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EP-4739670-A1 - MACROCYCLES FOR THE TREATMENT OF AUTOIMMUNE DISEASE

EP4739670A1EP 4739670 A1EP4739670 A1EP 4739670A1EP-4739670-A1

Abstract

The present invention relates to compounds of formula (I-2), wherein R 1 to R 3 , Q 1 , Q 2 , A 1 to A 7 and M 1 are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

Inventors

  • JIANG, MIN
  • KOU, Buyu
  • LIU, HAIXIA
  • SHEN, HONG
  • WU, YAO
  • ZHANG, ZHIWEI
  • ZHU, WEI

Assignees

  • F. Hoffmann-La Roche AG

Dates

Publication Date
20260513
Application Date
20240704

Claims (1)

  1. (I-1), wherein R 1 is H, C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 2 is C1-6alkyl, or together with R 9 form a heterocyclic ring; R 3 is ; wherein R 4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C 1-6 alkyl, haloC 1-6 alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3- 7cycloalkylcarbonyl, C3-7cycloalkylsulfonyl, haloC1-6alkyl, haloC1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C 1-6 alkoxyC 1-6 alkyl, C1-6alkyl, or cyanoazetidinyl; R 5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3- 7cycloalkoxy and trideuterioC1-6alkoxy; R 6 is H; A 1 is N; A 2 is CH or N; A 3 is CH; A 4 is CH; A 5 is CH; A 6 is CR 7 , wherein R 7 is H or halogen; A 7 is CH; Q 1 is CR 8 R 9 , C 3-7 cycloalkylene or oxetanylene; wherein R 8 is H, or together with R 9 form a heterocyclic ring or C3-7cycloalkyl ring; R 9 together with R 1 or R 2 form a heterocyclic ring, or together with R 8 form a heterocyclic ring or C 3-7 cycloalkyl ring; Q 2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 5. A compound of formula (I-1a) according to any one of claims 1-4, (I-1a), wherein R 1 is H, C 1-6 alkyl, or together with R 9 form a heterocyclic ring; R 2 is C1-6alkyl, or together with R 9 form a heterocyclic ring; 3 R is ; wherein R 4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by C1-6alkyl, haloC1-6alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3- 7 cycloalkylcarbonyl, C 3-7 cycloalkylsulfonyl, haloC 1-6 alkyl, haloC 1- 6alkylcarbonyl, hydroxyC3-7cycloalkylcarbonyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C 1-6 alkoxyC 1-6 alkyl, C1-6alkyl, or cyanoazetidinyl; R 5 is phenyl which is once, twice or three times substituted by substituents independently selected from halogen, C1-6alkoxy, haloC1-6alkoxy, C3- 7cycloalkoxy and trideuterioC1-6alkoxy; R 6 is H; A 1 is N; A 2 is CH or N; A 3 is CH; A 4 is CH; A 5 is CH; A 6 is CR 7 , wherein R 7 is H or halogen; A 7 is CH; Q 1 is CR 8 R 9 , C 3-7 cycloalkylene or oxetanylene; wherein R 8 is H, or together with R 9 form a heterocyclic ring or C3-7cycloalkyl ring; R 9 together with R 1 or R 2 form a heterocyclic ring, or together with R 8 form a heterocyclic ring or C3-7cycloalkyl ring; Q 2 is NH; m is 0, 1, 2 or 3; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. 6. A compound according to any one of claims 1-5, wherein R 1 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 1 is C1-6alkylene and R 9 is -C1-6alkylene-O-. 7. A compound according to any one of claims 1-6, wherein R 1 is methyl, or together with R 9 form a heterocyclic ring, wherein R 1 is methylene and R 9 is -methylene-O-. 8. A compound according to any one of claims 1-7, wherein R 2 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 2 is C 1-6 alkylene and R 9 is a bond, O or -C 1-6 alkylene-O-. 9. A compound according to any one of claims 1-8, wherein R 2 is methyl, or together with R 9 form a heterocyclic ring, wherein R 2 is ethylene or propylene, and R 9 is a bond, O or -methylene- O-. 10. A compound according to any one of claims 1-9, wherein R 4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC 1-6 alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3-7 cycloalkyl, C 3- 7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by haloC 1-6 alkyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl. 11. A compound according to any one of claims 1-10, wherein R 4 is H, [1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3- (oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-cyanoazetidin-1-yl, 3-cyclopropyl-2-oxo- 3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl. 12. A compound according to any one of claims 1-11, wherein R 5 is phenyl which is twice substituted by substituents independently selected from halogen, C1-6alkoxy and trideuterioC1- 6 alkoxy. 13. A compound according to any one of claims 1-12, wherein R 5 is phenyl which is twice substituted by substituents independently selected from fluoro, methoxy and trideuteriomethoxy. 14. A compound according to any one of claims 1-13, wherein R 5 is 2,4-difluorophenyl, 4- fluoro-2-methoxy-phenyl or 4-fluoro-2-(trideuteriomethoxy)phenyl. 15. A compound according to any one of claims 1-14, wherein R 7 is H or fluoro. 16. A compound according to any one of claims 1-15, wherein Q 1 is CR 8 R 9 . 17. A compound according to any one of claims 1-16, wherein R 8 is H. 18. A compound according to any one of claims 1-17, wherein m is 0, 1 or 2. 