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SUBSTITUTED HYDROXYETHYLAMINE ASPARTYL PROTEASE INHIBITORS

  • US 20090270367A1
  • Filed: 03/03/2009
  • Published: 10/29/2009
  • Est. Priority Date: 03/09/2004
  • Status: Active Grant
First Claim
Patent Images

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, whereinR1 is selected from wherein X, Y, and Z are independently, selected from—

  • C(H)0-2

    ,—

    O—

    ,—

    C(O)—

    ,—

    NH—

    , and—

    N—

    ,wherein at least one bond of the (IIf) ring may optionally be a double bond;

    L is selected from—

    O—

    ,—

    SO2

    ,—

    C(O)—

    ,—

    C(R55)(R60)—

    , and—

    CH(NR55R60)—

    ;

    R55 and R60 are each independently selected from hydrogen and alkyl;

    R50, R50a, and R50b are independently selected from—

    H,-halogen,—

    OH,—

    C(O)H,—

    C(O)CH3,—

    CH2OH,—

    SH,—

    S(O)0-2CH3,—

    CN,—

    NO2,—

    NH2,—

    NHCH3,—

    N(CH3)2

    C1

    C2 alkyl,—

    OCH2,—

    OCF3, and—

    CF3;

    R2 is selected from—

    H,wherein when R1 is benzyl, and RC is 6-Isopropyl-2,2-dioxo-2λ

    6-isothiochroman-4-yl, R2 is not —

    H;

    wherein, when R1 is 3,5-difluorobenzyl, and RC is 6-Ethyl-2,2-dioxo-2λ

    6-isothiochroman-4-yl, R2 is not —

    H;

    wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2is not —

    H;



    OH,—

    O-alkyl, optionally substituted with at least one group independently selected from R200;



    O-aryl, optionally substituted with at least one group independently selected from R200;

    -alkyl, optionally substituted with at least one group independently selected from R200;



    NH-alkyl, optionally substituted with at least one group independently selected from R200;

    -heterocycloalkyl, (wherein at least one carbon is optionally replaced with a group independently selected from —

    (CR245R250

    , —

    O—

    , —

    C(O)—

    , —

    C(O)C(O)—

    , —

    N(R200)0-1

    , and —

    S(O)0-2

    , and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R200);



    NH-heterocycloalkyl, wherein at least one carbon is optionally replaced with a group independently selected from —

    (CR245R250)—

    , —

    O—

    , —

    C(O)—

    , —

    C(O)C(O)—

    , —

    N(R200)0-2

    , and —

    S(O)0-2

    , and wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from R200;



    C(O)—

    N(R315)(R320),wherein R315 and R320 are each independently selected from —

    H, -alkyl, and phenyl,wherein when R1 is 3,5-difluorobenzyl, and RC is 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, R2 is not methylcarbamoyl;



    O—

    C(O)—

    N(R315)(R320),—

    NH—

    R400,—

    R400,—

    NH—

    R500,—

    R500

    NH—

    R600,—

    R600, and—

    NH—

    R700;

    R400 is wherein R405 is selected from —

    H, —

    N(R515)2, and O-alkyl;

    R500 is a heteroaryl selected from III(a) and III(b), wherein M1 and M4 are independently selected from—

    C(R505)—

    ,—

    N—

    ,—

    N(R515)—

    ,—

    S—

    , and—

    O—

    ;

    M2 and M3 are independently selected from—

    C(R510)—

    ,—

    N—

    ,—

    N(R520)—

    ,—

    S—

    , and—

    O—

    ;

    M5 is selected from —

    C— and



    N—

    ;

    R505 is independently selected from—

    H,-alkyl,-halogen,—

    NO2,—

    CN,—

    R200, andphenyl;

    R510 is independently selected from—

    H,-alkyl,-halogen,-amino,—

    CF3,—

    R200, and-phenyl;

    R515 is independently selected from—

    H,-alkyl, and-phenyl;

    R520 is independently selected from—

    H,-alkyl,—

    (CH2)0-2-phenyl, and—

    C(Ph)3;

    R600 is a monocyclic, bicyclic, or tricyclic heteroaryl ring system of 6, 7, 8, 9, 10, 11, 12, 13, or 14 atoms, optionally substituted with at least one group independently selected from R605;

