THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

• US 20160304556A1
• Filed: 06/29/2016
• Published: 10/20/2016
• Est. Priority Date: 01/19/2012
• Status: Abandoned Application

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Cai, Zhenwei, Popovici-Muller, Janeta, Saunders, Jeffrey O., Salituro, Francesco G., Zhou, Ding, Yan, Shunqi
• Application Number:
  US15/196,842
• Publication Number:
  US 20160304556A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/48 Sulfur atoms
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 215/48 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 233/61 with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/68 Halogen atoms
• CPC Class Codes: C07D 233/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 263/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 263/06 : with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 263/24 : with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C07D 265/30 : not condensed with other rings
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07K 5/0202 : containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/06026 : the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/0606 : the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• CPC Class Codes: C07K 5/06069 : Ser-amino acid
• CPC Class Codes: C07K 5/06078 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06165 : and Pro-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N

Abstract

Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, wherein:

2. The compound of claim 1, wherein:

R¹ is C₄-C₆ carbocyclyl optionally substituted with one to three R⁷ groups;

each R² and R³ is independently selected from aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R⁷ groups or acrylamido;

R⁴ is saturated heterocyclyl, —

CH(R⁵)N(R⁵)-heteroaryl, —

CH(R⁵)N(R⁵)-aryl, —

CH(R⁵)N(R⁵)-heterocyclyl, —

CH(R⁵)N(R⁵)-carbocyclyl, heteroaralkyl, —

CH₂-heterocyclyl, 1H-indol-2-yl, indolin-2-yl, 1,2,3,4-tetrahydroquinolin-2-yl, imidazo[1,2-a]pyridine-5-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-yl, —

(CR⁵R⁶)_1-4N(R⁵)C(O)O(C₁-C₆ alkyl), or —

(CR⁵R⁶)_1-4N(R⁵)SO₂(C₁-C₆ alkyl), wherein each saturated heterocyclyl, heteroaryl, aryl, heterocyclyl, or carbocyclyl is independently optionally substituted with one to three R⁷ groups;

each R⁵ is independently selected from hydrogen and methyl;

each R⁶ is independently selected from hydrogen, methyl, CH₂OH, CH(CH₃)OH, CH₂NH₂, or CH(CH₃)NH₂;

each R⁷ is independently halo, —

CF₃, —

CN, —

OR⁸, —

N(R⁸)₂, —

C(O)CH₃, —

C(O)OCH₃, —

SO₂(C₁-C₃ alkyl), —

C(O)N(R⁸)₂, —

O(CH₂)₂—

OR⁸, SO₂N(R⁸)₂, heteroaryl, —

C₁-C₃ haloalkyl, C₁-C₃ alkyl optionally substituted with —

OR⁸ or —

N(R⁸)₂; and

each R⁸ is independently H or C₁-C₃ alkyl; and

provided that;

(i) R⁴ is other than thien-2-ylmethyl, 1H-benizimidazol-1-ylmethyl, 1H-indol-3-ylmethyl, or 1H-benzotriazol-1-ylmethyl; and

(ii) the compound is not N-2-[[2-(cyclohexylamino)-1-(3-hydroxyphenyl)-2-oxoethyl]phenylamino]-2-oxoethyl]-carbamic acid 1,1-dimethylethyl ester or N-[2-[(2-benzoylphenyl)[2-(cyclohexylamino)-1-(3-hydroxyphenyl)-2-oxoethyl]amino]-2-oxoethyl]-carbamic acid 1,1-dimethylethyl ester.

3. The compound of any one of claims 1-2, wherein R¹ is C₄-C₆ cycloalkyl optionally substituted with one to two R⁷ groups.

4. The compound of claim 3, wherein R¹ is

5. The compound of claim 3, wherein each R² and R³ is independently aryl optionally substituted with one to three R⁷ groups.

6. The compound of claim 5, wherein R² is phenyl optionally substituted with one to two R⁷ groups and each R⁷ is independently F, Cl or methyl.

7. The compound of claim 5, wherein R³ is phenyl optionally substituted with one to two R⁷ groups wherein each R⁷ is independently F, CN, —

SO₂NH₂, —

SO₂NH(CH₃), acrylamido or oxadiazolyl.

8. The compound of claim 5, wherein R⁴ is 4-6 membered saturated heterocyclyl, —

CH₂-heteroaryl, —

CH₂-heterocyclyl, —

CH(R⁵)N(R⁵)-heteroaryl, 1H-indol-2-yl, indolin-2-yl, 1,2,3,4-tetrahydroquinolin-2-yl, imidazo[1,2-a]pyridine-5-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-yl, —

(CR⁵R⁶)_1-4N(R⁵)C(O)O(C₁-C₆ alkyl), or —

(CR⁵R⁶)_1-4N(R⁵)SO₂(C₁-C₆ alkyl), wherein each said saturated heterocyclyl, heteroaryl, or heterocyclyl is independently optionally substituted with one to three R⁷ groups.

9. The compound of claim 8, wherein R⁴ is:

10. The compound of claim 8, wherein R⁴ is —

CH₂—

NH(heteroaryl) or —

CH(CH₂OH)—

NH(heteroaryl), wherein heteroaryl is pyridinyl or pyrimidinyl each optionally substituted with one R⁷.

11. The compound of claim 8, wherein R⁴ is —

CH₂-heteroaryl wherein heteroaryl is imidazolyl, triazolyl, pyridinyl or tetrazole, each of imidazolyl, triazolyl, pyridinyl or tetrazole, optionally substituted with one to two R⁷ groups.

12. The compound of claim 8, wherein R⁴ is —

(CR⁵R⁶)N(R⁵)C(O)O(C₁-C₄ alkyl) wherein each R⁵ is independently H or methyl and R⁶ is methyl or CH₂OH.

13. The compound of claim 8, wherein R⁴ is 1,2,3,4-tetrahydroquinolin-2-yl, or 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-yl.

15. A pharmaceutical composition comprising a compound of any one of claims 1 to 14;

and a pharmaceutically acceptable carrier.

16. The composition of claim 15, further comprising a second therapeutic agent useful in the treatment of cancer.

17. A method of treating a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α

-ketoglutarate to R(−

)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of claim 15.

18. The method of claim 17, wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.

19. The method of claim 17, wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer in a patient.

20. The method of claim 19, further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of cancer.

14. The compound is selected from any one of compounds from Table 1.