ity of both resveratrol and LBSS to activa te Nrf2 signaling ex tends the known activities of these two (ram stilbenes to include both anti-inflammatory activities as inhibitors of the pro-inflammatory NF-kB signaling pathwa as well as anti-oxidative stress activities as activators of Nrf2, it is noteworthy that the extent of activation of Nrfi differs for these three activators (FIGURE 3, Table 2) LD55 was 5-fold better than resveratrol in the extent of Nrf2 activation. Concentrations that produced 50% activation (EC so) were obtained from dose-response curves. Resveratrol and LD55 show low EC50 values (5 4mM).

comparable to sulforaphane ( 1.2mM). The fact that these activators of bhf2 can vary both in their ECso values and in the extent of activation requires that both of these factors be considered in evaluation of the activities of Nrf2 activators.

3.2. Activation of Nrf2 by raonofluor© Warn stilbenes

A library of substituted tram stilbenes was screened to identify activators of Kri2. With few exceptions, such as resveratrol, only compounds with fluorine or methoxy

substituents showed significant activity. From this screen, a group of 56 substituted trans stilbenes was identified as activators of Mrf2 (FIGURES 3-5, Tables 2-4), A series of monofiuoro tram stilbenes was compared with resveratrol and LD55, The series was screened at Ί5mM concentrations of the compounds, a concentration that did not produce an solubility problems and was sufficiently higher than the EC*» values to allow a comparison of the differing extents of activation (FIGURES 3-5, Tables 2-4}. All of these monofiuoro (ram stilbenes were activators of Nri2, although the extent of activation varied almost 20-fold. Many of the compounds were better Nrf2 acti vators than sulforaphane and were much better than resveratrol. The EC ® values fo these monofiuoro tram stilbenes ranged from 0,?mM (tri s sulbene 2} to 12,4 mM {/rans stiibene 4) Comparison of tram stilbenes 2, 3 and 4, ail of which contain a single fluorine s ubstituent on one of the aromatic rings and ao subs tituent on the other ring, suggests that fluorine substitution in the ortho position, as in LD55, is preferred. However, thi is not consistently observed. Comparison of LD55 with 5 and 6, all of which contain a para methoxy substituent, shows little effect of altering the position of the fluorine on ECjo values which ranged from 4,2 to 8,9 mM (FIGURE 3, Table 2). Likewise, altering the positions of both the fluorine an methoxy substituents as in LD55, 5, 6, 16-13, all of which are isomers, has a modest effect with ECjo values ranging from 2.3 to 8.9 m,M The extent of activation, however, differs markedly. For example, isomer |0 is activated almost 10-fold more than isomer 6 (FIGURE 3, Table 2). Replacing the methoxy substituent with a methyl substituent (?, 8 and 9) lowers ECso to low or eve t sub-micramolar values.

Activation of ! : rf2 by poly floor» tram stilbenes

A series of polyfluoro tram stilbenes was compared with resveratro] and JLD55. EC 50 values ranged from 0.3 to >15 mM (Table 3 ) and extent of activation varied about 5 -fold, with all of these stilbenes better than resveratrol with respect to fold activation. As with the monofluoro tram stilbenes, the location of the fluorine substituents markedly affected BC ¾· , values and fold activations, but not in readily predictable patterns. For example, ECsy for the diffooro tram stilbene 33 is siib-micr olar (0.65 mM) while EC ¾i for its isomer 2$ is >15 mM. Likewise, the ECso for the Iriilnoro tmm stilbene 34 is sob-mieromo!ar (0.3 mM) while ECjofor its isomer 24 is >15 mM. Multiple iriilnoro isomers (34, 35, 38) exhibited submicromolar ECJO values. Isomer 34 was the most effective activator when expressed as fold activation divided by ECso. The conclusion from the data in Tables 2 (FIGURE 3) and 3 (FIGURE 4} is that all of these fluorine substituted tram stilbenes demonstrate measurable activity as activators of Nr .

Activation of A rf2 by nonfluoro trans stilbenes

A series of substituted tram stilbenes, most of which contained methoxy groups at one or more positions, demonstrated activity as activators of Nrf2 ; as shown in Table 4. EC50 values ranged from 0.8 mM (tram stilbene 56) to >15 mM. All of these tmm stilbenes were as good as or better than sulforaphane with respect to fold activation and were much better than resveratro! Compounds 51 and 54 demonstrated the highest fold activations of all of the tram stilbenes, 69 and 65.5 fold, respectively. The results from this study support the conclusion that the stilbene scaffold ts a useful structure upon which to explore chemical space to develop activators of Nrf2, especially those that include fluorine and methoxy functional groups as in LD55.

