Prodrugs of peptide epoxy ketone protease inhibitors

• US 9,309,283 B2
• Filed: 07/09/2013
• Issued: 04/12/2016
• Est. Priority Date: 07/09/2012
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Inventors: Phiasivongsa, Pasit, Luehr, Gary W., Peng, Ge, By, Kolbot, Anik, Shabbir T.
• Primary Examiner(s): Barker, Michael
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US13/938,160
• Publication Number:
  US 20140100168A1
• Time in Patent Office: 1,008 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/08 : Tripeptides
• CPC Class Codes: C07K 5/0806 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/081 : the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/0821 : with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 5/10 : Tetrapeptides
• CPC Class Codes: C07K 5/1008 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/1016 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/1021 : with the first amino acid being acidic
• CPC Class Codes: C07K 5/1024 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids

Abstract

Provided herein are compounds of formula (I):

which are pro-drugs of epoxy ketone protease inhibitors. The compounds disclosed herein include one or more moieties that (i) confer enhanced solubility, permeability, pharmacokinetics, and/or pharmacodynamics properties to epoxy ketone protease inhibitors, and (ii) can be released in vivo. Also provided herein are pharmaceutical compositions of the compounds of formula (I), and methods of using the compounds of formula (I) to treat diseases and conditions.

Claims

1. A compound having a formula (I):

2. The compound of claim 1, wherein R¹⁹ is divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, heteroalkylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, heterocycloalkylene including 3-9 ring atoms, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C_1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, or —

NHC(═

O)NH—

, wherein 6-10 membered arylene, 5-9 membered heteroarylene, and 6-10 membered cycloalkylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, cyano, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

3. The compound of claim 1, wherein R¹⁹ is divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, heteroalkylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, heterocycloalkylene including 3-9 ring atoms, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C_1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, or —

NHC(═

O)NH—

, wherein 6-10 membered arylene, 5-9 membered heteroarylene, and 6-10 membered cycloalkylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

4. The compound of claim 1, wherein R¹⁹ is a divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, heteroalkylene chain, phenylene, indolylene, indolinylene, thiophenylene, or furanylene, wherein phenylene, indolylene, indolinylene, thiophenylene, and furanylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

5. The compound of claim 1, wherein R¹⁹ is a divalent linker selected from the group consisting of

6. The compound according to claim 1, wherein R^S5 is H or C_1-6alkyl.

7. The compound according to claim 1, wherein R^S5 is H.

8. The compound according to claim 1, wherein PEG has a molecular weight of about or greater than 10 kDa.

9. The compound according to claim 1, wherein PEG has a molecular weight of about or greater than 20 kDa.

10. The compound according to claim 1, wherein PEG has a molecular weight of about or greater than 30 kDa.

11. The compound according to claim 1, wherein PEG comprises a plurality of reactive functional groups selected from the group consisting of azido, alkynyl, amino, carboxyl, and combinations thereof.

12. The compound according to claim 1,

wherein R¹¹ is:

—

CH₂OC(═

O)R²¹—

R²⁰-PEG;

wherein;

R²¹ is a divalent spacer comprising one or more of the following moieties;

heteroatom, alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, heterocycloalkylene including 3-9 ring atoms, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C_1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, —

NHC(═

)NH—

, cyclodextrin, human serum albumin, amino acid, amino acid mimetic, or hydrazine, wherein arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, and heterocycloalkylene including 3-9 ring atoms are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxyl, C_1-6 alkoxy, heteroalkyl, C_6-10 aryloxy, C_7-12 aralkoxy, CF₃, quaternary ammonium ion, sugar, C_1-6 alkyl, —

C(═

O)(C_1-6 alkyl), —

SO₂(C_1-6 alkyl), —

C(═

O)O(C_1-6 alkyl), —

C(═

O)O(heteroalkyl), —

C(═

O)NH(C_1-6 alkyl), —

C(═

O)NH(heteroalkyl), —

C(═

O)(phenyl), —

SO₂(phenyl), and phosphate or a salt thereof;

R²⁰ is

13. The compound of claim 12, wherein R²¹ is divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, heteroalkylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, heterocycloalkylene including 3-9 ring atoms, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C_1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, or —

NHC(═

O)NH—

, wherein 6-10 membered arylene, 5-9 membered heteroarylene, and 6-10 membered cycloalkylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, cyano, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

14. The compound of claim 12, wherein R²¹ is divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, heteroalkylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, heterocycloalkylene including 3-9 ring atoms, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C_1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, or —

NHC(═

O)NH—

, wherein 6-10 membered arylene, 5-9 membered heteroarylene, and 6-10 membered cycloalkylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

15. The compound of claim 12, wherein R²¹ is a divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, heteroalkylene chain, phenylene, indolylene, indolinylene, thiophenylene, or furanylene, wherein phenylene, indolylene, indolinylene, thiophenylene, and furanylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

16. The compound according claim 12, wherein R^S5 is H or C_1-6alkyl.

17. The compound according to claim 16, wherein R^S5 is H.

18. The compound according to claim 12, wherein the pharmaceutically acceptable anion is selected from chloride, iodide, acetate, mesylate, tosylate, and citrate.

