.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Claims for Patent: 7,217,713

« Back to Dashboard

Claims for Patent: 7,217,713

Title:N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase
Abstract:N-substituted 5-hydroxypyrimidin-6-one-4-carboxamides of formula: ##STR00001## are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds-are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.
Inventor(s): Crescenzi; Benedetta (Rome, IT), Gardelli; Cristina (Ariccia, IT), Muraglia; Ester (Rome, IT), Nizi; Emanuela (Siena, IT), Orvieto; Federica (Rome, IT), Pace; Paola (Rome, IT), Pescatore; Giovanna (Cosenza, IT), Petrocchi; Alessia (Rome, IT), Poma; Marco (Grosseto, IT), Rowley; Michael (Axa, IT), Scarpelli; Rita (Rome, IT), Summa; Vincenzo (Velletri, IT)
Assignee: Istituto Di Richerche Di Biologia Molecolare P. Angeletti S.p.A. (Pomezia (Rome), IT)
Application Number:11/491,815
Patent Claims: 1. A method for treating infection by HIV or for treating or delaying the onset of AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula I: ##STR00287## or a pharmaceutically acceptable salt thereof; wherein R.sup.1 is (1) --H, (2) --C.sub.1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, --OH, --CN, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a, --N(R.sup.aR.sup.b), --C(.dbd.O)--C.sub.0-6 alkyl-N(R.sup.aR.sup.b), N(R.sup.a)--C(.dbd.O)--C.sub.0-6 alkyl-N(R.sup.bR.sup.c), --SO.sub.2R.sup.a, --N(R.sup.a)SO.sub.2R.sup.b, --SO.sub.2N(R.sup.aR.sup.b), --N(R.sup.a)--C(.dbd.O)R.sup.b, ##STR00288## or --N(R.sup.a)C(.dbd.O)C(.dbd.O)N(R.sup.aR.sup.b), (3) --R.sup.k, (4) --C.sub.1-6 alkyl-R.sup.k, wherein: (i) the alkyl is optionally substituted with one or more substituents each of which is independently halogen, --OH, --CN, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --N(R.sup.aR.sup.b), --N(R.sup.a)CO.sub.2R.sup.b, --N(R.sup.a)C(.dbd.O)--C.sub.0-6 alkyl-N(R.sup.bR.sup.c), or --N(R.sup.a)--C.sub.2-6 alkyl-OH with the proviso that the --OH is not attached to the carbon alpha to N(R.sup.a); and (ii) the alkyl is optionally mono-substituted with --R.sup.s, --C.sub.1-6 alkyl-R.sup.s, --N(R.sup.a)--C(.dbd.O)--C.sub.0-6 alkyl-R.sup.s, --N(R.sup.a)--C.sub.0-6 alkyl-R.sup.s, --O--C.sub.0-6 alkyl-R.sup.s, or --N(R.sup.a)--C(.dbd.)--C.sub.0-6 alkyl-R.sup.s; wherein R.sup.s is (a) aryl which is optionally substituted with one or more substituents each of which is independently halogen, --OH, --C.sub.1-6 alkyl, --C.sub.1-6 alkyl-OR.sup.a, --C.sub.1-6 haloalkyl --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, methylenedioxy attached to two adjacent carbon atoms, or aryl; (b) a 4- to 8-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the saturated heterocyclic ring is optionally substituted with one or more substituents each of which is independently halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkyl-OR.sup.a, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --C(.dbd.O)--C.sub.0-6 alkyl-N(R.sup.aR.sup.b), --SO.sub.2R.sup.a, oxo, aryl, or --C.sub.1-6 alkyl-aryl; or (c) a 5- to 7-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heteroaromatic ring is optionally substituted with one or more substituents each of which is independently halogen, --C.sub.1-6 alkyl, --C.sub.1-6 alkyl-OR.sup.a, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, oxo, or aryl; (5) --C.sub.0-6 alkyl-O--C.sub.0-6 alkyl-R.sup.k, (6) --C.sub.0-6 alkyl-S(O).sub.n--C.sub.0-6 