Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-9969716-B2
Application number	US-201414911343-A
Country	US
Kind code	B2
Filing date	Aug 15, 2014
Priority date	Aug 15, 2013
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

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

First claim

The invention claimed is:

1. A compound having structural formula I:

or a substantially pure enantiomer thereof, or a pharmaceutically acceptable salt of either of the foregoing, wherein:
R 1 is selected from —Cl, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —NH(CH 3 ), —OCH 3 , —OCHF 2 , —OCF 3 , and —OCH 2 CF 3 ;
R 2 is selected from -aryl, -cycloalkyl, —CH 2 -aryl, —CH 2 -heteroaryl, —CH 2 -cycloalkyl, —CH 2 CH 2 -heterocyclyl, —S(O) 2 -aryl, —S(O) 2 -heteroaryl, —S(O) 2 -cycloalkyl, —S(O) 2 -heterocyclyl, —S(O) 2 —CH 2 CH 2 -heterocyclyl, —C(O)-cycloalkyl, —C(O)-aryl, —C(O)-heterocyclyl, —C(O)—CH 2 -aryl, —C(O)—CH 2 -heteroaryl, —C(O)—N(CH 3 ) 2 , —C(O)—[OCH 2 CH 2 ] 2-6 -OCH 3 , —C(O)CH 2 CN, —C(O)CH 2 CH 2 CH 3 , —C(O)CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CN, —CH 2 CH 2 S(O) 2 CH 3 , —CH 2 S(O) 2 CH 3 , —CH 2 CH 2 NHC(O)CH 3 , —CH 2 CH(OCH 3 )CF 3 , —CH 2 CH 2 CH 2 CF 3 , —CH 2 CH(OH)CF 3 , —CH(CH 2 F)CH 2 F, and —R 4 —C(R 5 )(R 6 )—R 7 , wherein:
R 4 is selected from —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —C(O)— and —S(O) 2 —;
each of R 5 and R 6 is independently selected from fluoro, —CH 3 , and —CH 2 CH 3 , or R 5 and R 6 are taken together to form ═O;
R 7 is selected from hydrogen, fluoro, —CN, —CH 3 , —CH 2 OH, —CH 2 OCH 3 , —CF 2 H, —CFH 2 , —CF 3 , —CF 2 CH 3 , —CH 2 CH 3 , —OCH 3 , and —N(C 1 -C 3 alkyl) 2 , and
any aryl, heteroaryl, heterocyclyl or cycloalkyl portion of R 2 is optionally substituted with up to two substituents independently selected from bromo, chloro, fluoro, —CN, —CH 3 , —CF 3 , —C(O)CH 3 , and morpholin-4-ylmethyl;
each R 3 , when present, is independently selected from ═O and fluoro;
n is 0, 1, 2, 3, or 4, wherein:
when n is 0, R 1 is —CH 3 , —CH 2 CH 3 , —OCH 3 , or —OCHF 2 , R 5 is fluoro, and R 6 is fluoro, then R 7 is other than fluoro;
when n is 0, R 1 is —CH 3 , —CH 2 CH 3 , —OCH 3 , or —OCHF 2 , R 5 is —CH 3 , and R 6 is —CH 3 , then R 7 is other than hydrogen; and
the compound is other than:

 or a substantially pure enantiomer thereof or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 having structural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and n are as defined as in claim 1 .

3. The compound of claim 1 having structural formula Ib:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and n are as defined as in claim 1 .

4. The compound of claim 3 , wherein R 1 is selected from —OCH 3 , chloro, methyl, —OCHF 2 , —NH(CH 3 ), —CH 2 CH 3 , —CH 2 CH 2 CH 3 , and —OCH 2 CF 3 .

