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Title:
1,4-BENZODIAZEPIN-2-ONES USEFUL AS HIV REVERSE TRANSCRIPTASE INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2000/073284
Kind Code:
A2
Abstract:
The present invention relates to 1,4-benzodiazepin-2-ones of Formula (I) or stereoisomeric forms, stereoisomeric mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, and methods of using the same for treating viral infection or as an assay standard or reagent.

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JP5322918Contraceptive composition
WO2001034119INHIBITORS OF CRYSTALLIZATION IN A SOLID DISPERSION
WO/1999/066065PROTEASOMAL ACTIVITY
Inventors:
RODGERS JAMES D
JOHNSON BARRY L
WANG HAISHENG
Application Number:
PCT/US2000/014001
Publication Date:
December 07, 2000
Filing Date:
May 19, 2000
Export Citation:
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Assignee:
DU PONT PHARM CO (US)
International Classes:
A61P31/18; C07D243/14; C07D401/06; C07D405/06; C07D409/06; C07D417/06; (IPC1-7): C07D243/14; C07D401/06; C07D405/06; C07D409/06; C07D417/06; A61K31/5513; A61P31/18
Domestic Patent References:
WO1996029329A11996-09-26
WO1995012583A11995-05-11
WO1995013273A11995-05-18
Foreign References:
US3682892A1972-08-08
US3714145A1973-01-30
US3864330A1975-02-04
US3801569A1974-04-02
US4021421A1977-05-03
US4045433A1977-08-30
US4316897A1982-02-23
EP0530994A11993-03-10
DE4320347A11994-12-22
US5519021A1996-05-21
Other References:
HOUPIS I N ET AL: "SYNTHESIS OF A NEW GENERATION REVERSE TRANSCRIPTASE INHIBITOR VIA THE BCl3/GACl3-INDUCED CONDENSATION OF ANILINES WITH NITRILES (SUGASAWA REACTION)" TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 35, no. 37, 1994, pages 6811-6814, XP002072025 ISSN: 0040-4039 cited in the application
TUCKER T J ET AL: "SYNTHESIS OF A SERIES OF 4-(ARYLETHYNYL)-6-CHLORO-4-CYCLOPROPYL- 3,4-D IGYDROQUINAZOLIN-2(1H)-ONES AS NOVEL NON-NUCLEOSIDE HIV-1 REVERSETRANSCRIPTASE INHIBITORS" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 37, no. 15, 1994, pages 2437-2444, XP002072024 ISSN: 0022-2623 cited in the application
HUFFMAN M A ET AL: "LITHIUM ALKOXIDES OF CINCHONA ALKALOIDS AS CHIRAL CONTROLLERS FOR ENANTIOSELECTIVE ACETYLIDE ADDITION TO CYCLIC N-ACYL KETIMINES" JOURNAL OF ORGANIC CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. EASTON, vol. 60, no. 6, 1995, pages 1590-1594, XP002072026 ISSN: 0022-3263 cited in the application
Attorney, Agent or Firm:
Van Atten, Mary K. (DE, US)
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Claims:
WHAT IS CLAIMED IS:
1. A compound of Formula (I): or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: A is O or S; W is N or CR3; X is N or CR3a ; Y is N or CR3b ; Z is N or CR3c; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; R1 is selected from the group cyclopropyl and C1_3 alkyl substituted with 07 halogen; R2 is selected from the group H,R2c,CH2C (=O) R2c,OR2c, OCHR2aR2b,OCH2CHR2aR2b, O(CH2)2CHR2aR2b, OCHR2aC#CR2b,SR2c,OCHR2aC=CR2b,OCHR2aC=R2c, SCHR2aR2B,SCH2CHR2aR2B, S(CH2)2CHR2aR2b, SCHR2aC#CR2b,NR2aR2c,SCHR2aC=CR2b,SCJHR2aC=R2c, NHCHR2aR2b,NHCH2CHR2aR2b, NH(CH2)2CHR2aR2b, NHCHR2aC=CR2b,NHCHR2aC=CR2b,NHCHR2aC=R2c, NHCHR2aC#CR2b; R2a