    R605 is selected from -hydrogen, -halogen, -alkyl, -phenyl, alkyl-O—

    C(O)—

    , -nitro, —

    CN, -amino, —

    NR220R225, -thioalkyl, —

    CF3, —

    OH, —

    O-alkyl, and -heterocycloalkyl;

    wherein when R1 is 3,5-difluoro-benzyl, and RC is 6-ethyl-2,2-dioxo-2λ

    6-isothiochroman-4-yl, R2 is not Benzothiazol-2-ylamino, or Benzooxazol-2-ylamino;

    wherein when R1 is 3,5-difluoro-benzyl, and RC is 3-methoxy-benzyl, R2 is not 3-methyl-5-nitro-3H-imidazol-4-ylamino, Benzooxazol-2-ylamino, 1-phenyl-1H-tetrazol-5-ylamino, Benzothiazol-2-ylamino;

    or 2,5-dimethyl-4-nitro-2H-pyrazol-3-ylamino;

    R700 is aryl optionally substituted with at least one R205;

    RC is selected from—

    (CH2)0-3-cycloalkyl wherein the cycloalkyl is optionally substituted with at least one group independently selected from —

    R205 and —

    CO2-(alkyl),-alkyl optionally substituted with at least one group independently selected from R205,—

    (CR245R250)0-4

    RX, wherein at least one —

    (CR245R250)13 is optionally replaced with a group independently selected from —

    O—

    , —

    N(R215)—

    , —

    C(O)1-2

    , —

    C(O)N(R215)—

    , and —

    S(O)0-2

    , and-formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), and (IVg);

    RX is selected from-hydrogen,-aryl,-heteroaryl,-cycloalkyl,-heterocycloalkyl, andRXa

    RXb, wherein RXa and RXb are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;

    wherein each aryl or heteroaryl group attached directly or indirectly to —

    (CR245R250)0-4

    is optionally substituted with at least one group independently selected from R200;

    wherein each cycloalkyl or heterocycloalkyl group attached directly or indirectly to —

    (CR245R250)0-4

    is optionally substituted with at least one group independently selected from R210 and —

    (CR245R250)0-4

    R200;

    wherein at least one atom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —

    (CR245R250)0-4

    is independently optionally replaced with a group selected from —

    O—

    , —

    C(O)—

    , —

    N(R215)0-1

    , and —

    S(O)0-2

    ;

    wherein at least one heteroatom of the heteroaryl or heterocycloalkyl group attached directly or indirectly to —

    (CR245R250)0-4

    is independently optionally substituted with a group selected from—

    (CO)0-1R215,—

    (CO)0-1R220,—

    S(O)0-2R200, and—

    N(R200)—

    S(O)0-2R200;

    R245 and R250 at each occurrence are independently selected from—

    H,—

    (CH2)0-4C(O)—

    OH,—

    (CH2)0-4C(O)—

    O—

    alkyl,—

    (CH2)0-4C(O)-alkyl,-alkyl,-hydroxyalkyl,—

    O-alkyl,-haloalkoxy,—

    (CH2)0-4-cycloalkyl,—

    (CH2)0-4-aryl,—

    (CH2)0-4-heteroaryl, and—

    (CH2)0-4-heterocycloalkyl;

    orR245 and R250 are taken together with the carbon to which they are attached to form a monocyclic or bicyclic ring system of 3, 4, 5, 6, 7, 8, 9, or 10 carbon 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 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—

    R255)—

    ,—

    N—

    ,—

    NR220

    ,—

    N((CO)0-1R200)—

    , and—

    N(SO2R200)—

    ,wherein the aryl, heteroaryl, and heterocycloalkyl groups included in R245 and R250 are optionally substituted with at least one group independently selected from -halogen, -alkyl, —

    N(R220)(R225), —

    CN, and —

    OH;

    wherein the monocyclic and bicyclic groups included in R245 and R250 are optionally substituted with at least one group independently selected from halogen, —

    (CH2)0-2

    OH, —

    O-alkyl, alkyl, —

    (CH2)0-2

    S-alkyl, —

    CF3, aryl, —

    N(R220)(R225), —

    CN, —

    (CH2)0-2

    NH2, —

    (CH2)0-2

    NH(alkyl), —

    NHOH, —

    NH—

    O-alkyl, —

    N(alkyl)(alkyl), —

    NH-heteroaryl, —

    NH-C(O)-alkyl, and —

    NHS(O2)-alkyl;

    formula (IVa) is wherein Q1 is selected from (—

    CH2

    )0-1, —

    CH(R200)—

    , —

    C(R200)2

    , and —

    C(O)—

    ;

