IP Library › Granted Patent US 6,965,033

Granted Patent B2

US 6,965,033 · App. 09/747,182 · Granted Nov 15, 2005

Bisamidate phosphonate prodrugs

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Patent No.: US 6,965,033
App. No.: 09/747,182
Granted: Nov 15, 2005
Kind: B2

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Abstract

Novel bisamidate phosphonate prodrugs of FBPase inhibitors of the Formula IA: and their use in the treatment of diabetes and other conditions associated with elevated blood glucose.

Claims (220)

1. A compound of formula IA:

wherein M is R 5 —X—,

wherein:

R 5 is represented by the formula

wherein:

each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;

A is selected from the group consisting of —H, —NR 4 2 , —CONR 4 2 , —CO 2 R 3 , halo, —S(O)R 3 , —SO 2 R 3 , alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4 2 , —CH 2 CN, —CN, —C(S)NH 2 , —OR 2 , —SR 2 , —N 3 , —NHC(S)NR 4 2 , —NHAc, and null;

each B is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 9 2 , —OR 3 , —SR 3 , perhaloalkyl, halo, —NO 2 , and null, all except —H, —CN, perhaloalkyl, —NO 2 , and halo are optionally substituted;

J is selected from the group consisting of —H and null;

X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there are 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2 2 ;

R 2 is selected from the group consisting of R 3 and —H;

R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R 4 is independently selected from the group consisting of —H and alkyl or, together, R 4 and R 4 form a cyclic alkyl group;

each R 9 is independently selected from the group consisting of —H, alkyl, aryl, aralkyl, and alicyclic or, together, R 9 and R 9 form a cyclic alkyl group;

R 11 is selected from the group consisting of alkyl, aryl, —NR 2 2 , and —OR 2 ;

each R 12 and R 13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R 12 and R 13 together are connected via 2-6 atoms, optionally including 1-2 heteroatoms selected from the group consisting of O, N and S, to form a cyclic group;

each R 14 is independently selected from the group consisting of —OR 17 , —N(R 17 ) 2 , —NHR 17 , —NR 2 OR 19 and —SR 17 ;

R 15 is selected from the group consisting of —H, lower alkyl, lower aryl, lower aralkyl, or together with R 16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;

R 16 is selected from the group consisting of —(CR 12 R 13 ) n —C(O)—R 14 , —H, lower alkyl, lower aryl, lower aralkyl, or together with R 15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;

each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17 and R 17 on N are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;

R 18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group;

each R 19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 ;

and with the proviso that:

1) at least one of A and B, is not —H or null;

2) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;

or a pharmaceutically acceptable salt thereof.

2. The compounds of claim 1 wherein R 5 is selected from the group consisting of pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, and 1,3-selenazolyl, all of which contain at least one substituent.

3. The compounds of claim 1 wherein

A is selected from the group consisting of —H, —NR 4 2 , —CONR 4 2 , —CO 2 R 3 , halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4 2 , CH 2 CN, —CN, —C(S)NH 2 , —OR 2 , —SR 2 , —N 3 , —NHC(S)NR 4 2 , —NHAc, and null;

each B and D is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 9 2 , —OR 3 , —SR 3 , perhaloalkyl, halo, and null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted;

E is selected from the group consisting of —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl, —C(O)OR 3 , —CONR 4 2 , —CN, —NR 9 2 , —OR 3 , —SR 3 , C1-C6 perhaloalkyl, halo, and null, all except —H, —CN, perhaloalkyl, and halo are optionally substituted; and

each R 4 is independently selected from the group consisting of —H and C1-C2 alkyl.

4. The compounds of claim 1 wherein R 5 is selected from the group consisting of:

wherein

A″ is selected from the group consisting of —H, —NR 4 2 , —CONR 4 2 , —CO 2 R 3 , halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, —CH 2 OH, —CH 2 NR 4 2 , —CH 2 CN, —CN, —C(S)NH 2 , —OR 2 , —SR 2 , —N 3 , —NHC(S)NR 4 2 , and —NHAc;

B″ is independently selected from the group consisting of —H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, aralkyl, alkoxyalkyl, —C(O)R 11 , —C(O)SR 3 , —SO 2 R 11 , —S(O)R 3 , —CN, —NR 9 2 , —OR 3 , —SR 3 , perhaloalkyl, and halo, all except —H, —CN, perhaloalkyl, and halo are optionally substituted; and

each R 4 is independently selected from the group consisting of —H and C1-C2 alkyl.