is selected from the group H, CH3, CH2CH3, CH (CH3) 2, and CH2CH2CH3; R2b is H or R2c; R2C is selected from the group Cl6 alkyl substituted with 02 R4; C25 alkenyl substituted with 02 R4; C25 alkynyl substituted with 01 R4; C3_6 cycloalkyl substituted with 02 R3d; phenyl substituted with 02 R3d; and 36 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 02 R3d ; alternatively, the groupNR2aR2c represents a 47 membered cyclic amine, wherein 01 carbon atoms are replaced by O or NR5; R3 is selected from the group H, C1_4 alkyl,OH, Ci4 alkoxy, OCF3, F, Cl, Br, I,NR5R5a,N02,CN,C (O) R6, NHC (0) R7,NHC (0) NR5R5a, NHSO2R10, SO2NR5R5a, and a 56 membered heteroaromatic ring containing 14 heteroatoms selected from the group O, N, and S; R3a is selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, Br, I,NR5R5a,N02,CN,C (0) R6, NHC (O) R7,NHC (O) NR5R5a, NHSO2R10, SO2NR5R5a, and a 56 membered heteroaromatic ring containing 14 heteroatoms selected from the group O, N, and S; alternatively, R3 and R3a together formOCH20 ; R3b is selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, Br, I, NR5R5a, NO2, CN, C (O) R6, NHC (0) R7,NHC (0) NR5R5a, NHSO2R10, andS02NR5R5a ; alternatively, R3a and R3b together formOCH20 ; R3c is selected from the group H, C1_4 alkyl,OH, Ci4 alkoxy, OCF3, F, I,NR5R5a,NO2,CN,C(O)R6,Br, NHC(O)R7, NHC(O)NR5R5a, SO2NR5R5a;and alternatively, R3b and R3c together formOCH20 ; R3d, at each occurrence, is independently selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, Br, I,NR5R5a,N02,CN,C (O) R6,NHC (O) R7, NHC (O) NR5R5a,NHS02R10, and SO2NR5R5a; R3e, at each occurrence, is independently selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, Br, I,NR5R5a,N02,CN,C (O) R6,NHC (O) R7, NHC (O) NR5R5a,NHSO2R10, andS02NR5R5a ; R3f, at each occurrence, is independently selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, Br, NO2,CN,C(O)R6,NHC(O)R7,I,NR5R5a, NHC (O) NR5R5a, NHSO2R10, andS02NR5R5a; R4 is selected from the group F, Cl, Br, I, CF3, C16 alkyl substituted with 02 R3e; C3_10 carbocycle substituted with 02 R3e; phenyl substituted with 05 R3e; and a 510 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 02 R3e ; R5 and R5a are independently selected from the group H and C14alkyl; alternatively, R5 and R5a, together with the nitrogen to which they are attached, combine to form a 56 membered ring containing 01 O or N atoms; R6 is selected from the group H, OH, C1_4 alkyl, C1_4 alkoxy, and NR5R5a ; R7 is selected from the group C1_3 alkyl and C13 alkoxy; R8 is selected from the group H, OH, C1_6 alkyl substituted with 02 R9; C2_6 alkenyl substituted with 02 R9; C2_6 alkynyl substituted with 02 R9; C3_5 cycloalkyl substituted with 02 R3f; phenyl substituted with 05 R3f; and a 56 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 02 R3f ; R9 is selected from the group benzoyl; C3_10 carbocycle substituted with 05 R3f; and a 510 membered heterocyclic system containing 13 heteroatoms selected from the group 0, N, and S, substituted with 02 R3f ; R10 is selected from the group C1_4 alkyl and phenyl; and Rll is selected from the group H, C16 alkyl, C16 alkenyl, C16 alkynyl, aralkyl, aryl.
