Pyrrole antifungal agents

A method of controlling a fungal infection in a plant, which method comprises applying to the locus of the plant an effective amount of a pyrrole derivative of formula (I), or an agriculturally acceptable salt thereof:

• wherein:
• R1 represents hydrogen, unsubstituted or substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO2(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4;
• A1 represents a C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• A2 and A3 are the same or different and represent C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• A4 is an unsubstituted or substituted 5- to 12-membered heterocyclyl group wherein 1 or 2 ring carbon atoms are replaced with a group selected from >C(═O), >S(═O)2, >C═CH2 or >C(OCH2CH2O), >C(═NOR7), where R7 is hydrogen or a C1-C4 alkyl group;
• L1 represents a bond, a C1-C6 alkylene group in which none, one, two or three —CH2- groups are independently replaced by —O—, —S— or —NR′—, or a 5- to 12-membered heterocyclyl group;
• L2 represents —NR′—, —O—, —CO—, —OCO—, —OCONR′R″—, —CONR′R″— or —SO2—,
• L3 represents a bond or a C1-C4 alkylene group in which none, one or two —CH2— groups are independently replaced by —O—, —S— or —NR′—;
• n is 1 or 2;
• R6 represents hydrogen or C1-C4 alkyl;
• R5 represents an unsubstituted or substituted group selected from C6-C10 aryl, a 5- to 12-membered heterocyclyl group, C1-C8 alkyl and C3-C6 cycloalkyl, halogen or a group of formula B1 B2 or -B3;
• B1 represents an unsubstituted or substituted C6-C10 aryl group;
• B2 represents an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• B3 is an unsubstituted or substituted 5- to 12-membered heterocyclyl group where 1 or 2 ring carbon atoms are replaced with a group selected from >C(═O), >S(═O)2, >C(═NOR11), >C═CH2 or >C(OCH2CH2O), where R11 is hydrogen or a C1-C4 alkyl group;
• R2 and R3 independently represent C6-C10 aryl, a 5- to 12-membered heterocyclyl group, C3-C6 cycloalkyl, hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO2R′, —SO2NR′R″, —SO3H,
• —NR′R″, —NR′COR′, —CO2R′, —CONR′R″, —COR′, —OCOR′, —CF3, —NSO2R′ or
• —OCONR′R″, or a group (C1-4) alkyl-A5, wherein none, one or two —CH2- groups are independently replaced by —O—, —S— or —NR′— and wherein A5 represents C6-10 aryl or a 5- to 12-membered heterocyclyl group;
• or R2 and R3 together with the ring atoms to which they are bonded form a 5- to 7-membered saturated or partially saturated ring containing a nitrogen atom from the adjacent pyrrole ring, and optionally one or two further heteroatoms selected from N, O and S, with the proviso that R2 and R3 do not form, together with the pyrrole ring to which they are bonded, a tetrahydroindolizine ring;
• R4 represents hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
• —OR′, —CO2R′, —CONR′R″, —COR′, —CN, —NO2, —NR′R″, CF3, —Y—Z, C6-C10 aryl, or 5- to 12-membered heterocyclyl group, or a group of formula Alk6 L5 A12, where Alk6 is a C1-C4 alkylene group, L5 is a group of formula OC(═O), C(═O) or NR13C(═O) and R13 is hydrogen or C1-C4 alkyl, and A12 is an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• Y represents C1-C8 alkylene, C2-C8 alkenylene or C2-C8 alkynylene;
• Z represents halogen, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO2R′, —SO2NR′R″, —SO3H, —NR′R″, —NR′COR′, —NO2, —CO2R′, —CONR′R″, —COR′, —OCOR′, —CN, —CF3, —NSO2R′, —OCONR′R″ or —CR′═NOR″;
• R′ and R″ independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl;
• and
• wherein an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group or moiety can be substituted or unsubstituted;
• and wherein:
• a substituted alkyl, alkenyl or alkynyl group or moiety is a said alkyl, alkenyl or alkynyl group or moiety which is substituted with up to three substituents selected from halogen, hydroxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, —S(C1-C4 alkyl), —CO2H, —CO2(C1-C4 alkyl), phenyl, 5- or 6-membered heterocyclyl, —CONRb′Rb″ and —NRb′CO(C1-C4 alkyl) where Rb′ and Rb″ are the same or different and represent hydrogen or unsubstituted C1-C4 alkyl, wherein the substitutents on a substituted alkyl, alkenyl or alkynyl group or moiety are themselves unsubstituted or, the case of C1-C4 alkoxy substituents, may be further substituted with unsubstituted methoxy or ethoxy;
• a substituted cycloalkyl group is a said cycloalkyl group which is substituted with up to three substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z;
• a substituted aryl or heterocyclyl group or moiety is a said aryl or heterocyclyl group or moiety which is substituted with up to three substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z,
• and optionally a second antifungal agent.

