US 6,262,055 B1Granted

HIV integrase inhibitors

AssigneeMerck & Co., Inc.

InventorsSteven D. Young, John S. Wai, Mark W. Embrey, Thorsten E. Fisher

Life of this patent

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Abstract

Sulfur-containing heteroaryl dioxo-butyric acid derivatives are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

Claims34

Dependent claims

The compound of structural formula (I):

and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) thienyl,
(2) thiazolyl,
R1 is selected from:
(1) —H,
(2) —CH3,
(3) —CF3,
(4) -halo,
(5) —NO2,
(6) —N(R4)(R5),
(7) -phenyl,
(8) 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;
(9) phenyl C1-3 alkyl-,
(10) substituted phenyl C1-3 alkyl-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;
(11) —C2-5 alkenyl-R3,
(12) —C2-5 alkynyl-R3, and
(13) —C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) —H,
(2) —R3,
(3) —C1-6 alkyl,
(4) —C1-6 alkyl substituted with R3,
(5) —O—R6,
(6) —O—C1-6 alkyl-OR6,
(7) —S(O)n—R6,
(8) —C1-6 alkyl (OR6)(R4),
(9) —C1-6 alkyl (OR4)(R6),
(10) —C0-6 alkyl-N(R4)(R6),
(11) —C1-6 alkyl S(O)n—R6,
(12) —C0-6 alkyl C(O)—R6,
(13) —C0-6 alkyl C(S)—R6,
(14) —C0-6 alkyl NR4C(O)—R6, and
(15) —C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 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;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two 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;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two 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;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two 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;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one or two 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;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one or two 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;
(13) C3-6 cycloalkyl;
(14) substituted C3-6 cycloalkyl 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, and
(h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl 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,
(g) ═O, and
(h) hydroxy;
(17) morpholinyl;
(18) 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, and
(h) hydroxy;
(19) naphthyl,
(20) 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;
(21) indolyl;
(22) 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;
(23) C3-6 cycloalkyl fused with a phenyl ring
(24) substituted C3-6 cycloalkyl fused with a phenyl ring 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,
(g) ═O, and
(h) hydroxy;
each R4 is independently selected from:
(1) —H,
(2) —C1-3 alkyl,
(3) —CF3,
(4) —R3,
(5) —C2-3 alkenyl,
(6) —C1-3 alkyl-R3,
(7) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —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) —C1-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —C(O)—R3;
each R6 is independently selected from:
(1) —C1-3 alkyl-R3, and
(2) —R3;
R7 is H;
R8 is selected from hydrogen, methyl and methoxy;
each n is independently selected from 0, 1 and 2, and
each m is independently selected from 0, 1, and 2;
and provided that
(A) when A is thienyl or thiazolyl and R2 is —H or —C1-6 alkyl, then R1 is not
(1) —H,
(2) —CH3, or
(7) -phenyl;
(B) when A is thienyl or thiazolyl and R2 is —R3 wherein R3 is unsubstituted phenyl, then R1 is not
(1) —H or
(2) —CH3;
(C) when A is thienyl and R2 is —H or —C1-6 alkyl, then R1 is not
(4) -halo,
(5) —NO2, or
(6) —N(R4)(R5) when R4 and R5 are both —H;
and
(D) when A is thienyl and R2 is —R3 wherein R3 is (7) imidiazolyl or (17) morpholinyl, then R1 is not
(1) —H,
(2) —CH3,
(4) -halo,
(5) —NO2, or
(6) —N(R4)(R5) when R4 and R5 are both —H.

260 more elements

A pharmaceutical composition comprising a therapeutically effective amount of a compound of structural formula (I):

