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WO1997008150A1 - Urees cycliques substituees et leurs derives utiles en tant qu'inhibiteurs de protease retrovirale - Google Patents

Urees cycliques substituees et leurs derives utiles en tant qu'inhibiteurs de protease retrovirale Download PDF

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Publication number
WO1997008150A1
WO1997008150A1 PCT/US1996/013765 US9613765W WO9708150A1 WO 1997008150 A1 WO1997008150 A1 WO 1997008150A1 US 9613765 W US9613765 W US 9613765W WO 9708150 A1 WO9708150 A1 WO 9708150A1
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Prior art keywords
substituted
alkyl
benzyl
heterocyclic ring
ring system
Prior art date
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PCT/US1996/013765
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English (en)
Inventor
George Vincent Delucca
Qi Han
Prabhakar Kondaji Jadhav
Jamal Mahmoud Kassir
Patrick Yuk-Sun Lam
Robert Joseph Mchugh, Jr.
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Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
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Priority to AU15926/97A priority Critical patent/AU1592697A/en
Publication of WO1997008150A1 publication Critical patent/WO1997008150A1/fr
Anticipated expiration legal-status Critical
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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    • C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring

Definitions

  • This invention relates generally to substituted cyclic ureas and analogs thereof useful as retroviral protease inhibitors, pharmaceutical compositions comprising the same, and methods of using the same for treating viral infection.
  • ADT adriamycin that inhibit viral DNA synthesis
  • compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell
  • Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
  • the ability to inhibit a viral protease provides a method for blocking viral replication and therefore a treatment for viral diseases, such as AIDS, that may have fewer side effects, be more efficacious, and be less prone to drug resistance when compared to current treatments.
  • WO93/07128 discloses cyclic carbonyls as inhibitors of HIV protease and synthetic procedures for preparing HIV protease inhibitors.
  • WO92/21647 discloses cyclic carbonyls and sulfones as inhibitors of HIV protease.
  • the present invention concerns novel substituted cyclic ureas and analogs thereof, which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases, such as AIDS. None of the above references teach or suggest the cyclic ureas of the present invention as inhibitors of HIV protease or for treatment of retroviral diseases, i.e., AIDS.
  • the substituted cyclic ureas, and analogs thereof, provided by the present invention are
  • the compounds of the present invention are of low molecular weight and may, therefore, have good oral absorption properties in mammals.
  • one object of the present invention is to provide novel retroviral protease inhibitors.
  • compositions with retroviral protease inhibiting activity comprising a
  • R 1 is -C(R 4 ) (R 4a )R 5 ;
  • R 2 is -C(R 7 ) (R 7a )R 6 ;
  • R 1 and R 2 can be taken together with the carbons to which they are attached to form a
  • carbocyclic or heterocyclic ring said carbocyclic or heterocyclic ring being optionally substituted with 0-5 R 5 , R 6 , R 4 , R 4a , R 7 or R 7a ;
  • R 4 and R 7 are independently selected from the following:
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 4a and R 7a are independently selected from the following:
  • R 4 and R 4a can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R 12 ;
  • R 7 and R 7a can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R 12 ;
  • R 5 and R 6 are independently selected from the following: hydrogen, halogen, -N(R 20 ) 2 , -SR 20 , -OR 20 , or C 1 -C 6 alkyl substituted with 0-3 R 11 ;
  • R 5 and R 6 can alternatively join to form -OCH 2 SCH 2 O-
  • R 11 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
  • R 12 when a substituent on carbon, is selected from the following:
  • a 5- or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
  • R 12 when a substituent on nitrogen, is selected from the following:
  • R 12a when a substituent on carbon, is selected from one or more of the following:
  • alkylcarbonyl C 1 -C 4 alkylcarbonylamino; -S(O) m Me;
  • R 12a when a substituent on nitrogen, is selected from the following:
  • R 13 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
  • R 14 is selected from the following:
  • 0-3 groups selected from OH, C 1 -C 4 alkoxy, halogen, NH 2 ;
  • R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 -; -(CH 2 ) 5 -;
  • R 15 is: hydrogen or methyl
  • R 20 is selected from the following:
  • phenylaminocarbonyl substituted with 0-3 R 12 or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl;
  • n 0, 1 or 2;
  • Z is O, S, NR 24 ;
  • Z' is O or NR 24 ;
  • R 22 and R 23 are independently selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 22a and R 22b are independently selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 24 is independently:
  • R 24a is selected from the following:
  • R 22 can alternatively join with R 4 or R 4a to form a
  • R 23 can alternatively join with R 7 or R 7a to form a
  • R 31 is selected from the following:
  • amino acids linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus;
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 32 when a substituent on carbon, is
  • heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring being
  • a 3- or 4- carbon chain wherein 0, 1 or 2 of the carbon atoms are replaced with a heteroatom independently selected from oxygen, nitrogen or sulfur, attached to an adjacent carbon on the ring to which it is appended to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being substituted on the aliphatic carbons with 0-3 halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, -NR 13 R 14 ;
  • R 32 when a substituent on nitrogen, is
  • R 40 is hydrogen or C 1 -C 3 alkyl
  • R 4 , R 4a , R 7 and R 7a are not all hydrogen and when R 4 , R 4a are hydrogen, then R 22 is not hydrogen;
  • T, R 1 , and R 2 are as defined above.