19. A compound according to any one of claims 1 to 5, wherein R 1 is C 1-6 alkyl, or together with R 9 form a heterocyclic ring, wherein R 1 is C 1-6 alkylene and R 9 is -C1-6alkylene-O-; R 2 is C1-6alkyl, or together with R 9 form a heterocyclic ring, wherein R 2 is C1-6alkylene and R 9 is a bond, O or -C 1-6 alkylene-O-; ; wherein R 4 is H, ((haloC1-6alkyl)azetidinyl)C1-6alkyl, 2,5-diazabicyclo[2.2.1]heptanyl substituted by haloC 1-6 alkyl or oxetanyl, 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted by C 1-6 alkyl, C 3-7 cycloalkyl, C3-7cycloalkylC1-6alkyl or oxetanyl, 3,6-diazabicyclo[3.1.1]heptanyl substituted by haloC1-6alkyl or oxetanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, C1-6alkoxyC1-6alkyl, C1-6alkyl, or cyanoazetidinyl; R 5 is phenyl which is twice substituted by substituents independently selected from halogen, C1-6alkoxy and trideuterioC1-6alkoxy; R 6 is H; A 1 is N; A 2 is CH or N; A 3 is CH; A 4 is CH; A 5 is CH; A 6 is CR 7 , wherein R 7 is H or halogen; A 7 is CH; Q 1 is CR 8 R 9 ; wherein R 8 is H; R 9 together with R 1 or R 2 form a heterocyclic ring; Q 2 is NH; m is 0, 1 or 2; n is 0, 1 or 2; with the proviso that m and n are not 0 simultaneously; or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 19, wherein R 1 is methyl, or together with R 9 form a heterocyclic ring, wherein R 1 is methylene and R 9 is -methylene-O-; R 2 is methyl, or together with R 9 form a heterocyclic ring, wherein R 2 is ethylene or propylene, and R 9 is a bond, O or -methylene-O-; 3 R is ; wherein R 4 is H, [1-(2,2,2-trifluoroethyl)azetidin-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl, 3-cyanoazetidin-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6- azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl; R 5 is 2,4-difluorophenyl, 4-fluoro-2-methoxy-phenyl or 4-fluoro-2- (trideuteriomethoxy)phenyl; R 6 is H; A 1 is N; A 2 is CH or N; A 3 is CH; A 4 is CH; A 5 is CH; A 6 is CR 7 , wherein R 7 is H or fluoro; A 7 is CH; Q 1 is CR 8 R 9 ; wherein R 8 is H; R 9 together with R 1 or R 2 form a heterocyclic ring; Q 2 is NH; m is 0, 1 or 2; n is 0, 1 or 2; with the proviso that m and n are not 0 simultaneously; or a pharmaceutically acceptable salt thereof. 21. A compound selected from: (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-16- 2,6 8,11 13,17 22,26 oxa-7,10,13,19,21,29-hexazahexacyclo[[17.6.1.1 .1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-20-methyl-16-oxa- 2,6 8,11 13,17 22,26 7,10,13,19,21,29-hexazahexacyclo[[17.6.1.1 .1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-16- 2,6 8,11 13,18 23,27 oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21- 2,6 8,11 13,18 23,27 methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17- 2,6 8,11 13,18 23,27 oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17- 2,6 8,11 13,18 23,27 oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- 2,6 8,11 13,17 23,27 methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa- 1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21- 2,6 8,11 13,17 23,27 methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 .1 .0 .0 ]nonacosa- 1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-fluoro-22- 2,6 8,11 13,18 24,28 methyl-16-oxa-7,10,13,21,23,30-hexazahexacyclo[19.6.1.1 .1 .0 .0 ]triaconta- 1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-26-fluoro-22- 2,6 8,11 13,18 24,28 methyl-16-oxa-7,10,13,21,23,30-hexazahexacyclo[19.6.1.1 .1 .0 .0 ]triaconta- 1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,18,20,28- 2,6 8,11 13,16 21,25 hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa-1(24),2(28),3,5,19,21(25),22-heptaen-12- one; (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl- 2,5 8,11 13,17 22,25 1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 13,15,17(26),18,20,22(25),23-heptaen-7-one; (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-6-methyl- 2,5 8,11 13,17 22,25 1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 .1 .1 .0 ]octacosa- 13,15,17(26),18,20,22(25),23-heptaen-7-one; (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18- 2,6 8,11 20,24 dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one; (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]- 25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2-ethoxy-4-fluoro-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R) -25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)-6-methyl-pyrazolo[3,4- d]pyrimidin-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4- 2,6 8,11 13,18 23,27 yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]- 2,6 8,11 13,18 23,27 21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- 2,6 8,11 13,18 23,27 heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidin-4- yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30- 2,6 8,11 13,18 23,27 heptazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl- 2,6 8,11 13,17 23,27 16-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ] triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25- fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6- yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; ((8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-22-fluoro-13,18- 