IP Library › Granted Patent US 9,206,128

Granted Patent B2

US 9,206,128 · App. 14/358,558 · Granted Dec 8, 2015

Modulators of methyl modifying enzymes, compositions and uses thereof

Inventors: Brian K. Albrecht (Cambridge, MA); James Edmund Audia (Cambridge, MA); Andrew S. Cook (Stow, MA); Alexandre Gagnon (Beaconsfield, CA); Jean-Christophe Harmange (Andover, MA); Christopher G. Nasveschuk (Stoneham, MA)

Assignee: Constellation Pharmaceuticals, Inc.

C07D213/64 C07D221/18 C07D401/12 C07D405/12 C07D413/12

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Quick Facts

Patent No.: US 9,206,128
App. No.: 14/358,558
Granted: Dec 8, 2015
Kind: B2

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Abstract

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

Claims (65)

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

Z is ═C(R 2 )— or ═N—;

ring A is phenyl, a monocyclic 5-6 membered heteroaryl comprising 1 to 3 hetero ring atoms independently selected from N, O and S, a carbocyclic comprising 4 or more ring atoms, or a heterocyclic, wherein ring A is optionally substituted with one or more R 6 ;

each R 1 and R 2 is independently selected from hydrogen, halo, —OH, —CN, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), N(R 7 ) 2 , —(C 0 -C 4 alkylene)-aryl, —(C 0 -C 4 alkylene) -heteroaryl, —(C 0 -C 4 alkylene)-heterocyclyl, —(C 0 -C 4 alkylene)-carbocyclyl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, and —O—(C 0 -C 4 alkylene)-carbocyclyl; or

one R 1 and R 2 are taken together with atoms to which they are bound to form an aryl, heteroaryl, heterocyclyl, or carbocyclyl;

each of R 3a , R 3b , and R 3c is independently selected from hydrogen, halo, —OH, —CN, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or alkynyl, —O—(C 1 -C 4 alkyl), N(R 7 ) 2 , —(C 0 -C 4 alkylene)-aryl, —(C 0 -C 4 alkylene) -heteroaryl, —(C 0 -C 4 alkylene)-heterocyclyl, —(C 0 -C 4 alkylene)-carbocyclyl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —C(O)OR 9 , —C(O)N(R 9 ) 2 , —S(O)R 8 , —S(O) 2 R 8 and —S(O) 2 N(R 9 ) 2 ;

each L 1 is independently selected from —C(R 4 ) 2 —, —C(R 4 )═C(R 4 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 , and —N(R 5 )—; or

any L 1 is optionally taken together with R 3a and any intervening atoms to form a fused aryl, heteroaryl, heterocyclyl or carbocyclyl ring;

wherein when ring A is phenyl, a 5-6 membered heteroaryl, or a heterocyclyl bound to L 1 through a ring nitrogen atom, then n is an integer from 1 to 6;

each R 4 is independently selected from hydrogen, halo, C 1 -C 4 alkyl, —CH 2 OH, —OH, —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-N(R 7 ) 2 , and —CN; or

two R 4 are taken together with a common carbon atom to which they are both bound to form a carbocyclic, heterocyclic, or =0; or

two R 4 bound to different carbon atoms are taken together with the different carbon atoms and any intervening atoms to form a carbocyclic, or heterocyclic;

R 5 is selected from hydrogen, C 1 -C 4 alkyl, and C 2 -C 4 haloalkyl; or

R 4 and R 5 are taken together with the atoms to which they are bound and any intervening atoms to form a heterocyclic;

each R 6 is independently selected from halo, —CN, ═O, —(C 1 -C 4 alkylene)-O—R 8 , —(C 0 -C 4 alkylene)-O—(C 0 -C 4 alkylene)-R 9 , —(C 0 -C 4 alkylene)-N(R 7 ) 2 , —(C 0 -C 4 alkylene)-R 8 , —(C 0 -C 4 alkylene)-C(O)—O—R 9 , —(C 0 -C 4 alkylene)-O—C(O)—R 9 , —(C 0 -C 4 alkylene)-C(O)—N(R 9 ) 2 , —(C 0 -C 4 alkylene)-S(O)—R 8 , —(C 0 -C 4 alkylene)-S(O) 2 —R 8 and —(C 0 -C 4 alkylene)-S(O) 2 —N(R 9 ) 2 ; or

