Biaryl compounds as serine protease inhibitors

Compound having the structure (I) shown below:

• pharmaceutically acceptable salts thereof;
• Each E1 is a 5 to 7 membered saturated or unsaturated carbon ring, bicyclic saturated or unsaturated carbon ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(O2) which may be saturated or unsaturated;
• wherein L is pyridine ring
• R is —CH═CH—R2, —C≡C—R2, —C(R2)═CH2, —C(R2)═C(R3), —CH═NR2, —C(R2)═N—R3, 4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R1, R2, or R3, these R, R1, R2, or R3 do not include —(C2-4 alkenyl)-CO2—C1-8 alkyl, —(C2-4 alkenyl)-CO2—C1-8 alkyl-phenyl, and —(C2-4 alkenyl)-CO2—C1-8 alkyl-O—C1-4 alkyl;
• R1 is H, —R, —NO2, —CN, -halo, —N3, —C1-8 alkyl, —(CH2)nCO2R2, —C2-8 alkenyl-CO2R2, —O(CH2)nCO2R2, —C(O)NR2R3, —P(O)(OR2)2, alkyl substituted tetrazol-5-yl, —(CH2)nO(CH2)n aryl, —NR2R3, —(CH2)n OR2, —(CH2)n SR2, —N(R2)C(O)R3, —S(O2)NR2R3, —N(R2)S(O2)R3, —(CHR2)n NR2R3, —C(O)R3, (CH2)n N(R3)C(O)R3, —N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (CH2)n-phenyl, or substituted or unsubstituted (CH2)n-heterocycle which may be saturated or unsaturated;
• m is 1 except that when E1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring;
• R2 is H, -halo, -alkyl, -haloalkyl, —(CH2)n-phenyl, —(CH2)1-3-biphenyl, —(CH2)1-4-Ph-N(SO2—C1-2-alkyl)2, —CO(CHR1)n—OR1, —(CHR1)n-heterocycle, —(CHR1)n—NH—CO—R1, —(CHR1)n-NH—SO2R1, —(CHR1)n-Ph-N(SO2—C1-2-alkyl)2, —(CHR1)n—C(O)(CHR1)—NHR1, —(CHR1)n—C(S)(CHR1)—NHR1, —(CH2)nO(CH2)nCH3, —CF3, —C2-5 acyl, —(CHR1)nOH, —(CHR1)nCO2R1, —(CHR1)n—O-alkyl, —(CHR1)n—O—(CH2)n—O-alkyl, —(CHR1)n—S-alkyl, —(CHR1)n—S(O)-alkyl, —(CHR1)n—S(O2)-alkyl, —(CHR1)n—S(O2)—NHR3, —(CHR3)n—N3, —(CHR3)nNHR4, 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated;
• When n is more than 1, the substitutions R1 and R3 may be same or different;
• R3 is H, —OH, —CN, substituted alkyl, —C2-8 alkenyl, substituted or unsubstituted cycloalkyl, —N(R1)R2, or 5-6 membered saturated substituted or unsubstituted hetero ring.
• —NR2R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring;
• wherein said ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted;
• W is a direct bond, —CHR2—, —CH═CR2—, —CR2═CH—, —CR2═CR2—, —C≡C—, —O—CHR2—, —CHR2—O—, —N(R2)—C(O)—, —C(O)—N(R2)—, —N(R2)—CH—(R3)—, —CH2—N(R2)—, —CH(R1)—N(R2)—, —S—CHR2—, —CHR2—S—, —S(O2)—N(R2)—, —C(O)N(R2)—(CHR2)n-, —C(R1R2)n-NR2—, —N(R2)—S(O2)—, —R2C(O)NR2—, —R2NC(O)NR2—, —CONR2CO—, —C(═NR2)NR2—, —NR2C(═NR2)NR2, —NR2O—, —N═NCHR2—, or —C(O)NR2SO2—;
• E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino;
• each X individually is a direct bond, substituted or unsubstituted C1-4 methylene chain, O, S, NR2, S(O), S(O2), or N(O) containing one or two C1-4 substituted or unsubstituted methylene chains;
• X at different places may be same or different;
• B is H, -halo, —CN, —NH2, —(CH2)n—C(═NR4)NHR5, —(CH2)n—NHR4, —(CH2)nNHC(═NR4)NR5, —(CH2)n—OR4, C1-8 substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated;
• B1 is selected from B;
• B1 and B may be same or different;
• There may be more than one similar or different R2 groups present on E2, when E2 is a cyclic of more than 5 atoms;
• p is 1 except that when E2 is a cyclic ring of more than 5 atoms;
• p is 1 or higher depending upon the size of the ring;
• n is 0-4 ;
• A is selected from R1;
• o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring;
• Each V and V1 individually is selected from R1 and N-alkyl substituted carboxamidyl (—CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic;
• N,N-disubstituted carboxamidyl of the formula —CONR1R2 where R1 and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different;
• mono- or disubstituted sulfonamides of the formula SO2NHR or —SO2NR1R2;
• and methylene- or polymethylene chain-extended variants thereof;
• Each R4 and R5 individually is H, —(CH2)nOH, —C(O)OR6, —C(O)SR6, —(CH2)n C(O)NR7R8, —O—C(O)—O—R7, an amino acid or a dipeptide;
• Each R6 is H, R7, —C(R7)(R8)—(CH2)n—O—C(O)—R9, —(CH2)n—C(R7)(R8)—O—C(O)R9, —(CH2)n—C(R7)(R8)—O—C(O)—O—R9, or —C(R7)(R8)—(CH2)n—O—C(O)—O—R9;
• and
• Each R7, R8 and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2CO2alkyl.