Heterobicyclic and tricyclic nitric oxide synthase inhibitors

A compound having the formula:

• 145
• and salts, pharmaceutically acceptable esters, and prodrugs thereof, wherein:
• R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, OR5, SR5, S(O)R5, S(O)2R5, C(O)R6, carboalkoxyalkyl, heterocyclyl, aromatic hydrocarbon and cycloalkyl, all of which may be optionally substituted by one or more of the groups selected from lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, P(R5)3, C(O) R5, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, NR5SO2R6, CONR5R6, PO(OR5)(OR6), amidino, and guanidino, wherein all said substituents may be optionally substituted with one or more selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, PO(OR5)(OR6), C(O)R6, carboalkoxyalkyl, cyano, nitro, amidino, and guanidino, wherein R5 and R6 of SO2NR5R6 and NR5SO2R6 may be taken together to form a N-containing heterocycle, optionally substituted by one or more selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, and carboxyalkyl;
• R1 may be
• 146
• wherein J is selected from the group consisting of O, S and NR;
• R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aromatic hydrocarbon, alkylaryl, alkylheterocycle, all of which may be optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro;
• NR and R20 may optionally form a heterocycle;
• R16 is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol., lower thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R6, carboalkoxyalkyl, CONR5R6, S(O)R5, S(O)2R5, SO2NR5R6, NR5SO2R6 PO(OR5)(OR6), amidino, and guanidino, wherein all said substituents may be optionally substituted with one or more of the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, S(O)R8, S(O)2R8, S(O)R10, S(O)2R10, SO2NR8R9, NR8SO2, PO(OR8)(OR9), amidino, and guanidino.
• R17 is selected from the group consisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocycle, aromatic hydrocarbon, alkylaryl, and alkylheterocycle, all except hydrogen may be optionally substituted by one or more of alkyl, hydroxy, alkoxy, thiol, alkylthiol, halogen, haloalkyl, carboxyl, cyano, amino, and nitro;
• R18 is selected from the group consisting of hydrogen, hydroxyl, R12, S(O)R11, SO2R11, CH2OC(O)—R11, and C(O)—R11 wherein C(O)—R11;
• R18 and R20 may be taken together to form a 5- or 6- membered heterocyclic ring containing two or more heteroatoms which may be optionally substituted by one or more of R16;
• R2 and L may be taken together to form a 3 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
• R2 and R17 may be taken together to form a 4 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
• R2 and R18 may be taken together to form a 6 to 9 membered heterocyclic ring which may be optionally substituted by one or more of R16;
• L and R17 may be taken together to form a 3 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
• L and R18 may be taken together to form a 4 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
• R17 and R18 and may be taken together to form a 4 to 9 membered heterocyclic ring which may be optionally substituted by one or more of R16;
• R17 and Q may be taken together to form a 3 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
• R18 and Q may be taken together to form a 4 to 9 membered heterocyclic ring which may be optionally by one or more of R16;
• R17 and R20 and may be taken together to form a 5 to 9 membered heterocyclic ring which may be optionally substituted by one or more of R16;
• R19 is hydrogen, R11, or C(O)—R11;
• R11 is selected from the group consisting of hydrogen, hydroxyl, alkenyl, alkynyl, heterocyclyl, aromatic hydrocarbon, cycloalkyl, dihydropyridyl, alkyl, alkylthiol, alkoxy, amino, and cycloalkoxy, which may be optionally substituted with one or more of amino, carboxyl, carboxamide, thioalkyl, aromatic hydrocarbon, alkyl, alkylaryl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, heterocyclyl, alkylheterocycle, and alkylthiol, which may be optionally substituted with one or more of hydroxy, amino, guanidino, iminoalkyl;
• R12 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkbyl, heterocycle, and aromatic hydrocarbon, all may be optionally substituted by one or more alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro, cyano, or amino groups;
• R20 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aromatic hydrocarbon, heterocycle, alkylaryl, and alkylheterocycle, which may be optionally substituted by one or more of halogen, haloalkyl, cyano, nitro, —CO2R, and —COR;
