WO2012092188A1 - Ligands p1 formant des liaisons hydrogène et procédés de traitement d'une infection par le vih - Google Patents

Ligands p1 formant des liaisons hydrogène et procédés de traitement d'une infection par le vih Download PDF

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Publication number
WO2012092188A1
WO2012092188A1 PCT/US2011/067160 US2011067160W WO2012092188A1 WO 2012092188 A1 WO2012092188 A1 WO 2012092188A1 US 2011067160 W US2011067160 W US 2011067160W WO 2012092188 A1 WO2012092188 A1 WO 2012092188A1
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compound
pharmaceutically acceptable
optionally substituted
alkyl
hydrogen
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PCT/US2011/067160
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English (en)
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Arun K. Ghosh
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Ghosh Arun K
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Publication of WO2012092188A1 publication Critical patent/WO2012092188A1/fr
Priority to US13/929,395 priority Critical patent/US9024038B2/en
Priority to US14/692,498 priority patent/US9499558B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the invention described herein pertains to compounds, to compositions and formulations comprising the compounds, and to methods of use of the compounds and their compositions and formulations for the treatment of diseases, including diseases such as HIV, AIDS, and AIDS-related diseases.
  • HAART highly active antiretroviral therapy
  • RTIs reverse transcriptase inhibitors
  • HIV 1 human immunodeficiency virus type 1
  • non-peptidyl compounds and compositions for treating patients in need of relief from HIV, AIDS, and AIDS-related diseases are also described herein.
  • methods for treating such diseases are also described herein.
  • the non-peptidyl compounds described herein are potent inhibitors of HIV-1 protease. It has also been discovered that those compounds may offer therapeutic benefits to patients suffering from or in need of relief from HIV-1/AIDS.
  • described herein is structure-based design of novel HIV-1 protease inhibitors (PI) incorporating hydrogen bonding residues as the P ⁇ ligand.
  • the inhibitors herein are designed to make extensive interactions including hydrogen bonding with the protein backbone of the HIV-1 protease active site.
  • the inhibitors described herein appear to show excellent enzyme inhibitory activity and antiviral potency. In one aspect, this antiviral potency may be comparable to that of approved protease inhibitors.
  • the inhibitors described herein may show excellent activity against multi-PI-resistant variants.
  • A is cycloheteroalkyl or cycloheteroalkyl-alkyl, each of which is optionally substituted;
  • Q is oxygen, sulfur, nitrogen, or C(R A R ⁇ ) where each of R A and R ⁇ is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;
  • W is oxygen or sulfur
  • R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent
  • X is C(R A R B ) N , where n is 1, 2, or 3, and each of R A and R ⁇ is defined as above;
  • R ⁇ is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is substituted, where at least one substituent is a hydrogen bond forming group;
  • R ⁇ is hydrogen, an oxygen protecting group, or a pro-drug substituent
  • R4 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;
  • Z is C(O), S(0) 2 , NH, NHC(O), or NHS(0) 2 ;
  • R ⁇ is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.
  • compositions containing one or more of the compounds are also described herein.
  • the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with HIV-1/AIDS.
  • methods for using the compounds and compositions for treating patients with HIV-1/AIDS are also described herein.
  • the methods include the step of administering one or more of the compounds and/or compositions containing them to a patient with HIV-1/AIDS.
  • the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions for treating patients with HIV-1/AIDS.
  • uses of the compounds and compositions in the manufacture of a medicament for treating patients with HIV-1/AIDS are also described herein.
  • the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with HIV-1/AIDS.
  • the compounds described herein may be used alone or in combination with other compounds useful for treating HIV/ AIDS, including those compounds that may operate by the same or different modes of action.
  • the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of HIV/ AIDS.
  • Ar is aryl or heteroaryl as defined herein. In another embodiment, Ar is selected from the group consisting of 4-methoxyphenyl,
  • Ar is optionally substituted aryl or heteroaryl. In another embodiment, Ar is optionally substituted aryl.
  • Ar ⁇ is substituted aryl or substituted heteroaryl having one or more of the following illustrative substituents: halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof such as oximes, hydrazones, and the like, cyano, alkylsulfonyl,
  • alkylsulfonylamino and the like, where at least one substituent is a hydrogen bond forming group
  • A, Q, W, R1, R4 and Ar have the meanings described above.
  • X a and are each independently selected from hydrogen, halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof such as oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino, and the like, or X a and together form alkylene dioxy; and
  • R1, Ar ⁇ , and R ⁇ have the meanings described above.
  • X a and X b are independently selected from hydrogen, OH or OR ⁇ A, where R ⁇ A is alkyl, alkylaryl, an oxygen protecting group or a pro-drug substituent; and A, Q, W, R1, Ar ⁇ and R4 have the meanings described above.
  • R ⁇ is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, heterocyclyloxy, heterocyclylalkoxy, amino, mono or dialkylamino, cycloalkylamino, heterocyclylamino, or heterocyclylalkylamino, each of which is optionally substituted.
  • R ⁇ is amino substituted alkyl or heterocycyl, or heterocyclylalkyl.
  • the nitrogen atom of the amino group is mono or disubstituted with alkyl, cycloalkyl, or acyl, or is included in another heterocyclic group such as a pyrrolidinyl, piperidinyl, or piperazinyl group.
  • the nitrogen atom of the hetetocylclyl group is substituted with alkyl, cycloalkyl, or acyl.