two R 6 bound to adjacent atoms in ring A are taken together with the atoms to which they are bound to form a monocyclic aryl, heteroaryl, heterocyclyl, or carbocyclyl;

each R 7 is independently selected from hydrogen, —(C 0 -C 4 alkylene)-R 9 , —(C 2 -C 4 alkylene)-O—R 8 , C 2 -C 4 haloalkyl, —S(O) 2 —R 8 , —C(═O)—R 8 , —C(═O)—N(R 9 )(R 9 ), —(C 2 -C 4 alkylene)-O—C(═O)—R 8 and —(C 0 -C 4 alkylene)-C(═O)—O—R 9 ; or

two R 7 are taken together with the nitrogen atom to which they are commonly bound to form an optionally substituted heterocyclyl or heteroaryl;

R 8 is selected from C 1 -C 4 alkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl;

each R 9 is independently selected from hydrogen and R 8 ;

represents a single or double bond;

n is 0 or an integer from 1 to 6;

wherein any portion of the compound designated as alkyl, alkylene, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl or carbocyclyl is optionally substituted; and each ring of any aryl, heteroaryl, heterocyclyl or carbocyclyl has not more than three substituents per ring.

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

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

4. The compound of claim 3 , wherein each R 1 is —CH 3 .

5. The compound of claim 1 , wherein one R 1 is —CH 3 and the other R 1 is selected from —OCH 3 and —NHCH 3 .

6. The compound of claim 1 , wherein -[L 1 ] n - is selected from —O—, —S(O)—, —S(O) 2 , —C(R 4 ) 2 —, —N(R 7 )—, —C(R 4 ) 2 —C(R 4 ) 2 —, —C(R 4 ) 2 —O-†, —C(R 4 ) 2 —C(R 4 ) 2 —O-†, —C(R 4 ) 2 —N(R 7 )-† and —O—C(R 4 ) 2 -†, wherein † represents the portion of -[L 1 ] n - bound to ring A.

7. The compound of claim 6 , wherein -[L 1 ] n - is selected from —O—, —S(O)—, —S(O) 2 , —CH 2 —, —CH 2 —O-†, —CH(CH 3 )—O-†, —N(CH 3 )-†, —N(CH 2 CH 3 )-†, —N(CH(CH 3 ) 2 )-†, —N(CH 2 CH(CH 3 ) 2 )-†, —NH-†, —CH 2 —N(CH 3 )-†, —CH 2 —NH-†, —CH(OH)—, —C(CH 3 )—, —O—CH 2 -†, —CH 2 —CH 2 —, —CH(CH 3 )—CH 2 -†, —CH(CH 3 )—CH 2 —O-†, —C((CH 3 ) 2 )—, —C(CH 3 )(OCH 3 )—, —CH(OCH 3 )—, —CH(CH 2 OH)—, —C(CH 3 )(OH)—, —CH(CH 2 CH 3 )—O-†, —CH(CH(CH 3 ) 2 )—O-† and —CH(CH 2 OCH 3 )—.

8. The compound of claim 7 , wherein -[L 1] n — is selected from —O—, —S(O)—, —S(O) 2 , —CH 2 —O-†, —CH(CH 3 )—O-†, —N(CH 3 )-†, —NH-†, —CH(OCH 3 )—, —CH 2 —N(CH 3 )-†, —CH 2 —NH-†, —CH(OH)—, —CH(CH 3 )—, —CH 2 —, —CH 2 —CH 2 —, —C(CH 3 )(OH)—, —CH(CH 2 CH 3 )—O-†, —CH(CH(CH 3 ) 2 )—O-† and —O—CH 2 -†.

9. The compound of claim 1 , wherein each R 3a , R 3b , and R 3c is independently selected from hydrogen, halo, C 1 -C 4 alkyl and —O—(C 1 -C 4 alkyl).

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

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

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 , wherein -[L 1 ] n - is selected from —CH(CH 3 )—CH 2 -† and —CH(CH 3 )-†; and ring A is phenyl optionally substituted with one or more R 6 .

