Pyrrole derivatives as ACC inhibitors

文档序号：976009 发布日期：2020-11-03 浏览：7次中文

阅读说明：本技术 作为acc抑制剂的吡咯衍生物 (Pyrrole derivatives as ACC inhibitors ) 是由霍尔迪·巴赫塔娜克里斯蒂娜·伊斯特福特里亚斯玛尔塔·米尔塞佩达于 2018-12-07 设计创作，主要内容包括：公开了新的式(I)的吡咯衍生物；以及它们的制备方法,包含它们的药物组合物以及它们在治疗中作为乙酰CoA羧化酶(ACC)抑制剂的用途。<Image he="410" wi="494" file="DDA0002534618800000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Novel pyrrole derivatives of formula (I); as well as processes for their preparation, pharmaceutical compositions containing them and their use in therapy as inhibitors of acetyl-CoA carboxylase (ACC).)

1. A pyrrole derivative, which is a compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or tautomer, or stereoisomer, or isotopically labeled derivative thereof:

wherein:

·R¹selected from hydrogen atoms, straight or branched chains C_1-4Alkyl, straight or branched C_1-4Haloalkyl, straight-chain or branched C_1-10Hydroxyalkyl, - (CH)₂)_0-3-(C_3-7Monocyclic cycloalkyl), - (CH)₂)_0-3- (monocyclic or bicyclic C)_6-14Aryl), - (CH)₂)_0-3- (4-to 7-membered heterocyclic group containing at least one heteroatom selected from N, O and S), - (CH)₂)_0-3- (monocyclic or bicyclic 5-to 14-membered heteroaryl containing at least one heteroatom selected from N, O and S), -and- (CH)₂)_0-4-[(CH₂)_1-3-O]_1-5-R^aGroup, - (CR)^aR^b)_1-3-OC(O)-R⁵Group and- (CH)₂)_1-3-C(O)NR⁵R^aThe radical(s) is (are),

wherein cycloalkyl, aryl, heterocyclyl and heteroaryl are unsubstituted or substituted with one or more substituents selected from: halogen atom, straight or branched C_1-4Alkyl and oxo groups;

·R²selected from the group consisting of hydrogen atoms, halogen atoms, -CN groups and straight-chain or branched C_1-4An alkyl group;

·R³represents a straight or branched chain C_9-20An alkyl group, a carboxyl group,

wherein alkyl is unsubstituted or substituted with one or more substituents selected from: halogen atom, hydroxy group, straight or branched C_1-4Alkyl, straight or branched C_1-6Alkoxy and straight or branched C_1-4A hydroxyalkyl group;

·R⁴selected from hydrogen atoms and straight or branched C_1-4An alkyl group;

·R⁵selected from hydrogen atoms, straight or branched chains C_1-10Alkyl, -O- (straight or branched C)_1-10Alkyl), -O- (CH)₂)_0-3-(C_3-7Monocyclic cycloalkyl), -O- (CH)₂)_0-3- (monocyclic or bicyclic C)_6-14Aryl), - (CH)₂)_0-3C(O)OR^aA group and-O- [ (CH)₂)_1-3-O]_1-5-R^aA group;

wherein alkyl is unsubstituted or substituted with one or more substituents selected from:

halogen atoms, hydroxyl groups and amino groups;

·R^aand R^bIndependently selected from hydrogen atoms and straight or branched C_1-4An alkyl group; wherein alkyl is unsubstituted or substituted with one or more substituents selected from: halogen atoms and hydroxyl groups; and

l represents a direct bond, - (CH)₂)_0-4-O-group, - (CH)₂)_0-4-S-group, - (CH)₂)_0-4-NR_aA group, -C (O) NR^a-group, -NR^aA C (O) -group or a carbonyl group; characterized in that when R is²When represents a hydrogen atom, L represents- (CH)₂)_0-4-O-group or-C(O)NR^a-a group.

2. The pyrrole derivative according to claim 1, wherein the compound of formula (I) is represented by formula (Ia):

3. the pyrrole derivative according to claim 1, wherein the compound of formula (I) is represented by formula (Ib):

4. the pyrrole derivative according to claims 1 to 3, wherein R²Represents a halogen atom.

5. The pyrrole derivative according to claim 4, wherein R²Represents a fluorine atom or a chlorine atom.

6. The pyrrole derivative according to claims 1 to 5, wherein R³Represents a straight or branched chain C_9-20An alkyl group, a carboxyl group,

wherein alkyl is unsubstituted or substituted with one or more substituents selected from: halogen atom, hydroxy group, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group.

7. The pyrrole derivative according to claim 1 to 6 wherein L represents a direct bond or-O-.

8. The pyrrole derivative according to claim 1, wherein:

·R²represents a halogen atom, preferably R²Represents a fluorine atom or a chlorine atom;

·R³represents a straight or branched chain C_9-20An alkyl group, a carboxyl group,

wherein alkyl is unsubstituted or substituted with one or more substituents selected from: halogen atom, hydroxy group, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group; and

l represents a direct bond or-O-.

9. The pyrrole derivative according to claim 1, wherein the compound of formula (I) is represented by formula (Ia):

wherein:

·R¹selected from hydrogen atoms, straight or branched chains C_1-4Alkyl, straight or branched C_1-4Haloalkyl, straight-chain or branched C_2-10Hydroxyalkyl, cyclohexyl, -CH₂-phenyl, - (CH)₂)_1-2- (5-to 6-membered heterocyclic group containing at least one heteroatom selected from N, O and S), - (CH)₂CH₂O)_1-4-R^aGroup, - (CR)^aR^b)_1-3-OC(O)-R⁵Group and- (CH)₂)_1-3-C(O)NR⁵R^aThe radical(s) is (are),

wherein the cyclohexyl, phenyl and heterocyclyl are unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen atom, straight or branched C_1-4Alkyl and oxo groups;

·R²represents a halogen atom;

·R³represents a straight or branched chain C_10-17An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen atom, hydroxy group, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group;

·R⁴represents a hydrogen atom;

·R⁵selected from-O- (straight or branched C)_1-10Alkyl), -O-cyclohexyl, -O-CH₂-phenyl, - (CH)₂)_1-2C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-3-R^aA group and-O-CH₂CH₂CH₂O-R^aA group;

·R^aselected from hydrogen atoms and straight or branched C_1-4An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen atoms and hydroxyl groups;

·R^brepresents a hydrogen atom; and

l represents a direct bond or-O-.

10. The pyrrole derivative according to claim 9, wherein:

·R¹selected from hydrogen atoms, straight or branched chains C_1-3Haloalkyl, straight-chain or branched C_3-9Hydroxyalkyl, - (CH)₂)_1-2- (5-membered heterocyclic group containing at least one hetero atom selected from N and O), - (CH)₂CH₂O)₂-R^aGroup, - (CR)^aR^b)-OC(O)-R⁵Group and- (CH)₂)-C(O)NR⁵R^aThe radical(s) is (are),

wherein heterocyclyl is unsubstituted or substituted with one or more substituents selected from: straight or branched C_1-4Alkyl and oxo groups;

·R²represents a fluorine atom or a chlorine atom;

·R³represents a straight or branched chain C_10-17An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine atom, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group;

·R⁵selected from-O- (straight or branched C)_2-4Alkyl), -O-cyclohexyl, -O-CH₂-phenyl, - (CH)₂)-C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-2-R^aA group and-O-CH₂CH₂CH₂O-R^aA group;

·R^aselected from hydrogen atoms and straight or branched C_1-4An alkyl group; wherein the alkyl group isUnsubstituted or substituted with one or more substituents selected from: halogen atoms and hydroxyl groups.