  • R ⁇ is optionally substituted alkyl or cycloalkyl, including both linear and branched variations thereof, such as methyl, ethyl, butyl, isobutyl, and the like, and cyclobutyl, cyclopentyl, 3-methylcyclopentyl, and the like.
  • R ⁇ is optionally substituted heterocyclyl or heterocyclylalkyl, where the heterocyclic portions includes, but is not limited to, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and the like.
  • Z is C(R c R d ) where each of R c and R d is independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl; R 4A , R 4B and R 4C are independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted, or R 4A , R 4B and the atoms to which they are attached form a ring, and R 4C is selected from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted; and A, R 1 and Ar ⁇ have the meanings disclosed above.
  • A is cycloheteroalkyl, which includes monocyclic and polycyclic rings that have at least one nitrogen, oxygen, or sulfur atom, where it is to be understood that the polycyclic rings may be fused and/or spiro ring systems.
  • monocyclic cycloheteroalkyls include, but are not limited to 5-, 6-, and 7-membered cyclic ethers and diethers, such as tetrahydrofurans, pyrans, 1,3-dioxo lanes, 1,3-dixoxanes, 1,4- dioxanes, 1,3-dioxepanes, and the like; pyrrolidines, piperidines, piperazines, and the like; and tetrahydrothiophenes, thiopyrans, including oxidized variations thereof, and the like.
  • polycyclic cycloheteroalkyls include, but are not limited to, the foregoing monocyclic rings fused to each other, or to cycloalkyls, and alternatively the spiro variations thereof.
  • fused or spiro ring systems include chiral centers, any and all possible stereoisomers are contemplated to be included herein.
  • both the pure enantiomers and diastereomers, as well as various mixtures of pure enantiomers and diastereomers are contemplated to be included herein.
  • the point of attachment of the cycloheteroalkyl groups described herein may be at any locus of the ring system.
  • Y 1 is C(R e R f ) or oxygen
  • Y 2 is C(R e Rf), CHNR e , oxygen, or S0 2
  • R e and R f are independently selected in each instance from hydrogen, alkyl, and alkoxy
  • m is an integer selected from 0, 1, 2, or 3
  • RB and R n each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy, each of which
  • ⁇ and Y 2 is methylene, and the other of ⁇ and Y 2 is defined as follows: Y 1 is C(R e R f ) or oxygen; Y 2 is C(R e Rf), CHNR e , oxygen, or S0 2 , where R e and R f are independently selected in each instance from hydrogen, alkyl, and alkoxy; m is an integer selected from 0, 1, 2, or 3; and RB and R n each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy, heterocyclyl
  • ⁇ is oxygen; or ⁇ is C(R e Rf), where R e is hydrogen, and R ⁇ is hydrogen or alkoxy, such as methoxy; or Y 2 is oxygen; or Y 2 is C(R e Rf), where R e is hydrogen, and Rf is hydrogen, such as methoxy.
  • A is a mono or polycyclic ether. In another embodiment, A is a radical having one of the following structures
  • (*) indicates the point of attachment of the group A; j is an integer that is independently selected in each instance from 0, 1, 2, or 3; k is an integer from 1 to 5; Y ⁇ is C(R a R ⁇ ) or oxygen; each of R a and R ⁇ is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy; and RJ and R ⁇ each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl ,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy ,aryl, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy
  • p is 1, 2, or 3;
  • Y 3 and Y 4 are in each instance independently selected from the group consisting of optionally substituted methylene, oxygen, and amino;
  • Y 5 and Y 6 are in each instance independently selected from the group consisting of amino, oxygen, alkylene, and heteroalkylene, providing that at least one of Y 3 and Y 4 is oxygen, and wherein when one of Y 3 and Y 4 is optionally substituted methylene, at least one of Y 5 and Y 6 is oxygen, and A does not include a peroxide bond, a sulfenate bond, or a sulfenamide bond;
  • Y ⁇ is a bond or optionally substituted methylene
  • R 1 is hydrogen, hydroxyl, carboxylate or derivative thereof, amino or derivative thereof, acyl, sulfonyl or derivative thereof, alkyl, or heteroalkyl.
  • Y 4 is oxygen. In one embodiment for any of the above descriptions of A, Y ⁇ is a bond. In one embodiment for any of the above descriptions of A, p is 1 or 2. In one embodiment for any of the above descriptions of A, p is 1. In one embodiment for any of the above descriptions of A, R1 is hydrogen. In one embodiment for any of the above descriptions of A, Y 4 is oxygen. In one embodiment for any of the above descriptions of A, or is oxygen. In one embodiment for any of the above descriptions of A, Y ⁇ and one of Y ⁇ and Y ⁇ are oxygen. In one embodiment for any of the above descriptions of A, Y ⁇ and Y ⁇ are oxygen. In one embodiment for any of the above descriptions of A, each of Y ⁇ , ⁇ 4 and Y ⁇ is oxygen. In one embodiment for any of the above descriptions of A, Y ⁇ is optionally substituted methylene.
  • A is a radical having one of the following structures
  • A is a radical having one of the following structures
  • the group A is cycloheteroalkyl-alkyl of the formula Het-(CH2)q-; where q is an integer selected from 1, 2, or 3; and Het is optionally substituted cycloheteroalkyl.
  • Het is oxazolidine, thiazolidine, pyrollidine, piperidine, piperazine, and the like, each of which is optionally substituted, including oxo substituents that form the corresponding oxazolidinones, thiazolidinones, pyrollidinones, piperidinones, piperazinones, and the like.