19. The compound according to claim 12, wherein PEG has a molecular weight of about or greater than 10 kDa.

20. The compound according to claim 12, wherein PEG has a molecular weight of about or greater than 20 kDa.

21. The compound according to claim 12, wherein PEG has a molecular weight of about or greater than 30 kDa.

22. The compound according to claim 12, wherein PEG comprises a plurality of reactive functional groups selected from the group consisting of azido, alkynyl, amino, carboxyl, and combinations thereof.

23. The compound according to claim 12 wherein R³ is:

—

OC(═

O)—

R²²—

R²⁰-PEG,

wherein;

R²² is a divalent spacer comprising one or more of the following moieties;

heteroatom, alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, heterocycloalkylene including 3-9 ring atoms, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, —

NHC(═

O)NH—

, cyclodextrin, human serum albumin, amino acid, amino acid mimetic, or hydrazine, wherein arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, and heterocycloalkylene including 3-9 ring atoms are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxyl, C_1-6 alkoxy, heteroalkyl, C_6-10 aryloxy, C_7-12 aralkoxy, CF₃, quaternary ammonium ion, sugar, C_1-6 alkyl, —

C(═

O)(C_1-6 alkyl), —

SO₂(C_1-6 alkyl), —

C(═

O)O(C_1-6 alkyl), —

C(═

O)O(heteroalkyl), —

C(═

O)NH(C_1-6 alkyl), —

C(═

O)NH(heteroalkyl), —

C(═

O)(phenyl), —

SO₂(phenyl), and phosphate or a salt thereof;

R²⁰ is

24. The compound of claim 23, wherein R²² is divalent spacer comprising one or more of the following moieties:

heteroatom , alkylene chain, heteroalkylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, heterocycloalkylene including 3-9 ring atoms, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C_1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, or —

NHC(═

O)NH—

, wherein 6-10 membered arylene, 5-9 membered heteroarylene, and 6-10 membered cycloalkylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, cyano, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

25. The compound of claim 23, wherein R²² is divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, heteroalkylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, heterocycloalkylene including 3-9 ring atoms, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C_1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, or —

NHC(═

O)NH—

, wherein 6-10 membered arylene, 5-9 membered heteroarylene, and 6-10 membered cycloalkylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

26. The compound of claim 23, wherein R²² is a divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, heteroalkylene chain, phenylene, indolylene, indolinylene, thiophenylene, or furanylene, wherein phenylene, indolylene, indolinylene, thiophenylene, and furanylene are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

27. The compound according to claim 23, wherein R^S5 is H or C_1-6alkyl.

28. The compound according to claim 23, wherein R^S5 is H.

29. The compound according to claim 23, wherein PEG has a molecular weight of about or greater than 10 kDa.

30. The compound according to claim 23, wherein PEG has a molecular weight of about or greater than 20 kDa.

31. The compound according to claim 23, wherein PEG has a molecular weight of about or greater than 30 kDa.

32. The compound according to claim 23, wherein PEG comprises a plurality of reactive functional groups, wherein the plurality of reactive functional groups are selected from the group consisting of azido, alkynyl, amino, carboxyl, and combinations thereof.

33. The compound of claim 1, wherein Het is:

34. The compound according to claim 1, wherein M is CH₂.

35. The compound according claim 1, wherein said ring nitrogen atom of Het is further substituted with a group R¹¹, thereby forming a quaternary nitrogen atom and wherein the positive charge associated with the quaternary nitrogen atom is balanced by a pharmaceutically acceptable anion.

36. The compound of claim 35, wherein R¹¹ is:

(i) —

CH₂OC(═

O)R¹⁵;

(ii) —

C(═

O)OCH₂OC(═

O)R¹⁵;

or

(iii) —

SR¹⁵;

wherein;

R¹⁵ is C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxyC_1-6alkyl, C_6-10aryl, C_7-12aralkyl, C_3-7cycloalkyl, heteroaryl including from 5-10 ring atoms, or heterocyclyl including from 3-7 ring atoms, each of which is optionally substituted;

or

R¹⁵ is Y_n—

Z;

wherein;

Y is a divalent spacer comprising one or more of the following moieties;

heteroatom, alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

C(═

O)—

, cyclodextrin, human serum albumin, amino acid, amino acid mimetic, or hydrazine;

Z is conjugate for enhancing solubility, stability, half-life, permeability, volume of distribution, and/or target specificity, which comprises one or more of the following moieties;

alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, cyclodextrin, alkylated cyclodextrin, human serum albumin, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

C(═

O)—

, monoclonal anti-body, quaternary ammonium ion, NH₂, docosahexenoic acid, hyaluronic acid, poly(L-glutamic acid), N-(2-hydroxypropyl) methacrylamide copolymer, or dedrimers; and

n is 0 or 1.

