Macrocyclic compounds as Trk kinase inhibitors
Compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein ring A, ring B, W, m, D, R 2 , R 2a , R 3 , R 3a , and Z are as defined herein, are inhibitors of Trk kinases and are useful in the treatment of pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.
1. A compound of the general Formula I
or pharmaceutically acceptable salts thereof, wherein:
ring A is selected from rings A-1, A-2 and A-3 having the structures:
wherein the wavy line labeled 1 indicates the point of attachment of ring A to ring B and the wavy line labeled 2 indicates the point of attachment of ring A to W;
X is N or CH;
Y is H or F;
R 1 is H, (1-3C)alkoxy or halogen;
ring B is B-1
wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[1,5-a]pyrimidine ring of Formula I;
W is O, NH or CH 2 , wherein when ring A is A-2, then W is CH 2 ;
m is 0, 1 or 2;
D is carbon, R 2 and R 2a are independently H, F, (1-3 C)alkyl or OH (provided that R 2 and R 2a are not both OH), and R 3 and R 3′ are independently H, (1-3 C)alkyl or hydroxy(l-3 C)alkyl, or
D is carbon or nitrogen, R 2 and R 3 are absent, and R 2a and R 3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;
Z is *—NR 4a C(═O)—, *—ONHC(═O)—, *—NR 4b CH 2 — or *—OC(═O)—, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R 3 ;
R 4a is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2-6C alkyl);
R 4b is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar 1 C(O)—, HO CH 2 C(O)—, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar 2 (SO 2 )—, HO 2 CCH 2 — or (1-6C alkyl)NH(CO)—;
Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy;
Ar 2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; and
R 5 and R 6 are independently H, halogen, OH, (1-6C)alkyl or hydroxy(l-6C)alkyl.
2. A compound of claim 1 having the general Formula
or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from rings A-1, A-2 and A-3 having the structures:
wherein the wavy line labeled 1 indicates the point of attachment of ring A to the pyrrolidine ring of Formula I and the wavy line labeled 2 indicates the point of attachment of ring A to W;
X is N or CH;
Y is H or F;
R 1 is H, (1-3C)alkoxy or halogen;
W is O, NH or CH 2 , wherein when ring A is A-2, then W is CH 2 ;
m is 0, 1 or 2;
R 2 and R 2a are independently H, F, or OH, provided that R 2 and R 2a are not both OH;
R 3 is H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl;
Z is *—NR 4a C(═O)—, *—ONHC(═O)—, *—NR 4b CH 2 — or *—OC(═O)—, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R 3 ;
R 4a is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2-6C alkyl);
R 4b is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(l-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar 1 C(O)—, HO CH 2 C(O)—, (1-6C alkyl)sulfonyl, (3-6C cyclo alkyl)sulfonyl, Ar 2 (SO 2 )—, HO 2 CCH 2 — or (1-6C alkyl)NH(CO)—;
Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy;
Ar 2 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; and
R 5 and R 6 are independently H, halogen, OH, (1-6C)alkyl or hydroxy(1-6C)alkyl.
3. A compound according to claim 1 , wherein ring A is ring A-1 having the structure
4. A compound according to claim 3 , wherein X is CH.
5. A compound according to claim 3 , wherein X is N.
6. A compound according to claim 1 , wherein ring A is ring A-3 having the structure
7. A compound according to claim 1 , wherein W is O.
8. A compound according to claim 1 , wherein W is NH.
9. A compound according to claim 1 , wherein W is CH.
10. A compound according to claim 1 , wherein ring A is ring A-2 having the structure
11. A compound according to claim 1 , wherein Y is F.
12. A compound according to claim 1 , wherein Y is H.
13. A compound according to claim 1 , wherein R 1 is H.
14. A compound according to claim 1 , wherein R 1 is (1-3 C)alkyl or (1-3C)alkoxy.
15. A compound according to claim 14 , wherein R 1 is methyl or methoxy.
16. A compound according to claim 1 , wherein R 1 is halogen.
17. A compound according to claim 16 , wherein R 1 is fluoro.
18. A compound according to claim 1 , wherein Z is *—NR 4a C(═O)—.
19. A compound according to claim 18 , wherein R 4a is hydrogen.
20. A compound according to claim 18 , wherein R 4a is (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(l-6C alkyl) or dihydroxy(2-6C alkyl).
