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Substituted pyrrolidine amides I

文档序号：1246647 发布日期：2020-08-18 浏览：9次 中文

阅读说明：本技术 经取代的吡咯烷酰胺i (Substituted pyrrolidine amides I ) 是由 F·雅各布 J·阿伦 S·克吕格 M·沙德 D·弗里贝 S·亨南 于 2018-12-18 设计创作，主要内容包括：本发明涉及根据通式(I)的化合物,<Image he="587" wi="639" file="DDA0002543421270000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>所述化合物充当糖皮质激素受体调节剂且可用于治疗和/或预防至少部分地由糖皮质激素受体介导的病症。(The invention relates to compounds according to the general formula (I),)

1. a compound according to the general formula (I),

wherein

R1represents-C1-10An alkyl group; -C3-10A cycloalkyl group; -C1-6alkylene-C3-10A cycloalkyl group; 3-to 7-membered heterocycloalkyl; -C1-6Alkylene- (3-to 7-membered heterocycloalkyl); an aryl group; -C1-6Alkylene-aryl; 5 or 6 membered heteroaryl; or-C1-6Alkylene- (5 or 6 membered heteroaryl);

R2represents-C (═ O) -C1-10An alkyl group; -C (═ O) -C3-10A cycloalkyl group; -C (═ O) -C1-6alkylene-C3-10A cycloalkyl group; -C (═ O) - (3 to 7 membered heterocycloalkyl); -C (═ O) -C1-6Alkylene- (3-to 7-membered heterocycloalkyl); -C (═ O) -aryl; -C (═ O) -C1-6Alkylene-aryl; -C (═ O) - (5 or 6 membered heteroaryl); -C (═ O) -C1-6Alkylene- (5 or 6 membered heteroaryl); -S (═ O)1-2-C1-10An alkyl group; -S (═ O)1-2-C3-10A cycloalkyl group; -S (═ O)1-2-C1-6alkylene-C3-10A cycloalkyl group; -S (═ O)1-2- (3 to 7 membered heterocycloalkyl); -S (═ O)1-2-C1-6Alkylene- (3-to 7-membered heterocycloalkyl); -S (═ O)1-2-an aryl group; -S (═ O)1-2-C1-6Alkylene-aryl; -S (═ O)1-2- (5-or 6-membered heteroaryl); or-S (═ O)1-2-C1-6Alkylene- (5 or 6 membered heteroaryl);

R3represents a 3-to 7-membered heterocycloalkyl group; -C1-6Alkylene- (3-to 7-membered heterocycloalkyl); 5 or 6 membered heteroaryl; -C1-6Alkylene- (5 or 6 membered heteroaryl); -C (═ O) - (3 to 7 membered heterocycloalkyl); -C (═ O) -C1-6Alkylene- (3-to 7-membered heterocycloalkyl); -C (═ O) - (5 or 6 membered heteroaryl); -C (═ O) -C1-6Alkylene- (5 or 6 membered heteroaryl); -S (═ O)1-2- (3 to 7 membered heterocycloalkyl); -S (═ O)1-2-C1-6Alkylene- (3-to 7-membered heterocycloalkyl); -S (═ O)1-2- (5-or 6-membered heteroaryl); or-S (═ O)1-2-C1-6Alkylene- (5 or 6 membered heteroaryl);

R4represents-H; -F; -Cl; -Br; -I; -CN; -CH3；-CF3；-CF2H；-CFH2Or cyclopropyl;

x represents N or CR5(ii) a Wherein R is5represents-H; -F; -Cl; -Br; -I; -CN; -C1-10Alkyl or-C3-10A cycloalkyl group;

y represents N or CR6(ii) a Wherein R is6represents-H; -F; -Cl; -Br; -I; -CN; -C1-10Alkyl or-C3-10A cycloalkyl group;

z represents N or CR7(ii) a Wherein R is7represents-H; -F; -Cl; -Br; -I; -CN; -C1-10Alkyl or-C3-10A cycloalkyl group;

wherein in each case-C1-10Alkyl, -C1-4Alkyl and-C1-6Alkylene-independently of one another, is straight-chain or branched, saturated or unsaturated;