11. The pyrrole derivative according to claim 1, wherein:

·R¹selected from hydrogen atoms, straight or branched chains C_1-4Alkyl, -CH₂CF₃Group, - (CH)₂)_2-9-OH group, -CH₂-CH(OH)-CH₂-OH、-CH(CH₂OH)₂Radical, cyclohexyl radical, - (CH)₂)₂- (2, 5-dioxopyrrolidin-1-yl) group, - (CH)₂)₂- (2-oxopyrrolidin-1-yl) radical, - (CH)₂) - (5-methyl-2-oxo-1, 3-dioxol-4-yl) group, -CH₂-phenyl, - (CH)₂CH₂O)_2-4-R^aGroup, -CH (CH)₃)-OC(O)OCH(CH₃)₂Group, -CH (CH)₃)-OC(O)OC(CH₃)₃Group, -CH (CH)₃)-OC(O)O(CH₂)₈CH₃Group, -CH (CH)₃) -OC (O) O-cyclohexyl, -CH (CH)₃)-OC(O)O-CH₂-phenyl, -CH (CH)₃)-OC(O)O(CH₂CH₂O)_1-2-R^aGroup, -CH (CH)₃)-OC(O)O(CH₂)₃OH group, - (CH)₂)₂-OC(O)C(NH₂)-CH(CH₃)₂A group and-CH₂-C(O)N(CH₃)CH₂CO₂R^aA group;

·R²represents a hydrogen atom, a methyl group, a fluorine atom, a chlorine atom, a bromine atom or a-CN group;

·R³represents a straight chain C_9-18An alkyl group, a carboxyl group,

wherein alkyl is unsubstituted or substituted with one or more substituents selected from: fluorine atom, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group;

·R⁴selected from hydrogen atoms and straight or branched C_1-4An alkyl group;

·R^aselected from the group consisting of hydrogen atoms andstraight or branched C_1-4An alkyl group;

l represents a direct bond, -O-, -S-, or a carbonyl group; characterized in that when R is²When represents a hydrogen atom, L represents-O-.

12. The pyrrole derivative according to claims 1 to 11, wherein the compound of formula (I) is one of the following compounds, or a pharmaceutically acceptable salt, or solvate, or N-oxide, or stereoisomer, or tautomer, or isotopically labeled derivative thereof:

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- (2, 5-dioxopyrrolidin-1-yl) ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- (2-oxopyrrolidin-1-yl) ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2,2, 2-trifluoroethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2-hydroxyethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 1- ((isopropoxycarbonyl) oxy) ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- ((2-ethoxy-2-oxoethyl) (methyl) amino) -2-oxoethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- ((L-valyl) oxy) ethyl ester

4- (Dodecyloxy) -1H-pyrrole-2-carboxylic acid (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester

4-decyl-3-fluoro-1H-pyrrole-2-carboxylic acid

3-fluoro-4-undecyl-1H-pyrrole-2-carboxylic acid

4-dodecyl-3-fluoro-1H-pyrrole-2-carboxylic acid

4-dodecyl-3-fluoro-1H-pyrrole-2-carboxylic acid 2,2, 2-trifluoroethyl ester

4-dodecyl-3-fluoro-1H-pyrrole-2-carboxylic acid 2- (2-ethoxyethoxy) ethyl ester

4-dodecyl-3-fluoro-1H-pyrrole-2-carboxylic acid 1- ((isopropoxycarbonyl) oxy) ethyl ester

4-dodecyl-3-fluoro-1H-pyrrole-2-carboxylic acid 1- (((2-methoxyethoxy) carbonyl) oxy) ethyl ester

4-dodecyl-3-fluoro-1H-pyrrole-2-carboxylic acid 4-oxo-3, 5,8, 11-tetraoxatridecan-2-yl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid methyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid isopropyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid tert-butyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid cyclohexyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid benzyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2,2, 2-trifluoroethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2- (2, 5-dioxopyrrolidin-1-yl) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2- (2-oxopyrrolidin-1-yl) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2- ((2-ethoxy-2-oxoethyl) (methyl) amino) -2-oxoethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2-hydroxyethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 3-hydroxypropyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 4-hydroxybutyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 5-hydroxypentyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 6-hydroxyhexyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 7-hydroxyheptyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 8-hydroxyoctyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 9-hydroxynonyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2, 3-dihydroxypropyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1, 3-dihydroxypropan-2-yl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2- (2-ethoxyethoxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- ((isopropoxycarbonyl) oxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- ((tert-butoxycarbonyl) oxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- (((nonyloxy) carbonyl) oxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- (((cyclohexyloxy) carbonyl) oxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- (((benzyloxy) carbonyl) oxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- (((2-methoxyethoxy) carbonyl) oxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- (((3-hydroxypropoxy) carbonyl) oxy) ethyl ester

3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid 4-oxo-3, 5,8, 11-tetraoxatridecan-2-yl ester

3-fluoro-4-tetradecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-4-pentadecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-4-heptadecyl-1H-pyrrole-2-carboxylic acid

5-dodecyl-3-fluoro-1H-pyrrole-2-carboxylic acid

3-chloro-4-decyl-1H-pyrrole-2-carboxylic acid

3-chloro-4-undecyl-1H-pyrrole-2-carboxylic acid

3-chloro-4-dodecyl-1H-pyrrole-2-carboxylic acid

3-chloro-4-dodecyl-1H-pyrrole-2-carboxylic acid 9-hydroxynonyl ester

3-chloro-4-dodecyl-1H-pyrrole-2-carboxylic acid 2- (2, 5-dioxopyrrolidin-1-yl) ethyl ester

3-chloro-4-tridecyl-1H-pyrrole-2-carboxylic acid

3-chloro-4-pentadecyl-1H-pyrrole-2-carboxylic acid

3-chloro-4-hexadecyl-1H-pyrrole-2-carboxylic acid

3-chloro-5-undecyl-1H-pyrrole-2-carboxylic acid

3-chloro-5-dodecyl-1H-pyrrole-2-carboxylic acid

3-chloro-5-tridecyl-1H-pyrrole-2-carboxylic acid

3-chloro-5-tetradecyl-1H-pyrrole-2-carboxylic acid

3-bromo-4-tridecyl-1H-pyrrole-2-carboxylic acid

1-butyl-3-fluoro-4-tridecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-1-isopropyl-4-tridecyl-1H-pyrrole-2-carboxylic acid

4- (decyloxy) -3-fluoro-1H-pyrrole-2-carboxylic acid

3-fluoro-4- (undecyloxy) -1H-pyrrole-2-carboxylic acid

4- (dodecyloxy) -3-fluoro-1H-pyrrole-2-carboxylic acid

3-fluoro-4- (tridecyloxy) -1H-pyrrole-2-carboxylic acid

3-fluoro-4- (tetradecyloxy) -1H-pyrrole-2-carboxylic acid

4- (dodecylthio) -3-fluoro-1H-pyrrole-2-carboxylic acid

3-chloro-4- (nonanyloxy) -1H-pyrrole-2-carboxylic acid

3-chloro-4- (decyloxy) -1H-pyrrole-2-carboxylic acid

3-chloro-4- (undecyloxy) -1H-pyrrole-2-carboxylic acid

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2,2, 2-trifluoroethyl ester

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 9-hydroxynonyl ester

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- (2-ethoxyethoxy) ethyl ester

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2, 3-dihydroxypropyl ester

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 1- ((isopropoxycarbonyl) oxy) ethyl ester

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 4-oxo-3, 5,8, 11-tetraoxatridecan-2-yl ester

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 1- (((3-hydroxypropoxy) carbonyl) oxy) ethyl ester

3-chloro-4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester

3-chloro-4- (tridecyloxy) -1H-pyrrole-2-carboxylic acid

3-chloro-4- (tetradecyloxy) -1H-pyrrole-2-carboxylic acid

3-fluoro-4-pentadecanoyl-1H-pyrrole-2-carboxylic acid

4- (12-ethoxydodecyl) -3-fluoro-1H-pyrrole-2-carboxylic acid

3-fluoro-4- (2-fluorotridecyl) -1H-pyrrole-2-carboxylic acid

4- (2, 2-Difluortridecyl) -3-fluoro-1H-pyrrole-2-carboxylic acid

4- (3, 3-dimethyldodecyl) -3-fluoro-1H-pyrrole-2-carboxylic acid

4- ((2, 2-Dimethyltridecyl) oxy) -3-fluoro-1H-pyrrole-2-carboxylic acid

4- ((2, 2-Difluorotetradecanyl) oxy) -3-fluoro-1H-pyrrole-2-carboxylic acid

4- ((2, 2-difluoroundecyl) oxy) -3-fluoro-1H-pyrrole-2-carboxylic acid

3-chloro-4- ((2-fluorotetradecyl) oxy) -1H-pyrrole-2-carboxylic acid

3-chloro-4- ((9-ethoxynonyl) oxy) -1H-pyrrole-2-carboxylic acid

3-methyl-4-tridecyl-1H-pyrrole-2-carboxylic acid

4- (2, 2-Dimethyldodecyl) -3-fluoro-1H-pyrrole-2-carboxylic acid

3-fluoro-4- (undecyloxy) -1H-pyrrole-2-carboxylic acid 2,2, 2-trifluoroethyl ester