The importance of inflammation and oxidative stress in many chronic diseases supports the concept that activation of anti-oxidant Nrf2 signaling may have therapeutic potential Cells have developed complex adaptive responses to oxidative stress to maintain redox homeostasis and to reduce oxidative stress 45 Stress activation of Nr!2 may be the result of exposure to xenobiotics, including many natural products. 46 Many of these Krf2 activators are electrophiles. One of the major mechanisms of Nrf2 activation is through covalent modification of select cysteine sullhydryl residues in Keapl Numerous Nrf2-aciivaiing chemicals, including natural products such as sulforaphane, are electrophiles that modify Keapl , often by Michael addition 4 ' ”49 Cysteine residues 273, 288 and 151 appear to be especially important targets, as-determined by site-directed mutagenesis. Kesveratrol and other natural product phenols activate Nrfi! after oxidation to electrophilic quinones that contain Michael acceptor functionalities.* 9 Moreover, some natural product phenols including resveratrol can activate Nr& by additional mechanism, such as increasing the level of NrfS mRNA. 4 *

A number of Nrf2 activators have entered into clinical trials. Bardoxolone methyl an oleanobc acid-derived synthetic tritetpene, is a potent Nrf2 activator that was evaluated for its ability to slow progression to end-stage renal disease in patients with type 2 diabetes and stage 4 chronic kidney disease. Bardoxolone methyl is able to modify Keapl as a Michael acceptor. The clinical trial was terminated in phase III owing to an increase in heart tailored Dimethyl iumarate, a simple derivative of the metabolic intermediate fumaric acid, has recently been FDA-approved lor the treatment of retapsing-reoiitting multiple sclerosis. 5 * Dimethyl fnmarate is active as the monometh yl deri vative formed by the action of nonspecific esterases. Monomethyl fnmarate modifies Keapl through electrophilic addition. For both bardoxolone methyl and dimethyl fumarate, however, mechanisms in addition to modification of Keapl may play a role in activation of rfiL

One concern with the design of Mr!2 activators that are electrophilic covalent modifiers of Keap l is the issue of selectiv ity Bardoxolone methyl for example, has been shown to react with multiple targets. 3i To address this concern a number of recent studies have focused on development of noR-eieeirophilic activators of Nrf% 5# aided by the

availability of the crystal structure of the BTB domain of Keapl, which contains residue cysteine 151 that is the target for covalent modification by hardoxo!one methyl 54 the Kelch domain of Keapl and the Keapl -Nrf2 interface. 6 ' * Peptide inhibitors of the Keapl -Nr£2 protein-protein interaction have been described 3 ’· 3 as well as a variety of small molecules that inhibit the Keapl -Nr£2 interaction. 39 62

There are additional mechanisms for activation of Nr£2 Epigenetic modifications of CpG methy!ation status of Nr£2 by the anti-cancer drag 3,3’-diindolyimethane resulted in enhanced expression of Nr£2 and of Nrf2 -target genes in cell-based studies.*·’ This was suggested as an explanation for the chetnoprev tive ac tivity of this drug. The promo ter of the gene encoding Nrf2 contains XRE sequence , winch can recruit the aromatic hydrocarbon receptor AhR; this allows the Nrf2 gene to be activate by polycyclic aromatic hydrocarbons 64 The promoter of the Nrf2 gene also contains ARE-!ike sequences, which allows Nr£2 to regulate its own expression. 65 The Nri2 promoter also contains an NF-KB binding site, which allows activation ofNrG by pro-inflammatory stimuli

The autophagy cargo receptor and signaling adaptor protein p62 contains a binding site for Keapl The attraction of Keapl to this site is further regulated by phosphorylation by mlORCl, which leads to autophagosome -mediate destruction of Keapl and activation of r£2 f, ' f,ii This is one example of proteins other than Nrf2 that interact specifically with Keap l , which indicates a broad role for Keap l and a complex set of mechanisms that impac t Nrf2 levels. 69 There are, therefore, numerous targets for potential activators of Nrf2.

In the present study, the inventors identified numerous substituted tram stiibenes as activators of Nrf2, especially tram stiibene with fluorine and/or niethoxy ring substituents. The double bond in the trans stilbene scaffold is generally a low-reactivity center which would be unlikely to modify Kea l by electrophilic addition. It remains to be determined which siteCs) is the target for activation of Nrf2 by substituted tram stiibenes. Likewise, it remains to be determined how different tram stiibenes produce markedly different fold activations, which are believe to involve e mechanisms.

