IP Library › Granted Patent US 12,351,591
Granted Patent B2
US 12,351,591 · App. 18/189,713 · Granted Jul 8, 2025

KRas inhibitors

Inventors: David Anthony Barda (Indianapolis, IN); Jolie Anne Bastian (Indianapolis, IN); Kelly Wayne Furness (Avon, IN); Deqi Guo (Carmel, IN); James Robert Henry (Indianapolis, IN); Richard Duane Johnston (Greenfield, IN); Jason Eric Lamar (Indianapolis, IN); Tao Liu (San Diego, CA); Michael John Rodriguez (Indianapolis, IN); Almudena Rubio (Carmel, IN); Chong Si (Zionsville, IN); Gaiying Zhao (Carmel, IN); Mohammad Sadegh Zia-Ebrahimi (Indianapolis, IN); Matthew Patrick Baumgartner (Aldan, PA); Isabel Rojo (Madrid, ES); Mario Barberis (Madrid, ES); Santiago Carballares Martin (Madrid, ES); Pablo Garcia Losada (Madrid, ES); Sonia Maria Gutierrez Sanfeliciano (Madrid, ES); Wenceslao Lumeras Amador (Madrid, ES); Victoriano Molero Florez (Madrid, ES); Maria Lourdes Prieto Vallejo (Madrid, ES)
Assignee: ELI LILLY AND COMPANY
C07D519/00C07D491/048C07B2200/05
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Quick Facts
Patent No.
US 12,351,591
App. No.
18/189,713
Granted
Jul 8, 2025
Kind
B2
Abstract

The present invention provides compounds of the formula: wherein A, B, D 1 , X, Y, Z, G, R 1 , R 2 , and R 3a are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients for cancer.

Claims (308)

1. A compound of the formula:

wherein:

A is —C(H)— or —N—;

B is —C(R 4 )— or —N—;

D 1 is —CH 2 —;

X is —S—;

Y is —C(CN)— or —N—;

Z is —C(R 3c )— or —N—;

G is —C(R 3b )— or —N—;

R 1 is methoxy, C 1-4 alkyl, C 2-4 heteroalkyl, azetidine, N-linked piperazine, piperidine, morpholine, or a group of the formula selected from

wherein the C 1-4 alkyl, C 2-4 heteroalkyl, azetidine, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, methoxy, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, difluoromethoxy, —O-trideuteromethyl, cyclopropyl, oxetane, pyrazole, imidazole, amino, —CONR 7 R 7 , —O—(CH 2 ) p —OC 1-3 alkyl, —O—(CH 2 ) p —OH, or —O—CO—C 1-3 alkyl, wherein the piperidine or the N-linked piperazine are optionally bridged by a C 1-3 alkyl and wherein the cyclopropyl, imidazole, or pyrazole are each optionally substituted with a hydroxyl or a C 1-3 alkyl substituted with one or more hydroxyl;

E 1 is —(CR 7 R 7 -) n , E 2 is —CR 7 R 7 —, —NR 7 — or —O— and E 3 is —(CR 7 R 7 -) m , wherein m+n is 1, 2, 3 or 4;

p is 1, 2, or 3;

R 2 is H, halogen, or methyl;

R 3a , R 3b , and R 3c are each independently H or halogen;

R 4 is H, methyl, —CH 2 —OH, —O—R 5 -R 6 , —O—R 6 , or azetidine optionally substituted with NR 7 R 7 , wherein R 5 is —CH 2 —, —CH(CH 3 )—, or —CH 2 —CH 2 —, wherein R 6 is H, C 1-3 alkyl, C 2-3 heteroalkyl, C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, 2-oxo-1,3-dihydrobenzimidazole, imidazole or pyrazole, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, or C 4-6 heterocycloalkyl are optionally substituted with one or more oxo, halogen, hydroxyl, methoxy, difluoromethoxy, NR 7 R 7 , C 1-4 alkyl, C 1-4 alkenyl, —CN, or —CO—CH 2 OH, wherein the C 1-4 alkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, or NR 7 R 7 , wherein the C 3-6 cycloalkyl or C 4-6 heterocycloalkyl are optionally fused with the C 1-4 alkyl to form a bicyclic ring, or the C 3-6 cycloalkyl or C 4-6 heterocycloalkyl are optionally bridged with a C 1-3 alkyl; and