5. The compounds of claim 1 wherein X is selected from the group consisting of -heteroaryl-, -alkylcarbanylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-.

6. The compounds of claim 1 wherein said compound is a compound of formulae II, III, or IV:

7. The compounds of claim 4 wherein X is selected from the group consisting of -heteroaryl-, -alkoxyalkyl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-.

8. The compounds of claim 1 wherein

n is 1;

R 12 and R 13 are independently selected from the group consisting of —H, lower alkyl, lower perhaloalkyl, and lower aryl, optionally substituted with —OR 19 , —NR 19 2 , —SR 19 , —C(O)NR 2 R 3 , halo, —CO 2 R 2 , 3-indolyl, 4-imidazolyl, or guanidinyl, or R 12 and R 13 are connected via 2-5 carbon atoms to form a cycloalkyl group;

R 14 is selected from the group consisting of —OR 17 , —SR 17 , and —NR 2 OR 19

R 15 and R 16 are independently selected from the group consisting of —H and C1-C6 alkyl, or together R 15 and R 16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N and S;

R 17 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, 3,4-(methylenedioxy)phenyl and benzyl, wherein said phenyl, indolyl, 3,4-(methylenedioxy)phenyl and benzyl may be optionally substituted with 1-3 groups selected from the group of —CO 2 R 2 , —OR 2 , —NHC(O)R 3 , halo and lower alkyl; and

R 18 is selected from the group consisting of —H, C1-C6 alkyl and benzyl.

9. The compounds of claim 1 wherein R 18 is selected from the group consisting of —H and C1-C6 alkyl.

10. The compounds of claim 9 wherein R 18 is selected from the group consisting of —H and methyl.

11. The compounds of claim 10 wherein R 18 is —H.

12. The compounds of claim 1 wherein each R 12 and R 13 is independently selected from the group consisting of —H, lower alkyl, lower perhaloalkyl, lower aralkyl, and lower aryl, all optionally substituted with —OR 19 , —NR 19 2 , —SR 19 , —C(O)NR 2 R 3 , halo, —CO 2 R 2 , 3-indolyl, 4-imidazolyl, or guanidinyl or, together, R 12 and R 13 are connected via 2-5 carbon atoms to form a cycloalkyl group.

13. The compounds of claim 12 wherein each R 12 and R 13 is independently selected from the group consisting of —H, C1-C4 alkyl, —CH 2 —O—C(CH 3 ) 3 , phenyl, and benzyl or, together, R 12 and R 13 are connected via 2 or 4 carbon atoms to form a cyclopropyl or cyclopentyl group.

14. The compounds of claim 13 wherein each R 12 and R 13 is independently selected from the group consisting of —H, and methyl or, together, R 12 and R 13 are connected via 4 carbon atoms to form a cyclopentyl group.

15. The compounds of claim 13 wherein R 12 and R 13 are both —H, both methyl, or R 12 is H and R 13 is selected from the group consisting of methyl, i-propyl, and benzyl.

16. The compounds of claim 15 wherein n is 1, and R 12 is —H, then the carbon attached to R 12 and R 13 has S stereochemistry.

17. The compounds of claim 1 wherein n is an integer of from 1-2.

18. The compounds of claim 17 wherein n is 1.

19. The compounds of claim 1 wherein each R 14 is independently selected from the group consisting of —OR 17 , —SR 17 , and —NR 2 OR 19 , and R 17 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, 3,4-(methylenedioxy)phenyl and benzyl, wherein said phenyl, indolyl, 3,4-(methylenedioxy)phenyl and benzyl may be optionally substituted with 1-3 groups selected from the group consisting of —CO 2 R 2 , —OR 2 , —NHC(O)R 3 , halo, and lower alkyl.

20. The compounds of claim 19 wherein R 14 is —OR 17 .

21. The compounds of claim 20 , wherein R 17 is selected from the group consisting of methyl, ethyl, i-propyl, n-propyl, t-butyl, isobutyl, neopentyl, cyclopentyl, and unsubstituted benzyl.