Activation of Nrf2 by dienoee analogues of the natural product cureumin Numerous analogues of curcumin acti vate Nrf2. Many of these analogues also inhibit NF-kB See, Deck, et ah, European J Med. Chem. 2018 Jan 1 ; 143:854-865 However, the number of analogues of resveratro! (i,e,, the trans stilbenes) and analogues of curcumin (i.e., dienones) that are both potent inhibitors of NF-kB and potent activators of Nri2 is limited. Figure 6 shows the structures of the trans stilbenes and dienones that are most potent as dual target anaiogtses. All are much more potent than resveratrol or curcumin.

Conclusions

Substituted irons stilbenes represent promising compounds for the development of drags that target oxidative stress in chronic diseases, through activation of the anti-oxidant Nrf2 signaling pathway.

References

1. Guerreiro, RJ,; Hardy, J, Bioehem, Soe. Trans. 2011, 39, 91§.

2. Bales, K,R G xp rt Opin. Drug Discov. 2012, 7, 28.1.

3. Fischer, O. Z, Gesamte. Psyehiatr 1910, 3, 371.

4. McGeer, E.G.; McGeer, P.L. J. Akheimers Dis. 2010, 19, 355,

5. Alexander, JJ.; Anderson, AJ.; Barnnm, S.fL; Stevens, B.; Tenner, A . J. Neurochem.

2008, 107, 1109.

6. Joshi, G.; Johnson, I. A. Recent Pat CNS Drug Discov 2012, 7, 218.

7. Sandberg, M; Patil, J,; D’Angelo, B,; Weber, S.G,; Mallard, C. Neuropharmacology 2014,

79, 298.

8. Cardozo L.F.; Pedraxxi, L.M.; Stenvinkel, P.; Stockier-Pinto, MB.; Dalepraoe, J.B.; Leite

Jr, M. Mafia, D. Biochemle 2013, 95, 1525.

9. Ruiz, S.; Pergola, R,E,; Zager, R.A,; Vaziri, N.D, Kidney Int. 2013, S3, 1029.

10. Wakabay shA ; Slocum, S,L,; Skohp, JJ,; Shin, S.; Kensler, T.W. Antioxid. Redox

Signal. 2010, JJ, 1649,

11. Ganesh Yerra, V.; Negi, G.; Shanna, S.S.; Kumar, A. Redox Biology 2013, J, 394,

12. Hybertson, B.M.; Gao, B.; Bose, S.K.; McCord, J.M. Mol Aspects Med. 2011, 32, 234. ang, 3.; Wang. X.; Yikask V.;Ye, Q.; Wu, D.; Liu, Y.: Dong, W. Oxid. Med. Cell

Longev. 2016. Fpub ahead of print

umar, H ; Kim, 1-S ; More, S.V.; Kim, B-W.; Choi, D-K Nat Prod. Rep. 2014, 31, 109.ojo, A.I.; Imiamoraio, N.G.; Martin-Moreno, A.M.; D Ceballos, MX.; Yamamoto, M.;

Cuadrado, A. Glia 2010, 58, 588.

hih, A.Y.; Li, P.; Murphy, T.H. J. Neurosci. 200$, 25, 10321.

n, W.; Wang, H.; Yan, W.; Zfau, L ; Hu, Z.; Ding, Y.; Tang, K. J. Neurotrauma 2QQ9,

2d, 131.

raft, A.D.; Johnson, D.A. Johnson, LA. J. Neurosci. 2QQ4, 24, 1 101.

amsey, C.P.; Glass, C.A.; Montgomery, M.B.; Lindl, K.A.; Ritson, G.P.; Chk, L.A.;

Hamilton, R.L.; Chu, C.T,; Jordan-Sciutto, K.L. L Neuropathol Exp. Neurol 2007, 66, 75. lberg N O.; Chamberlin, R.; Vigil, J.R.; Deck, L.M.; Beklrich J.E.; Brown, D.C.; Brady, CL; Yander Jagl, T.A.; Garwood, M : Bisoffi, M.; Severns, V ; " Vander Jagt, D.L.; Siilerud, L.O. 3. Alzbeimers Dis. 2014, 40, 195.

eynekamp. JX; Weber, WAV ; Hunsaker, L.A.; Gonzales, AM.; Orlando, R .A,; Deck, L. .; Vander Jagt, D.L. J. Med. Cheat 2006, 49, 7182.

iax-Gefevini, G.T.; Repossi, G.; Dalit A.; Tarres, M.C.; Das, U.N.; Eynard, A.R.

Nutrition 2016, 32, 174.

oughton, C.A.; Passed, R.G.; Coombes, J.S Nutr. Rev. 2013, 71, 709.