wherein in each case-C1-10Alkyl, -C1-4Alkyl, -C1-6Alkylene-, -C3-10Cycloalkyl and 3 to 7 membered heterocycloalkyl are independently from each other unsubstituted or mono-or polysubstituted with one or more substituents selected from: -F; -Cl; -Br; -I; -CN; -C1-6An alkyl group; -CF3；-CF2H；-CFH2；-CF2Cl；-CFCl2；-C(＝O)-C1-6An alkyl group; -C (═ O) -OH; -C (═ O) -OC1-6An alkyl group;-C(＝O)-NH2；-C(＝O)-NH(C1-6alkyl groups); -C (═ O) -N (C)1-6Alkyl radical)2；-OH；＝O；-OCF3；-OCF2H；-OCFH2；-OCF2Cl；-OCFCl2；-O-C1-6An alkyl group; -O-C (═ O) -C1-6An alkyl group; -O-C (═ O) -O-C1-6An alkyl group; -O- (CO) -NH (C)1-6Alkyl groups); -O-C (═ O) -N (C)1-6Alkyl radical)2；-O-S(＝O)2-NH2；-O-S(＝O)2-NH(C1-6Alkyl groups); -O-S (═ O)2-N(C1-6Alkyl radical)2；-NH2；-NH(C1-6Alkyl groups); -N (C)1-6Alkyl radical)2；-NH-C(＝O)-C1-6An alkyl group; -NH-C (═ O) -O-C1-6An alkyl group; -NH-C (═ O) -NH2；-NH-C(＝O)-NH(C1-6Alkyl groups); -NH-C (═ O) -N (C)1-6Alkyl radical)2；-N(C1-6Alkyl) -C (═ O) -C1-6An alkyl group; -N (C)1-6Alkyl) -C (═ O) -O-C1-6An alkyl group; -N (C)1-6Alkyl) -C (═ O) -NH2；-N(C1-6Alkyl) -C (═ O) -NH (C)1-6Alkyl groups); -N (C)1-6Alkyl) -C (═ O) -N (C)1-6Alkyl radical)2；-NH-S(＝O)2OH；NH-S(＝O)2-C1-6An alkyl group; -NH-S (═ O)2-O-C1-6An alkyl group; -NH-S (═ O)2-NH2；-NH-S(＝O)2-NH(C1-6Alkyl groups); -NH-S (═ O)2N(C1-6Alkyl radical)2；-N(C1-6Alkyl) -S (═ O)2-OH；-N(C1-6Alkyl) -S (═ O)2-C1-6An alkyl group; -N (C)1-6Alkyl) -S (═ O)2-O-C1-6An alkyl group; -N (C)1-6Alkyl) -S (═ O)2-NH2；-N(C1-6Alkyl) -S (═ O)2-NH(C1-6Alkyl groups); -N (C)1-6Alkyl) -S (═ O)2-N(C1-6Alkyl radical)2；-SCF3；-SCF2H；-SCFH2；-S-C1-6An alkyl group; -S (═ O) -C1-6An alkyl group; -S (═ O)2-C1-6An alkyl group; -S (═ O)2-OH；-S(＝O)2-O-C1-6An alkyl group; -S (═ O)2-NH2；-S(＝O)2-NH(C1-6Alkyl groups); -S (═ O)2-N(C1-6Alkyl radical)2；-C3-6A cycloalkyl group; 3-to 6-membered heterocycloalkyl; a phenyl group; 5 or 6 membered heteroaryl; -O-C3-6A cycloalkyl group; -O- (3 to 6 membered heterocycloalkyl); -O-phenyl; -O- (5 or 6 membered heteroaryl); -C (═ O) -C3-6A cycloalkyl group; -C (═ O) - (3 to 6 membered heterocycloalkyl); -C (═ O) -phenyl; -C (═ O) - (5 or 6 membered heteroaryl); -S (═ O)2-(C3-6Cycloalkyl groups); -S (═ O)2- (3 to 6 membered heterocycloalkyl); -S (═ O)2-phenyl or-S (═ O)2- (5-or 6-membered heteroaryl);