each R 7 is independently H, or C 1-3 alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein G is —N—, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein G is —N—, and Z is —C(R 3c )—, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein G is —C(R 3b )—, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 , wherein R 3b is F, or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein G is —C(R 3b )—, and Z is —N—, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein G is —C(R 3b )—; R 3a , R 3b , and R 3c are each independently H, or halogen; R 1 is C 1-4 alkyl, C 2-4 heteroalkyl, N-linked piperazine, piperidine, or a group of the formula

wherein the C 1-4 alkyl, C 2-4 heteroalkyl, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, —CONR 7 R 7 , —O—(CH 2 ) p —OC 1-3 alkyl, —O—(CH 2 ) p —OH, or —O—CO—C 1-3 alkyl, wherein the piperidine or the N-linked piperazine are optionally bridged by a C 1-3 alkyl and wherein the cyclopropyl, imidazole, or pyrazole are each optionally substituted with a C 1-3 alkyl substituted with one or more hydroxyl; and

R 4 is H, methyl, —CH 2 —OH, —O—R 5 -R 6 , —O—R 6 , or azetidine optionally substituted with NR 7 R 7 , wherein R 5 is —CH 2 —, —CH(CH 3 )—, or —CH 2 —CH 2 —, wherein R 6 is H, C 1-3 alkyl, C 2-3 heteroalkyl, C 3-6 cycloalkyl, C 4-6 heterocycloalkyl or 2-oxo-1,3-dihydrobenzimidazole, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, or C 4-6 heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, methoxy, NR 7 R 7 , C 1-4 alkyl, or C 1-4 alkenyl, wherein the C 1-4 alkyl is optionally substituted with one or more halogen or hydroxyl, wherein the C 3-6 cycloalkyl or C 4-6 heterocycloalkyl are optionally fused with the C 1-4 alkyl to form a bicyclic ring, or the C 3-6 cycloalkyl or C 4-6 heterocycloalkyl are optionally bridged with a C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein G is —C(R 3b )—; R 3a , R 3b , and R 3c are each independently H, or halogen; and R 1 is C 1-4 alkyl, C 2-4 heteroalkyl, N-linked piperazine, piperidine, or a group of the formula

wherein the C 1-4 alkyl, C 2-4 heteroalkyl, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, or —CONR 7 R 7 , wherein the piperidine or the N-linked piperazine are optionally bridged by a C 1-3 alkyl and wherein the cyclopropyl, imidazole, or pyrazole are each optionally substituted with a C 1-3 alkyl substituted with one or more hydroxyl; and R 4 is H, methyl, —CH 2 —OH, —O—R 5 -R 6 , —O—R 6 , or azetidine optionally substituted with NR 7 R 7 , wherein R 5 is —CH 2 —, —CH(CH 3 )—, or —CH 2 —CH 2 —, wherein R 6 is H, C 1-3 alkyl, C 2-3 heteroalkyl, C 3-6 cycloalkyl, C 4-6 heterocycloalkyl or 2-oxo-1,3-dihydrobenzimidazole, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, or C 4-6 heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, methoxy, NR 7 R 7 , C 1-4 alkyl, or C 1-4 alkenyl, wherein the C 1-4 alkyl is optionally substituted with one or more halogen or hydroxyl, wherein the C 3-6 cycloalkyl or C 4-6 heterocycloalkyl are optionally fused with the C 1-4 alkyl to form a bicyclic ring, or the C 3-6 cycloalkyl or C 4-6 heterocycloalkyl are optionally bridged with a C 1-3 alkyl; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein G is —C(R 3b )—; R 3a , R 3b , and R 3c are each independently H, or halogen; R 1 is C 1-4 alkyl, C 2-4 heteroalkyl, or N-linked piperazine, wherein the C 1-4 alkyl, C 2-4 heteroalkyl, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, cyclopropyl, oxetane, or amino, and wherein the N-linked piperazine is optionally bridged by the C 1-3 alkyl; and