22. The compounds of claim 1 wherein R 15 and R 16 are independently selected from the group consisting of —H and C1-C6 alkyl or, together, R 15 and R 16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S.

23. The compounds of claim 22 wherein —NR 15 R 16 is selected from the group consisting of morpholinyl and pyrrolidinyl.

24. The compounds of claim 1 wherein R 16 is —(CR 12 R 13 ) n —C(O)—R 14 , and each n is 1.

25. The compounds of claim 1 wherein

n is 1;

R 12 and R 13 are independently selected from the group consisting of —H, lower alkyl, lower perhaloalkyl, and lower aryl, optionally substituted with —OR 19 , —NR 19 2 , —SR 19 , —C(O)NR 2 R 3 , halo, —CO 2 R 2 , 3-indolyl, 4-imidazolyl, and guanidinyl, or R 12 and R 13 are connected via 2-5 carbon atoms to form a cycloalkyl group;

R 14 is selected from the group consisting of —OR 17, —SR 17 , and —NR 2 OR 19 ;

R 15 is selected from the group consisting of —H and C1-C6 alkyl;

R 16 is selected from the group consisting of —H, C1-C6 alkyl, and —(CR 12 R 13 ) n —C(O)—R 14 or, together, R 15 and R 16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of N, O and S;

R 17 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, 3,4-(methylenedioxy)phenyl, and benzyl, wherein said phenyl, indolyl, 3,4-(methylenedioxy)phenyl, and benzyl may be optionally substituted with 1-3 groups selected from the group of —CO 2 R 2 , —OR 3 , —NHC(O)R 3 , halo, and lower alkyl; and

R 18 is selected from the consisting of —H, C1-C6 alkyl, and benzyl.

26. The compounds of claim 25 that are of the formula:

27. The compounds of claim 26 wherein n is 1.

28. The compounds of claim 27 wherein when R 12 and R 13 are not the same, then R 18 HN—CR 12 R 13 —C(O)—R 14 is an ester or thioester of a naturally occurring amino acid; and R 14 is selected from the group consisting of —OR 17 and —SR 17 .

29. The compounds of claim 4 wherein

A″ is selected from the group consisting of —NH 2 , —CONH 2 , halo, —CH 3 , —CF 3 , —CH 2 -halo, —CN, —OCH 3 , —SCH 3 , and —H;

B″ is selected from the group consisting of —H, —C(O)R 11 , —C(O)SR 3 , alkyl, aryl, alicyclic, halo, —CN, —SR 3 , OR 3 , and —NR 2 ;

X is selected from the group consisting of -heteroaryl-, -alkoxycarbonyl-, and -alkylaminocarbonyl-, all optionally substituted;

R 2 is selected from the group consisting of R 3 and —H;

R 3 is selected from the group consisting of C1-C4 alkyl, C4-C6 aryl, C2-C7 alicyclic, and C5-C7 aralkyl, wherein said aryl, alicyclic, and aralkyl may be optionally substituted with 1-2 heteroatoms;

each R 12 and R 13 is independently selected from the group consisting of —H, C1-C4 alkyl, —CH 2 —O—C(CH 3 ) 3 , phenyl, and benzyl or, together, R 12 and R 13 are connected via 2 or 4 carbon atoms to form a cyclopropyl or cyclopentyl group;

n is 1;

each R 14 is independently selected from the group consisting of —OR 17 , —SR 17 , and —NR 2 OR 19 ;

R 15 is selected from the group consisting of —H, methyl, ethyl, and propyl;

R 16 is —(CR 12 R 13 ) n —C(O)—R 14 ;

R 17 is selected from the group consisting of C1-C7 alkyl, phenyl, indolyl, and benzyl, wherein said phenyl, indolyl, and benzyl may be optionally substituted with 1-3 groups selected from the group consisting of —CO 2 R 2 , —OR 3 , —NHC(O)R 3 , halo, and lower alkyl;

R 18 is selected from the group consisting of —H and methyl; and

R 19 is selected from the group of —H, C1-C4 alkyl, C4-C6 aryl, C2-C7 alicyclic, C5-C7 aralkyl, and —COR 3 .