or tautomers or pharmaceutically acceptable salts thereof, in combination with a therapeutically effective amount of an AIDS treatment agent selected from
(1) an AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator;
wherein
A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1 nitrogen atoms and substituted on carbon by R1, R2 and R8;
the heteroaromatic ring may optionally be fused with a phenyl ring or a C4-6 cycloalkyl ring, or with two six membered rings to form:
R1 is selected from:
(1) —H,
(2) —C1-5 alkyl,
(3) —CF3,
(4) -halo,
(5) —NO2,
(6) —N(R4)(R5),
(7) —R6,
(8) —C2-5 alkenyl-R3,
(9) —C2-5 alkynyl-R3,
(10) —O—R6,
(11) —O—C1-6 alkyl, and
(12) —C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) —H,
(2) —R3,
(3) —C1-6 alkyl,
(4) —C1-6 alkyl substituted with R3,
(5) —O—R6,
(6) —O—C1-6 alkyl-OR6,
(7) —S(O)n—R6,
(8) —C1-6 alkyl (OR6)(R4),
(9) —C1-6 alkyl (OR4)(R6),
(10) —C0-6 alkyl-N(R4)(R6),
(11) —C1-6 alkyl S(O)n—R6,
(12) —C0-6 alkyl C(O)—R6,
(13) —C0-6 alkyl C(S)—R6,
(14) —C0-6 alkyl NR4C(O)—R6, and
(15) —C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) —CF3,
(f) —OCF3,
(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;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 0 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) —CF3,
(f) —OCF3,
(g) —CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring;
wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) —C1-6 alkyl,
(c) —C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
each R4 is independently selected from:
(1) —H,
(2) —C1-3 alkyl,
(3) —CF3,
(4) —R3,
(5) —C2-3 alkenyl,
(6) —C1-3 alkyl-R3,
(7) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —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) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —C(O)—R3;
each R6 is independently selected from:
(1) —C1-3 alkyl-R3, and
(2) —R3;
R7 is selected from:
(1) —H, and
(2) C1-6 alkyl;
R8 is selected from:
(1) —H, and
(2) C1-6 alkyl-oxy-, and
(3) C1-6 alkyl-;
each n is independently selected from 0, 1 and 2, and
each m is independently selected from 0, 1, and 2.

125 more elements

A method of inhibiting HIV integrase, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of structural formula (I):

or tautomers or pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1 nitrogen atoms and substituted on carbon by R1, R2 and R8;
the heteroaromatic ring may optionally be fused with a phenyl ring or a C4-6 cycloalkyl ring, or with two six membered rings to form:
R1 is selected from:
(1) —H,
(2) —C1-5 alkyl,
(3) —CF3,
(4) -halo,
(5) —NO2,
(6) —N(R4)(R5),
(7) —R6,
(8) —C2-5 alkenyl-R3,
(9) —C2-5 alkynyl-R3,
(10) —O—R6,
(11) —O—C1-6 alkyl, and
(12) —C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) —H,
(2) —R3,
(3) —C1-6 alkyl,
(4) —C1-6 alkyl substituted with R3,
(5) —O—R6,
(6) —O—C1-6 alkyl-OR6,
(7) —S(O)n—R6,
(8) —C1-6 alkyl (OR6)(R4),
(9) —C1-6 alkyl (OR4)(R6),
(10) —C0-6 alkyl-N(R4)(R6),
(11) —C1-6 alkyl S(O)n—R6,
(12) —C0-6 alkyl C(O)—R6,
(13) —C0-6 alkyl C(S)—R6,
(14) —C0-6 alkyl NR4C(O)—R6, and
(15) —C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents 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;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 0 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) —CF3,
(f) —OCF3,
(g) —CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring;
wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) —C1-6 alkyl,
(c) —C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
each R4 is independently selected from:
(1) —H,
(2) —C1-3 alkyl,
(3) —CF3,
(4) —R3,
(5) —C2-3 alkenyl,
(6) —C1-3 alkyl-R3,
(7) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —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) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —C(O)—R3;
each R6 is independently selected from:
(1) —C1-3 alkyl-R3, and
(2) —R3;
R7 is selected from:
(1) —H, and
(2) C1-6 alkyl;
R8 is selected from:
(1) —H, and
(2) C1-6 alkyl-oxy-, and
(3) C1-6 alkyl-;
each n is independently selected from 0, 1 and 2, and
each m is independently selected from 0, 1, and 2.