R 4 is H, methyl, —CH 2 —OH, —O—R 5 -R 6 , or —O—R 6 , wherein R 5 is —CH 2 —, —CH 2 (CH 3 )—, or —CH 2 —CH 2 —, wherein R 6 is H, C 1-3 alkyl, C 2-3 heteroalkyl, C 4-6 cycloalkyl, or C 4-6 heterocycloalkyl, wherein the C 1-3 alkyl, C 4-6 cycloalkyl, or C 4-6 heterocycloalkyl are optionally substituted with one or more halogen, hydroxyl, methoxy, C 1-4 alkyl, or C 1-4 alkenyl, wherein the C 1-4 alkyl is optionally substituted with one or more halogen or hydroxyl, wherein the C 4-6 cycloalkyl or C 4-6 heterocycloalkyl are optionally fused with the C 1-4 alkyl to form a bicyclic ring, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein Y is —C(CN)—, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 , wherein Z is —C(R 3c )—, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein R 3a and R 3c are each independently H or F, or a pharmaceutically acceptable salt thereof.

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

14. The compound according to claim 1 , wherein Z is —N—, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 , wherein A is —N—, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , wherein A is —C(H)—, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 , wherein B is —C(R 4 )—, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 , wherein B is —C(H)—, or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 , wherein R 1 is N-linked piperazine, or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 , wherein R 1 is N-linked piperazine optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, or

—CONR 7 R 7 , and optionally bridged by a C 1-3 alkyl and wherein the cyclopropyl, imidazole, or pyrazole are each optionally substituted with a C 1-3 alkyl substituted with one or more hydroxyl, or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1 , wherein R 1 is C 1-4 alkyl, C 2-4 heteroalkyl, N-linked piperazine, piperidine, or a group of the formula

wherein the C 1-4 alkyl, C 2-4 heteroalkyl, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, or —CONR 7 R 7 , wherein the piperidine or the N-linked piperazine are optionally bridged by a C 1-3 alkyl and wherein the cyclopropyl, imidazole, or pyrazole are each optionally substituted with a C 1-3 alkyl substituted with one or more hydroxyl; or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 1 , wherein R 1 is N-linked piperazine substituted with one or more of methyl, trideuteromethyl, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, difluoromethoxy, —O-trideuteromethyl, cyclopropyl, oxetane, pyrazole, imidazole, —CONR 7 R 7 , —O—(CH 2 ) p —OC 1-3 alkyl, —O—(CH 2 ) p —OH, or —O—CO—C 1-3 alkyl, and wherein the cyclopropyl, imidazole, or pyrazole are each optionally substituted with a hydroxyl or a C 1-3 alkyl substituted with one or more hydroxyl, and wherein the N-linked piperazine is bridged by a C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 1 , wherein R 1 is selected from

or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1 , wherein R 4 is —O—CH 2 —R 6 or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 24 , wherein R 6 is azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, morpholine, cyclobutane, or 1,4-dioxane, or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1 , wherein R 4 is selected from

or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1 , wherein R 2 is F or Cl or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 1 , wherein R 2 is F, or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 1 , wherein R 2 is Cl, or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 1 , wherein Y is —C(CN)—, Z is —C(R 3c )—, R 2 is F or Cl, R 3a is H, R 3b is H, and R 3c is F, or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 1 , wherein the compound is selected from

Example

Chemical Name

Structure

24

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-(3-methyl-3,8- diazabicyclo[3.2.1]octan-8-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

25

2-Amino-4-[1-(3-ethyl-3,8- diazabicyclo[3.2.1]octan-8-yl)- 5-fluoro-3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

28

3-[8-[6-(2-Amino-1,3- benzothiazol-4-yl)-5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 1-yl]-3,8- diazabicyclo[3.2.1]octan-3- yl]propan-1-ol

46

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(2- hydroxyethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

48

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

49

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

51

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-(3-methyl-3,8- diazabicyclo[3.2.1]octan-8-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

52

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-(3-methyl-3,6- diazabicyclo[3.1.1]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

53

2-Amino-5-fluoro-4-[5-fluoro- 1-(3-methyl-3,6- diazabicyclo[3.1.1]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 2

55

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

56

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2S)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

57

2-Amino-4-[5-fluoro-1-[3- [(2S)-2-hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-methoxy-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

