IP Library › Granted Patent US 12,344,621
Granted Patent B2
US 12,344,621 · App. 17/617,873 · Granted Jul 1, 2025

CGRP antagonist compounds

Inventors: Giles Albert Brown (Cambridge, GB); Miles Stuart Congreve (Cambridge, GB); Stephen Paul Watson (Cambridge, GB); Julie Cansfield (Cambridge, GB); Michael Alistair O'Brien (Cambridge, GB); Francesca Deflorian (Cambridge, GB); Gregory R. Ott (North Wales, PA); Nigel Alan Swain (Cambridge, GB); Andrew David Cansfield (Cambridge, GB); John Andrew Christopher (Cambridge, GB); Andrea Bortolato (Cambridge, GB)
Assignee: Nxera Pharma UK Limited
C07D498/22
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Quick Facts
Patent No.
US 12,344,621
App. No.
17/617,873
Granted
Jul 1, 2025
Kind
B2
Abstract

The disclosures herein relate to novel compounds of Formula (1); and salts thereof, wherein A 1 , A 2 , Q, X, R 1 , R 2 and R 3 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with CGRP receptors.

Claims (103)

1. A compound of Formula (1):

or a salt thereof, wherein;

A 1 , A 2 and the atoms to which they are attached together represent an optionally substituted bicyclic or monocyclic ring system;

Q is a bond or 0;

X is O or NH;

R 1 is H, C 1-3 alkyl or halo;

R 2 is H or C 1-3 alkyl;

R 3 is H or C 1-3 alkyl;

and L is a C 4-15 linker group, wherein one, two or three, but not all, of the carbon atoms of the linker group may be optionally replaced by a heteroatom selected from O and N.

2. The compound according to claim 1 , which is a compound of Formula (2a), (2b), (2c) or (2d):

or a salt thereof.

3. The compound according to claim 1 , which is a compound of Formula (3a), (3b), (3c), (4a), (4b), or (4c):

or a salt thereof.

4. The compound according to claim 1 , which is a compound of Formula (5):

or a salt thereof.

5. The compound according to claim 1 , or a salt thereof, wherein A 1 , A 2 and the atoms to which they are attached together represent a ring system selected from the group consisting of:

6. The compound according to claim 1 , or a salt thereof, wherein Q is a bond.

7. The compound according to claim 1 , or a salt thereof, wherein Q is O.

8. The compound according to claim 1 , or a salt thereof, wherein X is NH.

9. The compound according to claim 1 , or a salt thereof, wherein X is O.

10. The compound according to claim 1 , or a salt thereof, wherein R 1 is methyl.

11. The compound according to claim 1 , or a salt thereof, wherein R 2 is H or methyl.

12. The compound according to claim 1 , or a salt thereof, wherein R 2 is H.

13. The compound according to claim 1 , or a salt thereof, wherein R 3 is methyl.

14. The compound according to claim 1 , or a salt thereof, wherein L is a linker group of the formula:

wherein “r” indicates the point of attachment to the ring and “a” indicates the point of attachment to the amide group; W, Y and Z are independently selected from a bond, O, CH 2 , NH and NMe; b, c, d and e are independently 1, 2 or 3 and the dotted line indicates that the bond may be a single or double bond.

15. The compound according to claim 1 , or a salt thereof, wherein L is selected from the group consisting of:

—CHCHCH 2 OCH 2 CH 2 OCH 2 CH 2 —;

—CHCHCH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 —;

—CH 2 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 —;

—CHCHCH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —;

—CHCHCH 2 OCH 2 CH 2 CH 2 CH 2 CH 2 —;

—CHCHCH 2 OCH 2 CH 2 CH 2 CH 2 —;

—CHCHCH 2 OCH 2 CH 2 CH 2 —;

—CHCHCH 2 OCH 2 CH 2 N(CH 3 )CH 2 CH 2 —;

—CHCHCH 2 OCH 2 CH 2 NHCH 2 CH 2 —;

—CHCHCH 2 N(CH 3 )CH 2 CH 2 CH 2 CH 2 CH 2 —;

—CH 2 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 —;

—CH 2 CH 2 CH 2 OCH 2 CH 2 CH 2 CH 2 CH 2 —;

—CH 2 CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 CH 2 —;

and

—CHCHCH 2 OCH 2 CH 2 OCH 2 CH 2 CH 2 —.