2. A compound according to Claim 1, wherein: A is O; W is N or CR3 ; X is N or CR3a ; Y is N or CR3b; Z is N or CH; R1 is selected from the group cyclopropyl and C1_3 alkyl substituted with 17 halogen; R2 is selected from the group H,R2c,CH2C (=O) R2c,OR2c, <BR> <BR> <BR> OCHR2aR2b,OCH2CHR2aR2b,0 (CH2) 2CHR2aR2b,<BR> <BR> <BR> <BR> <BR> <BR> andOCHR2aC#CR2b;OCHR2aC=CR2b,OCHR2aC=R2c, R2a is selected from the group H, CH3, CH2CH3, CH (CH3) 2, and CH2CH2CH3; R2b is H or R2c; R2C is selected from the group C1_5 alkyl substituted with 02 R4; C25 alkenyl substituted with 02 R4; C25 alkynyl substituted with 01 R4; C3_6 cycloalkyl substituted with 02 R3d; and phenyl substituted with 02 R3d ; R3, at each occurrence, is independently selected from the group H, C1_4 alkyl, OH, C1_4 alkoxy, F, Cl, Br, I, NR5R5a, N02,CN, C (O) R6, NHC (O) R7, NHC (O) NR5R5a, and a 56 membered heteroaromatic ring containing 14 heteroatoms selected from the group O, N, and S; R3a, at each occurrence, is independently selected from the group H, C1_4 alkyl, OH, C1_4 alkoxy, F, Cl, Br, I, NR5R5a, NO2,CN, C (O) R6, NHC (O) R7, NHC (O) NR5R5a, and a 56 membered heteroaromatic ring containing 14 heteroatoms selected from the group O, N, and S ; alternatively, R3 and R3a together formOCH20 ; R3b, at each occurrence, is independently selected from the group H, C1_3 alkyl, OH, C1_3 alkoxy, F, and Cl; alternatively, R3a and R3b together formOCH20 ; R3d, at each occurrence, is independently selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, CL, Br, I,NR5R5a,N02,CN,C (O) R6,NHC (O) R7, NHC (O) NR5R5a, NHSO2R10, andS02NR5R5a; R3e, at each occurrence, is independently selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, Br, I,NR5R5a,N02,CN,C (O) R6,NHC (O) R7, NHC (O) NR5R5a,NHS02R10, andS02NR5R5a; R3f, at each occurrence, is independently selected from the group H, C14 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, Br, I, NR5R5a, NO2, CN, C (O) R6,NHC (0) R7, NHC (O) NR5R5a,NHS02R1O, andS02NR5R5a ; R4 is selected from the group Cl, F, CF3; C1_4 alkyl substituted with 02 R3e ; C3_5 carbocycle substituted with 02 R3e ; phenyl substituted with 05 R3e; and a 56 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 02 R3e ; R5 and R5a are independently selected from the group H, CH3 and C2H5; R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a; R7 is selected from the group CH3, C2H5, CH (CH3) 2, OCH3, OC2Hs, and OCH (CH3) 2; and, R8 is selected from the group H, OH; C16 alkyl substituted with 02 R9; C2_6 alkenyl substituted with 02 R9; C2_6 alkynyl substituted with 02 R9; C35 cycloalkyl substituted with 02 R3f ; phenyl substituted with 05 R3f; and a 56 membered heterocyclic system containing 13 heteroatoms selected from the group 0, N, and S, substituted with 02 R3f; R9 is selected from the group benzoyl; C3_10 carbocycle substituted with 05 R3f; and a 510 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 02 R3f; Rll is selected from the group H, cyclopropyl, CH3, C2H5, and CH (CH3) 2, npropyl, nbutyl, isobutyl.