    Q2 and Q3 each are independently selected from (—

    CH2

    )0-1, —

    CH(R200)—

    , —

    C(R200)2

    , —

    O—

    , —

    C(O)—

    , —

    S—

    , —

    S(O)2

    , —

    NH—

    , and —

    N(R7)—

    ;

    Q4 is selected from a bond, (—

    CH2

    )0-1, —

    CH(R200)—

    , —

    C(R200)2

    , —

    O—

    , —

    C(O)—

    , —

    S—

    , —

    S(O)2

    , —

    NH—

    , and —

    N(R7); and

    P1, P2, P3, and P4 each are independently selected from —

    CH—

    , —

    C(R200)—

    , and —

    N—

    ;

    formula (IVb) is wherein R4 is selected from —

    H and -alkyl, and P1, P2, P3, and P4 at each occurrence are independently selected from —

    CH—

    , —

    C(R200)—

    , and —

    N—

    ;

    formula (IVc) is wherein R4 is selected from —

    H and -alkyl; and

    P1, P2, P3, and P4 at each occurrence are independently selected from —

    CH—

    , —

    CR200

    , and —

    N—

    ;

    formula (IVd) is wherein m is 0, 1, 2, 3, 4, 5, or 8;

    Y′

    is selected from —

    H, —

    CN, —

    OH, —

    O-alkyl, —

    CO2H, —

    C(O)OR215, -amino, -aryl, and -heteroaryl; and

    P1 and P2 at each occurrence are independently selected from —

    CH—

    , —

    C(R200)—

    , and —

    N—

    ,or P1 and P2 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms, P3 and P4 at each occurrence are independently selected from —

    CH—

    , —

    C(R200)—

    , and —

    N—

    ,or P3 and P4 are optionally taken together to form a monocyclic or bicyclic ring system of 3, 4, 5, 8, 7, 8, 9, or 10 carbon atoms, P5 at each occurrence is independently selected from —

    CH—

    , —

    C(R200)—

    , and —

    N—

    ,wherein at least one bond in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a double bond,wherein the bicyclic ring system included in P1 and P2 or P3 and P4 is optionally a fused or spiro ring system,wherein at least one carbon atom in the monocyclic or bicyclic ring system included in P1 and P2 or P3 and P4 is optionally replaced by a group independently selected from—

    O—

    ,—

    C(O)—

    ,—

    S(O)0-2

    ,—

    C(═

    N—

    R255)—

    ,—

    N—

    ,—

    NR220

    ,—

    N((CO)0-1R200

    , and—

    N(SO2R200)—

    ; and

    P5 at each occurrence is independently selected from —

    CH—

    , —

    C(R200)—

    , and —

    N—

    , formula (IVe) is wherein U is selected from —

    CH2

    CR100R101

    , —

    CH2

    S—

    , —

    CH2S(O)—

    , —

    CH2

    S(O)2

    , —

    CH2

    N(R100)—

    , —

    CH2

    C(O)—

    , —

    CH2

    O—

    , —

    C(O)—

    C(R100)(R101)—

    , —

    SO2

    N(R100)—

    , —

    C(O)—

    N(R55)—

    , —

    N(R55)—

    C(O)—

    N(R55)—

    , —

    O—

    C(O)—

    O—

    , —

    N(R55)—

    C(O)—

    O—

    -, and —

    C(O)—

    O—

    ;

    wherein R100 and R101 at each occurrence are independently selected from —

    H, -alkyl, -aryl, —

    C(O)-alkyl, —

    (CO)0-1R215, —

    (CO)0-1R220, and —

    S(O)2-alkyl;

    formula (IVf) is wherein the B ring is optionally substituted with at least one group independently selected from -alkyl, -halogen, —

    OH, —

    SH, —

    CN, —

    CF3, —

    O-alkyl, —

    N(R5)C(O)H, —

    C(O)H, —

    C(O)N(R5)(R6), —

    NR5R6, R280, R285, -aryl, and -heteroaryl;

    wherein R280 and R285, and the carbon to which they are attached form a C3

    C7 spirocycle which is optionally substituted with at least one group independently selected from -alkyl, —

    O-alkyl, -halogen, —

    CF3, and —

    CN;

    wherein the A ring is aryl or heteroaryl, each optionally substituted with at least one group independently selected from R290 and R295;

    wherein R290 and R295 at each occurrence are independently selected from -alkyl optionally substituted with at least one group selected from -alkyl, -halogen, —

