Tank-binding kinase-1 PROTACs and associated methods of use

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.

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

3. 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.

4. 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.

5. The bifunctional compound of claim 4 , wherein each A is independently, a bond, 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 0-6 R L1 and/or R L2 groups , C 3-11 heteocyclyl optionally substituted with 0-6 R L1 and/or R L2 groups, aryl optionally substituted with 0-6 R L1 and/or R L2 groups, heteroaryl optionally substituted with 0-6 R L1 and/or R L2 groups, wherein R L1 or R L 2 , each independently, can be linked to other A groups to form cycloalkyl and/or heterocyclyl moeity which can be further substituted with 0-4 R L5 groups; and

wherein R L1 , R L2 , R L3 , R L4 and R L5 are, each independently, H, halo, 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 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl) 2 , N(C 1-8 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 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH 2 .

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

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

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

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

10. 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;

X 1 , X 2 are each independently a bond, O, NR Y3 , CR Y3 R Y4 , C═O, C═S, SO, SO 2 ;

R Y3 , R Y4 are each independently: H; or linear or branched C 1-6 alkyl optionally substituted by 1 or more halo or C 1-6 ;

R P is 0, 1, 2, or 3 groups in the pyrrolidine moiety, wherein each R P is independently H, halo, —OH, 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 , R 1b is independently: H, a linear or branched C 1 -C 6 alkyl group optionally substituted by 1 or more halo, 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 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 Ci-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 0 to 6;

W 4 is

R 14a , 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;.

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

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

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

and combinations thereof.

14. 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 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 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′, —SO 2 R′, —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, —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 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.

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

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

17. A TBK1 binding moiety having the chemical structure:

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.

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.

20. The bifunctional compound 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.

21. 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.