3-fluoro-4- (undecyloxy) -1H-pyrrole-2-carboxylic acid 2- (2-ethoxyethoxy) ethyl ester

3-fluoro-4- (undecyloxy) -1H-pyrrole-2-carboxylic acid 1- ((isopropoxycarbonyl) oxy) ethyl ester

3-fluoro-4- (undecyloxy) -1H-pyrrole-2-carboxylic acid 1- (((2-methoxyethoxy) carbonyl) oxy) ethyl ester

3-fluoro-4- (undecyloxy) -1H-pyrrole-2-carboxylic acid 4-oxo-3, 5,8, 11-tetraoxatridecan-2-yl ester

3-chloro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2,2, 2-trifluoroethyl ester

3-chloro-4-tridecyl-1H-pyrrole-2-carboxylic acid 2- (2-ethoxyethoxy) ethyl ester

3-chloro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- ((isopropoxycarbonyl) oxy) ethyl ester

3-chloro-4-tridecyl-1H-pyrrole-2-carboxylic acid 1- (((2-methoxyethoxy) carbonyl) oxy) ethyl ester

3-chloro-4-tridecyl-1H-pyrrole-2-carboxylic acid 4-oxo-3, 5,8, 11-tetraoxatridecan-2-yl ester

3-chloro-5-dodecyl-1H-pyrrole-2-carboxylic acid 2,2, 2-trifluoroethyl ester

3-chloro-5-dodecyl-1H-pyrrole-2-carboxylic acid 2- (2-ethoxyethoxy) ethyl ester

3-chloro-5-dodecyl-1H-pyrrole-2-carboxylic acid 1- ((isopropoxycarbonyl) oxy) ethyl ester

3-chloro-5-dodecyl-1H-pyrrole-2-carboxylic acid 1- (((2-methoxyethoxy) carbonyl) oxy) ethyl ester

3-chloro-5-dodecyl-1H-pyrrole-2-carboxylic acid 4-oxo-3, 5,8, 11-tetraoxatridecan-2-yl ester

3-chloro-5-dodecyl-1H-pyrrole-2-carboxylic acid 2, 3-dihydroxypropyl ester

3-fluoro-5-undecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-5-tridecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-5-tetradecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-5-pentadecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-5-hexadecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-5-heptadecyl-1H-pyrrole-2-carboxylic acid

3-fluoro-5-octadecyl-1H-pyrrole-2-carboxylic acid

3-chloro-5- (2, 2-dimethyldodecyl) -1H-pyrrole-2-carboxylic acid

3-chloro-5- (3, 3-difluorododecyl) -1H-pyrrole-2-carboxylic acid

3-cyano-5-dodecyl-1H-pyrrole-2-carboxylic acid

3-chloro-5-dodecyl-1-methyl-1H-pyrrole-2-carboxylic acid

3-fluoro-5- (14-fluorotetradecyl) -1H-pyrrole-2-carboxylic acid

3-fluoro-4-hexadecyl-1H-pyrrole-2-carboxylic acid.

13. A pyrrole derivative as defined in any one of claims 1 to 12 for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of acetyl CoA carboxylase.

14. Pyrrole derivative according to any one of claims 1 to 12 for use according to claim 13, wherein a pathological condition or disease selected from the group consisting of: acne vulgaris, acne conglobata, inflammatory acne, acne vulgaris, rosacea hypertrophic rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, meibomian gland dysfunction of facial rosacea, mitotic alopecia, oily skin, plaque psoriasis, guttate psoriasis, wrinkled psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, pustular psoriasis, and palmoplantar pustulosis.

15. Pyrrole derivative according to any one of claims 1 to 12 for use according to claims 13 and 14, wherein a pathological condition or disease selected from the group consisting of: acne vulgaris, acne conglobata, inflammatory acne, acne vulgaris, plaque psoriasis, guttate psoriasis, fold psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and pustular psoriasis.

16. A pharmaceutical composition comprising a pyrrole derivative as defined in any one of claims 1 to 12 together with a pharmaceutically acceptable diluent or carrier.

17. Use of a pyrrole derivative as defined in any one of claims 1 to 12 in the manufacture of a medicament for the treatment of a pathological condition or disease as defined in claims 13 to 15.

18. A method of treating a subject suffering from a pathological condition or disease as defined in claims 13 to 15, comprising administering to the subject a therapeutically effective amount of a pyrrole derivative as defined in any one of claims 1 to 12 or a pharmaceutical composition as defined in claim 16.

19. A combination product comprising (i) at least one pyrrole derivative as defined in any one of claims 1 to 12, and (ii) one or more active ingredients selected from:

a) corticosteroids and glucocorticoids, such as beclomethasone, betamethasone dipropionate, budesonide, dexamethasone, fluticasone furoate, fluticasone propionate, hydrocortisone, methylprednisolone, mometasone furoate, prednisone, prednisolone, or prednisone;

b) dihydrofolate reductase inhibitors, such as methotrexate or pramipexole;

c) dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide or asan-003 or LAS 186323;

d) purine antagonists, such as azathioprine, mercaptopurine, or thioguanine;

e) antimalarial drugs such as hydroxychloroquine, chloroquine or quinacrine;

f) calcineurin inhibitors such as cyclosporin a, tacrolimus, pimecrolimus, or cyclosporine;

g) an inosine monophosphate dehydrogenase (IMPDH) inhibitor, such as mycophenolate mofetil, ribavirin or mizoribine;

h) fumaric acid esters such as dimethyl fumarate;

i) vitamin D3 derivatives, such as calcipotriol, calcitriol or tacalcitol;

j) retinoids, such as tazarotene, adapalene, alitretinoin tretinoin, avilam or isotretinoin;

k) anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibodies, such as infliximab, adalimumab, certolizumab pegol, or golimumab;

l) soluble tumor necrosis factor-alpha (TNF-alpha) receptors, such as etanercept or CC-11050;

m) anti-interleukin 6 receptor (IL-6R) antibodies, such as torilizumab, sarilumab, SA-237, or ALX-0061;

n) anti-interleukin 12 (IL-12)/interleukin 23(IL-23) antibodies, e.g., ubsumab;

o) anti-interleukin 17 receptor (IL-17R) antibodies, such as brodalumab;

p) anti-CD 20(B lymphocyte protein) antibodies, such as rituximab, ofatumumab, atolizumab, ocrelizumab, ublituximab, vetuzumab or ocartazumab;

q) anti-interleukin 5(IL-5) antibodies, such as mepiquat;

r) anti-interleukin 5 receptor (IL-5R) antibodies, such as benralizumab;

s) anti-interleukin-13 (IL-13) antibodies, such as lekuromumab or tralokinumab;

t) anti-interleukin 4 receptor (IL-4R)/interleukin 13 receptor (IL-13R) antibodies, such as dupilumab;

u) anti-interleukin 17(IL-17) antibodies, such as secukinumab, ixekizumab, or bimekizumab;

v) anti-IL-23 antibodies, such as tiltrakizumab, guselkumab or risankizumab;

w) anti-interleukin 1 receptor (IL-1R) antibodies;

x) anti-immunoglobulin e (lge) antibodies, such as omalizumab or quilizumab;

y) anti-B cell activating factor (BAFF), such as belimumab or asecept;

z) anti-CD 19 (B-lymphotein) monoclonal antibodies, such as Lantuzumab, MEDI-551 or MOR-208;

aa) kappa opioid agonists such as nalfuraphine, nalbuphine, asimadoline or CR-845;

bb) neurokinin receptor 1 antagonists, such as aprepitant, fosaprepitant, lapitant, orvepitant, tradipitant or serlopitant;

cc) dihydropteroate synthase inhibitors, such as dapsone or sulfadoxine;

dd) histamine 1(H1) receptor antagonists, such as azelastine, ebastine, desloratadine, promethazine, mizolastine, or cetirizine;

ee) cysteinyl leukotriene (CysLT) receptor antagonists, such as montelukast, zafirlukast, tuluekast, or marelukast;

ff) antagonists of chemokine receptor homologous molecules (CRTh2) expressed on TH2 cells, such as OC-459, AZD-1981, ADC-3680, ARRY-502 or setipransat;

gg) topical antibacterial agents, such as Benzoyl Peroxide (BPO), triclosan, chlorhexidine, crystal violet 0.3% or sodium hypochlorite water bath;

hh) antibiotics, such as tetracycline (doxycycline, minocycline, and tetracycline) macrolides (azithromycin, clarithromycin, erythromycin) or clindamycin;

ii) azelaic acid;

jj) alpha-hydroxy acids such as glycolic acid or lactic acid;

kk) beta-hydroxy acids such as salicylic acid; and

ll) PDE4 inhibitors, such as apremilast.