30. The compounds of claim 29 wherein

is selected from the group consisting of

wherein R 17 is selected from group consisting of ethyl, i-propyl, n-propyl, and neopentyl.

31. The compounds of claim 30 wherein C* has S stereochemistry.

32. The compounds of claim 29 wherein R 5 is

X is selected from the group consisting of methylenoxycarbonyl, and furan-2,5-diyl, or a pharmaceutically acceptable salt thereof.

33. The compounds of claim 32 wherein A″ is —NH 2 , X is furan-2,5-diyl, and B″ is —S(CH 2 ) 2 CH 3 .

34. The compounds of claim 32 wherein A″ is —NH 2 , X is furan-2,5-diyl, and B″ is —CH 2 —CH(CH 3 ) 2 .

35. The compounds of claim 32 wherein A″ is —NH 2 , X is furan-2,5-diyl, and B″ is —COOEt.

36. The compounds of claim 32 wherein A″ is —NH 2 , X is furan-2,5-diyl, and B″ is —SMe.

37. The compounds of claim 32 wherein A″ is —NH 2 , X is methyleneoxycarbonyl, and B″ is —CH(CH 3 ) 2 .

38. The compounds of claim 33 wherein

wherein R 17 is selected from the group consisting of ethyl, i-propyl, n-propyl, and neopentyl.

39. The compounds of claim 33 wherein

and wherein C* has S stereochemistry and wherein R 17 is selected from the group consisting of ethyl, i-propyl, n-propyl, and neopentyl.

40. The compounds of claim 34 wherein

41. The compounds of claim 34 wherein

wherein C* has S stereochemistry.

42. The compounds of claim 41 that are selected from the group consisting of a hydrochloride salt, a hydrobromide salt, an acetic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a p-toluenesulfonic acid salt, and maleic acid salt.

43. The compounds of claim 34 wherein

wherein R 17 is ethyl, n-propyl, i-propyl, and neopentyl and wherein C* has S stereochemistry.

44. The compounds of claim 43 that are selected from the group consisting of a hydrochloride salt, a hydrobromide salt, an acetic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a p-toluenesulfonic acid salt, and a maleic acid salt.

45. The compounds of claim 34 wherein

wherein R 12 and R 13 together form a cyclopentyl group.

46. The compounds of claim 45 that are selected from the group consisting of a hydrochloride salt, a hydrobromide salt, an acetic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a p-toluenesulfonic acid salt, and a maleic acid salt.

47. The compounds of claim 36 wherein

wherein C* has S sterochemistry.

48. The compounds of claim 47 that are selected from the group consisting of a hydrochloride salt, a hydrobromide salt, an acetic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a p-toluenesulfonic acid salt, and a maleic acid salt.

49. The compounds of claim 29 wherein R 5 is

X is selected from the group consisting of furan-2,5-diyl, and methyleneoxycarbonyl, A″ is —NH 2 , and pharmaceutically acceptable salts thereof.

50. The compounds of claim 49 wherein X is furan-2,5-diyl and B″ is —SCH 2 CH 2 CH 3 .

51. A method of treating diabetes comprising administering to an animal a pharmaceutically effective amount of a compound of formula (I):

wherein R 5 is represented by the formula:

wherein:

each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;

J is selected from the group consisting of —H and null;

X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there are 2 heteroatoms, measured by the shortest path between R 3 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2 2 ;

n is an integer from 1 to 3;

R 2 is selected from the group consisting of R 3 and —H;

R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R 4 is independently selected from the group consisting of —H and alkyl or, together, R 4 and R 4 form a cyclic alkyl group;

each R 9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic or, together, R 9 and R 9 form a cyclic alkyl group;

R 11 is selected from the group consisting of alkyl, aryl, —NR 2 2 , and —OR 2 ;

each R 14 is independently selected from the group consisting of —OR 17 , —N(R 17 ) 2 , —NHR 17 , —NR 2 OR 19 and —SR 17 ;

R 15 is selected from the group consisting of —H, lower alkyl, lower aryl, and lower aralkyl or, together, with R 16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;

R 16 is selected from the group consisting of —(CR 12 R 13 ) n —C(O)—R 14 , —H, lower alkyl, lower aryl, and lower aralkyl or, together, with R 13 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;

R 18 is independently selected from the group consisting of H, lower alkyl, aryl, and aralkyl or, together, with R 12 is connected via 1-4 carbon atoms to form a cyclic group;

each R 19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 ;

and with the provisos that:

1) at least one of A and B is not selected from the group consisting of —H or null;

2) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;

or a pharmaceutically acceptable salt thereof.

