Tau-protein targeting PROTACs and associated methods of use

Patent metadata

Field	Value
Publication number	US-11458123-B2
Application number	US-201715801243-A
Country	US
Kind code	B2
Filing date	Nov 1, 2017
Priority date	Nov 1, 2016
Publication date	Oct 4, 2022
Grant date	Oct 4, 2022

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.

First claim

What is claimed is:

1. A bifunctional compound having the chemical structure:
CLM-L-PTM,

or a pharmaceutically acceptable salt thereof,
wherein:
(a) the L is a chemical linking moiety connecting the CLM and the PTM;
(b) the CLM is an E3 ubiquitin ligase binding moiety that binds cereblon E3 ubiquitin ligase and that has a chemical structure selected from:

wherein:
W is selected from the group consisting of CH 2 , CHR, and C═O;
each X is independently selected from the group consisting of O, S, and absent;
Z is selected from the group consisting of O, S, and absent;
G and G′ are independently selected from the group consisting of H, OH, CH 2 -heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;
Q 1 , Q 2 , Q 3 , and Q 4 represent a carbon substituted with a group independently selected from H and R;
A is independently selected from the group consisting of H, alkyl, cycloalkyl, Cl, and F;
n is an integer from 1 to 4;
R is —CONR′R″, —OR′, —NR′R″, —SR′, —SO 2 R′, —SO 2 NR′R″, —CR′R″—, —CR′NR′R″—, -aryl, -heteroaryl, -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 or —OCF 3 , wherein one R is modified to be covalently joined to the chemical linking moiety;
R′ and R″ are independently selected from the group consisting of a bond, H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; and
represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

(c) the PTM is a Tau protein targeting moiety of Formula I:

wherein:
rings A and C are independently selected from a 5- or 6-membered aryl and 5- or 6-membered heteroaryl; and
ring B is a 5-membered aryl or 5-membered heteroaryl, wherein:
contact between circles indicates ring fusion; and
rings A, B, and C are each independently optionally substituted with 1-3 substituents independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, and cyano;
ring D is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl, wherein ring D is optionally substituted with 1-3 substituents independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, and cyano; and
L PTM is a bond or alkyl.

2. The compound according to claim 1 , wherein:
A and C rings are independently a 5- or 6-membered aryl or a 5- or 6-membered heteroaryl;
ring B is a 5-membered aryl or a 5-membered heteroaryl;
L PTM is selected from a bond and an alkyl; and
ring D is selected from a 6-membered aryl and a 6-membered heteroaryl,
wherein A, B, C and D rings are optionally substituted with 1-3 substituents independently selected from alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, and cyano.

3. The compound according to claim 1 , wherein rings A, B, C, and D are each optionally substituted with 1-3 substituents independently selected from alkyl, haloalkyl, and halogen.

4. The compound according to claim 1 , wherein ring D is a substituted 6-membered aryl or a substituted 6-membered heteroaryl, wherein ring D is substituted with 1-3 substituents independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, and cyano.

5. The compound according to claim 1 , wherein ring D is an unsubstituted 6-membered aryl or an unsubstituted 6-membered heteroaryl.

6. The compound of claim 1 , wherein ring D is a selected from a 6-membered heteroaryl, wherein ring D is optionally substituted with 1-3 substituents, each substituent independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, and cyano.

7. The compound according to claim 1 , wherein the CLM has a chemical structure represented by:

wherein:
W is independently selected from the group consisting of CH 2 and C═O;
A is independently selected from the group consisting of H, methyl, and alkyl;
n is an integer from 1 to 4;
one R is modified to be covalently joined to the chemical linking moiety; and
represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific.

8. The compound according to claim 1 , wherein the CLM has a chemical structure represented by:

wherein the

indicate the chemical linking moiety attachment points.

9. The compound according to claim 1 , wherein the chemical linking moiety comprises a chemical structural unit represented by the formula:
-(A L ) q -,

wherein:
A L is a group which is connected to the CLM or the PTM;
q is an integer greater than or equal to 1,
each A L is independently selected from the group consisting of 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), C 3-11 heterocycloalkyl optionally substituted with 1-6 R L1 and/or R L2 groups, C 3-11 heterocyclyl 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, and heteroaryl optionally substituted with 1-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently, are optionally linked to other groups to form a cycloalkyl or heterocyclyl moiety that is optionally 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 , C≡C—C 1-8 alkyl, C≡CH, 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 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 , or NHSO 2 NH 2 .

10. The compound according to claim 1 , wherein the PTM is represented by a chemical structure selected from the group consisting of:

Assignees

• Arvinas Inc
• Arvinas Operations Inc

Inventors

• Crew Andrew P
• Berlin Michael
• Dong Hanqing
• Ishchenko Alexey

Classifications

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61K31/495

  having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) · CPC title

• A61K31/4166 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin · CPC title