Modulators of methyl modifying enzymes, compositions and uses thereof

• US 9,206,128 B2
• Filed: 11/19/2012
• Issued: 12/08/2015
• Est. Priority Date: 11/18/2011
• Status: Active Grant

• Current Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Original Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Inventors: Albrecht, Brian K., Audia, James Edmund, Cook, Andrew S., Gagnon, Alexandre, Harmange, Jean-Christophe, Nasveschuk, Christopher G.
• Primary Examiner(s): Seaman, D M
• Application Number:
  US14/358,558
• Publication Number:
  US 20140288123A1
• Time in Patent Office: 1,114 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 221/18 Ring systems of four or more rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 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

Abstract

Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.

Claims

1. A compound of Formula II:

2. The compound of claim 1, wherein Z is ═

CH—

.

3. The compound of claim 1, wherein each R¹ is independently selected from hydrogen and —

CH₃.

4. The compound of claim 3, wherein each R¹ is —

CH₃.

5. The compound of claim 1, wherein one R¹ is —

CH₃ and the other R¹ is selected from —

OCH₃ and —

NHCH₃.

6. The compound of claim 1, wherein -[L¹]_n- is selected from —

O—

, —

S(O)—

, —

S(O)₂, —

C(R⁴)₂—

, —

N(R⁷)—

, —

C(R⁴)₂—

C(R⁴)₂—

, —

C(R⁴)₂—

O-†

, —

C(R⁴)₂—

C(R⁴)₂—

O-†

, —

C(R⁴)₂—

N(R⁷)-† and

—

O—

C(R⁴)₂-†

, wherein †

represents the portion of -[L¹]_n- bound to ring A.

7. The compound of claim 6, wherein -[L¹]_n- is selected from —

O—

, —

S(O)—

, —

S(O)₂, —

CH₂—

, —

CH₂—

O-†

, —

CH(CH₃)—

O-†

, —

N(CH₃)-†

, —

N(CH₂CH₃)-†

, —

N(CH(CH₃)₂)-†

, —

N(CH₂CH(CH₃)₂)-†

, —

NH-†

, —

CH₂—

N(CH₃)-†

, —

CH₂—

NH-†

, —

CH(OH)—

, —

C(CH₃)—

, —

O—

CH₂-†

, —

CH₂—

CH₂—

, —

CH(CH₃)—

CH₂-†

, —

CH(CH₃)—

CH₂—

O-†

, —

C((CH₃)₂)—

, —

C(CH₃)(OCH₃)—

, —

CH(OCH₃)—

, —

CH(CH₂OH)—

, —

C(CH₃)(OH)—

, —

CH(CH₂CH₃)—

O-†

, —

CH(CH(CH₃)₂)—

O-† and

—

CH(CH₂OCH₃)—

.

8. The compound of claim 7, wherein -[L^1]_n—

is selected from —

O—

, —

S(O)—

, —

S(O)₂, —

CH₂—

O-†

, —

CH(CH₃)—

O-†

, —

N(CH₃)-†

, —

NH-†

, —

CH(OCH₃)—

, —

CH₂—

N(CH₃)-†

, —

CH₂—

NH-†

, —

CH(OH)—

, —

CH(CH₃)—

, —

CH₂—

, —

CH₂—

CH₂—

, —

C(CH₃)(OH)—

, —

CH(CH₂CH₃)—

O-†

, —

CH(CH(CH₃)₂)—

O-† and

—

O—

CH₂-†

.

9. The compound of claim 1, wherein each R^3a, R^3b, and R^3c is independently selected from hydrogen, halo, C₁-C₄ alkyl and —

O—

(C₁-C₄ alkyl).

10. The compound of claim 9, wherein each R^3a, R^3b, and R^3c is independently selected from hydrogen, fluoro, chloro, —

CH₃ and —

OCH₃.

11. The compound of claim 1, having structural Formula I-i:

12. The compound of claim 11, wherein -[L¹]_n- is selected from —

CH(CH₃)—

CH₂-† and

—

CH(CH₃)-†

; and

ring A is phenyl optionally substituted with one or more R⁶.

13. The compound of claim 1, wherein ring A is selected from phenyl, cyclopentyl, cyclohexyl, pyrimindin-2-yl, 2,3-dihydrobenzofuran-2-yl, pyridin-2-yl, pyridin-4-yl, piperidin-1-yl, piperidin-4-yl, pyrrolidin-3-yl, pyrrolidin-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, 3-oxopiperazin-1-yl, morpholin-4-yl, morpholin-2-yl, tetrahydro-2H-pyran-4-yl, and tetrahydro-2H-pyran-3-yl, wherein ring A is optionally substituted with one or more R⁶.

14. The compound of claim 13, wherein each R⁶ is independently selected from ═

O, halo, —

CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl, —

O—

(C₁-C₄ alkyl), optionally substituted heterocyclyl, and optionally substituted heteroaryl.

15. The compound of claim 14, wherein ring A is selected from cyclopentyl, cyclohexyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, piperidin-1-yl, phenyl, pyrimidinyl, 2,3-dihydrobenzofuran-2-yl, pyridinyl, or 2-oxo-1H-pyridin-1-yl, wherein ring A is optionally substituted with up to two R⁶ independently selected from —

CN, —

CH₂CH₃, —

CH₃, —

OCH₃, ═

O, fluoro, pyridinyl, pyridazinyl, 1H-pyrazolyl, 1H-pyrrolyl, and pyrimidinyl.

16. The compound of claim 14, wherein each R⁶ is independently selected from fluoro, —

CH₃, —

CH₂CH₃, —

CF₃, —

OCH₃, —

CN, pyridin-4-yl, 1H-pyrrol-4-yl, pyridazin-4-yl, pyrimidin-4-yl, and 6-aminopyridin-3-yl.

17. A pharmaceutical composition comprising:

a) a compound of Formula II;