122 more elements

A method of treating infection by HIV, or of treating AIDS or ARC, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of structural formula (I):

or tautomers or pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 sulfur atom and 0 or 1 nitrogen atoms and substituted on carbon by R1, R2 and R8;
the heteroaromatic ring may optionally be fused with a phenyl ring or a C4-6 cycloalkyl ring, or with two six membered rings to form:
R1 is selected from:
(1) —H,
(2) —C1-5 alkyl,
(3) —CF3,
(4) -halo,
(5) —NO2,
(6) —N(R4)(R5),
(7) —R6,
(8) —C2-5 alkenyl-R3,
(9) —C2-5 alkynyl-R3,
(10) —O—R6,
(11) —O—C1-6 alkyl, and
(12) —C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) —H,
(2) —R3,
(3) —C1-6 alkyl,
(4) —C1-6 alkyl substituted with R3,
(5) —O—R6,
(6) —O—C1-6 alkyl-OR6,
(7) —S(O)n—R6,
(8) —C1-6 alkyl (OR6)(R4),
(9) —C1-6 alkyl (OR4)(R6),
(10) —C0-6 alkyl-N(R4)(R6),
(11) —C1-6 alkyl S(O)n—R6,
(12) —C0-6 alkyl C(O)—R6,
(13) —C0-6 alkyl C(S)—R6,
(14) —C0-6 alkyl NR4C(O)—R6, and
(15) —C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents 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;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 0 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) —C3,
(f) —OCF3,
(g) —CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring;
wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) —C1-6 alkyl,
(c) —C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
each R4 is independently selected from:
(1) —H,
(2) —C1-3 alkyl,
(3) —C3,
(4) —R3,
(5) —C2-3 alkenyl,
(6) —C1-3 alkyl-R3,
(7) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —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) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —C(O)—R3;
each R6 is independently selected from:
(1) —C1-3 alkyl-R3, and
(2) —R3;
R7 is selected from:
(1) —H, and
(2) C1-6 alkyl;
R8 is selected from:
(1) —H, and
(2) C1-6 alkyl-oxy-, and
(3) C1-6 alkyl-;
each n is independently selected from 0, 1 and 2, and
each m is independently selected from 0, 1, and 2.

122 more elements

A compound of structural formula (I):

and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) thienyl,
(2) thiazolyl,
R1 is selected from:
(1) —H,
(2) —CH3,
(3) —CF3,
(4) -halo,
(5) —NO2,
(6) —N(R4)(R5),
(7) -phenyl,
(8) 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;
(9) phenyl C1-3 alkyl-,
(10) substituted phenyl C1-3 alkyl-substituted with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(c) —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;
(11) —C2-5 alkenyl-R3,
(12) —C2-5 alkynyl-R3, and
(13) —C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) —R3,
(2) —C1-6 alkyl substituted with R3,
(3) —O—R6,
(4) —O—C1-6 alkyl-OR6,
(5) —S(O)n—R6,
(6) —C1-6 alkyl (OR6)(R4),
(7) —C1-6 alkyl (OR4)(R6),
(8) —C0-6 alkyl-N(R4)(R6),
(9) —C1-6 alkyl S(O)n—R6,
(10) —C0-6 alkyl C(O)—R6,
(11) —C0-6 alkyl C(S)—R6,
(12) —C0-6 alkyl NR4C(O)—R6, and
(13) —C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 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;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two 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;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two 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;
(7) substituted imidazolyl substituted on a carbon atom with one or two 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;
(8) pyrrolyl;
(9) substituted pyrrolyl substituted on a carbon atom with one or two 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;
(10) pyrazolyl;
(11) substituted pyrazolyl substituted on a carbon atom with one or two 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) C3-6 cycloalkyl;
(13) substituted C3-6 cycloalkyl 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, and
(h) hydroxy;
(14) piperidinyl;
(15) substituted piperidinyl 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,
(g) ═O, and
(h) hydroxy;
(16) 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, 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) C3-6 cycloalkyl fused with a phenyl ring
(22) substituted C3-6 cycloalkyl fused with a phenyl ring 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,
(g) ═O, and
(h) hydroxy;
each R4 is independently selected from:
(1) —H,
(2) —C1-3 alkyl,
(3) —CF3,
(4) —R3,
(5) —C2-3 alkenyl,
(6) —C1-3 alkyl-R3,
(7) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —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) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —C(O)—R3;
each R6 is independently selected from:
(1) —C1-3 alkyl-R3, and
(2) —R3;
R7 is H;
R8 is selected from hydrogen, methyl and methoxy;
each n is independently selected from 0, 1 and 2, and
each m is independently selected from 0, 1, and 2;
and provided that when A is thienyl or thiazolyl and R2 is —R3 wherein R3 is unsubstituted phenyl, then R1 is not
(1) —H or
(2) —CH3.