3. A compound according to Claim 2, wherein: A is O; W is CR3; X is CR3a; Y is CH; Z is CH; R1 is selected from the group CHF2, CF3, and C2F5 ; R2 is selected from the group H, R2c, CH2C (=O) R2C, OCH2C=CR2b,andOCH2C#CR2b;OCH2R2b,OCH2CH2R2b, R2b is H or R2c; R2C is selected from the group C1_4 alkyl substituted with 02 R4; C2_3 alkenyl substituted with 02 R4; C23 alkynyl substituted with 01 R4; and C36 cycloalkyl substituted with 02 R3d; R3, at each occurrence, is independently selected from the group H, C1_3 alkyl, OH, C1_3 alkoxy, F, Cl, Br, NR5R5a, N02,CN, C (O) R6, NHC (O) R7, and NHC (O) NR5R5a ; R3a, at each occurrence, is independently selected from the group H, C1_3 alkyl, OH, C1_3 alkoxy, F, Cl, Br, NR5R5a, N02,CN, C (O) R6, NHC (0) R7, and NHC (O) NR5R5a; alternatively, R3 and R3a together formOCH20 ; R3e, at each occurrence, is independently selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, NR5R5a,C (O) R6, andS02NR5R5a; R3f, at each occurrence, is independently selected from the group H, C1_4 alkyl,OH, C1_4 alkoxy, OCF3, F, Cl, NR5R5a,C (O) R6, andS02NR5R5a ; R4 is selected from the group Cl, F, CF3, C1_4 alkyl substituted with 01 R3e; C3_5 carbocycle substituted with 02 R3e; phenyl substituted with 02 R3e; and a 56 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 01 R3e ; R5 and R5a are independently selected from the group H, CH3 and C2H5; R6 is selected from the group H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a ; R7 is selected from the group CH3, C2H5, OCH3, and OC2H5 ; and, R8 is selected from the group H, OH; C16 alkyl substituted with 02 R9; C2_6 alkenyl substituted with 02 R9; C2_6 alkynyl substituted with 02 R9; C35 cycloalkyl substituted with 02 R3f ; phenyl substituted with 05 R3f; and a 56 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 02 R3f; R9 is selected from the group benzoyl; C3_6 carbocycle substituted with 05 R3f; and a 56 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 02 R3f ; Rll is selected from the group H, cyclopropyl, CH3, C2H5, and CH (CH3) 2, npropyl, nbutyl, isobutyl.
4. A compound according to Claims 3, wherein: A is O; W is CR3; X is CR3a ; Y is CH; Z is CH; R1 is CF3; R2 is selected from the group H,R2CB andCH2C (=O) R2c ; R2C is selected from the group C1_4 alkyl substituted with 1 R4; C2_3 alkenyl substituted with 1 R4; and C2_3 alkynyl substituted with 1 R4; R3, at each occurrence, is independently selected from the group H, methyl, ethyl, OH, methoxy, ethoxy, F, and Cl; R3a, at each occurrence, is independently selected from the group H, methyl, ethyl, OH, methoxy, ethoxy, F, and Cl; alternatively, R3 and R3a together formOCH20 ; R3e, at each occurrence, is independently selected from the group H, methyl, ethyl, OH, methoxy, ethoxy, F, and Cl; R3f, at each occurrence, is independently selected from the group H, methyl, ethyl, OH, methoxy, ethoxy, F, and Cl ; R4 is selected from the group Cl, F, CF3, CH3, CH2CH3, CH (CH3) 2; cyclopropylsubstituted with 01 R3e ; 1methylcyclopropylsubstituted with 01 R3e ; cyclobutyl substituted with 01 R3e ; phenyl substituted with 02 R3e; and a 56 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 01 R3e, wherein the heterocyclic system is selected from the group 2pyridyl, 3pyridyl, 4pyridyl, 2furanyl, 3furanyl, 2thienyl, 3thienyl, 2oxazolyl, 2thiazolyl, 4isoxazolyl, and 2imidazolyl; R5 and R5a are independently selected from the group H, CH3 and C2H5; R8 is selected from the group H, OH; C16 alkyl substituted with 01 R9; C2_6 alkenyl substituted with 01 R9; C2_6 alkynyl substituted with 01 R9 ; C35 cycloalkyl substituted with 02 R3f; and phenyl substituted with 05 R3f ; R9 is selected from the group benzoyl; C3_6 cycloalkyl substituted with 03 R3f; and a C3_6 phenyl substituted with 03 R3f; and a 56 membered heterocyclic system containing 13 heteroatoms selected from the group O, N, and S, substituted with 02 R3f; wherein the heterocyclic system is selected from the group 2pyridyl, 3pyridyl, 4pyridyl, 2furanyl, 3furanyl, 2thienyl, 3thienyl, 2oxazolyl, 2thiazolyl, 4isoxazolyl, and 2imidazolyl; and Rll is selected from the group H, cyclopropyl, CH3, C2H5, and CH (CH3) 2, npropyl, nbutyl, isobutyl.