    OH, —

    SH, —

    CN, —

    CF3, —

    O-alkyl, and —

    NR5R6,—

    OH,—

    NO2,-halogen,—

    CO2H,—

    CN,—

    (CH2)0-4

    C(O)—

    NR21R22,—

    (CH2)0-4

    CO2R20,—

    (CH2)0-4

    SO2

    NR21R22,—

    (CH2)0-4S(O)-alkyl),—

    (CH2)0-4

    S(O)2-(alkyl),—

    (CH2)0-4-S(O)2-(cycloalkyl),—

    (CH2)0-4

    N(H or R20)—

    C(O)—

    O—

    R20,—

    (CH2)0-4

    N(H or R20)—

    C(O)—

    N(R20)2,—

    (CH2)0-4

    N—

    C(S)—

    N(R20)2,—

    (CH2)0-4

    N(H or R20)—

    CO—

    R21,—

    (CH2)0-4

    NR21R22,—

    (CH2)0-4

    R11,—

    (CH2)0-4

    O—

    C(O)—

    (alkyl),—

    (CH2)0-4

    O—

    P(O)—

    (OR5)2,—

    (CH2)0-4

    O—

    C(O)—

    N(R20)2,—

    (CH2)0-4

    O—

    C(S)—

    N(R20)2,—

    (CH2)0-4

    O—

    (R20)2,—

    (CH2)0-4

    (R20)—

    CO2H,—

    (CH2)0-4

    S—

    (R20),—

    (CH2)0-4

    O-(alkyl optionally substituted with at least one halogen),-cycloalkyl,—

    (CH2)0-4

    N(H or R20)—

    S(O)2

    R21, and—

    (CH2)0-4-cycloalkyl;

    formula (IVg) is wherein a is 0 or 1;

    b is 0 or 1;

    S′

    is selected from —

    C(O)— and



    CO2

    ;

    T′

    is —

    (CH2)0-4

    ;

    U′

    is —

    (CR245R250)—

    ;

    V′

    is selected from -aryl- and -heteroaryl-;

    W′

    is selected from-a bond,-alkyl-substituted with at least one group independently selected from R205,—

    (CH2)0-4

    (CO)0-1

    N(R220)—

    ,—

    (CH2)0-4

    (CO)0-1

    ,—

    (CH2)0-4

    CO2

    ,—

    (CH2)0-4

    SO2

    N(R220)—

    ,—

    (CH2)0-4

    N(H or R215)—

    CO2

    ,—

    (CH2)0-4

    N(H or R215)—

    SO2

    ,—

    (CH2)0-4

    N(H or R215)—

    C(O)—

    N(R215)—

    ,—

    (CH2)0-4

    N(H or R215)—

    C(O)—

    ,—

    (CH2)0-4

    N(R220)—

    ,—

    (CH2)0-4

    O—

    , and—

    (CH2)0-4

    S—

    ;

    X′

    is selected from aryl and heteroaryl;

    wherein each cycloalkyl included in formula (IVg) is optionally substituted with at least one group independently selected from R205;

    wherein each aryl or heteroaryl group included in formula (IVg) is optionally substituted with at least one group independently selected from R200;

    wherein at least one heteroatom of the heteroaryl group included within formula (IVg) is optionally substituted with a group selected from—

    (CO)0-1R215,—

    (CO)0-1R220, and—

    S(O)0-2R200;

    R21 and R22 each independently are selected from—

    H,-alkyl optionally substituted with at least one group independently selected from —

    OH, amino, -halogen, -alkyl, -cycloalkyl, -(alkyl-cycloalkyl), -alkyl-O-alkyl, —

    R17, and —

    R18,—

    (CH2)0-4

    C(O)-(alkyl),—

    (CH2)0-4

    C(O)-(cycloalkyl),—

    (CH2)0-4

    C(O)—

    R17,—

    (CH2)0-4

    C(O)—

    R18,—

    (CH2)0-4

    C(O)—

    R19, and—

    (CH2)0-4

    C(O)—

    R11;

    R17 at each occurrence is aryl optionally substituted with at least one group independently selected from-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —

    OH, —

    SH, —

    NR5R6, —

    CN, —

    CF3, and —

    O-alkyl,-halogen,—

    O-alkyl optionally substituted with at least one group independently selected from halogen, —