  • Q is oxygen
  • W is oxygen
  • R1 is hydrogen
  • R ⁇ is hydrogen
  • R 4 is a group CH 2 -K-R 4D , where K is a bond or NHCH 2 , and R 4D is alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, each of which is optionally substituted; or R 4 ⁇ is isopropyl, furanyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolidinonyl, oxazolidinonyl, thiazolidinonyl, isoxazolidionyl, or isothiazolidinonyl, each of which is optionally substituted; or R4 is branched alkyl; or R4 is isobutyl; or R4 is
  • Z is S0 2 - or Z is CO; or Z is NH; and/or
  • R ⁇ is aryl or heteroaryl, each of which is optionally substituted; or R ⁇ is substituted phenyl; or R ⁇ is substituted phenyl, where the substituent is hydroxy or a derivative thereof, amino or a derivative thereof, thio or a derivative thereof, or any of the foregoing where the substituent is covalently attached to the aryl through a group C(R x R ); where each of R x and f is independently selected in each instance from the group consisting of hydrogen and alkyl; or R x and f are each hydrogen; and/or
  • R 5 is phenyl substituted with NH 2 , OH, OMe, CH 2 OH, and/or OCH 2 0; or R 5 is optionally substituted benzofuran; or R ⁇ is optionally substituted dihydrobenzofuran; or R ⁇ is optionally substituted benzothiopene; or R ⁇ is optionally substituted benzoxazole; or R ⁇ is optionally substituted benzothiazole; or R ⁇ is optionally substituted benzisoxazole; or R ⁇ is optionally substituted benzoisothiazole; and/or
  • R a and R b are each hydrogen; and/or
  • n 1.
  • R ⁇ or Ar ⁇ is phenyl substituted with hydroxy or a derivative thereof, amino or a derivative thereof, thio or a derivative thereof, or any of the foregoing where the substituent is covalently attached to the phenyl through a group C(R x R ); where each of R x and f is independently selected in each instance from the group consisting of hydrogen and alkyl; or both R x and f are hydrogen.
  • R ⁇ or Ar ⁇ is phenyl substituted with a hydroxy derivative, a thio derivative, or an amino derivative, where in each of the foregoing, derivatives include those that include a phosphorus-containing group; or R ⁇ or Ar ⁇ is phenyl substituted with OH, alkoxy, SH, alkylthio, NH 2 , alkylamino, or dialkylamino; or R ⁇ or Ar ⁇ is phenyl substituted with hydroxymethyl, alkoxymethyl, thiomethyl, alkylthiomethyl, H 2 N-methyl, alkylaminomethyl, or dialkylaminomethyl; or R ⁇ or Ar ⁇ is phenyl substituted with
  • heterocyclylalkyloxy such as morpholin-l-ylalkyloxy, pyrrolidin-l-ylalkyloxy, or piperidin-1- ylalkyloxy.
  • R ⁇ or Ar ⁇ is capable of forming a hydrogen bond with a group in the S2 site of an HIV protease.
  • the group in the S2 site is a glycine, such as Gly-48.
  • each ofY 3 , Y 4 and Y 5 is oxygen
  • Y 3 is methylene and each ofY 4 and Y ⁇ is oxygen;
  • Y 4 is methylene and each ofY 3 and Y ⁇ is oxygen;
  • Y ⁇ is methylene and each ofY 3 and Y 4 is oxygen;
  • each of pi and P2 is independently 1, 2 or 3;
  • A1 is selected from the group consisting of hydrogen, hydroxyl or derivative thereof, carboxylate or derivative thereof, amino or derivative thereof, or sulfonyl or derivative thereof, and the like;
  • R2 has any of the values defined above for R ⁇ ;
  • R 4 E is selected from the group consisting of isopropyl, alkyl, or heteroalkyl, and the like;
  • R ⁇ B is selected from the group consisting of methoxy, aminomethyl; amino, or heteroalkyl, and the like.
  • each ofY 3 , Y 4 and Y 5 is oxygen
  • Y 3 is methylene and each ofY 4 and Y ⁇ is oxygen;
  • Y 4 is methylene and each ofY 3 and Y ⁇ is oxygen; or is methylene and each of and is oxygen;
  • each of i and P2 is independently 1 , 2 or 3;
  • A1 is selected from the group consisting of hydrogen, hydroxyl or derivative thereof, carboxylate or derivative thereof, amino or derivative thereof, or sulfonyl or derivative thereof, and the like;
  • Ar ⁇ has any of the values defined above for Ar ⁇ ;
  • R4E i selected from the group consisting of isopropyl, alkyl, or heteroalkyl, and the like;
  • R ⁇ B is selected from the group consisting of methoxy, aminomethyl; amino, or heteroalkyl, and the like.
  • X 1 is oxygen or NR M and each of X ⁇ and is methylene;
  • each of X ⁇ and X ⁇ is methylene and is oxygen or NR M ;
  • each of X ⁇ and X ⁇ is methylene and X ⁇ is oxygen or NR M ;
  • R M is selected from the group consisting of hydrogen, methyl, methylsulfonyl, acetyl or methoxycarbonyl, and the like;
  • Ar ⁇ has any of the values defined above for Ar ⁇ ;
  • Ar has any of the values defined above for Ar.
  • composition comprising one or more compounds of any of the preceding descriptions and one or more carriers, diluents, or excipients, or a combination thereof.
  • a method for treating a patient in need of relieve from an HIV infection comprising the step of administering to a patient in need of relief from the HIV infection a therapeutically effective amount of one or more compounds or compositions of any of the preceding descriptions.
