Novel compounds useful for bradykinin B1 receptor antagonism

A method of preventing or treating conditions which benefit from inhibition of the bradykinin B1 receptor, comprising:

• administering to a host in need thereof a composition comprising a therapeutically effective amount of at least one compound of formula (I),
• or pharmaceutically acceptable salts thereof, wherein
• R1 is selected from formulae (IIa), (IIb), (IIc), (IId), (IIe), (IIf), and (IIg);
• (IIa) is
• R15, R20, and R25 are independently selected from hydrogen, alkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, and —(CH2)0-6-T;
• T is a monocyclic or bicyclic ring system of 5, 6, 7, 8, 9, 10, 11, or 12 atoms, wherein at least one bond in the monocyclic or bicyclic ring system is optionally a double bond, wherein the bicyclic ring system is optionally a fused or spiro ring system, wherein at least one ring in the monocyclic or bicyclic ring system is optionally aromatic, wherein at least one carbon atom in the monocyclic or bicyclic ring system is optionally replaced by a group independently selected from —O—, —C(O)—, —S(O)0-2—, —C(═N—R6)—, —N—, —NR6—, —N((CO)0-1R26)—, and —N(SO2R26)—;
• wherein R15, R20, and R25 are independently optionally substituted with at least one R26 group;
• R26 is selected from NO2, CN, halogen, alkyl (optionally substituted with at least one halogen), alkoxy (optionally substituted with at least one halogen), alkylenedioxy (optionally substituted with at least one halogen), benzyloxy, phenyl, —NH2, —OH, —CF3, alkylamino, dialkylamino, oxo, —C(O)R27, —COOR27, —C(O)NR27R27′, —NR27C(O)R27′, alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each of which is optionally substituted with at least one group independently selected from halogen, —NH2, —OH, —CN, —CF3, alkylamino, haloalkyl, oxo, alkoxy, alkoxyalkyl, benzyloxy, alkyl, dialkylamino, —C(O)R27, —COOR27, —C(O)NR27R27′, and NR27C(O)R27′;
• R27 and R27′ are independently selected from H, alkyl, aryl and heteroaryl, each of which is optionally substituted with at least one group independently selected from alkyl, halogen, alkoxy, OH, amino, monoalkylamino, dialkylamino, and CF3;
• (IIb) is
• R30 and R40 are independently selected from H, —CO2H and —CO2alkyl;
• R35 is phenyl optionally substituted with at least one halogen;
• A′ is selected from —(CH2)0-2—, —C(O)—, and —S(O)0-2—;
• R45 is selected from azabicycloalkyl, azatricycloalkyl, bicycloalkyl, tricycloalkyl, and phenyl substituted at the 2-position with a group selected from
• (a) alkyl optionally substituted with at least one group independently selected from amino, amino-alkoxy, phenylthio, alkyl-phenylthio, dialkylamino-alkoxy, alkylamino-alkoxy, alkylamino, di-alkylamino, hydroxy, alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, alkylenedioxy, acyloxy, oxo, morpholino, alkylaminocarbonyl-acylamino, alkoxycarbonyl-acylamino, alkoxycarbonylpiperazinyl, acylpiperazinyl, alkylthio, heterocyclic-alkoxy, (dialkylamino)(cycloalkyl)alkoxy, (alkylamino)(cycloalkyl)alkoxy, (amino)(cycloalkyl)alkoxy, phenylthio, and acylamino;
• (b) alkoxy or alkylthio, wherein the alkoxy or alkylthio is optionally substituted with at least one group independently selected from amino, amino-alkoxy, phenylthio, alkyl-phenylthio, di-alkylamino-alkoxy, alkylamino-alkoxy, alkylamino, dialkylamino, hydroxy, alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, alkylenedioxy, acyloxy, oxo, morpholino, alkylaminocarbonyl-acylmino, alkoxycarbonyl-acylamino, alkoxycarbonylpiperazinyl, acylpiperazinyl, alkylthio, heterocyclic-alkoxy, (dialkylamino)(cycloalkyl)alkoxy, (alkylamino)(cycloalkyl)alkoxy and (amino)(cycloalkyl)alkoxy;
• (c) amino, alkylamino, acylamino, aminoacetylamino, alkylsulfonylamino, halosubstituted-alkylsulfonylamino, halosubstituted-alkylamino and alkoxycarbonylaminoacetylamino;
• (d) piperazinylcarbonyl, morpholinocarbony, nitro, cyano, hydroxy, alkylsulfonyl, alkylsulfinyl and di-alkylaminosulphenyl;
• (e) alkylthio, acylthio, amino-acylthio, alkylsulfonylthio, halosubstituted-alkylthio and alkoxyaminoacetylthio;
• and
• (f) azacycloalkyl optionally substituted with at least one group independently selected from oxo and alkyl;
• (IIc) is
• U is selected from alkyl and alkyl-O-alkyl;
• R50 is selected from hydrogen and alkyl optionally substituted with at least one group independently selected from halogen, amide, and phenyl;
