US 12,005,054 B2
Piperidinyl-3-(aryloxy)propanamides and propanoates
Zacharia Cheruvallath, San Diego, CA (US); Jason Green, San Diego, CA (US); Ben Johnson, San Diego, CA (US); Kristin Schleicher, San Diego, CA (US); Huikai Sun, San Diego, CA (US); and Mingnam Tang, San Diego, CA (US)
Assigned to Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed by Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed on May 14, 2021, as Appl. No. 17/320,574.
Application 17/320,574 is a division of application No. 16/289,311, filed on Feb. 28, 2019, granted, now 11,045,457.
Claims priority of provisional application 62/637,295, filed on Mar. 1, 2018.
Prior Publication US 2023/0021834 A1, Jan. 26, 2023
Int. Cl. A61K 31/4439 (2006.01); A61K 31/40 (2006.01); A61K 31/4355 (2006.01); A61K 31/438 (2006.01); A61K 31/4468 (2006.01); A61K 31/4545 (2006.01); A61K 31/497 (2006.01); A61K 31/501 (2006.01); A61K 31/506 (2006.01); C07D 207/14 (2006.01); C07D 211/58 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); C07D 491/048 (2006.01)
CPC A61K 31/4439 (2013.01) [A61K 31/40 (2013.01); A61K 31/4355 (2013.01); A61K 31/438 (2013.01); A61K 31/4468 (2013.01); A61K 31/4545 (2013.01); A61K 31/497 (2013.01); A61K 31/501 (2013.01); A61K 31/506 (2013.01); C07D 207/14 (2013.01); C07D 211/58 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/12 (2013.01); C07D 491/048 (2013.01)] 19 Claims
 
1. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject a compound of Formula 1,

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof in which:
X1 is selected from N and CR1;
X2 is selected from N and CR2;
X3 is selected from N and CR3; and
X4 is selected from N and CR4, provided no more than two of X1, X2, X3, and X4 are N;
X13 is NR13 and X14 is CR15R16 or X13 is CH2 and X14 is NR14;
L is selected from NR8 and O;
r is selected from 0 and 1;
s is selected from 0 and 1;
R1, R2, and R3 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;
R4 is selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;
R5 is selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo, oxo, and phenyl which is substituted with 0 to 3 optional substituents independently selected from halo; or
R4 and R5, together with the carbon atoms to which they are attached, form a cyclopent-1-en-1,2-diyl or a furan-2,3-diyl;
R6 and R7 are each independently selected from halo and C1-3 alkyl, or R6 and R7, together with the carbon atom to which they are attached, form a C3-4 cycloalkan-1,1-diyl;
R8 is selected from H and C1-4 alkyl;
R9 and R10 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano;
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and
(c) phenyl and C1-5 heteroaryl, each substituted with 0 to 3 optional substituents independently selected from halo, C1-4 alkyl, and C1-4 alkoxy, wherein the C1-5 heteroaryl substituent is a monocyclic ring with 5 to 6 ring members in which 1 to 4 ring members are heteroatoms, each of the heteroatoms independently selected from N, O, and S, provided no more than one of the ring members is O or S, and wherein the C1-4 alkyl and C1-4 alkoxy optional substituents on phenyl and C1-5 heteroaryl are each independently substituted with 0 to 3 optional substituents independently selected from halo; or
R9 and R10, together with the carbon atom to which they are attached, form a C3-4 cycloalkan-1,1-diyl;
R11 and R12 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or
R11 and R12, together with the carbon atom to which they are attached, form a C3-4 cycloalkan-1,1-diyl;
R13 and R14 are each independently selected from
(a) hydrogen; and
(b) C1-4 alkyl, which is un substituted or substituted with a substituent selected from cyano and oxo; and
R15 and R16 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C1-4 alkyl, C3-6 cycloalkyl, and C1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or
R15 and R16, together with the carbon atom to which they are attached, form a C3-4 cycloalkan-1,1-diyl;
wherein the disease, disorder or condition is pain.