  • Z is O, or NR 24 ;
  • R 1 is -C(R 4 ) (R 4a )R 5 ;
  • R 2 is -C(R 7 ) (R 7a )R 6 ;
  • R 1 and R 2 may, together, be
  • J may also be S(O) m ; m is 0, 1 or 2;
  • R 22 and R 23 may, independently, also be C 1-6 alkyl
  • R 31 may also be OR 13 or a C 5-7 carbocyclic residue; and R 32 may also be C 1-4 alkyl substituted with 1-2 -OR 13 ;
  • R 4 and R 7 are independently selected from the following:
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 4a and R 7a are independently selected from the following:
  • R 5 and R 6 are independently selected from the following:
  • R 11 is selected from the following:
  • a C 5 -C 14 carbocyclic residue substituted with 0-3 R 12 a 5- to 10-membered heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
  • R 11a is selected from the following:
  • cycloalkylmethyl phenoxy; benzyloxy; nitro; C 3 -C 6 cycloalkoxy; C 1 -C 4 alkyl substituted with -NH 2 ; C 1 -C 4 hydroxyalkyl; methylenedioxy; ethylenedioxy; C 1 -C 4 haloalkyl; C 1 -C 4 haloalkoxy; C 1 -C 4 alkoxycarbonyl; C 1 -C 4 alkylcarbonyl; C 1 -C 4 alkylcarbonylamino;
  • R 12 when a substituent on carbon, is selected from the following:
  • phenyl halogen; hydroxy; nitro; cyano; C 1 -C 4 alkyl substituted with 0-2 OR 13 , SR 13 , or NR 11 R 13 ; C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkylmethyl; C 7 -C 10 arylalkyl; C 1 -C 4 alkoxy; -CO 2 H; hydroxamic acid; hydrazide; boronic acid; sulfonamide; formyl; C 3 -C 6 cycloalkoxy; -OR 13 ;
  • R 12 when a substituent on nitrogen, is selected from the following:
  • R 12a when a substituent on carbon, is selected from the following:
  • R 12a when a substituent on nitrogen, is selected from the following:
  • R 13 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
  • R 14 is selected from: hydrogen; hydroxy; C 1 -C 6 alkoxy; NH 2 ; -NH(C 1 -C 4 alkyl); C 2 -C 6 alkenyl; phenyl; benzyl; an amine protecting group when R 14 is bonded to
  • R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 -; -(CH 2 ) 5 -;
  • R 20 is selected from:
  • R 22 and R 23 are independently selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 22 and R 23 can independently be unsubstituted C 2-8 alkenyl when either R 5 or R 6 or both are halogen;
  • R 22a and R 22b are independently selected from the following:
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 24 is selected from: hydrogen; hydroxy; amino; C 1 - C 4 alkyl; C 1 -C 4 alkoxy; mono-(C 1 -C 6 alkyl) amino; di-(C 1 -C 6 alkyl) amino; cyano; nitro; benzyloxy; or -NHSO 2 aryl, aryl being substituted with 0-1 (C 1 -C 6 ) alkyl;
  • R 24a is selected from: hydroxy; amino; C 1 -C 4 alkyl;
  • alkyl amino; benzyloxy; or phenoxy;
  • -C(R 14 ) N(OR 14 ); 1-3 amino acids, linked together via amide bonds, said amino acid being linked via the amine or carboxylate terminus; a C 5 -C 14 carbocyclic residue substituted with 1-5 R 32 ; and,
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 32 when a substituent on carbon, is selected from:
  • phenyl phenethyl; phenoxy; C 3 -C 10 cycloalkyl; C 3 -C 6 cycloalkylmethyl; C 7 -C 10 arylalkyl; hydrazide; hydroxamic acid; boronic acid; oxime; C 1-6 alkoxy-C 1-6 alkyl;
  • heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring being
  • a 3- or 4- carbon chain wherein 0, 1 or 2 of the carbon atoms are replaced with a heteroatom independently selected from oxygen, nitrogen or sulfur, attached to an adjacent carbon on the ring to which it is appended to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted on the aliphatic carbons with 0-3 halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, -NR 13 R 14 ; or,
  • alkoxycarbonyl; -CO 2 H; C 1 -C 4 alkylcarbonyloxy; C 1 -C 4 alkylcarbonyl; -C(R 14 ) N(OR 14 );
  • R 33 is selected from the following:
  • a hydroxy protecting group when R 13 is bonded to O or, a 5- to 10-membered heterocyclic.
