THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

• US 20150018328A1
• Filed: 07/11/2014
• Published: 01/15/2015
• Est. Priority Date: 07/11/2013
• Status: Active Grant

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Konteatis, Zenon D., Popovici-Muller, Janeta, Travins, Jeremy, Zahler, Robert, Cai, Zhenwei, Zhou, Ding
• Granted Patent: US 9,579,324 B2
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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: C07D 251/18 with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
• CPC Class Codes: C07D 251/48 Two nitrogen atoms
• 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 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

Provided are compounds useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described herein.

Claims

1. A compound having Formula I or a pharmaceutically acceptable salt or hydrate thereof:

10. The compound of claim 1 or 2 wherein R³ and R⁶ are both hydrogen, R¹ and R⁴ are each independently selected from C₁-C₄ alkyl and C₁-C₄ haloalkyl, and R² and R⁵ are each —

(C₁-C₆ alkyl).

13. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier.

14. The composition of claim 13, further comprising a second therapeutic agent useful in the treatment of cancer.

15. 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 13.

16. The method of claim 15, wherein the IDH1 mutation is an IDH1 R132H or R132c mutation.

17. The method of claim 16, wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, or angio-immunoblastic non-Hodgkin'"'"'s lymphoma (NHL) in a patient.

18. The method of claim 16, further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of cancer.

2. A compound having Formula Ia or a pharmaceutically acceptable salt or hydrate thereof:

3. The compound of claim 2, wherein

R¹, R³, R⁴, and R⁶ are each independently selected from hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, —

O—

C₁-C₄ alkyl, and CN, wherein each said alkyl moiety of R¹, R³, R⁴, and R⁶ are each independently optionally substituted with —

OH, —

NH₂, —

CN, —

O—

C₁-C₄ alkyl, —

NH(C₁-C₄ alkyl), or —

N(C₁-C₄ alkyl)₂; and

R² and R⁵ are each independently selected from;

—

(C₁-C₆ alkyl), —

(C₁-C₆ alkyl)-C(O)—

NH₂, —

(C₁-C₆ alkyl)-CO₂H, —

(C₂-C₆ alkenyl or alkynyl), —

(C₁-C₆ alkylene)-O—

(C₁-C₆ alkyl), —

(C₀-C₆ alkylene)-C(O)N(R⁶)—

(C₁-C₆ alkyl), and —

(C₀-C₆ alkylene)-C(O)—

(C₁-C₆ alkyl), wherein;

any alkyl or alkylene moiety present in R² and R⁵ is optionally substituted with one or more —

OH, —

O(C₁-C₄ alkyl), —

CO₂H, or halo; and

any terminal methyl moiety present in R² and R⁵ is optionally replaced with —

CH₂OH, CF₃, —

CH₂F, —

CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;

R¹ and R³ are optionally taken together with the carbon atom to which they are attached to form C(═

O);

or

R⁴ and R⁶ are optionally taken together with the carbon atom to which they are attached to form C(═

O);

or

R¹ and R² are optionally taken together to form an optionally substituted carbocyclyl;

or

R⁴ and R⁵ are optionally taken together to form an optionally substituted carbocyclyl, wherein, when A is an optionally substituted phenyl, 2-pyrrolyl, or 1-imidazolyl, then N(R⁷)C(R⁴)(R⁵)(R⁶) is not the same as N(R⁸)C(R¹)(R²)(R³), and the compound is not 2-(1,2-dibromoethyl)-4-phenyl-6-(1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexyl-1,3,5-Triazine.

4. The compound of claim 2, wherein ring A is a substituted 5-6 member monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from halo, —

C₁-C₄ alkyl, —

C₁-C₄ haloalkyl, —

C₁-C₄ hydroxyalkyl, —

NH—

S(O)₂—

(C₁-C₄ alkyl), —

S(O)₂NH(C₁-C₄ alkyl), —

CN, —

S(O)₂—

(C₁-C₄ alkyl), C₁-C₄ alkoxy, —

NH(C₁-C₄ alkyl), —

OH, —

OCF₃, —

CN, —

NH₂, —

C(O)NH₂, —

C(O)NH(C₁-C₄ alkyl), —

C(O)—

N(C₁-C₄ alkyl)₂, —

(C₁-C₆ alkylene)-O—

(C₁-C₆ alkyl), azetidinyl, phenyl, and cyclopropyl optionally substituted with OH.

5. A compound having Formula B, or pharmaceutically acceptable salt or hydrate thereof:

6. The compound of claim 5, wherein R⁴ and R⁵ are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

7. A compound having Formula C, or pharmaceutically acceptable salt or hydrate thereof:

8. The compound of claim 7 wherein:

R^9c is halo, —

OH, CN, —

NH₂, —

O—

C₁-C₄ alkyl, —

NH(C₁-C₄ alkyl), —

N(C₁-C₄ alkyl)₂, —

C₁-C₄ alkyl, —

C₁-C₄ haloalkyl, and —

(C₁-C₆ alkylene)-O—

(C₁-C₆ alkyl);

R¹ and R⁴ are each hydrogen;

R³ and R⁶ are each independently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, —

O—

C₁-C₄ alkyl, and CN; and

R² and R⁵ are each —

(C₁-C₆ alkyl), wherein;

the alkyl moiety present in R² and R⁵ is optionally substituted with one or more —

OH, —

O(C₁-C₄ alkyl), —

CO₂H, or halo; and

any terminal methyl moiety present in R² and R⁵ is optionally replaced with —

CH₂OH, CF₃, —

CH₂F, —

CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H.

9. The compound of claim 7 wherein R¹ and R⁴ are each independently selected from C₁-C₄ alkyl and C₁-C₄ haloalkyl, and R² and R⁵ are each —

(C₁-C₆ alkyl).

11. A compound having Formula III, or pharmaceutically acceptable salt or hydrate thereof:

12. The compound of claim 11, wherein G is substituted with 1 or 2 substituents selected from halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —

CN, ═

O, —

OH, aryl, heteroaryl —

SO₂C₁-C₄ alkyl, —

CO₂C₁-C₄ alkyl, —

C(O)aryl, and —

C(O)C₁-C₄ alkyl.