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 R 6 .

14. The compound of claim 13 , wherein each R 6 is independently selected from ═O, halo, —CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—(C 1 -C 4 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 R 6 independently selected from —CN, —CH 2 CH 3 , —CH 3 , —OCH 3 , ═O, fluoro, pyridinyl, pyridazinyl, 1H-pyrazolyl, 1H-pyrrolyl, and pyrimidinyl.

16. The compound of claim 14 , wherein each R 6 is independently selected from fluoro, —CH 3 , —CH 2 CH 3 , —CF 3 , —OCH 3 , —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:

or a pharmaceutically acceptable salt thereof, wherein:

Z is ═C(R 2 )— or ═N—;

one R 1 and R 2 are taken together with atoms to which they are bound to form an aryl, heteroaryl, heterocyclyl, or carbocyclyl;

each of R 3a , R 3b and R 3c is independently selected from hydrogen, halo, —OH, —CN, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or alkynyl, —O—(C 1 -C 4 alkyl), N(R 7 ) 2 , —(C 0 -C 4 alkylene)-aryl, —(C 0 -C 4 alkylene) -heteroaryl, —(C 0 -C 4 alkylene)-heterocyclyl, —(C 0 -C 4 alkylene)-carbocyclyl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —C(O)OR 9 , —C(O)N(R 9 ) 2 , —S(O)R 8 , —S(O) 2 R 8 and —S(O) 2 N(R 9 ) 2 ;

each L 1 is independently selected from —C(R 4 ) 2 —, —C(R 4 )═C(R 4 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 , and —N(R 5 )—; or

any L 1 is optionally taken together with R 3a and any intervening atoms to form a fused aryl, heteroaryl, heterocyclyl or carbocyclyl ring;

wherein when ring A is phenyl, a 5-6 membered heteroaryl, or a heterocyclyl bound to L 1 through a ring nitrogen atom, then n is an integer from 1 to 6;

each R 4 is independently selected from hydrogen, halo, C 1 -C 4 alkyl, —CH 2 OH, —OH, —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-N(R 7 ) 2 , and —CN; or

two R 4 are taken together with a common carbon atom to which they are both bound to form a carbocyclic, heterocyclic, or ═O; or

two R 4 bound to different carbon atoms are taken together with the different carbon atoms and any intervening atoms to form a carbocyclic, or heterocyclic;

R 5 is selected from hydrogen, C 1 -C 4 alkyl, and C 2 -C 4 haloalkyl; or

R 4 and R 5 are taken together with the atoms to which they are bound and any intervening atoms to form a heterocyclic;

two R 6 bound to adjacent atoms in ring A are taken together with the atoms to which they are bound to form a monocyclic aryl, heteroaryl, heterocyclyl, or carbocyclyl;

each R 7 is independently selected from hydrogen, —(C 0 -C 4 alkylene)-R 9 , —(C 2 -C 4 alkylene)-O—R 8 , C 2 -C 4 haloalkyl, —S(O)2-R 8 , —C(═O)—R 8 , —C(═O)—N(R 9 )(R 9 ), —(C 2 -C 4 alkylene)-O—C(═O)—R 8 and —(C 0 -C 4 alkylene)-C(═O)—O—R 9 ; or

two R 7 are taken together with the nitrogen atom to which they are commonly bound to form an optionally substituted heterocyclyl or heteroaryl;

R 8 is selected from C 1 -C 4 alkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl;

each R 9 is independently selected from hydrogen and R 8 ;

n is 0 or an integer from 1 to 6;

b) a pharmaceutically acceptable carrier.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 27, 2014

From: ALBRECHT, BRIAN K.; AUDIA, JAMES EDMUND; COOK, ANDREW; GAGNON, ALEXANDRE; HARMANGE, JEAN-CHRISTOPHE; NASVESCHUK, CHRISTOPHER G.

To: CONSTELLATION PHARMACEUTICALS, INC.

Reel/Frame 033617/0503 →

Continuity (3)

Provisional Application 61561822 · Nov 18, 2011

Provisional Application 61593809 · Feb 1, 2012

Related Publication 20140288123A1 · Sep 25, 2014