  • the formulae include and represent not only all pharmaceutically acceptable salts of the compounds, but also include any and all hydrates and/or solvates of the compound formulae. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination compounds with water and/or various solvents, in the various physical forms of the compounds. Accordingly, the above formulae are to be understood to include and represent those various hydrates and/or solvates. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent any and all crystalline forms, partially crystalline forms, and non crystalline and/or amorphous forms of the compounds.
  • Illustrative derivatives include, but are not limited to, both those compounds that may be synthetically prepared from the compounds described herein, as well as those compounds that may be prepared in a similar way as those described herein, but differing in the selection of starting materials.
  • described herein are compounds that include various functional groups, such as hydroxy groups, amino groups and carboxylate groups from which derivatives may formed by e.g. acylation and esterification.
  • derivatives may include prodrugs of the compounds described herein, compounds described herein that include one or more protection or protecting groups, including compounds that are used in the preparation of other compounds described herein.
  • the compounds described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. It is to be understood that in one embodiment, the invention described herein is not limited to any particular sterochemical requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be optically pure, or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. It is also to be understood that such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.
  • the compounds described herein may be include geometric centers, such as cis, trans, E, and Z double bonds. It is to be understood that in another embodiment, the invention described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be pure, or may be any of a variety of geometric isomer mixtures. It is also to be understood that such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.
  • the term "alkyl” includes a chain of carbon atoms, which is optionally branched.
  • alkenyl and alkynyl includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond or triple bond, respectively. It is to be understood that alkynyl may also include one or more double bonds. It is to be further understood that in certain embodiments, alkyl is advantageously of limited length, including C1-C24, C1-C12, Ci-Cs, Ci-C 6 , and C1-C4. It is to be further understood that in certain embodiments alkenyl and/or alkynyl may each be advantageously of limited length, including C2-C24, C 2 -C 12 , C 2 -C8, C 2 -C6, and C 2 -C4.
  • alkyl, alkenyl, and/or alkynyl groups may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior.
  • Illustrative alkyl groups are, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2- pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl and the like.
  • cycloalkyl includes a chain of carbon atoms, which is optionally branched, where at least a portion of the chain in cyclic. It is to be understood that cycloalkylalkyl is a subset of cycloalkyl. It is to be understood that cycloalkyl may be polycyclic. Illustrative cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, and the like.
  • cycloalkenyl includes a chain of carbon atoms, which is optionally branched, and includes at least one double bond, where at least a portion of the chain in cyclic. It is to be understood that the one or more double bonds may be in the cyclic portion of cycloalkenyl and/or the non-cyclic portion of cycloalkenyl. It is to be understood that cycloalkenylalkyl and cycloalkylalkenyl are each subsets of cycloalkenyl. It is to be understood that cycloalkyl may be polycyclic.
  • Illustrative cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexylethen-2-yl, cycloheptenylpropenyl, and the like. It is to be further understood that chain forming cycloalkyl and/or cycloalkenyl is advantageously of limited length, including C3- C24, C3-C12, C3-C8, C3-C6, and C5-C6. It is appreciated herein that shorter alkyl and/or alkenyl chains forming cycloalkyl and/or cycloalkenyl, respectively, may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior.
  • heteroalkyl includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched.
  • Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
  • cycloheteroalkyl including heterocyclyl and heterocycle, includes a chain of atoms that includes both carbon and at least one
  • heteroatom such as heteroalkyl
  • heteroalkyl is optionally branched, where at least a portion of the chain is cyclic.
  • Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
  • Illustrative cycloheteroalkyl include, but are not limited to, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.
  • aryl includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may be optionally substituted.
  • Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like.
  • heteroaryl includes aromatic heterocyclic groups, each of which may be optionally substituted.
  • Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,
  • amino includes the group NH 2 , alkylamino, and dialkylamino, where the two alkyl groups in dialkylamino may be the same or different, i.e. alkylalkylamino.
  • amino includes methylamino, ethylamino, dimethylamino, methylethylamino, and the like.
  • amino modifies or is modified by another term, such as aminoalkyl, or acylamino the above variations of the term amino are included therein.
  • aminoalkyl includes H 2 N-alkyl, methylaminoalkyl, ethylaminoalkyl, dimethylaminoalkyl, methylethylaminoalkyl, and the like.
  • acylamino includes acylmethylamino, acylethylamino, and the like.
  • amino and derivatives thereof includes amino as described herein, and alkylamino, alkenylamino, alkynylamino, heteroalkylamino,
  • heteroalkenylamino heteroalkynylamino, cycloalkylamino, cycloalkenylamino,
  • cycloheteroalkylamino cycloheteroalkenylamino, arylamino, arylalkylamino
  • amino derivative also includes urea, carbamate, and the like.
  • hydroxy and derivatives thereof includes OH, and alkyloxy, alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy, heteroalkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloheteroalkyloxy, cycloheteroalkenyloxy, aryloxy, arylalkyloxy, arylalkenyloxy, arylalkynyloxy, heteroaryloxy, heteroarylalkyloxy,
  • heteroarylalkenyloxy heteroarylalkynyloxy, acyloxy, and the like, each of which is optionally substituted.
  • hydroxy derivative also includes carbamate, and the like.
