Patent EA-003147-B1 (EA)
Title: N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
Inventor: KO SOO S
IPC: C07D211/28
Filed: 1999-12-17
Abstract: ) piperidinyl] methyl] cyclohexyl]-urea, N-(2,4-di1. A compound of formula (I): or stereoisomers or fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(3,4,5-trimethoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]-urea, N-(3,5-dimethylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]-urea, N- (3-trifluoromethyl-4-chlorophenyl)-N'- [ (1R, 2S)-2 [ [ (3S)-3- (4-fluorophenyl) methyl) piperidinyl] methyl] cycfrom O and S; E is selected from: ring A is a C3-6[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(4-ethoxyphenyl)-N'-[(1R,2Sdependently selected from H, C1-6 alkyl, C2-8 alke methyl] cyclohexyl]urea, N-(4-thiomethylphenyl)-N)rC3-10 carbocyclic residue substituted with 0-5R<A>; R<A> at each occurrence, is selected from C1-6 alkyl, C2-8alkenyl, C2-8 alkynyl, (CH2) rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, N02, CN, (CH2)rNnyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyR<C>, (CH2)rC (O) R<B>, (CH2)rC (O) NR<B>R<B>, (CHchloropyridin-4-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluoC>, (CH2)rCH(=NR<B>)NR<B>R<B>, (CH2)rNHC(=NR<B>)NR<B>R<B>, (CH2)rS(O)pR<C>, (CH2)rS(O)2NR<B>R<B>, (Cluorophenyl) methyl) piperidinyl] methyl] cyclohexch occurrence, is selected from H, C1-6 alkyl, C3-3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl; alternatively, R<2> and R<3> join to forridinyl] methyl] cyclohexyl]urea, N-(4-(methylsulfonyl)phenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenycarbocyclic residue substituted with 0-5 R<15> and-(3-(methylsulfonyl)phenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-[2-((1H)-pyrrol-1-yl)phenyl]-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(1,3-benzodioxol-5-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(1-ace, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)qC (O) R<4B>, (CH2)qC (O) NR<4>R<4A'>, (CH2)qC (O) OR<4B>, and a (CH2)r-C3-10 carbocyclic residue substituted with 0-3 R<4C> ; R<4A> and R<4A'>, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl; R<4B>, at (3S)-3- (4- fluorophenyl) methyl) piperidinyl] me8 alkenyl, (CH2)rC3-6 cycloalkyl, C2-8 alkynyl, an)phenyl)-N'-[(1R,2S)-2-[[(3S) 3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(4ycloalkyl, Cl, F, Br, I, CN, NO2, (CF2) rCF3, (CH2luorophenyl) methyl) piperidinyl] methyl] cyclohexrNR<4A>R<4'> and (CH2)rphenyl; alternatively, R<4> joins with R<7>, R<9>, R<11>, or R<14> to form a 5, 6 or 7 membered piperidinium spirocycle or pyrr3R)-3-(4-fluorophenyl) methyl) piperidinyl] methyl5> is selected from a (CR<5>'R<5>")t-C3-10 carbocyclic residue substituted with 0-5 R<16> and a (CR< methyl) piperidinyl] methyl] cyclohexyl]urea, N-(ining 1-4 heteroatoms selected from N, O, and S, shenyl) methyl) piperidinyl] methyl] cyclohexyl]ureh occurrence, are selected from H, C1-6 alkyl, (CH)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] rrence, is selected from C1-6 alkyl, C2-8 alkenyl,R,2S)-2-[[(3S)-3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(4-fluoro-3-methylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(3-)rOC(O)R<6B>, (CH2)rS (O) pR<6B>, (CH2)rS(O)2NR<6Afluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(4-chloro-3-methylphenyl)-N'-[(1R,2S)-t each occurrence, are selected from H, C1-6 alkylethyl] cyclohexyl]-urea, N-(4-(N-methylcarboxamide)phenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) m C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R<6C>; R<6C>, at each occurrence, is s methyl) piperidinyl] methyl] cyclohexyl]urea, N-(quinolin-5-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(quinolin-6-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluoralkyl, and C3-6 cycloalkyl; with the proviso that when either of J or K is CR<6>R<6> and R<6> is hal-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(isoquinolin-5-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(4-(sulfonamide)phenyl)-N7> selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR<7D>, (CH2)q-5-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) met (O) R<7B>, (CH2)qNR<7A>C(O)R<7A>, (CH2)qNR<7A>C(O)H, (CH2)rC(O)NR<7A>R<7A'>, (CH2)rC (O) OR<7B>, (Cuorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(3-hydroxy-4-methylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(2-methyl-benzothiazol-5-clic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R<7C>; R<7A> oxylphenyl)methyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorH, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rCrea, N-((4-fluorophenyl)methyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl]red