Thiazole and oxazole-substituted arylamides as P2X3 and P2X2/3 antagonists

摘要

Compounds of the formula I:;
or a pharmaceutically acceptable salt thereof, wherein, R1 is a group of formula A or formula B,
;
and X, R2, R3, R4, R5, R6, Ra and Rb are as defined herein. Also provided are methods of using the compounds for treating diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist and methods of making the subject compounds.

主权项

1. A compound of formula I:wherein:
R1 is a group of formula A or formula B; wherein:
X is —S— or —O—; andRa and Rb each independently is:
hydrogen;C1-6alkyl;C1-6alkoxy;C1-6alkylsulfonyl-C1-6alkyl;halo-C1-6alkyl;halo-C1-6alkoxy;hetero-C1-6alkyl;C3-6-cycloalkyl;C3-6cycloalkyl-C1-6alkyl;aminocarbonyl;C1-6alkoxycarbonyl; orcyano;or, when Ra and Rb are attached to adjacent carbon atoms they can form an optionally substituted benzoxazole, benzothiazole, 1,2-benzisoxazole or 1,2-benzoisothiazole; R2 is:
optionally substituted phenyl; or,optionally substituted pyridinyl; R3 is:
hydrogen;C1-6alkyl;hetero-C1-6alkyl; orcyano; R4 is:
hydrogen;C1-6alkyl; orhetero-C1-6alkyl; or R3 and R4 together with the atom to which they are attached may form a C3-6 carbocyclic ring that is optionally substituted by hydroxyl; R5 is:
C1-6alkyl;hetero-C1-6alkyl;halo-C1-6alkyl;N—C1-6alkylamino;N,N-di-(C1-6alkyl)-amino;C3-7cycloalkyl;aryl;heteroaryl;heterocyclyl;C3-7cycloalkyl-C1-6alkyl;aryl-C1-6alkyl;heteroaryl-C1-6alkyl;heterocyclyl-C1-6alkyl;heterocyclyloxy;aryloxy-C1-6alkyl;—(CRcRd)m—C(O)—R8 wherein:
m is 0 or 1;Rc and Rd each independently is:
hydrogen; orC1-6alkyl; andR8 is:
hydrogen;C1-6alkyl;hetero-C1-6alkyl;C3-7cycloalkyl;aryl;heteroaryl;heterocyclyl;C3-7cycloalkyl-C1-6alkyl;aryl-C1-6alkyl;heteroaryl-C1-6alkyl;heterocyclyl-C1-6alkyl;C3-7cycloalkyloxy;aryloxy;heteroaryloxy;heterocyclyloxy;C3-7cycloalkyloxy-C1-6alkyl;aryloxy-C1-6alkyl;heteroaryloxy-C1-6alkyl;heterocyclyloxy-C1-6alkyl; or—NR9R10, wherein: R9 is: hydrogen; or C1-6alkyl; and R10 is: hydrogen; C1-6alkyl; hetero-C1-6alkyl; C3-7cycloalkyl; aryl; heteroaryl; heterocyclyl; C3-7cycloalkyl-C1-6alkyl; aryl-C1-6alkyl; heteroaryl-C1-6alkyl; or heterocyclyl-C1-6alkyl; and R6 is:
hydrogen;C1-6alkyl;C1-6alkyloxy;halo;C1-6haloalkyl;halo-C1-6alkoxy; orcyano; or,or a pharmaceutically acceptable salt thereof.