) Horner, L,; Hoffman, H.; WippeL H.G.; Kiahre, G Chem. Ber. 1959, 92, 2499 (b)

Wadsworth, W.S Ir.; Emmons, W.D. J. Am. Chem. Soc. 1961, 83, 1733.

as, J.; Pany, S.; Majhi. A. Bioorg. Med. Chem. 2011, 19, 53 1

rbuzov, B.A Pore Appi Chem 1964, .0, 307.

ivera, H.; Morales-Rios, M.S.; Bautista, W.; Shibayama, M.; Tsutsumi, V.; Muriel, P.;

Perez- Alvarez, V Can J. Physiol Pharmacol. 2011, 89, 759.

unes, S.; Tchani, G.; Baziard-Mouysset, G.; Stiglianl, J.L.; Payard, M.; Bonnafous, R.;

Tisne-Versailles, J. Eur. J. Med. Chem. 1994, 29, 87.

ang, X.; Zeng, W.; Yang, Y.; Huang, H.: Liang, Y. Synleti 2013, 24, 1687

ust, R.; Schoenenberger, H. Arch Pharmazie, 1 95, 328 , 595

ao, C.; Sheng, B.; Chen, G. J. Phys. Org. Chem Gust, R.; Schoenenberger, H. Arch

Pharmazie 2012, 25, 1315

ang, S.; Cuendet, M.; Endrmger, D.C.; Crov, V.L.; Pezzleto, J.M.; Lipton, M.A. Bioorg.

Med. Che . 2009, 17, 1044 . SUE, B.; Hoshino, J.; Jermihov, K.; Martero. L.; Pezzuio, J.M.; Meseear, A.D.; Cushman,

M. Bioorg. Med. Chem. 2010, 18. 5352.

. Lion, Stevens,

I 292.

. Dunne, B.C.; Coyne, EX; Crowley, P.B.; Gilheafty, D.G. Tetrahedron Let. 2002, 43,

2449.

. Buu-Hoi, N.P.; Xuong, N.D.; Diep, B.K..; Quang, N.N. J. Org. Chem. 1962, 27, 2669.. Zhang, M ; Jla, T.; Sagamanova, ί ; Pericas, M.A.: Walsh, PA Org. Lett. 2015, 17,

1 164.

. Karki, S.S.; Bhutle, S.R.; Sahoo, S.; Reddy, R,; Ba arini. J.; De Clercq, E.; Darji, S.Y. Me , Chem . Res. 2011 , 20, 1349.

. KLarke, S.S.; Bhut!e, S R .; Pedgaonkar, G.S.: Znbaidha, P.K.; Shaikh, R.M.; Rajput, C.G. Shendarkar, G.S. Med. Chem. Res 2 H . 39, 1 158.

. ChalaS, M.; Verva».<fier-Fa$seui\. D.; Meunier, P ; Catey, H.; ffierso, J-G. Tetrahedron 2012, 68, 3899.

. Ao, J.; Chen, Xu, X.; Zhang, X.; Yu, Y.; Yu, P.; Hua, E Asian I. Chem. 2014, 26,

2092,

. Saiyed, A.S.; Patel, K.N.; Karaath, B.Y.; Bedekar, A.V, Tetrahedron Lett 2012. 53, 4692,. Motoshima, K.; Sugita, K ; Hashiinoto, Y.· Ishikawa, M. Bioorg. Med. Chem. Lett 2011 ,

21, 3041.

, Khandelwal, M.; Hwang, L; Nair, P.C.; Lee, J-W. Bull. Korean Chem, Soe, 2012, 33, 1 190.

. Hayes, J.D.; Dinkova-Kostova, A.T. Trends Blochem, Set, 2014, 39, 199.

. Kama, II.; Kirn, 1-$.; More, S.V.; Kim, B-W.; Choi, D~K. Nat Prod. Rep 2014, 31, 109.. Zhang, D.D ; Hamimk, M Mol, Cell Biol. 2003, 23, 8137,

. Keuai, Y-S.; Choi, B.Y. Molecules 2014, 19, 10074.

. Mag sh. S.; Chen, Y.; Hu, L Med. Res. Rev. 201 , 32, 687.

, Chin. M.P.: Wrolsta , D ; Bakris. G.L.; Chertpw, G.M.; De Zeenw. D.: Goklberry, A,;

Linde, P.G.; McCullough, P.A.; McMuny, J.J.; Wites, J., Meyer, C J. J. Cardiac Fail. 2014, 20, 953.