5. The compound of claim 4 , wherein R 1 is selected from chloro, —OCH 3 and —OCHF 2 .

6. The compound of claim 5 , wherein R 2 is selected from —(CH 2 ) 3 CF 3 , —CH 2 CH(OH)CF 3 , —CH 2 CH(OCH 3 )CF 3 , —CH 2 CF 2 H, —CH 2 CF 2 CH 3 , —CH 2 CF 2 CH 2 CH 3 , —CH 2 CF 2 CF 3 , —CH 2 CF 2 CF 2 H, —CH 2 C(O)N(CH 2 CH 3 ) 2 , —CH 2 C(O)CH 3 , —CH 2 C(CH 3 ) 2 OCH 3 , —CH 2 C(CH 3 ) 2 F, —CH 2 C(CH 3 ) 2 CF 3 , —CH(CFH 2 ) 2 , —C(O)N(CH 3 ) 2 , —C(O)C(CH 3 ) 3 , —C(O)C(CH 3 ) 2 CF 3 , —C(O)—[OCH 2 CH 2 ] 6 CH 3 , —C(O)—[OCH 2 CH 2 ] 2 CH 3 , —C(CH 3 ) 2 C(O)CH 3 , —C(O)C(CH 3 ) 2 CH 2 CH 3 , —C(O)C(CH 3 ) 2 OCH 3 , —C(O)C(O)CH 3 , —C(O)CF 2 CH 2 OCH 3 , —C(O)CH(CH 3 )CH 2 CH 3 , —CH(CH 3 )CF 2 H, —CH 2 C(CH 3 ) 2 CN, —CH 2 CF 2 CH 2 OCH 3 , —CH 2 CF 2 CH 2 OH, —S(O) 2 C(CH 3 ) 3 , —CH 2 -cyclopropyl, —S(O) 2 -phenyl, —S(O) 2 -cyclopropyl, —C(O)-phenyl, —C(O)-cyclopropyl, 4-cyanophenylcarbonyl, benzylcarbonyl, 2-methyl-1H-imidazol-1-ylacetyl, 3-methylisoxazol-5 acetyl, 1-fluorocyclobutylcarbonyl, 1-methylcyclopentylcarbonyl, 1-methylcyclopropylcarbonyl, 2,2-difluorocyclopropylcarbonyl, 3,3-difluorocyclopentylcarbonyl, 4-methylcyclohexylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, 1,3-dimehtylazetidin-3-ylcarbonyl, 1-methyl-4-fluoropiperidin-4-ylcarbonyl, 1-methylpiperidin-4-ylcarbonyl, 2,2-difluoropyrrolidin-1-ylcarbonyl, 3-methyloxetan-3-ylcarbonyl, 4,4-difluoropiperidine-1-ylcarbonyl, tetrahydrofuran-3-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, 3-fluorobenzyl, 4-cyanobenzyl, 1-methyl-1H-pyrazol-2-ylmethyl, 1-methyl-1H-pyrazol-3-ylmethyl, 1-methyl-1H-pyrazol-4-ylmethyl, 2,6-dimethylpyridin-4-ylmethyl, 2-cyanopyridin-4-ylmethyl, 2-methylpyridin-4-ylmethyl, 2-trifluoromethylpyridin-4-ylmethyl, 3-fluoropyridin-4-ylmethyl, 4-cyanopyridin-3-ylmethyl, 5-cyanopyridin-2-ylmethyl, 5-fluoropyridin-3-ylmethyl, 6-methylpyridin-2-ylmethyl, 6-methylpyrimidin-4-ylmethyl, pyrazin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyridin-3-ylsulfonyl, pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, pyrimidin-5-ylmethyl, cyclopropyl, azetidin-3-ylsulfonyl, morpholin-4-ylethylsulfonyl, morpholin-4-ylcarbonyl, pyrrolidin-1-ylethylsulfonyl, pyridin-2-ylmethyl, piperidin-4-ylsulfonyl, 4-methylpiperazin-1-ylcarbonyl, 4-fluorophenylsulfonyl, 4-fluorophenylmethyl, 4-fluorophenyl, 4-chlorophenyl, 4-(morpholin-1-ylmethyl)phenyl, 3,5-difluorophenylmethyl, 3-(morpholin-4-ylmethyl)phenyl, 2,6-difluorophenylmethyl, 1-trifluoromethylcycloprop-1-ylmethyl, 1-trifluoromethylcycloprop-1-ylcarbonyl, 1-trifluoromethylcyclobut-1-ylmethyl, 1-trifluoromethylcyclobut-1-ylcarbonyl, 1-methylpiperidin-4-ylsulfonyl, 1-methylazetidin-3-ylsulfonyl, 1-fluorocycloprop-1-ylmethyl, and 1-fluorocyclobut-1-ylmethyl.