239 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/323,457Filed 1 Jun 1999 · us provisional application
Priority: 3 Jun 1998
Granted: 17 Jul 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 409/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 277/42
Nitrogen atoms: amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
C07D 333/24
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms: radicals substituted by…
C07D 333/32
Hetero atoms other than halogen: oxygen atoms

Family

Application60/087,846Us provisional application · filed 3 Jun 1998
US 6,262,055 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Citations

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Abstract

The compound of structural formula (I):

and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) thienyl,
(2) thiazolyl,
R1 is selected from:
(1) —H,
(2) —CH3,
(3) —CF3,
(4) -halo,
(5) —NO2,
(6) —N(R4)(R5),
(7) -phenyl,
(8) 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;
(9) phenyl C1-3 alkyl-,
(10) substituted phenyl C1-3 alkyl-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;
(11) —C2-5 alkenyl-R3,
(12) —C2-5 alkynyl-R3, and
(13) —C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) —H,
(2) —R3,
(3) —C1-6 alkyl,
(4) —C1-6 alkyl substituted with R3,
(5) —O—R6,
(6) —O—C1-6 alkyl-OR6,
(7) —S(O)n—R6,
(8) —C1-6 alkyl (OR6)(R4),
(9) —C1-6 alkyl (OR4)(R6),
(10) —C0-6 alkyl-N(R4)(R6),
(11) —C1-6 alkyl S(O)n—R6,
(12) —C0-6 alkyl C(O)—R6,
(13) —C0-6 alkyl C(S)—R6,
(14) —C0-6 alkyl NR4C(O)—R6, and
(15) —C0-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 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;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two 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;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two 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;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two 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;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one or two 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;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one or two 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;
(13) C3-6 cycloalkyl;
(14) substituted C3-6 cycloalkyl 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, and
(h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl 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,
(g) ═O, and
(h) hydroxy;
(17) morpholinyl;
(18) 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, and
(h) hydroxy;
(19) naphthyl,
(20) 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;
(21) indolyl;
(22) 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;
(23) C3-6 cycloalkyl fused with a phenyl ring
(24) substituted C3-6 cycloalkyl fused with a phenyl ring 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,
(g) ═O, and
(h) hydroxy;
each R4 is independently selected from:
(1) —H,
(2) —C1-3 alkyl,
(3) —CF3,
(4) —R3,
(5) —C2-3 alkenyl,
(6) —C1-3 alkyl-R3,
(7) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —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) —C1-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —C(O)—R3;
each R6 is independently selected from:
(1) —C1-3 alkyl-R3, and
(2) —R3;
R7 is H;
R8 is selected from hydrogen, methyl and methoxy;
each n is independently selected from 0, 1 and 2, and
each m is independently selected from 0, 1, and 2;
and provided that
(A) when A is thienyl or thiazolyl and R2 is —H or —C1-6 alkyl, then R1 is not
(1) —H,
(2) —CH3, or
(7) -phenyl;
(B) when A is thienyl or thiazolyl and R2 is —R3 wherein R3 is unsubstituted phenyl, then R1 is not
(1) —H or
(2) —CH3;
(C) when A is thienyl and R2 is —H or —C1-6 alkyl, then R1 is not
(4) -halo,
(5) —NO2, or
(6) —N(R4)(R5) when R4 and R5 are both —H;
and
(D) when A is thienyl and R2 is —R3 wherein R3 is (7) imidiazolyl or (17) morpholinyl, then R1 is not
(1) —H,
(2) —CH3,
(4) -halo,
(5) —NO2, or
(6) —N(R4)(R5) when R4 and R5 are both —H.

260 more elements

Facts

Application

09/323,457Filed 1 Jun 1999 · us provisional application

Priority

3 Jun 1998

Granted

17 Jul 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 409/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 277/42
Nitrogen atoms: amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
C07D 333/24
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms: radicals substituted by…
C07D 333/32
Hetero atoms other than halogen: oxygen atoms