alkyl-R.sup.k, (7) --O--C.sub.1-6 alkyl-OR.sup.k, (8) --O--C.sub.1-6alkyl-O--C.sub.1-6alkyl-R.sup.k, (9) --O--C.sub.1-6 alkyl-S(O).sub.nR.sup.k, (10) --C.sub.0-6 alkyl-N(R.sup.a)--R.sup.k, (11) --C.sub.0-6 alkyl-N(R.sup.a)--C.sub.1-6 alkyl-R.sup.k, (12) --C.sub.0-6 alkyl-N(R.sup.a)--C.sub.1-6 alkyl-OR.sup.k, (13) --C.sub.0-6 alkyl-C(.dbd.O)-R.sup.k, (14) --C.sub.0-6 alkyl-C(.dbd.O)N(R.sup.a)--C.sub.0-6 alkyl-R.sup.k, (15) --C.sub.0-6 alkyl-N(R.sup.a)C(.dbd.O)--C.sub.0-6 alkyl-R.sup.k, (16) --C.sub.0-6 alkyl-N(R.sup.a)C(.dbd.O)--O--C.sub.0-6 alkyl-R.sup.k, or (17) --C.sub.0-6 alkyl-N(R.sup.a)C(.dbd.O)C(.dbd.O)R.sup.k; R.sup.2 is --C.sub.1-6 alkyl which is optionally substituted with one or more substituents each of which is independently (1) halogen, (2) --OH, (3) --CN, (4) --O--C.sub.1-6 alkyl, (5) --O--C.sub.1-6 haloalkyl, (6) --C(.dbd.O)R.sup.a, (7) --CO.sub.2R.sup.a, (8) --SR.sup.a, (9) --S(.dbd.O)R.sup.a, (10) --N(R.sup.aR.sup.b), (11) --C(.dbd.O)N(R.sup.aR.sup.b), (12) --N(R.sup.a)--C(.dbd.O)--C.sub.1-6 alkyl-N(R.sup.bR.sup.c), (13) --SO.sub.2R.sup.a, (14) --N(R.sup.a)SO.sub.2R.sup.b, (15) --SO.sub.2N(R.sup.aR.sup.b), (16) --N(R.sup.a)--C(R.sup.b).dbd.O, (17) --C.sub.3-8 cycloalkyl, (18) aryl, wherein the aryl is optionally substituted with one or more substituents each of which is independently halogen, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --C.sub.0-6 alkyl-N(R.sup.aR.sup.b), or --C.sub.1-6 alkyl substituted with a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently --C.sub.1-6 alkyl, oxo, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; or (19) a 5- to 8-membered monocyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heterocycle is optionally substituted with one or more substituents each of which is independently --C.sub.1-6 alkyl, --O--C.sub.1-6 alkyl, oxo, phenyl, or naphthyl; with the proviso that none of the following substituents is attached to the carbon atom in the --C.sub.1-6 alkyl group that is attached to the ring nitrogen: halogen, --OH, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --SR.sup.a, --S(.dbd.O)R.sup.a, or --N(R.sup.a)--C(R.sup.b).dbd.O; R.sup.3 is --H or --C.sub.1-6 alkyl; R.sup.4 is (1) H, (2) C.sub.1-6 alkyl which is optionally substituted with one or more substituents each of which is independently halogen, --OH, O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --NO.sub.2, --N(R.sup.aR.sup.b), --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a, --SO.sub.2R.sup.a, or --N(R.sup.a)CO.sub.2R.sup.b, (3) C.sub.1-6 alkyl which is optionally substituted with one or more substituents each of which is independently halogen, --OH, or O--C.sub.1-4 alkyl, and which is substituted with 1 or 2 substituents each of which is independently: (i) C.sub.3-8 cycloalkyl, (ii) aryl, (iii) a fused bicyclic carbocycle consisting of a benzene ring fused to a C.sub.5-7 cycloalkyl, (iv) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, (v) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (vi) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic, (4) C.sub.2-5 alkynyl optionally substituted with aryl, (5) C.sub.3-8 cycloalkyl optionally substituted with aryl, (6) aryl, (7) a fused bicyclic carbocycle consisting of a benzene ring fused to a C.sub.5-7 cycloalkyl, (8) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, (9) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (10) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic; wherein each aryl in (3)(ii) or the aryl in (4), (5) or (6) or each fused carbocycle in (3)(iii) or the fused carbocycle in (7) is optionally substituted with one or more substituents each of which is independently halogen, --OH, --C.sub.1-6 alkyl, --C.sub.1-6 alkyl-OR.sup.a, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --CN, --NO.sub.2, --N(R.sup.aR.sup.b), --C.sub.1-6 alkyl-N(R.sup.aR.sup.b), --C(.dbd.O)N(R.sup.aR.sup.b), --C(.dbd.0)R.sup.a, --CO.sub.2R.sup.a, --C.sub.1-6 alkyl-CO.sub.2R.sup.a, --OCO.sub.2R.