Pyrrolo[2,1-c][1,2,4] thiadiazoles and Pyrollo[2,1-c][1,12,4]oxadiazoles useful as nitric oxide synthase inhibitors

A compound having the formula:

• or pharmaceutically acceptable salts 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, aryl 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, 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, aryl, hydroxy, lower alkoxy, aryloxy, mercaptoalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, carboxy, and carboxyalkyl;
• R1 may be
• 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, aryl, alkylaryl, alkylheterocyclyl, 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, aryl, hydroxy, lower alkoxy, aryloxy, mercaptoalkyl, mercaptoalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, 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, aryl, hydroxy, lower alkoxy, aryloxy, mercaptoalkyl, mercaptoalkoxy, 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, heterocyclyl, aryl, alkylaryl, and alkylheterocyclyl, all except hydrogen may be optionally substituted by one or more of alkyl, hydroxy, alkoxy, mercaptoalkyl, 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, aryl, cycloalkyl, dihydropyridyl, alkyl, mercaptoalkyl, alkoxy, amino, and cycloalkoxy, which may be optionally substituted with one or more of amino, carboxyl, carboxamide, aryl, alkyl, alkylaryl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, heterocyclyl, alkylheterocyclyl, and mercaptoalkyl, 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, cycloalkyl, heterocyclyl, and aryl, all 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, aryl, heterocyclyl, alkylaryl, and alkylheterocyclyl, 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, alkylpolyhydroxy, 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, heterocyclyl, aryl, amidino, guanidino, CO2H, amino, hydroxy, 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, aryl, 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, arylamino, alkylaminoaryl, 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, mercaptoalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, carboxy, carboxyalkyl, C(O)R6, carboalkoxyalkyl, CONR5R6, NR5SO2R6, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, 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, aryl, hydroxy, lower alkoxy, aryloxy, mercaptoalkoxy, 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 (CH2)p, wherein p is 0 to 3;
• A is (CH2)q, wherein q is 0 to 3;
• B is (CH2)v, wherein v is 0 to 3,
• with the proviso that the sum of p, q, and v is three;
• R1 and R2 may optionally be taken together to form an alicyclic hydrocarbon, heterocycle 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, aryl, 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, heterocycle 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, carboxy, carboxyalkyl, CONR5R6, NR5SO2R6, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, 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, aryl, hydroxy, lower alkoxy, aryloxy, mercaptoalkoxy, 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, aryl, 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, aryl , lactonyl, lactamyl, amidino, 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, aryl, 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 aryl;
• 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, aryl, and alkylaryl, wherein all said substituents may be optionally substituted by one or more carboalkoxy, 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, aryl and alkylaryl wherein all said substituents may be optionally substituted by one or more carboalkoxy, amino, hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo, cyano, nitro, and carboxyalkyl;
• R7 is selected from the group consisting of hydroxy, alkoxy, and aryloxyl;
• X is selected from the group consisting of C(═O), and C(═S);
• Y is a bond;
• Z is selected from the group consisting of O and S.