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Compounds Useful as Antagonists of CCR2

  • US 20090197884A1
  • Filed: 10/26/2006
  • Published: 08/06/2009
  • Est. Priority Date: 11/01/2005
  • Status: Active Grant
First Claim
Patent Images

1. A compound of formula I:

  • or a pharmaceutically acceptable salt thereof, wherein;

    n is 1 or 2;

    Y is —

    Y1-Y2

    , or —

    Y3-Y4

    wherein;

    Y1 is —

    SO2N(R′

    )—

    , —

    C(O)N(R′

    )—

    ;



    C(O)N(R′

    )C(O)—

    , —

    N(R′

    )SO2

    , or —

    N(R′

    )SO2N(R′

    )—

    ,Y2 is absent or is an optionally substituted C1-6 alkylene chain, wherein one or two methylene units of Y2 are optionally and independently interrupted by —

    O—

    , —

    S—

    , —

    N(R′

    )—

    , —

    C(O)—

    , —

    OC(O)—

    , —

    C(O)O—

    , —

    S(O)—

    , —

    S(O)2

    , —

    C(O)N(R′

    )—

    , —

    N(R′

    )C(O)—

    , —

    N(R′

    )C(O)N(R′

    )—

    , —

    N(R′

    )C(O)O—

    , —

    OC(O)N(R′

    )—

    , —

    N(R′

    )S(O)2

    , or —

    S(O)2N(R′

    )—

    , or wherein Y2, or a portion thereof, is an optionally substituted ring selected from 3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-membered aryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

    Y3 is —

    N(R′

    )C(O)—

    , —

    NR′

    C(O)N(R′

    )—

    , —

    N(R′

    )C(O)O—

    ; and

    Y4 is an optionally substituted C1-6 alkylene chain, wherein one or two methylene units of Y4 are optionally and independently interrupted by —

    O—

    , —

    S—

    , —

    N(R′

    )—

    , —

    C(O)—

    , —

    OC(O)—

    , —

    C(O)O—

    , —

    S(O)—

    , —

    S(O)2

    , —

    C(O)N(R′

    )—

    , —

    N(R′

    )C(O)—

    , —

    N(R′

    )C(O)N(R′

    )—

    , —

    N(R′

    )C(O)O—

    , —

    OC(O)N(R′

    )—

    , —

    N(R′

    )S(O)2

    , or —

    S(O)2N(R′

    )—

    ,each R′

    is independently hydrogen or optionally substituted C1-6aliphatic;

    R1 is an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

    ring A is substituted at one or more carbon atoms with m independent occurrences of R2;

    m is 0-6;

    each occurrence of R2 is independently halogen, ═

    O, ═

    S, —

    CN, —

    R2b, —

    N(R2a)2, —

    OR2a, —

    SR2b, —

    S(O)2R2b, —

    C(O)R2a, —

    C(O)OR2a, —

    C(O)N(R2a)2, —

    S(O)2N(R2a)2, —

    OC(O)N(R2a)2, —

    N(R′

    )C(O)R2a, —

    N(R′

    )SO2R2b, —

    N(R′

    )C(O)OR2a, —

    N(R′

    )C(O)N(R2a)2, or —

    N(R′

    )SO2N(R2a)2, or two occurrences of R2a or R2b are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R2a, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

    each occurrence of R2a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

    each occurrence of R2b is independently an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

    ring B is substituted with r independent occurrences of —

    R3;

    r is 0-6;

    each occurrence of R3 is independently —

    R3a, -T1-R3d, or —

    V1-T1-R3d, wherein;

    each occurrence of —

    R3a independently halogen, —

    CN, —

    NO2, —

    R3c, —

    N(R3b)2, —

    OR3b, —

    SR3c, —

    S(O)2R3c, —

    C(O)R3b, —

    C(O)OR3b, —

    C(O)N(R3b)2, —

    S(O)2N(R3b)2, —

    OC(O)N(R3b)2, —

    N(R′

    )C(O)R3b, —

    N(R′

    )SO2R3c, —

    N(R′

    )C(O)OR3b, —

    N(R′

    )C(O)N(R3b)2, or —

    N(R′

    )SO2N(R3b)2, or two occurences of R3b or R3c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R3b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

    each occurrence of R3b is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

    each occurrence of R3c is independently an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 611-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

    each occurrence of R3d is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

    each occurrence of V1 is independently —

    C(R′

    )═

    C(R′

    )—

    , —

    C≡

    C—

    , —

    N(R′

    )—

    , —

    O—

    , —

    S—

    , —

    S(O)—

    , —

    S(O)—

    , —

    C(O)—

    , —

    C(O)O—

    , —

    C(O)N(R′

    )—

    , —

    S(O)2N(R′

    )—

    , —

    OC(O)N(R′

    )—

    , —

    N(R′

    )C(O)—

    , —

    N(R′

    )SO2

    , —

    N(R′

    )C(O)O—

    , —

    NR′

    C(O)N(R′

    )—

    , —

    N(R′

    )SO2N(R′

    )—

    , —

    OC(O)—

    , or —

    C(O)N(R′

    )O—

    ;

    each occurrence of T1 is independently C1-6 alkylene chain optionally substituted with R3a, wherein the alkylene chain optionally is interrupted by —