  • R 40 is hydrogen or C 1 -C 3 alkyl
  • R 4 , R 4a , R 7 and R 7a are not all hydrogen
  • R 1 does not represent unsubstituted straight or branched alkyl.
  • invention provides novel compounds of formula (IIa):
  • R 4 and R 7 are independently selected from the following:
  • R 5 and R 6 are independently selected from the following:
  • R 11 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
  • R 11a is selected from the following:
  • R 12 when a substituent on carbon, is selected from the following:
  • phenyl halogen; hydroxy; nitro; cyano; C 1 -C 4 alkyl substituted with 0-2 OR 13 , SR 13 , or NR 11 R 13 ; C 3 -C 6 cycloalkylmethyl; C 1 -C 4 alkoxy; -CO 2 H; hydroxamic acid; hydrazide; boronic acid; sulfonamide; formyl; C 3 -C 6 cycloalkoxy; -OR 13 ; -NR 13 R 14 ; C 1 -C 4 alkyl substituted with -NR 13 R 14 ; C 1 - 6 alkoxy C 1 _ ⁇ alkyl; C 1 -C 4 hydroxyalkyl;
  • alkylcarbonylamino -S(O) m R 13 ; -SO 2 NR 13 R 14 ; -NHSO 2 R 14 ;
  • R 14 is selected from the following:
  • R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 - or -(CH 2 ) 5 -;
  • R 20 is selected from the following:
  • R 22 and R 23 are independently selected from the following:
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 22 and R 23 can independently be unsubstituted C 2-8 alkenyl when either R 5 or R 6 or both are halogen;
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 32 is selected from the following:
  • heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring being
  • R 33 is selected from the following:
  • R 4 and R 7 are independently selected from the following:
  • R 5 and R 6 are independently selected from the following:
  • R 11 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 11 a is selected from the following:
  • halogen cyano; -CH 2 NH 2 ; -NH 2 ; -NH(C 1 -C 3 alkyl); -OH;
  • R 12 is selected from the following: phenyl; halogen; hydroxy; nitro; cyano; C 1 -C 4 alkyl substituted with 0-2 OR 13 , SR 13 , or NR 11 R 13 ; C 3 -C 6 cycloalkylmethyl; C 1 -C 4 alkoxy; -CO 2 H; C 3 -C 6 cycloalkoxy;
  • R 13 is selected from the following:
  • R 14 is selected from the following:
  • R 20 is selected from the following:
  • n 0, 1 or 2;
  • R 22 and R 23 are independently selected from the following:
  • R 22 and R 23 can independently be unsubstituted C 2-8 alkenyl when either R 5 or R 6 or both are halogen;
  • R 31 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 32 is selected from the following:
  • phenyl phenethyl; phenoxy; benzyloxy; C 3-6 cycloalkyl; halogen; -CO 2 R 13 ; cyano; C 3 -. 6 cycloalkoxy; -NR 13 R 14 ; NO 2 ;
  • R 11 NR 14 , or -NR 13 R 14 ;
  • R 4 and R 5 together do not represent unsubstituted straight or branched alkyl.
  • the present invention provides novel compounds of formula (lib) or pharmaceutically acceptable salt or prodrug forms thereof, wherein;
  • R 4 and R 7 are independently C 1-4 alkyl substituted with 0-2 R 11 or -N(CH 3 )(OCH 3 );
  • R 11 is selected from the following: hydrogen
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 13 is selected from the following:
  • R 20 is hydrogen or any group that, when
  • R 22 and R 23 are independently selected from the following:
  • R 22 and R 23 can independently be unsubstituted C 2-8 alkenyl when either R 5 or R 6 or both are halogen;
  • R 31 is selected from the following:
  • R 32 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 4 and R 5 together do not represent unsubstituted straight or branched alkyl.