16. The compound according to claim 5 , or a salt thereof, wherein L is:

—CHCHCH 2 OCH 2 CH 2 OCH 2 CH 2 —

or

CHCHCH 2 OCH 2 CH 2 CH 2 CH 2 CH 2 —.

17. The compound according to claim 1 which is selected from the group consisting of:

(1S,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-5,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-5,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10S,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-5,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,23E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18,21-trioxa-5,9,12,27,29-pentazapentacyclo[23.5.2.11,4.13,7.028,31]tetratriaconta-3,5,7(33),23,25(32),26,28(31)-heptaene-8,11,30-trione;

(1S,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-5,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-18-oxa-5,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,19E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-17-oxa-5,9,12,23,25-pentazapentacyclo[19.5.2.11,4.13,7.024,27]triaconta-3,5,7(29),19,21(28),22,24(27)-heptaene-8,11,26-trione;

(1S,10R)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-5,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),22(29),23,25(28)-hexaene-8,11,27-trione;

(1S,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-6,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-6,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-12,18-dimethyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-6,9,12,18,24,26-hexazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,20E)-10-[(1,7-dimethylindazol-5-yl)methyl]-12-methyl-15,18-dioxa-6,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-10-[(1,7-dimethylindazol-5-yl)methyl]-12-methyl-15,18-dioxa-6,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-10-[(1,7-dimethylindazol-5-yl)methyl]-12-methyl-18-oxa-6,9,12,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,19E)-10-[(1,7-dimethylindazol-5-yl)methyl]-12-methyl-17-oxa-6,9,12,23,25-pentazapentacyclo[19.5.2.11,4.13,7.024,27]triaconta-3, 5,7(29),19,21(28),22,24(27)-heptaene-8,11,26-trione;

(1R,10R,20E)-10-[(1,7-dimethylindazol-5-yl)methyl]-12,18-dimethyl-6,9,12,18,24,26-hexazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-10-[(1,7-dimethylindazol-5-yl)methyl]-12,15-dimethyl-18-oxa-6,9,12,15,24,26-hexazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,18E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-16-oxa-9,12,22,24-tetrazapentacyclo[18.5.2.11,4.13,7.023,26]nonacosa-3,5,7(28),18,20(27),21,23(26)-heptaene-8,11,25-trione;

(1S,10R,19E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-17-oxa-9,12,23,25-tetrazapentacyclo[19.5.2.11,4.13,7.024,27]triaconta-3,5,7(29),19,21(28),22,24(27)-heptaene-8,11,26-trione;

(1S,10R,20E)-12,15-dimethyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-18-oxa-9,12,15,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-18-oxa-9,12,15,24,26-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-10-[(1,7-dimethylindazol-5-yl)methyl]-12-methyl-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,20E)-10-[(1,7-dimethylindazol-5-yl)methyl]-12-methyl-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,20E)-10-[(7-chloro-1H-indazol-5-yl)methyl]-12-methyl-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),22(29),23,25(28)-hexaene-8,11,27-trione;

(1S,10R)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-9,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),22(29),23,25(28)-hexaene-8,11,27-trione;

(1S,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-9,15,18-trioxa-5,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10S,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-9,15,18-trioxa-5,12,24,26-tetrazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1S,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-9,15,18-trioxa-12,24,26-triazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(1R,10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-9,15,18-trioxa-12,24,26-triazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22(29),23,25(28)-heptaene-8,11,27-trione;

(7R,17E)-9-methyl-7-[(7-methyl-1H-indazol-5-yl)methyl]-12,15,25-trioxa-4,6,9,21,23-pentazatetracyclo[17.6.2.21,4.022,26]nonacosa-17,19(27),20,22(26)-tetraene-5,8,24-trione;

(7R,17E)-9-methyl-7-[(7-methyl-1H-indazol-5-yl)methyl]-6,12,15,25-tetraoxa-4,9,21,23-tetrazatetracyclo[17.6.2.21,4.022,26]nonacosa-17,19(27),20,22(26)-tetraene-5,8,24-trione;

