TANK-BINDING KINASE-1 PROTACs AND ASSOCIATED METHODS OF USE

Abstract

The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) TBK1. In particular, the present invention is directed to compounds, which contain on one end an E3 ubiquitin ligase binding moiety which binds to an E3 ubiquitin ligase and on the other end a moiety which binds TBK1 such that TBK1 is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of TBK1. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of TBK1.

What is claimed is: 
     
         1 . A method of treating a disease or disorder in a subject, the method comprising administering a composition comprising a bifunctional compound and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the bifunctional compound is effective in treating or ameliorating at least one symptom of the disease or disorder and has the chemical structure:
   TBM-L-ULM,   wherein:
 TBM is a TBK1 binding moiety; 
 L is a bond or a chemical linker that covalently couples the TBM and the ULM; and 
 ULM is an E3 ubiquitin ligase binding moiety. 
   
     
     
         2 . The method of  claim 1 , wherein the disease or disorder is at least one of cancer, an inflammatory disease, an autoimmune disease, septic shock, or a viral infection. 
     
     
         3 . The method of  claim 1 , wherein the TBM structure is represented by: 
       
         
           
           
               
               
           
         
         wherein R 1  is a group selected from Cl, CF 3 , cyclobutyl, I, F, methyl, ethyl, vinyl, cyclopropyl, or Br. 
       
     
     
         4 . The method of  claim 1 , wherein the TBM has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the ULM is a moiety that binds an E3 ubiquitin ligase selected from the group consisting of Von Hippel-Lindau (VHL) E3 ubiquitin ligase, IAP, cereblon, and MDM2. 
     
     
         6 . The method of  claim 1 , wherein the chemical linker (L) is a group having the structure:
   -(A′) q -,
   wherein:
 -(A′) q - is coupled to the ULM and the TBM; and 
 q is an integer greater than or equal to 0. 
   
     
     
         7 . The method of  claim 6 , wherein:
 each A is independently CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 1-6 R L1  and/or R L2  groups, C 3-11 heteocyclyl optionally substituted with 1-6 R L1  and/or R L2  groups, aryl optionally substituted with 1-6 R L1  and/or R L2  groups, or heteroaryl optionally substituted with 1-6 R L1  and/or R L2  groups, wherein R L1  or R L2 , each independently, can be linked to other A groups to form cycloalkyl and/or heterocyclyl moiety which can be further substituted with 1-4 R L5  groups; and   R L1 , R L2 , R L3 , R L4  and R L5  are, each independently, H, halogen, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 3-8 cycloalkyl, SC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8 cycloalkyl) 2 , N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , or NH SO 2 NH 2 .   
     
     
         8 . The method of  claim 1 , wherein the chemical linker (L) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 1 , wherein the ULM has the chemical structure: 
       
         
           
           
               
               
           
         
         wherein:
 the dashed line indicates the attachment of the ULM to the chemical linker group or the TBM; 
 X 1  and X 2  are each independently a bond, O, NR Y3 , CR Y3 R Y4 , C═O, C═S, SO, or SO 2 ; 
 R Y3  and R Y4  are each independently: H; or linear or branched C 1-6  alkyl optionally substituted by 1 or more halogen or C 1-6  alkoxyl; 
 R P  is 0, 1, 2, or 3 groups in the pyrrolidine moiety, wherein each R P  is independently H, halogen, —OH, or C 1-3 alkyl; 
 W 3  is an optionally substituted -T-N(R 1a R 1b ), -T-Aryl, an optionally substituted -T-Heteroaryl, an optionally substituted -T-Heterocycle, an optionally substituted —NR 1 -T-Aryl, an optionally substituted —NR 1 -T-Heteroaryl, or an optionally substituted —NR 1 -T-Heterocycle, where T is covalently bonded to X 1 ; 
 each R 1 , R 1a , and R 1b  is independently: H; a linear or branched C 1-6  alkyl group optionally substituted by 1 or more halogen or —OH; R Y3 C═O; R Y3 C═S; R Y3 SO; R Y3 SO 2 ; N(R Y3 R Y4 )C═O; N(R Y3 R Y4 )C═S; N(R Y3 R Y4 )SO; or N(R Y3 R Y4 )SO 2 ; 
 T is an optionally substituted —(CH 2 ) n — group, wherein each one of the methylene groups may be optionally substituted with one or two substituents, selected from: halogen; a linear or branched C 1 -C 6  alkyl group optionally substituted by 1 or more halogen or OH; or the sidechain of an amino acid, which may be optionally substituted; 
 n is an integer from 0 to 6; 
 W 4  is 
 
