SMALL MOLECULE RAS INHIBITORS

• US 20170304383A1
• Filed: 05/19/2015
• Published: 10/26/2017
• Est. Priority Date: 05/20/2014
• Status: Active Grant

• Current Assignee: Ohio State Innovation Foundation (Ohio State University)
• Original Assignee: Dehua Pei, Ohio State Innovation Foundation (Ohio State University), Punit Upadhyaya, Roger Briesewitz
• Inventors: BRIESEWITZ, Roger, PEI, Dehua, UPADHYAYA, Punit
• Granted Patent: US 10,736,932 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 2039/627 characterised by the linker
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/01 Hydrocarbons
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/012 from animals
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: C07K 14/4703 Inhibitors; Suppressors
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

Disclosed herein are novel compounds that are Ras inhibitors. Also disclosed are compositions comprising the compounds and methods of using the compounds in treating various diseases. In another aspect, provided is an antibody-drug-conjugate comprising an antibody conjugated with a compound described herein. In still another aspect, provided is a pharmaceutical composition comprising a compound or antibody-drug-conjugate described herein. In a further aspect, provided is method of treating a cancer comprising administering a therapeutically effective amount of a compound or antibody-drug-conjugate described herein to a patient in need thereof.

Claims

1. A compound of formula A

4. The compound of claim 1, wherein R¹, R² and R⁴ are independently selected

from the group consisting of C₁-C₆ alkyl or C₁-C₆ alkyl substituted with R²⁰, wherein R²⁰ is —

NH₂, —

NHC(═

NH)NH₂, —

NHR³⁰ or —

NHC(═

NH)NHR³⁰; and

wherein R³⁰ is a fluorescent label, provided that only one of R¹, R² and R⁴ is C₁-C₆ alkyl, wherein R¹, R² and R⁴ are optionally independently selected from

—

CH₃, —

(CH₂)₃NHC(═

NH)NH₂, —

(CH₂)₃NHC (′

NH)NHR³⁰, —

(CH₂)₄NH₂ and —

(CH₂)₄NHR³⁰.

7. The compound of claim 1, wherein:

a) R³ is —

(CH₂)_p-L³-R²³, wherein p is 0, 1, 2 or 3, L³ is a covalent bond, C(O)NH or NHC(O), and R²³ is phenyl or naphthyl;

or

b) R⁵ is —

(CH₂)_p-L⁵-R²⁵, wherein p is 0, 1, 2 or 3, L⁵ is a covalent bond, C(O)NH or NHC(O), and R²⁵ is phenyl or pyridyl, wherein the phenyl and pyridyl are optionally substituted with 1 to 3 substituents independently selected from halo, cyano and OH.

9. The compound of claim 1, wherein:

a) R⁶ is selected from the group consisting of H, phenyl, C₁-C₆ alkyl or C₁-C₆ alkyl substituted with R²⁶, wherein R²⁶ is selected from the group consisting of NH₂, C(O)NH₂, NHC(═

NH)NH₂, and NH-L⁶-R³⁶, wherein L⁶ is a covalent bond, C(O), C(O)CH═

CH, C(O)NH or C(S)NH, and R³⁶ is selected from the group consisting of phenyl, pyridyl, or a fluorescent label, wherein the phenyl or pyridyl are optionally substituted with 1 to 3 halo;

or

b) R⁷ is —

(CH₂)_q-L⁷-R²⁷, wherein q is 0, 1, 2 or 3, L⁷ is a covalent bond, C(O)NH or NHC(O), and R²⁷ is H, OH, C(O)NH₂, heteroaryl, phenyl or naphthyl, wherein the heteroaryl, phenyl or naphthyl is optionally substituted with 1 to 3 substituents independently selected from halo and OH; and

wherein R⁷ is optionally selected from the group consisting of —

CH₃, —

CH₂Ph, —

CH₂Ph(4-fluoro), —

CH₂(Ph(4-OH), —

CH₂-indolyl, —

CH₂OH, —

CH₂CH₂C(O)NH₂, —

CH₂-naphthyl, —

CH₂CH₂C(O)NH₂ and —

CH₂C(O)NH₂.