  • thio and derivatives thereof includes SH, and alkylthio, alkenylthio, alkynylthio, heteroalkylthio, heteroalkenylthio, heteroalkynylthio, cycloalkylthio, cycloalkenylthio, cycloheteroalkylthio, cycloheteroalkenylthio, arylthio, arylalkylthio, arylalkenylthio, arylalkynylthio, heteroarylthio, heteroarylalkylthio,
  • thio derivative also includes thiocarbamate, and the like.
  • acyl includes formyl, and alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, heteroalkylcarbonyl, heteroalkenylcarbonyl,
  • heteroalkynylcarbonyl cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloheteroalkylcarbonyl, cycloheteroalkenylcarbonyl, arylcarbonyl, arylalkylcarbonyl, arylalkenylcarbonyl,
  • arylalkynylcarbonyl heteroarylcarbonyl, heteroarylalkylcarbonyl, heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl, acylcarbonyl, and the like, each of which is optionally substituted.
  • carbonyl and derivatives thereof includes the group C(O), C(S), C(NH) and substituted amino derivatives thereof.
  • carboxylate and derivatives thereof includes the group C0 2 H and salts thereof, and esters and amides thereof, and CN.
  • sulfinyl or a derivative thereof includes S0 2 H and salts thereof, and esters and amides thereof.
  • sulfonyl or a derivative thereof includes SO 3 H and salts thereof, and esters and amides thereof.
  • phosphinyl or a derivative thereof includes P(R)0 2 H and salts thereof, and esters and amides thereof, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cyclohetero alkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.
  • phosphonyl or a derivative thereof includes P0 3 H 2 and salts thereof, and esters and amides thereof.
  • Phosphorous-containing group includes phosphinyl or a derivative thereof and phosphonyl or a derivative thereof.
  • hydroxylamino and derivatives thereof includes NHOH, and alkyloxylNH alkenyloxylNH alkynyloxylNH heteroalkyloxylNH
  • heteroarylalkenyloxylNH heteroarylalkynyloxylNH acyloxy and the like, each of which is optionally substituted.
  • hydrozino and derivatives thereof includes alkylNHNH, alkenylNHNH, alkynylNHNH, heteroalkylNHNH, heteroalkenylNHNH, heteroalkynylNHNH, cycloalkylNHNH, cycloalkenylNHNH, cycloheteroalkylNHNH, cycloheteroalkenylNHNH, arylNHNH, arylalkylNHNH, arylalkenylNHNH, arylalkynylNHNH, heteroarylNHNH, heteroarylalkylNHNH, heteroarylalkenylNHNH, heteroarylalkynylNHNH, acylNHNH, and the like, each of which is optionally substituted.
  • optionally substituted includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted.
  • Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
  • any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
  • optionally substituted aryl and “optionally substituted heteroaryl” include the replacement of hydrogen atoms with other functional groups on the aryl or heteroaryl that is optionally substituted. Such other functional groups
  • illustratively include, but are not limited to, amino, hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
  • any of amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
  • Illustrative substituents include, but are not limited to, a radical -(CH 2 ) X Z X , where x is an integer from 0-6 and Z x is selected from halogen, hydroxy, alkanoyloxy, including Ci-C 6 alkanoyloxy, optionally substituted aroyloxy, alkyl, including Ci-C 6 alkyl, alkoxy, including Ci-C 6 alkoxy, cycloalkyl, including C 3 -C 8 cycloalkyl, cycloalkoxy, including C 3 -C 8 cycloalkoxy, alkenyl, including C 2 -C 6 alkenyl, alkynyl, including C 2 -C 6 alkynyl, haloalkyl, including Ci-C 6 haloalkyl, haloalkoxy, including Ci-C 6 haloalkoxy, halocycloalkyl, including C 3 -C 8 halocycloalkyl, hal
  • Z x is selected from -C0 2 R 4 and -CONR 5 R 6 , where R 4 , R 5 , and R 6 are each independently selected in each occurrence from hydrogen, Ci-C 6 alkyl, aryl-Ci-C 6 alkyl, and heteroaryl-Ci-C6 alkyl.
  • prodrug generally refers to any compound that when administered to a biological system generates a biologically active compound as a result of one or more spontaneous chemical reaction(s), enzyme-catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination thereof.
  • the prodrug is typically acted upon by an enzyme (such as esterases, amidases, phosphatases, and the like), simple biological chemistry, or other process in vivo to liberate or regenerate the more pharmacologically active drug. This activation may occur through the action of an endogenous host enzyme or a non- endogenous enzyme that is administered to the host preceding, following, or during
  • prodrug administration of the prodrug. Additional details of prodrug use are described in U.S. Pat. No. 5,627, 165; and Pathalk et al, Enzymic protecting group techniques in organic synthesis, Stereosel. Biocatal. 775-797 (2000). It is appreciated that the prodrug is advantageously converted to the original drug as soon as the goal, such as targeted delivery, safety, stability, and the like is achieved, followed by the subsequent rapid elimination of the released remains of the group forming the prodrug.
  • Prodrugs may be prepared from the compounds described herein by attaching groups that ultimately cleave in vivo to one or more functional groups present on the compound, such as -OH-, -SH, -C0 2 H, -NR 2 .
  • Illustrative prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
  • esters also referred to as active esters, include but are not limited to 1-indanyl, N- oxysuccinimide; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl,
  • alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, a-ethoxycarbonyloxyethyl, ⁇ -ethoxycarbonyloxyethyl, and the like
  • dialkylaminoalkyl groups including di-lower alkylamino alkyl groups, such as
  • Further illustrative prodrugs contain a chemical moiety, such as an amide or phosphorus group functioning to increase solubility and/or stability of the compounds described herein.