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a, --SO.sub.2R.sup.a, --N(R.sup.a)SO.sub.2R.sup.b, --SO.sub.2N(R.sup.aR.sup.b), --N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)CO.sub.2R.sup.b, --C.sub.1-6 alkyl-N(R.sup.a)CO.sub.2R.sup.b, aryl, --C.sub.1-6 alkyl-aryl, --O-aryl, or --C.sub.0-6 alkyl-het wherein het is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, and het is optionally fused with a benzene ring, and is optionally substituted with one or more substituents each of which is independently --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, oxo, or --CO.sub.2R.sup.a; each saturated heterocyclic ring in (3)(iv) or the saturated heterocyclic ring in (8) is optionally substituted with one or more substituents each of which is independently halogen, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --O--C.sub.1-6alkyl, --O--C.sub.1-6 haloalkyl, oxo, aryl, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; and each heteroaromatic ring in (3)(v) or the heteroaromatic ring in (9) or each fused bicyclic heterocycle in (3)(vi) or the fused bicyclic heterocycle in (10) is optionally substituted with one or more substituents each of which is independently halogen, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, oxo, aryl, or --C.sub.1-6 alkyl-aryl; or alternatively R.sup.3 and R.sup.4 together with the N to which both are attached form a C.sub.3-7 azacycloalkyl which is optionally substituted with one or more substituents each of which is independently --C.sub.1-6 alkyl or oxo; each R.sup.a, R.sup.b, R.sup.c and R.sup.d is independently --H or --C.sub.1-6 alkyl; R.sup.k is carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more substituents each of which is independently (1) halogen, (2) --OH, (3) --CN, (4) --C.sub.1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, --OH, --CN, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a, --N(R.sup.aR.sup.b), --C(.dbd.O)--(CH.sub.2).sub.0-2N(R.sup.aR.sup.b), N(R.sup.a)--C(.dbd.O)--(CH.sub.2).sub.0-2N(R.sup.bR.sup.c), --SO.sub.2R.sup.a, --N(R.sup.a)SO.sub.2R.sup.b, --SO.sub.2N(R.sup.aR.sup.b), or --N(R.sup.a)--C(R.sup.b).dbd.O, (5) --O--C.sub.1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, --OH, --CN, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a, --N(R.sup.aR.sup.b), --C(.dbd.O)--(CH.sub.2).sub.0-2N(R.sup.aR.sup.b), N(R.sup.a)--C(.dbd.O)--(CH.sub.2).sub.0-2N(R.sup.bR.sup.c), --SO.sub.2R.sup.a, --N(R.sup.a)SO.sub.2R.sup.b, --SO.sub.2N(R.sup.aR.sup.b), or --N(R.sup.a)--C(R.sup.b).dbd.O, (6) --NO.sub.2, (7) oxo, (8) --C(.dbd.O)R.sup.a, (9) --CO.sub.2R.sup.a, (10) --SR.sup.a, (11) --S(.dbd.O)R.sup.a, (12) --N(R.sup.aR.sup.b), (13) --C(.dbd.O)N(R.sup.aR.sup.b), (14) --C(.dbd.O)--C.sub.1-6 alkyl-N(R.sup.aR.sup.b), (15) --N(R.sup.a)C(.dbd.O)R.sup.b, (16) --SO.sub.2R.sup.a, (17) --SO.sub.2N(R.sup.aR.sup.b), (18) --N(R.sup.a)SO.sub.2R.sup.b, (19) --R.sup.m, (20) --C.sub.1-6 alkyl-R.sup.m, wherein