21. A compound according to claim 20 , wherein R 4a is (1-6C)alkyl.
22. A compound according to claim 1 , wherein Z is *—ONHC(═O)—.
23. A compound according to claim 1 , wherein Z is *—NR 4b CH 2 —.
24. A compound according to claim 23 , wherein R 4b is H.
25. A compound according to claim 23 , wherein R 4b is selected from (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl and trifluoro(1-6C)alkyl.
26. A compound according to claim 25 , wherein R 4b is (1-6C)alkyl.
27. A compound according to claim 23 , wherein R 4b is selected from (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar 1 C(O)— and HOCH 2 C(O)—.
28. A compound according to claim 27 , wherein R 4b is (1-6C alkyl)C(O)—.
29. A compound according to claim 23 , wherein R 4b is selected from (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, and Ar 2 (SO 2 )—.
30. A compound according to claim 29 , wherein R 4b is (1-6C alkyl)sulfonyl.
31. A compound according to claim 23 , wherein R 4b is HO 2 CCH 2 —.
32. A compound according to claim 23 , wherein R 4b is (1-6C alkyl)NH(CO)—.
33. A compound according to claim 1 , wherein D is carbon, R 2 and R 2a are independently H, F, (1-3 C)alkyl or OH (provided that R 2 and R 2a are not both OH), and R 3 and R 3′ are independently H, (1-3 C)alkyl or hydroxy(l-3 C)alkyl.
34. A compound according to claim 1 , wherein R 2 and R 2a are each hydrogen.
35. A compound according to claim 1 , wherein R 2 and R 2a are each fluoro.
36. A compound according to claim 1 , wherein R 2 is hydrogen and R 2a is fluoro.
37. A compound according to claim 1 , wherein R 2 is hydrogen and R 2a is OH.
38. A compound according to claim 1 , wherein R 2 is H and R 2a is methyl, or R 2 and R 2a are both methyl.
39. A compound according to claim 1 , wherein:
R 3 and R 3a are H; or
R 3a is methyl and R 3 is H; or
R 3a and R 3a are both methyl.
40. A compound according to claim 1 , wherein D is carbon or nitrogen, R 2 and R 3 are absent, and R 2a and R 3a together with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms.
41. A compound according to claim 1 , wherein ring B is ring B-1:
and
R 5 and R 6 are independently H, F, OH, methyl, ethyl, HOCH 2 — or HOCH 2 CH 2 —.
42. A compound according to claim 41 , wherein R 5 is hydrogen and R 6 is H, F, OH, methyl, ethyl, HOCH 2 — or HOCH 2 CH 2 —.
43. A compound according to claim 42 , wherein R 6 is H.
44. A compound according to claim 1 , wherein m is 0.
45. A compound according to claim 1 , wherein m is 1.
46. A compound according to claim 1 , wherein m is 2.
47. A compound according to claim 1 , having the absolute configuration of Figure 1-a:
48. A compound according to claim 1 , having the absolute configuration of Figure 1-b
49. A pharmaceutical composition, which comprises a compound of Formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
50. A process for the preparation of a compound of claim 1 , which comprises:
(a) for a compound of Formula I wherein Z is *—NHC(═O)—, and ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula II
where P 1 is H or a carboxyl protecting group, in the presence of a coupling reagent and a base; or
(b) for a compound of Formula I wherein W is 0, ring A is formula A-1:
X is N, and ring B, D, Z, Y, R 1 , R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula III
where n is 1, 2, 3 or 4 and L 1 is a leaving group or atom, in the presence of a base; or
(c) for a compound of Formula I wherein W is CH 2 , ring A is formula A-2:
and ring B, Z, D, Y, R 1 , R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula IV
where L 2 is a leaving group or atom, in the presence of a base; or
(d) for a compound of Formula I wherein Z is *—NHC(═O)—, and ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula V
in the presence of a base and a coupling reagent; or
(e) for a compound of Formula I wherein Z is *—NHCH 2 —, and ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula VI
in the presence of a reducing agent; or
(f) for a compound of Formula I wherein Z is *—NHCH 2 —, and ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, cyclizing a corresponding compound having the formula VII
in the presence of triphenylphosphine; or
(g) for a compound of Formula I wherein ring A, ring B, W, D, m, R 2 , R 2a , R 3 , and R 3a are as defined for Formula I, Z is *—NR 4b CH 2 —, and R 4b is (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar 1 C(O)—, HOCH 2 C(O)—, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, or Ar 2 (SO 2 )—, coupling a corresponding compound having the formula VIII
with a reagent having the formula (1-6C alkyl)C(O)-L 3 , (3-6C cycloalkyl)C(O)-L 3 , Ar 1 C(O)-L 3 , HOCH 2 C(O)-L 3 , (1-6C alkyl)(SO 2 )-L 3 , (3-6C cycloalkyl)(SO 2 )-L 3 , or Ar 2 (SO 2 )-L 3 , respectively, where L 3 is a leaving atom, in the presence of a base; or