A method of preventing or treating a fungal infection in a subject in need thereof, which method comprises the administration to said subject of an effective amount of (i) a pharmaceutical combination comprising a combination of a pyrrole derivative of formula (I) or a pharmaceutically acceptable salt thereof:

• wherein:
• R1 represents hydrogen, unsubstituted or substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO2(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4;
• A1 represents a C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• A2 and A3 are the same or different and represent C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• A4 is an unsubstituted or substituted 5- to 12-membered heterocyclyl group wherein 1 or 2 ring carbon atoms are replaced with a group selected from >C(═O), >S(═O)2, >C(═NOR7), >C═CH2 or >C(OCH2CH2O), where R7 is hydrogen or a C1-C4 alkyl group;
• L1 represents a bond, a C1-C6 alkylene group in which none, one, two or three —CH2— groups are independently replaced by —O—, —S— or —NR′—, or a 5- to 12-membered heterocyclyl group;
• L2 represents —NR′—, —O—, —CO—, —OCO—, —OCONR′R″—, —CONR′R″— or —SO2;
• L3 represents a bond or a C1-C4 alkylene group in which none, one or two —CH2— groups are independently replaced by —O—, —S— or —NR′—;
• n is 1 or 2;
• R6 represents hydrogen or C1-C4 alkyl;
• R5 represents an unsubstituted or substituted group selected from C6-C10 aryl, a 5- to 12-membered heterocyclyl group, C1-C8 alkyl and C3-C6 cycloalkyl, halogen or a group of formula -B1, -B2 or -B3;
• B1 represents an unsubstituted or substituted C6-C10 aryl group;
• B2 represents an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• B3 is an unsubstituted or substituted 5- to 12-membered heterocyclyl group where 1 or 2 ring carbon atoms are replaced with a group selected from >C(═O), >S(═O)2, >C(═NOR11), >C═CH2 or >C(OCH2CH2O), where R11 is hydrogen or a C1-C4 alkyl group;
• R2 and R3 independently represent C6-C10 aryl, a 5- to 12-membered heterocyclyl group, C3-C6 cycloalkyl, hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO2R′, —SO2NR′R″, —SO3H,
• —NR′R″, —NR′COR′, —CO2R′, —CONR′R″, —COR′, —OCOR′, —CF3, —NSO2R′ or
• —OCONR′R″, or a group (C1-4) alkyl-A5, wherein none, one or two —CH2- groups are independently replaced by —O—, —S— or —NR′— and wherein A5 represents C6-10 aryl or a 5- to 12-membered heterocyclyl group;
• or R2 and R3 together with the ring atoms to which they are bonded form a 5- to 7-membered saturated or partially saturated ring containing a nitrogen atom from the adjacent pyrrole ring, and optionally one or two further heteroatoms selected from N, O and S, with the proviso that R2 and R3 do not form, together with the pyrrole ring to which they are bonded, a tetrahydroindolizine ring;
• R4 represents hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
• —OR′, —CO2R′, —CONR′R″, —COR′, —CN, —NO2, —NR′R″, CF3, —Y—Z, C6-C10 aryl, or 5- to 12-membered heterocyclyl group, or a group of formula Alk6 L5 A12, where Alk6 is a C1-C4 alkylene group, L5 is a group of formula OC(═O), C(═O) or NR13C(═O) and R13 is hydrogen or C1-C4 alkyl, and A12 is an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• Y represents C1-C8 alkylene, C2-C8 alkenylene or C2-C8 alkynylene;
• Z represents halogen, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO2R′, —SO2NR′R″, —SO3H, —NR′R″, —NR′COR′, —NO2, —CO2R′, —CONR′R″, —COR′, —OCOR′, —CN, —CF3, —NSO2R′, —OCONR′R″ or —CR′═NOR″;
• R′ and R″ independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl;
• and
• wherein an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group or moiety can be substituted or unsubstituted;
• and wherein:
• a substituted alkyl, alkenyl or alkynyl group or moiety is a said alkyl, alkenyl or alkynyl group or moiety which is substituted with up to three substituents selected from halogen, hydroxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, —S(C1-C4 alkyl), —CO2H, —CO2(C1-C4 alkyl), phenyl, 5- or 6-membered heterocyclyl, —CONRb′Rb″ and —NRb′CO(C1-C4 alkyl) where Rb′ and Rb″ are the same or different and represent hydrogen or unsubstituted C1-C4 alkyl, wherein the substitutents on a substituted alkyl, alkenyl or alkynyl group or moiety are themselves unsubstituted or, the case of C1-C4 alkoxy substituents, may be further substituted with unsubstituted methoxy or ethoxy;
• a substituted cycloalkyl group is a said cycloalkyl group which is substituted with up to three substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z;
• a substituted aryl or heterocyclyl group or moiety is a said aryl or heterocyclyl group or moiety which is substituted with up to three substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z,
• with a second antifungal agent;
