Granted Patent B2

US 8,686,009 · App. 12/823,102 · Granted Apr 1, 2014

Abstract

Claims (120)

1. A compound of Formula XVII, XVIII or XIX:

and the geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof;

wherein F 1 is R 5 -A-Cy 1 -B-D-;

wherein, A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —S—, —O—, —S(O)—, —S(O) 2 —, —S[C(R 30 )(R 31 )] u —, —S(O)[C(R 30 )(R 31 )] u —, —S(O) 2 [C(R 30 )(R 31 )] u —, —O[C(R 30 )(R 31 )] u —, —N(R 30 )—, —N(R 30 [C(R 31 )(R 32 )] u —, —[C(R 30 )(R 31 )] u , —C(O)[C(R 30 )(R 31 )] u —;

wherein each u is independently 1, 2, 3, 4, 5, 6 or 7;

Cy 1 is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

B is absent, or a linker;

D is selected from —O—, —NR 33 , —C(R 34 )(R 35 )—S—, —S(O)—, —S(O) 2 —, —C(O)—;

each R 5 , R 30 , R 31 , R 32 , R 33 , R 34 , and R 35 is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

each R 10 and R 11 is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 10 and R 11 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;

R 1 is selected from —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)NR 20 R 21 , —(C(R A )(R B ))—OPO 3 MY, —(C(R A )(R B ))—OP(O)(OR 20 )(OR 21 ), —[C(R A )(R B )O] z —R 20 , —[C(R A )(R B )O] z —C(O)OR 20 , —[C(R A )(R B )O] z —C(O)R 20 , —[C(R A )(R B )O] z —C(O)NR 20 R 21 , —[C(R A )(R B )O] z —OPO 3 MY, —[C(R A )(R B )O] z —P(O) 2 (OR 20 )M and —[C(R A )(R B )O] z —P(O)(OR 20 )(OR 21 );

wherein z is 2 or 3;

wherein each R A and R B is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and,

Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation;

wherein the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic.

2. A compound having the formula:

or a pharmaceutically acceptable salt thereof;

wherein Cy 2 is an optionally substituted heterocyclic ring;

X 5 is selected from absent, —S—, —O—, —S(O)—, —S(O) 2 —, —N(R 10 )—, —C(O)—, —C(OR 10 )(R 11 )—, —[C(R 10 )(R 11 )] v —,—O[C(R 10 )(R 11 )] v —,—O[C(R 10 )(R 11 )] v O—,—S[C(R 10 )(R 11 )] v O—, ——S[C(R 10 )(R 11 )] v —, —C(O)[C(R 10 )(R 11 )] v —, and —C(R 10 )(R 11 )═C(R 10 )(R 11 )—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

each R 10 and R 11 is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 10 and R 11 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;

R 1 is selected from —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)R 20 , —C(R A )(R B )—OC(O)NR 20 R 21 , —(C(R A )(R B ))—OPO 3 MY, —(C(R A )(R B ))—OP(O)(OR 20 )(OR 21 ), —[C(R A )(R B )O] z —R 20 , —[C(R A )(R B )O] z —C(O)OR 20 , —[C(R A )(R B )O] z —C(O)R 20 , —[C(R A )(R B )O] z —C(O)NR 20 R 21 , —[C(R A )(R B )O] z —OPO 3 MY, —[C(R A )(R B )O] z —P(O) 2 (OR 20 )M and —[C(R A )(R B ) 0 ] z —P(O)(OR 20 )(OR 21 );

wherein z is 2 or 3;

wherein each R A and R B is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and,

Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.

3. A compound having the formula XXIV, XXV or XXVI, or a pharmaceutically acceptable salt thereof:

wherein R 1 is selected from —C(R A )(R B )—OR 20 , —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)R 20 , —C(R A )(R B )—OC(O)NR 20 R 21 , —(C(R A )(R B ))—OPO 3 MY, —(C(R A )(R B ))—OP(O)(OR 20 )(OR 21 ), —[C(R A )(R B )O] z —R 20 , —[C(R A )(R B )O] z —C(O)OR 20 , —[C(R A )(R B )O] z —C(O)R 20 , —[C(R A )(R B )O] z —C(O)NR 20 R 21 , —[C(R A )(R B )O] z —OPO 3 MY, —[C(R A )(R B )O] z —P(O) 2 (OR 20 )M and —[C(R A )(R B )O] z —P(O)(OR 20 )(OR 21 );

wherein z is 2 or 3;

wherein each R A and R B is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and,

Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.