       
       
         
           
           
               
               
           
         
         
           R 14a  and R 14b , is each independently H, haloalkyl, or optionally substituted alkyl; 
           W 5  is a phenyl or a 5-10 membered heteroaryl; and 
           R 15  is H, halogen, CN, OH, NO 2 , N R 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR 14a R 14b , NR 14a  SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl; or 
         
       
       
         
           
           
               
               
           
         
         
            wherein: R 17  is H, halogen, optionally substituted C 3-6  cycloalkyl, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, and C 1-6  haloalkyl; and 
         
         Xa is S or O. 
       
     
     
         10 . The method of  claim 1 , wherein the ULM has the chemical structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein   indicates the point of attachment to the chemical linker or the TBM. 
     
     
         11 . The method of  claim 1 , wherein the compound has the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 1 , wherein the compound has the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and combinations thereof. 
     
     
         14 . The method of  claim 1 , wherein the ULM has a chemical structure selected the group consisting of: 
       
         
           
           
               
               
           
         
         wherein:
 W is independently selected from the group CH 2 , CHR, C═O, SO 2 , NH, and N-alkyl; 
 X is independently selected from the group absent, O, and S; 
 Y is independently selected from the group NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; 
 Z is independently selected from the group absent, O, and S, except that both X and Z cannot be absent; 
 G and G′ are independently selected from the group H, alkyl, OH, CH 2 -heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′; 
 Q1-Q4 represent a N or a C with a group independently selected from H and R; 
 A is independently selected from the group H, alkyl, cycloalkyl, Cl, and F; 
 n is an integer from 1-4; 
 R is: —CONR′R″, —OR′, —NR′R″, —SR′, —SO 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF 3 , —CN, —NR′SO 2 NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO 2 )NR′R″, —SO 2 NR′COR″, —NO 2 , —CO 2 R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF 5  and —OCF 3 , wherein one R is modified to be covalently joined to the chemical linker (L) or the TBM: 
 R′ and R″ are independently selected from a bond, H, alkyl, cycloalkyl, aryl, hetaryl, and heterocyclyl; and 
    represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific. 
 
       
     
     
         15 . The method of  claim 1 , wherein the composition further comprises at least one additional bioactive agent. 
     
     
         16 . The method of  claim 15 , wherein the bioactive agent is an anti-cancer agent. 
     
     
         17 . The method of  claim 15 , wherein the bioactive agent is at least one anti-cancer agent selected from selected from the group consisting of: everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, an androgen receptor inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR 1  KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1 H—pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(But) 6,Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH 2 acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X  where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase,  Bacillus  Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox,gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof. 
     
     
         18 . A method of treating a disease or disorder in a subject, the method comprising administering a composition comprising a bifunctional compound and a pharmaceutically acceptable carrier to a subject in need thereof, wherein the bifunctional compound is effective in treating or ameliorating at least one symptom of the disease or disorder and has the chemical structure:
   TBM-L-ULM,   wherein:
 TBM includes a means for recruiting TBK1; 
 L is a bond or a chemical linker that covalently couples the TBM and the ULM; and 
 ULM includes a means for recruiting an E3 ubiquitin ligase. 
   
     
     
         19 . The method of  claim 18 , wherein the disease or disorder is at least one of cancer, an inflammatory disease, an autoimmune disease, septic shock, or a viral infection.