Granted Patent B2

US 10,532,054 · App. 15/710,200 · Granted Jan 14, 2020

Abstract

Claims (161)

1. A compound of Formula II:

wherein:

X is CR 11 ;

Y is CO;

R 11 is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;

R 1 and R 3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;

R 2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;

R 6 and R 8 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;

R 5 and R 9 are each hydrogen;

R 7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;

R 10 is selected from hydrogen and methyl;

each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;

for W—(R 10 ) p , W is N and p is 1;

for W—(R 7 ) p , W is C and p is 1;

for W—(R 4 ) p , W is N and p is 0;

Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;

with the proviso that if R 1 is hydrogen, then R 3 is alkoxy;

with the proviso that if R 3 is hydrogen, then R 1 is selected from amino and alkoxy;

with the proviso that if R 7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R 6 and R 8 is independently selected from alkyl, alkoxy, amino, and halogen;

and pharmaceutically acceptable salts and hydrates thereof.

2. The compound according to claim 1 , wherein

R 10 is hydrogen; and

R 7 is amino.

3. The compound according to claim 1 , wherein

R 10 is hydrogen; and

R 7 is selected from hydroxyl and alkoxy.

4. The compound according to claim 3 , wherein

R 6 and R 8 are each independently alkyl;

R 2 is hydrogen; and

R 7 is selected from hydroxyl and alkoxy substituted with a hydroxyl.

5. The compound according to claim 1 , wherein R 1 and R 3 are each methoxy.

6. The compound according to claim 1 , wherein R 7 is selected from an amino or an alkoxy selected from the group represented by Formula III:

wherein:

A is selected from O and NR 20 ;

n is selected from 0, 1, 2, 3, 4 and 5;

B is selected from —C(O)N(R h ) 2 —, —S(O) 2 N(R h ) 2 —, —C(O)—, —S(O) 2 —, —C(O)O—, wherein each R h is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and

R 20 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.

7. The compound according to claim 1 , wherein the compound of Formula II is selected from:

2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)- one;

7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;

7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;

7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;

2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one;

7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one;

and pharmaceutically acceptable salts and hydrates thereof.

8. A compound selected from:

7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one;

4-(1,6-naphthyridin-7-yl)phenol;

and pharmaceutically acceptable salts and hydrates thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a compound according to claim 7 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier.

12. A compound of Formula II:

wherein:

X is CH;

Y is CO;

R 1 and R 3 are each independently selected from alkoxy and hydrogen;

R 2 is selected from alkoxy, alkyl, and hydrogen;

R 6 and R 8 are each independently selected from alkyl, alkoxy, halogen, and hydrogen;

R 5 and R 9 are each hydrogen;

R 7 is selected from amino, hydroxyl, a substituted ethoxy group, and alkyl substituted with a heterocyclyl;

R 10 is hydrogen;

each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;

for W—(R 10 ) p , W is N and p is 1;

for W—(R 4 ) p , W is N and p is 0;

Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;

with the proviso that if R 2 is alkoxy or hydrogen, then at least one of R 1 and R 3 is alkoxy;

with the proviso that if R 7 is selected from hydroxyl and alkoxy, then at least one of R 6 and R 8 are independently selected from alkyl, alkoxy, and chloride;

with the proviso that if for W—(R 7 ) p , W is N and p is 0, then at least one of R 6 and

R 8 is selected from alkyl, alkoxy, and chloride;

and pharmaceutically acceptable salts and hydrates thereof.

13. The compound according to claim 12 , wherein R 7 is selected from an amino or an alkoxy selected from the group represented by Formula III:

wherein:

A is selected from O and NR 20 ;

n is selected from 0, 1, 2, 3, 4 and 5;

B is selected from —C(O)N(R h ) 2 —, —S(O) 2 N(R h ) 2 —, —C(O)—, —S(O) 2 —, and —C(O)O—, wherein each R h is independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and

R 20 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and

with the proviso that if A is O and B is —C(O)NH—, then R 20 is not an unsaturated cycloalkyl.