• R55 is selected from hydrogen, alkyl, aryl, alkylaryl, and —(CH2)0-6-T;
• wherein R55 is optionally substituted with at least one R26 group;
• (IId) is
• m is 0, 1, or 2;
• n is 0, 1, 2, or 3;
• R60 and R65 are independently selected from H and alkyl;
• or
• R60 and R65 together form an aryl or heteroaryl ring optionally substituted with at least one group independently selected from halogen, —NH2, —OH, —CN, —CF3, alkylamino, oxo, alkoxy, dialkylamino, —C(O)R27, —COOR27, —C(O)NR27R27′, —NR27C(O)R27′, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is optionally substituted with at least one group independently selected from halogen, —NH2, —OH, —CN, —CF3, -alkylamino, haloalkyl, oxo, alkoxy, alkoxyalkyl, alkyl, dialkylamino, —C(O)R27, —COOR27, —C(O)NR27R27′, and NR27C(O)R27′;
• R70 is selected from hydrogen, alkyl, aryl, alkylaryl, and (CH2)0-6-T;
• wherein R70 is optionally substituted with at least one R26 group;
• (IIe) is
• V is —(CH2)1-7—C(O)—;
• W is selected from —NHC(O)—, —NHC(O)—(CH2)0-4aryl(CH2)0-4—, NHC(O)—(CH2)0-4aryl-C(O)—, —NHC(O)NH(CH2)0-4aryl(CH2)0-4—, —NHC(O)NH(CH2)0-4aryl-C(O)—, —OC(O)—, —OC(O)NH(CH2)0-4aryl(CH2)0-4—, —OC(O)NH(CH2)0-4aryl-C(O)—, —(CH2)1-3—C(O)—, —(CH2)1-3—C(O)—NH(CH2)0-4aryl(CH2)0-4—, and —(CH2)1-3—C(O)—NH(CH2)0-4aryl-C(O)—;
• R80 is selected from alkyl (optionally substituted with at least one halogen), alkyloxy-, alkyl, -alkyl-cycloalkyl, -alkylaryl, aryl, heteroaryl, and -alkylheteroaryl, wherein the aryl or heteroaryl is optionally substituted with at least one group independently selected from alkyl (optionally substituted with at least one halogen), alkyloxy-, alkylcarboxy-, alkylamido-, OH, halogen, nitro, amino, and cyano, or
• R80 is selected from formula (IIIa) and (IIIb),
• R81 and R81′ are independently selected from H, alkyl (optionally substituted with at least one halogen), alkyloxy-, -alkylaryl, aryl, -alkylcycloalkyl, and cycloalkyl;
• R85 and R85′ are independently selected from H, NO2, halogen, cyano, OH, amino, alkylthio-, alkyl (optionally substituted with at least one halogen), alkyloxy-, -alkylaryl, aryl, -alkylheteroaryl, heteroaryl, —C(O)—(CH2)0-2aryl, —C(O)—(CH2)0-2heteroaryl, —C(O)—O-aryl, —C(O)—O-heteroaryl, —C(O)—NH—(CH2)0-2aryl, —C(O)—NH(CH2)0-2heteroaryl, —C(O)—N(alkyl)-(CH2)0-2aryl, and —C(O)—N(alkyl)(CH2)0-2heteroaryl, wherein the aryl or heteroaryl is optionally substituted with at least one group independently selected from alkyl, alkyloxy-, alkylcarboxy-, alkylamido-, OH, halogen, nitro, amino, and cyano;
• R90 is selected from H, alkyl (optionally substituted with at least one halogen), alkyloxy-, -alkylaryl, -alkyl-cycloalkyl, and cycloalkyl;
• (IIf) is
• R100 and R100′ are independently selected from H and alkyl;
• R105 is selected from alkyl (optionally substituted with at least one group independently selected from hydroxyethyl, halogen, nitro, cyano, —OR111, —SR111, —COR111, —SO2R112, —CO2R111, —OC(O)R111, —NR113R114, —NR113C(O)R111, —NR113CO2R111, —C(O)NR113R114, and cycloalkyl), cycloalkyl (optionally substituted with at least one group independently selected from halogen, nitro, cyano and phenyl), (CH2)0-2-aryl (optionally substituted with at least one group independently selected from halogen, nitro, cyano, OR111, SR111, CO2R111, alkyl and haloalkyl), —(CH2)0-2-T (optionally substituted with at least one group independently selected from halogen, nitro, cyano, OR111, SR111, alkyl and haloalkyl), —CO2R111, and —C(O)NR113R114;
• R110 and R110′ are independently selected from hydrogen, halogen, and alkyl optionally substituted with at least one group independently selected from halogen, OR111, OC(O)R111, S(O)0-2R112, OS(O)2R112, and NR100R100′, or
• R110 and R110′ together with the carbon atom to which they are both attached form an exo-cyclic methylene optionally substituted with at least one group selected from alkyl (optionally substituted with at least one halogen) and alkyloxy;
• R111 is selected from hydrogen, alkyl (optionally substituted with at least one halogen), phenyl (optionally substituted with at least one group independently selected from halogen, cyano, nitro, OH, alkyloxy, cycloalkyl and alkyl optionally substituted with at least one halogen), cycloalkyl, and pyridyl optionally substituted with at least one group independently selected from halogen and alkyl;
