Granted Patent B2

US 12,441,727 · App. 17/810,915 · Granted Oct 14, 2025

Inventors: Pei Gan (Wilmington, DE); Jeffrey Yang (Wilmington, DE); Yong Li (Wilmington, DE); Le Zhao (Wilmington, DE); Chunhong He (Wilmington, DE); Chunyin Marshall Law (Wilmington, DE); Xiaozhao Wang (Mt. Laurel, NJ); Wenqing Yao (Wilmington, DE)

Assignee: Incyte Corporation

C07D471/04A61P35/00

Abstract

Claims (113)

1. A compound having Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Y is N or CH;

R 1 is selected from Cl, CH 3 , CH 2 F, CHF 2 , and CF 3 ;

Cy 1 is selected from

R 2 is selected from F and Cl;

R 3 is selected from

and,

Cy 2 is selected from

provided that the compound of Formula I is other than,

2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-

methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-

1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile,

2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-

dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-

yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile, and

2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(6-

fluoro-5-methyl-1H-indazol-4-yl)-8-methyl-1H-[1,2,3]triazolo[4,5-

c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile.

2. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from Cl and CH 3 ;

Cy 1 is selected from

R 3 is selected from

and

Cy 2 is selected from

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

Y is N or OH;

R 1 is selected from Cl, CH 3 , CH 2 F, CHF 2 , and CF 3 ;

Cy 1 is selected from

R 2 is selected from F and Cl;

R 3 is selected from

and,

Cy 2 is selected from

provided that the compound of Formula I is other than

2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-

methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-

1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile and

2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-

dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-

yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

Y is N or OH;

R 1 is selected from Cl, CH 3 , CH 2 F, CHF 2 , and OF 3 ;

Cy 1 is selected from

R 2 is selected from F and Cl;

R 3 is selected from

and,

Cy 2 is selected from

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is N.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is selected from Cy 1 -a, Cy 1 -b, Cy 1 -c, Cy 1 -d, and Cy 1 -e.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is selected from Cy 1 -f, Cy 1 -g, Cy 1 -h, Cy 1 -i, Cy 1 -j, and Cy 1 -k.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is selected from Cy 1 -a and Cy 1 -b.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is selected from Cy 1 -l, Cy 1 -m, Cy 1 -n, Cy 1 -o, Cy 1 -p, Cy 1 -q, Cy 1 -r, Cy 1 -s, and Cy 1 -t.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is selected from Cy 1 -c, Cy 1 -m, Cy 1 -n, Cy 1 -o, Cy 1 -p, Cy 1 -q, Cy 1 -r, Cy 1 -s, and Cy 1 -t.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 , CH 2 F, CHF 2 , and CF 3 .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 and CF 3 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is F.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is Cl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from R 3 -a and R 3 -b.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from R 3 -b and R 3 -c.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 2 is selected from Cy 2 -a, Cy 2 -b, and Cy 2 -d.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 2 is selected from Cy 2 -a and Cy 2 -b.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 2 is selected from Cy 2 -b and Cy 2 -d.

21. The compound of claim 1 , wherein the compound of Formula I is selected from

2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(2-methoxy-3-methylphenyl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(7-(3-chloro-2-methoxyphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;

1-(4-(6-fluoro-7-(5-fluoroquinolin-8-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)piperidin-1-yl)prop-2-en-1-one;

2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(2,3-dimethylphenyl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-6-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-8-methyl-7-(6-methylpyridin-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methyl-1H-indazol-3-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-7-(4-fluorophenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;

8-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile;

2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(7-(2-chloro-3-methylphenyl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-imidazo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

8-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile;

2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)azetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

8-(6-fluoro-1-(1-((E)-4-fluorobut-2-enoyl)piperidin-4-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile;

8-(1-((2S,4S)-2-(cyanomethyl)-1-(2-fluoroacryloyl)piperidin-4-yl)-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-naphthonitrile;

2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6,8-dichloro-4-(3-(dimethylamino)-3-methylazetidin-1-yl)-7-(5-fluoroquinolin-8-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile; and

2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 , wherein the compound of Formula I is selected from:

2-((2S,4S)-4-(6-fluoro-7-(4-fluoroisoquinolin-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-7-(4-fluoroisoquinolin-1-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-8-methyl-7-(3-methylisoquinolin-4-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-8-methyl-7-(3-methylisoquinolin-4-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-7-(7-fluoro-2-methylquinolin-8-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-8-methyl-7-(1-methylisoquinolin-4-yl)-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-7-(7-fluoroquinolin-8-yl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