wherein in each case aryl and 5-or 6-membered heteroaryl are, independently of one another, unsubstituted or mono-or polysubstituted by one or more substituents selected from the group consisting of: -F; -Cl; -Br; -I; -CN; -C1-6An alkyl group; -CF3；-CF2H；-CFH2；-CF2Cl；-CFCl2；-C1-4alkylene-CF3；-C1-4alkylene-CF2H；-C1-4alkylene-CFH2；-C(＝O)-C1-6An alkyl group; -C (═ O) -OH; -C (═ O) -OC1-6An alkyl group; -C (═ O) -nh (oh); -C (═ O) -NH2；-C(＝O)-NH(C1-6Alkyl groups); -C (═ O) -N (C)1-6Alkyl radical)2；-OH；＝O；-OCF3；-OCF2H；-OCFH2；-OCF2Cl；-OCFCl2；-O-C1-6An alkyl group; -O-C3-6A cycloalkyl group; -O- (3 to 6 membered heterocycloalkyl); -NH2；-NH(C1-6Alkyl groups); -N (C)1-6Alkyl radical)2；-NH-C(＝O)-C1-6An alkyl group; -N (C)1-6Alkyl) -C (═ O) -C1-6An alkyl group; -NH-C (═ O) -NH2；-NH-C(＝O)-NH(C1-6Alkyl groups); -NH-C (═ O) -N (C)1-6Alkyl radical)2；-N(C1-6Alkyl) -C (═ O) -NH (C)1-6Alkyl groups); -N (C)1-6Alkyl) -C (═ O) -N (C)1-6Alkyl radical)2；-NH-S(＝O)2-C1-6An alkyl group; -SCF3；-S-C1-6An alkyl group; -S (═ O) -C1-6An alkyl group; -S (═ O)2-C1-6An alkyl group; -S (═ O)2-NH2；-S(＝O)2-NH(C1-6Alkyl groups); -S (═ O)2-N(C1-6Alkyl radical)2；-C3-6A cycloalkyl group; -C1-4alkylene-C3-6A cycloalkyl group; 3-to 6-membered heterocycloalkyl; -C1-4Alkylene- (3-to 6-membered heterocycloalkyl); phenyl or 5 or 6 membered heteroaryl;

the compound is in the form of a free compound or a physiologically acceptable salt thereof.

2. The compound of claim 1, wherein

X represents CR5Y represents CR6(ii) a And Z represents CR7(ii) a Or

X represents N, Y represents CR6(ii) a And Z represents CR7(ii) a Or

X represents CR5Y represents N; and Z represents CR7(ii) a Or

X represents CR5Y represents CR6(ii) a And Z represents N; or

X represents N, Y represents N; and Z represents CR7(ii) a Or

X represents N, Y represents CR6(ii) a And Z represents N; or

X represents CR5Y represents N; and Z represents N; or

X represents N, Y represents N; and Z represents N.

3. The compound of claim 2, wherein optionally present R5represents-H; optionally present R6represents-H; and/or optionally present R7represents-H

4. A compound according to any preceding claim, wherein

R1represents-C3-10A cycloalkyl group; -C1-6alkylene-C3-10A cycloalkyl group; an aryl group; or 5 or 6 membered heteroaryl.

5. A compound according to any preceding claim, wherein

R2represents-C (═ O) -C1-10An alkyl group; -C (═ O) -C3-10A cycloalkyl group; -C (═ O) -C1-6alkylene-C3-10A cycloalkyl group; -C (═ O) - (3 to 7 membered heterocycloalkyl); -C (═ O) - (5 or 6 membered heteroaryl); -S (═ O)2-C1-10An alkyl group; -S (═ O)2-C3-10A cycloalkyl group; -S (═ O)2-C1-6alkylene-C3-10A cycloalkyl group; or-S (═ O)2- (5-or 6-membered heteroaryl).

6. A compound according to any preceding claim, wherein

R3Represents a 3-to 7-membered heterocycloalkyl group; 5 or 6 membered heteroaryl; or-C1-6Alkylene- (5 or 6 membered heteroaryl).

