Substituted pyrimidin-5-carboxamides 281

A method for producing an 11βHSD1 inhibitory effect in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I) wherein:

• Q is O, S, N(R8) or a single bond;
• R8 is selected from hydrogen, C1-4alkyl, C3-5cycloalkyl and C3-5cycloalkylmethyl (each of which is optionally substituted by 1, 2 or 3 fluoro atoms);
• R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, heterocyclyl, heteroaryl, aryl, arylC1-3alkyl, heteroarylC1-3alkyl, C3-7cycloalkylC1-3alkyl, heterocyclylC1-3alkyl, C3-7cycloalkylC2-3alkenyl and C3-7cycloalkylC2-3alkynyl, [each of which is optionally substituted, on available carbon atoms, by 1, 2 or 3 substituents independently selected from C1-3alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl, C1-3alkoxy, C1-3alkylS(O)n— (wherein n is 0, 1, 2 or 3), R5CON(R5′)-, (R5′)(R5″)N—, (R5′)(R5″)NC(O)—, R5′C(O)O—, R5′OC(O)—, (R5′)(R5″)NC(O)N(R5′″)-, R5SO2N(R5″)-, (R5′)(R5″)NSO2— and C1-2alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxy, halo, carboxy and C1-3alkoxy (wherein R5 is C1-3alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxyl, halo and cyano;
• and
• R5′, R5″ and R5′″ are independently selected from hydrogen and C1-3alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxyl, halo, C1-3alkoxy, carboxy and cyano or R5′ and R5″ together with the nitrogen atom to which they are attached form a 4-7 membered saturated ring) and optionally substituted, on an available nitrogen, by a substituent independently selected from C1-4alkyl, C2-4alkanoyl and C1-4alkanesulphonyl each of which is optionally substituted by 1, 2 or 3 substituent independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano];
• or
• R1 and R8 together with the nitrogen atom to which they are attached form a saturated mono, bicyclic or bridged ring system optionally containing 1 or 2 additional ring heteroatoms independently selected from nitrogen, oxygen and sulphur and optionally fused to a saturated, partially saturated or unsaturated monocyclic ring wherein the resulting ring system is optionally substituted, on available carbon atoms, by 1, 2, or 3 substituents independently selected from R9 and optionally substituted, on an available nitrogen, by a substituent independently selected from C1-4alkyl, C2-4alkanoyl and C1-4alkanesulphonyl each of which is optionally substituted by 1, 2 or 3 substituent independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano;
• R2 is selected from C3-7cycloalkyl(CH2)m—, and C6-12polycycloalkyl(CH2)m— (wherein m is 0, 1 or 2 and the rings optionally contain 1 or 2 ring atoms independently selected from nitrogen, oxygen and sulphur are optionally substituted, on available carbon atoms, by 1, 2 or 3 substituents independently selected from R6 and optionally substituted, on an available nitrogen, by a substituent independently selected from C1-4alkyl, C2-4alkanoyl and C1-4alkanesulphonyl each of which is optionally substituted by 1, 2 or 3 substituent independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano);
• R3 is selected from hydrogen, C1-4alkyl, C3-5cycloalkyl and C3-5cycloalkylmethyl (each of which is optionally substituted by 1, 2 or 3 fluoro atoms);
• R2 and R3 together with the nitrogen atom to which they are attached form a saturated mono, bicyclic or bridged ring system optionally containing 1 or 2 additional ring heteroatoms independently selected from nitrogen, oxygen and sulphur and optionally fused to a saturated, partially saturated or unsaturated monocyclic ring wherein the resulting ring system is optionally substituted, on available carbon atoms, by 1, 2, or 3 substituents independently selected from R7 and optionally substituted, on an available nitrogen, by a substituent independently selected from C1-4alkyl, C2-4alkanoyl and C1-4alkanesulphonyl each of which is optionally substituted by 1, 2 or 3 substituent independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano;
• R4 is selected from hydrogen, R10, —OR10, —SR10 and —NR11R12;
• R10 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, heterocyclyl, arylC1-3alkyl, heteroarylC1-3alkyl, heterocyclylC1-3alkyl, C3-7cycloalkylC1-3alkyl, C3-7cycloalkylC2-3alkenyl and C3-7cycloalkylC2-3alkynyl, [each of which is optionally substituted, on available carbon atoms, by 1, 2 or 3 substituents independently selected from C1-3alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl, C1-3alkoxy, C1-3alkylS(O)p— (wherein p is 0, 1, 2 or 3), R13CON(R13′)—, (R13′)(R13″)N—, (R13′)(R13″)NC(O)—, R13″C(O)O—, R13′ OC(O), (R13′)(R13″)NC(O)N(R13′″)-, R13SO2N(R13″)—, (R13′)(R13″)NSO2— and C1-2alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxy, halo, carboxy and C1-3alkoxy (wherein R13 is C1-3alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxyl, halo and cyano;
