Tau-protein targeting protacs and associated methods of use

Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.

What is claimed is: 
     
         1 . A bifunctional compound having the chemical structure:
   ULM-L-PTM,   
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       (a) ULM is:
 (i) represented by the structure: 
 
       
         
           
           
               
               
           
         
         
           wherein:
 X 1  and X 2  are each independently selected from a bond, O, NR Y3 , CR Y3 R Y4 , C═O, C═S, SO, and SO 2 ; 
 R Y3  and R Y4  are each independently selected from H and linear or branched C 1-6  alkyl optionally substituted by 1 or more halogen or C 1-6  alkoxyl; 
 R P  is 1, 2, or 3 groups, each independently selected from the group H, halogen, —OH, and C 1-3  alkyl; 
 W 3  is an optionally substituted -T-N(R 1a R 1b ), an optionally substituted -T-N(R 1a R 1b )X 3 , -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; 
 X 3  is C═O, R 1 , R 1a , or R 1b ; 
 each R 1 , R 1a , and R 1b  is independently selected from H, 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, and N(R Y3 R Y4 )SO 2 , and linear or branched C 1-6  alkyl group optionally substituted by 1 or more halogen or —OH groups; 
 T is —(CH 2 ) n —, wherein each one of the methylene groups is optionally substituted with one or two substituents independently selected from halogen, methyl, a linear or branched C 1-6  alkyl group optionally substituted by 1 or more halogen or —OH, and an optionally substituted amino acid side chain; 
 n is 0, 1, 2, 3, 4, 5, or 6; 
 W 4  is 
 
         
       
       
         
           
           
               
               
           
         
         
           
             R 14a  and R 14b  are each independently selected from H and 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 haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl, 
                indicates the site of attachment of L; or 
           
         
         (ii) represented by: 
       
       
         
           
           
               
               
           
         
         
           wherein:
 W is CH 2 , CHR, C═O, SO 2 , NH, or N-alkyl; 
 each X is independently selected from O, S, and H 2 ; 
 Y is CH 2 , —C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, or S; 
 Z is O, S, or H 2 ; 
 G and G′ are independently selected from H, OH, R′OCOOR, R′OCONRR″, linear or branched alkyl optionally substituted with R′, CH 2 -heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′; 
 each of Q 1 , Q 2 , Q 3 , and Q 4  independently represents N, CH, or CR; 
 A is H, alkyl, cycloalkyl, Cl, or F; 
 n is 1, 2, 3, or 4; 
 each R is independently selected from —CONR′R″, —OR′, —NR′R″, —SR′, —SO 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, -aryl, -heteroaryl, optionally substituted linear or branched 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 covalently linked to L; 
 R′ and R″ are each independently selected from a bond, H, N, N-oxide, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted aryl, heteroaryl, optionally substituted heterocyclic, or optionally substituted heterocyclyl; and 
    represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; 
 
         
       
       (b) PTM is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2  and R 3  are each independently selected from H, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; 
 R 4  and R 5  are each independently selected from H, methyl, ethyl, and halogen; and 
 R 6  is 1 to 2 substituents independently selected from H, methyl, ethyl, and halogen; and 
 
       
       (c) L is a bond or a chemical linking moiety connecting ULM and PTM. 
     
     
         2 . The compound of  claim 1 , wherein the ULM is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein the ULM is represented by the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 W 3  is an optionally substituted aryl, optionally substituted heteroaryl, or 
 
       
         
           
           
               
               
           
         
         R 9  and R 10  are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heteroaryl, or R 9 , R 10 , and the carbon atom to which they are attached form an optionally substituted cycloalkyl; 
         R 11  is an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, 
       
       
         
           
           
               
               
           
         
         R 12  is H or optionally substituted alkyl; 
         R 13  is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; 
         R 14a  and R 14b  are each independently selected from H or optionally substituted alkyl; 
         W 5  is a phenyl or a 5-10 membered heteroaryl; 
         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 haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl; 
         each R 16  is independently selected from H, halogen, optionally substituted alkyl, hydroxy, and optionally substituted haloalkoxy; 
         o is 0, 1, 2, 3, or 4; 
         each R 18  is independently selected from halogen, optionally substituted alkoxy, cyano, and optionally substituted alkyl; and 
         p is 0, 1, 2, 3, or 4; and 
            indicates the site of attachment of L. 
       
     
     
         4 . The compound of  claim 1 , wherein the ULM has a chemical structure selected from: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; 
 R 14a  is H, haloalkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; 
 R 15  is H, halogen, CN, OH, NO 2 , optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl; 
 X is C, CH 2 , or C═O; 
 R 3  is a bond or an optionally substituted 5 or 6 membered heteroaryl; and 
    indicates the site of attachment of L. 
 
     
     
         5 . The compound of  claim 11 , wherein the ULM has the chemical structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 14a  is H, haloalkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; 
 R 9  is H; 
 R 10  is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; 
 R 11  is 
 
       
         
           
           
               
               
           
         
       
       or optionally substituted heteroaryl;
 p is 0, 1, 2, 3, or 4; 
 each R 18  is independently selected from halogen, optionally substituted alkoxy, cyano, and optionally substituted alkyl; 
 R 12  is H or C═O; 
 R 13  is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; and 
 R 15  is H, halogen, Cl, CN, OH, NO 2 , optionally substituted heteroaryl, optionally substituted aryl, 
 
       
         
           
           
               
               
           
         
       
       and
    indicates the site of attachment of L. 
 