  • the present invention provides novel compounds of formula
  • R 5 and R 6 are independently selected from the following: hydrogen, hydroxy, F, Cl, Br, I, or CH 2 OH;
  • R 22 and R 23 are independently -CH 2 -R 31 ;
  • R 22 and R 23 independently nay also be allyl when either R 5 or R 6 or both are halogen;
  • R 31 is selected from the following: cyclopropyl, phenyl substituted with 1-2 R 32 , naphthyl, pyridyl; or a 5- to 10-membered heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 12 is selected from the following: methyl, ethyl, propyl, n-butyl, t-butyl, amino, methylamino,
  • R 11 is selected from the following: hydrogen
  • heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 14 is selected from the following: hydrogen, -CH 2 OH, or -CH 2 CH 2 OH.
  • the present invention provides novel compounds of formula (IIc) or pharmaceutically acceptable salt or prodrug forms thereof, wherein;
  • R 5 and R 6 are independently selected from H, OH, F,
  • R 22 and R 23 are as follows :
  • R 22 is cyclopropylmethyl and R 23 is 3-hydroxybenzyl ;
  • R 22 is cyclopropylmethyl and R 23 is 4-hydroxybenzyl ;
  • R 22 is cyclopropylmethyl and R 23 is 3-aminobenzyl
  • R 22 is cyclopropylmethyl and R 23 is 4-pyridylmethyl ;
  • R 22 is 3-aminobenzyl and R 23 is 2-naphthylmethyl ;
  • R 22 is 3-aminobenzyl and R 23 is 4-hydroxymethylbenzyl ;
  • R 22 is 3-aminobenzyl and R 23 is 3-hydroxybenzyl ;
  • R 22 is 4-hydroxymethylbenzyl and R 23 is 3-hydroxybenzyl
  • R 22 is 2-naphthylmethyl and R 23 is 4-hydroxymethylbenzyl ;
  • R 22 is allyl and R 23 is benzyl ;
  • R 22 is benzyl and R 23 is 3-hydroxybenzyl ;
  • R 22 is benzyl and R 23 is 2-naphthylmethyl ;
  • R 22 is benzyl and R 23 is 4-pyridylmethyl ;
  • R 22 and R 23 are independently the same group and are selected from the following:
  • R 22 or R 23 may, independently, both be allyl.
  • R 5 and R 6 are as follows:
  • R 5 and R 6 are both F
  • R 5 and R 6 are both H
  • R 5 and R 6 are both CH 2 OH
  • R 5 is H and R 6 is CH 2 OH;
  • R 5 is H and R 6 is OH;
  • R 5 is H and R 6 is Br.
  • the present invention provides novel compounds of formula (II) or pharmaceutically acceptable salt or prodrug forms thereof, wherein;
  • R 4 and R 7 are independently C 1-2 alkyl substituted with 0-1 R 11 ;
  • R 11 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 12 is selected from the following:
  • R 13 O-C 1-2 alkyl-
  • R 13 is selected from the following:
  • R 14 is selected from the following:
  • R 22 and R 23 are independently selected from the following:
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 31 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 32 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 .