• and
• R13′, R13″ and R13′″ are independently selected from hydrogen and C1-3alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxyl, halo, C1-3alkoxy, carboxy and cyano or R13′ and R13″ together with the nitrogen atom to which they are attached form a 4-7 membered saturated ring) and optionally substituted, on an available nitrogen, by a substituent independently selected from C1-4alkyl, C2-4alkanoyl and C1-4alkanesulphonyl each of which is optionally substituted by 1, 2 or 3 substituent independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano];
• R11 is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, heterocyclyl, arylC1-3alkyl, heteroarylC1-3alkyl, heterocyclylC1-3alkyl, C3-7cycloalkylC1-3alkyl, C3-7cycloalkylC2-3alkenyl and C3-7cycloalkylC2-3alkynyl, [each of which is optionally substituted, on available carbon atoms, by 1, 2 or 3 substituents independently selected from C1-3alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl, C1-3alkoxy, C1-3alkylS(O)q— (wherein q is 0, 1, 2 or 3), R14CON(R14′)-, (R14′)(R14″)NC(O)—, R14″C(O)O—, R14′OC(O)—, (R14′)(R14″)NC(O)N(R14′″)-, R14SO2N(R14″)-, (R14′)(R14″)NSO2— and C1-2alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxy, halo, carboxy and C1-3alkoxy (wherein R14 is C1-3alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxyl, halo and cyano;
• and
• R14′, R14″ and R14′″ are independently selected from hydrogen and C1-3alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxyl, halo, C1-3alkoxy, carboxy and cyano or R14′ and R14″ together with the nitrogen atom to which they are attached form a 4-7 membered saturated ring) and optionally substituted, on an available nitrogen, by a substituent independently selected from C1-4alkyl, C2-4alkanoyl and C1-4alkanesulphonyl each of which is optionally substituted by 1, 2 or 3 substituent independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano];
• and
• R12 is selected from hydrogen, C1-4alkyl, C3-5cycloalkyl and C3-5cycloalkylmethyl (each of which is optionally substituted by 1, 2 or 3 fluoro atoms);
• or
• R11 and R12 together with the nitrogen atom to which they are attached form a saturated mono, bicyclic or bridged ring system optionally containing 1 or 2 additional ring heteroatoms independently selected from nitrogen, oxygen and sulphur and optionally fused to a saturated, partially saturated or unsaturated monocyclic ring (optionally containing 1 or 2 additional ring heteroatoms independently selected from nitrogen, oxygen and sulphur) wherein the resulting ring system is optionally substituted, on available carbon atoms, by 1, 2, or 3 substituents independently selected from R15 and optionally substituted on an available nitrogen by a substituent independently selected from C1-4alkyl, C2-4alkanoyl and C1-4alkanesulphonyl each of which is optionally substituted by 1, 2 or 3 substituent independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano;
• R6, R7, R9 and R15 are independently selected from hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, R16, R16O—, R16CO, R16C(O)O, R16CON(R16′)-, (R16′) (16″)NC(O)—, (R16′)(R16″)N—, R16S(O)a— wherein a is 0 to 2, R16′OC(O)—, (R16′)(R16″)NSO2—, R16SO2N(R16″)—, (R16′)(R16″)NC(O)N(R16′″)—, phenyl and heteroaryl [wherein the phenyl and heteroaryl groups are optionally fused to a phenyl, heteroaryl or a saturated or partially-saturated 5- or 6-membered ring optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur and the resulting ring system is optionally substituted, on available carbon atoms, by 1, 2 or 3 substituents independently selected from C1-4alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, halo, C1-4alkoxy, C1-4alkoxyC1-4alkyl, amino, N—C1-4alkylamino, di-N,N—(C1-4alkyl)amino, N—C1-4alkylcarbamoyl, di-N,N—(C1-4alkyl)carbamoyl, C1-14alkylS(O)r— and C1-4alkylS(O)rC1-4alkyl (wherein r is independently selected 0, 1 and 2) and optionally substituted, on an available nitrogen, by a substituent independently selected from C1-4alkyl, C2-4alkanoyl and C1-4alkanesulphonyl each of which is optionally substituted by 1, 2 or 3 substituent independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano];
• R16 is independently selected from, C1-3alkyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano;
• R16′, R16″ and R16′″ are independently selected from hydrogen and C1-3alkyl optionally substituted by 1, 2, or 3 substituents independently selected from hydroxyl, halo, C1-4alkoxy, carboxy and cyano);
• or a pharmaceutically-acceptable salt thereof.