95

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-(3-methyl-3,6- diazabicyclo[3.1.1]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

96

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- hydroxybutyl)-3,6- diazabicyclo[3.1.1]heptan-6- yl]-7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

98

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- hydroxypropyl)-3,6- diazabicyclo[3.1.1]heptan-6- yl]-7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

99

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 1

100

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

103

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)- oxetan-2-yl]methyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 2

106

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(oxetan-3- ylmethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 2

107

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 2

108

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-(3-methyl-3,8- diazabicyclo[3.2.1]octan-8-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

110

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[1-(2- hydroxyethyl)pyrazol-4- yl]methyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

113

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

117

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(oxetan-3- ylmethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

118

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

119

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(2- methoxyethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

120

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- methoxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

121

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-(3-methyl-3,8- diazabicyclo[3.2.1]octan-8-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

122

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

123

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)- oxetan-2-yl]methyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

124

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(2- methoxyethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

125

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(2- hydroxyethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

126

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- methoxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

127

2-Amino-4-[1-(3-ethyl-3,8- diazabicyclo[3.2.1]octan-8-yl)- 5-fluoro-3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]-7-fluoro-thieno[3,2- c]pyridine-3-carbonitrile

130

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(oxetan-3- ylmethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

131

2-Amino-7-fluoro-4-[5-fluoro- 1-[3-(2-methoxyethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[(2-methoxy-1,2,3,5,6,7- hexahydropyrrolizin-8- yl)methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]thieno[3,2-c]pyridine-3- carbonitrile

137

2-Amino-4-[3-[[(2R,8S)-2- fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

138

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

139

2-Amino-4-[3-[3- (dimethylamino)azetidin-1-yl]- 5-fluoro-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]-5-fluoro- benzothiophene-3-carbonitrile

140

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-[3- (3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

141

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S)-1-(2- fluoroethyl)pyrrolidin-2- yl]methoxy]-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

142

2-Amino-4-[3-[[(2R)-1,4- dioxan-2-yl]methoxy]-5- fluoro-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]-5-fluoro- benzothiophene-3-carbonitrile

143

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[[(2R)-tetrahydrofuran-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

144

2-Amino-4-[3-[2- (dimethylamino)ethoxy]-5- fluoro-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]-5-fluoro- benzothiophene-3-carbonitrile

145

2-Amino-5-fluoro-4-[5-fluoro- 3-[2-[(3S)-3-fluoropyrrolidin- 1-yl]ethoxy]-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

146

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-(2-morpholinoethoxy)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

148

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[[(2S)-1-methylazetidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

149

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-1-[3-(oxetan-3- ylmethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

150

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(2-methoxyethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

151

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(3-methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

153

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-(3- methyl-3,6- diazabicyclo[3.1.1]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

156

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(4-hydroxybutyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

157

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-[[2- (hydroxymethyl)cyclopropyl] methyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

158

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,6- diazabicyclo[3.1.1]heptan-6- yl]-7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 1

161

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 2

162

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

170

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

171

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2S)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

172

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1 ]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

175

2-Amino-4-[3-[(2R,8S)-2- fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

177

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-[(2R)-2-hydroxypropyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-3-[[(2S)-1- methylpyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

178

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-[3- [(2R)-2-hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

179

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-[(2R)-2-hydroxypropyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-3-[(2S)-1- methylazetidin-2-yl]methoxy]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

180

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S)-1-(2- hydroxyethyl)azetidin-2- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

181

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S)-1-(2- hydroxyethyl)pyrrolidin-2- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

182

2-Amino-5-fluoro-4-[5-fluoro- 3-[[2-(hydroxymethyl)-1- methyl-pyrrolidin-2- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 1

183

2-Amino-5-fluoro-4-[5-fluoro- 3-[[2-(hydroxymethyl)-1- methyl-pyrrolidin-2- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 2

184

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-hydroxy-1- methyl-pyrrolidin-2- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

185

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,3S)-3-hydroxy-1- methyl-pyrrolidin-2- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

186

2-Amino-5-fluoro-4-[5-fluoro- 3-[(2S,4S)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-[3- [(2R)-2-hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