  • X is CR 6 , C-OR 13 , or N;
  • Y is CR 7 , C-OR 13, or N;
  • each A is a double bond
  • R 4 and R 7 are independently selected from the following:
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 5 and R 6 are independently selected from the following:
  • R 11 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
  • R 11a is selected from the following:
  • R 12 when a substituent on carbon, is selected from the following:
  • a 5- or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
  • R 12 when a substituent on nitrogen, is selected from the following:
  • R 12a when a substituent on carbon, is selected from one or more of the following:
  • alkylcarbonyl C 1 -C 4 alkylcarbonylamino; -S(O) m Me;
  • R 12a when a substituent on nitrogen, is selected from the following:
  • R 13 is selected from the following:
  • R 14 is selected from the following:
  • R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 -; -(CH 2 ) 5 -;
  • R 15 is hydrogen or methyl
  • R 20 is selected from the following:
  • phenylaminocarbonyl substituted with 0-3 R 12 or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl;
  • n 0, 1 or 2;
  • T is selected from:
  • Z is O, S, or NR 24 ;
  • R 22 and R 23 are independently selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 22 and R 23 may both be hydrogen when at least one of X or Y is N;
  • R 22 and R 23 may, when at least one of X or Y is C- OR 13 or N, independently be C 2-8 alkenyl substituted with
  • R 22a ana R 22b are independently selected from the following:
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 24 is selected from the following:
  • R24a is selected from the following:
  • R 31 is selected from the following:
  • R 32 when a substituent on carbon, is selected from the following:
  • phenyl phenethyl; phenoxy; C 3 -C 10 cycloalkyl; C 3 -C 6 cycloalkylmethyl; C 7 -C 10 arylalkyl; hydrazide; hydroxamic acid; boronic acid; oxime; C 1-6 alkoxy-C 1-6 alkyl;
  • heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring being
  • R 32 when a substituent on nitrogen, is selected from the following:
  • phenyl; benzyl; phenethyl; hydroxy; C 1 -C 4 hydroxyalkyl; C 1 -C 4 alkoxy; C 1 -C 4 alkyl; C 3 -C 6 cycloalkyl; C3-C 6 cycloalkylmethyl; -CH 2 NR 13 R 14 ; -NR 13 R 14 ; C 1-6 alkoxy-C 1-6 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkoxycarbonyl; -CO 2 H; C 1 -C 4 alkylcarbonyloxy; and, -C(R 14 ) N(OR 14 ) ;
  • R 40 is hydrogen or C 1 -C 3 alkyl
  • R 41 is selected from the following:
  • the present invention provides novel compounds of formula (lid) or pharmaceutically acceptable salt or prodrug forms thereof, wherein:
  • X is CH, C-OR 13 , or N;
  • R 4 is hydrogen
  • R 22 and R 23 are independently selected from the following: OR 22a and C 1-2 alkyl substituted with R 31 ;
  • R 22 and R 23 may both be hydrogen when at least one of X or Y is N;
  • R 22 and R 23 may, when at least one of X or Y is C- OR 13 or N, independently be C 2-8 alkenyl substituted with 1-3 C 3 -C 14 carbocyclic ring systems each ring system being substituted with 1-5 R 31 ;
  • R 22a is selected from the following:
  • R 12 is selected from the following: C 1-4 alkyl substituted with 0-2 OR 13 , amino, methylamino,
  • R 13 is selected from the following:
  • heterocyclic ring system containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 32 ;
  • R 31 is C 1-3 alkoxy-C 1-3 alkoxy
  • R 32 is C 1-2 alkyl substituted with 0-2 OR 13 .
  • R is O, S(O) m , NH, or NOR 13 ;
  • Y is C(H)(R 7 );
  • each A is a single bond
  • R 4 and R 7 are independently selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-2 R 12 ;
  • R 11 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, said heterocyclic ring system being substituted with 0-3 R 12 ;
  • R 11a is selected from the following:
  • R 12 when a substituent on carbon, is selected from the following:
  • a 5- or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
  • R 12 when a substituent on nitrogen, is selected from the following:
  • R 12a when a substituent on carbon, is selected from one or more of the following:
  • alkylcarbonyl C 1 -C 4 alkylcarbonylamino; -S(O) m Me;
  • R 12a when a substituent on nitrogen, is selected from the following:
  • R 13 is selected from the following:
  • heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R 12a ;
  • R 14 is selected from the following:
  • 0-3 groups selected from OH, C 1 -C 4 alkoxy, halogen, NH 2 ;
  • R 13 and R 14 when attached to the same N atom, can alternatively join to form: -(CH 2 ) 4 -; -(CH 2 ) 5 -;
  • R 15 is: hydrogen or methyl
  • R 20 is selected from the following:
  • phenylaminocarbonyl substituted with 0-3 R 12 or any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl;
  • n 0, 1 or 2;

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Abstract

L'invention concerne des urées cycliques substituées et leurs analogues représentés par la formule (I) dans laquelle T est sélectionné dans: -N(R22)C(=Z)N(R23)-; -N(R22)C(=Z)C(=Z)N(R23)-; -N(R22)S(=Z')N(R23)-; -N(R22)S(=Z')¿2N(R?23)-; ou -N(R22)P(=O)(R?24a)N(R23¿)-; Z représente O, S, NR24; et, Z' représente O ou NR24 ou leurs sels ou leurs promédicaments, qui sont utiles en tant qu'inhibiteurs de protéase rétrovirale, ainsi que des compositions pharmaceutiques comprenant ces composés et des procédés d'utilisation de ces compositions afin de traiter l'infection virale.