     
     
         6 . The compound of  claim 1 , wherein the ULM is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 the phenyl ring in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 is optionally substituted with fluorine, C 1-3  alkyl, or alkoxy; and 
    indicates the site of attachment of L. 
 
     
     
         7 . The compound of  claim 1 , wherein the ULM has a chemical structure represented by: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the ULM has the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein the ULM has the chemical structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 W is CH 2 , C═O, NH, or N-alkyl; 
 each R is independently selected from a H and alkyl, wherein one R covalently linked to L; and 
    represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific. 
 
     
     
         10 . The compound of  claim 1 , wherein the ULM has a chemical structure represented by: 
       
         
           
           
               
               
           
         
       
       wherein   indicate point of attachment to L. 
     
     
         11 . The compound of  claim 1 , wherein the L is represented by the formula -(A L ) q -, wherein:
 -(A L ) q -is connected to the ULM and the PM;   q is an integer greater than or equal to 1;   each A is independently selected from 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 groups independently selected from R L1  and R L2 , C 3-11 heterocyclyl optionally substituted with 1-6 groups independently selected from R L1  and R L2 , aryl optionally substituted with 1-6 groups independently selected from R L1  and R L2 , and heteroaryl optionally substituted with 1-6 groups independently selected from R L1  and R L2 , where R L1  or R L2 , each independently are optionally linked to other groups to form a cycloalkyl or heterocyclyl moiety, optionally substituted with 1-4 independently selected R L5  groups; and   each R L1 , R L2 , R L3 , R L4 , and R L5  is independently selected from 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, 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 , and NH SO 2 NH 2 .   
     
     
         12 . The compound of  claim 1 , wherein the L is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       —N(R)—(CH 2 ) m —O(CH 2 ) n —O(CH 2 ) o —O(CH 2 ) p —O(CH 2 ) q —O(CH 2 ) r —OCH 2 —, —O—(CH 2 ) m —O(CH 2 ) n —O(CH 2 ) o —O(CH 2 ) p —O(CH 2 ) q —O(CH 2 ) r —OCH 2 —, —O—(CH 2 ) m —O(CH 2 ) n —O(CH 2 ) o —O(CH 2 ) p —O(CH 2 ) q —O(CH 2 ) r —O—; —N(R)—(CH 2 ) m —O(CH 2 ) n —O(CH 2 ) o —O(CH 2 ) p —O(CH 2 ) q —O(CH 2 ) r —O—; —(CH 2 ) m —O(CH 2 ) n —O(CH 2 ) o —O(CH 2 ) p —O(CH 2 ) q —O(CH 2 ) r —O—; —(CH 2 ) m —O(CH 2 ) n —O(CH 2 ) o —O(CH 2 ) p —O(CH 2 ) q —O(CH 2 ) r —OCH 2 —; 
       
         
           
           
               
               
           
         
       
       wherein:
 each m, n, o, p, q, and r of L is independently 0, 1, 2, 3, 4, 5, or 6, with the proviso that when the number is zero, there is no N—O or O—O bond; 
 R of L is H, methyl, or ethyl; and 
 X of L is H or F. 
 
     
     
         13 . The compound of  claim 1 , wherein the L is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein the L is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each n and m of L is independently 0, 1, 2, 3, 4, 5, or 6. 
     
     
         15 . The compound according to  claim 1 , wherein the L is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units. 
     
     
         16 . A composition comprising a bifunctional compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . The composition of  claim 16 , wherein the composition further comprises at least one of additional bioactive agent 
     
     
         18 . The composition of  claim 17 , wherein the additional bioactive agent is an anti-neurodegenerative agent. 
     
     
         19 . The composition of  claim 17 , wherein the additional bioactive agent is a P-gp inhibitor. 
     
     
         20 . The composition of  claim 19 , wherein the P-gp inhibitor is Amiodarone, Azithromycin, Captopril, Clarithromycin, Cyclosporine, Piperine, Quercetin, Quinidine, Quinine, Reserpine, Ritonavir, Tariquidar, Elacridar, or Verapamil. 
     
     
         21 . A method of treating a Tau-related disease or disorder, comprising administering an effective amount of a compound of  claim 1  to a subject in need thereof, wherein the compound effectuates degradation of Tau protein thereby treating or ameliorating at least one symptom of a Tau disease or disorder, wherein the Tau disease or disorder is associated with Tau accumulation and aggregation. 
     
     
         22 . The composition of  claim 21 , wherein the disease or disorder is a neurodegenerative disease associated with Tau accumulation and aggregation. 
     
     
         23 . The composition of  claim 21 , wherein the disease or disorder is a neurological disorder with at least one of Huntington's disease, muscular dystrophy, Parkinson's disease, Alzheimer's disease, Batten disease, Injuries to the spinal cord and brain, Seizure disorders, epilepsy, brain tumors, meningitis, autoimmune diseases such as multiple sclerosis, neurofibromatosis, Depression, Amyotrophic Lateral Sclerosis, Arteriovenous Malformation, Brain Aneurysm, Dural Arteriovenous Fistulae, Headache, Memory Disorders, Peripheral Neuropathy, Post-Herpetic Neuralgia, Spinal Cord Tumor and Stroke. 
     
     
         24 . The composition of  claim 21 , wherein the disease or disorder is Alzheimer's disease.