Granted Patent B2

US 8,853,394 · App. 13/708,420 · Granted Oct 7, 2014

Abstract

Claims (246)

1. A compound of the formula A:

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 1 is selected from lower alkyl;

R 2 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 3 is selected from C 1 -C 4 alkyl, lower alkenyl and lower alkynyl, wherein the C 1 -C 4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and

—X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

A is N or C—H;

B is N, C—H, C—(SO 2 —R 4 ), or C—CO—R 4 ;

D is N, C—H, C—(SO 2 —R 4 ) or C—CO—R 4 ;

E is N or C—H;

wherein only one of A, B or E is N, and one of B or D is C—(SO 2 —R 4 ) or C—CO—R 4 ;

R 4 is a group having the formula:

—NH—R 41 ,

—N(R 42 )(R 43 ),

or

—N(R 46 ) 2 ;

R 41 is selected from straight-chain C 3 -C 6 alkyl, branched-chain C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );

R 51 is selected from C 4 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

a is 1 to 6;

R 42 is selected from straight-chain alkyl, branched-chain alkyl, and C 2 -C 6 alkyl-O-alkyl-;

R 43 is selected from C 4 -C 6 alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ), and —(CH 2 ) a —N(R 52 )(R 53 );

R 44 is selected from the group consisting of

—(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 ,

—(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and

—(CH 2 ) r O—(CH 2 ) s —C(O)R 14 ,

each R 11 is independently selected from H, C 3 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, C 2 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

q is 1 to 6:

r is 0 to 6;

s is 0 to 6;

R 45 is selected from the group consisting of

—(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 ,

—(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), and

—(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;

each R 21 is independently selected from H, C 5 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

t is 0 to 6;

v is 1 to 6;

w is 0 to 6;

x is 1 or 2;

y is 1 or 2; and

R 46 are both selected from C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.

2. The compound of claim 1 , having the formula A 1 :

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 1 is selected from lower alkyl;

R 2 is selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 3 is selected from C 1 -C 4 alkyl, lower alkenyl and lower alkynyl, wherein the C 1 -C 4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 4 is a group having the formula:

—NH—R 41 ,

—N(R 42 )(R 43 ),

or

—N(R 46 ) 2 ;

R 41 is selected from straight-chain C 3 -C 6 alkyl, branched-chain C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );

R 51 is selected from C 4 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

a is 1 to 6;

R 42 is selected from straight-chain alkyl, branched-chain alkyl, and C 2 -C 6 alkyl-O-alkyl-;

R 43 is selected from C 4 -C 6 alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ), and —(CH 2 ) a —N(R 52 )(R 53 );

R 44 is selected from the group consisting of

—(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 ,

—(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and

—(CH 2 ) r —O—(CH 2 ) s —C(O)R 14 ,

each R 11 is independently selected from H, C 3 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, C 2 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

q is 1 to 6:

r is 0 to 6;

s is 0 to 6;

R 45 is selected from the group consisting of

-(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 ,

—(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), and

—(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;

each R 21 is independently selected from H, C 5 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

t is 0 to 6;

v is 1 to 6;

w is 0 to 6;

x is 1 or 2;

y is 1 or 2; and

R 46 are both selected from C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.

3. The compound of claim 2 , having the formula A 2 :

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

R 4 is a group having the formula:

—NH—R 41 ,

—N(R 42 )(R 43 ),

or

—N(R 46 ) 2 ;

R 41 is selected from straight-chain C 3 -C 6 alkyl, branched-chain C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );

R 51 is selected from C 4 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

a is 1 to 6;

R 42 is selected from straight-chain alkyl, branched-chain alkyl, and C 2 -C 6 alkyl-O-alkyl-;

R 43 is selected from C 4 -C 6 alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ), and —(CH 2 ) a —N(R 52 )(R 53 );

R 44 is selected from the group consisting of

—(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 ,

—(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and

—(CH 2 ) r O—(CH 2 ) s —C(O)R 14 ,

each R 11 is independently selected from H, C 3 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, C 2 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

q is 1 to 6:

r is 0 to 6;

s is 0 to 6;

R 45 is selected from the group consisting of

—(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 ,

—(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), and

—(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;

each R 21 is independently selected from H, C 5 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

t is 0 to 6;

v is 1 to 6;

w is 0 to 6;

x is 1 or 2;

y is 1 or 2; and

R 46 are both selected from C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.

4. The compound of claim 1 , having the formula B 1 :

wherein,

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 1 is selected from lower alkyl;

R 2 is selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 3 is selected from C 1 -C 4 alkyl, lower alkenyl and lower alkynyl, wherein the C 1 -C 4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 41 is selected from straight-chain C 3 -C 6 alkyl, branched-chain C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );

R 51 is selected from C 4 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, and

a is 1 to 6.

5. The compound of claim 4 , having the formula B 2 :

wherein,

R 41 is selected from straight-chain C 3 -C 6 alkyl, branched-chain C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, —(CH 2 ) a —N(H)(R 51 ) and —(CH 2 ) a —N(R 52 )(R 53 );

R 51 is selected from C 4 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, and

a is 1 to 6.

