US 12,441,703 B2
Carboxamides as modulators of sodium channels
Stephen Andrew Thomson, Del Mar, CA (US); Nadia Ahmad, Didcot (GB); Corey Anderson, Brighton, MA (US); Vijayalaksmi Arumugam, San Marcos, CA (US); Iuliana Luci Asgian, San Diego, CA (US); Joanne Louise Camp, Didcot (GB); Lev Tyler Dewey Fanning, San Marcos, CA (US); Sara Sabina Hadida Ruah, La Jolia, CA (US); Dennis Hurley, San Marcos, CA (US); Yvonne Schmidt, San Diego, CA (US); David Shaw, Oxford (GB); Urvi Patel, San Diego, CA (US); and Lidio Marx Carvalho Meireles, San Marcos, CA (US)
Assigned to VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US)
Appl. No. 17/421,944
Filed by VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US)
PCT Filed Jan. 9, 2020, PCT No. PCT/US2020/012994
§ 371(c)(1), (2) Date Jul. 9, 2021,
PCT Pub. No. WO2020/146682, PCT Pub. Date Jul. 16, 2020.
Claims priority of provisional application 62/790,897, filed on Jan. 10, 2019.
Claims priority of provisional application 62/791,011, filed on Jan. 10, 2019.
Prior Publication US 2023/0062053 A1, Mar. 2, 2023
Int. Cl. C07D 401/12 (2006.01); A61P 3/12 (2006.01); C07D 213/56 (2006.01); C07D 213/89 (2006.01); C07D 239/36 (2006.01); C07D 405/12 (2006.01)
CPC C07D 401/12 (2013.01) [A61P 3/12 (2018.01); C07D 213/56 (2013.01); C07D 213/89 (2013.01); C07D 239/36 (2013.01); C07D 405/12 (2013.01)] 23 Claims
 
1. A compound of formula (I) or (II)

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
each R is independently H or C1-C6 alkyl;
R3a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R4a is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R1b is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R3b is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R4b is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R5, R6, R7, and R8 are defined as follows:
(i) R5, R6, and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; and R8 is C1-C6 alkyl;
(ii) R5 is W—(CH2)n—Rz, C1-C6 alkylsulfanyl, —O—(CH2)p—Rw, or —O—(CH2)p—N(C1-C6 alkyl)2; R6 and R7 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; and R8 is H;
(iii) R5 and R6 are each independently H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R7 is W—(CH2)n—Rz, —C═C—Rx, or 3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituents selected from a group consisting of C1-C6 alkoxy, CN, and —C(O)NH2; and R8 is H; or
(iv) R5 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R6 and R7, together with the carbon atoms to which they are attached, form a ring of formula

OG Complex Work Unit Chemistry
and R8 is H;
R9 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R10 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R11 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R12 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R13 is H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
each R14 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
each W is independently O or a single bond;
Rx is C1-C6 alkyl or 3-6 membered cycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl;
each Rw is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl;
Rz is 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl, wherein said 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy, or wherein 2 substituents together with the atom to which they are attached form a 5-6 membered heterocyclyl ring;
n is 0 or 1; and
p is 2 or 3.