2-(4-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-methyl-1H-indazol-3-yl)acetonitrile;

2-((2S,4S)-4-(4-(3-(ethyl(methyl)amino)-3-methylazetidin-1-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)-3-methylazetidin-1-yl)-6-fluoro-8-methyl-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

2-(4-(1-((2R,4S)-1-acryloyl-2-methylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-methyl-1H-indol-3-yl)acetonitrile;

2-(4-(1-(1-acryloylpiperidin-4-yl)-6-fluoro-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-1-methyl-1H-indol-3-yl)acetonitrile;

2-((2S,4S)-4-(8-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-4-(3-(ethyl(methyl)amino)-3-methylazetidin-1-yl)-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

2-((2S,4S)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-8-methyl-4-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile; and

2-((2S,4S)-4-(8-chloro-4-(3-(ethyl(methyl)amino)-3-methylazetidin-1-yl)-6-fluoro-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-(2-fluoroacryloyl)piperidin-2-yl)acetonitrile;

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

24. The compound of claim 1 , wherein the compound of Formula I is 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising the compound of claim 24 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

26. A compound that is 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

27. The compound of claim 26 , wherein the compound is diastereomer 1 of 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

28. The compound of claim 26 , wherein the compound is diastereomer 1 of 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile, wherein the diastereomer is characterized by a trifluoroacetic acid salt that has a 1 H NMR spectrum measured at 600 MHz in DMSO-d6 substantially as follows: δ 10.80 (s, 1H), 8.87 (dd, J=4.2, 1.7 Hz, 1H), 8.62 (dd, J=8.5, 1.7 Hz, 1H), 8.41 (s, 1H), 7.82 (dd, J=8.0, 5.8 Hz, 1H), 7.70 (dd, J=8.5, 4.2 Hz, 1H), 7.65 (dd, J=9.8, 8.0 Hz, 1H), 6.90-6.77 (m, 2H), 5.93 (s, 1H), 5.32 (s, 1H), 5.24-5.20 (m, 1H), 5.12 (dd, J=3.6, 1.2 Hz, 1H), 4.97 (s, 1H), 4.76 (s, 1H), 4.57 (s, 1H), 4.37-4.21 (m, 2H), 3.61 (d, J=12.7 Hz, 1H), 3.39-3.21 (m, 2H), 2.84 (s, 6H), 2.46-2.22 (m, 4H), 1.70 (s, 3H).

29. The compound of claim 26 , wherein the compound is diastereomer 2 of 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-fluorobut-2-enoyl)piperidin-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

30. A compound that is 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.

31. The compound of claim 30 , wherein the compound is a single diastereomer of 2-((2S,4S)-4-(4-(3-(dimethylamino)-3-methylazetidin-1-yl)-6-fluoro-7-(5-fluoroquinolin-8-yl)-8-(trifluoromethyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)-1-((E)-4-methoxybut-2-enoyl)piperidin-2-yl)acetonitrile, wherein the single diastereomer is characterized by a trifluoroacetic acid salt that has a 1 H NMR spectrum measured at 600 MHz in DMSO-d6 substantially as follows: δ 10.80 (s, 1H), 8.87 (dd, J=4.2, 1.7 Hz, 1H), 8.62 (dd, J=8.5, 1.8 Hz, 1H), 8.41 (s, 1H), 7.82 (dd, J=8.0, 5.9 Hz, 1H), 7.70 (dd, J=8.5, 4.1 Hz, 1H), 7.65 (dd, J=9.7, 8.0 Hz, 1H), 6.81-6.72 (m, 2H), 5.93 (s, 1H), 5.31 (s, 1H), 4.96 (m, 2H), 4.76-4.32 (m, 2H), 4.11 (d, J=3.1 Hz, 2H), 3.67-3.34 (m, 2H), 3.33 (s, 3H), 3.19 (td, J=16.6, 10.1 Hz, 2H), 2.84 (s, 6H), 2.49-2.43 (m, 2H), 2.33 (s, 1H), 2.21 (d, J=15.7 Hz, 1H), 1.71 (s, 3H).

Assignments (1)

Continuity (4)

References Cited (87)