Compounds and methods for the targeted degradation of bromodomain-containing proteins

1. A bifunctional compound according to the structure,

PTM-L -UTM, or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof, wherein:

a) the UTM has a structure according to:

wherein:

W 3 is selected from the group of an optionally substituted aryl, optionally substituted heteroaryl, or

R 9 and R 10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R 9 , R 10 , and the carbon atom to which they are attached form an optionally substituted cycloalkyl;

R 11 is selected from the group of an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,

R 12 is selected from the group of H or optionally substituted alkyl;

R 13 is selected from the group of 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 , R 14b , are each independently selected from the group of H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;

W 5 is selected from the group of an optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl,

R 15 is selected from the group of H, halogen, CN, OH, NO 2 , NR 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; optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycle;

R 16 is independently selected from the group of halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;

o is 0, 1, 2, 3, or 4;

R 18 is independently selected from the group of halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or an attachment of L; and

p is 0, 1, 2, 3, or 4,

b) the PTM has a structure according to:

wherein:

Y 1 is selected from the group of carbon, or nitrogen;

Y 2 and Y 3 are independently selected from the group of carbon, nitrogen or oxygen and together with the atoms to form an aromatic fused ring;

A and B are independently selected from the group of a 5-membered aromatic ring, a 6-membered aromatic ring, a heteroaromatic ring, a carbocyclic, each optionally substituted with alkyl, alkoxy, halogen, an aromatic and a heteroaromatic ring; wherein ring A is fused to the central azepine (Y1=C) or diazepine (Y1=N) moiety; and

Z1 is selected from the group of methyl or an alkyl group; and wherein the dashed line indicates the site of attachment of a UTM or L coupling the PTM to the UTM;

c) L is a chemical linking moiety connecting UTM and PTM, wherein L has a structure represented by the formula: -(A L ) q -, wherein:

q is an integer greater than or equal to 1,

each A L is independently selected from the group consisting of, 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 , 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 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, 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 cycloalkyl and/or heterocyclyl moiety, optionally substituted with 1-4 R L5 groups;

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 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 , NH SO 2 NH 2 ,

wherein:

(1) the L includes at least one of S, SO, SO 2 , SO 2 NR L3 , SONR 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 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 0-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 1-4 R L5 groups, or

(2) the linker has 6-10 optionally substituted ethylene glycol units wherein each O is optionally replaced with an optionally substituted N, S, P, or Si atom.

2. The compound of claim 1 , wherein the UTM has a chemical structure selected from the group of:

wherein:

R 1 is H, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, or optionally substituted heteroaryl;

R 14a is H, optionally substituted alkyl, or cyclopropyl;

R 15 is selected from the group consisting of 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 or C═O

R 3 is an optionally substituted 5 or 6 membered heteroaryl;

wherein the dashed line indicates the site of attachment of L coupling the PTM to the UTM.

3. The compound according to claim 2 , wherein UTM is a group according to the chemical structure:

wherein:

R14a is H, haloalkyl, optionally substituted alkyl, or cyclopropyl;

R9 is H;

R10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R11 is

optionally substituted heteroaryl,

p is 0, 1, 2, 3, or 4; and

each R 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, or a linker;

R12 is H, C═O

R13 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 15 is selected from the group consisting of H, halogen, Cl, CN, OH, NO 2 , optionally substituted heteroaryl, optionally substituted aryl;

and wherein the dashed line indicates the site of attachment of at least one PTM, another UTM (UTM′) or L coupling at least one PTM or a UTM′ or both to UTM-a.

4. The compound according to claim 2 , wherein UTM is a group selected from the group consisting of:

5. The compound according to claim 4 , wherein the phenyl ring is substituted with a member selected from fluorine, a lower alkyl, or a lower alkoxy group.

6. The compound according to claim 1 , wherein PTM has a chemical structure selected from the group consisting of:

7. The compound according to any of claim 1 or 6 , wherein PTM-a is selected from the group consisting of:

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

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, with the proviso that when the number is zero, there is no N—O or 0-0 bond, R is selected from the group H, methyl and ethyl, and X is selected from the group H and F;

9. The compound according to claim 1 , wherein the L is selected from the group consisting of:

10. The compound according to claim 1 , wherein L is a polyethylene group optionally substituted with aryl or phenyl comprising from 5 to 10 ethylene glycol units.

11. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally in further combination with an additional bioactive agent.

12. The pharmaceutical composition according to claim 11 , wherein the additional bioactive agent is an anticancer agent.

13. A method of treating cancer in a subject, the method comprising administering to the patient in need thereof an effective amount of a compound according to claim 1 , wherein the compound is effective in treating or ameliorating a symptom of the cancer in the subject and the cancer is prostate cancer, ovarian cancer, breast cancer, or B-cell lymphoma.

14. The bifunctional compound according to claim 1 , wherein the linker includes S, SO, SO 2 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L3 , 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 13 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 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, 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 cycloalkyl and/or heterocyclyl moiety, optionally substituted with 1-4 R L5 groups.

15. The compound according to claim 1 , wherein the linker has 6-10 optionally substituted ethylene glycol units wherein each O is optionally replaced with an optionally substituted N atom.

16. The bifunctional compounds according to claim 1 , wherein the linker includes 7 optionally substituted ethylene glycol units.

17. The bifunctional compounds according to claim 1 , wherein the linker includes 8 optionally substituted ethylene glycol units.

18. The bifunctional compounds according to claim 1 , wherein the linker includes 9 optionally substituted ethylene glycol units.

19. The bifunctional compounds according to claim 1 , wherein the linker includes 10 optionally substituted ethylene glycol units.

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

or a pharmaceutically acceptable salt, enantiomer, or diasteromers thereof.

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

or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

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

or a pharmaceutically acceptable salt, enantiomer, or diastereomer, thereof.

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

or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.