2,6 8,11 20,24 dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 .1 .0 ]hexacosa- 1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-(3-oxa-6- azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6- yl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11- 6,9 18,21 2,7 8,13 oxa-8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one; (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl-11- 6,9 18,21 2,7 8,13 oxa-8,16,19,22,27,29-hexazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one; (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-16-methyl- 6,9 18,21 2,7 8,13 9,12,16,19,22,27,29-heptazahexacyclo[21.3.1.1 .1 .0 .0 ]nonacosa- 1(26),2,4,6(29),7,23(27),24-heptaene-11,17-dione; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-7,10,13,16,22,24,31- 2,6 8,11 13,18 25,29 heptazahexacyclo[20.6.1.1 .1 .0 .0 ]hentriaconta-1(29),2,4,6(31),23,25,27-heptaen-12- one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(trideuteriomethoxy)phenyl]-6-[[1-(2,2,2- trifluoroethyl)azetidin-3-yl]methyl]pyrazolo[3,4-d]pyrimidin-4-yl]-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan- 6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa- 2,6 8,11 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3- carbonitrile; (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4- difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30- 2,6 8,11 13,18 23,27 hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12- one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[ (1R,5S)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan- 6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6- diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1- (2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa- 2,6 8,11 13,18 23,27 7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 .1 .1 .0 ]triaconta- 1(26),2(30),3,5,21,23(27),24-heptaen-12-one; or a pharmaceutically acceptable salt thereof. 22. A process for the preparation of a compound according to any one of claims 1 to 21 comprising the following step: a) the formation of compound of formula (I) via nucleophilic substitution between compound of formula (VI), (VI), and R 3 X, in the presence of a base; or via condensation reaction between compound of formula (VI) and R 3 OH in the presence of coupling reagent; b) the formation compound of formula (IX), via nucleophilic substitution between compound of (Ic), when R 4 contains reactive primary or secondary amino group; or via photoredox coupling between compound of formula (Ic) and halide R 4 X or XR c BoC in the presence of a catalyst; c) the formation of compound of formula (IX) via reaction between compound of formula (VIII), anhydride or acid; wherein X is halogen; R e is a divalent substituent bearing reactive primary or secondary amino groups; the base in step a) is DIEA; the coupling reagent in step a) is PyBOP; the catalyst in step b) is Ir[dF(CF3)ppy]2(dtbbpy)PF6; R 1 to R 5 , Q 1 , Q 2 , A 1 to A 7 are as defined as in any one of claim 1 to 20. 23. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for use as therapeutically active substance. 24. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 21 and a pharmaceutically acceptable excipient. 25. The use of a compound according to any one of claims 1 to 21 for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. 26. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for the preparation of a medicament for the treatment or prophylaxis of autoimmune diseases, inflammatory diseases, neurological disorders diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancers where overexpression or activation of STING is implicated. 27. The use of a compound according to any one of claims 1 to 21 for the treatment to subjects suffered from an inteferonopathy or auto-inflammatory diseases in which the STING activation are the root-cause of disease pathologies. 28. The use of a compound according to any one of claims 1 to 21 for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi- Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. 29. The use of a compound according to any one of claims 1 to 21 for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythematosus (SLE), dermatomyositis, diabetic kidney disease (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) vasculitis, STING-associated vasculopathy with onset in infancy (SAVI), familial chilblain lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Goutières Syndrome (AGS), COPA syndrome or Wiskott-Aldrich syndrome. 30. The use of a compound according to any one of claims 1 to 21 for the inhibition of STING. 31. The use of a compound according to any one of claims 1 to 21 for the preparation of a medicament for the inhibition of STING. 32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21, when manufactured according to a process of claim 22. 33. A method for the treatment or prophylaxis of autoimmune diseases, which method comprises administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 21.