Technical Field

The present invention relates to novel compounds having ACC inhibitory activity. The invention also relates to pharmaceutical compositions containing them, to processes for their preparation and to their use in the treatment of several disorders.

Background

Acetyl CoA Carboxylase (ACC) is a rate-limiting enzyme in the de novo synthesis of fatty acids (Strable MS and Ntambi JM. crit RevBiochem Mol biol. 2010; 45: 199. 214) and in the transport of fatty acids to mitochondria for beta-oxidation (Schreurs M et al. Obes Rev. 2010; 11: 380-8). ACC is also key to the elongation of fatty acids, including essential fatty acids (Kim CW et al cell Metab.2017; 26: 394-406). ACC catalyzes the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA (Barber MC et al Biochim Biophys acta.2005Mar; 1733: 1-28). In mammals, ACC activity is produced by 2 isoenzymes, ACC1 (also known as ACC α) and ACC2 (also known as ACC β) encoded by 2 different genes (Acc 1 and Acc2, respectively) (Barber MC et al Biochim Biophys acta.2005 Mar; 1733: 1-28). ACC1 is located in the cytosol and is involved in fatty acid synthesis and extension. ACC2 is located on the cytoplasmic surface of the outer mitochondrial membrane and is involved in the inhibition of carnitine palmitoyl transferase I (CPT-I), a determinant enzyme that transports long chain fatty acids to mitochondria for beta-oxidation (Tong L.cell Mol Life Sci.2013; 70: 863-91). ACC1 and ACC2 are citrate stimulated for their activity in mammals, inhibited by long chain saturated acyl-CoA and inactivated by phosphorylation, especially by AMP-activated protein kinase (AMPK) and cAMP-dependent Protein Kinase (PKA) (Brown sey RW et al biochem Soc trans.2006; 34: 223-7). ACC activity is also critical for the survival of several organisms, some of which are associated with human pathologies such as bacteria, viruses and parasites (Tong l.cell Mol Life sci.2013; 70: 863-91). In several immune cell types, including T cells and macrophages, ACC activity is essential for differentiation, survival and production of cytokines such as IL-17 (Buck M.et al.cell.2017; 169: 570-86). The decisive role of ACC enzymes in several (patho) physiological processes makes them attractive Drug targets for diseases associated with altered fatty acid metabolism, skin diseases such as acne or psoriasis, diabetes, obesity, non-alcoholic steatohepatitis (NASH), cancer, atherosclerosis, inflammation, autoimmunity, infections and infections, etc. (Luo d. et al. recent Pat Anticancer Drug disc drive disc 2012; 7: 168-84). Indeed, several skin diseases are associated with ACC activity, for example acne is characterized by increased sebum production (Pappas a. et al. dermatoendkrinol. 2009; 1: 157-61; Williams H et al. lancet.2012; 379: 361-72) and increased T cells and IL-17 in both acne and psoriatic lesions (Agak g. et al. j. invest. dermatol.2014; 134: 366-73; Greb j. et al. nat Rev Dis primers.2016; 2: 1-17). Excessive acne activation of sebaceous glands leading to increased sebum production is a well-known feature of the disease. Sebum is formed primarily from lipids such as Triglycerides (TAG), free fatty acids, wax esters, squalene, cholesterol and cholesterol esters. Human sebum is formed primarily from lipids derived from fatty acids such as TAG and wax esters (Pappas a. dermatoncrinol. 2009; 1: 72-6), and it has been shown that in humans, a large proportion of sebum is produced by de novo synthesis of fatty acids, an ACC-dependent activity process (esper W.P et al. wo 2015/036892). Both T cells and IL-17 are increased in acne lesions, with Th17 cells dependent on ACC-mediated fatty acid synthesis for several functions, such as the activity of the Th17 major gene ROR γ T and the production of pro-inflammatory cytokines such as IL-17 (stoking b.and omeentti s.nat. rev. immunol.2017; 17: 535-44). Current acne treatments can be divided into topical and systemic treatments. Topical treatments include retinoids (such as adapalene, tretinoin, and tazarotene), Benzoyl Peroxide (BPO), and antibiotics. BPO and retinoids cause skin irritation, which may compromise treatment compliance and efficacy. Topical antibiotics have limited efficacy and are associated with antibiotic resistance. The most effective systemic treatments are oral isotretinoin and oral antibiotics (Savage l.and Layton a. expert Rev Clin pharmacol.2010; 13: 563-80). Oral isotretinoin treatment is associated with serious side effects including teratogenicity and lipid changes etc. (Layton A. Dermatoendocrinol. 2009; 1: 162-9), and oral antibiotics can induce antibiotic resistance. Genetic and pharmacological evidence suggests that ACC inhibitors may be useful in reducing sebum production and blocking IL-17 expression. However, ACC inhibitors have not been approved for dermatological indications and the only ACC inhibitor currently being developed for dermatological indications (Olumacostat Glasaretil for acne) has been shown to have low potency in inhibiting sebum production by sebaceous gland cells and poor activity in an in vivo model of sebaceous gland activity (Hunt d.et al.j Invest dermatolog.2017; 137: 1415-23).

In view of the numerous conditions that are expected to benefit from treatment involving modulation of the ACC pathway or AC carboxylase, it is apparent that novel compounds that modulate the ACC pathway and the use of these compounds should provide substantial therapeutic benefit to many types of patients.

Provided herein are novel pyrrole derivatives for use in the treatment of conditions in which targeting of the ACC pathway or inhibition of AC carboxylase may be therapeutically useful.

It has now been found that certain pyrrole derivatives are novel and potent ACC inhibitors and are therefore useful in the treatment or prevention of these diseases.

Disclosure of Invention

Accordingly, the present invention relates to novel compounds having ACC inhibitory activity. Accordingly, there is provided a pyrrole derivative which is a compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or tautomer, or stereoisomer, or isotopically labeled derivative thereof:

wherein:

·R¹selected from hydrogen atoms, straight or branched chains C_1-4Alkyl, straight or branched C_1-4Haloalkyl, straight-chain or branched C_1-10Hydroxyalkyl, - (CH)₂)_0-3-(C_3-7Monocyclic cycloalkyl), - (CH)₂)_0-3- (monocyclic or bicyclic C)_6-14Aryl), - (CH)₂)_0-3- (4-to 7-membered heterocyclic group containing at least one heteroatom selected from N, O and S), - (CH)₂)_0-3- (containing at least one member selected from N,Monocyclic or bicyclic 5-to 14-membered heteroaryl of heteroatoms of O and S), - (CH)₂)_0-4-[(CH₂)_1-3-O]_1-5-R^aGroup, - (CR)^aR^b)_1-3-OC(O)-R⁵Group and- (CH)₂)_1-3-C(O)NR⁵R^aThe radical(s) is (are),

wherein cycloalkyl, aryl, heterocyclyl and heteroaryl are unsubstituted or substituted with one or more substituents selected from: halogen atom, straight or branched C_1-4Alkyl and oxo groups;

·R²selected from the group consisting of hydrogen atoms, halogen atoms, -CN groups and straight-chain or branched C_1-4An alkyl group;

·R³represents a straight or branched chain C_9-20An alkyl group, a carboxyl group,

·R⁴selected from hydrogen atoms and straight or branched C_1-4An alkyl group;

wherein alkyl is unsubstituted or substituted with one or more substituents selected from:

halogen atoms, hydroxyl groups and amino groups;

l represents a direct bond,-(CH₂)_0-4-O-group, - (CH)₂)_0-4-S-group, - (CH)₂)_0-4-NR_aA group, -C (O) NR^a-group, -NR^aA C (O) -group or a carbonyl group; characterized in that when R is²When represents a hydrogen atom, L represents- (CH)₂)_0-4an-O-group or-C (O) NR^a-a group.