37. The compound of claim 36, wherein R¹¹ is —

CH₂OC(═

O)R¹⁵.

38. The compound of claim 37, wherein R¹⁵ is C_1-6alkyl.

39. The compound according to claim 1, wherein the pharmaceutically acceptable anion is selected from chloride, iodide, acetate, mesylate, tosylate, and citrate.

40. The compound according to claim 1, wherein R^S1 and R^S3 are each independently C_1-6alkyl, and R^S2 and R^S4 are each independently C_7-12aralkyl.

41. The compound according to claim 40, wherein R^S1 and R^S3 are both isobutyl, R^S4 is phenylethyl, and R^S2 is phenylmethyl.

42. The compound according to claim 1, wherein R¹³ is present.

43. The compound of claim 42, wherein R¹³ is selected from acylhydrazone, acyloxime, carbamoyl oxime, acyloxyalkyl oxime, acyloxyalkyloxy oxime, oximinophosphate, oximinophosphonate, oximinophosphoramidate, oxazolidine or thiazolidine, protected hydroxyl, and protected hydroxymethyl.

44. The compound of claim 43, wherein R¹³ is ═

N-A-R¹⁷;

wherein A is NH or O, and

R¹⁷ is H, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxyC_1-6alkyl, C_6-10aryl, C_7-12aralkyl, C_3-7cycloalkyl, heteroaryl including from 5-10 ring atoms, heterocyclyl including from 3-7 ring atoms, —

C(═

O)C_1-6alkyl, —

C(═

O)C_1-6haloalkyl, —

C(═

O)C_6-10aryl, —

C(═

O)C_7-12aralkyl, —

C(═

O)C_3-7cycloalkyl, —

C(═

O)heteroaryl, or C(═

O)heterocyclyl, each of which is optionally substituted;

or

R¹⁷ is —

Y″

_q—

Z″

or —

C(═

O)—

Y″

_q—

Z″

;

wherein;

Y″

is a divalent spacer comprising one or more of the following moieties;

heteroatom, alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

C(═

O)—

, cyclodextrin, human serum albumin, amino acid, amino acid mimetic, or hydrazine;

Z″

is conjugate for enhancing solubility, stability, half-life, permeability, volume of distribution, and/or target specificity, which comprises one or more of the following moieties;

alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, cyclodextrin, alkylated cyclodextrin, human serum albumin, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

C(═

O)—

, monoclonal anti-body, quaternary ammonium ion, NH₂, docosahexenoic acid, hyaluronic acid, poly(L-glutamic acid), N-(2-hydroxypropyl) methacrylamide copolymer, or dedrimers; and

q is 0 or 1.

45. The compound according to claim 1, wherein R¹⁴ is present.

46. The compound of claim 45, wherein R¹⁴ is:

(i) —

CH₂OC(═

O)R¹⁸;

—

C(═

O)OCH₂OC(═

O)R¹⁸;

or

(iii) —

SR¹⁸;

wherein;

R¹⁸ is C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxyC_1-6alkyl, C_6-10aryl, C_7-12aralkyl, C_3-7cycloalkyl, heteroaryl including from 5-10 ring atoms, or heterocyclyl including from 3-7 ring atoms, each of which is optionally substituted;

or

R¹⁵ is —

Y′

″

_r—

Z′

″

;

wherein;

Y′

″

is a divalent spacer comprising one or more of the following moieties;

heteroatom, alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

C(═

O)—

, cyclodextrin, human serum albumin, amino acid, amino acid mimetic, or hydrazine;

Z′

″

is conjugate for enhancing solubility, stability, half-life, permeability, volume of distribution, and/or target specificity, which comprises one or more of the following moieties;

alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, cyclodextrin, alkylated cyclodextrin, human serum albumin, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

C(═

O)—

, monoclonal anti-body, quaternary ammonium ion, NH₂, docosahexenoic acid, hyaluronic acid, poly(L-glutamic acid), N-(2-hydroxypropyl) methacrylamide copolymer, or dedrimers; and

r is 0 or 1.

47. The compound of claim 1, wherein each of R^N1, R^N2, R^N3, and R^N4 is H.

48. The compound of claim 1, wherein one of R¹¹, R¹², R¹³, and R¹⁴ is present.

49. The compound according to claim 1, wherein the compound is a prodrug of:

51. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

52. A method for treating a disease or condition associated with proteasome activity selected from the group consisting of cancer, autoimmune disease, graft or transplant-related condition, neurodegenerative disease, fibrotic-associated condition, ischemic-related conditions, infection (viral, parasitic or prokaryotic) and diseases associated with bone loss, the method comprising administering to a patient a therapeutically effective amount of the compound of claim 1.

53. The method of claim 52, wherein the disease or condition is cancer.

54. The method of claim 53, wherein the cancer is multiple myeloma.

50. A compound selected from the group consisting of: