PYRAZOLE-SUBSTITUTED ARYLAMIDES AS P2X3 AND P2X2/3 ANTAGONISTS

摘要

Compounds of the formula I:;;or a pharmaceutically acceptable salt thereof, wherein, R1 is optionally substituted pyrazolyl, and R2, R3, R4, R5, R6, R7 and R8 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X3 and/or a P2X2/3 receptor antagonists and methods of making the compounds.

主权项

1. A compound of formula I: or pharmaceutically acceptable salts thereof, wherein:
R1 is 1H-pyrazol-1-yl (1A) optionally independently substituted with one, two or three groups independently selected from C1-6alkyl; C1-6alkoxy; C1-6alkylsulfonyl; phenyl; amino; N—C1-6alkyl-amino; N,N-di-C1-6alkyl-amino halo-C1-6alkyl; halo-C1-6alkoxy; heterocyclyl, hetero-C1-6alkyl; C3-6-cycloalkyl; C3-6cycloalkyl-C1-6alkyl; aminocarbonyl; heterocyclylcarbonyl; C1-6alkoxycarbonyl; or cyano; or Ra and Rb together with the atoms to which they are attached may form a phenyl, pyridinyl or pyrimidinyl group, each optionally substituted; and wherein Rc is hydrogen, C1-6alkyl or halo-C1-6alkyl;
R2 is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl or optionally substituted thiophenyl;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;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;heteroaryl-C1-6alkyl;heterocyclyl-C1-6alkyl;aryl-C1-6alkyl;aryloxy-C1-6alkyl;—(CRaRb)m—C(O)—R8 wherein:
m is 0 or 1;Ra and Rb 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; orC1-6alkyl; andR10 is:hydrogen;C1-6alkyl;hetero-C1-6alkyl;C3-7cycloalkyl;aryl;heteroaryl;heterocyclyl;C3-7cycloalkyl-C1-6alkyl;aryl-C1-6alkyl;heteroaryl-C1-6alkyl; orheterocyclyl-C1-6alkyl;or R4 and R5 together with the atom to which they are attached may form a C3-6 carbocyclic ring that is optionally substituted with hydroxy;or R4 and R5 together with the atom to which they are attached may form a C4-6 heterocyclic ring containing one or two heteroatoms each independently selected from O, N and S;or R3, R4 and R5 together with the atom to which they are attached may form a six-membered heteroaryl containing one or two nitrogen atoms, and which is optionally substituted with halo, amino or C1-6alkyl; andR6, R7 and R8 each independently is:
hydrogenC1-6alkyl;C1-6alkyloxy;halo;C1-6haloalkyl; orcyano.