The invention also provides synthetic methods and intermediates described herein, which are useful for preparing the pyrrole derivatives.

The invention also relates to pyrrole derivatives of the invention as described herein for use in the treatment of the human or animal body by therapy.

The invention also provides a pharmaceutical composition comprising a pyrrole derivative of the invention and a pharmaceutically acceptable diluent or carrier.

The present invention also relates to pyrrole derivatives of the invention as described herein for use in the treatment of pathological conditions or diseases susceptible to amelioration by inhibition of Acetyl CoA Carboxylase (ACC), in particular wherein the pathological conditions or diseases are selected from skin diseases, inflammatory or autoimmune mediated diseases and metabolic/endocrine dysfunction. More particularly, wherein the pathological condition or disease is selected from the group consisting of acne vulgaris, acne conglobata, inflammatory acne, chloracne, rosacea, hypertrophic rosacea, seborrhea, seborrheic dermatitis, sebaceous hyperplasia, meibomian gland dysfunction of facial rosacea, mitotic alopecia, oily skin, plaque psoriasis, guttate psoriasis, fold psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, pustular psoriasis, and palmoplantar pustulosis; preferably for the treatment of acne vulgaris, acne conglobata, inflammatory acne, chloracne, plaque psoriasis, guttate psoriasis, fold psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and pustular psoriasis.

The present invention also relates to the use of a pyrrole derivative of the invention as described herein for the preparation of a medicament for the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Acetyl CoA Carboxylase (ACC), in particular wherein the pathological condition or disease is selected from skin diseases, inflammatory or autoimmune mediated diseases and metabolic/endocrine dysfunction. More particularly, wherein the pathological condition or disease is selected from the group consisting of acne vulgaris, acne conglobata, inflammatory acne, chloracne, rosacea, hypertrophic rosacea, seborrhea, seborrheic dermatitis, sebaceous hyperplasia, meibomian gland dysfunction of facial rosacea, mitotic alopecia, oily skin, plaque psoriasis, guttate psoriasis, fold psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, pustular psoriasis, and palmoplantar pustulosis; preferably for the treatment of acne vulgaris, acne conglobata, inflammatory acne, chloracne, plaque psoriasis, guttate psoriasis, fold psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and pustular psoriasis.

The invention also provides a method of treating a pathological condition or disease susceptible to amelioration by inhibition of acetyl CoA carboxylase, in particular wherein the pathological condition or disease is selected from skin diseases, inflammatory or autoimmune mediated diseases and metabolic/endocrine dysfunction. More particularly, wherein the pathological condition or disease is selected from the group consisting of acne vulgaris, acne conglobata, inflammatory acne, chloracne, rosacea, hypertrophic rosacea, seborrhea, seborrheic dermatitis, sebaceous hyperplasia, meibomian gland dysfunction of facial rosacea, mitotic alopecia, oily skin, plaque psoriasis, guttate psoriasis, fold psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis, pustular psoriasis, and palmoplantar pustulosis; preferably for the treatment of acne vulgaris, acne conglobata, inflammatory acne, chloracne, plaque psoriasis, guttate psoriasis, fold psoriasis, erythrodermic psoriasis, scalp psoriasis, nail psoriasis and pustular psoriasis.

The present invention also provides a conjugate product comprising (i) a pyrrole derivative of the invention as described herein; (ii) one or more other active substances.

Detailed Description

When describing the pyrrole derivatives, compositions, conjugates, and methods of the present invention, the following terms have the following meanings, unless otherwise indicated.

As used herein, the term C_1-10The alkyl group includes a straight or branched chain group having 1 to 10 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, heptyl, octyl, nonyl and decyl. Such alkyl groups are typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different.

As used herein, the term C_1-4The alkyl group includes an unsubstituted or substituted straight or branched chain group having 1 to 4 carbon atoms. Similarly, the term C_1-3Alkyl includes straight or branched chain groups having 1 to 3 carbon atoms, the term C_1-2Alkyl groups include straight or branched chain groups having 1 to 2 carbon atoms. Similarly, the term C_2-4Alkyl groups include straight or branched chain groups having 2 to 4 carbon atoms. C_1-4Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Such alkyl groups are typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. Unless otherwise stated, C_1-4Alkyl groups are generally unsubstituted.

As used herein, the term C_9-20The alkyl group includes a straight or branched chain group having 9 to 20 carbon atoms. Similarly, the term C_10-17The alkyl group includes a straight or branched chain group having 10 to 17 carbon atoms. C_9-20Examples of alkyl groups include nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, 3-dimethylundecyl, 2-dimethyldodecyl and 2, 2-dimethyltridecyl. Such alkyl groups are typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different.

As used herein, the term C_1-4Haloalkyl is a straight-chain or branched alkyl group which is substituted by one or more, preferably 1, 2 or 3, halogen atoms. Similarly, the term C_1-3Haloalkyl is a straight-chain or branched alkyl group which is substituted by one or more, preferably 1, 2 or 3, halogen atoms. Examples of haloalkyl groups include CCl₃、CF₃、CHF₂、CH₂CF₃And CH₂CHF₂。

As used herein, the term C_1-10Hydroxyalkyl groups include straight or branched chain alkyl groups having 1 to 10 carbon atoms, any of which may be substituted with one or more hydroxyl groups. Similarly, the term C_2-10Hydroxyalkyl includes straight or branched alkyl groups having 2 to 10 carbon atoms, any of which may be substituted by one or more hydroxy groups, the term C_3-9Hydroxyalkyl groups include straight or branched chain alkyl groups having 3 to 9 carbon atoms, any of which may be substituted with one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, hydroxyheptyl, hydroxyoctyl, hydroxynonyl, hydroxydecyl, 2, 3-dihydroxypropyl and 1, 3-dihydroxypropan-2-yl.

As used herein, the term C_1-4Hydroxyalkyl groups include straight or branched chain alkyl groups having 1 to 4 carbon atoms, any of which may be substituted with one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl.

As used herein, the term C₁-C₆Alkoxy (or alkyloxy) groups include straight or branched chain oxygen-containing groups, each group having an alkyl moiety of 1 to 6 carbon atoms. C₁-C₆Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

As used herein, the term C₁-C₃Alkoxy (or alkyloxy) groups include straight or branched chain oxygen-containing groups, each group having an alkyl moiety of 1 to 3 carbon atoms. C₁-C₃Examples of alkoxy groups include methylOxy, ethoxy, n-propoxy and isopropoxy.

The term monocyclic C as used herein_3-7Cycloalkyl includes saturated monocyclic carbocyclic groups having 3 to 7 carbon atoms. Monocyclic ring C_3-7Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Such a C_3-7Cycloalkyl groups are generally unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different.

As used herein, the term monocyclic or bicyclic C_6-14Aryl groups generally include C_6-14More preferably C_6-10Monocyclic or bicyclic aryl radicals, such as phenyl, naphthyl, anthryl and phenanthryl. Phenyl is preferred. Such a C_6-14Aryl groups are generally unsubstituted or substituted with 1, 2 or 3 substituents, which may be the same or different.