7. A compound according to any preceding claim, wherein

R4represents-H.

8. A compound according to any preceding claim, wherein

R1To represent

Cyclopropyl, unsubstituted;

-CH2-cyclopropyl, unsubstituted;

phenyl, unsubstituted or mono-or disubstituted with substituents independently selected from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN, cyclopropyl and-OCH3Wherein phenyl is optionally substituted by-O-CH2CH2-O-is attached to the dioxolane ring; or

Pyridinyl, unsubstituted or mono-or disubstituted, independently of each other, with substituents selected from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN and-OCH3。

9. A compound according to any preceding claim, wherein

R2To represent

-C(＝O)-C1-10Alkyl, unsubstituted or mono-or disubstituted with substituents independently selected from the group consisting of: -F, -Cl and-Br;

-C (═ O) -cyclopropyl, unsubstituted or mono-or disubstituted with substituents independently selected from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN and-OCH3；

-C (═ O) -cyclobutyl, unsubstituted or mono-or disubstituted with substituents selected independently of one another from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN and-OCH3；

-C (═ O) -2-tetrahydrofuranyl, unsubstituted;

-C (═ O) - (5 to 6 membered heteroaryl), wherein said 5 to 6 membered heteroaryl is selected from the group consisting of: thiazolyl, pyrazolyl, oxazolyl and 1-oxa-2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, isoxazolyl, isothiazolyl, wherein in each case the 5-to 6-membered heteroaryl is unsubstituted or mono-or disubstituted with substituents selected independently of one another from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN, ═ O and-OCH3；

-S(＝O)2-C1-10Alkyl, unsubstituted;

-S(＝O)2-cyclopropyl, unsubstituted;

-S(＝O)2-CH2-cyclopropyl, unsubstituted; or

-S(＝O)2- (5-to 6-membered heteroaryl), wherein the 5-to 6-membered heteroaryl is selected from the group consisting of: thiazolyl, pyrazolyl, oxazolyl and 1-oxa-2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, isoxazolyl, isothiazolyl, wherein in each case the 5-to 6-membered heteroaryl is unsubstituted or mono-or disubstituted with substituents selected independently of one another from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN, ═ O and-OCH3。

10. A compound according to any preceding claim, wherein

R3To represent

Piperidinyl, unsubstituted or substituted with-C (═ O) -cyclopropyl;

a5 to 6 membered heteroaryl selected from the group consisting of: pyrazolyl, pyridinyl and pyrimidinyl, wherein in each case the 5-to 6-membered heteroaryl is unsubstituted or mono-or disubstituted independently of one another by substituents selected from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN, ═ O and-OCH3(ii) a Or

-CH selected from the group consisting of2- (5-to 6-membered heteroaryl): -CH2-pyrazolyl, -CH2-pyridyl and-CH2-pyrimidinyl, wherein the 5-to 6-membered heteroaryl is in each case unsubstituted or mono-or disubstituted independently of one another by substituents selected from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN, ═ O and-OCH3。

11. A compound according to any preceding claim, wherein

R1Represents phenyl, unsubstituted or mono-or disubstituted independently of each other with substituents selected from the group consisting of: -F, -Cl, -Br, -CH3、-CF3-CN, cyclopropyl and-OCH3(ii) a And/or

R2represents-C (═ O) -C1-6An alkyl group; -C (═ O) -cyclopropyl; or-C (═ O) -cyclobutyl, unsubstituted or mono-or disubstituted with substituents selected independently of one another from the group consisting of: -F, -Cl and-Br; and/or

R3Represents N-methyl-2-oxo-pyridyl.

12. The compound according to any one of the preceding claims, selected from the group consisting of:

1N- [ (2R,3S) -2- (3-chlorophenyl) -1- [1- (1-methyl-6-oxo-3-pyridyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] -2, 2-difluoro-propionamide

22, 2-difluoro-N- [ rac- (2R,3S) -2- (2, 4-difluorophenyl) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] propionamide

32, 2-difluoro-N- [ rac- (2R,3S) -2- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] propionamide

42, 2-difluoro-N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

52, 2-difluoro-N- [ (2R,3S) -2- (3-fluorophenyl) -1- [1- (1-methyl-6-oxo-3-pyridyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] propionamide

62, 2-difluoro-N- [ (2R,3S) -2- (2-fluorophenyl) -1- [1- (1-methyl-6-oxo-3-pyridyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] propionamide

72, 2-difluoro-N- [ rac- (2R,3S) -5-oxo-2-phenyl-1- [1- (3-pyridinyl) indazol-5-yl ] pyrrolidin-3-yl ] propionamide

92, 2-difluoro-N- [ rac- (2R,3S) -1- [1- (5-fluoro-2-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

135-methyl-N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] thiazole-2-carboxamide

152, 2-difluoro-N- [ (2R,3S) -2- (4-fluoro-3-methoxy-phenyl) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] propanamide

172, 2-difluoro-N- [ (2R,3S) -2- (4-fluorophenyl) -1- [1- (1-methyl-6-oxo-3-pyridyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] propionamide

181-fluoro-N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] cyclopropanecarboxamide

222, 2-difluoro-N- [ rac- (2R,3S) -1- [1- (6-methoxy-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

232, 2-difluoro-N- [ rac- (2R,3S) -5-oxo-2-phenyl-1- [1- (4-pyridinyl) indazol-5-yl ] pyrrolidin-3-yl ] propionamide

242, 2-difluoro-N- [ rac- (2R,3S) -1- [1- (6-methyl-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

252, 2-difluoro-N- [ rac- (2R,3S) -1- [1- (2-methyl-4-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

261-methyl-N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] cyclopropanecarboxamide

272, 2-difluoro-N- [ rac- (2R,3S) -1- [1- (2-methoxy-4-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

312, 2-difluoro-N- [ rac- (2R,3S) -1- [1- [ (2-methoxy-4-pyridinyl) methyl ] indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

322, 2-difluoro-N- [ rac- (2R,3S) -1- [1- [ (1-methylpyrazol-3-yl) methyl ] indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

332, 2-difluoro-N- [ rac- (2R,3S) -1- [1- [ (6-methoxy-3-pyridinyl) methyl ] indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

342, 2-difluoro-N- [ rac- (2R,3S) -1- [1- [ (1-methyl-6-oxo-3-pyridinyl) methyl ] indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

352, 2-difluoro-N- [ rac- (2R,3S) -1- [1- [1- (cyclopropanecarbonyl) -4-piperidinyl ] indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

382, 2-difluoro-N- [ rac- (2R,3S) -1- [1- [ (1-methyl-2-oxo-4-pyridyl) methyl ] indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

39N- [ (2R,3S) -2- (2-fluorophenyl) -1- [1- (1-methyl-6-oxo-3-pyridyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] cyclopropanecarboxamide

40N- [ rac- (2R,3S) -1- [1- [ (2-methoxy-4-pyridinyl) methyl ] indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] cyclopropanecarboxamide

41N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -2- (o-tolyl) -5-oxo-pyrrolidin-3-yl ] cyclopropanecarboxamide

422, 2-difluoro-N- [ (2R,3S) -2- (2-methoxy-4-pyridyl) -1- [1- (1-methyl-6-oxo-3-pyridyl) indazol-5-yl ] -5-oxo-pyrrolidin-3-yl ] propionamide

432, 2-difluoro-N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -2- (o-tolyl) -5-oxo-pyrrolidin-3-yl ] propionamide

44N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] thiazole-4-carboxamide

451-methyl-N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] pyrazole-3-carboxamide

462, 2-difluoro-N- [ rac- (2R,3S) -1- [1- (1-methylpyrazol-4-yl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

472, 2-difluoro-N- [ rac- (2R,3S) -1- [1- (5-fluoropyrimidin-2-yl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] propionamide

48(R) -N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] tetrahydrofuran-2-carboxamide

49N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] oxazole-2-carboxamide

50N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] oxazole-4-carboxamide

515-methyl-N- [ (2R,3S) -1- [1- (1-methyl-6-oxo-3-pyridinyl) indazol-5-yl ] -5-oxo-2-phenyl-pyrrolidin-3-yl ] -1,2, 4-oxadiazole-3-carboxamide

The compound is in the form of a free compound or a physiologically acceptable salt thereof.

13. A pharmaceutical dosage form comprising a compound according to any one of claims 1 to 12.

14. A compound according to any one of claims 1 to 12 for use in the treatment and/or prevention of pain and/or inflammation.

15. A compound according to claim 14 for use in the treatment and/or prevention of asthma, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, cystic fibrosis, osteoarthritis, polymyalgia rheumatica, giant cell arteritis, sjogren's syndrome, duchenne muscular dystrophy, vasculitis, behcet's disease, ulcerative colitis and/or crohn's disease.

Example 1: n- ((2R,3S) -2- (3-chlorophenyl) -1- (1- (1-methyl-6-oxo-1, 6-dihydropyridine-3-) 1H-indazol-5-yl) -5-oxopyrrolidin-3-yl-2, 2-difluoropropanamide

Step 1:to a stirred solution of intermediate a1(0.25g, 1.19mmol, 1.0 equiv) in DMF (10mL) were added HATU (0.68g, 1.78mmol, 1.5 equiv), DIPEA (1.0mL, 5.95mmol, 5.0 equiv) and 2, 2-difluoropropionic acid (0.17g, 1.54mmol, 1.3 equiv) and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with EtOAc and diluted with ice cold water, saturated NaHCO3And saturated NH4And (5) washing with a Cl solution. The combined organic layers were concentrated to give the crude product which was purified by column chromatography (100-f-value-0.5) to yield trans-N- (2- (3-chlorophenyl) -5-oxopyrrolidin-3-yl) -2, 2-difluoropropionamide (0.19g, 53%).

Step 2:stirring trans-N- (2- (3-chlorophenyl) -5-oxopyrrolidin-3-yl) -2, 2-difluoropropionamide (0.30g, 0.99mmol, 1.0 eq.), 5- (5-iodo-1H-indazol-1-yl) -1-methylpyridin-2 (1H) -one (0.41g, 1.19mmol, 1.2 eq.) and K3PO4A solution of (0.42g, 1.98mmol, 2.0 equiv) in 1, 4-dioxane (20mL) was degassed with argon for 15 minutes. trans-N, N' -dimethylcyclohexane-1, 2-diamine (0.056g, 0.40mmol, 0.4 equiv.) and CuI (0.038g, 0.20mmol, 0.2 equiv.) were then added and the reaction mixture was stirred at 90 ℃ for 16 h. Upon completion, the reaction mixture was filtered through a celite bed and the celite bed was washed 2-3 times with EtOAc. The combined organic layers were concentrated to give the crude product which was purified by column chromatography (100-f-value-0.5) to give the racemic product and further enantiomeric separation by chiral preparative HPLC to give N- ((2R,3S) -2- (3-chlorophenyl) -1- (1- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indazol-5-yl) -5-oxopyrrolidin-3-yl) -2, 2-difluoropropionamide (0.07g, RT 15.9min, column name CHIRALPAK IA (250 × 4.6.6 mm)5 μm, mobile phase hexane/EtOH/EA/DEA 70/15/15/0.1, flow rate 1.0ml/min) and [ N- ((2S,3R) -2- (3-chlorophenyl) -1- (1- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1H-indazol-5-yl) -5-oxopyrrolidin-3-yl) -2, 2-difluoropropanamide (0.06 g; RT 10.6min, column name CHIRALPAK IA (250 × 4.6.6 mm)5 μm, mobile phase hexane/EtOH/EA/DEA 70/15/15/0.1, flow rate 1.0ml/min)]。

1H NMR(DMSO-d6):9.46(d,1H),8.26(s,1H),8.19(d,1H),7.86(s,1H),7.71(dd,1H),7.62-7.58(m,2H),7.45(s,1H),7.34-7.28(m,3H),6.53(d,1H),5.34(d,1H),4.30(bs,1H),3.49(s,3H),3.14-3.08(m,1H)2.67-2.62(m,1H),1.78(t,3H)。

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