COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES

• US 20180179183A1
• Filed: 12/22/2017
• Published: 06/28/2018
• Est. Priority Date: 12/23/2016
• Status: Active Grant

• Current Assignee: Arvinas Operations, Inc. (Arvinas, Inc.), Yale University
• Original Assignee: Arvinas, Inc., Yale University
• Inventors: Crew, Andrew P., Hornberger, Keith R., Wang, Jing, Dong, Hanqing, Qian, Yimin, Crews, Craig M., Jaime-Figueroa, Saul
• Granted Patent: US 10,723,717 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

Claims

1. A bifunctional compound having the chemical structure:

ULM-L-PTM,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph or prodrug thereof,

wherein;

the ULM is a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase;

the PTM is a small molecule comprising a rapidly accelerated fibrosarcoma (RAF) protein targeting moiety; and

the L is a bond or a chemical linking moiety connecting the ULM and the PTM.

2. The bifunctional compound according to claim 1, wherein the E3 ubiquitin ligase binding moiety that targets an E3 ubiquitin ligase selected from the group consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mouse double-minute homolog2 (MLM), and IAP (ILM).

3. The bifunctional compound according to claim 1, wherein the PTM is represented by chemical structure PTM-Ia or PTM-Ib:

4. The bifunctional compound according to claim 1, wherein the PTM is represented by chemical structure PTM-IIa or PTM-IIb:

5. The bifunctional compound according to claim 4, wherein:

when R_PTM9 is the covalently joined position, R_PTM7 and R_PTM8 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM7 and R_PTM8 are attached;

or

when R_PTM18 is the covalently joined position, R_PTM9 and R_PTM10 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM9 and R_PTM10 are attached;

or

when RPTM10 is the covalently joined position, RPTM8 and RPTM9 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which RPTM8 and RPTM9 are attached.

6. The bifunctional compound according to claim 1, wherein the PTM is represented by chemical structure PTM-III:

7. The compound according to claim 6, wherein:

when R_PTM12 is the covalently joined position, R_PTM13 and R_PTM14 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM13 and R_PTM14 are attached, and/or R_PTM15 and R_PTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM15 and R_PTM16 are attached;

when R_PTM13 is the covalently joined position, R_PTM12 and R_PTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM12 and R_PTM16 are attached, and/or R_PTM15 and R_PTM16 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM15 and R_PTM16 are attached;

or

when R_PTM16 is the covalently joined position, R_PTM12 and R_PTM13 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM12 and R_PTM13 are attached, and/or R_PTM13 and R_PTM14 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM13 and R_PTM14 are attached

8. The bifunctional compound according to claim 1 or 2, wherein the PTM is represented by chemical structure PTM-IVa or PTM-IVb:

9. The bifunctional compound according to claim 8, wherein:

when R_PTM24 is the covalently joined position, R_PTM31 and R_PTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM31 and R_PTM32 are attached, or R_PTM29 and R_PTM30 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM29 and R_PTM30 are attached;

or

when R_PTM29 is the covalently joined position, R_PTM24 and R_PTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM24 and R_PTM32 are attached, and/or R_PTM31 and R_PTM32 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM31 and R_PTM32 are attached;

or when R_PTM32 is the covalently joined position, R_PTM24 and R_PTM29 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM24 and R_PTM29 are attached, and/or R_PTM29 and R_PTM30 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R_PTM29 and R_PTM30 are attached.

10. The bifunctional compound according to claim 1, wherein the PTM is selected from the group consisting of PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, and PTM-8:

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

12. The bifunctional compound according to claim 1, wherein ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with a chemical structure represented by:

13. The bifunctional compound according to claim 1, wherein ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with a chemical structure represented by:

14. The bifunctional compound according to claim 1, wherein the ULM has a chemical structure selected from the group of:

15. The bifunctional compound according to claim 1, wherein the ULM comprises a group according to the chemical structure:

16. The bifunctional compound according to claim 1, wherein the ULM comprises a group according to the chemical structure:

17. The bifunctional compound according to claim 1, wherein the ULM is a cereblon E3 ligase-binding moiety (CLM) selected from the group coinsisting of a thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

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

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

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

21. The bifunctional compound according to claim 1, wherein the ULM is a (MDM2) binding moiety (MLM) with a chemical moiety selected from the group consisting of a substituted imidazolines, a substituted spiro-indolinones, a substituted pyrrolidines, a substituted piperidinones, a substituted morpholinones, a substituted pyrrolopyrimidines, a substituted imidazolopyridines, a substituted thiazoloimidazoline, a substituted pyrrolopyrrolidinones, and a substituted isoquinolinones.

22. The bifunctional compound according to claim 1, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM) comprising the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or their unnatural mimetics.

23. The bifunctional compound according to claim 1, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM) comprising a AVPI tetrapeptide fragment or derivative thereof.

