# US 10,946,017 B2 · Tank-binding kinase-1 PROTACs and associated methods of use

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- Number: US 10,946,017 B2
- Document ID: US10946017B2
- Status: Granted
- Kind: B2
- Application number: 16/284,790
- Filed: 2019-02-25
- Published: 2019-06-27
- Granted: 2021-03-16
- Earliest claimed: 2015-06-05
- Assignees: Arvinas Operations, Inc.
- Applicants: Arvinas Operations, Inc.
- Inventors: Andrew P. Crew; Jing Wang; Hanqing Dong; Yimin Qian
- Web page: https://patentgrep.com/patent/US10946017B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/665: {the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems}
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07K 5/06034: {the side chain containing 2 to 4 carbon atoms}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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.

## Claims

### Claim 1

A bifunctional compound comprising 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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the TBM has the structure:

### Claim 3 (depends on 1)

The bifunctional compound of claim 1, wherein 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.

### Claim 4 (depends on 1)

The bifunctional compound 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 TBM moiety; and
q is an integer greater than or equal to 0.

### Claim 5 (depends on 4)

The bifunctional compound of claim 4, wherein each A is independently, a bond, CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3, SONRL3, CONRL3,NRL3CONRL4, NRL3SO2NRL4, CO, CRL1═CRL2, C≡C, SiRL1RL2, P(O)RL1, P(O)ORL1, NRL3C(═NCN)NRL4, NRL3C(═NCN), NRL3C(═CNO2)NRL4, C3-11cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups , C3-11heteocyclyl optionally substituted with 0-6 RL1 and/or RL2 groups, aryl optionally substituted with 0-6 RL1 and/or RL2 groups, heteroaryl optionally substituted with 0-6 RL1 and/or RL2 groups, wherein RL1 or RL2, each independently, can be linked to other A groups to form cycloalkyl and/or heterocyclyl moeity which can be further substituted with 0-4 RL5 groups; and
wherein RL1, RL2, RL3, RL4 and RL5 are, each independently, H, halo, C1-8alkyl, OC1-8alkyl, SC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OC1-8cycloalkyl, SC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalkyl)2, N(C1-8cycloalkyl)(C1-8alkyl), OH, NH2, SH, SO2C1-8alkyl, P(O)(OC1-8alkyl)(C1-8alkyl), P(O)(OC1-8alkyl)2, CC—C1-8alkyl, CCH, CH═CH(C1-8alkyl), C(C1-8alkyl)=CH(C1-8alkyl), C(C1-8alkyl)=C(C1-8alkyl)2, Si(OH)3, Si(C1-8alkyl)3, Si(OH)(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, CON(C1-8alkyl)2, N(C1-8alkyl)CONH(C1-8alkyl), N(C1-8alkyl)CON(C1-8alkyl)2, NHCONH(C1-8alkyl), NHCON(C1-8alkyl)2, NHCONH2, N(C1-8alkyl)SO2NH(C1-8alkyl), N(C1-8alkyl)SO2N(C1-8alkyl)2, NHSO2NH(C1-8alkyl), NHSO2N(C1-8alkyl)2, NHSO2NH2.

### Claim 6 (depends on 1)

The bifunctional compound of claim 1, wherein the linker (L) is selected from the group consisting of:

### Claim 7 (depends on 1)

A composition comprising an effective amount of the bifunctional compound of claim 1, and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the composition further comprises at least one additional bioactive agent.

### Claim 9 (depends on 8)

The composition of claim 8, wherein the bioactive agent is an anti-cancer agent.

### Claim 10 (depends on 3)

The bifunctional compound of claim 3, wherein the ULM has the chemical structure:
wherein:
a dashed line indicates the attachment of the ULM to the chemical linker group or the TBM;
X1, X2 are each independently a bond, O, NRY3, CRY3RY4, C═O, C═S, SO, SO2;
RY3, RY4 are each independently: H; or linear or branched C1-6 alkyl optionally substituted by 1 or more halo or C1-6 ;
RP is 0, 1, 2, or 3 groups in the pyrrolidine moiety, wherein each RP is independently H, halo, —OH, C1-3 alkyl;
W3 is an optionally substituted —T-N(R1aR1b), —T-Aryl, an optionally substituted —T-Heteroaryl, an optionally substituted —T-Heterocycle, an optionally substituted —NR1-T-Aryl, an optionally substituted -NR1-T-Heteroaryl or an optionally substituted -NR1-T-Heterocycle, where T is covalently bonded to X1;
each R1, R1a, R1b is independently: H, a linear or branched C1-C6 alkyl group optionally substituted by 1 or more halo, or —OH; RY3C═O; RY3C═S; RY3SO; RY3SO2; N(RY3RY4)C═O; N(RY3RY4)C═S; N(RY3RY4)SO2;
T is an optionally substituted —(CH2)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 Ci-C6 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 0 to 6;
W4 is
R14a, R14b, is each independently H, haloalkyl, or optionally substituted alkyl;
W5 is a phenyl or a 5-10 membered heteroaryl; and
R15 is H, halogen, CN, OH, NO2, N R14aR14b, OR14a, CONR14aR14b, NR14aCOR14b, SO2NR14aR14b, NR14a SO2R14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl, cycloheteroalkyl;.

### Claim 11 (depends on 1)

The bifunctional compound of claim 1, wherein the compound has the chemical structure:

### Claim 12 (depends on 1)

The bifunctional compound of claim 1, wherein the compound has the chemical structure:

### Claim 13 (depends on 1)

The bifunctional compound of claim 1, wherein the compound is selected from the group consisting of:
and combinations thereof.

### Claim 14 (depends on 1)

The bifunctional compound of claim 1, wherein the ULM has a chemical structure selected the group consisting of:
wherein:
W is independently selected from the group CH2, CHR, C═O, SO2, 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, CH2-heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;
Q1-Q4 represent a carbon C substituted with a group independently selected from H, R, N or N-oxide;
A is independently selected from the group H, alkyl, cycloalkyl, Cl and F;
R is: —CONR′R″, —OR′, —NR′R″, —SR′, —SO2R′, —SONR′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, —CF3, —CN, —NR′SO2NR′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—NO2)NR′R″, —SO2NR′COR″, —NO2, —CO2R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF5 and —OCF3, wherein one R is modified to be covalently joined to the chemical linker group or the TBM:
R′ and R″ are independently selected from a bond, H, alkyl, cycloalkyl, aryl, hetaryl, heterocyclyl;
n is an integer from 1-4; and
represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific.

### Claim 15 (depends on 13)

A composition comprising an effective amount of the compound of claim 13, and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 15)

The composition of claim 15, wherein the composition further comprises at least one additional bioactive agent.

### Claim 17

A TBK1 binding moiety having the chemical structure:

### Claim 18

A method of making a bifunctional molecule comprising the chemical structure TBM-L-ULM, the method comprising:
covalently linking the TBM to the L; and
covalently linking the L to the ULM,
wherein:
the TBM is a TBK1 binding moiety,
the L is a chemical linker that covalently couples the TBM and the ULM, and
the ULM is an E3 ubiquitin ligase binding moiety.

### Claim 19

A bifunctional compound comprising 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.

### Claim 20 (depends on 1)

The bifunctional compound of claim 1, wherein the TBM structure is represented by:
wherein R1 is a group selected from Cl, CF3, cyclobutyl, I, F, methyl, ethyl, vinyl, cyclopropyl, or Br.

### Claim 21 (depends on 1)

The bifunctional compound of claim 1, wherein the ULM has the chemical structure:
wherein
indicates the point of attachment to the chemical linker or the TBM.