5. A compound of Claims 1,2,3 or 4, wherein the compound is of Formula (Ic):.
6. A compound of Claims 1,2,3 or 4, wherein the compound is of Formula (Id):.
7. A compound of Claims 1,2,3 or 4, wherein the compound is of formula le:.
8. A compound of Claims 1,2,3 or 4, wherein the compound is of Formula (If):.
9. The compound according to Claim 1, wherein the compound is selected from the group: 7Chloro4butyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4 (3methyl2butenyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2pyridylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2methyl5thiazolylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (5methyl2pyridylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (6chloro2pyridylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4propyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4hexyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4pentyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; <BR> <BR> 7Chloro4 (3phenylpropyl)1, 5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; 7Chloro4benzyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4pentyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4 (5pentenyl)1, 5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4 (2methylbenzyl)1, 5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (2bromobenzyl)1, 5dihydro5 (trifluoromethyl)<BR> 1,4benzodiazepin2one;<BR> <BR> 7Chloro4 (2chloro6fluorobenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (2cyanobenzyl)1, 5dihydro5 (trifluoromethyl)<BR> 1,4benzodiazepin2one;<BR> <BR> 7Chloro4 (2, 6difluorobenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (3methoxybenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Cloro4 (2, 6diclorobenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (3cyanobenzyl)1, 5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; 7Chloro4 (2methoxybenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2thienylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (3thienylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2furanylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (3methylpentyl)1, 5dihydro5 (trifluoromethyl)<BR> 1,4benzodiazepin2one;<BR> <BR> 7Chloro4 (3methoxy2pyridylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (3cyclopropyl2propynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5butyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4(2hexynyl)1, 5dihydro5(trifluoromethyl)1,(2hexynyl)1, 5dihydro5(trifluoromethyl)1, 4 benzodiazepin2one; 7Chloro4 (4methyl2pentynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (3methylpentyl)1, 5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; 6,7Difluoro4 (2fluoro6methoxybenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 6,7Difluoro4hydroxy5 (3methyl1butynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5(3methyl1butynyl)1,(3methyl1butynyl)1, 5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5 (2thienylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4butyl5 (3methyl1butynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro4(2fluorobenzyl)1, 5dihydro5(trifluoromethyl) 1,4benzodiazepin2one; 7Chloro4 (2 (2chlorophenyl) ethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4benzoyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4 (2 (2iodophenyl) ethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2 (3chlorophenyl) ethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4(3fluorobenzyl)1,5dihydro5(trifluoromethyl) 1,4benzodiazepin2one; 7Chloro4 (1, 6dimethoxybenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (2, 5dimethoxybenzyl)1,5dihydro5<BR> (trifluoromethyl)1,4benzodiazepin2one;<BR> <BR> 7Chloro4 (2, 5dimethoxy6fluorobenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2methoxy6fluorobenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2, 3difluorobenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2, 5difluorobenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (2pentynyl)1, 5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4 (4bromothien2ylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (3methylbutyl)1, 5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (4penten1yl)1, 5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (2penten1yl)1, 5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; 7Chloro4 (3phenyl2propynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (4 (5chloro2,3thiadiazole) methyl)1,5dihydro<BR> 5 (trifluoromethyl)1,4benzodiazepin2one;<BR> <BR> 7Chloro4 (3 (2furanyl)2propenyl)1,5,dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2, 3difluoro6methoxybenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4 (2fluoro6methoxybenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4phenyl5butyl1,5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; <BR> <BR> 7Chloro4 (2pentynyl)1, 5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro5 (cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4phenyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4 (2propynyl)1, 5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4(2butynyl)1, 5dihydro5(trifluoromethyl)1,(2butynyl)1, 5dihydro5(trifluoromethyl)1, 4 benzodiazepin2one; 7Chloro5 (2cyclopropyl2ethanonyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5benzyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; <BR> <BR> 7Chloro5 (2methylpropyl)1, 5dihydro5 (trifluoromethyl) 1,4benzodiazepin2one; <BR> <BR> 7Chloro5(2phenylethyl)1, 5dihydro5(trifluoromethyl)<BR> 1,4benzodiazepin2one;<BR> <BR> 7Chloro3methyl5 (4methylbutyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro3methyl5 (cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5 (cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5 (S) (cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro4methyl5 (cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro3 (2methylpropyl)5pentyl1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro3methyl5(2cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5pentyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro4 (2fluoro6methylbenzyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 3Methyl5pentyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; <BR> <BR> 7Chloro3methyl5 (2cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 3(R)Methyl5(2cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 3 (S)Methyl5 (cyclopropylethynyl)1, 5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 3Ethyl5 (cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5pentyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; <BR> <BR> 7Chloro5 (3methylbutyl)1, 5dihydro5 (trifluoromethyl)<BR> 1,4benzodiazepin2one; 7Chloro5benzyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro5 (2cyclopropylEethenyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5hexyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; 7Chloro5(2cyclopropylethyl)1,(2cyclopropylethyl)1, 5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; <BR> <BR> 7Chloro3methyl5 (2cyclopropylethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 6,7Difluoro5 (2cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5 (cyclopropylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5 (4,4,4trifluorobutyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Methoxy5 (cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Fluoro5 (cyclopropylethynyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Fluoro5 (2cyclopropylZethenyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 3trifluoropropyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5 (2pyridylmethyl)1,5dihydro5 (trifluoromethyl)1,4benzodiazepin2one; 7Chloro5butyl1,5dihydro5 (trifluoromethyl)1,4 benzodiazepin2one; or a pharmaceutically acceptable salt form thereof.
