US 12,281,057 B2
Carboxamides as modulators of sodium channels
Nadia M. 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 Jolla, CA (US); Dennis Hurley, San Marcos, CA (US); Yvonne Schmidt, San Diego, CA (US); David Shaw, Oxford (GB); Urvi Patel, San Diego, CA (US); Stephen Andrew Thomson, Del Mar, CA (US); and Lidio Marx Carvalho Meireles, San Marcos, CA (US)
Assigned to VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US)
Filed by VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US)
Filed on Dec. 13, 2022, as Appl. No. 18/065,208.
Application 18/065,208 is a division of application No. 16/824,255, filed on Mar. 19, 2020, granted, now 11,603,351.
Application 16/824,255 is a division of application No. 16/032,799, filed on Jul. 11, 2018, granted, now 10,647,661, issued on May 12, 2021.
Claims priority of provisional application 62/608,283, filed on Dec. 20, 2017.
Claims priority of provisional application 62/531,313, filed on Jul. 11, 2017.
Prior Publication US 2023/0286907 A1, Sep. 14, 2023
Int. Cl. C07C 235/64 (2006.01); A61K 31/165 (2006.01); C07C 237/42 (2006.01); C07D 213/69 (2006.01); C07D 213/81 (2006.01); C07D 213/82 (2006.01); C07D 213/89 (2006.01); C07D 239/34 (2006.01); C07D 239/42 (2006.01); C07D 307/79 (2006.01); C07D 307/86 (2006.01); C07D 317/46 (2006.01); C07D 405/12 (2006.01)
CPC C07C 235/64 (2013.01) [A61K 31/165 (2013.01); C07C 237/42 (2013.01); C07D 213/69 (2013.01); C07D 213/81 (2013.01); C07D 213/82 (2013.01); C07D 213/89 (2013.01); C07D 239/34 (2013.01); C07D 239/42 (2013.01); C07D 307/79 (2013.01); C07D 307/86 (2013.01); C07D 317/46 (2013.01); C07D 405/12 (2013.01); C07B 2200/05 (2013.01); C07C 2601/02 (2017.05)] 15 Claims
 
1. A compound of formula (II)

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
L is O;
X1b is N or CR1b;
X2b is N or CR2b;
X3b is N or CR3b;
X4b is N or CR4b;
X5 is N or CR5;
X6 is N or CR6;
X7 is N or CR7;
X9 is N or CR9;
X10 is N or CR10;
X11 is N or CR11;
each R is independently H or CH3;
R1b is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R2b is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R3b is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R4b is H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
R5, R6, and R7 are defined as follows:
(i) R5, R6, and R7 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, or —W—(CH2)n—Rw;
(ii) R5 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, or —W—(CH2)n—Rw; and R6 and R7, together with the carbon atoms to which they are attached, form a ring of formula:

OG Complex Work Unit Chemistry
 or
(iii) R5 and R6, together with the carbon atoms to which they are attached, form a ring of formula:

OG Complex Work Unit Chemistry
 and
R7 is H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or —W—(CH2)n—Rw;
R8 is H or —O—(CH2)n—Rw;
R9, R10, and R11 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or —W—(CH2)n—Rw;
R12 and R13 are each independently H, halo, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or —W—(CH2)n—Rw; or R12 and R13, together with the carbon atoms to which they are attached, form a ring of formula:

OG Complex Work Unit Chemistry
Y1, Y2, Z1, and Z2 are each independently O or C (R14)2;
each R14 is independently H, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
each W is independently O or a single bond;
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; and
n is 0 or 1;
wherein when R8 is H, then at least one of X5, X6, and X7 is not N or CH;
wherein no more than two of X1b, X2b, X3b, and X4b is N;
wherein no more than one of X5, X6, and X7 is N;
wherein no more than one of X9, X10, and X11 is N.