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HIV integrase inhibitors

  • US 6,380,249 B1
  • Filed: 06/01/1999
  • Issued: 04/30/2002
  • Est. Priority Date: 06/03/1998
  • Status: Expired due to Fees
First Claim
Patent Images

1. A compound of structural formula (I):

  • embedded imageand tautomers and pharmaceutically acceptable salts thereof, wherein;

    A is a six-membered aromatic ring substituted on carbon by R1, R2, R8, and R9, optionally fused with another ring system, and is selected from;

    (1) phenyl, (2) naphthyl, embedded imageR1 is selected from;

    (1) —

    H, (2) —

    C1-5 alkyl, (3) —

    C1-6 alkyl-OR7;

    (4) —

    O—

    C1-6 alkyl-OR7, (5) —

    O—

    C1-6 alkyl-SR7, (6) —

    CF3 or —

    CH2CF3, (7) —

    F, Cl, or Br, (8) —

    NO2, (9) —

    C0-3 alkyl —

    N(R4)(R5), (10) -phenyl, (11) substituted phenyl substituted with 1 or 2 substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) —

    CF3, (f) —

    OCF3, (g) —

    CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    CF3, (f) —

    SCH3, (g) —

    CN, (h) hydroxy, (i) phenyloxy, (j) —

    C0-6 alkyl-N(R7)2, embedded image(l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (13) —

    O—

    R6, (14) —

    O—

    C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (15) —

    O—

    C1-6 alkyl-NH—

    C(O)—

    OR7;

    (16) —

    O—

    C2-6 alkyl-N(R4)(R5);

    (17) —

    S—

    C1-3 alkyl;

    (18) —

    C(O)CH2C(O)C(O)OR7;

    (19) —

    CH2

    CH(OH)—

    CH2

    O—

    R7; and

    (20) —

    C(OH)(CH3)—

    CH2N(R4)(R5);

    R2 is selected from;

    (1) —

    R3, (2) —

    C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (3) —

    O—

    C1-6 alkyl-SR6;

    (4) —

    C1-6 alkyl (OR6)(R4), (5) —

    C0-6 alkyl-N(R4)(R6), (6) —

    C1-6 alkyl S—

    R6, (7) —

    C0-6 alkyl C(O)—

    R6, (8) —

    C0-6 alkyl C(O)CH2

    C(O)—

    OH, (9) —

    C1-6 alkyl NR4C(O)—

    R6, (10) —

    C1-6 alkyl-C(O)N(R4)(R5), and (11) —

    CH2(OR7)—

    R6;

    each R3 is independently selected from;

    (1) phenyl;

    (2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    CN, (f) hydroxy, (g) phenyloxy, (h) —

    C0-6 alkyl-N(R7)2, embedded image(j) oxo, and (k) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (7) substituted imidazolyl substituted on carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (8) pyrrolyl, (9) substituted pyrrolyl substituted on carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (10) pyrazolyl, (11) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (12) piperidinyl, (13) substituted piperidinyl substituted on carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, (g) ═

    O, (h) benzyl, and (i) hydroxy;

    (14) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, (g) ═

    O, (h) benzyl, and (i) hydroxy;

    (15) hexahydrothieno[3,4-d]imidazolyl, (16) substituted hexahydrothieno[3,4-d]substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents independently selected from;

    (a) oxo, (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) —

    CF3, (f) —

    OCF3, (g) —

    CN, and (h) hydroxy, (17) naphthyl, (18) substituted naphthyl with 1, 2, or 3 substituents independently selected from;

    (a) -halogen, (b) —

    C1-6 alkyl, (c) —

    C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, and (g) -hydroxy, (19) indolyl, (20) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from;

    (a) -halogen, (b) —

    C1-6 alkyl, (c) C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, and (g) -hydroxy;

    (21) C3-5 cycloalkyl fused with a phenyl ring, (22) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, (g) ═

    O, and (h) hydroxy;

    (23) pyrazinyl;

    (24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (25) pyrimidinyl;

    (26) substituted pyrimidinyl substituted on nitrogen or carbon with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (27) triazolyl;

    (28) substituted triazolyl with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (29) tetrazolyl;

    (30) substituted tetrazolyl with a substituent selected from;

    (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) —

    S—

    C1-6 alkyl, (f) —

    CN, (g) hydroxy, (h) phenyloxy, (i) —

    C0-6 alkyl-N(R7)2, embedded image(k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from;

    (i) halogen, (ii) C1-6 alkyl, (iii) —

    CF3, and (iv) hydroxy;

    (31) C3-6 cycloalkyl;

    (32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, (g) ═

    O, (h) benzyl, and (i) hydroxy;

    (33) tetrahydrofuran;

    (34) substituted tetrahydrofuran substituted with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, (g) ═

    O, (h) benzyl, and (i) hydroxy;

    (35) piperazinyl;

    (36) substituted piperazinyl substituted with one or two substituents independently selected from;

    (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, (g) ═

    O, (h) benzyl, and (i) hydroxy;

    (37) benzotriazolyl, (38) substituted benzotriazolyl substituted on a carbon atom with one or two substituents independently selected from;

    (a) -halogen, (b) —

    C1-6 alkyl, (c) —

    C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, and (g) -hydroxy;

    (39) benzoimidazolyl, (40) substituted benzoimidazolyl substituted on a carbon atom with one or two substituents independently selected from;

    (a) -halogen, (b) —

    C1-6 alkyl, (c) —

    C1-6 alkyloxy-, (d) —

    CF3, (e) —

    OCF3, (f) —

    CN, and (g) -hydroxy;

    each R4 is independently selected from;

    (1) —

    H, (2) —

    C1-4 alkyl, (3) —

    CF3, (4) —

    R3, (5) —

    C2-3 alkenyl, (6) —

    C1-3 alkyl-R3, (7) —

    C2-3 alkenyl-R3, and (8) —

    C(O)—

    R3;

    each R5 is independently selected from;

    (1) —

    H, (2) —

    C1-3 alkyl, (3) —

    CF3, (4) —

    R3, (5) —

    C2-3 alkenyl, (6) —

    C1-3 alkyl-R3, (7) —

    S(O)n

    R3, (8) —

    C(O)—

    R3, (9) —

    C(O)OR4, and (10) —

    C(O)C(O)OH;

    each R6 is independently selected from;

    (1) —

    C1-3 alkyl-R3, and (2) —

    R3;

    each R7 is independently selected from;

    (1) —

    H, and (2) —

    C1-6 alkyl;

    R8 is selected from hydrogen, methyl and —

    O—

    C1-6 alkyl;

    R9 is selected from;

    (1) —

    H, (2) —

    O—

    C1-3 alkyl, (3) —

    OH, and (4) oxo;

    and each n is independently selected from 0, 1 and 2; and

    PROVIDED THAT when A is phenyl;

    (1) R1 is not;

    (a) phenyl para to the dioxobutyric acid moiety, (b) substituted phenyl para to the dioxobutyric acid moiety, (c) —

    C1-3 alkyl phenyl para to the dioxobutyric acid moiety, or (d) substituted —

    C1-3 alkyl phenyl para to the dioxobutyric acid moiety; and

    (2) R2 is not selected from;

    (a) phenyl para to the dioxobutyric acid moiety, (b) substituted phenyl para to the dioxobutyric acid moiety, (c) —

    C1-6 alkyl phenyl para to the dioxobutyric acid moiety, and (d) substituted —

    C1-6 alkyl phenyl para to the dioxobutyric acid moiety; and

    (3) at least one of R1, R2, and R8 is not;

    (a) —

    H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl.

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