Thiadiazole-substituted arylamides as P2X3 and P2X2/3 antagonists

A compound of formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is a group of formula A or B;
• Ra is:
• hydrogen;
• C1-6alkyl;
• C1-6alkoxy;
• C1-6alkylsulfonyl;
• phenyl;
• amino;
• N—C1-6alkyl-amino;
• N,N-di-C1-6alkyl-amino halo-C1-6alkyl;
• halo-C1-6alkoxy;
• hetero-C1-6alkyl;
• C3-6-cycloalkyl;
• C3-6cycloalkyl-C1-6alkyl;
• aminocarbonyl;
• heterocyclylcarbonyl;
• C1-6alkoxycarbonyl;
• or cyano;
• R2 is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl or optionally substituted thiophenyl;
• R3 is:
• hydrogen;
• C1-6alkyl;
• ;
• or
• cyano;
• R4 is:
• hydrogen;
• or
• 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;
• C1-6alkoxy-C1-6alkyl;
• hydroxy-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;
• —(CRa′Rb)m—C(O)—R8′wherein:
• m is 0 or 1;
• Ra′and Rb each independently is:
• hydrogen;
• or
• C1-6alkyl;
• and
• R8 is:
• hydrogen;
• C 1-6alkyl;
• C3-7cycloalkyl;
• aryl;
• heteroaryl;
• heterocyclyl;
• C3-7 cycloalkyl-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
• —NR9R 10, wherein:
• R9 is:
• hydrogen;
• or
• C1-6alkyl;
• and
• R10 is:
• hydrogen;
• C1-6alkyl;
• C3-7cycloalkyl;
• aryl;
• heteroaryl;
• heterocyclyl;
• C3-7cycloalkyl-C1-6alkyl;
• aryl-C1-6alkyl;
• heteroaryl-C1-6alkyl;
• or
• heterocyclyl-C1-6alkyl;
• or R4 and R5 together with the atom to which they are attached 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 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 form a six-membered heteroaryl containing one or two nitrogen atoms, and which is optionally substituted with halo, amino or C1-6alkyl;
• and
• R6, R7 and R8 each independently is:
• hydrogen;
• C1-6alkyl;
• C1-6alkyloxy;
• halo;
• C1-6haloalkyl;
• or
• cyano.