    NR21R22, —

    OH, —

    CN, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —

    OH, —

    SH, —

    CN, —

    CF3, —

    O-alkyl, and —

    NR5R6,—

    C(O)-(alkyl),—

    S(O)—

    O—

    NR5R6,—

    C(O)—

    NR5R6, and—

    S(O)2-(alkyl);

    R18 at each occurrence is heteroaryl optionally substituted with at least one group independently selected from-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —

    OH, —

    SH, —

    CN, —

    CF3, —

    O-alkyl, and —

    NR5R6,-halogen,—

    O-alkyl optionally substituted with at least one group independently selected from -halogen, —

    NR21R22, —

    OH, and —

    CN,-cycloalkyl optionally substituted with at least one group independently selected from -halogen, —

    OH, —

    SH, —

    CN, CF3, —

    O-alkyl, and —

    NR5R6,—

    C(O)-(alkyl),—

    S(O)2

    NR5R6,—

    C(O)—

    NR5R6, and—

    S(O)2-(alkyl);

    R19 at each occurrence is heterocycloalkyl wherein at least one carbon is optionally replaced with —

    C(O)—

    , —

    S(O)—

    , and —

    S(O)2

    , wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from-alkyl optionally substituted with at least one group independently selected from -alkyl, -halogen, —

    OH, —

    SH, —

    CN, —

    CF3, —

    O-alkyl, and —

    NR5R6,-halogen,—

    O-alkyl optionally substituted with at least one group independently selected from -halogen, —

    OH, —

    CN, —

    NR21R22, and -cycloalkyl optionally substituted with at least one group independently selected from -halogen, —

    OH, —

    SH, —

    CN, —

    CF3, —

    O-alkyl, and —

    NR5R6,—

    C(O)-(alkyl),—

    S(O)2

    NR5R6,—

    C(O)—

    NR5R6, and—

    S(O)2-(alkyl);

    R11 at each occurrence is heterocycloalkylwherein at least one carbon of the heterocycloalkyl is optionally replaced with —

    C(O)—

    , —

    S(O)—

    , and —

    S(O)2

    ,wherein the heterocycloalkyl is optionally substituted with at least one group independently selected from -alkyl, —

    O-alkyl, and -halogen;

    R20 is selected from -alkyl, -cycloalkyl, —

    (CH2)0-2

    (R17), and —

    (CH2)0-2

    (R18);

    R200 at each occurrence is Independently selected from-alkyl optionally substituted with at least one group independently selected from R205,—

    OH,—

    NO2,—

    NH2,-halogen,—

    CN,—

    CF3,—

    OCF3,—

    (CH2)0-4

    C(O)H,—

    (CO)0-1R215,—

    (CO)0-1R220,—

    (CH2)0-4

    C(O)—

    NR220R225,—

    (CH2)0-4

    (C(O))0-1R215,—

    (CH2)0-4

    (C(O))0-1

    R220,—

    (CH2)0-4

    C(O)-alkyl,—

    (CH2)0-4

    (C(O))0-1-cycloalkyl,—

    (CH2)0-4

    (C(O))0-1-heterocycloalkyl,—

    (CH2)0-4

    (C(O))0-1-aryl,—

    (CH2)0-4

    (C(O))0-1-heteroaryl,—

    (CH2)0-4

    C(O)—

    O—

    R215,—

    (CH2)0-4

    S(O)0-2

    NR220R225,—

    (CH2)0-4

    S(O)0-2-alkyl,—

    (CH2)0-4

    S(O)0-2-cycloalkyl,—

    (CH2)0-4

    N(H or R215)—

    C(O)—

    O—

    R215,—

    (CH2)0-4

    N(H or R215)—

    S(O)1-2

    R220,—

    (CH2)0-4

    N(H or R215)—

    C(O)—

    N(R215)2,—

    (CH2)0-4

    N(H or R215)—

    C(O)—

    R220,—

    (CH2)0-4

    NR220R225,—

    (CH2)0-4

    O—

    C(O)-alkyl,—

    (CH2)0-4

    O—

    (R215),—

    (CH2)0-4

    S—

    (R215),—

    (CH2)0-4

    C(O)H,—

    (CH2)0-4

    O-(alkyl optionally substituted with at least one halogen), and-adamantane,wherein each aryl and heteroaryl group included within R200 is optionally substituted with at least one group independently selected from—

    R205,R210, and-alkyl optionally substituted with at least one group independently selected from R205 and R210;

    wherein each cycloalkyl or heterocycloalkyl group included within R200 is optionally substituted with at least one group independently selected from—