(h) for a compound of Formula I wherein ring A, ring B, W, D, R 2 , R 2a , R 3 , R 3a and m are as defined for Formula I, Z is *—NR 4b CH 2 —, and R 4b is (1-6C alkyl)NH(CO)—, reacting a compound having the formula VIII
with a reagent having the formula (1-6C alkyl)N═C═O in the presence of a base; or
(i) for a compound of Formula I wherein R 2 is F, R 2a is H, and ring A, ring B, Z, W, D, R 3 , R 3a , and m are as defined for Formula I, reacting a corresponding compound having the formula IX
with a fluorination reagent;
(j) for a compound of Formula I wherein W is O, ring A is formula A-1,
X is CH, and Y, R 1 , D, ring B, Z, R 2 , R 2a , R 3 and m are as defined for Formula I, cyclizing a corresponding compound having the formula X
where n is 1, 2, 3 or 4 and L 1 is a leaving group or atom, in the presence of a base; and
optionally removing any protecting groups and optionally preparing a salt thereof.
51. The method of claim 50 , wherein:
ring B is ring B-1 having the structure:
D is carbon;
R 2 and R 2a are independently H, F, (1-3 C)alkyl or OH, provided that R 2 and R 2a are not both OH; and
R 3 and R 3a are independently H, (1-3 C)alkyl or hydroxy(l-3 C)alkyl.
52. The compound of claim 1 selected from:
(6R)-9-fluoro-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;
(6R)-12-oxa-2,16,20,21,24,26-hexaazapentacyclo[16.5.2.1 7,11 .0 2,6 .0 21,25 ]hexacosa-1(24),7(26),8,10,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R,13S)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;
(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R,13R)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;
(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0 2,6 .0 7,12 .0 23,27 ]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;
(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.1 7,11 .0 2,6 .0 21,25 ]hexacosa-1(24),7,9,18(25),19,22-hexaene-17,26-dione;
(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]-pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-14-oxa-2,11,18,19,22-pentaazapentacyclo[14.5.2.1 7,11 .0 2,6 .0 19,23 ]tetracosa-1(22),7,9,16(23),17,20-hexaene-15,24-dione;
(6R)-9-fluoro-13,16-dioxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R,13R)-9,13-difluoro-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .20,24]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;
(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaene;
1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-16-yl]ethan-1-one;
1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-16-yl]-2-hydroxyethan-1-one;
(6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 . 0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaene;
(6R)-9-fluoro-16-methanesulfonyl-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaene;
2-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-16-yl]acetic acid;
(6R)-9-fluoro-17-methanesulfonyl-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaene;
(6R)-N-ethyl-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo 17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaene-17-carboxamide;
(6R)-N-ethyl-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaene-16-carboxamide;
(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0 2,6 . 0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R,13R)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;
(6R,13S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .0 20,4 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;
(6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-15,15-dimethyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-13-oxa-2,11,16,17,21,25,26,29-octaazahexacyclo[21.5.2.0 2,6 .0 7,12 .0 16,20 .0 26,30 ]triaconta-1(29),7,9,11,17,19,23(30),24,27-nonaen-22-one;
(6R)-9-fluoro-13-oxa-2,11,19,21,25,26,29-heptaazahexacyclo[21.5.2.0 2,6 .0 7,12 .0 15,20 .0 26,30 ]triaconta-1(29),7,9,11,15(20),16,18,23(30),24,27-decaen-22-one;
(6R)-9-fluoro-13,13-dimethyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1 7,11 .0 2,6 .0 20,24 ]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;
(4R,6R,15S)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;
(4R,6S,15S)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;
(4R,6R)-9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;
(4R,65)-9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;
(4R,6R)-9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(4R,65)-9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0 2,6 .0 7,12 .0 21,25 ]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(4R,6R,15R)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;
(4R,6S,15R)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;
Diastereomer 1 of (15S)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one; and
Diastereomer 2 of (15S)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0 2,6 .0 7,12 .0 22,26 ]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one.