52. A method of treating complications of diabetes or cardiovascular diseases in an animal comprising administering to said animal a pharmaceutically effective amount of a compound of formula (I):

wherein R 5 represented by the formula:

wherein:

each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;

J is selected from the group consisting of —H and null;

X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2 2 ;

n is an integer from 1 to 3;

R 2 is selected from the group consisting of R 3 and —H;

R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R 4 is independently selected from the group consisting of —H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group;

each R 9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group;

R 11 is selected from the group consisting of alkyl, aryl, —NR 2 2 , and —OR 2 ;

each R 14 is independently selected from the group consisting of —OR 17 , —N(R 17 ) 2 , —NHR 17 , —NR 2 OR 19 and —SR 17 ;

each R 17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, all optionally substituted, or together R 17 and R 17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from group consisting of O, N, and S;

R 18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group;

each R 19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 ;

and with the proviso that:

1) at least one of A and B is not selected from the group consisting of —H or null;

2) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;

or a pharmaceutically acceptable salt thereof.

53. A method of lowering blood glucose comprising administering to an animal a pharmaceutically effective amount of compound of formula (I):

wherein R 5 represented by the formula:

wherein:

each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;

J is selected from the group consisting of —H and null;

X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2 2 ;

n is an integer from 1 to 3;

R 2 is selected from the group consisting of R 3 and —H;

R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R 4 is independently selected from the group consisting of —H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group;

each R 9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group;

R 11 is selected from the group consisting of alkyl, aryl, —NR 2 2 , and —OR 2 ;

each R 14 is independently selected from the group consisting of —OR 17 , —N(R 17 ) 2 , —NHR 17 , —NR 2 OR 19 and —SR 17 ;

R 18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group;

each R 19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 ;

and with the proviso that:

1) at least one of A and B is not selected from the group consisting of —H or null;

2) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;

and pharmaceutically acceptable salts thereof.

54. A method of treating glycogen storage diseases, by administering to a patient a pharmaceutically effective amount of a compound of formula (I):

wherein R 5 is selected from the group consisting of:

wherein

each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;

J is selected from the group consisting of —H and null;

X is an optionally substituted linking group that links R 5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R 5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with —COOR 2 , —SO 3 H, or —PO 3 R 2 2 ;

n is an integer from 1 to 3;

R 2 is selected from the group consisting of R 3 and —H;

R 3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

each R 4 is independently selected from the group consisting of —H, and alkyl, or together R 4 and R 4 form a cyclic alkyl group;

each R 9 is independently selected from the group consisting of —H, alkyl, aralkyl, and alicyclic, or together R 9 and R 9 form a cyclic alkyl group;

R 11 is selected from the group consisting of alkyl, aryl, —NR 2 2 , and —OR 2 ;

each R 14 is independently selected from the group consisting of —OR 17 , —N(R 17 ) 2 , —NHR 17 , —NR 2 OR 19 and —SR 17 ;

R 18 is independently selected, from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R 12 is connected via 1-4 carbon atoms to form a cyclic group;

each R 19 is independently selected from the group consisting of —H, lower alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR 3 ;

and with the proviso that:

1) at least one of A and B is not selected from the group consisting of —H or null;

2) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;

and pharmaceutically acceptable salts thereof.

55. A method of inhibiting gluconeogenesis in an animal comprising administering to said animal a pharmaceutically effective amount of a compound of claim 1 .

Assignments (1)

SECURITY INTEREST Recorded Oct 18, 2023

From: CYDEX PHARMACEUTICALS, INC.; LIGAND PHARMACEUTICALS INCORPORATED; METABASIS THERAPEUTICS, INC.; PFENEX INC.

To: CITIBANK, N.A., AS ADMINISTRATIVE AGENT

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