6. The compound of claim 1 , having a structure selected from the group consisting of:

7. The compound of claim 1 , having the formula C 1 :

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 1 is selected from lower alkyl;

R 2 is selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 3 is selected from C 1 -C 4 alkyl, lower alkenyl and lower alkynyl, wherein the C 1 -C 4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 42 is selected from straight-chain alkyl, branched-chain alkyl, and C 2 -C 6 alkyl-O-alkyl-; and

R 43 is selected from C 4 -C 6 alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ), and —(CH 2 ) a —N(R 52 )(R 53 ).

8. The compound of claim 7 , having the formula C 2 :

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 42 is selected from straight-chain alkyl, branched-chain alkyl, and C 2 -C 6 alkyl-O-alkyl-; and

R 43 is selected from C 4 -C 6 alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, —(CH 2 ) a —N(H)(R 51 ), and —(CH 2 ) a —N(R 52 )(R 53 ).

9. A compound having a structure selected from the group consisting of:

10. The compound of claim 1 , having the formula D 1 :

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 1 is selected from lower alkyl;

R 2 is selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 3 is selected from C 1 -C 4 alkyl, lower alkenyl and lower alkynyl, wherein the C 1 -C 4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 44 is selected from the group consisting of

—(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 ,

—(CH 2 ) r C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and

—(CH 2 ) r O—(CH 2 ) s —C(O)R 14 ,

each R 11 is independently selected from H, C 3 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, C 2 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

q is 1 to 6:

r is 0 to 6;

s is 0 to 6; and

x is 1 or 2.

11. The compound of claim 10 , having the formula D 2 :

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 1 is selected from lower alkyl;

R 2 is selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 3 is selected from C 1 -C 4 alkyl, lower alkenyl and lower alkynyl, wherein the C 1 -C 4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 44 is selected from the group consisting of

—(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 ,

—(CH 2 ) r C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and

—(CH 2 ) r —(CH 2 ) s —C(O)R 14 ,

each R 11 is independently selected from H, C 3 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, C 2 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

q is 1 to 6:

r is 0 to 6; and

s is 0 to 6.

12. The compound of claim 11 , having the formula D 3 :

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 44 is selected from the group consisting of

—(CH 2 ) q —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) q —C(O)R 14 ,

—(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), and

—(CH 2 ) r O—(CH 2 ) s —C(O)R 14 ,

each R 11 is independently selected from H, C 3 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, C 2 -C 6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

q is 1 to 6:

r is 0 to 6; and

s is 0 to 6.

13. The compound of claim 12 , having a structure:

14. The compound of claim 1 , having the formula E 1 :

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 1 is selected from lower alkyl;

R 2 is selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 3 is selected from C 1 -C 4 alkyl, lower alkenyl and lower alkynyl, wherein the C 1 -C 4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 45 is selected from the group consisting of

—(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 ,

—(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), and

—(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;

each R 21 is independently selected from H, C 5 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

t is 0 to 6;

v is 1 to 6; and

w is 0 to 6.

15. The compound of claim 14 , having the formula E 2 :

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 45 is selected from the group consisting of

—(CH 2 ) v —N(R 25 )(R 26 ), —(CH 2 ) v —N(R 21 )—(CH 2 ) w —C(O)R 24 , —(CH 2 ) v —C(O)R 24 ,

—(CH 2 ) t —C(O)—(CH 2 ) w OR 21 , —(CH 2 ) t —C(O)(CH 2 ) w —N(R 22 )(R 23 ), and

—(CH 2 ) v —O—(CH 2 ) w —C(O)R 24 ;

each R 21 is independently selected from H, C 5 -C 6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

each R 24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

t is 0 to 6;

v is 1 to 6; and

w is 0 to 6.

16. A compound of having a structure selected from the group consisting of:

17. The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 1 is selected from lower alkyl;

R 2 is selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

R 3 is selected from C 1 -C 4 alkyl, lower alkenyl and lower alkynyl, wherein the C 1 -C 4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, alkylthio, and —X—C(═O)—R or —C(═O)X—R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group; and

R 46 are both selected from C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.

18. The compound of claim 17 , having the formula:

or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein

R 46 are both selected from C 2 -C 6 alkyl-O—C 2 -C 6 alkyl.

19. A method of treating erectile dysfunction comprising:

administering a therapeutically effective amount of a compound according to any one of claims 1 - 18 in combination with a pharmaceutically acceptable excipient to a patient suffering from erectile dysfunction.

20. A method of treating cardiovascular disorders comprising:

administering a therapeutically effective amount of a compound according to any one of claims 1 - 18 in combination with a pharmaceutically acceptable excipient to a patient suffering from a cardiovascular disorder.

21. The method of claim 20 , wherein the cardiovascular disorder is hypertension.

22. A compound having the structure:

23. A method of treating erectile dysfunction comprising:

administering a therapeutically effective amount of a compound according to claim 22 in combination with a pharmaceutically acceptable excipient to a patient suffering from erectile dysfunction.

24. A method of treating cardiovascular disorders comprising:

administering a therapeutically effective amount of a compound according to claim 22 in combination with a pharmaceutically acceptable excipient to a patient suffering from a cardiovascular disorder.

25. The method of claim 22 , wherein the cardiovascular disorder is hypertension.

Assignments (8)