• R20 may also be selected from the group consisting of alkylhydroxy, alkylpolyhydrox)y, alkyl(poly)oxyacyl, CH2C(=O)OR12, CH2C(=O)NHR12, CH2OC(=O)R12, and CH2OC(=O)VR12, wherein the CH2 may be optionally substituted by one or more of lower alkyl, cycloalkyl, heterocycle, aromatic hydrocarbon, amidino, guanidino, CO2H, amino, hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;
• V is selected from the group consisting of O, S, CH2, CHR12, C(R12)2, NH, and NR12;
• R2, R3, R4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aromatic hydrocarbon, heterocyclyl, C(O)R6, carboalkoxyalkyl, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, NR5SO2R6, CONR5R6, PO(OR5)(OR6), halogen, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylarino, alkylaminoaryl, acylamino, carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano, aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl, carboxyaldehyde, and haloalkyl, wherein all said substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R6, carboalkoxyalkyl, CONR5R6, NR5SO2R6, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro, C(O)NR5OR5,OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, PO(OR5)(OR6), amidino, and guanidino, wherein all said substitutions may be optionally substituted with one or more of the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, NR5SO2, PO(OR5)(OR6), amidino, and guanidino;
• G is selected from the group consisting of NR5, O, S, SO, SO2, (CH2)p, and CH=CH, wherein p is 0 to 6;
• A is selected from the group consisting of NR5, O, S, SO, SO2, (CH2)q, and CH=CH, q is 0to 6;
• B is selected from the group consisting of NR5, O, S, SO, SO2, (CH2)v, and CH=CH, v is 0 to 6;
• R1 and R2 may optionally be taken together to form an alicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and said optionally formed ring may be optionally substituted with one or more selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, PO(OR5)(OR6), amidino, and guanidino;
• R2 and R3 may optionally be taken together to form an alicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and said optionally formed ring may be optionally substituted with one or more selected from the group consisting of, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, CONR5R6, NR5SO2R6, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, PO(OR5)(OR6), amidino, and guanidino, wherein all said substitutions may be optionally substituted with one or more of the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, NR5SO2, PO(OR5)(OR6), amidino, and guanidino.
• L and Q are independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, heterocyclyl, cycloalkyl, aromatic hydrocarbon, and (CH2)m—M—(CH2)n—, —(CH2)k—, wherein all said substituents may optionally be substituted by one or more lower alkyl, lower alkenyl, lower alkynyl, C(O)R6, carboalkoxyalkyl, OR5, SR5, S(O)R5, S(O)2R5, SO2NR5R6, NR5SO2R6, C(O)R5, heterocyclyl, halogen, nitro, cyano, haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl, lactamyl, amidino, isourea, isothiourea, guanidino, and substituted guanidino;
• k is 0 to 8;
• m is 0 to 7;
• n is 0 to 5;
• M is selected from the group consisting of cycloalkyl, heterocyclyl, aromatic hydrocarbon, O, S, SO, SO2, SO2NR5, NR5SO2, NR5, POOR5, PON(R5)2, POOR5NR5, NR5POOR5, C(O), C(O)O, Se, SeO, SeO2, C(O)NR13, and SiE2, wherein R13 is selected from the group consisting of hydrogen, lower alkyl, alkaryl, heterocyclyl, COR14, and CO2R14 wherein R14 is lower alkyl or aromatic hydrocarbon;
• E is lower alkyl or aryl;
• L and R2 may be taken together to form a lower alkylidene;
• R5 is selected from the group consisting of hydrogen, halogen lower alkyl, aromatic hydrocarbon, and alkylaryl, wherein all said substituents may be optionally substituted by one or more carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;
• R6 is selected from the group consisting of hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein all said substituents may be optionally substituted by one or more carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;
• R7 is selected from the group consisting of hydroxy, alkoxy, and aryloxyl;
• X is selected from the group consisting of O, S, C(=O), C(=S), C=C(R11)2, S(=O), SO2, and C(R11)2;
• Y is a bond, or is selected from the group consisting of O, S, C(=O), C(=S), C=C(R11)2, S(=O), SO2, and C(R111)2;
• Z is selected from the group consisting of O, S, C(=O), C(=S), C=C(R11)2, S(=O), SO2, and C(R11)2.