10. 8 A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1 or pharmaceutically acceptable salt form thereof.
11. 9 A method for treating HIV infection, comprising: administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1 or pharmaceutically acceptable salt form thereof.
12. A method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of: (a) a compound of Claim 1 or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
13. The method according to Claim 10, wherein the reverse transcriptase inhibitor is selected from the group AZT, ddC, ddI, d4T, 3TC, delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC442, HBY 097, ACT, UC781, UC782, RD42025, and MEN 10979, and the protease inhibitor is selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS232623, GS3333, KNI413, KNI272, LG71350, CGP61755, PD 173606, PD 177298, PD 178390, PD 178392, U140690, and ABT378.
14. The method according to Claim 11, wherein the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.
15. The method according to Claim 13, wherein the reverse transcriptase inhibitor is AZT.
16. The method according to Claim 13, wherein the protease inhibitor is indinavir.
17. A pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of: (a) a compound of Claim 1; and, (b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.
18. A 1,4benzodiazepin2one for use in therapy.
19. A 1,4,benzodiazepin2one for the manufacture of a medicament for the treatment of HIV infection.
Description:
INTERNATIONALSEARCHREPORT| InteS malApWlicationNo PCT/US00/14001 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT Category ° Cilation of document,withindication.whereappropriate,oftherelevantpassag esRelevanttoclaimNo. AUS3801569A(STERNBACHLET AL)1,8 2April1974(1974-04-02) column3,line71-column4,line19 Xcolumn3,line71-column4,line1916 AUS4021421A(KISFALUDYLAJOSETAL)1,8 3May1977(1977-05-03) column9,line9-line34;claim1 Xabstract;claim116 AUS4045433A(ROHRICHTJULIAETAL)1,8 30August1977(1977-08-30) column1,line5-line44 Xcolumn1,line8-line5016 XUS4316897A(LOTZWOLFGANG)16 23February1982(1982-02-23) abstract;claims AWO9629329A(DUPONT)1,8-13 26September1996(1996-09-26) citedintheapplication claims1,13,19,20 AEP0530994A(MERCK&COINC)1,8-10 10March1993(1993-03-10) citedintheapplication abstract;claims1,8-10 &WO9304047A4March1993(1993-03-04) citedintheapplication AWO9512583A(MERCK&COINC)1,8-10 11May1995(1995-05-11) citedintheapplication claims1,8-11 ADE4320347A(BOEHRINGERMANNHEIMGMBH)1,8,9 22December1994(1994-12-22) citedintheapplication claims1,10,11 ~~ ~-- AUS5519021A(PAYNELINDASETAL)1,8,9 21May1996(1996-05-21) citedintheapplication claims1,2,4,5 AWO9513273A(MERCK&COINC)1 18May1995(1995-05-18) citedintheapplication page1,line20-page2,line16 INTERNATIONALSEARCHREPORTInte Inal Apblication No