. Bomprezzi, R. Ther. Adv. Neurol. Disord. 2015, 8, 20

. Yore, M.M.; Retienbach, A.N.; Sporn, M B.; Gerber, S.A.; Liby, K.T. PLoS One, 2011,

6, e22862. . Richardson, B.G.; Jain, A.D.; Spelt , T.E ; Moore, T.W. Bioorg. Med. Chem. Lett. 2015,

25. 2261

. Cleasby, A,; Yon, Day P.J.: Richardson, C.; Tickle, I.J.; Williams, P.A.; Callahan,

J.F.; Carr, R , Concha, N.: Kerns. J.K .; Qi, H.; Sweii/er, T.: Ward. P. Davies, T.G, PLoS One 2014, 9. evggoo,

. Li , X.; Zhang, D.: Hannink, M.; Beamer, L.l J. Biol Chem. 2064, 4, 279.

. Lo, S.C; Li, X.; Head, MX; Beamer, I.J.; Hannink, M. EMBO J 2006, 25, 3605.. Hancock , R.; Bertrand, H.C.; Tsujita, T.; Naz, S.; El-Bakry, A.; Laoruchupong, J.;

Hayes, ID.; Wells, G. Free Radk. Biol. Med 2012, 52, 444.

. Steel, R ; Cowan, J.; Payeme, E ; O’Connell, M.A.; Seareey M. ACS Med. Chem. Let.

2012, 3, 407.

. Hu, L,; Magesh, S.; Chen, L.; Lewis, T.A.; Chen, Y.; Khodier, C.: Inoyama, D.; Beamer,

L J.; Emge, T.J.; Slieu, J.; Kerrigan, J.E.; Kong, A.N.; Dan apani, S.; Palmer, M.; Schreiber, S.L.; Munoz, B. Bioorg Med. Chem. Lett 2013, 23, 3039.

. Jnoff, E.; Albrecht, C.; Barker, J.J.; Barker; 0.; Beaumont, E.; Bromidge, S.; Brookfield,

F.; Brooks, M.; Bobert, C.; Ceska, T.; Corden, V.; Dawson, G.; Dados, S.; Fryatt, I .; Geoicot, C. jigorel, E.; KwongJ.; Magliames, R.; Mus i , L; Pike, R.; Sands, Z.A.; Smith, M.A.; Stimson, C.C.; Courade, IP. ChemMedCheni. 2014, 9, 699.

. Marcotte, D.; Zeng, W.; Bus, i-C.; McKenzie, A.; Hession, C ; Jin, P.; Bergeron, C;

Lugovskoy, A,; Enyedy, i.; Cuervo, H.; Wang, D. Atmanene, C.; Roecklin, D.; Vecchi, M.; Vivat, V.; Kraemer, J.; Winkler, D.; Hong, V,; Chao, J.; Lukashev, M.; SiMan, L. Biorg. Med Chem 2013, 21, 4011.

. Sun, H~P.; Jiang, Z-Y.; Zhang, M-Y.; Lu, M-C.; Yang, T-T.; Pan, Y ; Huang, H-Z.;

Zhang, X-J.; You, Q-D MedChemComm 2014, i, 93

. Wa, T.Y.; Khor, T.O.; So, Z.Y.; Saw, C.L.; Shu, L.; Cheung, K.L.; Huang, Y.; Yu, S.;

Kong, A.N. AAPS i. 2013, 15, 864.

. Ma, Q.; Kinneer, K.; Bi, Y.; Chan, J.Y.; Kan, Y W Biochem. I 2004, 377, 205.

. Kwak, M-K.; Itoh, K,; Yamamoto, M.; Render, T,W. Mol. Cell Biol 2602, 22, 2883. Rushworth, S.A.; Zaitseva, L.; Murray, MX; Shah, N.M.; Bowles, K.M.; MaeBwan, DJ

Blood 2012, 120, 5188.

Lao, A.; Wang, X-J.; Zhao, F.; Viileneuve, N.F.; Wu,T.: Jiang, T ; Sim,Z.; White, E.;

Zhang, D.D. Mol. Ceil. Biol. 2010, 30, 3275.

Ichimnra, Y.; Waguri, S.; Son, Y.; Kageyanm, S.; Hasegawa, J ; Ishimura, R.; Sarto, T.;

Yang, Y.; Kouno, T.; Fakatamo, T.; Hoshii, T.; ffimo, A.; Takagi, K,; Mkushima, T.; Motohashi, H.; Lee, M.S.; Yosbiraori, T,; Tanaka, K,; Yamamoto, M,; Komatsu, M, Mol Cell 2013 , 5J . 6 I S.

bay, L.E.; Robertson. H.; Durant, S.T.: Vitale, S.R.; Penning, T.M.; D kova-Kostova, A .; Hayes. J.D. Fre Radio. Biol. Med. 20:15, 88 108.