187

2-Amino-4-[3-[[1- (dimethylamino)cyclopropyl] methoxy]-5-fluoro-1-[3-[(2R)- 2-hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]-5-fluoro- benzothiophene-3-carbonitrile

189

3-[8-[6-(2-amino-3-cyano-5- fluoro-benzothiophen-4-yl)-5- fluoro-3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 1-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]- N-methyl-propanamide

190

3-[8-[6-(2-Amino-3-cyano-5- fluoro-benzothiophen-4-yl)-5- fluoro-3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 1-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl]- N,N-dimethyl-propanamide

191

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3- (trideuteriomethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

192

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3- (trideuteriomethyl)-3,6- diazabicyclo[3.1.1]heptan-6- yl]-7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

194

3-[8-[6-(2-Amino-5,7- difluoro-1,3-benzothiazol-4- yl)-5-fluoro-3-[[(2R,8S)-2- fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 1-yl]-3,8- diazabicyclo[3.2.1]octan-3- yl]propan-1-ol

212

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(2- methoxyethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

213

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- methoxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

214

2-Amino-4-[3-[[(2R)-1,4- dioxan-2-yl]methoxy]-5- fluoro-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile, Isomer 2

216

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-[(2R)-2-methoxypropyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-3-[(2S)-1- methylpyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

217

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[2-(3-methoxyazetidin-1- yl)ethoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

218

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

220

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[2-(2- methoxyethoxy)ethyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

224

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[2-(2- hydroxyethoxy)ethyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

225

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[3-(2- hydroxyethoxy)propyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

226

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[3-(2- methoxyethoxy)propyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

227

2-Amino-4-[1-[3-[(3R)-3,4- dihydroxybutyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 5-fluoro-3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]-7-fluoro-thieno[3,2- c]pyridine-3-carbonitrile

228

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[3-hydroxy- 2-(hydroxymethyl)propyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

229

2-Amino-7-fluoro-4-[5-fluoro- 3-[(2-methoxy-1,2,3,5,6,7- hexahydropyrrolizin-8- yl)methoxy]-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

231

2-Amino-7-fluoro-4-[5-fluoro- 3-[(2-methoxy-1,2,3,5,6,7- hexahydropyrrolizin-8- yl)methoxy]-1-[3-[[(2R)- oxetan-2-yl]methyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile methanesulfonic acid

232

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-methoxy- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

234

2-amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-methoxy- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)- oxetan-2-yl]methyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile methanesulfonic acid

235

2-Amino-7-fluoro-4-[5-fluoro- 1-(3-methyl-3,8- diazabicyclo[3.2.1]octan-8-yl)- 3-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]thieno[3,2-c]pyridine-3- carbonitrile

236

2-Amino-7-fluoro-4-[5-fluoro- 1-[3-(3-methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]thieno[3,2-c]pyridine-3- carbonitrile

237

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-[3- (3-methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

238

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-methoxy-1- methyl-pyrrolidin-2- yl]methoxy]-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

239

2-Amino-7-fluoro-4-[5-fluoro- 3-(1,2,3,5,6,7- hexahydropyrrolizin-8- ylmethoxy)-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile formic acid

241

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2SR,8SR)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

242

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2SR,8SR)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(2- methoxyethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

243

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-[(2R)-2-hydroxypropyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-3-[[(2S,4R)-4-methoxy- 1-methyl-pyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

247

2-Amino-7-fluoro-4-[5-fluoro- 3-(1,2,3,5,6,7- hexahydropyrrolizin-8- ylmethoxy)-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

248

2-Amino-4-[3-[(6,6-difluoro- 2,3,5,7-tetrahydro-1H- pyrrolizin-8-yl)methoxy]-5- fluoro-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]-7-fluoro- thieno[3,2-c]pyridine-3- carbonitrile

249

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2SR,8SR)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(2R)-2- hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

327

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[2- (trideuteriomethoxy)ethyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

328

2-Amino-4-[3-[(4,4-difluoro- 1-methyl-3- piperidyl)methoxy]-5-fluoro- 1-[3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]-7-fluoro- thieno[3,2-c]pyridine-3- carbonitrile, Isomer 1

331

2-Amino-4-[3-[(4,4-difluoro- 1-methyl-3- piperidyl)methoxy]-5-fluoro- 1-[3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]-5-fluoro- benzothiophene-3-carbonitrile, Isomer 2