PCT/US00/14001 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT Category Chation ofdocument,withindication.whereappropriate,oftherelevantpass agesRelevanttoclaimNo. AHOUPISINETAL:"SYNTHESISOFANEW1 GENERATIONREVERSETRANSCRIPTASEINHIBITOR VIATHEBC13/GAC13-INDUCEDCONDENSATIONOF ANILINESWITHNITRILES(SUGASAWA REACTION)" TETRAHEDRONLETTERS,NL,ELSEVIERSCIENCE PUBLISHERS,AMSTERDAM, vol.35,no.37,1994,pages6811-6814, XP002072025 ISSN:0040-4039 citedintheapplication thewholedocument ATUCKERTJETAL:"SYNTHESISOFASERIES1 OF4- (ARYLETHYNYL)-6-CHLORO-4-CYCLOPROPYL- 3,4-DIGYDROQUINAZOLIN-2(1H)-ONESASNOVEL NON-NUCLEOSIDEHIV-1REVERSETRANSCRIPTASE INHIBITORS" JOURNALOFMEDICINALCHEMISTRY,US,AMERICAN CHEMICALSOCIETY.WASHINGTON, vol.37,no.15,1994,pages2437-2444, XP002072024 ISSN:0022-2623 citedintheapplication thewholedocument AHUFFMANMAETAL:"LITHIUMALKOXIDESOF 1 CINCHONAALKALOIDSASCHIRALCONTROLLERS FORENANTIOSELECTIVEACETYLIDEADDITIONTO CYCLICN-ACYLKETIMINES" JOURNALOFORGANICCHEMISTRY,US,AMERICAN CHEMICALSOCIETY.EASTON, vol.60,no.6,1995,pages1590-1594, XP002072026 ISSN:0022-3263 citedintheapplication thewholedocument INTERNATIONALSEARCHREPORT Inte) nal ApWllcaNlonNo Information on patent family members PCT/US 00/14001 PatentdocumentPublication Patent family Publication citedinsearchreportdate member(s)date US3682892A08-08-1972AR 193717 A 22-05-1973 AT 323177 B 25-06-1975 AT 323183 B 25-06-1975 AU 458903 B 19-02-1975 AU 3723571 A 28-06-1973 BE 777100 A 22-06-1972 CA 974990 A 23-09-1975 CH 568989 A 14-11-1975 DE 2163625 A 13-07-1972 ES 398223 A 16-03-1975 FR 2119071 A 04-08-1972 GB 1325630 A 08-08-1973 HU 165057 B 28-06-1974 IL 38420 A 29-11-1974 NL 7117761 A 27-06-1972 PH 9269 A 30-07-1975 PH 9269 A 30-07-1975 US3714145A30-01-1973NONE US3864330A04-02-1975JP 48078195 A 20-10-1973 JP 49001585 A 08-01-1974 JP 48032896 A 02-05-1973 JP 51002475 B 26-01-1976 JP 48052788 A 24-07-1973 JP 50025478 B 23-08-1975 JP 809774 C 31-03-1976 JP 48072182 A 29-09-1973 JP 50025479 B 23-08-1975 BE 788230 A 18-12-1972 CA 976158 A 14-10-1975 CH 576457 A 15-06-1976 DE 2242873 A 08-03-1973 FR 2151003 A 13-04-1973 GB 1394195 A 14-05-1975 NL 7211886 A 02-03-1973 SE 399257 B 06-02-1978 SE 399257 B 06-02-1978 US3801569A02-04-1974DE 2401751 A 18-07-1974 FR 2273547 A 02-01-1976 GB 1390602 A 16-04-1975 JP 49101392 A 25-09-1974 US4021421A03-05-1977HU 170623 B 28-07-1977 AT 344698 B 10-08-1978- AT 481975 A 15-12-1977 AU 499054 B 05-04-1979 AU 8223875 A 23-12-1976 BE 830582 A 16-10-1975 BG 32569 A 16-08-1982 BG 32570 A 16-08-1982 CA 1047493 A 30-01-1979 CH 634835 A 28-02-1983 CH 632254 A 30-09-1982 CS 195707 B 29-02-1980 DD 123887 A 19-01-1977 DE 2527901 A 15-01-1976 DK 284675 A 26-12-1975 FR 2276054 A 23-01-1976 INTERNATIONALSEARCHREPORT Inter nal Apoiication No mlormation on patent family