As used herein, the term 4-to 7-membered heterocyclyl generally includes non-aromatic, saturated or unsaturated C_4-7Carbocyclic ring systems in which one or more carbon atoms, for example 1, 2,3 or 4 carbon atoms, preferably 1 or 2 carbon atoms, are replaced by a heteroatom selected from N, O and S. Examples of 4-to 7-membered heterocyclic groups include oxetanyl, azetidinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pyrazolidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, 4, 5-dihydrooxazolyl, 1, 3-dioxol-2-one, tetrahydrofuryl, 3-aza-tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1, 4-azathioheterocycloalkyl, 2, 5-dioxopyrrolidinyl, 2-oxopyrrolidinyl), 1, 3-dioxol-4-yl or 1, 3-dioxolyl. Such heterocyclic groups are typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. Similarly, the term 5-to 6-membered heterocyclyl generally includes non-aromatic, saturated or unsaturated C_5-6Carbocyclic ring systems in which one or more carbon atoms, for example 1, 2,3 or 4 carbon atoms, preferably 1 or 2 carbon atoms, are replaced by a heteroatom selected from N, O and S. Examples of 5-to 6-membered heterocyclic groups include piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl, morpholinylA linyl group, a thiomorpholinyl group, a pyrrolyl group, a pyrazolinyl group, a pyrazolidinyl group, a triazolyl group, a pyrazolyl group, a tetrazolyl group, an imidazolidinyl group, a 4, 5-dihydrooxazolyl group, a 1, 3-dioxol-2-one, a tetrahydrofuryl group, a 3-aza-tetrahydrofuryl group, a tetrahydrothienyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a 1, 4-azathioheterocycloalkyl group, a 2, 5-dioxopyrrolidinyl group, a 2-oxopyrrolidinyl group, a 1, 3-dioxol-4-yl group or a 1, 3-dioxolyl group. As used herein, the term monocyclic or bicyclic 5-to 14-membered heteroaryl generally comprises a 5-to 14-membered ring system comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, preferably S and N. The 5-to 14-membered heteroaryl group can be a single ring or two fused rings, wherein at least one ring contains a heteroatom. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzo [ b]Thienyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo [3, 4-d]Pyrimidinyl, 1H-pyrazolo [3, 4-d]Pyrimidinyl, benzo [ b ]]Thienyl, thieno [2, 3-d]Pyrimidinyl, thieno [3, 2-d]Pyrimidinyl and various pyrrolopyridinyl, pyridopyrimidinyl, pyrimidopyridazinyl, pyrazolopyrimidinyl, imidazotriazinyl, pyridotriazinyl and triazolopyrimidinyl groups.

As used herein, the term halogen atom includes chlorine, fluorine, bromine and iodine atoms. The halogen atom is usually a fluorine atom, a chlorine atom or a bromine atom. The term halo has the same meaning when used as a prefix.

As used herein, the term carbonyl refers to a-c (o) -moiety [ i.e., a divalent moiety comprising a carbon atom connected to an oxygen atom by a double bond.

As used herein, the term oxo refers to an ═ O moiety [ i.e., a substituted oxygen atom connected to another atom by a double bond.

As used herein, some of the atoms, groups, moieties, chains and rings present in the general structures of the present invention are "unsubstituted or substituted. This means that these atoms, groups, moieties, chains and rings may be unsubstituted or substituted in any position by one or more (e.g. 1, 2,3 or 4) substituents, whereby the hydrogen atoms attached to the unsubstituted atoms, groups, moieties, chains and rings are replaced by chemically acceptable atoms, groups, moieties, chains and rings.

Compounds containing one or more chiral centers can be used in enantiomerically or diastereomerically pure form, in the form of a racemic mixture, and in the form of a mixture enriched in one or more stereoisomers. The scope of the invention as described and claimed includes racemic forms of the compounds as well as individual enantiomers, diastereomers, and stereoisomerically-enriched mixtures.

Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates using, for example, chiral High Pressure Liquid Chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or an acid or base, such as tartaric acid or 1-phenylethylamine, in the case of compounds containing an acidic or basic moiety. The resulting diastereomeric mixtures can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomers by methods well known to those skilled in the art. The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on asymmetric resins using a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0% to 50% (typically 2% to 20%) isopropanol and 0% to 5% alkylamine (typically 0.1% diethylamine). The eluate is concentrated to obtain an enriched mixture. Stereoisomeric agglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g., "Stereochemistry of organic Compounds", Ernest L.Eliel (Wiley, New York, 1994).

The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need thereof.

The term "treating" as used herein refers to treating a disease or medical condition in a human patient, including:

(a) preventing the occurrence of a disease or medical condition, i.e., prophylactically treating a patient;

(b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in the patient;

(c) inhibiting the disease or medical condition, i.e., slowing the progression of the disease or medical condition in the patient; or

(d) Alleviating a symptom of the disease or medical condition in the patient.

The phrase "pathological conditions or diseases susceptible to amelioration by inhibition of ACC" includes all disease states and/or conditions now recognized or discovered in the future that are associated with increased ACC activity. These disease states include, but are not limited to, skin disorders, inflammatory or autoimmune mediated diseases, and metabolic/endocrine dysfunction.

The term pharmaceutically acceptable salt, as used herein, refers to a salt prepared from a base or an acid that is acceptable for administration to a patient (e.g., a mammal). The salts may be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

As used herein, an N-oxide is formed from a basic tertiary amine or imine present in the molecule using a suitable oxidizing agent.

The pyrrole derivatives of the present invention may exist in both non-solvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is used when the solvent is water. Examples of solvate forms include, but are not limited to, compounds of the present invention in combination with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.

The present invention also encompasses isotopically-labeled pyrrole derivatives of the present invention, wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in compounds of the invention include the following isotopes: hydrogen, e.g.²H and³h; carbon, e.g.¹¹C、¹³C and¹⁴c; chlorine, e.g.³⁶Cl; fluorine, e.g.¹⁸F; iodine, e.g.¹²³I and¹²⁵i; nitrogen, e.g.¹³N and¹⁵n; oxygen, e.g.¹⁵O、¹⁷O and¹⁸o; phosphorus, e.g.³²P; and sulfur, e.g.³⁵And S. Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the present invention. As used herein, the term deuterated derivative includes compounds of the invention wherein at least one hydrogen atom at a particular position is replaced by deuterium. Deuterium (D or²H) Is a stable isotope of hydrogen that is present in a natural abundance of 0.015 mole%.

Isotopically-labeled pyrrole derivatives of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the unlabeled reagent originally employed.

As used in the present invention, the term tautomer refers to two or more forms or isomers of an organic compound that can be readily converted into each other by a common chemical reaction known as tautomerization. This reaction typically results in the formal migration of hydrogen atoms or protons, with the conversion of single bonds and adjacent double bonds. The concept of tautomerization is referred to as tautomerism. Tautomers are generally considered to be identical chemical compounds due to rapid interconversion. In a solution where tautomerization is possible, the chemical equilibrium of the tautomer will be reached. The exact ratio of tautomers depends on several factors including temperature, solvent and pH.

Prodrugs of the pyrrole derivatives described herein are also within the scope of the invention. Thus, certain derivatives of the pyrrole derivatives of the invention (which may themselves have little or no pharmacological activity) may be converted to the compounds of the invention having the desired activity when administered to the body or body surface, for example by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, volume 14, ACS Symposium Series (t.higuchi and w.stella) and Bioreversible Carriers in drug Design, Pergamon Press, 1987(e.b. roche eds., American pharmaceutical association).

Prodrugs of the invention may be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in Design of Prodrugs by h. bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.

In the case of pyrrole derivatives as solids, it will be understood by those skilled in the art that the compounds and salts of the present invention may exist in different crystalline or polymorphic forms, or in amorphous form, all of which are intended to be included within the scope of the present invention.

The compounds of formula (I) may contain more than one R_aAnd (4) partial. When the compound contains more than one R_aIn part, each R_aThe portions may be the same or different.

The compounds of formula (I) contain a divalent-L-moiety, wherein L is as defined herein. When L represents- (CH)₂)_0-4-O-group, - (CH)₂)_0-4-S-group, - (CH)₂)_0-4-NR_aA group, -C (O) NR^a-group, -NR^aC (O) -group, the L moiety may be positioned (a) such that the bond to the left of the L moiety is linked to R³A moiety is bonded and the bond to the right of the L moiety is bonded to the central pyrrole ring, or (b) a bond to the right of the L moiety is bonded to R³The moiety is bonded and the bond to the left of the L moiety is bonded to the central pyrrole ring, orientation (a) is generally preferred. For example, in L represents- (CH)₂)_0-4In the case of the-O-group, - (CH)₂)_0-4the-O-group may be located at (a) such that- (C)H₂)_0-4Moiety is attached to R³And the O-moiety is attached to the central pyrrole ring, or (b) such that- (CH)₂)_0-4With a moiety attached to the central pyrrole ring, and an-O-moiety attached to R³。

When R is³Represents a straight or branched chain C_9-20Alkyl substituted by one or more groups selected from straight or branched C_1-4Alkyl, straight or branched C_1-6Alkoxy and straight or branched C_1-4When substituted with a hydroxyalkyl group, R is preferred³The total number of carbon atoms in the moiety is maintained at 9-20.