12. The compound of claim 1, wherein R⁸ is selected from the group consisting of H, phenyl, C₁-C₆ alkyl or C₁-C₆ alkyl substituted with R²⁸, wherein R²⁸ is selected from the group consisting of OH, phenyl, naphthyl, heteroaryl, NH₂, NHC(═

NH)NH₂, and NH-L⁸-R³⁸, wherein the phenyl, naphthyl, and heteroaryl are optionally substituted with 1 to 3 halo or aralkyl;

L⁸ is a covalent bond, C(O), C(O)CH═

CH, C(O)NH, NHC(O)CH═

CH, or C(S)NH, and R³⁸ is selected from the group consisting of H, alkyl, phenyl, pyridyl, or a fluorescent label, wherein the phenyl or pyridyl are optionally substituted with 1 to 3 halo; and

wherein R⁸ is optionally selected from the group consisting of H, phenyl, n-butyl, isobutyl, —

CH₂-indolyl, —

(CH₂)₃NHC(═

NH)NH₂, —

CH₂C(O)NH₂, —

(CH₂)₂COOH,

14. The compound of claim 1, wherein:

a) R⁹ is —

(CH₂)_p-L⁹-R²⁹, wherein p is 0, 1, 2 or 3, L⁹ is a covalent bond, C(O)NH or NHC(O), and R²⁹ is H, OH, aryl or heteroaryl, wherein the aryl or heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halo, cyano and OH; and

wherein R⁹ is optionally selected from the group consisting of C₁-C₃ alkyl, —

C(CH₃)₃, —

CH₂OH, and —

CH (CH₃)OH;

or

b) R²⁹ is selected from the group consisting of OH, phenyl, imidazole and pyridyl, and wherein the phenyl, imidazole and pyridyl are optionally substituted with 1 to 3 substituents independently selected from halo, cyano and OH;

or

c) R¹⁰ is H or C₁-C₆ alkyl.

18. The compound of claim 1, wherein R¹¹ is —

(CH2)p-R⁴¹, wherein p is 0, 1, 2 or 3, and R⁴¹ is C(O)NH₂, NHC(═

NH)NH₂, C(O)NHR⁴², NHC(═

NH)NHR⁴², and wherein R⁴² is an amino acid residue; and

wherein R¹¹ is optionally —

CH₂CH₂C(O)NH₂, —

(CH₂)₃—

NHC(═

NH)NH₂, —

CH₂CH₂C(O)NHR⁴², or —

(CH₂)₃—

NHC(═

NH)NH—

R⁴², wherein R⁴² is a norleucine residue, a lysine residue or an arginine residue.

20. The compound of claim 1, wherein the compound is selected from Table 1 or 2 or a pharmaceutically acceptable salt or solvate thereof.

21. An antibody-drug-conjugate comprising an antibody conjugated with a compound of claim 1, wherein the antibody optionally is a monoclonal antibody or a biologically active fragment or derivative of each thereof, that specifically binds EGFR.

23. A composition comprising a compound of claim 1 and a carrier, optionally, a pharmaceutically acceptable carrier.

24. A method for inhibiting the binding of Ras to a cognate ligand in a cell or tissue expressing Ras, comprising contacting the cell or tissue with an effective amount of the compound of claim 1.

25. A method of treating a cancer comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

26. A method of treating a disease mediated at least in part by Ras comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof, wherein the Ras is optionally K-Ras or a Ras mutant.

29. A method of treating a patient in need of a Ras inhibitor, which method comprises:

determining the amount of phospho-Mek and/or phospho-Erk in a cell isolated from the patient;

administering a therapeutically effective amount of a compound of claim 1 to the patient; and

optionally, further comprising determining the amount of phospho-Mek and/or phospho-Erk in a cell of the patient after the administration; and

continuing to administer a therapeutically effective amount of the compound to the patient if a decrease in phospho-Mek and/or phospho-Erk is detected.

30. A method of inhibiting phosphorylation of Akt, Mek and/or Erk, which method comprises contacting a cell or tissue in need of such inhibition with an effective amount of a compound of claim 1.

31. A method of treating a disease mediated at least in part by epidermal growth factor receptor (EGFR) or a disease resistant to or likely resistant to an EFGR inhibitor, which method comprises administering an effective amount of a compound of claim 1 to a patient in need thereof.

33. A kit comprising a compound of claim 1 and instructions for use.

2. A compound of formula I, II or III

3. A compound of formula IB, IIB, IIIB, IVB, VB or VIB:

6. The compound of claim 3, wherein R³⁰ is

5. (canceled)

8. (canceled)

10-11. -11. (canceled)

13. (canceled)

15-17. -17. (canceled)

19. (canceled)

22. (canceled)

27-28. -28. (canceled)

32. (canceled)