members PCT/US 00/14001 PatentdocumentPublication Patent family Publication citedinsearchreportdate member(s)date US4021421AGB 1509445 A 04-05-1978 IL 47495 A 12-03-1979 JP 969426 C 31-08-1979 JP 51019783 A 17-02-1976 JP 54001716 B 27-01-1979 JP 1305553 C 28-02-1986 JP 53077079 A 08-07-1978 JP 60026113 B 21-06-1985 NL 7507556 A 30-12-1975 SE 423711 B 24-05-1982 SE 7507039 A 29-12-1975 YU 161075 A 21-01-1983 YU 161075 A 21-01-1983 US4045433A30-08-1977AT 343665 B 12-06-1978 AT 406375 A 15-10-1977 AU 502405 B 26-07-1979 AU 8095175 A 11-11-1976 BE 829595 A 15-09-1975 BG 26529 A 12-04-1979 BG 26377 A 15-03-1979 CA 1063605 A 02-10-1979 CH 628036 A 15-02-1982 CS 195291 B 31-01-1980 CS 195290 B 31-01-1980 DD 121516 A 05-08-1976 DE 2523250 A 18-12-1975 DK 236675A,B,30-11-1975 FR 2272674 A 26-12-1975 GB 1505543 A 30-03-1978 IL 47268 A 30-01-1981 JP 51001486 A 08-01-1976 JP 1022269 B 25-04-1989 JP 1548200 C 09-03-1990 JP 54055591 A 02-05-1979 NL 7506272 A 02-12-1975 SE 426242 B 20-12-1982 SE 7506053 A 01-12-1975 SU 942594 A 07-07-1982 SU776559 A30-10-1980 SU 1318158 A 15-06-1987 US 4342755 A 03-08-1982 US 4406835 A 27-09-1983 YU 102382 A 31-10-1982 -YU 136075 A 31-10-1982 -YU 136075 A 31-10-1982 US4316897A23-02-1982 NONE WO9629329A26-09-1996US 5683999 A 04-11-1997 AU 5310096 A 08-10-1996 CA 2215536 A 26-09-1996 EP 0815108 A 07-01-1998 EP 0815108 A 07-01-1998 EP0530994A10-03-1993AU 2436792 A 16-03-1993 CN 1071917 A 12-05-1993 MX 9204720 A 01-07-1993 WO 9304047 A 04-03-1993 ZA 9206130 A 28-04-1993 INTERNATIONALSEARCHREPORT InteralApplicationNo nformation on patent famUy members PCT/US00/14001 PatentdocumentPublication Patent family Publication citedinsearchreportdate member(s)date WO9512583A11-05-1995AU 1046895 A 23-05-1995 DE4320347A22-12-1994NONE US5519021A21-05-1996AU 1694295 A 15-08-1995 WO 9520389 A 03-08-1995 US 5663169 A 02-09-1997 US 5665720 A 09-09-1997 US 5811423 A 22-09-1998 AT 197295 T 15-11-2000 AU 4449693 A 10-02-1994 BG 62612 B 31-03-2000 BG 99383 A 29-09-1995 CA 2101572 A 08-02-1994 CN 1090277A,B03-08-1994 CN 1250652 A 19-04-2000 CZ 9500286 A 13-09-1995 DE 69329608 D 07-12-2000 EP 0582455 A 09-02-1994 FI 950508 A 06-02-1995 HR 931102 A 31-10-1997 HU 71219 A 28-11-1995 IL 106507 A 20-11-1997 JP 2063220 C 24-06-1996 JP 6184124 A 05-07-1994 JP 7080860 B 30-08-1995 MX 9304775 A 31-05-1994 NO 950424 A 06-04-1995 NZ 255216 A 28-05-1996 PL 307348 A 15-05-1995 PL 176679 B 30-07-1999 PL 176649 B 30-07-1999 RO 113641 B 30-09-1998 SG 52698 A 28-09-1998 SI 9300419 A 30-06-1994 SK 16195 A 11-07-1995 WO 9403440 A 17-02-1994 ZA 9305724 A 03-03-1994 ZA 9305724 A 03-03-1994 WO9513273A18-05-1995US 5434152 A 18-07-1995 AU 1048695 A 29-05-1995 HR 940906 A 31-12-1996 HR 940906 A 31-12-1996



 
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