Preferably, a pyrrole derivative is provided, wherein the pyrrole derivative is a compound of formula (I), or a pharmaceutically acceptable salt, or solvate, or N-oxide, or tautomer, or stereoisomer, or isotopically labeled derivative thereof:

wherein:

wherein cycloalkyl, aryl, heterocyclyl and heteroaryl are unsubstituted or substituted by one or more

Substituted with a substituent selected from: halogen atom, straight or branched C_1-4Alkyl radicalAnd an oxo group;

·R²selected from hydrogen atoms, halogen atoms and straight or branched C_1-4An alkyl group;

·R³represents a straight or branched chain C_9-20An alkyl group, a carboxyl group,

·R⁴selected from hydrogen atoms and straight or branched C_1-4An alkyl group;

wherein alkyl is unsubstituted or substituted with one or more substituents selected from:

halogen atoms, hydroxyl groups and amino groups;

l represents a direct bond, - (CH)₂)_0-4-O-group, - (CH)₂)_0-4-S-group, - (CH)₂)_0-4-N-group, -C (O) NR^a-group, -NR^aA C (O) -group or a carbonyl group; characterized in that when R is²When represents a hydrogen atom, L represents- (CH)₂)_0-4an-O-group or-C (O) NR^a-a group, preferably wherein (a) L represents a direct bond, - (CH)₂)_0-4-O-group, - (CH)₂)_0-4-S-group, -C (O) NR^a-group, -NR^aA C (O) -group or a carbonyl group; specially for treating diabetesCharacterized in that when R is²When represents a hydrogen atom, L represents- (CH)₂)₀-₄an-O-group or-C (O) NR^a-a group, or (b) L represents a direct bond, - (CH)₂)_0-4-O-group, - (CH)₂)_0-4-S-group, - (CH)₂)_0-4-NR_aA group, -C (O) NR^a-group, -NR^aA C (O) -group or a carbonyl group; characterized in that when R is²When represents a hydrogen atom, L represents- (CH)₂)_0-4an-O-group or-C (O) NR^a-a group.

Typically, the compound of formula (I) is a compound of formula (Ia) or a compound of formula (Ib),

preferably, the compound of formula (I) is a compound of formula (Ia).

It is also preferred that the compound of formula (I) is a compound of formula (Ib).

Typically, R¹Selected from hydrogen atoms, straight or branched chains C_1-4Alkyl, straight or branched C_1-4Haloalkyl, straight-chain or branched C_2-10Hydroxyalkyl, cyclohexyl, -CH₂-phenyl, - (CH)₂)_1-2- (5-to 6-membered heterocyclic group containing at least one heteroatom selected from N, O and S), - (CH)₂CH₂O)_1-4-R^aGroup, - (CR)^aR^b)_1-3-OC(O)-R⁵Group and- (CH)₂)_1-3-C(O)NR⁵R^aWherein the cyclohexyl, phenyl and heterocyclyl are unsubstituted or substituted with one or more substituents selected from: halogen atom, straight or branched C_1-4Alkyl and oxo groups.

Preferably, R¹Selected from hydrogen atoms, straight or branched chains C_1-3Haloalkyl, straight-chain or branched C_3-9Hydroxyalkyl, - (CH)₂)_1-2- (5-membered heterocyclic group containing at least one hetero atom selected from N and O), - (CH)₂CH₂O)₂-R^aGroup, - (CR)^aR^b)-OC(O)-R⁵Group and- (CH)₂)-C(O)NR⁵R^aA group wherein heterocyclyl is unsubstituted or substituted with one or more substituents selected from: straight or branched C_1-4Alkyl and oxo groups.

More preferably, R¹Selected from the group consisting of hydrogen atoms, -CH₂CF₃Group, - (CH)₂)₉-OH group, -CH₂CH(OH)CH₂OH group, -CH (CH)₂OH)₂Group, - (CH)₂)₂- (2, 5-dioxopyrrolidin-1-yl) group, - (CH)₂) - (5-methyl-2-oxo-1, 3-dioxol-4-yl) group, - (CH)₂CH₂O)₂-R^aGroup, - (CR)^aH)_1-3-OC(O)-R⁵A group and-CH₂-C(O)NR⁵R^aThe radical(s) is (are),

typically, R²Represents a halogen atom, a methyl group or a hydrogen atom.

Preferably, R²Represents a halogen atom.

More preferably, R²Represents a fluorine atom or a chlorine atom.

Also preferred is R²Represents a hydrogen atom, a methyl group, a fluorine atom, a chlorine atom or a bromine atom.

Typically, R³Represents a straight or branched chain C_9-20An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen atom, hydroxy group, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group.

Preferably, R³Represents a straight or branched chain C_10-17An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: a halogen atom,Hydroxy, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group.

More preferably, R³Represents a straight or branched chain C_10-17An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine atom, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group.

Even more preferably, R³Represents a straight or branched chain C_10-17An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine atom, methyl group and ethoxy group.

Also preferred is R³Represents a straight or branched chain C_9-17An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine atom, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group.

Typically, R⁴Represents a hydrogen atom and a linear or branched C_1-4An alkyl group.

Preferably, R⁴Represents a hydrogen atom.

Typically, R⁵Selected from-O- (straight or branched C)_1-10Alkyl), -O-cyclohexyl, -O-CH₂-phenyl, - (CH)₂)_1-2C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-3-R^aA group and-O-CH₂CH₂CH₂O-R^aA group.

Preferably, R⁵Selected from-O- (straight or branched C)_2-4Alkyl), -O-cyclohexyl, -O-CH₂-phenyl, - (CH)₂)-C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-2-R^aA group and-O-CH₂CH₂CH₂O-R^aA group. More preferably, R⁵Is selected from-O-CH (CH)₃)₂Group, -O-C (CH)₃)₃The group, -O-cyclohexyl, -O-CH₂-phenyl, -CH₂-C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-2-R^aA group and-O-CH₂CH₂CH₂O-R^aA group.

Typically, R^aSelected from hydrogen atoms and straight or branched C_1-4An alkyl group; wherein alkyl is unsubstituted or substituted with one or more substituents selected from: halogen atoms and hydroxyl groups.

Preferably, R^aSelected from hydrogen atoms and straight or branched C_1-4An alkyl group; wherein alkyl is unsubstituted or substituted with one or more hydroxy groups.

More preferably, R^aSelected from hydrogen atoms and straight or branched C_1-4An alkyl group.

Even more preferably, R^aSelected from hydrogen atoms and straight or branched C_1-2An alkyl group.

Also preferred is R^aRepresents a hydrogen atom or a linear or branched C_1-3An alkyl group; wherein alkyl is unsubstituted or substituted with one or more hydroxy groups.

Typically, R^bSelected from hydrogen atoms and straight or branched C_1-4An alkyl group.

Preferably, R^bRepresents a hydrogen atom.

Typically, L represents a direct bond, - (CH)₂)_0-4an-O-group or- (CH)₂)_0-4an-S-group, characterized in that when R²When represents a hydrogen atom, L represents- (CH)₂)_0-4-O-。

Preferably, L represents a direct bond, -O-or-S-, characterized in that when R is²When represents a hydrogen atom, L represents-O-.

More preferably, L represents a direct bond or- (CH)₂)_0-4-an O-group.

Even more preferably, L represents a direct bond or- (CH)₂)_0-1-an O-group.

Still more preferably, L represents a direct bond or-O-.

It is particularly preferred that L represents a direct bond.

It is also particularly preferred that L represents-O-.

In a particularly preferred embodiment, in the compounds of the formula (I)

·R²Represents a halogen atom, preferably R²Represents a fluorine atom or a chlorine atom;

·R³represents a straight or branched chain C_9-20An alkyl group, a carboxyl group,

l represents a direct bond or-O-.

In one embodiment, the compound of formula (I) is represented by formula (Ia),

wherein:

·R²represents a halogen atom;

·R⁴represents a hydrogen atom;

·R⁵is selected from-O- (straight or branched chain C)_1-10Alkyl), -O-cyclohexyl, -O-CH₂-phenyl, - (CH)₂)_1-2C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-3-R^aA group and-O-CH₂CH₂CH₂O-R^aA group;

·R^brepresents a hydrogen atom; and

l represents a direct bond or-O-.

