N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamide analogs as modulators of sodium channels

Patent metadata

Field	Value
Publication number	US-2024400544-A1
Application number	US-202218566282-A
Country	US
Kind code	A1
Filing date	Jun 3, 2022
Priority date	Jun 4, 2021
Publication date	Dec 5, 2024
Grant date	—

Abstract

Compounds of formula (I) 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 2a is N, N + —O − , or C—R 2a ;
X 3a is N or N + —O − ;
X 5a is N, N + —O − , or C—R 5a ;
X 6a is N, N + —O − , or C—R 6a ;
R d is (CH 2 ) m (CHR e ) n (CH 2 ) p H;
m, n, and p are each independently 0 or 1;
R e is H, OH, halo, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 2a and R 6a are each independently H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 5a is H, halo, CH 2 OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or R 5a and R d form a CH 2 CH 2 chain linking the C atoms to which R 5a and R d are attached, wherein the CH 2 group that is bound to the C atom to which R 5a is attached may be replaced with O;
R 4b1 and R 4b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;
R 5b1 and R 5b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;
X 3c is N or C—R 3c ;
X 4c is N or C—R 4c ;
X 5c is N or C—R 5c ;
X 6c is N or C—R 6c ;
R 2c is H, OH, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, O—CH 2 —C(R 2c1 )(R 2c2 )(R 2c3 ), O—CH(R 2c4 )(R 2c5 ), or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;
R 2c1 and R 2c2 are each independently H or C 1 -C 6 alkyl, or R 2c1 and R 2c2 together with the C atom to which they are attached form C═O;
R 2c3 is OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or N(R 2c6 )(R 2c7 ); or R 2c2 and R 2c3 together with the C atom to which they are attached form a 3-7 membered heterocycloalkyl;
R 2c4 and R 2c5 together with the C atom to which they are attached form a 3-7 membered heterocycloalkyl;
R 2c6 and R 2c7 are each C 1 -C 6 alkyl, or R 2c6 and R 2c7 together with the N atom to which they are attached form a 3-8 membered heterocycloalkyl;
L 1 is a bond or O;
L 2 is a bond or C 1 -C 6 alkylene;
R 3c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or X 3c is C—R 3c , and R 2c and R 3c , together with the carbon atoms to which they are attached, form a ring of formula:

Z 1 and Z 2 are each independently O or CH 2 ;
each R is independently H or halo;
R 4c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 5c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
R 6c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
provided that no more than two of X 2a , X 3a , X 5a , and X 6a are N or N + —O − ; and
provided that no more than one of X 3 , X 4c , X 5c , and X 6c is N; and
provided that:
R 1a and R d form a CH 2 CH 2 chain linking the C atoms to which R a and R d are attached, wherein the CH 2 group that is bound to the C atom to which R a is attached may be replaced with O; or
R 2c is O—CH 2 —C(R 2c1 )(R 2c2 )(R 2c3 ) or O—CH(R 2c4 )(R 2c ).

2 . The compound of claim 1 , wherein the compound has formula (I-A), (I-A-1), (I-A-2), (I-A-3), (I-B), (I-B-1), (I-B-2), (I-B-3), (I-C), (I-C-1), (I-C-2), (I-C-3), (I-D), (I-D-1), (I-D-2), (I-D-3), and (I-D-4):

or a pharmaceutically acceptable salt thereof.

3 - 10 . (canceled)

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2a is C—R 2a ; and R 2a is H.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 3a is N.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 5a is N; or X 5a is C—R 5a ; and R 5a is H.

14 . (canceled)

15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 6a is C—R 6a ; and R 6a is H.

16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R e is H, OH, or C 1 -C 6 alkoxy.

17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4b1 is H or C 1 -C 6 alkyl, optionally CH 3 ; and/or R 4b2 is H or C 1 -C 6 alkyl, optionally CH 3 .

18 . (canceled)

19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 5b1 is C 1 -C 6 alkyl, optionally CH 3 , or C 1 -C 6 haloalkyl, optionally CF 3 ; and/or R 5b2 C 1 -C 6 alkyl, optionally CH 3 , or C 1 -C 6 haloalkyl optionally CF 3 .

20 . (canceled)

21 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2c is C 1 -C 6 alkoxy, optionally O—CH 2 —C(R 2c1 )(R 2c2 )(R 2c3 ) or O—CH(R 2c4 )(R 2c5 ).

22 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 3c is C—R 3c ; and R 3c is halo, optionally F, or C 1 -C 6 alkyl, optionally CH 3 .

23 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 4c is C—R 4c ; and wherein R 4c is halo, optionally F.

24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 5c is C—R 5c ; and wherein R e is H.

25 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 6c is C—R 6c ; and wherein R 6c is H.

26 . A compound selected from:

or a pharmaceutically acceptable salt thereof.

27 . The compound of claim 1 in non-salt form.

28 . (canceled)

29 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

30 . A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof,
optionally wherein the voltage-gated sodium channel is Na V 1.8.

31 . (canceled)

32 . A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically accepta

Assignees

• Vertex Pharma

Inventors

• Beck Elizabeth Mary
• Pullin Robert
• Etxebarria Jardi Gorka
• Stamos Dean
• Schmidt Yvonne
• Pontillo Joseph
• Thomson Stephen Andrew
• Shaw David Matthew
• Ahmad Nadia M
• Carvalho Meireles Lidio Marx
• Skerratt Sarah
• Hadida Ruah Sara S
• Neubert Timothy Donald
• Hurley Dennis James
• Kintzer Alexander
• Durrant Steven John
• Wray Christopher
• Virani Anisa Nizarali
• North Kiri
• Jacques Reece
• Miller Mark Thomas
• Zhou Jinglan
• Knegtel Ronald Marcellus
• Chudyk Ewa Iwona
• Pinder Joanne Louise
• Sousa Bruno Artur
• Dodd James
• O'Donnell Michael Edward
• Galan Bhairavi
• Stevens Rebecca E

Classifications

• C07D491/04

  Ortho-condensed systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D405/12

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

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title