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

A method for treating a gastrointestinal disorder selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), diarrhea-dominant IBS, and pain associated with GI distension comprising administering to a patient in need thereof an effective amount of a compound of formula (I),

• wherein:
• R1 is a group of formula A or formula B;
• wherein:
• X is —S — or —O—:
• Ra and Rb each independently selected from:
• hydrogen;
• C1-6alkyC1-6alkoxy;
• C1-6alkylsulfonyl-C1,6alkyl;
• halo-C1-6alkyl;
• halo-C1-6alkoxy;
• hetero-C1-6alkyl;
• C3-6-cycloalkyl;
• C3-6cycloalkyl-C1-6alkyl;
• aminocarbonyl;
• C1-6alkoxycarbonyl;
• or cyano;
• 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;
• R3 is hydrogen;
• C1-6alkyl;
• hetero-C1-6alkyl;
• or cyano:
• R4 is hydrogen;
• C1-6alkyl;
• or hetero-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—C 1-6alkylamino;
• 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;
• or C1-6alkyl:
• and,
• R8 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:
• 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;
• or cyano:
• or, or a pharmaceutically acceptable salt thereof.