In a preferred embodiment, in the compound of formula (Ia),

wherein heterocyclyl is unsubstituted or substituted with one or more substituents selected from:

straight or branched C_1-4Alkyl and oxo groups;

·R²represents a fluorine atom or a chlorine atom;

·R³represents a straight or branched chain C_10-17An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine atom, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group;

·R⁵selected from-O- (straight or branched C)_2-4Alkyl), -O-cyclohexyl, -O-CH₂-phenyl, - (CH)₂)-C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-2-R^aA group and-O-CH₂CH₂CH₂O-R^aA group;

·R^aselected from hydrogen atoms and straight or branched C_1-4An alkyl group; wherein alkyl is unsubstituted or substituted with one or more substituents selected from: halogen atoms and hydroxyl groups.

In a still more preferred embodiment, in the compound of formula (Ia),

·R¹selected from the group consisting of hydrogen atoms, -CH₂CF₃Group, - (CH)₂)₉-OH group, -CH₂CH(OH)CH₂OH group, -CH (CH)₂OH)₂Group, - (CH)₂)₂- (2, 5-dioxopyrrolidin-1-yl) group, - (CH)₂) - (5-methyl-2-oxo-1, 3-dioxol-4-yl) group, - (CH)₂CH₂O)₂-R^aGroup, - (CR)^aH)_1-3-OC(O)-R⁵A group and-CH₂-C(O)NR⁵R^aThe radical(s) is (are),

·R⁵is selected from-O-CH (CH)₃)₂Group, -O-C (CH)₃)₃The group, -O-cyclohexyl, -O-CH₂-phenyl, -CH₂-C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-2-R^aA group and-O-CH₂CH₂CH₂O-R^aA group;

·R^aselected from hydrogen atoms and straight or branched C_1-2An alkyl group.

In one embodiment, the compound of formula (I) is represented by formula (Ib),

wherein:

·R¹selected from hydrogen atoms, straight or branched chains C_1-4Alkyl, straight or branched C_1-4Alkyl halidesRadical, straight-chain or branched C_2-10Hydroxyalkyl, cyclohexyl, -CH₂-phenyl, - (CH)₂)_1-2- (5-to 6-membered heterocyclic group containing at least one heteroatom selected from N, O and S), - (CH)₂CH₂O)_1-4-R^aGroup, - (CR)^aR^b)_1-3-OC(O)-R⁵Group and- (CH)₂)_1-3-C(O)NR⁵R^aThe radical(s) is (are),

·R²represents a halogen atom;

·R⁴represents a hydrogen atom;

·R⁵selected from-O- (straight or branched C)_1-10Alkyl), -O-cyclohexyl, -O-CH₂-phenyl, - (CH)₂)_1-2C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-3-R^aA group and-O-CH₂CH₂CH₂O-R^aA group;

·R^brepresents a hydrogen atom; and

l represents a direct bond or-O-.

In a preferred embodiment, in the compounds of formula (Ib),

·R¹selected from hydrogen atoms, straight or branched chains C_1-3Haloalkyl, straight-chain or branched C_3-9Hydroxyalkyl, - (CH)₂)_1-2- (containing at least one member selected from the group consisting of N and5-membered heterocyclic group of hetero atom of O), - (CH)₂CH₂O)₂-R^aGroup, - (CR)^aR^b)-OC(O)-R⁵Group and- (CH)₂)-C(O)NR⁵R^aThe radical(s) is (are),

wherein heterocyclyl is unsubstituted or substituted with one or more substituents selected from:

straight or branched C_1-4Alkyl and oxo groups;

·R²represents a fluorine atom or a chlorine atom;

·R³represents a straight or branched chain C_10-17An alkyl group, wherein the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: fluorine atom, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group;

·R⁵selected from-O- (straight or branched C)_2-4Alkyl), -O-cyclohexyl, -O-CH₂-phenyl, - (CH)₂)-C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-2-R^aA group and-O-CH₂CH₂CH₂O-R^aA group;

In a more preferred embodiment, in the compound of formula (Ib),

·R⁵is selected from-O-CH (CH)₃)₂Group, -O-C (CH)₃)₃The group, -O-cyclohexyl, -O-CH₂-phenyl, -CH₂-C(O)OR^aGroup, -O- (CH)₂CH₂O)_1-2-R^aA group and-O-CH₂CH₂CH₂O-R^aA group;

·R^aselected from hydrogen atoms and straight or branched C_1-2An alkyl group.

In one embodiment, in the compounds of formula (I),

·R²represents a hydrogen atom, a methyl group, a fluorine atom, a chlorine atomA bromine atom or a-CN group;

·R³represents a straight chain C_9-18An alkyl group, a carboxyl group,

wherein alkyl is unsubstituted or substituted with one or more substituents selected from: fluorine atom, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group;

·R⁴selected from hydrogen atoms and straight or branched C_1-4An alkyl group;

·R^aselected from hydrogen atoms and straight or branched C_1-4An alkyl group;

l represents a direct bond, -O-, -S-, or a carbonyl group; characterized in that when R is²When represents a hydrogen atom, L represents-O-.

In one embodiment, in the compounds of formula (I),

·R¹selected from hydrogen atoms, straight or branched chains C_1-4Alkyl, -CH₂CF₃Group, - (CH)₂)_2-9-OH group, -CH₂-CH(OH)-CH₂-OH、-CH(CH₂OH)₂Radical, cyclohexyl radical, - (CH)₂)₂- (2, 5-dioxopyrrolidin-1-yl) group, - (CH)₂)₂- (2-oxopyrrolidin-1-yl) radical, - (CH)₂) - (5-methyl-2-oxo-1, 3-dioxol-4-yl) group, -CH₂-phenyl, - (CH)₂CH₂O)_2-3-R^aGroup, -CH (CH)₃)-OC(O)OCH(CH₃)₂Group, -CH (CH)₃)-OC(O)OC(CH₃)₃Group, -CH (CH)₃)-OC(O)O(CH₂)₈CH₃Group, -CH (CH)₃) -OC (O) O-cyclohexyl, -CH (CH)₃)-OC(O)O-CH₂-phenyl, -CH (CH)₃)-OC(O)O(CH₂CH₂O)_1-2-R^aGroup, -CH (CH)₃)-OC(O)O(CH₂)₃OH group, - (CH)₂)₂-OC(O)C(NH₂)-CH(CH₃)₂A group and-CH₂-C(O)N(CH₃)CH₂CO₂R^aA group;

·R²represents a hydrogen atom, a methyl group, a fluorine atom, a chlorine atom or a bromine atom;

·R³represents a straight chain C_9-17An alkyl group, a carboxyl group,

wherein alkyl is unsubstituted or substituted with one or more substituents selected from: fluorine atom, straight or branched C_1-4Alkyl and straight or branched C_1-3An alkoxy group;

·R⁴selected from hydrogen atoms and straight or branched C_1-4An alkyl group;

·R^aselected from hydrogen atoms and straight or branched C_1-4An alkyl group;

l represents a direct bond, -O-or-S-; characterized in that when R is²When represents a hydrogen atom, L represents-O-.

In a particular embodiment, it is preferred that,

·R³represents a straight chain C_9-17An alkyl group, a carboxyl group,

wherein alkyl is unsubstituted or substituted with one or more substituents selected from: fluorine atom, methyl group and ethoxy group;

·R⁴selected from hydrogen atoms and straight or branched C_1-4An alkyl group; preferably, R⁴Selected from the group consisting of hydrogen atom, isopropyl group and n-butyl group.

In a particular embodiment, it is preferred that the compound of formula (I) is represented by formula (Ia).

In a particular embodiment, it is preferred that the compound of formula (I) is represented by formula (Ib).

Specific individual compounds of the invention include the following compounds, or pharmaceutically acceptable salts, or solvates, or N-oxides, or tautomers, or stereoisomers, or isotopically labeled derivatives thereof:

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- (2, 5-dioxopyrrolidin-1-yl) ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- (2-oxopyrrolidin-1-yl) ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2,2, 2-trifluoroethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2-hydroxyethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 1- ((isopropoxycarbonyl) oxy) ethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- ((2-ethoxy-2-oxoethyl) (methyl) amino) -2-oxoethyl ester

4- (dodecyloxy) -1H-pyrrole-2-carboxylic acid 2- ((L-valinyl) oxy) ethyl ester