Heteroaryl compounds for the treatment of pain

Patent metadata

Field	Value
Publication number	US-2025388541-A1
Application number	US-202318858142-A
Country	US
Kind code	A1
Filing date	Apr 21, 2023
Priority date	Apr 22, 2022
Publication date	Dec 25, 2025
Grant date	—

Abstract

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.

First claim

1 . A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X is CR 5b or N;

R 2a and R 3a are defined as follows:
(i) R 2a is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)(C 1 -C 6 haloalkyl), or —N(C 1 -C 6 haloalkyl) 2 ; and
R 3a is H, halo, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —(C 1 -C 6 alkylene)-OH, —(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), —(C 1 -C 6 alkylene)-NH 2 , —(C 1 -C 6 alkylene)-NH(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , —C(O)(C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —C(O)O(C 1 -C 6 alkyl), —S(O) 2 —(C 1 -C 6 alkyl), —S(O)(NH)(C 1 -C 6 alkyl), —CH 2 C(O)NH 2 , —CH 2 C(O)NH(C 1 -C 6 alkyl), —CH 2 C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), —CH 2 NHC(O)CH(CH 3 )(NH 2 ), —CH 2 N(CH 3 )C(O)CH(CH 3 )(N(CH 3 ) 2 ), —CH 2 CH 2 NHC(O)CH(CH 3 )(NH 2 ), —NHC(O)CH(CH 3 )(NH 2 ), —C(O)NHC(O)(C 1 -C 6 alkyl), —NHS(O) 2 CH 3 , —S(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, wherein said heterocyclyl or heteroaryl is optionally substituted with 1-2 R a′ ; or

(ii) R 3a is —S(O)R′, —S(O) 2 R′, —S(O)(NH)R′, —S(O)(N(C 1 -C 6 alkyl))R′, or —S(O) 2 NCH 3 R′; and
R 2a and R′, together with the atoms to which they are attached, join together to form a 4-7 membered heterocyclyl;

R 5a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CH 2 OH, —CH 2 O(C 1 -C 6 alkyl), —CH 2 O(C 1 -C 6 haloalkyl), —C(O)O(C 1 -C 6 alkyl), —C(O)O(C 1 -C 6 haloalkyl), or 4-10 membered heteroaryl, wherein said heteroaryl is optionally substituted with R a′ ;
each R is independently halo, —CN, —OH, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), —C(O)NH 2 , —C(O)OH, —S(O) 2 (C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, 4-10 membered heterocyclyl, or -(4-10 membered heterocyclyl)-(C 1 -C 6 alkyl);

R 2b , R 3b , and R 4b are defined as follows:
(i) R 2b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OH, —CH 2 OH, —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)-, wherein cycloalkyl in said C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)- is optionally substituted with one or more halogen;
R 3b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —OH, —CH 2 OH, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or —(C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl), wherein cycloalkyl in said C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)- is optionally substituted with one or more halogen; and
R 4b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —OH, —CH 2 OH, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)-, or

 wherein cycloalkyl in said C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)- is optionally substituted with one or more halogen; or

(ii) R 2b and R 3b , together with the carbon atoms to which they are attached, form a ring of formula:

R 4b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —OH, —CH 2 OH, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or —(C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl), wherein said cycloalkyl is optionally substituted with one or more halogen; or

(iii) R 2b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OH, —CH 2 OH, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)-, wherein cycloalkyl in said C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)- is optionally substituted with one or more halogen; and
R 3b and R 4b , together with the carbon atoms to which they are attached, form a ring of formula:

R 5b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —OH, —CH 2 OH, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)-, wherein cycloalkyl in said C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)- is optionally substituted with one or more halogen; and
R 6b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OH, —CH 2 OH, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)-, wherein cycloalkyl in said C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)- is optionally substituted with one or more halogen;
R n is H or C 1 -C 6 alkyl,

provided that:
(i) if X is N, then R 3b and R 4b , together with the carbon atoms to which they are attached, form a ring of formula:

 and
(ii) if R 2a is H, then R 3a is halo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —(C 1 -C 6 alkylene)-OH, —(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), —(C 1 -C 6 alkylene)-NH 2 , —(C 1 -C 6 alkylene)-NH(C 1 -C 6 alkyl), —(C 1 -C 6 alkylene)-N(C 1 -C 6 alkyl) 2 , —C(O)(C 1 -C 6 alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 —(C 1 -C 6 alkyl), —S(O)(NH)(C 1 -C 6 alkyl), —CH 2 C(O)NH 2 , —CH 2 C(O)NH(C 1 -C 6 alkyl), —CH 2 C(O)N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), —CH 2 NHC(O)CH(CH 3 )(NH 2 ), —CH 2 N(CH 3 )C(O)CH(CH 3 )(N(CH 3 ) 2 ), —CH 2 CH 2 NHC(O)CH(CH 3 )(NH 2 ), or —NHC(O)CH(CH 3 )(NH 2 ); and
(iii) if R 3a is —C(O)O(C 1 -C 2 alkyl), then R 4b is H, fluoro, chloro, C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, —OH, —CH 2 OH, —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)-, wherein cycloalkyl in said C 3 -C 6 cycloalkyl, (C 1 -C 6 alkyl)-(C 3 -C 6 cycloalkyl)-, or (C 1 -C 6 haloalkyl)-(C 3 -C 6 cycloalkyl)- is optionally substituted with one or more halogen; and
(iv) no more than four of R 2b , R 3b , R 4b , R 5b , and R 6b are H; and
(v) no more than one of R 2b , R 3b , R 4b , R 5b , and R 6b is fluoro; and
(vi) no more than one of R 2b , R 3b , R 4b , R 5b , and R 6b is chloro; and
(vii) if any of R 2b , R 3b , R

Assignees

• Vertex Pharma

Inventors

• Miller Mark Thomas
• Vogel Carl Victor
• Bedell Thomas Aaron
• Hurley Dennis James
• Neubert Timothy Donald
• Nesan Savariar Elamprakash
• Patel Urvi
• Hadida Ruah Sara Sabina
• Mccartney Jason
• Zhou Jinglan
• Demoret Robert Martin
• Valiulin Roman Askatovich
• Kintzer Alexander Frederick
• Webb Peter
• Slochower David Robert
• Aertgeerts Kathleen
• Beck Elizabeth Mary
• Knegtel Ronald Marcellus Alphonsus
• Chudyk Ewa Iwona
• Pinder Joanne Louise
• Gulevich Anton V
• Ishihara Yoshihiro
• Tran Joe A

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title