the alkyl is optionally substituted with one or more substituents each of which is independently halogen, --OH, --CN, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a, --N(R.sup.aR.sup.b), --N(R.sup.a)CO.sub.2R.sup.b, --SO.sub.2R.sup.a, --N(R.sup.a)SO.sub.2R.sup.b, --SO.sub.2N(R.sup.aR.sup.b), or --N(R.sup.a)--C(R.sup.b).dbd.O, (21) --C.sub.0-6 alkyl-N(R.sup.a)--C.sub.0-6 alkyl-R.sup.m, (22) --C.sub.0-6 alkyl-O--C.sub.0-6 alkyl-R.sup.m, (23) --C.sub.0-6 alkyl-S--C.sub.0-6 alkyl-R.sup.m, (24) --C.sub.0-6 alkyl-C(.dbd.O)--C.sub.0-6 alkyl-R.sup.m, (25) --C(.dbd.O)--O--C.sub.0-6 alkyl-R.sup.m, (26) --C(.dbd.O)N(R.sup.a)--C.sub.0-6 alkyl-R.sup.m, (27) --N(R.sup.a)C(.dbd.O)--R.sup.m, (28) --N(R.sup.a)C(.dbd.O)--C.sub.1-6 alkyl-R.sup.m, wherein the alkyl is optionally substituted with one or more substituents each of which is independently halogen, --OH, --CN, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a, --N(R.sup.aR.sup.b), --N(R.sup.a)CO.sub.2R.sup.b, --SO.sub.2R.sup.a, --N(R.sup.a)SO.sub.2R.sup.b, --SO.sub.2N(R.sup.aR.sup.b), or --N(R.sup.a)--C(R.sup.b).dbd.O, (29) --N(R.sup.a)--C(.dbd.O)--N(R.sup.b)--C.sub.0-6 alkyl-R.sup.m, (30) --N(R.sup.a)--C(.dbd.O)--O--C.sub.0-6 alkyl-R.sup.m, (31) --N(R.sup.a)--C(.dbd.O)--N(R.sup.b)--SO.sub.2--C.sub.0-6 alkyl-R.sup.m, (32) --C(.dbd.O)--C(.dbd.O)--N(R.sup.aR.sup.b), (33) --C(.dbd.O)--C.sub.1-6 alkyl-SO.sub.2R.sup.a, or (34) --C(.dbd.O)--C(.dbd.O)R.sup.m, carbocycle in R.sup.k is (i) a C.sub.3 to C.sub.8 monocyclic saturated or unsaturated ring, (ii) a C.sub.7 to C.sub.12 bicyclic ring system, or (iii) a C.sub.11 to C.sub.16 tricyclic ring system, wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated; heterocycle in R.sup.k is (i) a 4- to 8-membered, saturated or unsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ring system, or (iii) an 11 to 16-membered tricyclic ring system; wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated; the monocyclic ring, bicyclic ring system or tricyclic ring system contains from 1 to 6 heteroatoms selected from N, O and S and a balance of carbon atoms; and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally be oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized; each R.sup.m is independently C.sub.3-8 cycloalkyl; aryl; a 5- to 8-membered monocyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S; or a 9- to 10-membered bicyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S; wherein any one or more of the nitrogen and sulfur heteroatoms in the heterocycle or bicyclic heterocycle is optionally oxidized and any one or more of the nitrogen heteroatoms is optionally quaternized; and wherein the cycloalkyl or the aryl defined in R.sup.m is optionally substituted with one or more substituents each of which is independently halogen, --C.sub.1-6 alkyl optionally substituted with --O--C.sub.1-4 alkyl, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, --N(R.sup.aR.sup.b), aryl, or --C.sub.1-6 alkyl-aryl; and the monocyclic or bicyclic heterocycle defined in R.sup.m is optionally substituted with one or more substituents each of which is independently halogen, --C.sub.1-6 alkyl, --C.sub.1-6 haloalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 haloalkyl, oxo, aryl, --C.sub.1-6 alkyl-aryl, --C(.dbd.O)-aryl, --CO.sub.2-aryl, --CO.sub.2--C.sub.1-6 alkyl-aryl, a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; and each n is independently an integer equal to zero, 1 or 2.