4. A compound of claim 3 , wherein R 1 is selected from table 1 or a pharmaceutically acceptable salt thereof;

TABLE 1

5. A compound having the formula XXVII, XXVIII or XXIX:

or a pharmaceutically acceptable salt thereof;

wherein R 1 is selected from —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)R 20 , —C(R A )(R B )—OC(O)NR 20 R 21 , —(C(R A )(R B )) —OPO 3 MY, —(C(R A )(R B ))—OP(O)(OR 20 )(OR 21 ), —[C(R A )(R B )O] z —R 20 , —[C(R A )(R B )O] z —C(O)OR 20 , —[C(R A )(R B )O] z —C(O)R 20 , —[C(R A )(R B )O] z —C(O)NR 20 R 21 , —[C(R A )(R B )O] z —OPO 3 MY, —[C(R A )(R B )O] z —P(O) 2 (OR 20 )M and —[C(R A )(R B )O] z —P(O)(OR 20 )(OR 21 );

wherein z is 2 or 3;

wherein each R A and R B is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and,

Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation;

wherein the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic.

6. A compound selected from Table G or a pharmaceutically acceptable salt thereof:

TABLE G

No.

Structure

1000.

1001.

1002.

1003.

1004.

1005.

1006.

1007.

1008.

1009.

1010.

1011.

1012.

1013.

1014.

1015.

1016.

1017.

1018.

1019.

1020.

1021.

1022.

1023.

1024.

1025.

1026.

1027.

1028.

1029.

1030.

1031.

1032.

1033.

1034.

1035.

1036.

1037.

1038.

1039.

1040.

1041.

7. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from table 1:

TABLE 1

8. A compound of claim 5 , wherein R 1 is selected from table 2 or a pharmaceutically acceptable salt thereof:

TABLE 2

9. A compound of claim 5 , wherein R 1 is selected from table 3 or a pharmaceutically acceptable salt thereof:

TABLE 3

10. A compound of claim 5 , wherein R 1 is selected from table 4 or a pharmaceutically acceptable salt thereof:

TABLE 4

11. A compound of claim 2 , wherein R 1 is —C(R A )(R B )—OC(O)OR 20 ; wherein R 20 is C 7 -C 24 alkyl, C 7 -C 24 alkenyl or C 7 -C 24 alkynyl, or a pharmaceutically acceptable salt thereof.

12. A compound of claim 2 , wherein R 1 is —C(R A )(R B )—OC(O)R 20 ; wherein R 20 is C 7 -C 24 alkyl, C 7 -C 24 alkenyl or C 7 -C 24 alkynyl, or a pharmaceutically acceptable salt thereof.

13. A compound of claim 3 , wherein R 1 is —C(R A )(R B )—OC(O)OR 20 ; wherein R 20 is C 7 -C 24 alkyl, C 7 -C 24 alkenyl or C 7 -C 24 alkynyl, or a pharmaceutically acceptable salt thereof.

14. A compound of claim 3 , wherein R 1 is —C(R A )(R B )—OC(O)R 20 ; wherein R 20 is C 7 -C 24 alkyl, C 7 -C 24 alkenyl or C 7 -C 24 alkynyl, or a pharmaceutically acceptable salt thereof.

15. A compound of Formula XVII, XVIII or XIX:

and the geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof;

wherein F 1 is R 5 -A- Cy 1 —B-D-;

wherein, A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —S—, —O—, —S(O)—, —S(O) 2 —, —S[C(R 30 )(R 31 )] u —, —S(O)[C(R 30 )(R 31 )] u —, —S(O) 2 [C(R 30 )(R 31 )] u —, —O[C(R 30 )(R 31 )] u —,—N(R 30 )—, —N(R 30 )[C(R 31 )(R 32 )] u —, —[C(R 30 )(R 31 )] u , —C(O)[C(R 30 )(R 31 )] u —;

wherein each u is independently 1, 2, 3, 4, 5, 6 or 7;

Cy 1 is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

B is absent, or a linker;

D is selected from absent, —O—, —NR 33 , —C(R 34 )(R 35 )—,—S—, —S(O)—, —S(O) 2 —,—C(O)—;

each R 5 , R 30 , R 31 , R 32 , R 33 , R 34 , and R 35 is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;

each R 10 and R 11 is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 10 and R 11 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;

R 1 is —C(R A )(R B )—OC(O)R 20 ;

wherein R A and R B are independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

R 20 is C 7 -C 24 alkyl, C 7 -C 24 alkenyl or C 7 -C 24 alkynyl;

wherein the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic.

16. A compound of claim 3 , wherein R 1 is selected from Table 2 or a pharmaceutically acceptable salt thereof:

TABLE 2

17. A compound of claim 3 , wherein R 1 is selected from Table 3 or a pharmaceutically acceptable salt thereof:

TABLE 3

18. A compound of claim 3 , wherein R 1 is selected from Table 4 or a pharmaceutically acceptable salt thereof:

TABLE 4

Assignments (9)