(7R,20E)-9-methyl-7-[(7-methyl-1H-indazol-5-yl)methyl]-6,12,15,18,28-pentaoxa-4,9,24,26-tetrazatetracyclo[20.6.2.21,4.025,29]dotriaconta-20,22(30),23,25(29)-tetraene-5,8,27-trione;

(7R,17E)-9-methyl-7-[(7-methyl-1H-indazol-5-yl)methyl]-6,15,25-trioxa-4,9,21,23-tetrazatetracyclo[17.6.2.21,4.022,26]nonacosa-17,19(27),20,22(26)-tetraene-5,8,24-trione;

(7R,18E)-9-methyl-7-[(7-methyl-1H-indazol-5-yl)methyl]-6,13,16,26-tetraoxa-4,9,22,24-tetrazatetracyclo[18.6.2.21,4.023,27]triaconta-18,20(28),21,23(27)-tetraene-5,8,25-trione;

(7R)-9-methyl-7-[(7-methyl-1H-indazol-5-yl)methyl]-6,12,15,18,28-pentaoxa-4,9,24,26-tetrazatetracyclo[20.6.2.21,4.025,29]dotriaconta-22(30),23,25(29)-triene-5,8,27-trione;

(7R)-9-methyl-7-[(7-methyl-1H-indazol-5-yl)methyl]-6,15,25-trioxa-4,9,21,23-tetrazatetracyclo[17.6.2.21,4.022,26]nonacosa-19(27),20,22(26)-triene-5,8,24-trione;

(7R)-9-methyl-7-[(7-methyl-1H-indazol-5-yl)methyl]-6,13,16,26-tetraoxa-4,9,22,24-tetrazatetracyclo[18.6.2.21,4.023,27]triaconta-20(28),21,23(27)-triene-5,8,25-trione;

(10R,20E)-12-methyl-10-[(7-methyl-1H-indazol-5-yl)methyl]-15,18-dioxa-9,12,24,26,30-pentazapentacyclo[20.5.2.11,4.13,7.025,28]hentriaconta-3,5,7(30),20,22,24,28-heptaene-8,11,27-trione;

and salts thereof.

18. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

19. A method of treating migraine, comprising administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, to a subject in need thereof.

20. The method according to claim 19 , wherein the migraine is chronic migraine.

21. The method according to claim 19 , wherein the migraine is pure menstrual migraine.

22. The method according to claim 19 , wherein the migraine is frequent episodic migraine.

23. The method according to claim 19 , wherein the migraine is menstrually-related migraine.

24. The method according to claim 19 , wherein the migraine is migraine with aura.

25. The method according to claim 19 , wherein the migraine is migraine without aura.

26. The method according to claim 19 , wherein the migraine is familial hemiplegic migraine.

27. The method according to claim 19 , wherein the migraine is sporadic hemiplegic migraine.

28. The method according to claim 19 , wherein the migraine is basilar-type migraine.

29. The method according to claim 19 , wherein the migraine is abdominal migraine.

30. The method according to claim 19 , wherein the migraine is retinal migraine.

31. The method according to claim 19 , wherein the migraine is status migrainosus.

Assignments (3)
CHANGE OF NAME Recorded Sep 25, 2024
From: HEPTARES THERAPEUTICS LIMITED
To: NXERA PHARMA UK LIMITED
Reel/Frame 068695/0754 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 16, 2022
From: BROWN, GILES ALBERT; CONGREVE, MILES STUART; WATSON, STEPHEN PAUL; CANSFIELD, JULIE; O'BRIEN, MICHAEL ALISTAIR; DEFLORIAN, FRANCESCA; SWAIN, NIGEL ALAN; CANSFIELD, ANDREW DAVID; CHRISTOPHER, JOHN ANDREW; BORTOLATO, ANDREA
To: HEPTARES THERAPEUTICS LIMITED
Reel/Frame 059028/0650 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 16, 2022
From: OTT, GREGORY R.
To: HEPTARES THERAPEUTICS LIMITED
Reel/Frame 059127/0459 →
Priority Claims (1)
GB 1908420 · Jun 12, 2019 · national
Continuity (1)
Related Publication 20220306651A1 · Sep 29, 2022
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