• or
• (ii) a pharmaceutical composition comprising (a) a pyrrole derivative of formula (I) wherein:
• R1 represents hydrogen, unsubstituted or substituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —COR′ or —SO2(C1-C4 alkyl), or a group -A2, -L2-A2, -L3-A2, -A2-L3-A3 or -A4;
• A1 represents a C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• A2 and A3 are the same or different and represent C3-C6 cycloalkyl or an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• A4 is an unsubstituted or substituted 5- to 12-membered heterocyclyl group wherein 1 or 2 ring carbon atoms are replaced with a group selected from >C(═O), >S(═O)2, >C═CH2 or >C(OCH2CH2O), >C(═NOR7), where R7 is hydrogen or a C1-C4 alkyl group;
• L1 represents a bond, a C1-C6 alkylene group in which none, one, two or three —CH2— groups are independently replaced by —O—, —S— or —NR′—, or a 5- to 12-membered heterocyclyl group;
• L2 represents —NR′—, —O—, —CO—, —OCO—, —OCONR′R″—, —CONR′R″— or —SO2f,
• L3 represents a bond or a C1-C4 alkylene group in which none, one or two —CH2— groups are independently replaced by —O—, —S— or —NR′—;
• n is 1 or 2;
• R6 represents hydrogen or C1-C4 alkyl;
• R5 represents an unsubstituted or substituted group selected from C6-C10 aryl, a 5- to 12-membered heterocyclyl group, C1-C8 alkyl and C3-C6 cycloalkyl, halogen or a group of formula -B1, -B2 or -B3;
• B1 represents an unsubstituted or substituted C6-C10 aryl group;
• B2 represents an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• B3 is an unsubstituted or substituted 5- to 12-membered heterocyclyl group where 1 or 2 ring carbon atoms are replaced with a group selected from >C(═O), >S(═O)2, >C(═NOR11), >C═CH2 or >C(OCH2CH2O), where R11 is hydrogen or a C1-C4 alkyl group;
• R2 and R3 independently represent C6-C10 aryl, a 5- to 12-membered heterocyclyl group, C3-C6 cycloalkyl, hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO2R′, —SO2NR′R″, —SO3H,
• —NR′R″, —NR′COR′, —CO2R′, —CONR′R″, —COR′, —OCOR′, —CF3, —NSO2R′ or —OCONR′R″, or a group (C1-4) alkyl-A5, wherein none, one or two —CH2- groups are independently replaced by —O—, —S— or —NR′— and wherein A5 represents C6-10 aryl or a 5- to 12-membered heterocyclyl group;
• or R2 and R3 together with the ring atoms to which they are bonded form a 5- to 7-membered saturated or partially saturated ring containing a nitrogen atom from the adjacent pyrrole ring, and optionally one or two further heteroatoms selected from N, O and S, with the proviso that R2 and R3 do not form, together with the pyrrole ring to which they are bonded, a tetrahydroindolizine ring;
• R4 represents hydrogen, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
• —OR′, —CO2R′, —CONR′R″, —COR′, —CN, —NO2, —NR′R″, CF3, —Y—Z, C6-C10 aryl, or 5- to 12-membered heterocyclyl group, or a group of formula Alk6 L5 A12, where Alk6 is a C1-C4 alkylene group, L5 is a group of formula OC(═O), C(═O) or NR13C(═O) and R13 is hydrogen or C1-C4 alkyl, and A12 is an unsubstituted or substituted C6-C10 aryl or 5- to 12-membered heterocyclyl group;
• Y represents C1-C8 alkylene, C2-C8 alkenylene or C2-C8 alkynylene;
• Z represents halogen, C3-C6 cycloalkyl, —OR′, —SR′, —SOR′, —SO2R′, —SO2NR′R″, —SO3H, —NR′R″, —NR′COR′, —NO2, —CO2R′, —CONR′R″, —COR′, —OCOR′, —CN, —CF3, —NSO2R′, —OCONR′R″ or —CR′═NOR″;
• R′ and R″ independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl;
• and
• wherein an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group or moiety can be substituted or unsubstituted;
• and wherein:
• a substituted alkyl, alkenyl or alkynyl group or moiety is a said alkyl, alkenyl or alkynyl group or moiety which is substituted with up to three substituents selected from halogen, hydroxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino, C1-C4 alkoxy, —S(C1-C4 alkyl), —CO2H, —CO2(C1-C4 alkyl), phenyl, 5- or 6-membered heterocyclyl, —CONRb′Rb″ and —NRb′CO(C1-C4 alkyl) where Rb′ and Rb″ are the same or different and represent hydrogen or unsubstituted C1-C4 alkyl, wherein the substitutents on a substituted alkyl, alkenyl or alkynyl group or moiety are themselves unsubstituted or, the case of C1-C4 alkoxy substituents, may be further substituted with unsubstituted methoxy or ethoxy;
• a substituted cycloalkyl group is a said cycloalkyl group which is substituted with up to three substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z;
• a substituted aryl or heterocyclyl group or moiety is a said aryl or heterocyclyl group or moiety which is substituted with up to three substituents selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Z and —Y—Z,
• or a pharmaceutically acceptable salt thereof, (b) a second antifungal agent and (c) a pharmaceutically acceptable carrier or diluent.