• R112 is selected from alkyl (optionally substituted with at least one halogen), alkyloxy, and phenyl optionally substituted with at least one group independently selected from halogen, cyano, nitro, OH, alkyloxy, cycloalkyl and alkyl optionally substituted with at least one halogen;
• R113 and R114 are independently selected from hydrogen, alkyl (optionally substituted with at least one group independently selected from halogen, amino, monoalkylamino, dialkylamino, and SO2R112), —(CH2)0-2-phenyl (optionally substituted with at least one group independently selected from halogen, cyano, nitro, OH, alkyloxy, cycloalkyl and alkyl (optionally substituted with at least one halogen)), and cycloalkyl;
• or
• R113 and R114 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered ring wherein at least one carbon atom within the ring is optionally replaced with a group selected from —N—, —NR26—, —S—, and —O—;
• or
• R113 and R114 together with the nitrogen atom to which they are attached form a cyclic imide;
• (IIg) is
• D is selected from —(CH2)0-6C(O)—, —(CH2)0-6NR121C(O)—, —(CH2)0-6NR121—, —(CH2)0-6O—, —C(O)—, —(CH2)0-6CO2—, —(CH2)0-6S(O)0-2—, —(CH2)0-6S—, —HC═CH—, and —(CH2)0-6—;
• R120 is selected from hydrogen, alkyl (optionally substituted with at least one halogen), -alkyl-aryl, —S(O)0-2R123′, cycloalkyl, —(CH2)0-6C(O)R123, —(CH2)0-6CO2R123, and —(CH2)0-6C(O)NR121R121′;
• R121 and R121′ are independently selected from hydrogen, alkyl (optionally substituted with at least one halogen), cycloalkyl, and aryl optionally substituted with at least one group independently selected from alkyl, halogen, nitro, cyano, OH, —O-alkyl (optionally substituted with at least one halogen), —C(O)OR122, —C(O)NR122R122′, and —NR122R122′;
• or
• R121 and R121′ and the nitrogen atom to which they are attached together form a 4, 5, 6, or 7 membered ring, optionally;
• comprising a heteroatom selected from —O—, —S—, and —N(R6)—;
• R122 is selected from hydrogen and alkyl;
• R123 is selected from hydrogen, alkyl (optionally substituted with at least one halogen), cycloalkyl, aryl (optionally substituted with at least one group independently selected from alkyl, halogen, nitro, cyano, —OH, O-alkyl (optionally substituted with at least one halogen), and NR121R121′), and heteroaryl optionally substituted with at least one group independently selected from alkyl, halogen, nitro, cyano, —OH, O-alkyl (optionally substituted with at least one halogen), and NR121R121′;
• R123′ is selected from alkyl (optionally substituted with at least one halogen), cycloalkyl, aryl (optionally substituted with at least one group independently selected from alkyl, halogen, nitro, cyano, —OH, O-alkyl (optionally substituted with at least one halogen), and NR121R121′), and heteroaryl optionally substituted with at least one group independently selected from alkyl, halogen, nitro, cyano, OH, O-alkyl (optionally substituted with at least one halogen), and NR121R121′;
• R125 is selected from —(CH2)1-6CO2R123, —(CH2)1-6C(O)NR121R121′, —S(O)0-2R123, —C(O)R123, —CO2R123, and alkyl (optionally substituted with at least one group independently selected from halogen, cyano, and aryl (optionally substituted with at least one group independently selected from halogen, cyano, —OR123, —NR121R121′, —C(O)NR121R121′, and phenyl optionally substituted with at least one group independently selected from —CO2R123, halogen, nitro, cyano, —OR123, and NR121R121′));
• R2 is selected from hydrogen, heterocycloalkyl, heteroaryl, and aryl, wherein the heterocycloalky, heteroaryl, and aryl groups within R2 are each optionally substituted with at least one R105 group;
• L is —[C(R3)(R4)]0-3—, wherein R3 and R4 at each occurrence are independently selected from H and alkyl;
• Q is selected from formulae (IVa), (IVb), (IVc), and (IVd);
• (IVa) is
• wherein A and B are independently selected from —CH— and —N—;
• R5 is selected from H, heterocycloalkyl, and heteroaryl;
• (IVb) is
• R6 is selected from H and alkyl;
• (IVc) is
• wherein the cyclic ring in formula (IIc) optionally contains at least one double bond;
• wherein X is selected from —CH2—, —N—, and —N(R7)—;
• Y is selected from —NH—, —O—, —S(O)0-2—, N(R7)(R8), and —C(R9)(R10)—;
• or X and Y together form a fused aromatic ring;
• and
• (IVd) is
• Z is selected from —CH2— and —C(O)—;
• R7 and R8 each independently are selected from H and alkyl;
• R9 and R10 each independently are selected from H and phenyl.