PCT/US1996/013765 1995-08-22 1996-08-21 Urees cycliques substituees et leurs derives utiles en tant qu'inhibiteurs de protease retrovirale Ceased WO1997008150A1 (fr)

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US5925635A (en) * 1996-04-17 1999-07-20 Dupont Pharmaceuticals Company N-(amidinophenyl) cyclourea analogs as factor XA inhibitors
US6143743A (en) * 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
EP1640368A2 (fr) 2000-06-13 2006-03-29 The Centre National de la Recherche Scientifique Composés urées cycliques et leur procédé de préparation
US7259174B2 (en) 2004-05-25 2007-08-21 National Health Research Institutes Imidazolidinone compounds
JP2008538366A (ja) * 2005-04-19 2008-10-23 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 置換された環状尿素誘導体及び医薬の製造へのその使用
US7501445B2 (en) 2001-08-21 2009-03-10 National Health Research Institutes Imidazolidinone compounds
WO2009011910A3 (fr) * 2007-07-18 2009-04-30 Us Gov Health & Human Serv Composés d'imidazolidinone, procédés pour inhiber une désubiquitination et procédés de traitement
US8263635B2 (en) 2009-06-26 2012-09-11 Novartis Ag Inhibitors of CYP 17
US8268868B2 (en) 2007-01-10 2012-09-18 Albany Molecular Research, Inc. 5-pyridinone substituted indazoles
US8273770B2 (en) 2007-07-21 2012-09-25 Albany Molecular Research, Inc. 5-pyridinone substituted indazoles
WO2013062024A1 (fr) * 2011-10-28 2013-05-02 石原産業株式会社 Agent de lutte contre des maladies de plantes contenant un dérivé arylamidine ou un sel de celui-ci
US8518968B2 (en) 2009-12-04 2013-08-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hydrazone and diacyl hydrazine compounds and methods of use
US9029399B2 (en) 2011-04-28 2015-05-12 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925635A (en) * 1996-04-17 1999-07-20 Dupont Pharmaceuticals Company N-(amidinophenyl) cyclourea analogs as factor XA inhibitors
US6143743A (en) * 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6362180B1 (en) 1997-07-03 2002-03-26 Bristol-Myers Squibb Pharma Company Imidazopyridines for the treatment of neurological disorders
US6642230B2 (en) 1997-07-03 2003-11-04 Bristol-Myers Squibb Pharma Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
EP1640368A2 (fr) 2000-06-13 2006-03-29 The Centre National de la Recherche Scientifique Composés urées cycliques et leur procédé de préparation
US7501445B2 (en) 2001-08-21 2009-03-10 National Health Research Institutes Imidazolidinone compounds
US7259174B2 (en) 2004-05-25 2007-08-21 National Health Research Institutes Imidazolidinone compounds
JP2008538366A (ja) * 2005-04-19 2008-10-23 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 置換された環状尿素誘導体及び医薬の製造へのその使用
US8207182B2 (en) 2005-04-19 2012-06-26 Gruenenthal Gmbh Substituted cyclic urea derivatives and the use thereof as vanilloid receptor 1 modulators
US8268868B2 (en) 2007-01-10 2012-09-18 Albany Molecular Research, Inc. 5-pyridinone substituted indazoles
WO2009011910A3 (fr) * 2007-07-18 2009-04-30 Us Gov Health & Human Serv Composés d'imidazolidinone, procédés pour inhiber une désubiquitination et procédés de traitement
US8637560B2 (en) 2007-07-18 2014-01-28 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Imidazolidinone compounds, methods to inhibit deubiquitination and methods of treatment
US8273770B2 (en) 2007-07-21 2012-09-25 Albany Molecular Research, Inc. 5-pyridinone substituted indazoles
US8263635B2 (en) 2009-06-26 2012-09-11 Novartis Ag Inhibitors of CYP 17
USRE45173E1 (en) 2009-06-26 2014-09-30 Novartis Ag Inhibitors of CYP 17
US8518968B2 (en) 2009-12-04 2013-08-27 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hydrazone and diacyl hydrazine compounds and methods of use
US9029399B2 (en) 2011-04-28 2015-05-12 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
US9339501B2 (en) 2011-04-28 2016-05-17 Novartis Ag 17a-hydroxylase/C17,20-lyase inhibitors
WO2013062024A1 (fr) * 2011-10-28 2013-05-02 石原産業株式会社 Agent de lutte contre des maladies de plantes contenant un dérivé arylamidine ou un sel de celui-ci

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