  • Further illustrative prodrugs for amino groups include, but are not limited to, (C 3 - C 2 o)alkanoyl; halo-(C 3 -C 2 o)alkanoyl; (C 3 -C 2 o)alkenoyl; (C4-Cy)cycloalkanoyl; (C 3 -C 6 )- cycloalkyl(C 2 -Ci6)alkanoyl; optionally substituted aroyl, such as unsubstituted aroyl or aroyl substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulphonyloxy, (Ci-C 3 )alkyl and (Ci-C 3 )alkoxy, each of which is optional
  • prodrugs themselves may not possess significant biological activity, but instead undergo one or more spontaneous chemical reaction(s), enzyme- catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination thereof after administration in vivo to produce the compound described herein that is biologically active or is a precursor of the biologically active compound.
  • the prodrug is biologically active.
  • prodrugs may often serves to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half- life, and the like.
  • Prodrugs also refer to derivatives of the compounds described herein that include groups that simply mask undesirable drug properties or improve drug delivery.
  • one or more compounds described herein may exhibit an undesirable property that is advantageously blocked or minimized may become pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug application, such as low oral drug absorption, lack of site specificity, chemical instability, toxicity, and poor patient acceptance (bad taste, odor, pain at injection site, and the like), and others. It is appreciated herein that a prodrug, or other strategy using reversible derivatives, can be useful in the optimization of the clinical application of a drug.
  • therapeutically effective amount refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.
  • the therapeutically effective amount is advantageously selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein.
  • the co-therapies described herein may allow for the administration of lower doses of compounds that show such toxicity, or other undesirable side effect, where those lower doses are below thresholds of toxicity or lower in the therapeutic window than would otherwise be administered in the absence of a cotherapy.
  • composition generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It is to be understood that the compositions described herein may be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and/or other morphological forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various hydrates and/or solvates of the compounds described herein. Accordingly, such pharmaceutical compositions that recite compounds described herein are to be understood to include each of, or any combination of, the various morphological forms and/or solvate or hydrate forms of the compounds described herein.
  • compositions may include one or more carriers, diluents, and/or excipients.
  • the compounds described herein, or compositions containing them may be formulated in a therapeutically effective amount in any conventional dosage forms appropriate for the methods described herein.
  • the compounds described herein, or compositions containing them, including such formulations may be administered by a wide variety of conventional routes for the methods described herein, and in a wide variety of dosage formats, utilizing known procedures (see generally, Remington: The Science and Practice of Pharmacy, (21 st ed., 2005)).
  • administering includes all means of introducing the compounds and compositions described herein to the patient, including, but are not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like.
  • the compounds and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.
  • the individual components of a co-administration, or combination can be administered by any suitable means, contemporaneously, simultaneously, sequentially, separately or in a single pharmaceutical formulation.
  • the number of dosages administered per day for each compound may be the same or different.
  • the compounds or compositions may be administered via the same or different routes of administration.
  • the compounds or compositions may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.
  • Illustrative routes of oral administration include tablets, capsules, elixirs, syrups, and the like.
  • Illustrative routes for parenteral administration include intravenous, intraarterial, intraperitoneal, epidurial, intraurethral, intrasternal, intramuscular and subcutaneous, as well as any other art recognized route of parenteral administration.
  • Illustrative means of parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques, as well as any other means of parenteral administration recognized in the art.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH in the range from about 3 to about 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen- free water.
  • a suitable vehicle such as sterile, pyrogen- free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. Parenteral administration of a compound is illustratively performed in the form of saline solutions or with the compound incorporated into liposomes.
  • a solubilizer such as ethanol can be applied.
  • the dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the condition to be treated, the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect the dosage used.
  • a therapeutically effective amount of one or more compounds in any of the various forms described herein may be mixed with one or more excipients, diluted by one or more excipients, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • Excipients may serve as a diluent, and can be solid, semi-solid, or liquid materials, which act as a vehicle, carrier or medium for the active ingredient.
  • the formulation compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the compositions may contain anywhere from about 0.1% to about 99.9% active ingredients, depending upon the selected dose and dosage form.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents;
  • compositions can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. It is appreciated that the carriers, diluents, and excipients used to prepare the compositions described herein are advantageously GRAS (generally regarded as safe) compounds.
  • emulsifying agents are naturally occurring gums (e.g., gum acacia or gum tragacanth) and naturally occurring phosphatides (e.g., soybean lecithin and sorbitan monooleate derivatives).
  • antioxidants are butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, butylated hydroxy anisole, and cysteine.
  • preservatives are parabens, such as methyl or propyl p- hydroxybenzoate, and benzalkonium chloride.
  • humectants are glycerin, propylene glycol, sorbitol, and urea.
  • Examples of penetration enhancers are propylene glycol, DMSO, triethanolamine, N,N-dimethylacetamide, ⁇ , ⁇ -dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol, and AZONE.
  • Examples of chelating agents are sodium EDTA, citric acid, and phosphoric acid.
  • Examples of gel forming agents are
  • CARBOPOL cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone.
  • ointment bases are beeswax, paraffin, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span), polyethylene glycols, and condensation products between sorbitan esters of fatty acids and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate (TWEEN)).
  • a compound of the invention disclosed herein may be prepared by a route analogous to one previously disclosed for the preparation of protease inhibitors with a similar backbone structure, such as for example WO 2008/133734.