14. A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier.

15. A compound of Formula II:

wherein:

X is CR 11 ;

Y is selected from CO;

R 11 is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;

R 1 and R 3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;

R 2 is selected from —N—C(O)—R 18 , —N—SO 2 —R 18 , —CH 2 —C(R 18 ) 3 , —CH 2 —N(R 18 ) 2 , and —CH 2 —O—R 18 , wherein each R 18 is independently selected from alkoxy, alkyl, alkenyl, amide, amino, aryl, arylalkyl, cycloalkyl, haloalkyl, halogen, heteroaryl, heterocyclyl, and hydrogen;

R 6 and R 8 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;

R 5 and R 9 are each hydrogen;

R 7 is selected from amino, amide, alkyl, hydroxyl, and alkoxy;

R 10 is selected from hydrogen and methyl;

each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;

for W—(R 10 ) p , W is N and p is 1;

for W—(R 7 ) p , W is C and p is 1;

for W—(R 4 ) p , W is N and p is 0;

Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;

with the proviso that if R 7 is selected from alkyl, hydroxyl, and alkoxy, then at least one of R 6 and R 8 is independently selected from alkyl, alkoxy, amino, and halogen;

and pharmaceutically acceptable salts and hydrates thereof.

16. The compound according to claim 15 , wherein R 1 and R 3 are each independently selected from methoxy, alkyl, amino, chloride, and hydrogen.

17. The compound according to claim 15 , wherein R 6 and R 8 are each independently selected from methyl, alkoxy, amino, chloride, fluoride, and hydrogen.

18. The compound according to claim 15 , wherein R 10 is hydrogen.

19. The compound according to claim 15 , wherein

X is CH;

R 10 is hydrogen; and

R 7 is selected from hydroxyl and alkoxy.

20. The compound according to claim 15 , wherein

R 6 and R 8 are each independently alkyl; and

R 7 is selected from hydroxyl and alkoxy substituted with a hydroxyl.

21. The compound according to claim 15 , wherein R 7 is selected from an amino or an alkoxy selected from the group represented by Formula III:

wherein:

A is selected from O and NR 20 ;

n is selected from 0, 1, 2, 3, 4 and 5;

B is selected from —C(O)N(R h ) 2 —, —S(O) 2 N(R h ) 2 —, —C(O)—, —S(O) 2 —, —C(O)O—, wherein each R h is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen;

R 20 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and

with the proviso that if A is O and B is —C(O)NH—, then R 20 is not an unsaturated cycloalkyl.

22. The compound according to claim 21 , wherein R 6 and R 8 are each independently alkyl.

23. A pharmaceutical composition comprising a compound according to claim 15 and a pharmaceutically acceptable carrier.

24. A compound of Formula II:

wherein:

X is selected from CR 11 ;

Y is selected from CO;

R 11 is selected from hydrogen, unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted alkynyl;

R 1 is selected from alkoxy or amino;

R 3 is alkoxy;

R 2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;

R 6 and R 8 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;

R 5 and R 9 are each hydrogen;

R 7 is selected from amino, amide, alkyl, and alkoxy;

R 10 is selected from hydrogen and methyl;

each W is independently selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;

for W—(R 10 ) p , W is N and p is 1;

for W—(R 7 ) p , W is C and p is 1;

for W—(R 4 ) p , W is N and p is 0;

Z 1 is a double bond, and Z 2 and Z 3 are each a single bond;

and pharmaceutically acceptable salts and hydrates thereof.

25. The compound according to claim 24 , wherein

R 1 is selected from methoxy and amino; and

R 3 is methoxy.

26. The compound according to claim 24 , wherein R 2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, bromide, chloride, and hydrogen.

27. The compound according to claim 24 , wherein R 6 and R 8 are each independently selected from alkyl, alkoxy, amino, chloride, fluoride, and hydrogen.

28. The compound according to claim 24 , wherein

X is CH;

R 10 is hydrogen; and

R 7 is selected from hydroxyl and alkoxy.

29. The compound according to claim 24 , wherein

X is CH;

R 10 is hydrogen; and

R 7 is selected from amide and amino.

30. The compound according to claim 24 , wherein

X is CH;

R 10 is hydrogen; and

R 7 is alkyl.

31. The compound according to claim 24 , wherein R 6 and R 8 are each independently alkyl.

32. The compound according to claim 24 , wherein R 7 is selected from an amino or an alkoxy selected from the group represented by Formula III:

wherein:

A is selected from O and NR 20 ;

n is selected from 0, 1, 2, 3, 4 and 5;

B is selected from —C(O)N(R h ) 2 —, —S(O) 2 N(R h ) 2 —, —C(O)—, —S(O) 2 —, —C(O)O—, wherein each R h is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen;

R 20 is selected from C 1 -C 6 (C 1 -C 6 ) alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and

with the proviso that if A is O and B is —C(O)NH—, then R 20 is not an unsaturated cycloalkyl.

33. The compound according to claim 32 , wherein R 6 and R 8 are each independently alkyl.

34. A pharmaceutical composition comprising a compound according to claim 24 and a pharmaceutically acceptable carrier.

Assignments (7)