332

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-[3- (3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

334

2-Amino-4-[3-[[1- [(dimethylamino)methyl]cyclo- propyl]methoxy]-5-fluoro-1- [3-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]-7-fluoro- thieno[3,2-c]pyridine-3- carbonitrile

336

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-[(1- hydroxycyclopropyl)methyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

340

2-Amino-5-fluoro-4-[5-fluoro- 1-(3-methyl-3,6- diazabicyclo[3.1.1]heptan-6- yl)-3-[[(2R)-4- methylmorpholin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile, Isomer 2

341

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-(3- methyl-3,6- diazabicyclo[3.1.1]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

343

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-(3-methyl-3,6- diazabicyclo[3.1.1]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

344

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- methoxypropyl)-3,6- diazabicyclo[3.1.1]heptan-6- yl]-7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

348

2-Amino-4-[5-fluoro-3- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[2,3- b]pyridine-3-carbonitrile

351

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,3S)-3-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-[3- [(2R)-2-hydroxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

354

2-Amino-5-fluoro-4-[5-fluoro- 1-[3-[(2R)-2-hydroxypropyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-3-[[(2R)-4- methylmorpholin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]benzothiophene-3- carbonitrile

356

2-Amino-7-fluoro-4-[5-fluoro- 1-[3-[(2R)-2-hydroxypropyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-3-[(1S)-1-methyl-2- morpholino-ethoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]thieno[3,2-c]pyridine-3- carbonitrile

358

2-Amino-7-fluoro-4-[5-fluoro- 1-[3-[(2R)-2-hydroxypropyl]- 3,8-diazabicyclo[3.2.1]octan- 8-yl]-3-[(2S)-2- morpholinopropoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]thieno[3,2-c]pyridine-3- carbonitrile

363

2-Amino-4-[1-[3-[(2R)-2- ethoxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 5-fluoro-3-[[(2S,4R)-4-fluoro- 1-methyl-pyrrolidin-2- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]-7-fluoro-thieno[3,2- c]pyridine-3-carbonitrile

364

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-[3- [(2R)-2-methoxypropyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile; acetic acid

367

2-Amino-5-fluoro-4-[5-fluoro- 3-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-1-[3- [(2R)-2-hydroxypropyl]-3,6- diazabicyclo[3.1.1]heptan-6- yl]-7,9-dihydrofuro[3,4- f]quinazolin-6- yl]benzothiophene-3- carbonitrile

372

2-Amino-7-fluoro-4-[5-fluoro- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-1-[3-(3- fluoropropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl]thieno[3,2- c]pyridine-3-carbonitrile

374

2-Amino-7-fluoro-4-[5-fluoro- 1-[3-(2-fluoroethyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]- 3-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl]thieno[3,2-c]pyridine-3- carbonitrile

or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

33. A pharmaceutical composition comprising a compound according to claim 31 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 13, 2023
From: BARBERIS, MARIO; BARDA, DAVID ANTHONY; BASTIAN, JOLIE ANNE; BAUMGARTNER, MATTHEW PATRICK; CARBALLARES MARTIN, SANTIAGO; FURNESS, KELLY WAYNE; GARCIA LOSADA, PABLO; GUO, DEQI; GUTIERREZ SANFELICIANO, SONIA MARIA; HENRY, JAMES ROBERT; JOHNSTON, RICHARD DUANE; LAMAR, JASON ERIC; LIU, TAO; LUMERAS AMADOR, WENCESIAO; MOLERO FLOREZ, VICTORIANO; PRIETO VALLEJO, MARIA LOURDES; RODRIGUEZ, MICHAEL JOHN; ROJO, ISABEL; RUBIO, ALMUDENA; SI, CHONG; ZHAO, GAIYING; ZIA-EBRAHIMI, MOHAMMAD SADEGH
To: ELI LILLY AND COMPANY
Reel/Frame 064268/0001 →
Continuity (4)
Provisional Application 63386404 · Dec 7, 2022
Provisional Application 63406906 · Sep 15, 2022
Provisional Application 63323607 · Mar 25, 2022
Related Publication 20240043451A1 · Feb 8, 2024
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