2. The method according to claim 1, wherein the compound of Formula I is a compound selected from the group consisting of: N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-d- ihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide; N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxa- diazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamid- e; and pharmaceutically acceptable salts thereof.

3. The method according to claim 2, wherein the compound of Formula I is N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo-1,6-d- ihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide or a pharmaceutically acceptable salt thereof.

4. The method according to claim 2, wherein the compound of Formula I is N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxa- diazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamid- e or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1, wherein in the compound of Formula I or a pharmaceutically acceptable salt thereof: R.sup.1 is: (1) --H. (2) --C.sub.1-6 alkyl, which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, --OH, --CN, --O--C.sub.1-4 alkyl, --O--C.sub.1-4 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.a, --N(R.sup.aR.sup.b), --C(.dbd.O)--C.sub.0-4 alkyl-N(R.sup.aR.sup.b), N(R.sup.a)--C(.dbd.O)--C.sub.0-4 alkyl-N(R.sup.bR.sup.c), --SO.sub.2R.sup.a, --N(R.sup.a)SO.sub.2R.sup.b, --SO.sub.2N(R.sup.aR.sup.b), --N(R.sup.a)--C(.dbd.O)R.sup.b, ##STR00289## or --N(R.sup.2)C(.dbd.O)C(.dbd.O)N(R.sup.aR.sup.b), (3) --R.sup.k, (4) --C.sub.1-4 alkyl-R.sup.k, wherein: (i) the alkyl is optionally substituted with from 1 to 4 substituents each of which is independently halogen, --OH, --CN, --O--C.sub.1-4 alkyl, --O--C.sub.1-4 haloalkyl, --N(R.sup.aR.sup.b), --N(R.sup.a)CO.sub.2R.sup.b, --N(R.sup.a)C(.dbd.O)--C.sub.0-4 alkyl-N(R.sup.bR.sup.c), or --N(R.sup.a)--(CH.sub.2).sub.2-4--OH; and (ii) the alkyl is optionally mono-substituted with --R.sup.s, --N(R.sup.a)--C(.dbd.O)--C.sub.0-4 alkyl-R.sup.s; wherein R.sup.2 is (a) aryl which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, --OH, --C.sub.1-4 alkyl, --C.sub.1-4 alkyl-OR.sup.a, --C.sub.1-4 haloalkyl --O--C.sub.1-6 alkyl, --O--C.sub.1-4 haloalkyl, methylenedioxy attached to two adjacent carbon atoms, or phenyl; (b) a 5- to 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, --C.sub.1-4 alkyl, --C.sub.1-4 alkyl-OR.sup.a, --C.sub.1-4 haloalkyl, --O--C.sub.1-4 alkyl, --O--C.sub.1-4 haloalkyl, oxo, or phenyl; or (c) a 5- to 6-membered saturated heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, --C.sub.1-4 alkyl, --C.sub.1-4 alkyl-OR.sup.a, --C.sub.1-4 haloalkyl, --O--C.sub.1-4 alkyl, --O--C.sub.1-4 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --C.sub.1-4 alkyl-N(R.sup.aR.sup.b), --SO.sub.2R.sup.a, oxo, or phenyl, (5) --(CH.sub.2).sub.0-3--C(.dbd.O)N(R.sup.a)--(CH.sub.2).sub.0-3--R.sup.k, (6) --C(C.sub.1-4 alkyl).sub.2N(R.sup.a)C(.dbd.O)R.sup.b, (7) --C(C.sub.1-4 alkyl).sub.2N(R.sup.a)C(.dbd.O)R.sup.k, or (8) --C(C.sub.1-4 alkyl).sub.2N(R.sup.a)C(.dbd.O)C(.dbd.O)N(R.sup.bR.sup.c).