7. The compound of claim 5 , wherein R 2 is selected from —(CH 2 ) 3 CF 3 , —CH 2 CH(OH)CF 3 , —CH 2 CH(OCH 3 )CF 3 , —CH 2 CF 2 H, —CH 2 CF 2 CH 3 , —CH 2 CF 2 CH 2 CH 3 , —CH 2 CF 2 CF 3 , —CH 2 CF 2 CF 2 H, —CH 2 C(O)N(CH 2 CH 3 ) 2 , —CH 2 C(O)CH 3 , —CH 2 C(CH 3 ) 2 OCH 3 , —CH 2 C(CH 3 ) 2 F, —CH 2 C(CH 3 ) 2 CF 3 , —CH(CFH 2 ) 2 , —C(O)N(CH 3 ) 2 , —C(O)C(CH 3 ) 3 , —C(O)C(CH 3 ) 2 CF 3 , —C(O)—[OCH 2 CH 2 ] 6 CH 3 , —C(O)—[OCH 2 CH 2 ] 2 CH 3 , —CH 2 -cyclopropyl, —S(O) 2 -phenyl, —S(O) 2 -cyclopropyl, —C(O)-phenyl, —C(O)-cyclopropyl, azetidin-3-ylsulfonyl, morpholin-4-ylethylsulfonyl, morpholin-4-ylcarbonyl, pyrrolidin-1-ylethylsulfonyl, pyridin-2-ylmethyl, piperidin-4-ylsulfonyl, 4-methylpiperazin-1-ylcarbonyl, 4-fluorophenylsulfonyl, 4-fluorophenylmethyl, 4-fluorophenyl, 4-chlorophenyl, 4-(morpholin-1-ylmethyl)phenyl, 3,5-difluorophenylmethyl, 3-(morpholin-4-ylmethyl)phenyl, 2,6-difluorophenylmethyl, 1-trifluoromethylcycloprop-1-ylmethyl, 1-trifluoromethylcycloprop-1-ylcarbonyl, 1-trifluoromethylcyclobut-1-ylmethyl, 1-trifluoromethylcyclobut-1-ylcarbonyl, 1-methylpiperidin-4-ylsulfonyl, 1-methylazetidin-3-ylsulfonyl, 1-fluorocycloprop-1-ylmethyl, and 1-fluorocyclobut-1-ylmethyl.

8. The compound of claim 5 , wherein
R 2 is selected from —CH 2 -aryl, —CH 2 -cycloalkyl, —C(O)-cycloalkyl, and —R 4 —C(R 5 )(R 6 )—R 7 , wherein:
R 4 is —CH 2 —;
each of R 5 and R 6 is independently selected from fluoro and —CH 3 ;
R 7 is selected from hydrogen, fluoro, —CH 3 , —CF 2 H, —CF 3 , and —CF 2 CH 3 , any aryl or cycloalkyl portion of R 2 is optionally substituted with up to two substituents independently selected from fluoro and —CF 3 ; and
n is 0.

9. The compound of claim 5 , wherein R 2 is selected from —CH 2 CF 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CHF 2 , —CH 2 CHF 2 , —CH 2 CF 2 CH 2 CH 3 , —CH 2 CF(CH 3 ) 2 , —C(CH 3 ) 2 C(O)CH 3 , —C(O)C(CH 3 ) 2 CH 2 CH 3 , —C(O)C(CH 3 ) 2 OCH 3 , —C(O)CF 2 CH 2 OCH 3 , —C(O)CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CF 2 H, —CH 2 C(CH 3 ) 2 OCH 3 , —CH 2 CF 2 CH 2 OCH 3 , —CH 2 CH 2 CN, —S(O) 2 C(C

Assignees

• Constellation Pharmaceuticals Inc

Inventors

• Albrecht Brian K
• Audia James Edmund
• Dakin Les A
• Duplessis Martin
• Gehling Victor S
• Harmange Jean-Christophe
• Nasveschuk Christopher G
• Vaswani Rishi G

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title