  • the compound may be prepared by acylating the corresponding amine with an acylating agent of formula A-Q-C(W)-L in which L denotes a leaving group.
  • A is cycloheteroalkyl or cycloheteroalkyl-alkyl, each of which is optionally substituted;
  • Q is oxygen, sulfur, nitrogen, or C(R A R ⁇ ) where each of R A and R ⁇ is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;
  • W is oxygen or sulfur
  • R1 is hydrogen, a nitrogen protecting group, or a pro-drug substituent
  • X is C(R A R B ) N , where n is 1, 2, or 3, and each of R A and R ⁇ is defined as above;
  • R2 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is substituted, where at least one substituent is a hydrogen bond forming group;
  • R4 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;
  • Z is C(O), S(0) 2 , NH, NHC(O), or NHS(0) 2 ;
  • R ⁇ is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.
  • Ar is aryl or heteroaryl, each of which is optionally substituted.
  • A, Q, W, R 1 , X, R 2 , and R 4 have any of the values of Clause 1 or Clause 2; and Ar is an optionally substituted aryl or heteroaryl.
  • Ar is 4-methoxyphenyl, 4-(hydroxymethyl)phenyl, a 3 -substituted phenyl, a 4-substituted phenyl, an optionally substituted benzisoxazole, an optionally substituted benzoxazole; an optionally substituted benzodioxane or an optionally substituted benzodioxolane.
  • Ar is aryl or heteroaryl, each of which is optionally substituted; and Ar 2 is substituted aryl or substituted heteroaryl having one or more of the following illustrative substituents: halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and oxime or hydrazone derivatives thereof, cyano, alkylsulfonyl, and alkylsulfonylamino, where at least one substituent is a hydrogen bond forming group.
  • X a and are each independently selected from halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydro xyalkyl, hydro xyalkenyl, amino alkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof such as oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino; or X a and together form alkylenedioxy.
  • X a and X b are independently selected from OH or OR ⁇ A, where R ⁇ A i s alkyl, alkylaryl, an oxygen protecting group or a pro-drug substituent; and A, Q, W, R1, Ar ⁇ and R ⁇ have the meanings described in any of the preceding clauses.
  • R4 is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy,
  • heterocyclyloxy amino, mono or dialkylamino, cycloalkylamino, heterocyclylamino, or heterocyclylalkylamino, each of which is optionally substituted.
  • R4 is amino substituted alkyl or heterocycyl, or heterocyclylalkyl.
  • R4 is methyl, ethyl, butyl, isobutyl, cyclobutyl, cyclopentyl, or 3-methylcyclopentyl.
  • R4 is optionally substituted heterocyclyl or heterocyclylalkyl, where the heterocyclic portions includes, but is not limited to, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.
  • Z is C(R c R d ) where each of R c and R d is independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl;
  • R 4A , R 4B and R 4C are independently selected in each instance from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted, or R 4A , R 4B and the atoms to which they are attached form a ring, and R 4C is selected from the group consisting of hydrogen, alkyl, and arylalkyl, each of which may be optionally substituted.
  • Y 1 is C(R e R f ) or oxygen
  • Y 2 is C(R e Rf), CHNR e , oxygen, or S0 2
  • R e and R f are independently selected in each instance from hydrogen, alkyl, and alkoxy
  • m is an integer selected from 0, 1, 2, or 3
  • RB and R n each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy, aryl, arylalkoxy, heterocyclyloxy, heterocyclyloxy, hetero
  • (*) indicates the point of attachment of the group A; j is an integer that is independently selected in each instance from 0, 1, 2, or 3; k is an integer from 1 to 5; Y ⁇ is C(R a R ⁇ ) or oxygen; each of R a and R ⁇ is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy; and RJ and R ⁇ each represent one or more optional substituents, each of which is independently selected in each instance from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl ,aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkylalkoxy ,aryl, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, heteroaryloxy, and heteroarylalkoxy
  • R a and R ⁇ are both hydrogen; and/or RJ and R ⁇ are both hydrogen; and/or R a , R b , RJ and R k are each hydrogen; one or more of RJ and R ⁇ is alkoxy.
  • p is 1, 2, or 3;
  • Y 3 and Y 4 are in each instance independently selected from the group consisting of optionally substituted methylene, oxygen, and amino;
  • Y 5 and Y 6 are in each instance independently selected from the group consisting of amino, oxygen, alkylene, and heteroalkylene, providing that at least one of Y 3 and Y 4 is oxygen, and wherein when one of Y 3 and Y 4 is optionally substituted methylene, at least one of Y 5 and Y 6 is oxygen, and A does not include a peroxide bond, a sulfenate bond, or a sulfenamide bond;
  • Y ⁇ is a bond or optionally substituted methylene
  • R1 is hydrogen, hydroxyl, carboxylate or derivative thereof, amino or derivative thereof, acyl, sulfonyl or derivative thereof, alkyl, or heteroalkyl.