    C(R′

    )═

    C(R′

    )—

    , —

    C≡

    C—

    , —

    N(R′

    )—

    , —

    O—

    , —

    S—

    , —

    S(O)—

    , —

    S(O)2

    , —

    C(O)—

    , —

    C(O)O—

    , —

    C(O)N(R′

    )—

    , —

    S(O)2N(R′

    )—

    , —

    OC(O)N(R′

    )—

    , —

    N(R′

    )C(O)—

    , —

    N(R′

    )SO2

    , —

    N(R′

    )C(O)O—

    , —

    NR′

    C(O)N(R′

    )—

    , —

    N(R′

    )SO2N(R′

    )—

    , —

    OC(O)—

    , or —

    C(O)N(R′

    )—

    O—

    or wherein T1 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;

    X is —

    O—

    , —

    S—

    , —

    SO2

    , or —

    N(W—

    R4)—

    ;

    W is absent or is a group selected from —

    W1-L2-W2

    , wherein W1 and W2 are each independently absent or are an optionally substituted C1-3alkylene chain, and L2 is absent or is a group selected from —

    N(R)—

    , —

    O—

    , —

    S—

    , —

    S(O)—

    , —

    S(O)2

    , —

    C(O)—

    , —

    C(O)O—

    , —

    C(O)N(R)—

    , —

    S(O)2N(R)—

    , —

    OC(O)N(R)—

    , —

    N(R)C(O)—

    , —

    N(R)SO2

    , —

    N(R)C(O)O—

    , —

    N(R)C(O)N(R)—

    , —

    N(R)SO2N(R)—

    , —

    OC(O)—

    , or —

    C(O)N(R)—

    O—

    , wherein R is hydrogen or C1-C4alkyl, provided that if W1 is absent then L2 is selected from —

    C(O)—

    , —

    C(O)O—

    , —

    C(O)O—

    , —

    S(O)—

    , —

    S(O)2

    , —

    C(O)N(R)—

    , or —

    S(O)2N(R)—

    R4 is an optionally substituted monocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, provided that the compound is other than;

    a) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α

    -(cyclohexylmethyl)-γ

    -oxo-;

    b) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-thiopyran-4-yl)-3-pyrrolidinyl]-α

    -(cyclohexylmethyl)-γ

    -oxo-;

    c) 4-Morpholinecarboxamide, N-[(1S)-2-[[3-cyano-1-(1-methyl-4-piperidinyl)-3-pyrrolidinyl]amino]-1-(cyclohexylmethyl)-2-oxoethyl]-;

    d) 4-Morpholinebutanamide, N[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α

    -(cyclohexylmethyl)-γ

    -oxo;

    e) Benzeneacetamide, N-[(3S)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-, monohydrochloride;

    f) Benzeneacetamide, 3,4-difluoro-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride;

    g) Benzeneacetamide, 3,4-difluoro-α

    -1-methylethyl)-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride;

    h) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α

    -(1-methylethyl), (α

    S)—

    ;

    i) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α

    -(1-methylethyl)-, (α

    R)-;

    j) Benzeneacetamide, N-[1′

    -(2-cyanophenyl)[1,4′

    -bipiperidin]-3-yl]-3,4-difluoro-;

    k) [1,4′

    -Bipiperidine]-3-carboxamide, N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-1′

    -propyl-;

    l) [1,4′

    -Bipiperidine]-3-carboxamide, N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-1′

    -(phenylmethyl)-;

    m) [1,4′

    -Bipiperidine]-3-carboxamide, 1′

    -[[2,6-bis(4-chlorophenyl)-4-pyridinyl]carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-, (3R)-;

    n) Benzeneacetamide, N-[1′

    -(2-cyanophenyl)[1,4′

    -bipiperidin]-3-yl]-3,4-difluoro-, monohydrochloride; and

    o) Benzeneacetamide, N-[1′

    -(2-cyanophenyl)[1,4′

    -bipiperidin]-3-yl]-3,4-difluoro-.

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