24. The bifunctional compound according to claim 1, wherein the linker (L) comprises a chemical structural unit represented by the formula:

-(A^L)_q-,

wherein;

(A^L)_q is a group which is connected to a ULM or PTM moiety;

q is an integer greater than or equal to 1;

each A^L is independently selected from the group consisting of, a bond, CR^L1R^L2, O, S, SO, SO₂, NR^L3, SO₂NR^L3, SONR^L3, CONR^L3, NR^L3CONR^L4, NR^L3SO₂NR^L4, CO, CR^L1═

CR^L2, C≡

C, SiR^L1R^L2, P(O)R^L1, P(O)OR^L1, NR^L3C(═

NCN)NR^L4, NR^L3C(═

NCN), NR^L3C(═

CNO₂)NR^L4, C_3-11cycloalkyl optionally substituted with 0-6 R^L1 and/or R^L2 groups, C_3-11heteocyclyl 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, where R^L1 or R^L2, each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R^L5 groups; and

R^L1, R^L2, R^L3, R^L4 and R^L5 are, each independently, H, halo, C_1-8alkyl, OC_1-8alkyl, SC_1-8alkyl, NHC_1-8alkyl, N(C_1-8alkyl)₂, C_3-11cycloalkyl, aryl, heteroaryl, C_3-11heterocyclyl, OC_1-8cycloalkyl, SC_1-8cycloalkyl, NHC_1-8cycloalkyl, N(C_1-8cycloalkyl)₂, N(C_1-8cycloalkyl)(C_1-8alkyl), OH, NH₂, SH, SO₂C_1-8alkyl, P(O)(OC_1-8alkyl)(C_1-8alkyl), P(O)(OC_1-8alkyl)₂, CC—

C_1-8alkyl, CCH, CH═

CH(C_1-8alkyl), C(C_1-8alkyl)═

CH(C_1-8alkyl), C(C_1-8alkyl)=C(C_1-8alkyl)₂, Si(OH)₃, Si(C_1-8alkyl)₃, Si(OH)(C_1-8alkyl)₂, COC_1-8alkyl, CO₂H, halogen, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅, SO₂NHC_1-8alkyl, SO₂N(C_1-8alkyl)₂, SONHC_1-8alkyl, SON(C_1-8alkyl)₂, CONHC_1-8alkyl, CON(C_1-8alkyl)₂, N(C_1-8alkyl)CONH(C_1-8alkyl), N(C_1-8alkyl)CON(C_1-8alkyl)₂, NHCONH(C_1-8alkyl), NHCON(C_1-8alkyl)₂, NHCONH₂, N(C_1-8alkyl)SO₂NH(C_1-8alkyl), N(C_1-8alkyl) SO₂N(C_1-8alkyl)₂, NH SO₂NH(C_1-8alkyl), NH SO₂N(C_1-8alkyl)₂, NH SO₂NH₂.

25. The bifunctional compound according to claim 24, wherein the linker (L) comprises a group represented by a general structure selected from the group consisting of:

—

N(R)—

(CH2)_m-O(CH2)_n—

O(CH2)_o-O(CH2)_p-O(CH2)_q-O(CH2)_r-OCH2-,

—

O—

(CH2)_m-O(CH2)_n—

O(CH2)_oO(CH2)_p-O(CH2)_q-O(CH2)_r-OCH2-,

—

O—

(CH2)_m-O(CH2)_n—

O(CH2)_oO(CH2)_p-O(CH2)_q-O(CH2)_r-O—

;

—

N(R)—

(CH2)_m-O(CH2)_n—

O(CH2)_o-O(CH2)_p-O(CH2)_q-O(CH2)_r-O—

;

—

(CH2)_m-O(CH2)_n—

O(CH2)_oO(CH2)_p-O(CH2)_q-O(CH2)_r-O—

;

—

(CH2)_m-O(CH2)_n—

O(CH2)_o-O(CH2)_p-O(CH2)_q-O(CH2)_r-OCH2-;

26. The bifunctional compound according to claim 24, wherein the linker (L) is selected from the group consisting of:

27. The bifunctional compound according to claim 24, wherein the linker (L) is selected from the group consisting of:

28. The bifunctional compound according to claim 24, wherein the linker (L) is selected from the group consisting of:

29. The bifunctional compound according to claim 1, wherein the linker (L) comprises the following chemical structure:

30. The bifunctional compound according to claim 1, wherein the linker (L) comprises the following chemical structure:

31. The bifunctional compounds according to claim 24, wherein the linker (L) is selected from the group consisting of:

32. The bifunctional compound according to claim 24, wherein the linker (L) is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units.

33. The bifunctional compound according to claim 24, wherein the linker is selected from the group consisting of:

34. The bifunctional compound of claim 1, wherein the compound is selected from Table 1 through Table 42.

35. The bifunctional compound according to claim 1, wherein the PTM is a small molecule comprising a B-RAF protein targeting moiety.

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

37. The composition according to claim 30, wherein the composition further comprises at least one of an additional bioactive agent or another bifunctional compound of claim 1.

38. The composition according to claim 37, wherein the additional bioactive agent is anti-cancer agent.

39. A composition comprising a pharmaceutically acceptable carrier and an effective amount of at least one compound according to claim 1 for treating a disease or disorder in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.

40. The composition according to claim 39, wherein the disease or disorder is associated with BRaf accumulation and aggregation.

41. The composition according to claim 39, wherein the disease or disorder is cancer;

cardiofaciocutaneous syndrome;

neurofibromatosis type 1;

Costello syndrome;

Noonan Syndrome;

or Lentigo, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth, Deafness (LEOPARD) syndrome associated with RAF accumulation and aggregation.

42. The composition according to claim 41, wherein the cancer is renal cell carcinoma;

pancreatic cancer, colorectal cancer;

lung cancer;

ovarian cancer;

thyroid cancer;

pilocytic astrocytoma;

prostate cancer;

gastric cancer;

hepatocellular carcinoma;

or melanoma.