6. The method according to claim 5, wherein in the compound of Formula I or a pharmaceutically acceptable salt thereof: R.sup.2 is methyl R.sup.3 is --H; and R.sup.4 is --CH.sub.2-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents, each of which is independently --F, --Br, --Cl, --OH, --C.sub.1-4 alkyl, --C.sub.1-4 fluoroalkyl, --O--C.sub.1-4 alkyl, --SO.sub.2--C.sub.1-4 alkyl, --S--C.sub.1-4 alkyl, --N(CH.sub.3).sub.2, or --O--C.sub.1-4 fluoroalkyl.

7. The method according to claim 6, wherein in the compound of Formula I or a pharmaceutically acceptable salt thereof: R.sup.k is phenyl; a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from 1 or 2 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; a 5- or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms selected from 1 or 2 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; or a bicyclic heterocycle which is a benzene ring fused to a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms; wherein: (a) the phenyl, the saturated heterocyclic ring, heteroaromatic ring, or bicyclic heterocycle is optionally substituted with from 1 to 3 substituents each of which is independently (1) fluoro, (2) chloro, (3) bromo, (4) --OH (5) --CF.sub.3, (6) --C.sub.1-4 alkyl, which is optionally substituted with 1 or 2 substituents each of which is independently --OH, --CN, --O--C.sub.1-4 alkyl, --OCF.sub.3, --N(R.sup.aR.sup.b), --C(.dbd.O)N(R.sup.aR.sup.b), or N(R.sup.a)--C(.dbd.O)--(CH.sub.2).sub.0-2N(R.sup.bR.sup.c), (7) --OCF.sub.3, (8) --O--C.sub.1-4 alkyl (9) --C(.dbd.O)R.sup.a, (10) --CO.sub.2R.sup.a, (11) --SR.sup.a, (12) --SR.sup.a, (13) --N(R.sup.aR.sup.b), (14) --C(.dbd.O)N(R.sup.aR.sup.b), (15) --C(.dbd.O)--(CH.sub.2).sub.1-2--N(R.sup.aR.sup.b), (16) --N(R.sup.a)C(.dbd.O)R.sup.b, or (17) --SO.sub.2R.sup.a; (b) the phenyl is optionally mono-substituted with (1) --(CH.sub.2).sub.1-2--R.sup.m, or (2) --(CH.sub.2)0-2--N(R.sup.a)--(CH.sub.2).sub.0-2--R.sup.m; and (c) the saturated heterocyclic ring, heteroaromatic ring, or bicyclic heterocycle is optionally mono- or di-substituted with (1) oxo (2) --(CH.sub.2).sub.1-2--R.sup.m, (3) --O--(CH.sub.2).sub.1-2--R.sup.m, or (4) --(CH.sub.2).sub.0-1--C(.dbd.O)--(CH.sub.2).sub.0-2--R.sup.m; and each R.sup.m is independently cyclopropyl; phenyl; a 5- or 6-membered saturated heterocyclic ring selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl; or a 5- or 6-membered heteroaromatic ring selected from thienyl, pyridyl optionally in the form of an N-oxide, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, and pyridazinyl; wherein the cyclopropyl is unsubstituted; the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, --C.sub.1-4 alkyl, --CF.sub.3, --O--C.sub.1-4 alkyl, --OCF.sub.3, or --N(R.sup.aR.sup.b); the saturated heterocyclic ring is optionally substituted with 1 or 2 substituents each of which is independently --C.sub.1-4 alkyl, --CF.sub.3, --O--C.sub.1-4 alkyl, --OCF.sub.3, oxo, phenyl, --(CH.sub.2).sub.1-2-phenyl, --C(.dbd.O)-phenyl, --CO.sub.2-phenyl, or --C.sub.2--CH.sub.2-phenyl; and the heteroaromatic ring is optionally substituted with 1 or 2 substituents each of which is independently --C.sub.1-4 alkyl, --CF.sub.3, --O--C.sub.1-4 alkyl, --OCF.sub.3, oxo, phenyl, or --(CH.sub.2).sub.1-2-phenyl.