Description

Case 38652 Macrocycles for the treatment of autoimmune disease The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to antagonist of STING useful for treating autoimmune diseases. FIELD OF THE INVENTION Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), refer to a spectrum of conditions where the immune system mistakenly attacks one's own body, leading to unresolved and inappropriately activated inflammation that become pathogenic. Many of the autoimmune diseases are poorly managed by existing treatments that provide only symptomatic relief. Steroid and broad immunosuppressant drugs (e.g. mycophenolate and cyclophosphamide) constitute the stand of care, but are associated with significant treatment-related toxicity. Pathway selective agents such as Adalizumab (anti-TNF antibody, for RA and IBD) occasionally resulting in infection or insufficient tumor surveillance. And Belimumab (anti-BAFF antibody, the only FDA-approved new drug for SLE) shows a slow onset of remission with modest efficacy in the clinic. In addition, the heterogeneity of many autoimmune diseases with no-existing treatment illustrates the difficulty in finding efficacy through the blockade of one immune pathway. Thus, currently available treatments fail to fulfill a greater unmet needs of autoimmune inflammatory diseases with limited remission, severe side effects, opportunistic infection, and poor quality of life with chronic inflammation. Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-located transmembrane protein that is pivotal in mediating the host's innate sensing of pathogen-/ damage-associated molecular patterns (PAMPs or DAMPs). In particular, the cyclic-GMP-AMP synthase (cGAS)-STING pathway has emerged as a critical mechanism for coupling cytosolic DNA recognition to the induction of type-I interferon (IFN) and broader immune defense programs. The binding of cGAS to double-stranded DNA (dsDNA) allosterically activates its catalytic site, leading to the production of 2'3'- cyclic GMP-AMP (cGAMP), a secondary messenger molecule that is agonistic to STING. Upon activation, STING translocates from ER to Golgi and recruits TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB) to initiate the expression of type-I IFN and a myriad of pro-inflammatory cytokines (e.g., IL-6 and TNFα), respectively. Besides 2'3'-cGAMP, STING can be activated by other types of cyclic-di-nucleotides (CDNs), such as c-di-AMP, c-di- GMP, and 3’,3’-cGAMP from bacteria. Following the signal transduction, STING is rapidly degraded to prevent it from constitutive signaling of the inflammatory responses. While eliciting robust host defense responses, aberrant STING signaling fuels dysregulated immune responses associated with many pathologies. Gain-of-function (GoF) human STING mutations are the root cause of STING-associated vasculopathy with onset in infancy (SAVI), a monogenic disease characterized by the onset of auto-inflammation conditions called type I interferonopathies. Mechanistically, the disease-causing substitutions trigger ligand-independent, constitutive STING activation. Besides, STING is implicated in DNA-driven inflammations, such as Aicardi-Goutières Syndrome (AGS) and genetic forms of lupus known as familial chilblain lupus (FCL). Unlike SAVI, the STING mediated continuous innate immune activation in AGS is caused by deficiencies in self-DNA clearance and metabolisms due to mutations in endonuclease gene TREX1 and/or DNASE2. Consistently, genetic and pharmacological inhibition of STING ameliorates systemic inflammation and morbidity in the Trex1-/- mouse model. In addition, mutations in proteins, such as COP and WAS protein, that regulates STING intracellular trafficking and signaling also presented monogenic disorders known as COPA syndrome and Wiskott-Aldrich syndrome, respectively. Apart from genetic disorders, robust preclinical and clinical evidence supports a general pathogenic role of STING in a range of inflammation-associated disorders including but not limited to: SLE, IBD, RA, dermatomyositis, diabetic kidney disease (DKD), age-related macular degeneration (AMD), diabetic retinopathy (DR) and Anti-Neutrophilic Cytoplasmic Autoantibodies (ANCA) associated vasculitis. For example: a direct link between the cGAS-STING pathway and SLE was established by observing that PBMC from a subset of SLE patients has elevated cytosolic cGAMP than healthy controls. In addition, membrane vesicles from apoptotic cells in SLE sera have high ISGs- stimulating activities dependent on cGAS-STING. And that disrupting STING signaling ameliorated the development of lupus-like phenotypes in FcγrIIb-/- mice. Furthermore, multiple recent studies associate STING with distinct types of neurodegeneration. Taking Parkinson's di