  • Q is oxygen
  • W is oxygen
  • R1 is hydrogen
  • R3 is hydrogen
  • R 4 is a group CH 2 -K-R 4D , where K is a bond or NHCH 2 , and R 4D is alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, each of which is optionally substituted; or R 4 ⁇ is isopropyl, furanyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolidinonyl, oxazolidinonyl, thiazolidinonyl, isoxazolidionyl, or isothiazolidinonyl, each of which is optionally substituted; or R4 is branched alkyl; or R4 is isobutyl; or R4 is lactamylalkyl; or R ⁇ is pyrrolidin-4-on-2-ylalkyl; or R ⁇ is pyrrolidin
  • Z is S0 2 - or Z is CO; or Z is NH; and/or
  • R ⁇ is aryl or heteroaryl, each of which is optionally substituted; or R ⁇ is substituted phenyl; or R ⁇ is substituted phenyl, where the substituent is hydroxy or a derivative thereof, amino or a derivative thereof, thio or a derivative thereof, or any of the foregoing where the substituent is covalently attached to the aryl through a group C(R x Ry); where each of R x and RY is independently selected in each instance from the group consisting of hydrogen and alkyl; or R x and Ry are each hydrogen; and/or
  • R 5 is phenyl substituted with NH 2 , OH, OMe, CH 2 OH, and/or OCH 2 0; or R 5 is optionally substituted benzofuran; or R ⁇ is optionally substituted dihydrobenzofuran; or R ⁇ is optionally substituted benzothiopene; or R ⁇ is optionally substituted benzoxazole; or R ⁇ is optionally substituted benzothiazole; or R ⁇ is optionally substituted benzisoxazole; or R ⁇ is optionally substituted benzoisothiazole; and/or
  • R a and R b are each hydrogen; and/or
  • n 1.
  • R ⁇ or Ar ⁇ is phenyl substituted with hydroxy or a derivative thereof, amino or a derivative thereof, thio or a derivative thereof, or any of the foregoing where the substituent is covalently attached to the phenyl through a group C(R x Ry); where each of R x and Ry is independently selected in each instance from the group consisting of hydrogen and alkyl; or both R x and Ry are hydrogen.
  • R ⁇ or Ar ⁇ is phenyl substituted with a hydroxy derivative, a thio derivative, or an amino derivative, where in each of the foregoing, derivatives include those that include a phosphorus-containing group; or R ⁇ or Ar ⁇ is phenyl substituted with OH, alkoxy, SH, alkylthio, NH 2 , alkylamino, or dialkylamino; or R ⁇ or Ar ⁇ is phenyl substituted with hydroxymethyl, alkoxymethyl, thiomethyl, alkylthiomethyl, H 2 N-methyl, alkylaminomethyl, or dialkylaminomethyl; or R ⁇ or Ar ⁇ is phenyl substituted with heterocyclylalkyloxy.
  • each ofY 3 , Y 4 and Y 5 is oxygen
  • Y 3 is methylene and each ofY 4 and Y ⁇ is oxygen;
  • Y 4 is methylene and each ofY 3 and Y ⁇ is oxygen;
  • Y ⁇ is methylene and each ofY 3 and Y 4 is oxygen;
  • each of pi and P2 is independently 1, 2 or 3;
  • A1 is hydrogen, hydroxyl or derivative thereof, carboxylate or derivative thereof, amino or derivative thereof, or sulfonyl or derivative thereof;
  • R 4 E is selected from the group consisting of isopropyl, alkyl, or heteroalkyl, and the like;
  • R5B is methoxy, aminomethyl; amino, or heteroalkyl.
  • each ofY 3 , Y 4 and Y 5 is oxygen
  • Y 3 is methylene and each ofY 4 and Y ⁇ is oxygen;
  • Y 4 is methylene and each ofY 3 and Y ⁇ is oxygen; or is methylene and each of and is oxygen;
  • each of i and P2 is independently 1, 2 or 3;
  • R 1 is hydrogen, hydroxyl or derivative thereof, carboxylate or derivative thereof, amino or derivative thereof, or sulfonyl or derivative thereof;
  • R4E i selected from the group consisting of isopropyl, alkyl, or heteroalkyl, and the like;
  • R ⁇ B is methoxy, aminomethyl; amino, or heteroalkyl.
  • ⁇ is oxygen or NR m and each of X ⁇ and X ⁇ is methylene;
  • each of X ⁇ and X ⁇ is methylene and X ⁇ is oxygen or NR m ; or
  • each of X ⁇ and is methylene and X ⁇ is oxygen or NR m ;
  • R m is selected from the group consisting of hydrogen, methyl, methylsulfonyl, acetyl or methoxycarbonyl, and the like.
  • a pharmaceutical composition comprising one or more compounds of any of the preceding clauses and one or more carriers, diluents, or excipients, or a combination thereof.
  • a method for treating a patient in need of relieve from an HIV infection comprising the step of administering to a patient in need of relief from the HIV infection a therapeutically effective amount of one or more compounds or compositions of any of the preceding clauses.
  • the scoring in the biological screens is as follows:
  • IC50 values are means of at least two experiments.
  • the IC50 values of amprenavir (APV), saquinavir (SQV), and indinavir (IDV) were 0.03 ⁇ , 0.015 ⁇ , and 0.03 ⁇ , respectively.

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Abstract

La présente invention concerne des inhibiteurs de la protéase du VIH-1 et des compositions les contenant. La présente invention concerne également l'utilisation des inhibiteurs et des compositions les contenant pour traiter une infection par le VIH, le SIDA, et les maladies liées au SIDA.
PCT/US2011/067160 2010-12-27 2011-12-23 Ligands p1 formant des liaisons hydrogène et procédés de traitement d'une infection par le vih WO2012092188A1 (fr)

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US10294234B2 (en) 2017-02-06 2019-05-21 Gilead Sciences, Inc. HIV inhibitor compounds
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US11052087B2 (en) 2018-07-30 2021-07-06 Gilead Sciences, Inc. Anti-HIV compounds
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