heterocyclic system containing 1-4 heteroatoms1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperid<7E>; R<7B>, at each occurrence, is selected from thyl]-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(1-ace, and a (CH2)r-5-6 membered heterocyclic system cohenyl) methyl) piperidinyl] methyl] cyclohexyl]ure, substituted with 0-3 R<7E>; R<7C>, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, methyl] cyclohexyl]urea, N-(3-acetyl-4-hydroxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(4-(piperidin-1-yl)phenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluor)rC(O)NR<7F>R<7F>, (CH2)rC (O) OC1-4 alkyl, (CH2)rrea, N-(cyclohexyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl](O)2NR<7F>R<7F>, (CH2)rNR<7F>S (O)2R<7B>, and (CH24-fluorophenyl) methyl) piperidinyl] methyl] cycloch occurrence, is selected from C1-6 alkyl substit[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(2-ethylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N- (2,4, 6-trimethylphenyCl, F, Br, I, CN, NO2, (CF2) rCF3, (CH2)rOC1-5alkyl, OH, SH, (CH2)rSC1-5alkyl, (CH2) rNR<7F>R<7F>, athoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N> is selected from H, C1-6 alkyl, C3-6 cycloalkyl, methyl) piperidinyl] methyl] cyclohexyl]urea, N-(A>, at each occurrence, is selected from C1-6 alkymethyl) piperidinyl] methyl] cyclohexyl]urea, N-(e, F, Br, I, CN, NO2, (CF2) rCF3, (CH2) rOC1-5 alkyl, OH, SH, (CH2) rSC1-5 alkyl, (CH2) rNR<7F>R<7F>, and (CH2) rphenyl; alternatively, R<7> and R<8> join to form C3-7 cycloalkyl, or =NR<8B>; R<8B> is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, l)-2-methyl-propyl]-N'-[(1R,2S)-2-[[(3S)-3-(4 fluoC1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, N02, CN, (CH2) rOH, (CH2) rSH, (CH2) rOR<9D>, (CH2) rSR<9D>, (CH2) rNR<9A>R<9A>, (CH2) rC(O) OH, (CH2)rC(0)R<9B>, (CH2)rC(O)NR<9A>R<9A'>, (CH2)rNR<9A>C(O)R<9A>, (CH2) rNR<9A>C (o) H, (CH2) rNR<9A>C (O) NHR<9A>, (CH2)rC (O) OR<9B>, (CH2)rOC(O)R<9B>, (CH2)rOC(O)NHR<9A>, (CH2)rS(O)pR<9B>, (CH2)rS (O) 2NR<9A>R<9A'>, (CH2)rNR<9A>S(O)2R<9B>, C1-6haloorophenyl) methyl) piperidinyl] methyl] cyclohexylted with 0-5R<9C>, and a (CH2)r-5-10 membered hete4-fluorophenyl) methyl) piperidinyl] methyl] cyclod from N, O, and S, substituted with 0-3 R<9C>; R<9A> and R<9A'>, at each occurrence, are selected fhyl] cyclohexyl]urea, N-[(1S)-1-(phenyl)ethyl]-N'-H2)r-C3-10 carbocyclic residue substituted with 0-5 R<9E>, and a (CH2) r-5-10 membered heterocyclic l)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N(1-naphthyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N(2-(phenyl)phenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N(pheteroatoms selected from N, O, and S, substituted w) methyl) piperidinyl] methyl] cyclohexyl]urea, N(cted from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, orophenyl) methyl) piperidinyl] methyl] cyclohexyl2, CN, (CH2)rNR<9F>R<9F>, (CH2)rOH, (CH2)rOC1-4 alR,2S)-2-[[(3S) 3- (4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(3-pyridinyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piper>, (CH2) rC (=NR<9F>)NR<9F>R<9F>, (CH2)rS(O) pR<9B>,(CH2) rNHC(=NR<9F>)NR<9F>R<9F>, (CH2)rS(O)2NR<9Fethyl) piperidinyl] methyl] cyclohexyl]urea, N-(2- substituted with 0-3 R<9E>; R<9D>, at each occurrorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(2-methylnaphth-1-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N (4-((lH)-1-propyl-tetrazol-5-yl) phenyl)-N'-[(lR,2S)-2[[(3S)-3-(4- fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N(3-aminophenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluoropheny)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2) rC-(3-(acetylamino)phenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4(CH2)rNR<9F>R<9F>, and (CH2)rphenyl; R<9F>, at each occurrence, is selected from H, C1-6 alkyl, and R,2S)-2-[[(3S-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N(2-nitro-4-methoxyphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) meth>, (CH2)rC(O)OH, (CH2)rC(O)R<10B,>(CH2)rC(O)NR<10Aroxyquinolin-5-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorC (O) H, (CH2) rC (O) OR<10B>, (CH2) rOC (O) R<10Burea, N-(3-methylpyridin-2-yl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] CH2)rC3-10 carbocyclic residue substituted with 0-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclohexyl]urea, N-(3-acetylphenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidind R<10A'>, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)r-C3-10 carbocyclic residue substituted with 0-5 R<10nyl)-N'-[(1R,2R)-2-[[(3S)-3-(4-fluorophenyl) methyl) piperidinyl] methyl] cyclopentyl]urea, N-(3-cyanophenyl)-N'-[(1R,2S)-2-[[(3S)-3-(4-fluorophenyl)