    R205,—

    R210 , and-alkyl optionally substituted with at least one group independently selected from R205 and R210;

    R205 at each occurrence is independently selected from-alkyl,-heteroaryl,-heterocycloalkyl,-aryl,-haloalkoxy,—

    (CH2)0-3-cycloalkyl,-halogen,—

    (CH2)0-6

    OH,—

    O-phenyl,—

    SH,—

    (CH2)0-4

    C(O)CH3

    (CH2)0-4

    C(O)H—

    (CH2)0-4

    CO2H,—

    (CH2)0-6

    CN,—

    (CH2)0-6

    C(O)—

    NR235R240,—

    (CH2)0-6

    C(O)—

    R235,—

    (CH2)0-4

    N(H or R215)—

    SO2

    R235,—

    CF3,—

    CN,—

    OCF3,—

    C(O)2-benzyl,—

    O-alkyl,—

    C(O)2-alkyl, and—

    NR235R240;

    R210 at each occurrence is independently selected from—

    OH,—

    CN,—

    (CH2)0-4

    C(O)H,-alkyl wherein a carbon atom is optionally replaced with —

    C(O)—

    , and a carbon atom is optionally substituted with at least one group independently selected from R205,—

    S-alkyl,-halogen,—

    O-alkyl,-haloalkoxy,—

    NR220R225,-cycloalkyl optionally substituted with at least one group independently selected from R205,—

    C(O)-alkyl,—

    S(O)2

    NR235R240,—

    C(O)—

    NR235R240, and—

    S(O)2-alkyl;

    R215 at each occurrence is independently selected from-alkyl,—

    (CH2)0-2-aryl,—

    (CH2)0-2-cycloalkyl,—

    (CH2)0-2-heteroaryl, and—

    (CH2)0-2-heterocycloalkyl;

    wherein the aryl groups included within R215 are optionally substituted with at least one group independently selected from R205 or R210;

    wherein the heterocycloalkyl and heteroaryl groups included within R215 are optionally substituted with at least one group independently selected from R210;

    R220 and R225 at each occurrence are independently selected from—

    H,—

    OH,-alkyl,—

    (CH2)0-4

    C(O)H,-alkyl-OH,—

    (CH2)0-4

    CO2-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,-aminoalkyl,—

    S(O)2-alkyl,—

    (CH2)0-4

    C(O)-alkyl, wherein alkyl is optionally substituted with at least one group independently selected from R205,—

    (CH2)0-4

    C(O)—

    NH2,—

    (CH2)0-4

    C(O)—

    NH(alkyl), wherein alkyl is optionally substituted with at least one group independently selected from R205,—

    (CH2)0-4

    C(O)—

    N(alkyl)(alkyl),-haloalkyl,—

    (CH2)0-2-cycloalkyl,-alkyl-O-alkyl,O-alkyl,-aryl,-heteroaryl, and-heterocycloalkyl;

    wherein the aryl, heteroaryl and heterocycloalkyl groups included within R220 and R225 are each optionally substituted with at least one group independently selected from R270;

    R270 at each occurrence is independently selected fromR205,-alkyl optionally substituted with at least one group independently selected from R205,-phenyl,-halogen,—

    O-alkyl,-haloalkoxy,—

    NR235R240,—

    OH,—

    CN,-cycloalkyl optionally substituted with at least one group independently selected from R205,—

    C(O)-alkyl,—

    S(O)2

    NR235R240,—

    CO—

    NR235R240,—

    S(O)2-alkyl, and—

    (CH2)0-4

    C(O)H;

    R235 and R240 at each occurrence are independently selected from—

    H,-alkyl,—

    C(O)-alkyl,—

    OH,—

    CF3,—

    OCH3,—

    NH—

    CH3,—

    N(CH3)2,—

    (CH2)0-4

    C(O)—

    (H or alkyl),—

    SO2-alkyl, and-phenyl;

    R255 is selected from -hydrogen, —

    OH, —

    N(R220)(R225), and —

    O-alkyl;

    R5 and R6 are independently selected from —

    H and -alkyl, or R5 and R6, and the nitrogen to which they are attached, form a 5 or 6 membered heterocycloalkyl ring; and

    R7 is independently selected from—

    H,-alkyl optionally substituted with at least one group independently selected from —

    OH, amino, and halogen,-cycloalkyl, and-alkyl-O-alkyl.

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