8. The method according to claim 7, wherein in the compound of Formula I or a pharmaceutically acceptable salt thereof: R.sup.1 is: (1) --H, (2) --C.sub.1-4 alkyl, which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, --O--C.sub.1-4 alkyl, --O--C.sub.1-4 haloalkyl, --C(.dbd.O)R.sup.a, --CO.sub.2R.sup.a, --N(R.sup.aR.sup.b), or --C(.dbd.O)--(CH.sub.2).sub.0-2--N(R.sup.aR.sup.b), (3) --R.sup.k, (4) --(CH.sub.2).sub.1-4--R.sup.k, wherein: (i) the --(CH.sub.2).sub.1-4-moiety is optionally substituted with 1 or 2 substituents each of which is independently halogen, --OH, --O--C.sub.1-4 alkyl, --O--C.sub.1-4 haloalkyl, or --N(R.sup.aR.sup.b); and (ii) the --(CH.sub.2).sub.14-moiety is optionally mono-substituted with --R.sup.s or --N(R.sup.a)--(CH.sub.2).sub.1-2--R.sup.s; wherein R.sup.s is (a) phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently halogen, --C.sub.1-4 alkyl, --C.sub.1-4 alkyl-OR.sup.a, --C.sub.1-4 haloalkyl, --O--C.sub.1-4 alkyl, or --O--C.sub.1-4 haloalkyl; or (b) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, --C.sub.1-4 alkyl, --C.sub.1-4 alkyl-OR.sup.a, --C.sub.1-4 haloalkyl, --O--C.sub.1-4 alkyl, or --O--C.sub.1-4 haloalkyl; or (c) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently halogen, --C.sub.1-4 alkyl, --C.sub.1-4 alkyl-OR.sup.a, --C.sub.1-4 haloalkyl, --O--C.sub.1-4 alkyl, --O--C.sub.1-4 haloalkyl, --C(=O)R.sup.a, or --CO.sub.2R.sup.a, (5) --C(.dbd.O)N(R.sup.a)--(CH.sub.2).sub.0-3--R.sup.k, (6) --C(CH.sub.3).sub.2N(R.sup.a)C(.dbd.O)R.sup.b, (7) --C(CH.sub.3).sub.2N(R.sup.a)C(.dbd.O)R.sup.k, or (8) --C(CH.sub.3).sub.2N(R.sup.a)C(.dbd.O)C(.dbd.O)N(R.sup.bR.sup.c).

9. The method according to claim 1, which is a method for treating infection by HIV.

10. The method according to claim 9, which is a method for treating infection by HIV-1.

11. The method according to claim 10, wherein the compound of Formula I is a compound selected from the group consisting of: N1-[1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6-oxo- 1,6-dihydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide; N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-( 1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1- ,6-dihydropyrimidine-4-carboxamide; and pharmaceutically acceptable salts thereof.

12. The method according to claim 11, wherein the compound of Formula I is N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-- oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxa- mide or a pharmaceutically acceptable salt thereof.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc