WO2007103456A2 - Piperazine and piperidine biaryl derivatives - Google Patents

Piperazine and piperidine biaryl derivatives Download PDF

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WO2007103456A2
WO2007103456A2 PCT/US2007/005858 US2007005858W WO2007103456A2 WO 2007103456 A2 WO2007103456 A2 WO 2007103456A2 US 2007005858 W US2007005858 W US 2007005858W WO 2007103456 A2 WO2007103456 A2 WO 2007103456A2
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group
alkyl
cycloalkyl
methyl
heteroaryl
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PCT/US2007/005858
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French (fr)
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WO2007103456A3 (en
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Rong Jian Lu
Jason C. Pickens
John Alan Tucker
Tanya Zinevitch
Sergey Sviridov
Vitali Konoplev
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Trimeris, Inc.
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Publication of WO2007103456A2 publication Critical patent/WO2007103456A2/en
Publication of WO2007103456A3 publication Critical patent/WO2007103456A3/en

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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates to piperazine derivatives, and to processes of preparation, compositions and methods of using the same. More specifically, the present invention relates piperazine derivatives and compositions, and to methods of using the same in the treatment of Human Immunodeficiency Virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS).
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immunodeficiency Syndrome
  • gp120 plays an important role in HIV entry and serves as a potential target for the development of HIV-1 entry inhibitors, a new class of anti-HIV drugs that currently includes has one regulatory-approved member, enfuvirtide (T-20, Fuzeon).
  • piperazine and piper ⁇ dine derivatives have been previously described.
  • WO 2005/004801 and US 2004/0009985 describe piperazine and piperadine deriviatives that incorporate an indole, azaindole, or other fused aromatic ring system linked to a piperazine ring through a ketoamide linker.
  • Embodiments of the present invention provide compounds that may be useful as an active ingredient used in the treatment of HIV infection, in some embodiments, in the treatment of HIV-1 infection.
  • W is null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene or cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, amino, thio, sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with at least one halogen atom;
  • a 1 is a monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene or monocyclic heteroarylene, each optionally substituted with an alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy, phosphoramide, phosphoramidealkyl, phosphonate, phosphonatealkyl or -R 9 Q, wherein Rg is null or alkylene and Q is -NR10R11, - -CN, -CO2R12, -SR13, -SOR 14 , -SO2R15, -SO 2 NR 16 R 17 , -NR 18 COR 19 , -NR20CONR21R22, -CONR23R24, -NR25SOR26, -R27COR28, Or-OR 29 ;
  • a 2 is null, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with at least one of an alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and/or -R 9 Q, wherein R 9 and Q are as defined above;
  • R25, R 2 6 ⁇ R27, R28 and R 29 are each independently hydrogen, alkyl, aryl, heteroaryl, allyl, alkoxy, cycloalkyl, heterocycloalkyl, fluoroalkyl, fluorocycloalkyl, arylalkyl or heteroarylalkyl; or wherein R 10 and R 11 , R ⁇ and Ri7 > R2 1 and R22 or R23 and R24, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl;
  • Ri, R2, R3, R4, R5, Re, R7 and R 8 are each independently hydrogen or alkyl; and/or at least one of R 1 , R 2 , R 3 , R 4 is taken together with at least one of R5, Re. R7 and Re to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with at least one halogen, amino, hydroxyl, -CN, -NO 2 , alkoxy, -CF 3 , -OCF 3 , alkyl, allyl, fluoroalkyl, cycloalkyl, flu ⁇ rocycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether and/or R 3 i-Q' group, wherein R 3 i is null or alkylene and Q * is -SO 2 NR 32 R 33 , -NR 34 COR 35 . -CONR 36 R 3 7 or -COOR 38
  • R37 and R 38 are each hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; or R 32 and R 33 or R 36 and R 37 , taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with at least one hydrogen, halo, alkoxy, - CF 3 , -OCF 3 and/or -CN;
  • R 41 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with at least one alkyl, cycloalkyl, alkoxy, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, halo, -CN 1 -CF3, alkylthio, hydroxy, alkenyl, alkenoxy, acetyl a ⁇ d/or -RgQ 1 wherein Rg and Q are defined above;
  • R 42 is aryl or heteroaryl, optionally substituted with at least one halo, alkoxy, -CF 3 , -OCF 3 , -CN, alkyl, -cycloalkyl, -fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, acetyl, alkenyf, alkenoxy and/or -RgQ, wherein R 9 and Q are defined above;
  • R 43 is hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with at least one halo, alkyl, alkoxy, -CF 3 , -OCF 3 , -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and/or -RgQ, wherein R 9 and Q are defined above;
  • R39 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with at least one halogen, alkyl, alkoxy, -CF 3 , -OCF 3 , -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, S-alkyl, hydroxy, alkenyl, alkenoxy, acetyl and/or -R 9 Q, wherein Rg and Q are defined above; and
  • R 40 is hydrogen, -CN, alkyl, halo, -CF 3 , cycloalkyl, fluoroalkyl, fluorocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are optionally substituted with at least one halo, alkyl, alkoxy, - CF 3 , -OCF 3 , -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and/or -RgQ, wherein Rg and Q are defined above.
  • Ai is phenylene or monocyclic heteroarylene, wherein the phenylene and monocyclic heteroarylene are optionally substituted with 1 to 5 functional groups, wherein each functional group may be a CrC 6 alkyl, Ci-Ce alkoxy, Ci-C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, hydroxy, halo, Ci-C 6 fluoroalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkenoxy or -R 9 Q, wherein R 9 is null or Ci-C 2 alkylene and Q is -NRioRii, -CN, -CO 2 Ri 2 , -SRi 3 , -SORi 4 , -SO 2 Ri 5 , -SO 2 NRi 6 Ri7, - NRi 8 COR 19 , -NR 20 CONR 2 I R22, -CONR 23 R 24 , -NR 25 SOR 26 , -R 27 COR 28
  • a 2 is phenyl or heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1 to 5 functional groups, wherein each functional group may be a Ci-C 6 alkyl, C 1 -C 6 alkoxy, Ci-C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, hydroxy, halogen, Ci-C 6 fluoroalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkenoxy or -RgQ, wherein R 9 is null or Ci-C 2 alkylene and Q is defined above;
  • R255 R26, R27. R28 and R 29 are each independently hydrogen, Ci-C 6 alkyl, allyl, Ci-C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 fluorocycfoalkyl, Ci-C 6 alkoxy, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroarylmethyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl or heterocycloalkylethyl; or wherein R 10 and Rn, Ri 6 and R 17 , R 2 i and R 22 , or R 23 and R 24 , taken together with the nitrogen to which they are attached, are part of a ring selected from the group consisting of azetidine, azetidin-2-one, pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-one, prperidine, piperidin-2-one, piperidin-3-one,
  • R x is alkyl, fluoroalkyl, alkoxyalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyj, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; wherein each heteroaryl ring is optionally substituted with 1 to 5 functional groups wherein each functional group may be halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, -CF 3 , -OCF 3 or -CN;
  • Ri, R 2 , R3, R4, R5, Re, R7, and Re are each independently hydrogen or Ci-
  • Ci-C 6 alkyl wherein the Ci-C 6 alkyl is optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, amino, hydroxyl, -CN, - NO 2 , Ci-C 6 alkoxy, -CF 3 , -OCF 3 , C 1 -C 6 alkyl, allyl, Ci-C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, C3-C7 fluorocycloalkyl, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroaryl methyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl, heterocycloalkylethyl, (CR a Rb)u-T-(CRcRd)u R ⁇ or R 3 iQ' wherein R 31 is null or Ci-C 2 alkylene and Q' is -SO 2 NR 32 R 3 3, - NR 34 COR
  • R3C R32 , R331 R34 > R35> R36, R371 R38, Ra, Rb, Rc, Ra and R ⁇ are each independently hydrogen, Ci-C 6 alkyl, allyl, Ci-C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 fluorocycloalkyl, Ci-C 6 alkoxy, phenyl-(C 0 -C 2 alkyl), heteroaryl-(C 0 -C 2 alkyl) or heterocycloalkyl-(C 0 -C 2 alkyl); wherein the heterocycloalkyl includes
  • heteroaryl group is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, or quinoxalinyi; wherein the phenyl, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 5
  • U and U' are each independently 0, 1 or 2;
  • T is null or oxy
  • R4 1 is phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazoyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl; each of which is optionally substituted with at least one Ci - C 3 alkyl, C 3 - Ce cycloalkyl, C 1 -C 3 alkoxy, Ci-C 6 fluoroalkoxy, Ci-C 6 fluoroalkyl, C 3 -C 7 fluorocycloalkyl, -CN, -F, -Cl, -Br, -CF 3 , C 0 -C 3 alkylthio, hydroxy, C 2 -C 6 alkenyl, C 2 -C 6 alken
  • R 42 is phenyl, heteroaryl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, benzothienyl, benzofuryl, benzoindazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, quinoxalinyi, thienopyridine, thienopyrimidine, thienopyridazine, thienopyrazine, furopyridine, furoopyrimidine, furopyridazine, furopyrazine, oxazolopyridine, oxazolopyrimidine, oxazolopyridazine.oxazolopyrazine, thiazolopyridine, thiazolopyrimidine, thiazolopyridazine.thiazolopyrazine, napthyridine, pyrrdopyrfmidine, pyridopyridazln
  • R 43 is hydrogen, -CN, Ci-C 6 alkoxy, C 1 -C 6 fluoroalkoxy, Ci-C 6 alkyl, Ci-
  • R39 is phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; each optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, Ci - C 6 alkyl, C 1 -C 6 alkoxy, -CF 3 , -OCF 3 , -CN, C 1 - C 3 alkyl, C 3 - C 6 cycloalkyl, Ci
  • R 40 is hydrogen, -CN, C 1 - C 6 alkyl, halo, -CF 3 , C 3 - C 6 cycloalkyl, Ci- C 6 fluoroalkyl, C 3 -C 7 fluorocycloalkyl, heterocycloalkyl, heterocycloalkylmethyl, heterocydoalkylethyl, R41, -CH2R41 and -CH2CH 2 R41; wherein the heterocycloalkyl includes
  • R41 is phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; and is optionally substituted with 1 to 5 functional groups, wherein each functional group may be halogen, C 1 - C 6 alkyl, Ci-C 6 alkoxy,
  • W is null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene or cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, amino, thtoj sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with 1-3 halogen atoms;
  • Ai is a monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene and monocyclic heteroarylene, optionally substituted with 1 to 5 functional groups, wherein each functional group may be alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy or -RgQ, wherein Q is -NR 10 Rn, -CN, -CO 2 Ri 2 , -SRi 3 , : SOR 14l -SO 2 Ri 5 , -SO 2 NR 16 Ri 7 , - NR 18 CORi 9 , -NR20CONR21R22, -CONR23R24, -NR25SOR26, -R 2 7COR 28 or- OR 29 ;
  • a 2 is null, cycloalkyl, heterocycloalkyl, aryl pr heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 5 functional groups, wherein each functional group may be alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and -R 9 Q, wherein R 9 and Q are as defined above;
  • R3, R*, R5, Re, R7 and Re are each independently hydrogen or alkyl; and/or at least one of R 1 , R 2, R 3 , R4 is taken together with at least one of R5, Re, R7 and R 8 to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with 1 to 3 functional groups, wherein each functional group may be halogen, amino, hydroxyl, -CN 1 -NO 2 , alkoxy, -CF 3 , -OCF 3 , alkyl, allyl, fluoroalkyl, cycloalkyl, fluorocycloalkylj heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether or R 31 -Q 1 wherein R 3 i is null or alkylene and Q" is -S ⁇ 2NR 3 2R 3 3, - NR 34 COR 35 , -CONR 36 R 3 7 or -
  • R37 and R 38 are each independently hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl or heteroarylalkyl; or wherein R 32 and R 33 or R 3 6 and R 37 , taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, alkoxy, -CF 3 , -OCF 3 and -CN; and
  • X is O, S or NR 3 g, wherein R 3 g is hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl; thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo,
  • W is -(CH 2 ) x (CO)y(CH 2 ) z -, wherein x, y and z are each independently O, 1 , 2 or 3;
  • a 1 is a cycloalkylidene, heterocycloalkylidene, arylene or heteroarylene, each optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, hydroxy, amino, alkylamino, dialkylamino or thiol;
  • a 2 is a monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocycloalkyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl, each optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, -CN, alkyl, alkoxy, acetyl, oxo, fluoroalkyl, fluoroalkoxy, hydroxy, amino, methylamino, dimethylamino, -SH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or arylcarbonyl; wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted onto the monocyclic or bicyclic ring is optionally substituted with a halo, alkyl, acetyl or alkoxycarbonyl;
  • Y is or -SO2-, wherein m and n are each independently 0; 1, 2 or 3;
  • Ri, R2, R3, R4, Rs, Re, R7 and R 8 are each independently hydrogen or alkyl; and/or at least one of Ri 1 R 2 , R3, R ⁇ is taken together with at least one of R5, Re, R7 and R 8 to form an alkylene bridge; and
  • X is O or N-O-alkyl.
  • Formula (I) and Formula (II) are present as racemic mixtures. However, in some embodiments, compound of Formula (I) and Formula (II) are present substantially as the (R) enanti ⁇ mer, or in the enantiomerically pure (R) form. According to other embodiments of the invention, provided are pharmaceutical compositions that include a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof; and a pharmaceutically acceptable carrier, excipient or diluent. According to some embodiments, provided are novel intermediates, in the synthesis of the compounds of Formula (I) and Formula (W).
  • Embodiments of the present invention provide uses of the compounds described herein for the preparation of medicaments for carrying out the utilities described herein.
  • kits including one or. more containers having pharmaceutical dosage units including an effective amount of the compounds described herein, wherein the container is packaged with optional instructions for the use thereof
  • methods for the inhibition of transmission of an HIV virus to a cell which include contacting the cell with an effective concentration of the compound according to an embodiment of the invention, under conditions sufficient wherein fusion of the virus is inhibited.
  • methods of treating HIV-1 infection in a subject which include administering to the subject an effective amount of the compound according to an . embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof.
  • the method further includes administering an effective amount of at least one other therapeutic agent, such as a reverse transcriptase inhibitor, a viral protease inhibitor, a cytokine, a cytokine inhibitor, a glycosylation inhibitor or a viral mRNA processing inhibitor.
  • a nucleoside analogue such as azidothymidine (AZT), ddl, ddC, ddA, d4T or 3TC, is the therapeutic agent.
  • the therapeutic agent is interferon- ⁇ , interferon- ⁇ or interferon- ⁇ .
  • the therapeutic agent is a protease inhibitor that is an inhibitor of HIV-1 protease, such as indavir.
  • administration of a compound according to the present invention and another therapeutic agent is sequential, such as with cycling therapy, which may be repeated at least one time in a fixed order.
  • a compound according to an embodiment of the invention may be administered before or after another therapeutic agent.
  • the cycling therapy includes the administration of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, in alternation with at least one therapeutic agent selected from the group consisting of a reverse transcriptase inhibitor, a viral protease inhibitor, a cytokine, a cytokine inhibitor, a glycosylation inhibitor or a viral mRNA processing inhibitor.
  • administration of a compound according to the present invention and another therapeutic agent is simultaneous.
  • the administration of at least one of the therapeutic agents is oral, and in some embodiments, administration of at least one of the therapeutic agents is parenteral, such as subcutaneous. According to some embodiments of the invention, methods of treating
  • HIV infection in an individual include administering an effective amount of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof.
  • the compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof is administered with at least one other therapeutic agent.
  • kits for inhibiting HIV replication including administering to a subject an effective amount of the compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof.
  • the compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof is administered with at least one other therapeutic agent.
  • a compound according to an embodiment of the invention or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof.
  • the compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof is administered with at least one other therapeutic agent.
  • Embodiments of the present invention provide uses of the compounds described herein for the preparation of medicaments for carrying out the utilities described herein.
  • kits including one or more containers having pharmaceutical dosage units including an effective amount of the compounds described herein, wherein the container is packaged with optional instructions for the use thereof
  • C x refers to such group having x number of carbon atoms.
  • C 3 alkyl refers to an alkyl group having 3 carbon atoms.
  • C 1 -C 6 alkyl refers to any alkyl having from one to six carbon atoms.
  • null in reference to a functional group means that the group is not present in the structure, and if the null group connects two other groups, it is understood that a bond, a single bond unless otherwise specified, connects the two other functional groups.
  • alkyl and alkylene refer to a straight or branched monovalent or divalent, respectively, hydrocarbon moiety. Unless specified otherwise, the term alkyl encompasses saturated hydrocarbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, and the like) and • unsaturated hydrocarbons, such as alkenyl (including at least one carbon- carbon double bond) and alkynyl (including at least one carbon-carbon triple bond). Thus, the terms alkynyl and alkenyl also encompass both straight and branched chains.
  • saturated hydrocarbons e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, and the like
  • unsaturated hydrocarbons such as alkenyl (including at least one carbon- carbon double bond
  • the alkyl groups may be Ci-C2o> in some embodiments, C1-C10, in some embodiments Ci-C ⁇ and, in some embodiments C1-3.
  • the alkyl groups may also be unsubstituted or substituted.
  • cycloalkyl and “cycloalkylidene” refers to a monovalent or divalent, respectively, monocyclic or polycyclic fused ring hydrocarbon moiety. 5
  • the cycloalkyl is a C 3 -C 12 cycloalkyl, and in some embodiments, a C 4 -C 6 cycloalkyl.
  • the term cycloalkyl includes both saturated cyclic alkyl groups and unsaturated cycloalkyl groups such as cycloalkenyl and cycloalkynyl groups, provided that a conjugated pi-electron system is not present.
  • Exemplary saturated alkyl include monocyclic cycloalkyl including 10 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, as well as other cycloalkyl such as norbonanyl and adamantyl.
  • Exemplary unsaturated cycloalkyl groups include cyclopentenyl, cyclohexadienyl, cycloheptatrienyl and norbornenyl.
  • a cycloalkyl may include an alkyl, as defined herein, in combination with a cyclic hydrocarbon moiety.
  • a 15 cycloalkyl group may be a -(CH 2 )x-cyclic alkyl-(CH2)y wherein x and y are each independently integers such as 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10.
  • alkoxy refers to an -OR group, wherein R is an alkyl or a cycloalkyl group, both as defined herein.
  • alkylthio refers to an -SR group, wherein R is an alkyl or a 20 cycloalkyl group, both as defined herein.
  • fluoroalkyl refers to an alkyl, as defined herein, wherein at least one hydrogen atom of the alkyl is substituted with a fluoro group.
  • fluoroalkoxy refers to an alkoxy, as defined herein, wherein at least one hydrogen atom of the alkoxy is substituted with a fluoro group.
  • fluorocycloalkyl refers to a cycloalkyl, as defined herein, wherein at least one hydrogen atom of the cycloalkyl is substituted with a fluoro group.
  • alkenoxy refers to an alkoxy, as defined herein, wherein the alkyl group is an alkenyl group, as defined herein.
  • halogen and "halo” refers to a halogen group, such as a fluoro, chloro, bromo or iodo group.
  • oxy refers to an -O- group.
  • hydroxy refers to an -OH group.
  • allyl refers to a wherein Ri and R 2 may each independently be hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or another group as otherwise specified.
  • amino refers to primary, secondary and tertiary amino groups, such as -IMH 2 , -NHRi and NR 1 R 2 , respectively, wherein Ri and R 2 may each independently be an alkyf, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or another group as otherwise specified.
  • thio refers to a -S- group.
  • Ri and R 2 may each independently be an alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
  • aryl refers to a monocyclic or fused-ring polycyclic (e.g., mono-, bf-or tricyclic) carbocyclic aromatic group.
  • the aryl is a C 5 -C 12 aryl, and in some embodiments a C 5 -C 9 aryl.
  • Exemplary aryl include phenyl, naphthyl, anthracenyl, and the like. The aryl may be unsubstituted or substituted.
  • heterocycloalkyl(idene) refers to a cycloalkyl, as defined herein, wherein at least one of the atoms comprising the ring(s) is substituted with a heteroatom (O, N or S).
  • the heterocycloalkyl may include 1 , 2, 3, 4, 5 or 6 heteroatoms.
  • heterocycloalkyl include azetidinyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl, oxiranyl, 2H-pyranyl, 4H-pyranyl, parathiazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, and the like.
  • heteroaryl(ene) refers to an aryl(ene), as defined herein, wherein at least one of the ring carbon atoms is substituted with a heteroatom.
  • a heteroaryl group may include 1, 2, 3, 4, 5 or 6 heteroatoms.
  • the heteroaryl includes 1 to 3 heteroatoms.
  • heteroaryl groups are pyridinyl, pyridaziny.l, pyrimidyi; pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)- triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isothiazolyl, thiazolyl, furyl, isoxazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, pyridonyl, quinolinylene, isoquinolinylene, benzimidazolylene, azabenzimidazol, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, and quinoxalinyl.
  • a heteroaryl group can be unsubstituted or substituted.
  • arylalkyl (
  • heteroarylalkyl "alkoxyalkyl”
  • phosphonatealkyl and “phosphoramidealkyl” refer to an alkyl group, as defined herein, wherein at least one hydrogen atom of the alkyl is substituted with an aryl, heteroaryl, alkoxy group, phosphonate or phosphoramide, respectively, each as defined herein.
  • polyether refers to an alkyl, as defined herein, that includes at least two ether (R-O-R) linkages.
  • Exemplary polyether are polyethylene oxide [-(CH 2 CH 2 O)-] and straight or branched polypropylene oxide [e.g., -(CH 2 CH 2 CH 2 O)-] or mixtures thereof.
  • optionally substituted is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents.
  • various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted).
  • a substitution is made provided that any atom's normal valency is not exceeded and that the substitution results in a stable compound.
  • pharmaceutically acceptable salt refers to a salt or salts prepared from at least one pharmaceutically acceptable non-toxic acid or base including inorganic acids and bases, and organic acids and bases.
  • Pharmaceutically acceptable salts of compounds according to embodiments of the invention include the acid addition and base salts thereof, and may be made using techniques known in the art, such as, but not limited to, reacting the compound with the desired base or acid.
  • Suitable pharmaceutically acceptable base addition salts for compounds according to embodiments of • the present invention include metallic salts (e.g., alkali metal salts and/or alkaline earth metal salts) made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc; or organic salts made from lysine, N 1 N'- dibenzylethyl- enediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine.
  • metallic salts e.g., alkali metal salts and/or alkaline earth metal salts
  • organic salts made from lysine, N 1 N'- dibenzylethyl- enediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine.
  • Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic
  • polymorph refers to one or more forms into which a compound of the present invention may crystallize. For example, depending on changes in temperature, pressure, or both, or other variations during the crystallization process, it is possible that one or more polymorphs of a compound according to the present invention may result. Polymorphs can generally be distinguished from each other by physical characteristics, biophysical properties, and by other techniques well know in the art
  • solvate refers to a molecular complex comprising a compound according to an embodiment of the present invention with one or more pharmaceutically acceptable solvent molecules.
  • a solvent may include, but is not limited to, ethanol.
  • Pharmaceutically acceptable solvates in accordance with the present invention include those wherein the solvent of crystallization may be isotopically substituted; e.g., D 2 O, d ⁇ -acetone, d 6 - DMSO.
  • prodrug refers to a derivative of a compound according to an embodiment of the present invention which may have minimal or no pharma-cological activity itself, but when administered in vivo, can be converted into a compound of the present invention that has the desired pharmacological activity.
  • the prodrug can hydrolyze (e.g., via it's biohydrolyzable moiety(s) such as a biohydrolyzable amide, a biohydrolyzable ester, a biohydrolyzable carba.mate; a biohydrolyzable carbonate, and a biohydrolyzable. phosphate), oxidize, or otherwise react in vivo to provide the compound of the present invention.
  • prodrugs can be prepared using methods well known in the art, such as those described by Burger's Medicinal Chemistry and Drug Discovery. 172-178, 949-982 (Manfred E. Wolff ed:, 5th ed. 1995).
  • a prodrug is a compound that is substantially biologically inactive, but is converted in vivo to a biologically active compound according to an embodiment of the invention.
  • derivative when used in reference to a compound according to an embodiment of the present invention means a compound: (a) which otherwise may have structural formula different from those of the active compounds of the present invention, but which is converted in the body to a compound of the present invention upon administration to an individual (e.g., prodrug, or pharmaceutically acceptable bioprecursor); or (b) is a metabolite of a compound of the present invention, formed in the body after administration of a compound according to the present invention to an individual.
  • an active drug may be modified into a derivative of the active drug, to improve any undesired pharmaceutical property (e.g., related to one or more of stability, solubility, absorbability, and the like) of the active drug.
  • the derivative may have efficacious activity by being converted in the body to the active drug, or may be derived physiologically from a compound of the present invention and exhibit antiviral activity.
  • an effective amount refers to that amount of a compound according to the present invention sufficient to result in amelioration of one or more symptoms of HIV infection and/or AIDS.
  • an effective amount is also meant to include the amount of the compound of the present invention sufficient to result in inhibition of, or interference with, HIV binding events, viral entry, or viral infection.
  • the term also encompasses the inhibition of viral transmission or prevention of viral establishment in its host, as observed by measuring one or more parameters.
  • Such parameters may include, but are not limited to, reduction in viral load (e.g., such as measuring HIV viral RNA in plasma) or viral pathogenesis, or decrease in mortality and/or morbidity associated with HIV infection of an individual treated with a compound " according to the present invention, or increase in immune parameters in the treated individual, such as an increase in overall CD4+ cells circulating in the blood, as compared to baseline (before treatment, or at an earlier point in the treatment history of the individual) level of circulating CD4+ cells.
  • antiviral activity refers to the ability of a compound according to the present invention to inhibit viral infection of cells, via, for example, inhibiting the ability of HIV-1 to bind to cell receptors and/or co- receptors of human cells which are capable of being infected by HIV-1.
  • a compound according to the present invention has antiviral activity, against typical strains of HIV-1, as represented by an IC 50 of no more than 5 ⁇ m (see, for example, Example 1 , and Table 3, herein).
  • target cell is used herein and in the claims to refer to a human cell capable of being infected by HIV, and in some embodiments, HIV-1.
  • a compound of the present invention with antiviral activity can also interfere with or inhibit or prevent viral entry into a host ("viral entry inhibitor"), viral transmission to a host, or viral establishment in its host, as observed by measuring one or more parameters.
  • Such parameters may include, but are not limited to, reduction in viral load (e.g., such as measuring HIV viral RNA in plasma) or viral pathogenesis, or decrease in mortality and/or morbidity associated with HIV infection of an individual treated with a compound according to the present invention, or increase in immune parameters in the treated individual, such as an increase in overall CD4+ cells circulating in the blood, as compared to baseline level of circulating CD4+ cells.
  • antiviral activity refers to the activity of that ingredient alone.
  • antiviral activity refers to a combination of active ingredient comprising administering a compound according to the present invention with other therapeutic agents used in the treatment of HIV infection and/or AIDS (antiviral agents, immunomodulators, vaccines, and the like)
  • the term refers to the activity of the combination treatment (e.g., whether administered simultaneously or sequentially, as part of a treatment regimen).
  • viral refers to, or are concerning, HIV 1 and in some embodiments, HIV-1.
  • Subjects as used herein, also referred to as “individuals”, are generally human subjects.
  • the subjects may be male or female and may be of any race or ethnicity, including, but not limited to, Caucasian, African- American, African, Asian, Hispanic, Indian, etc.
  • the subjects may be of any age, including newborn, neonate, infant, child, adolescent, adult, and geriatric.
  • Subjects may also include animal subjects, particularly mammalian subjects such as dog, cat, horse, mouse, rat, etc., screened for veterinary medicine or pharmaceutical drug development purposes.
  • Subjects further include, but are not limited, to those who may have, possess, have been exposed to, or have been previously diagnosed as afflicted with HIV or AIDS or one or more risk factors for HIV or AIDS.
  • the terms “treat”, “treating” and “treatment” means preventing or ameliorating diseases associated with HIV infection. Thus, the terms apply to prophylactic and/or therapeutic applications.
  • composition and “medicament” are used interchangeably herein to mean a composition comprising a pharmaceutically acceptable carrier and effective amount of a compound according to the present invention.
  • pharmaceutically acceptable carrier is used herein and for the claims to refer to a carrier medium that does not significantly alter the biological activity of the active ingredient (e.g., the antiviral activity of a compound according to the present invention) to which it is added.
  • the one or more substances of which the pharmaceutically acceptable carrier is comprised typically depends on factors (or desired features for its intended use) of the pharmaceutical composition such as the intended mode of administration, desired physical state (e.g., solid, liquid, gel, suspension, etc.), desired consistency, desired appearance, desired taste (if any), desired pharmacokinetic properties once administered (e.g., solubility, stability, biological half life), desired release characteristics (e.g., (a) immediate release (e.g., fast-dissolving, fast-disintegrating), or (b) modified release (e.g., delayed release, sustained release, controlled release)), and the like.
  • desired physical state e.g., solid, liquid, gel, suspension, etc.
  • desired consistency e.g., desired appearance, desired taste (if any)
  • desired pharmacokinetic properties e.g., solubility, stability, biological half life
  • desired release characteristics e.g., (a) immediate release (e.g., fast-dissolving, fast-disintegrating), or
  • a suitable pharmaceutically acceptable carrier may comprise one or substances, including but not limited to, a diluent, water, buffered water, saline, 0.3% glycine, aqueous alcohol, isotonic aqueous buffer; a water-soluble polymer, glycerol, polyethylene glycol, glycerin, oil, salt (e.g., such as sodium, potassium, magnesium and ammonium), phosphonate, carbonate ester, fatty acid, saccharide, polysaccharide, stabilizing agent (e.g., glycoprotein, and the like for imparting enhanced stability, as necessary and suitable for manufacture and/or distribution of the pharmaceutical composition), excipient, preservative (e.g., to increase shelf-life, as necessary and suitable for manufacture and distribution of the pharmaceutical composition), bulking agent (e.g., microcrystalline cellulose, and the like), suspending agent (e.g., alginic acid, sodium alginate, and the like), viscosity
  • an active ingredient may be formulated into a pharmaceutical composition using methods and one or more pharmaceutically acceptable carriers well known in the art, taking the desired features of the pharmaceutical composition, as described above, in mind during formulation.
  • typically a pharmaceutical composition may comprise from about 1% by weight to about 80% by weight of an active ingredient, and from about 10% by weight to about 99% by weight of pharmaceutically acceptable carrier.
  • Administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two compounds can be administered simultaneously (i.e., concurrently) or sequentially.
  • Simultaneous administration can be carried out by mixing the compounds prior to administration, or by administering the compounds at the same point in time- but at different anatomic sites or using different routes of administration.
  • the phrases "concurrent administration”, “administration in combination”, “simultaneous administration” or “administered simultaneously” as used herein means that the compounds are administered at the same point in time or immediately following one another. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time.
  • the most suitable route in any given case will depend on the nature and severity of the condition being treated.
  • the compounds described herein can be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9th Ed. 1995).
  • the compounds described herein are typically admixed with, inter alia, an acceptable carrier.
  • the carrier can be a solid or a liquid, or both, and is optionally formulated as a unit-dose formulation, which can be prepared by any of the well-known techniques of pharmacy.
  • compositions for oral administration may be, for example, solid preparations such as tablets, sugar-coated tablets, hard capsules, soft capsules, granules, powders and the like, with suitable carriers and additives being starches, sugars, binders, diluents, granulating agents, lubricants, disintegrating agents and the like. Because of their ease of use and higher patient compliance, tablets and capsules represent the most advantageous oral dosage forms for many medical conditions.
  • compositions for liquid preparations include solutions, emulsions, dispersions, suspensions, syrups, elixirs, and the like with suitable carriers and additives being water, alcohols, oils, glycols, preservatives, flavoring agents, coloring agents, suspending agents, and the like.
  • suitable carriers and additives being water, alcohols, oils, glycols, preservatives, flavoring agents, coloring agents, suspending agents, and the like.
  • suitable carriers and additives include aqueous gums, celluloses, silicates or oils.
  • the carrier is typically a liquid, such as sterile pyrogen- free water, pyrogen-free phosphate-buffered saline solution, bacteriostatic water, or Cremophor EL[R] (BASF, Parsippany, N.J.), parenterally acceptable oil including polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil, with other additives for aiding solubility or preservation may also be included.
  • the carrier can be either solid or liquid.
  • the compounds described herein can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.
  • the compounds described herein can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like.
  • inactive ingredients examples include red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, edible white ink and the like.
  • Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric- coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges including the compounds described herein in a flavored base, " usually sucrose and acacia or tragacanth; and pastilles including the compounds described herein in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations of the present invention suitable for parenteral administration can include sterile aqueous and non-aqueous injection solutions of the compounds described herein, which preparations are generally isotonic with the blood of the intended recipient. These preparations can contain anti-oxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions can include suspending agents and thickening agents.
  • the formulations can be presented in unit ⁇ dose or multi- dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.
  • sterile liquid carrier for example, saline or water-for-injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.
  • an injectable, stable, sterile composition including compounds described herein of the invention, in a unit dosage form in a sealed container.
  • the composition is provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
  • Formulations suitable for rectal or vaginal administration can be presented as suppositories. These can be prepared by admixing the compounds described herein with one or more conventional excipients or carriers, for example, cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compounds described herein.
  • excipients or carriers for example, cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compounds described herein.
  • Formulations suitable for topical application to the skin can take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers that can be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution. Suitable formulations comprise citrate or bisXtris buffer (pH 6) or ethanol/water.
  • the compounds described herein can be formulated for nasal administration or otherwise administered to the lungs of a subject by any suitable means, for example, by an aerosol suspension of respirable particles including the compounds described herein, which the subject inhales.
  • the respirable particles can be liquid or solid.
  • aerosol includes any gas-borne suspended phase, which is capable of being inhaled into the bronchioles or nasal passages.
  • aerosol includes a gas-borne suspension of droplets, as can be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition suspended in air or other carrier gas, which can be delivered by insufflation from an inhaler device, for example. See Ganderton & Jones, Drug Delivery to the Respiratory Tract, Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313; and Raeburn et al. (1992) J. Pharmacol. Toxicol. Methods 27:143-159.
  • Aerosols of liquid particles can be produced by any suitable means, such as with a pressure-driven aerosol nebulizer or an ultrasonic nebulizer, as is known to those of skill in the art. See, e.g., U.S. Patent No. 4,501,729. Aerosols of solid particles including the compounds described herein can likewise be produced with any solid particulate medicament aerosol generator, by techniques known in the pharmaceutical art. Alternatively, one can administer the compounds described herein in a local rather than systemic manner, for example, in a depot or sustained- release formulation.
  • administration is by subcutaneous or intradermal administration.
  • Subcutaneous and intradermal administration can be by any method known in the art including, but not limited to, injection, gene gun, powderject device, bioject device, microenhancer array, microneedles, and scarification (i.e., abrading the surface and then applying a solution including the compounds described herein).
  • the compounds described herein are administered intramuscularly, for example, by intramuscular injection or by local administration.
  • Novel compounds ⁇ include the compounds of Formula (I)
  • W is null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene or cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, amino, thio, sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with at least one halogen atom;
  • Ai is a monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene or monocyclic heteroarylene, each optionally substituted with at least one alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy, phosphoramide, phosphoramidealkyl, phosphonate, phosphonatealkyl or -R 9 Q, wherein R 9 is null or alkylene and Q is -NR10R11, -CN 1 -CO2R12, -SR13, -SOR 14 , -SO 2 Ri 5 , -SO 2 NR 16 R 17 , - NR 18 COR 19 , -NR 2 oCONR 21 R22, -CONR23R24, -NR 25 SOR 26 , -R 27 COR 28 , or- OR 29 ;
  • A2 is null, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with at least one of an alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and/or -RgQ, wherein R 9 and Q are as defined above;
  • R25, R26, R271 R28 and R 29 are each independently hydrogen, alkyl, aryl, ⁇ heteroaryl, allyl, alkoxy, cycloalkyl, heterocycloalkyl, fluoroalkyl, fluorocycloalkyl, arylalkyl or heteroarylalkyl; or wherein R 1 O and R 11 , R 16 and R 17 , R 21 and R 22 or R 2 3 and R 2 4, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl;
  • R 1 , R 2 , R3, R4, R5, Re, Rr and R 8 are each independently hydrogen or alkyl; and/or at least one of R 1 , R 2 , R 3 , R 4 is taken together with at least one of R 5 , Re, R7 and Re to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with at least one halogen, amino, hydroxyl, -CN, -NO 2 , alkoxy, -CF 3 , -OCF 3 , alkyl, allyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether and/or R 31 -Q' group, wherein R 31 is null or alkylene and Q' is -SO 2 NR 32 R 33 , -NR 34 COR 35 , -CONR 36 R 37 or -COOR
  • R37 and R 38 are each hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; or R 32 and R 33 or R 36 and R 37 , taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with at least one hydrogen, halo, alkoxy, CF 3 , -OCF 3 and/or -CN;
  • R 41 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with at least one alkyl, cycloalkyl, alkoxy, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, halo, -CN, -CF 3 , alkylthio, hydroxy, alkenyl, alkenoxy, acetyl and/or -RgQ, wherein R 9 and Q are defined above;
  • R 42 is aryl or heteroaryl, optionally substituted with at least one halo, alkoxy, -CF 3 , -OCF 3 , -CN, alkyl, -cycloalkyl, -fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, acetyl, alkenyl, alkenoxy and/or -R 9 Q, wherein R9 and Q are defined above;
  • R43 is hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with at least one halo, alkyl, alkoxy, -CF 3 , -OCF 3 , -CN 1 cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and/or -R 9 Q, wherein R 9 and Q are defined above;
  • R39 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with at least one halogen, alkyl, alkoxy, -CF 3 , -OCF 3 , -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, S-alkyl, hydroxy, alkenyl, alkenoxy,. acetyl.
  • R 40 is hydrogen, -CN, alkyl, halo, -CF 3 , cycloalkyl, fluoroalkyl, fluorocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are optionally substituted with at least one halo, alkyl, alkoxy, - CF 3 , -OCF 3 , -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl; fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and/or -RgQ, wherein R 9 and Q are defined above.
  • Ai is phenylene or monocyclic heteroarylene, wherein the phenylene and monocyclic heteroarylene are optionally substituted with 1 to 5 functional groups, wherein each functional group may be a Ci-C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, hydroxy, halo, Ci-C 6 fluoroalkoxy, C 2 -C 6 alkenyl, C2-C 6 alkenoxy or -RgQ, wherein R 9 is null or C 1 -C 2 alkylene and Q is -NRioRii, -CN, -CO 2 Ri 2 , -SRi 3 , -SOR 14 , -SO 2 Ri 5 , -SO 2 NR 16 Ri7, - NRi 8 CORi 9 , -NR 20 CONR 21 R 22 , -CONR 23 R 24 , -NR 25 SOR 26 , -R
  • a 2 is phenyl or heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1 to 5 functional groups, wherein each functional group may be a Ci-C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, hydroxy, halogen, C 1 -C 6 fluoroalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkenoxy or -R 9 Q, wherein R 9 is null or C 1 -C 2 alkylene and Q is defined above; R'j RiO> Ri1) Ri2» Ri3» Ri4> Ri5» Ri6i Ri7> Ri8i Ri9> R20> R21» R22» R23> R24>
  • R27, R28 and R29 are each independently hydrogen, C 1 -C 6 alkyl, allyl, C 1 -C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 fluorocycloalkyl, C 1 -C 6 alkoxy, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroarylmethyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl or heterocycloalkylethyl; or wherein R 10 and R 11 , R 16 and R 17 , R 21 and R 22 , or R 2 3 and R24, taken together with the nitrogen to which they are attached, are part of a ring selected from the group consisting of azetidine, azetidin-2-one, pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-one, piperidine, piperidin-2-one, piperidin-3
  • R x is alkyl, fluoroalkyl, alkoxyalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; wherein each heteroaryl ring is optionally substituted with 1 to 5 functional groups wherein each functional group may be halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -CF 3 , -OCF 3 or -
  • R30, R32 , R33, R34, R35, R36, R3 7 , R38, Ra, Rb, Rc, Rd and R e are each independently hydrogen, C 1 -C 6 alkyl, allyl, C 1 -C 6 fluoroalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 fluorocycloalkyl, C 1 -C 6 alkoxy, phenyl-(C 0 -C2 alkyl), heteroaryl-(Co-C 2 alkyl) or heterocycloalkyl-(C 0 -C2 alkyl); wherein the heterocycloalkyl includes 0 to 4 nitrogen atoms;
  • heteroaryl group is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, or quinoxalinyl; wherein the phenyl, heteroary
  • U and U' are each independently O, 1 or 2; T is null or oxy;
  • R4 1 is phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazoyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl; each of which is optionally substituted with at least one Ci - C 3 alkyl, C 3 - C 6 cycloalkyl, Ci -C 3 alkoxy, C 1 -C 6 fluoroalkoxy, C 1 -C 6 fluoroalkyl, C 3 -C 7 fluorocycloalkyl, -CN 1 -F, -Cl, -Br, -CF 3 , Co-C 3 alkylthio, hydroxy, C 2 -C 6 alkenyl, C 2 -Ce al
  • R 42 is phenyl, heteroaryl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, benzothienyl, benzofuryl, benzoindazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, quinoxalinyl, thienopyridine, thienopyrimidine, thienopyridazine, thienopyrazine, furopyridine, furoopyrimidine, furopyrida.zine, furopyrazine, oxazolopyridine, oxazolopyrimidine, oxazolopyridazine.oxazolopyrazine, thiazolopyridine, thiazolopyrimidine, thiazolopyridazine.thiazolopyrazine, napthyridine, pyridopyrimidine, pyridopyridazine or
  • R43 is hydrogen, -CN, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkyl, C 1 -
  • R 39 is phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyi.isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; each optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, Ci - C 6 alkyl, Ci-C 6 alkoxy, -CF 3 , -OCF 3 , -CN, Ci - C 3 alkyl, C 3 - C 6 cycloalkyl, C 1 -
  • R 40 is hydrogen, -CN, Ci - C 6 alkyl, halo, -CF 3 , C 3 - C 6 cycloalkyl, Ci-
  • C 6 fluoroalkyl C 3 -Cz fluorocycloalkyl, heterocycloalkyl, heterocycloalkylmethyl, heterocycloalkylethyl, R 41 , -CH 2 R 4I and wherein the heterocycloalkyl includes 0 to 4 nitrogen atoms; 0 to 2 nitrogen atoms and 0 to 1 oxygen atom;
  • R 4I is phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; and is optionally substituted with 1 to 5 functional groups, wherein each functional group may be halogen, Ci - C 6 alkyl, C 1 -C 6 alkoxy
  • Novel compounds according to embodiments of the invention also include compounds of Formula (II)
  • W is null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene or cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, -amino, thio, sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with 1-3 halogen atoms;
  • Ai is a monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene and monocyclic heteroarylene, optionally substituted with 1 to 5 functional groups, wherein each functional group may be alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy or -RgQ, wherein Q is -NR10R11, -CN, -CO 2 Ri2, -SR13, -SORi 4 , -SO 2 Ri 5 , -SO 2 NR 16 Ri 7 , - NR 18 CORi 9 , -NR20CONR21R22, -CONR23R24, -NR 25 SOR 2 S, ⁇ 27COR 28 or- OR 29 ;
  • a 2 is null, cycloalkyl, heterocycloalkyl, aryl pr heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 5 functional groups, wherein each functional group may be alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and -RgQ, wherein Rg and Q are as defined above;
  • Ri, R2, R3, R4, R5, Re. R7 and R 8 are each independently hydrogen or alkyl; and/or at least one of R 1 , R 2 , R 3 , R4 is taken together with at least one of R 5 , Re, R7 and Re to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with 1 to 3 functional groups, wherein each functional group may be halogen, amino, hydroxyl, -CN, -NO 2 , alkoxy, -CF 3 , -OCF 3 , alkyl, allyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether or R 31 -Q' wherein Rs 1 is null or alkylene and Q' is -SO 2 NR 32 R 33 , - NR34COR35. -CONR36R37 or -
  • R351 R36, R37 and R38 are each independently hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl or heteroarylalkyl; or wherein R 32 and R 33 or R 3 6 and R 37 , taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, alkoxy, -CF 3 , -OCF 3 and -CN; and
  • X is O, S or NR 39 , wherein R 39 is hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, q ⁇ inazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; optionally substituted with 1 to 5 functional groups, wherein each s functional group may be halo
  • W is -(CH 2 )x(CO) y (CH 2 )z-, wherein x, y and z are each independently 0, ' 1 , 2 or 3;
  • 5 Ai is a cycloalkylidene, heterocycloalkylidene, arylene or heteroarylene, each optionally substituted with 1 to 3 functional groups, - wherein each functional group may be halo, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, hydroxy, amino, alkylamino, dialkylamino or thiol;
  • a 2 is a monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocycloalkyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl, each optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, -CN, alkyl, alkoxy, acetyl, oxo, fluoroalkyl, 5 fluoroalkoxy, hydroxy, amino, methylamino, dimethylamino, -SH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or arylcarbonyl; wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted onto the monocyclic or bicyclic ring is optionally substituted with a halo, alkyl, acetyl or alkoxycarbonyl; 0
  • Y is or -SO 2 -, wherein m and n are each independently 0, 1, 2 or 3;
  • Ri, R2, R3, R4, R 5 , Re, R7 and R 8 are each independently hydrogen or alkyl; and/or at least one of Ri 1 R ⁇ , R 3 , R 4 is taken together with at least one of Rs 1 Re, R7 and Re to form an alkylene bridge; and
  • X is O, -CN or N-O-alkyl.
  • any of the R groups and/or functional groups represented thereby can be excluded from a particular compound or composition.
  • Formula .(I) and Formula (II) are present as racemic mixtures. However, in some embodiments, compound of Formula (I) and Formula (II) are present substantially as one enantiomer or in the enantiomerically pure (R) form.
  • compositions of embodiments of the invention include a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof; and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound according to the present invention or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or as part of a pharmaceutical composition may be used in antiviral treatment alone (also known as "monotherapy"), or in combination or in a treatment regimen (e.g., when used simultaneously, or in a cycling on with one drug and cycling off with another) with other therapeutic agents (including antiviral drugs) used for treatment of HIV (e.g., including, but not limited to, other HIV entry inhibitors (e.g., gp41 fusion inhibitors, CCR5 inhibitors, retrocyclin, CD4 inhibitors, gp120 inhibitors, and the like), HIV integrase inhibitors, reverse transcriptase inhibitors (e.g., nucleoside or nonnucleoside), protease inhibitors, viral- specific transcription inhibitors, viral processing inhibitors, HIV maturation inhibitors, inhibitors of uridine
  • HAART Highly Active Anti- Retroviral Therapy
  • HAART typically combines three or more drugs with antiviral activity against HIV, and typically involves more than one class of drug (a "class” referring to the mechanism of action, or viral protein or process targeted by the drug).
  • a method of treatment, a compound, and a pharmaceutical composition, according to the present invention may be administered alone (e.g., as monotherapy) or may be administered in a treatment regimen, or co-administered, involving a combination of additional therapeutic agents for the treatment of HIV infection and/or AIDS, as " . described in more detail herein.
  • one or more therapeutic agents may be combined in treatment with a compound (by itself, or in a pharmaceutical composition) according to the present invention.
  • the combination comprises two or more antiviral agents to increase the efficacy of the treatment by, for example, reducing the ability of the virus to become resistant to the antiviral agents used in the treatment (as compared to monotherapy).
  • antiviral agents useful in treating of HIV infection
  • additional therapeutic agents selected from the following: reverse transcriptase inhibitor, including but not limited to, abacavir, AZT (zidovudine), ddC (zalcitabine), nevirapine, ddl (didanosine), FTC (emtricitabine), (+) and (-) FTC, reverset, 3TC (lamivudine), GS 840, GW-1592, GW-8248, GW-5634, HBY097, delaviridine, efavirenz, d4T (stavudine), FLT, TMC125, adefovir, tenofovir, and alovudine; protease inhibitor, including but not limited to, amprenivir, CGP-73547, CGP-61755, DMP-450, indinavir, and alovudine; protease inhibitor, including but not limited to, amprenivir, CGP-73547
  • a combination drug treatment may comprise two or more therapeutic agents having the same mechanism of action (viral protein or process as a target), or may comprise two or more therapeutic agents having a different mechanism of action.
  • administration of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, and another therapeutic agent is sequential, and in other embodiments, administration of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, and another therapeutic agent is simultaneous. According to some embodiments, administration of a compound according to the present invention and another therapeutic agent is simultaneous.
  • the administration of at least one of the therapeutic agents is oral, and in some embodiments, administration of at least one of the therapeutic agents is parenteral, such as subcutaneous.
  • methods of treating HIV infection in a subject include administering an effective amount of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, and an effective amount of at least one therapeutic agent.
  • methods of inhibiting HIV replication including administering to a subject an effective amount of the compound according to an embodiment of the invention, or a pharmaceutically acceptable. prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, and an effective amount of at least one therapeutic agent.
  • Effective dosages of these illustrative additional therapeutic agents which may be. used in combinations with a compound, or pharmaceutical composition, according to the present invention, are known in the art. Such combinations may include a number of antiviral agents or therapeutic agents that can be administered by one or more routes, sequentially or simultaneously, depending on the route of administration and desired pharmacological effect, as is apparent to one skilled in the art.
  • Effective dosages of a compound or pharmaceutical composition according to the present invention to be administered may be determined through procedures well known to those in the art; e.g., by determining potency, biological half-life, bioavailability, and toxicity.
  • an effective amount of a compound according to the present invention and its dosage range are determined by one skilled in the art using data from routine in vitro and in vivo studies well know to those skilled in the art.
  • in vitro infectivity assays of antiviral activity such as described herein, enables one skilled in the art to determine the mean inhibitory concentration (IC) of the compound, as the sole active ingredient or in combination with other active ingredients, necessary to inhibit a predetermined range of viral infectivity (e.g., 50% inhibition, IC 50 ; or 90% inhibition, ICg 0 ) or viral replication.
  • IC mean inhibitory concentration
  • an exemplary dosage range of a compound according to the present invention, as an active ingredient may be from about 1 mg/kg body weight to about 100 mg/kg body weight; and more preferably no less thani mg/kg body weight to no more than 10 rng/kg body weight.
  • a compound or pharmaceutical composition according to the present invention may be administered to an individual by any means that enables the active ingredient to reach the target cells.
  • a compound or pharmaceutical composition according to the present invention may be administered by. any suitable technique, including oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, or subcutaneous injection or . infusion, intradermal, or implant), nasal (e.g., inhalation spray), pulmonary, vaginal, rectal, sublingual, or other suitable routes of administration; and can be formulated in dosage forms appropriate for each route of administration.
  • a compound or pharmaceutical composition according to the present invention is administered to an individual orally.
  • a compound or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention in an effective amount to inhibit infection of the cell by HIV.
  • the method may further include administering a compound, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention in combination with other therapeutic agents used to treat HIV infection and/or AIDS to an individual by administering to the individual the combination (simultaneously or sequentially, or a part of a therapeutic regimen) of therapeutic agents which includes an effective amount of the compound, pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention.
  • Also provided are methods for inhibiting HIV entry comprising administering to an individual in need of treatment a compound or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof or pharmaceutical composition according to the present invention in an effective amount to inhibit viral entry of a target cell.
  • the methods may further include administering a compound, a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention in combination with one or more additional inhibitors of viral entry useful in treating HIV infection, in an effective amount.
  • Embodiments of the present invention provide prophylaxis of the diseases and disorders described herein.
  • the inventive methods eliminate or reduce the incidence or onset of the disease or disorder, as compared to that which would occur in the absence of the measure taken.
  • the present methods slow, delay, control, or decrease the likelihood or probability of the disease or disorder in the subject, as compared to that which would occur in the absence of the measure taken.
  • Embodiments of the invention further provide kits that can include at least one compound according to embodiments of the present invention or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention, and optionally instructions for administering the same. Further, the kits can include additional therapeutic agents useful for the treatment of HIV. In some embodiments, the components of the kits may be packaged together in a common container. EXAMPLES EXAMPLE 1
  • an HIV-1 infection assay was used to determine the antiviral potency for compounds of the present invention.
  • an in vitro assay for demonstrating antiviral potency it is important to note that antiviral effect demonstrated in the in vitro assay has been correlated with antiviral effect in. vivo.
  • one or more antiviral agents known to have an antiviral effect in vivo were used to demonstrate that such antiviral agents also demonstrated an antiviral effect in this in vitro virus assay.
  • an HIV-1 pseudotyped virus assay was used to determine the respective antiviral potencies of each compound tested in the assay for comparison.
  • the pseudotyped assay scores for a reduction in infection as indicated by decreased signal from the reporter gene encoding a luciferase enzyme ("reporter gene").
  • reporter gene a reporter gene encoding a luciferase enzyme
  • the assay employs cell lines expressing CD4 and either of the primary chemokine receptors (CCR5 or CXCR4) that HIV uses as a co-receptor ("target cells").
  • Pseudotyped virus was prepared by co-tra ⁇ sfection of 293T cells with: 1) a plasmid construct carrying the HIV-1 envelope of choice, in combination with 2) a pseudotyped virus backbone construct in which (a) envelope expression has been abrogated due to a frameshift in the envelope sequence, and (b) the reporter gene replaces nef. Expression of HIV-1 envelope on 293T packaging ceils results in the production of a pseudotyped virus carrying the reporter gene that is capable of a single cycle of infection.
  • the compounds of the present invention. being tested for antiviral activity were serially diluted and dose responses determined in duplicate in two separate experiments.
  • the compounds to be tested were added directly to the plated, target cells, followed by the addition of pseudotyped virus described above.
  • the cells were cultured for three days prior harvest. Media and compound were removed, the cell monolayer was washed, lysed by detergent, and then frozen at -80 degrees C for a minimum of 30 minutes. Following thawing and acclimation to room temperature, luciferase production was quatified by injecting 100 Dl of a substrate (of the enzyme encoded by the reporter gene) into each well followed by detecting the signal (light emitted from the interaction between the enzyme and substrate) after 5 seconds.
  • IC 50 is defined as the dilution resulting in a 50% reduction in enzymatic activity as interpolated from a titration curve.
  • Representative compounds according to the present invention, and their antiviral activity, are illustrated in Table 3.
  • the sulfonyl chloride 1, acid halide 4, or carboxylic acid 6 is coupled with a cyclic amine of general structure 2 using methods well known in the art.
  • the cyclic amine may be a monoprotected piperazine derivative or a carbonyl-protected analog of 4-piperidinone.
  • the protecting group is then cleaved after the reaction steps illustrated in Scheme 2, and additional synthetic transformations are performed on the liberated amino or keto group to provide the final target compounds or the intermediates.
  • the identity of the deprotecting agent will depend on the identity other groups present in the molecule.
  • cyclic amine 2 is a monoprotected piperazine derivative
  • a protecting group such as tert- butoxycarbonyl (“BOC”) or benzyloxycarbonyl (“CBZ”) may be appropriate. These protecting groups are commonly cleaved with the use of trifluoroacetic acid and hydrogen gas with a palladium catalyst respectively.
  • 2 is a carbonyl-protected 4-piper ⁇ dinone
  • dimethylacetal may be a suitable protecting group, and cleavage may be effected with the use of hydrogen chloride in aqueous methanol.
  • Other useful protecting groups, procedures for the introduction and cleavage are found in the text "Protective Groups in Organic Synthesis" by Theodora W. Greene. Peter G. M.
  • the acid of formula 6 (activated by suitable reagents such as 3-(diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3H)-one (DEPBT), or HBTU/HATU
  • HBTU is O-benzotriazoM-yl-N.N.N'.N 1 - tetramethyluronium hexafluorophosphate
  • HATU is O-(7-azabenzotriazoI-1- yl)- N,N,N',N',-tetrarnethyl-uroniurn hexafluorophosphate) and HOBt/HOAt
  • HOBt is 1-hydroxybenzotriazole hydrate
  • HOAt is 1-Hydroxy-7- azabenzotriazole
  • the appropriate cyclic amine of formula 2 and excess amount of an acid acceptor such as triethyl
  • reaction may conveniently be carried out by reacting the relevant piperazine, 1.0 equivalent of the relevant carboxylic acid, 1.2 to about 2 equivalent of HATU, with 1.2 to about 2 equivalent of HOAT, 2.2 to about 10 • equivalent of triethylamine in DMF at room temperature for 12 hours.
  • the acyl chloride of formula 4 the appropriate cyclic amine of formula 2, and excess amount of an acid acceptor such as triethylamine or N, N-diisopropyl-N-ethylamine or N-methyl morpholine, are reacted in a solvent such as haloalkane (e. g. dichloromethane), an ether (e. g. tetrahydrofuran), or DMF at room temperature for about 4 to 48 hours.
  • haloalkane e. g. dichloromethane
  • an ether e. g. tetrahydrofuran
  • DMF e.g. tetrahydrofuran
  • the reaction may conveniently be carried out by reacting the relevant piperazine, 1.0 equivalent of the relevant acyl chloride, about 2 to10 equivalent N-methyl morpholine in DCE at room temperature for 12 hours.
  • the sulfonyl chloride of formula 1, the cyclic amine of formula 2, and excess amount of an acid acceptor such as triethylamine or N, N-diisopropyl-N-ethylamine or N-methyl morpholine or pyridine or the combination of different acid acceptors are reacted in a solvent such as haloalkane (e. g. dichloromethane), an ether (e. g. tetrahydrofuran), or DMF at room temperature for about 4 to 48 hours.
  • a solvent such as haloalkane (e. g. dichloromethane), an ether (e. g. tetrahydrofuran), or DMF at room temperature for about 4 to 48 hours.
  • the reaction may conveniently be carried out by reacting the relevant piperazine, 1.0 equivalent of the relevant sulfonyl chloride, about 2 to10 equivalent N- methyl morpholine in DCE at room temperature for 12 hours.
  • Piperazines with a single unsubstituted ring nitrogen are available commercially, and can also be produced by a variety of procedures that are illustrated in Scheme 2.
  • Piperazines with two unsubstituted ring nitrogens typically react with electrophiles such as acid chlorides, activated carboxylic acids, aryl halides, carboxylic esters, imidate esters, etc. to give a mixture of products arising from substitution of one or both nitrogens.
  • electrophiles such as acid chlorides, activated carboxylic acids, aryl halides, carboxylic esters, imidate esters, etc.
  • treatment of piperazine itself with a butyllithium followed by benzoyl chloride provides primarily the monobenzoyl derivative 13 (Wang, T. et al., J. Organic Chemistry 1999, vol
  • Scheme 3 shows a representative synthesis of a monoacylated piperazine using 15 as starting material.
  • the monoprotected piperazine 15 is treated with an acid chloride in the presence of triethylamine as an acid acceptor, and the Boc group is removed from the acylation product by the action of trifluoroacetic acid.
  • Scheme 3 shows a representative synthesis of a monoacylated piperazine using 15 as starting material.
  • the monoprotected piperazine 15 is treated with an acid chloride in the presence of triethylamine as an acid acceptor, and the Boc group is removed from the acylation product by the action of trifluoroacetic acid.
  • Monoprotected piperazines may be converted into mono amidino derivatives such as 22 in an analogous fashion (Scheme 4).
  • compounds of formulas 19 are treated with 1 equivalent of an appropriate carboximidoyl chloride in a solvent such as haloalkane (e. g. dichloromethane, "DCM"), or an ether (e. g. tetrahydrofuran) and are treated with excess amount of an acid acceptor such as triethylamine or N, N-diisopropyl-N- ethylamine or N-methyl morpholine at room temperature for approximately 1 to 2 hours.
  • a solvent such as haloalkane (e. g. dichloromethane, "DCM"), or an ether (e. g. tetrahydrofuran)
  • an acid acceptor such as triethylamine or N, N-diisopropyl-N- ethylamine or N-methyl morpholine at room
  • N-Aryl and N-Heteroaryl piperazines may be prepared according to Scheme 5. Electron-deficient heteroaryl halides such as haloquinolines will react with substituted piperazines when heated together in the presence of an acid acceptor such as diisopropylethylamine. In some cases, improved yields will be obtained by the use of a solvent such as dimethylpropylene urea. In some cases, improved yields will be obtained by the use of a catalyst, such as copper powder or a copper salt. A variety of other methods are available for the N-substitution of piperazines with heteroaryl groups, including less electron-deficient aryls and heteroaryls (Antilla, J.C.
  • LG is a leaving group, such as alkoxy, halogen, or alkylthio 1 Ar-LG
  • PG is a protecting group
  • Ar is an aryl or heteroaryl group
  • LG is a leaving group, such as alkoxy, halogen, or alkylthio I ⁇ r .i_e
  • PG is a protecting group ⁇
  • Ar is an aryl or heteroaryl group
  • Scheme 10 shows a method for the synthesis of alkylidene piperidines of general structure 42.
  • an N-protected piperidinone is treated with an active methylene compound in the presence of a suitable base to provide protected alkylidene derivatives of general structure 41.
  • Deprotection of 41 gives the free NH derivative 42, which is an example of generic structure 2.
  • PG is a protecting group
  • Ar is an aryl or heteroaryl group
  • EWG is a group capable of acidifying a hydrogen on an adjacent carbon
  • alkylidene piperidines may be prepared according to Scheme 11.
  • an arylmethylphosphonium salt is treated with strong base and then added to a protected piperidinone according to well-known literature methods.
  • Treating the intermediate 44 with bromine and potassium carbonate in chloroform followed by treatment with sodium hydroxide in aqueous methanol gives the bromide 50.
  • methods well-known in the art Miyura, N et al., Chemical Reviews 1995, vol 95, 2457. Mitchell, T. N., Synthesis 1992, 803. StHIe, J. K., Angewandte Chemie Int. Ed.
  • the bromide 50 can be coupled with aryltin or arylboron compounds in the presence of a palladium catalyst to give the protected alkylidene derivatives 51. Deprotection gives the free NH intermediate 52.
  • the bromide can be subjected to metal halogen exchange with butyllithium, typically in a solvent such as tetrahydrofuran at -78° C, and treated with carbon dioxide to give the carboxylic acid 46.
  • Carboxylic acids are well- known precursors for a variety of heterocyles, and Scheme 10 illustrates the conversion of a carboxylic acid group into oxadiazole substituents by coupling with a carboxylic acid hydrazide followed by dehydration. Deprotection gives the free NH compound 49.
  • PG is a protecting group Ar is an aryl or heteroaryl group
  • aryllithium or aryl Grignard reagent with sulfur dioxide gives an aryl sulfinate salt, which upon treatment with N-chlorosuccinimide provides sulfonyl chlorides of general structure 53.
  • Compounds 53 may be examples of generic structure 1 , or the aryl group may be modified by further synthetic operations at a later point in the synthesis to give the compounds of the invention as shown in Scheme 13.
  • Ar-M is an aryllithium or aryl Grignard reagent Scheme 13.
  • aryl ketoacids of generic structure 57 A variety of methods well known in the art are available for the synthesis of aryl ketoacids of generic structure 57. Treating an aryl bromide 55 with magnesium gives an arylmagnesium bromide, which is treated directly with by methyl chlorooxalate and a copper catalyst to give an aryl ketoester 56 (Babudr ⁇ , F. et al., Tetrahedron 1996, vol 52, 13513). Hydrolysis of the ketoester with sodium hydroxide in a mixture of methanol and water gives a ketoacid of general structure 57.
  • a methyl-substituted arene of general structure 58 is treated with NBS in the presence of light or a free radical initiator to give a bromide of general structure 59.
  • Displacement of the bromine with cyanide gives a nitrile of general structure 60.
  • This reaction may be performed in a variety of solvents, most commonly a polar solvent such as DMSO or DMF.
  • Partial hydrolysis of the nitrile to an ester 61 may be conducted by treating the nitrile with hydrochloric acid in methanol. Oxidation of the resulting ester to a ketoester 56 may be performed in a variety of literature methods, commonly by the use of selenium dioxide.
  • cyanohydrin 63 which can be partially hydrolysed to a hydroxyester 64 using hydrochloric acid in methanol.
  • Hydroxyesters 64 can be oxidized to ketoesters 56 using a variety of methods known in the art.
  • Generic structure 57 may be an example of generic structure 6, or it may be a synthetic intermediate that is converted to 6 by further transformations.
  • a methyl ketone is brominated with bromine, commonly in acetic acid as solvent at room temperature to reflux. Treating this bromoketone with a thioamide in a polar solvent such as DMF at temperatures of 25 0 C to reflux provides 67. Treating an aldehyde with hydroxylamine generated in situ from hydroxylamine hydrochloride and base gives an oxime, which can be chlorinated with NCS in warm DMF to give 69. Adding this chloride slowly to a solution of an acetylene and base at room temperature gives an isoxazole of structure 70.
  • amideoxime 71 which is cyclized to 72 by adding an acid chloride, optionally in the presence of a tertiary amine base, and heating to temperatures of 70 0 C to 120 0 C.
  • treating 68 with toluenesulfonyl isocyanate (TOSMIC) gives an oxazole 73. Further examples of this approach are well known in the art of heterocyclic chemistry.
  • treating the nitrile 74 with methanol and hydrogen chloride in ether at temperatures of -10 0 C to 10 0 C gives an imidate hydrochloride of general structure 77. This reaction typically gives best results when only 1.0 to 1.2 equivalents of methanol are used.
  • diethyl ether as a dilutant for the reaction.
  • Treating aryl bromide 79 with trimethylsilylacetylene and a palladium catalyst in an amine solvent followed by treatment with methanolic base gives the aryl acetylene 80.
  • a second commonly used approach to the synthesis of compounds 83 containing an aryl-aryl bond is to use a palladium catalyst to couple an aryl halide with an arylzinc, arylboronate or aryltin compound (See, Miyura, N. et al., Chemical Reviews 1995, vol 95, 2457; Mitchell, T. N. Synthesis 1992, 803; Stille, J. K. Angewandte Chemie Int. Ed. English 1986, 508; Negishi, E- I. et al., J. Organic Chemistry 1977 , 1821 ; Erdik, E., Tetrahedron 1992, 9577), This approach is exemplified in Scheme 16.
  • the coupling reaction between an aryl halide 82 and an aryltin compound is commonly performed using PhCH 2 PdCI(Pr» 3 P)2 as catalyst in refluxing chloroform.
  • Other solvents and catalysts are occasionally useful for this transformation, and in some cases additives such as lithium chloride or copper salts facilitate the reaction.
  • the coupling between an aryl halide and an aryl boron compound is commonly performed using a two phase mixture of benzene, aqueous sodium carbonate, and ethanol as solvent, and tetrakis(triphenylphosphine) palladium(O) as catalyst.
  • the use of other solvents, catalysts, and bases gives superior results as well known in the art.
  • Coupling between an aryl halide and an arylzinc reagent is usually performed in tetrahydrofuran, dimethylformamide, or a mixture of these two solvents using tetrakis(tri ⁇ henylphosphine) palladium(O) as catalyst.
  • aryltin, arylzinc, and arylboronate compounds are commercially available. Others can be prepared by the routes shown in the scheme below. Treating an aryl bromide with butyllithium in tetrahydrofuran at -78 0 C gives an aryllithium species that is treated in situ with trimethylborate. Hydrolysis of the resulting borate salt with hydrochloric acid gives the boronic acid 85.
  • aryllithium species treating the aryllithium species with trimethylstannyl chloride gives an isolate aryltin compound 86.
  • Treating an aryflithium with zinc chloride gives the arylzinc species 87 which is usually used directly in a palladium catalyzed coupling step without isolation.
  • Aryltin compounds may also be formed by treating an aryl bromide or iodide with hexamethylditin and a catalytic PhCH 2 PdCI(Ph 3 Pk in dioxane at temperatures of 50 0 C to 120 0 C (See, Stille, J. K. Angewandte Chemie Int. Ed. English 1986, 508).
  • Arylboronic esters can be formed by treating an aryl bromide or iodide with a palladium catalyst and bis(pinacolborane) in the presence of sodium acetate (See, Baudoin, O. et al., J. Organic Chem. 2000, vol 65, 9268). In palladium- catalyzed coupling reactions, the boronate esters 89 often give results that are equivalent to those obtained with the boronic acids 85.'
  • Diaryl ketones may be prepared by treating an aryl aldehyde with a Gringard or organolithium reagent to give a carbinol 88. Oxidation of the carbinol with a suitable oxidizing agent such as manganese dioxide or pyridinium dichromate gives the ketone 89. Scheme 18.
  • dtaryl ketones 91 may be prepared from acid chlorides (Dieter, K. R. Tetrahedron 1999, vol 55, 4177).
  • One method involves treating an acid chloride 90 with an arylzinc or aryltin compound in the presence of a palladium catalyst
  • a palladium catalyst In the case of the arylzinc reagents, tetrakis(triphenylphosphine)palladium(o) is commonly a useful catalyst and the reaction is performed at 25 0 C to 65 0 C in THF.
  • the catalyst is commonly PhCH2PdCI(Ph3P) 2 and the reaction is performed in refluxing chloroform.
  • the acid chloride can be treated with an aryl Gringard reagent and a copper salt as catalyst.
  • Certain compounds of this invention are prepared by nucleophilic aromatic substitution reactions.
  • Compounds 94 containing a direct aryl-aryl bond, in which one of the aryl rings is bonded through a ring nitrogen, may be formed by treating an aryl halide 92 with a heterocylic amine in the presence of a base such as potassium hydroxide and a copper catalyst such as copper iodide or copper powder. Temperatures for this reaction may vary between 80 0 C to 180 0 C, and in some cases the use of a solvent such as DMPU may facilitate the reaction.
  • compounds 97 containing two aryl rings linked through a sulfur atom may be prepared by treating a aryl halide 95 with an aromatic thiol 96 in the presence of a base such as potassium carbonate and a copper catalyst such as copper oxide.
  • A(I) 1 A(2), A(3), and A(4) 94 are carbon, nitrogen, oxygen or sulfur.
  • Example 102 1-f(R)-4-Benzoyl-2-methyl-p ⁇ perazin-1-v ⁇ -2-r4-f3-methyl- isoxazol-5-v ⁇ -phenv ⁇ -ethane-1,2-dione
  • Example 103 1 -f (R)-4-Benzoyl-2-methyl-piperazin-1 -vO-2-(4-thiazol-2-yl- phenyl)-ethane-1 ,2-dione
  • Example 104 1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-r4-(2-methyl- thiazol-4-yl)-phenyl1-ethane-1.2-dione
  • Example 105 1-((R)-4-Benzoyl-2-methyl-piperazin-1-vO-2-r4-(2-rnethyl- 2H-tetrazol-5-yl)-phenyll-ethane-1,2-dione
  • Example 106 1-((R)-4-friVIethoxyimino1-phenyl-methyl
  • Example 107 ⁇ f3-Methyl-4-r5-(3-methyl-ri.2.4Toxadiazol-5-vn-thiophene- 2-sulfonv ⁇ -piperazin-i-ylVphenyl-methanone
  • Example 109 r3-Methyl-4-(5-H .2.41triazol-1 -yl-thiophene-2-sulfonyl)- piperazirt-1-vH-phenyl-m ⁇ thanone
  • Triethylamine (0.50 mL, 3.6 mmol) was added to a solution of 5-bromo- thiophene-2-sulfonyl chloride (0.94 g, 3.6 mmol) and (3-methyl-piperazin-1-yl)- phenyl-methanone (0.72 g, 3.6 mmol) in DCM (20 mL).
  • the reaction mixture was stirred at 40 0 C for 2 hours (TLC monitoring, MeOHZCHCI 3 5:95), washed with water, dried over sodium sulfate and filtered.
  • Example 110 f4-r5-(Furan-2-carbonyl)-thiophene-2-sulfonvn-3-methyl- piperazin-1-yli-phenylmetha ⁇ one (General Procedure B)
  • Triethylamine (2.8 mL, 19.5 mmol) was added to a mixture of 2- chlorosulfonyl-thiophene (3.56 g, 19.5 mmol) and 3-methyl-piperazirie-1- carboxylic acid fert-butyl ester (3.90 g, 19.5 mmol) in DCM (50 mL).
  • the reaction mixture was kept at room temperature for 1 hour under stirring (TLC monitoring, MeOH/CHCI 3 5:95), washed with water, dried with sodium sulfate, and evaporated.
  • Example 111 f4-r5-(3H-lmidazole-4-carbonyl)-thiophene-2-sulfonv ⁇ -3- methy.-p.perazin-1-yll-phenyl-methanone
  • Example 112 (4-r5-(>soxazole-3-carbonyl ⁇ -thiophene-2-sulfonvn-3- m ⁇ thyl-piperazin-1-yl>-phenyl-methanone
  • Triethylamine (2.11 g, 2.9 ml_, 21 mmol) was added to a solution of 3- bromo-benzenesulfonyl chloride (5.00 g, 20 mmol) and (3-methyl-piperazin-1- yl)-phenyl-methanone (4.10 g , 20 mmol) in DCM (5OmL).
  • the reaction mixture was stirred at 40 0 C for 2 hours (TLC monitoring, MeOH/CHCI 3 5:95), washed with water (3x20mL), dried over sodium sulfate and filtered.
  • Example 114 r3-Methyl-4-(3-H,2,41triazol-1-yl-benze ⁇ esulfonyl)- piperazin-i-yli-phenyl-methanone
  • Examples 116 and 117 r3-Methyl-4-(4-M .2.31triazol-1 -yl- benzenesulfonyl)-piDerazin-1-vn-phenyl-methanone and r3-methyl-4-(4- n.2.31triazol-2-vl-benzenesulfonvn-piperazin-1-vn-phenvl-methanone
  • Example 118 r3-Methyl-4-(4- ⁇ .2,41triazol-1 -yl-benzenesulfonyl)- piperazin-1-vn-phenvl-methanone
  • Example 120 f(Ri-3-Methyl-4-r4-( 1 H-M .2.31triazol-4-v»)-benzenesulfonyl1- piperazin-1-yl)-phe ⁇ yl-methanone
  • a heterogeneous mixture containing [(R)-4-(4-bromo-benzenesulfonyl)- 3-methyl-piperazin-1-yl]-phenyl-methanone (800 mg, 1.9 mmol), trimethyisilylacetylene (222 mg, 2.2 mmol), palladium dichloride bis(triphenyl)phosphene (67 mg, 5 mol%), copper iodide (5 mol%) and diisopropyl ethylamine (575 mg, 5.7 mmol) in anhydrous tetrahydrofuran (20 ml_) was heated at 50 0 C for 12 hours.
  • Example 121 «R)-4-f4-(1-teobutyl-1H-ri.2.3ltriazol-4-yl)- benzenesulfonvn-3-methyl-piperazin-1-yll-phenyl-methanone
  • Example 123 1-(4-f4-r4(fR)-4-Benzoyl-2-methyl-p ⁇ perazine-1-sulfonyl)- phenyli-n .2.31triazol-1 -ylV-phenyl-ethanone
  • Example 125 I i R)-3-Methvt-4-r5-f 1 H-M ,2,3ttriazol-4-vM-thiophene-2- sulfonvIl-piperazin-i-vD-phenyl-methanone
  • Example 126 f I RM-M-d -lsobutyl-1 H-M .2.31triazol-4-yl)- benzenesulfonvH-3-methvl-piperazin-1 -yl)-phenyl-methanone
  • Example 130 4-C4-r5-((R>-4-Benzoyl-2-nnethyl-piperazine-1-sulfonv ⁇ - thiophen-2-vn-M,2.3Ttriazo[-1-yl>-2-methvtsulfanyl-thiazo[e-5-carboxylic acid ethyl ester
  • Example 165 r(R)-3-Methyl-4-(5-ri.2.31thiadiazol-4-yl-thiophene-2- sulfonyl)-piperazin-1-v ⁇ -phenyl-methanone
  • Example 166 f3-Methyl-4-(4-oxazol-5-yl-benzenesulfonyl)-piperazin-1-v ⁇ - phenyl methanone
  • Example 168 1-(4-Benzoyl-2-methyl-piperazin-1-V-)-2-r4-(2H-pyraz ⁇ l-3- yl)-phen yli-etha ⁇ e-1.2-dio ⁇ e
  • Example 170 1 -(4-Benzoyl-2-metriyl-piperazin-1 -yl)-2-(4-ri .2,41triazol-1 - yl-phenyl)-ethane-1 ,2-dione
  • Example 171 1-(4-Benzovt-2-methyl-piperazin-1-vO-2-(4-furan-2-yl- phenv ⁇ -etharte-1 ,2-dione
  • Example 172 1-(4-Benzoyl-2-methyl-piperazin-1-vD-2-r4-(1-methyl-1f/- pyrazol-3-yl)-phenv ⁇ -ethane-1.2-dione
  • Example 173 1 -(4-Benzoyl-2-methyl-piperazin-1 -yl)-2-r4-f 5-methyl-furan- 2-yl>-phenv ⁇ -ethane-1.2-dione
  • Example 174 1-(4-Benzovi-2-methyl-piperazin-1 -vn-2-(4-li .2.31triazol-2- yl-phenvD-ethane-1.2-dione
  • Example 181 1-(fR)-4-Benzoyl-2-methvI-piperazin-1-yl)-2-r2-methyl-4- (1 //-pvrazol-3-v ⁇ -phe ⁇ v ⁇ -ethane-1.2-dione
  • Example 184 1-((R)-4-Benzoyl-2-methyl-piperazin-1-v ⁇ -2-r3-methyl-4- (1 /-/-pyrazol-3-yl)-phen v ⁇ -ethane-1 ,2-dione
  • Example 193 1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -vQ-2-(4-pyrazol-1 -y
  • Example 214 1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(6-pyrazol-1-yl- pyridin-3-yl)-ethane-1 ,2-dione
  • Example 215 1 -((R)-4-Benzoyl-2-meth yl-piperazin-1 -yl)-2-(4-imidazol-1 - yl-2-methyl-phenyl)-ethane-1 ,2-dione
  • Example 212 1-((RM-Benzoyl-2-methyl-piperazin-1-yl)-2-r4-(2-oxo- oxazolidin-3-v ⁇ -phenvn-ethane-1.2-dione
  • EXAMPLE 4 illustrated are compounds of Formula (I) according to some embodiments of the present invention. Measurements for antiviral activity, performed according to the methods described in Example 1 herein, are noted by reference to a range in Table 3, with "A” denoting antiviral activity represented by an IC 50 less than 5 ⁇ m; and "B” denoting antiviral activity represented by an IC 50 greater than 5 ⁇ m. Where the stereochemistry is depicted, the activity of the compound was assayed using an ena ⁇ tiomerically purified compound.

Abstract

This invention relates to piperazine and piperidine biaryl compounds of Formula (I) or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof; and to processes for preparing the compounds or pharmaceutical compositions containing the same. The compounds and pharmaceutical compositions of the present invention are provided for use in the treatment of HIV infection and/or AIDS.

Description

PIPERAZINE AND PIPERIDINE BIARYL DERIVATIVEiS
RELATED APPLICATION DATA
This application claims the benefit of U.S. Provisional Patent Application Serial No.60/779,462, filed on March 6, 2006, the contents of which are incorporated herein by reference in its entirety.
FIELD OF INVENTION
The present invention relates to piperazine derivatives, and to processes of preparation, compositions and methods of using the same. More specifically, the present invention relates piperazine derivatives and compositions, and to methods of using the same in the treatment of Human Immunodeficiency Virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS).
BACKGROUND OF THE INVENTION
Currently, it is estimated that over 42 million individuals, including 2.5 million children, are infected with HlV worldwide. In addition, it is estimated that worldwide over 14,000 people are infected with HIV daily and that 3 million people die each year from HIV-related causes. Advances in antiretroviral therapy, used in the treatment of HIV and AIDS, have. resulted in relatively fewer people dying of AIDS. However, the number of HIV-infected people continues to rise. In addition to the personal costs associated with HIV infection, over $10 billion is spent annually on drugs to treat HIV infection and AIDS.
It is estimated that even with antiviral therapy adherence rates of 80 to 90 percent, over time there is up to a 50 percent or greater failure rate for HIV therapy. A number of factors play a role in the development of resistance to antiretroviral therapy, including: the infecting virus subtype; the infected individual's genetics and compliance with therapy; and the therapeutic regimen(s) used. However, the eventual high rates of virologic failure are often ascribed to the ability of the virus to readily mutate to escape the action of a class of drugs, such that a few mutations, or even a single mutation, in the viral sequence may be sufficient to enable resistance broadly across a
i class of drugs. Currently, there are only a few classes of drugs available for inclusion in a therapeutic regimen of antiretroviral therapy. Thus,. there is a need for new drugs to treat HIV infection and AIDS.
It is now well known that cells can be infected by HIV, such as HIV-1 , through a process by which fusion occurs between the cellular membrane and the viral membrane. The generally accepted model of this process is that the viral envelope glycoprotein complex (gp120/gp41) interacts with cell surface receptors on the membranes of the target cells. The process involves the interaction of the envelope glycoprotein gp120 with the cell surface receptor CD4. Such interaction may trigger a conformational change in gp120 facilitating its binding to co-receptors (a chemokine receptor such as CCR5 or CXCR4). Following binding. of gp120 to cellular receptors, a conformational change may be induced in the gp120/gp41 complex that allows gp41 to insert into the membrane of the target cell and mediate membrane fusion. Thus, gp120 plays an important role in HIV entry and serves as a potential target for the development of HIV-1 entry inhibitors, a new class of anti-HIV drugs that currently includes has one regulatory-approved member, enfuvirtide (T-20, Fuzeon).
Some piperazine and piperϊdine derivatives have been previously described. For example, WO 2005/004801 and US 2004/0009985 describe piperazine and piperadine deriviatives that incorporate an indole, azaindole, or other fused aromatic ring system linked to a piperazine ring through a ketoamide linker.
SUMMARY OF THE INVENTION
Embodiments of the present invention provide compounds that may be useful as an active ingredient used in the treatment of HIV infection, in some embodiments, in the treatment of HIV-1 infection.
According to some embodiments of the invention are compounds of Formula (I)
Figure imgf000004_0001
or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, wherein:
W is null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene or cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, amino, thio, sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with at least one halogen atom;
A1 is a monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene or monocyclic heteroarylene, each optionally substituted with an alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy, phosphoramide, phosphoramidealkyl, phosphonate, phosphonatealkyl or -R9Q, wherein Rg is null or alkylene and Q is -NR10R11, - -CN, -CO2R12, -SR13, -SOR14, -SO2R15, -SO2NR16R17, -NR18COR19, -NR20CONR21R22, -CONR23R24, -NR25SOR26, -R27COR28, Or-OR29;
A2 is null, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with at least one of an alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and/or -R9Q, wherein R9 and Q are as defined above;
R-IOJ Ri1j RI2J Ri3> Ri4> Ri5> R"I6> Ri7> Ri8j Ri9> R∑OJ R2IJ R∑2I R23> R24>
R25, R26τ R27, R28 and R29 are each independently hydrogen, alkyl, aryl, heteroaryl, allyl, alkoxy, cycloalkyl, heterocycloalkyl, fluoroalkyl, fluorocycloalkyl, arylalkyl or heteroarylalkyl; or wherein R10 and R11, R^ and Ri7> R21 and R22 or R23 and R24, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl;
Y is-CO-CO-, -SO2-, -C=NRx-CO-, and -CO-C=NRx-, -O-CO-, or - NR30CO-; wherein Rx is alkyl, fluoroalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with at least one
> halogen, alkyl, alkoxy, -CF3, -OCF3, and/or -CN; '
Ri, R2, R3, R4, R5, Re, R7 and R8 are each independently hydrogen or alkyl; and/or at least one of R1 , R2, R3, R4 is taken together with at least one of R5, Re. R7 and Re to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with at least one halogen, amino, hydroxyl, -CN, -NO2, alkoxy, -CF3, -OCF3, alkyl, allyl, fluoroalkyl, cycloalkyl, fluόrocycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether and/or R3i-Q' group, wherein R3i is null or alkylene and Q* is -SO2NR32R33, -NR34COR35. -CONR36R37 or -COOR38;
R30, R32, R33, R34> R35i R36. R37 and R38 are each hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; or R32 and R33 or R36 and R37, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with at least one hydrogen, halo, alkoxy, - CF3, -OCF3 and/or -CN;
Figure imgf000005_0001
Z is-COR4i, -C(=NR43)R4i or R42;
R41 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with at least one alkyl, cycloalkyl, alkoxy, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, halo, -CN1 -CF3, alkylthio, hydroxy, alkenyl, alkenoxy, acetyl aήd/or -RgQ1 wherein Rg and Q are defined above;
R42 is aryl or heteroaryl, optionally substituted with at least one halo, alkoxy, -CF3, -OCF3, -CN, alkyl, -cycloalkyl, -fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, acetyl, alkenyf, alkenoxy and/or -RgQ, wherein R9 and Q are defined above;
R43 is hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with at least one halo, alkyl, alkoxy, -CF3, -OCF3, -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and/or -RgQ, wherein R9 and Q are defined above;
R39 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with at least one halogen, alkyl, alkoxy, -CF3, -OCF3, -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, S-alkyl, hydroxy, alkenyl, alkenoxy, acetyl and/or -R9Q, wherein Rg and Q are defined above; and
R40 is hydrogen, -CN, alkyl, halo, -CF3, cycloalkyl, fluoroalkyl, fluorocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are optionally substituted with at least one halo, alkyl, alkoxy, - CF3, -OCF3, -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and/or -RgQ, wherein Rg and Q are defined above.
In particular embodiments of the invention, in a compound of Formula
O.
W is null, C0 - C6 alkylene, (C0 - C3 alkylene)-O-(C0 - C3 alkylene), (C0 - C3 alkylene)-NR'-(C0 - C3 alkylene), (C0 - C3 alkylene)-S-(C0 - C3 alkylene), (C0 - C3 alkylene)-S(=O)-(C0 - C3 alkylene), (C0 - C3 alkyleπe)-SO2-(C0 - C3 alkylene), (C0 - C3 alkylene)-C(=O)-(C0 - C3 alkylene), (C0 - C3 alkylene)- C(=O)NR'-(C0 - C3 alkylene) or (C0 - C6 cycloalkylidene), wherein the alkylene and cycloalkylidene groups are optionally substituted with 1 to 3 halogen atoms;
Ai is phenylene or monocyclic heteroarylene, wherein the phenylene and monocyclic heteroarylene are optionally substituted with 1 to 5 functional groups, wherein each functional group may be a CrC6 alkyl, Ci-Ce alkoxy, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, hydroxy, halo, Ci-C6 fluoroalkoxy, C2-C6 alkenyl, C2-C6 alkenoxy or -R9Q, wherein R9 is null or Ci-C2 alkylene and Q is -NRioRii, -CN, -CO2Ri2, -SRi3, -SORi4, -SO2Ri5, -SO2NRi6Ri7, - NRi8COR19, -NR20CONR2I R22, -CONR23R24, -NR25SOR26, -R27COR28, or- OR29;
A2 is phenyl or heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1 to 5 functional groups, wherein each functional group may be a Ci-C6 alkyl, C1-C6 alkoxy, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, hydroxy, halogen, Ci-C6 fluoroalkoxy, C2-C6 alkenyl, C2-C6 alkenoxy or -RgQ, wherein R9 is null or Ci-C2 alkylene and Q is defined above;
R's RiO» R-11. Ri2ι Ri3> Ri4» Ri5» Ri6» Ri7» Ri8» Ri9» R∑Oj R21j R22> R23J R∑4»
R255 R26, R27. R28 and R29 are each independently hydrogen, Ci-C6 alkyl, allyl, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycfoalkyl, Ci-C6 alkoxy, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroarylmethyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl or heterocycloalkylethyl; or wherein R10 and Rn, Ri6 and R17, R2i and R22, or R23 and R24, taken together with the nitrogen to which they are attached, are part of a ring selected from the group consisting of azetidine, azetidin-2-one, pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-one, prperidine, piperidin-2-one, piperidin-3-one, piperidin-4-one, morpholine, morpholin-2-one, morpholin-3- one and N-alkylpiperazine; wherein the heterocycloalkyl includes
0 to 4 nitrogen atoms;
0 to 2 nitrogen atoms and 0 to 1 oxygen atom; 0 to 2 nitrogen atoms and 0 to 1 sulfur atom; or
0 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulphur atom; and wherein the heteroaryl imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; and wherein the phenyl, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, C1-C6 alkoxy, -CF3, -OCF3 or -CN;
Rx is alkyl, fluoroalkyl, alkoxyalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyj, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; wherein each heteroaryl ring is optionally substituted with 1 to 5 functional groups wherein each functional group may be halo, Ci-C6 alkyl, Ci-C6 alkoxy, -CF3, -OCF3 or -CN;
Ri, R2, R3, R4, R5, Re, R7, and Re are each independently hydrogen or Ci-
C6 alkyl, wherein the Ci-C6 alkyl is optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, amino, hydroxyl, -CN, - NO2, Ci-C6 alkoxy, -CF3, -OCF3, C1-C6 alkyl, allyl, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycloalkyl, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroaryl methyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl, heterocycloalkylethyl, (CRaRb)u-T-(CRcRd)u Rβ or R3iQ' wherein R31 is null or Ci-C2 alkylene and Q' is -SO2NR32R33, - NR34COR35, -CONR36R37 or -COOR38;
R3C R32 , R331 R34> R35> R36, R371 R38, Ra, Rb, Rc, Ra and Rθ are each independently hydrogen, Ci-C6 alkyl, allyl, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycloalkyl, Ci-C6 alkoxy, phenyl-(C0-C2 alkyl), heteroaryl-(C0-C2 alkyl) or heterocycloalkyl-(C0-C2 alkyl); wherein the heterocycloalkyl includes
0 to 4 nitrogen atoms;
0 to 2 nitrogen atoms and 0 to 1 oxygen atom;
0 to 2 nitrogen atoms and 0 to 1 sulfur atom; or 0 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulphur atom; and wherein the heteroaryl group is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, or quinoxalinyi; wherein the phenyl, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, Ci-C6 alkoxy, -CF3, -OCF3 or -CN; or wherein R32 and R33 or R35 and R37, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl selected from the group consisting of aziridine, azetidine, pyrrolidine, pyrrolidin-2-one, piperidine, morpholine and N-alkylpiperazine;
U and U' are each independently 0, 1 or 2;
T is null or oxy;
R41 is phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazoyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl; each of which is optionally substituted with at least one Ci - C3 alkyl, C3 - Ce cycloalkyl, C1 -C3 alkoxy, Ci-C6 fluoroalkoxy, Ci-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, -CN, -F, -Cl, -Br, -CF3, C0-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl and/or -R9Q, wherein R9 is null or C1-C2 alkylene and Q is defined above;
R42 is phenyl, heteroaryl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, benzothienyl, benzofuryl, benzoindazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, quinoxalinyi, thienopyridine, thienopyrimidine, thienopyridazine, thienopyrazine, furopyridine, furoopyrimidine, furopyridazine, furopyrazine, oxazolopyridine, oxazolopyrimidine, oxazolopyridazine.oxazolopyrazine, thiazolopyridine, thiazolopyrimidine, thiazolopyridazine.thiazolopyrazine, napthyridine, pyrrdopyrfmidine, pyridopyridazlne or pyridopyrazine; each optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, C1-C6 alkoxy, -CF3, -OCF3 or -CN, Ci - C3 alkyl, C3 - C6 cycloalkyl, Ci-C6 fluoroalkoxy, C1-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, Co-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl or -R9Q, wherein Rg is null or Ci-C2 alkylene and Q is defined above;
R43 is hydrogen, -CN, Ci-C6 alkoxy, C1-C6 fluoroalkoxy, Ci-C6 alkyl, Ci-
C6 fluoroalkyl, C3-C7 cycloalkyl or C3-C7 fluorocycloalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; wherein the aryl or heteroaryl are optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, C1 - C6 alkyl, C1-C6 alkoxy, -CF3, -OCF3 or -CN, Ci - C3 alkyl, C3 - C6 cycloalkyl, Ci-C6 fluoroalkoxy, Ci-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, Co-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl or -RgQ, wherein R9 is null or C1-C2 alkylene and Q is defined above;
R39 is phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; each optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, Ci - C6 alkyl, C1-C6 alkoxy, -CF3, -OCF3, -CN, C1 - C3 alkyl, C3 - C6 cycloalkyl, Ci-C6 fluoroalkoxy, C1-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, S-(C0-C3 alkyl), hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl Or-R9Q, wherein R9 is null or C1-C2 alkylene and Q is defined above; and
R40 is hydrogen, -CN, C1 - C6 alkyl, halo, -CF3, C3 - C6 cycloalkyl, Ci- C6 fluoroalkyl, C3-C7 fluorocycloalkyl, heterocycloalkyl, heterocycloalkylmethyl, heterocydoalkylethyl, R41, -CH2R41 and -CH2CH2R41; wherein the heterocycloalkyl includes
0 to 4 nitrogen atoms; 0 to 2 nitrogen atoms and 0 to 1 oxygen atom;
0 to 2 nitrogen atoms and 0 to 1 sulfur atom; or
0 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulphur atom; and wherein R41 is phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; and is optionally substituted with 1 to 5 functional groups, wherein each functional group may be halogen, C1 - C6 alkyl, Ci-C6 alkoxy, -CF3, -OCF3, -CN, hydrogen, Ci - C3 alkyl, C3 - C6 cycloalkyl, O-(Ci-C6 fluoroalkyl), C1-C6 fluoroalkyJ, C3-C7 fluorocycloalkyl, S- (C0-C3 alkyl), hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl or -R9Q, wherein Rg is null or C1-C2 alkylene and Q is defined above.
According to some embodiments of the invention, provided are compounds of Formula (II)
Figure imgf000011_0001
or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, wherein:
W is null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene or cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, amino, thtoj sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with 1-3 halogen atoms;
Ai is a monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene and monocyclic heteroarylene, optionally substituted with 1 to 5 functional groups, wherein each functional group may be alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy or -RgQ, wherein Q is -NR10Rn, -CN, -CO2Ri2, -SRi3, :SOR14l -SO2Ri5, -SO2NR16Ri7, - NR18CORi9, -NR20CONR21R22, -CONR23R24, -NR25SOR26, -R27COR28 or- OR29;
A2 is null, cycloalkyl, heterocycloalkyl, aryl pr heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 5 functional groups, wherein each functional group may be alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and -R9Q, wherein R9 and Q are as defined above;
RiO. R-11. Ri2» Ri3» Ri4j Ri5> Ri6. Ri7» Ri8> R"19» R∑OS R21» R22» R23> R∑4> R25, R26, R27, R28 and R29 are hydrogen, alkyl, aryl, heteroaryl, allyl, alkoxy, cycloalkyl, heterocycloalkyl, fluoroalkyl, fluorocycloalkyl, arylalkyl or heteroarylalkyl; or wherein Ri0 and Rn, R^ and R17, R2i and R22, or R23 or R24, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl;
Y is -CO-CO-, -SO2-, -C=NRx-CO-, and -CO-C=NRx-, -O-CO-, or - NR30CO-; wherein Rx is alkyl, fluoroalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with 1 to 5 functional groups, wherein each functional group may be halogen, alkyl, alkoxy, -CF3, - OCF3 and -CN;
Ri, R2. R3, R*, R5, Re, R7 and Re are each independently hydrogen or alkyl; and/or at least one of R1, R2, R3, R4 is taken together with at least one of R5, Re, R7 and R8 to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with 1 to 3 functional groups, wherein each functional group may be halogen, amino, hydroxyl, -CN1 -NO2, alkoxy, -CF3, -OCF3, alkyl, allyl, fluoroalkyl, cycloalkyl, fluorocycloalkylj heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether or R31-Q1 wherein R3i is null or alkylene and Q" is -Sθ2NR32R33, - NR34COR35, -CONR36R37 or -COOR38;
R3O, R32, R33, R34, R35, R36». R37 and R38 are each independently hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl or heteroarylalkyl; or wherein R32 and R33 or R36 and R37, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, alkoxy, -CF3, -OCF3 and -CN; and
X is O, S or NR3g, wherein R3g is hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl; thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, alkyl, alkoxy, -CF3, -OCF3 or -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy, acetyl or -RgQ, wherein R9 and Q are defined above.
In particular embodiments of the invention, for the compound of Formula (II),
W is -(CH2)x(CO)y(CH2)z-, wherein x, y and z are each independently O, 1 , 2 or 3;
A1 is a cycloalkylidene, heterocycloalkylidene, arylene or heteroarylene, each optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, hydroxy, amino, alkylamino, dialkylamino or thiol;
A2 is a monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocycloalkyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl, each optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, -CN, alkyl, alkoxy, acetyl, oxo, fluoroalkyl, fluoroalkoxy, hydroxy, amino, methylamino, dimethylamino, -SH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or arylcarbonyl; wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted onto the monocyclic or bicyclic ring is optionally substituted with a halo, alkyl, acetyl or alkoxycarbonyl;
Y is
Figure imgf000014_0001
or -SO2-, wherein m and n are each independently 0; 1, 2 or 3;
Ri, R2, R3, R4, Rs, Re, R7 and R8 are each independently hydrogen or alkyl; and/or at least one of Ri1 R2, R3, RΛ is taken together with at least one of R5, Re, R7 and R8 to form an alkylene bridge; and
X is O or N-O-alkyl.
According to some embodiments of the invention, the compounds of
Formula (I) and Formula (II) are present as racemic mixtures. However, in some embodiments, compound of Formula (I) and Formula (II) are present substantially as the (R) enantiόmer, or in the enantiomerically pure (R) form. According to other embodiments of the invention, provided are pharmaceutical compositions that include a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof; and a pharmaceutically acceptable carrier, excipient or diluent. According to some embodiments, provided are novel intermediates, in the synthesis of the compounds of Formula (I) and Formula (W).
Embodiments of the present invention provide uses of the compounds described herein for the preparation of medicaments for carrying out the utilities described herein.
Embodiments of the present invention provide kits including one or. more containers having pharmaceutical dosage units including an effective amount of the compounds described herein, wherein the container is packaged with optional instructions for the use thereof According to other embodiments of the invention, provided are methods for the inhibition of transmission of an HIV virus to a cell, which include contacting the cell with an effective concentration of the compound according to an embodiment of the invention, under conditions sufficient wherein fusion of the virus is inhibited. According to some embodiments of the invention, provided, are methods of treating HIV-1 infection in a subject, which include administering to the subject an effective amount of the compound according to an . embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof.
In particular embodiments, the method further includes administering an effective amount of at least one other therapeutic agent, such as a reverse transcriptase inhibitor, a viral protease inhibitor, a cytokine, a cytokine inhibitor, a glycosylation inhibitor or a viral mRNA processing inhibitor. In some embodiments, a nucleoside analogue, such as azidothymidine (AZT), ddl, ddC, ddA, d4T or 3TC, is the therapeutic agent. In some embodiments, the therapeutic agent is interferon-α, interferon-β or interferon-γ. In some embodiments, the therapeutic agent is a protease inhibitor that is an inhibitor of HIV-1 protease, such as indavir. According to some embodiments, administration of a compound according to the present invention and another therapeutic agent is sequential, such as with cycling therapy, which may be repeated at least one time in a fixed order. A compound according to an embodiment of the invention may be administered before or after another therapeutic agent. In some embodiments, the cycling therapy includes the administration of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, in alternation with at least one therapeutic agent selected from the group consisting of a reverse transcriptase inhibitor, a viral protease inhibitor, a cytokine, a cytokine inhibitor, a glycosylation inhibitor or a viral mRNA processing inhibitor.
According to some embodiments, administration of a compound according to the present invention and another therapeutic agent is simultaneous.
According to some embodiments, the administration of at least one of the therapeutic agents is oral, and in some embodiments, administration of at least one of the therapeutic agents is parenteral, such as subcutaneous. According to some embodiments of the invention, methods of treating
HIV infection in an individual include administering an effective amount of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof. In addition, in some embodiments, the compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, is administered with at least one other therapeutic agent. According to some embodiments of the invention, provided are methods of inhibiting HIV replication including administering to a subject an effective amount of the compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof. In addition, in some embodiments, the compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, is administered with at least one other therapeutic agent. According to some embodiments of the invention, provided are methods for the inhibition of transmission of an HIV retrovirus to a cell, including contacting the cell with an effective amount of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof. In addition, in some embodiments, the compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, is administered with at least one other therapeutic agent.
Embodiments of the present invention provide uses of the compounds described herein for the preparation of medicaments for carrying out the utilities described herein.
Embodiments of the present invention provide kits including one or more containers having pharmaceutical dosage units including an effective amount of the compounds described herein, wherein the container is packaged with optional instructions for the use thereof
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION The invention is described more fully hereinafter. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. As used herein, the singular forms "a", "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms
"comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein
Definitions
Certain terms and phrases used herein and in the claims have the meanings provided below, unless otherwise stated. A functional group below may be referred to as including both monovalent or divalent radicals. The definition may describe embodiments in terms of the monovalent radicals, but one of skill in the art will understand that the corresponding divalent radicals are also encompassed.
The designation of a group as "Cx" refers to such group having x number of carbon atoms. Thus, for example, C3 alkyl refers to an alkyl group having 3 carbon atoms. Likewise, C1-C6 alkyl refers to any alkyl having from one to six carbon atoms.
The term "null" in reference to a functional group means that the group is not present in the structure, and if the null group connects two other groups, it is understood that a bond, a single bond unless otherwise specified, connects the two other functional groups.
The term "alkyl" and "alkylene" refer to a straight or branched monovalent or divalent, respectively, hydrocarbon moiety. Unless specified otherwise, the term alkyl encompasses saturated hydrocarbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, and the like) and • unsaturated hydrocarbons, such as alkenyl (including at least one carbon- carbon double bond) and alkynyl (including at least one carbon-carbon triple bond). Thus, the terms alkynyl and alkenyl also encompass both straight and branched chains. In particular embodiments of the invention, the alkyl groups may be Ci-C2o> in some embodiments, C1-C10, in some embodiments Ci-Cε and, in some embodiments C1-3. The alkyl groups may also be unsubstituted or substituted.
The terms "cycloalkyl" and "cycloalkylidene" refers to a monovalent or divalent, respectively, monocyclic or polycyclic fused ring hydrocarbon moiety. 5 In some embodiments, the cycloalkyl is a C3-C12 cycloalkyl, and in some embodiments, a C4-C6 cycloalkyl. The term cycloalkyl includes both saturated cyclic alkyl groups and unsaturated cycloalkyl groups such as cycloalkenyl and cycloalkynyl groups, provided that a conjugated pi-electron system is not present. Exemplary saturated alkyl include monocyclic cycloalkyl including 10 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, as well as other cycloalkyl such as norbonanyl and adamantyl. Exemplary unsaturated cycloalkyl groups include cyclopentenyl, cyclohexadienyl, cycloheptatrienyl and norbornenyl. Furthermore a cycloalkyl may include an alkyl, as defined herein, in combination with a cyclic hydrocarbon moiety. For example, a 15 cycloalkyl group may be a -(CH2)x-cyclic alkyl-(CH2)y wherein x and y are each independently integers such as 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10.
The term "alkoxy" refers to an -OR group, wherein R is an alkyl or a cycloalkyl group, both as defined herein.
The term "alkylthio" refers to an -SR group, wherein R is an alkyl or a 20 cycloalkyl group, both as defined herein.
The term "fluoroalkyl" refers to an alkyl, as defined herein, wherein at least one hydrogen atom of the alkyl is substituted with a fluoro group.
The term "fluoroalkoxy" refers to an alkoxy, as defined herein, wherein at least one hydrogen atom of the alkoxy is substituted with a fluoro group. 25 The term "fluorocycloalkyl" refers to a cycloalkyl, as defined herein, wherein at least one hydrogen atom of the cycloalkyl is substituted with a fluoro group.
The term "alkenoxy" refers to an alkoxy, as defined herein, wherein the alkyl group is an alkenyl group, as defined herein.
30. The term "halogen" and "halo" refers to a halogen group, such as a fluoro, chloro, bromo or iodo group.
The term "oxy" refers to an -O- group.
The term "oxo" refers to a =O group.
The terms "hydroxy" or "hydroxyl" refer to an -OH group. The term "allyl" refers to a
Figure imgf000020_0001
wherein Ri and R2 may each independently be hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or another group as otherwise specified.
The term "amino" refers to primary, secondary and tertiary amino groups, such as -IMH2, -NHRi and NR1R2, respectively, wherein Ri and R2 may each independently be an alkyf, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or another group as otherwise specified.
The term "thio" refers to a -S- group.
The term "sulfinyl" refers to a -S(=O)- group, which may also be referred to herein as -SO-.
The term "sulfonyl" refers to a -S(=O)2- group, which may also be referred to herein as -SO2-.
The term "amide" refers to a -NC(=O)- or an -C(=O)N- group, also referred herein as -NCO-. The term "phosphonate" refers to a radical -P(=O)(ORi)(OR2) or -
P(=O)(OH)(OR2), wherein Ri and R2 may each independently be an alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
The term "phosphoramide" refers to a radical -P(=O)(NR2)3, wherein each R may independently be an alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
The term "aryl" refers to a monocyclic or fused-ring polycyclic (e.g., mono-, bf-or tricyclic) carbocyclic aromatic group. In some embodiments the aryl is a C5-C12 aryl, and in some embodiments a C5-C9 aryl. Exemplary aryl include phenyl, naphthyl, anthracenyl, and the like. The aryl may be unsubstituted or substituted.
The term "heterocycloalkyl(idene)" refers to a cycloalkyl, as defined herein, wherein at least one of the atoms comprising the ring(s) is substituted with a heteroatom (O, N or S). For example, the heterocycloalkyl may include 1 , 2, 3, 4, 5 or 6 heteroatoms. Exemplary heterocycloalkyl include azetidinyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl, oxiranyl, 2H-pyranyl, 4H-pyranyl, parathiazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, and the like.
The term "heteroaryl(ene)" refers to an aryl(ene), as defined herein, wherein at least one of the ring carbon atoms is substituted with a heteroatom. For example, a heteroaryl group may include 1, 2, 3, 4, 5 or 6 heteroatoms. In some embodiments, the heteroaryl includes 1 to 3 heteroatoms. Exemplary heteroaryl groups are pyridinyl, pyridaziny.l, pyrimidyi; pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)- triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isothiazolyl, thiazolyl, furyl, isoxazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, pyridonyl, quinolinylene, isoquinolinylene, benzimidazolylene, azabenzimidazol, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, and quinoxalinyl. A heteroaryl group can be unsubstituted or substituted. The terms "arylalkyl"(e.g., phenylmethyl, phenylethyl, and the like),
"heteroarylalkyl" "alkoxyalkyl" "phosphonatealkyl" and "phosphoramidealkyl" refer to an alkyl group, as defined herein, wherein at least one hydrogen atom of the alkyl is substituted with an aryl, heteroaryl, alkoxy group, phosphonate or phosphoramide, respectively, each as defined herein. The term "polyether" refers to an alkyl, as defined herein, that includes at least two ether (R-O-R) linkages. Exemplary polyether are polyethylene oxide [-(CH2CH2O)-] and straight or branched polypropylene oxide [e.g., -(CH2CH2CH2O)-] or mixtures thereof.
The term "optionally substituted" is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted). A substitution is made provided that any atom's normal valency is not exceeded and that the substitution results in a stable compound.
The term "pharmaceutically acceptable salt" refers to a salt or salts prepared from at least one pharmaceutically acceptable non-toxic acid or base including inorganic acids and bases, and organic acids and bases. Pharmaceutically acceptable salts of compounds according to embodiments of the invention include the acid addition and base salts thereof, and may be made using techniques known in the art, such as, but not limited to, reacting the compound with the desired base or acid. Suitable pharmaceutically acceptable base addition salts for compounds according to embodiments of • the present invention include metallic salts (e.g., alkali metal salts and/or alkaline earth metal salts) made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc; or organic salts made from lysine, N1N'- dibenzylethyl- enediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include xinofoate, hydrochloride mesylate, zinc, potassium, or iron salts. In certain embodiments, both water-soluble and water-insoluble salts will be useful based on the mode of administration. The term "polymorph" refers to one or more forms into which a compound of the present invention may crystallize. For example, depending on changes in temperature, pressure, or both, or other variations during the crystallization process, it is possible that one or more polymorphs of a compound according to the present invention may result. Polymorphs can generally be distinguished from each other by physical characteristics, biophysical properties, and by other techniques well know in the art
The term "solvate" refers to a molecular complex comprising a compound according to an embodiment of the present invention with one or more pharmaceutically acceptable solvent molecules. A solvent may include, but is not limited to, ethanol. Pharmaceutically acceptable solvates in accordance with the present invention include those wherein the solvent of crystallization may be isotopically substituted; e.g., D2O, dβ-acetone, d6- DMSO.
The term "prodrug" refers to a derivative of a compound according to an embodiment of the present invention which may have minimal or no pharma-cological activity itself, but when administered in vivo, can be converted into a compound of the present invention that has the desired pharmacological activity. For example, the prodrug can hydrolyze (e.g., via it's biohydrolyzable moiety(s) such as a biohydrolyzable amide, a biohydrolyzable ester, a biohydrolyzable carba.mate; a biohydrolyzable carbonate, and a biohydrolyzable. phosphate), oxidize, or otherwise react in vivo to provide the compound of the present invention. Typically, prodrugs can be prepared using methods well known in the art, such as those described by Burger's Medicinal Chemistry and Drug Discovery. 172-178, 949-982 (Manfred E. Wolff ed:, 5th ed. 1995). In some embodiments, a prodrug is a compound that is substantially biologically inactive, but is converted in vivo to a biologically active compound according to an embodiment of the invention. The term "derivative" when used in reference to a compound according to an embodiment of the present invention means a compound: (a) which otherwise may have structural formula different from those of the active compounds of the present invention, but which is converted in the body to a compound of the present invention upon administration to an individual (e.g., prodrug, or pharmaceutically acceptable bioprecursor); or (b) is a metabolite of a compound of the present invention, formed in the body after administration of a compound according to the present invention to an individual. It is well known in the pharmaceutical field that an active drug may be modified into a derivative of the active drug, to improve any undesired pharmaceutical property (e.g., related to one or more of stability, solubility, absorbability, and the like) of the active drug. The derivative may have efficacious activity by being converted in the body to the active drug, or may be derived physiologically from a compound of the present invention and exhibit antiviral activity. The term "an effective amount" refers to that amount of a compound according to the present invention sufficient to result in amelioration of one or more symptoms of HIV infection and/or AIDS. The term "an effective amount" is also meant to include the amount of the compound of the present invention sufficient to result in inhibition of, or interference with, HIV binding events, viral entry, or viral infection. The term also encompasses the inhibition of viral transmission or prevention of viral establishment in its host, as observed by measuring one or more parameters. Such parameters may include, but are not limited to, reduction in viral load (e.g., such as measuring HIV viral RNA in plasma) or viral pathogenesis, or decrease in mortality and/or morbidity associated with HIV infection of an individual treated with a compound " according to the present invention, or increase in immune parameters in the treated individual, such as an increase in overall CD4+ cells circulating in the blood, as compared to baseline (before treatment, or at an earlier point in the treatment history of the individual) level of circulating CD4+ cells.
The term "antiviral activity" refers to the ability of a compound according to the present invention to inhibit viral infection of cells, via, for example, inhibiting the ability of HIV-1 to bind to cell receptors and/or co- receptors of human cells which are capable of being infected by HIV-1. In some embodiments, a compound according to the present invention has antiviral activity, against typical strains of HIV-1, as represented by an IC50 of no more than 5 μm (see, for example, Example 1 , and Table 3, herein). The term "target cell" is used herein and in the claims to refer to a human cell capable of being infected by HIV, and in some embodiments, HIV-1. A compound of the present invention with antiviral activity can also interfere with or inhibit or prevent viral entry into a host ("viral entry inhibitor"), viral transmission to a host, or viral establishment in its host, as observed by measuring one or more parameters. Such parameters may include, but are not limited to, reduction in viral load (e.g., such as measuring HIV viral RNA in plasma) or viral pathogenesis, or decrease in mortality and/or morbidity associated with HIV infection of an individual treated with a compound according to the present invention, or increase in immune parameters in the treated individual, such as an increase in overall CD4+ cells circulating in the blood, as compared to baseline level of circulating CD4+ cells. When the term "antiviral activity" is used in relation to an individual active ingredient comprising administering a compound according to the present invention by itself, the term refers to the activity of that ingredient alone. When the term "antiviral activity" is used in relation to a combination of active ingredient comprising administering a compound according to the present invention with other therapeutic agents used in the treatment of HIV infection and/or AIDS (antiviral agents, immunomodulators, vaccines, and the like), the term refers to the activity of the combination treatment (e.g., whether administered simultaneously or sequentially, as part of a treatment regimen). As used herein and in the claims, unless otherwise specified, the terms "viral", "antiviral", "retroviral", and "virus", refer to, or are concerning, HIV1 and in some embodiments, HIV-1.
"Subjects" as used herein, also referred to as "individuals", are generally human subjects. The subjects, may be male or female and may be of any race or ethnicity, including, but not limited to, Caucasian, African- American, African, Asian, Hispanic, Indian, etc. The subjects may be of any age, including newborn, neonate, infant, child, adolescent, adult, and geriatric. Subjects may also include animal subjects, particularly mammalian subjects such as dog, cat, horse, mouse, rat, etc., screened for veterinary medicine or pharmaceutical drug development purposes. Subjects further include, but are not limited, to those who may have, possess, have been exposed to, or have been previously diagnosed as afflicted with HIV or AIDS or one or more risk factors for HIV or AIDS.
As used herein and in the claims, the terms "treat", "treating" and "treatment" means preventing or ameliorating diseases associated with HIV infection. Thus, the terms apply to prophylactic and/or therapeutic applications.
The terms "pharmaceutical composition" and "medicament" are used interchangeably herein to mean a composition comprising a pharmaceutically acceptable carrier and effective amount of a compound according to the present invention. The term "pharmaceutically acceptable carrier" is used herein and for the claims to refer to a carrier medium that does not significantly alter the biological activity of the active ingredient (e.g., the antiviral activity of a compound according to the present invention) to which it is added. The one or more substances of which the pharmaceutically acceptable carrier is comprised, typically depends on factors (or desired features for its intended use) of the pharmaceutical composition such as the intended mode of administration, desired physical state (e.g., solid, liquid, gel, suspension, etc.), desired consistency, desired appearance, desired taste (if any), desired pharmacokinetic properties once administered (e.g., solubility, stability, biological half life), desired release characteristics (e.g., (a) immediate release (e.g., fast-dissolving, fast-disintegrating), or (b) modified release (e.g., delayed release, sustained release, controlled release)), and the like. As known to those skilled in the art, a suitable pharmaceutically acceptable carrier may comprise one or substances, including but not limited to, a diluent, water, buffered water, saline, 0.3% glycine, aqueous alcohol, isotonic aqueous buffer; a water-soluble polymer, glycerol, polyethylene glycol, glycerin, oil, salt (e.g., such as sodium, potassium, magnesium and ammonium), phosphonate, carbonate ester, fatty acid, saccharide, polysaccharide, stabilizing agent (e.g., glycoprotein, and the like for imparting enhanced stability, as necessary and suitable for manufacture and/or distribution of the pharmaceutical composition), excipient, preservative (e.g., to increase shelf-life, as necessary and suitable for manufacture and distribution of the pharmaceutical composition), bulking agent (e.g., microcrystalline cellulose, and the like), suspending agent (e.g., alginic acid, sodium alginate, and the like), viscosity enhancer (e.g., methylcellulose), taste enhancer (e.g., sweetner, flavoring agent, taste-masking agent), binder (generally, to impart cohesive quality to a tablet or solid formulation; e.g., gelatin, natural and/or synthetic gums, polyvinylpyrrolidone, polyethylene glycol, and the like), extender, disintegrant (e.g., sodium starch glycolate, sodium carboxymethyl cellulose, starch, and the like), dispersant, coating (generally to impart a surface active agent to a tablet or solid formulation; e.g., polysorbate, talc, silicon dioxide, and the like), lubricant (e.g., magnesium stearate, calcium stearate, sodium lauryl sulphate, and the like), or colorant. As known to those skilled in the art, an active ingredient may be formulated into a pharmaceutical composition using methods and one or more pharmaceutically acceptable carriers well known in the art, taking the desired features of the pharmaceutical composition, as described above, in mind during formulation. Depending on such desired features, typically a pharmaceutical composition may comprise from about 1% by weight to about 80% by weight of an active ingredient, and from about 10% by weight to about 99% by weight of pharmaceutically acceptable carrier. Administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two compounds can be administered simultaneously (i.e., concurrently) or sequentially. Simultaneous administration can be carried out by mixing the compounds prior to administration, or by administering the compounds at the same point in time- but at different anatomic sites or using different routes of administration. The phrases "concurrent administration", "administration in combination", "simultaneous administration" or "administered simultaneously" as used herein, means that the compounds are administered at the same point in time or immediately following one another. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time. In terms of specific administration of the compounds and compositions described herein, the most suitable route in any given case will depend on the nature and severity of the condition being treated.
The compounds described herein can be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9th Ed. 1995). In the manufacture of a pharmaceutical formulation according to the invention, the compounds described herein are typically admixed with, inter alia, an acceptable carrier. The carrier can be a solid or a liquid, or both, and is optionally formulated as a unit-dose formulation, which can be prepared by any of the well-known techniques of pharmacy.
The carriers and additives used for such pharmaceutical compositions can take a variety of forms depending on the anticipated mode of administration. Thus, compositions for oral administration may be, for example, solid preparations such as tablets, sugar-coated tablets, hard capsules, soft capsules, granules, powders and the like, with suitable carriers and additives being starches, sugars, binders, diluents, granulating agents, lubricants, disintegrating agents and the like. Because of their ease of use and higher patient compliance, tablets and capsules represent the most advantageous oral dosage forms for many medical conditions. Similarly, compositions for liquid preparations include solutions, emulsions, dispersions, suspensions, syrups, elixirs, and the like with suitable carriers and additives being water, alcohols, oils, glycols, preservatives, flavoring agents, coloring agents, suspending agents, and the like. In the case of a solution, it can be lyophilized to a powder and then reconstituted immediately prior to use. For dispersions and suspensions, appropriate carriers and additives include aqueous gums, celluloses, silicates or oils.
For injection, the carrier is typically a liquid, such as sterile pyrogen- free water, pyrogen-free phosphate-buffered saline solution, bacteriostatic water, or Cremophor EL[R] (BASF, Parsippany, N.J.), parenterally acceptable oil including polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil, with other additives for aiding solubility or preservation may also be included. For other methods of administration, the carrier can be either solid or liquid.
For oral administration, the compounds described herein can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. The compounds described herein can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like. Examples of additional inactive ingredients that can be added to provide desirable color, taste, stability, buffering capacity, dispersion or other known desirable features are red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, edible white ink and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric- coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. Formulations suitable for buccal (sub-lingual) administration include lozenges including the compounds described herein in a flavored base, " usually sucrose and acacia or tragacanth; and pastilles including the compounds described herein in an inert base such as gelatin and glycerin or sucrose and acacia.
Formulations of the present invention suitable for parenteral administration can include sterile aqueous and non-aqueous injection solutions of the compounds described herein, which preparations are generally isotonic with the blood of the intended recipient. These preparations can contain anti-oxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions can include suspending agents and thickening agents. The formulations can be presented in unit\dose or multi- dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.
Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets. For example, in one aspect of the present invention, there is provided an injectable, stable, sterile composition including compounds described herein of the invention, in a unit dosage form in a sealed container. Optionally, the composition is provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
Formulations suitable for rectal or vaginal administration can be presented as suppositories. These can be prepared by admixing the compounds described herein with one or more conventional excipients or carriers, for example, cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compounds described herein.
Formulations suitable for topical application to the skin can take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers that can be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
Formulations suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution. Suitable formulations comprise citrate or bisXtris buffer (pH 6) or ethanol/water. The compounds described herein can be formulated for nasal administration or otherwise administered to the lungs of a subject by any suitable means, for example, by an aerosol suspension of respirable particles including the compounds described herein, which the subject inhales. The respirable particles can be liquid or solid. The term "aerosol" includes any gas-borne suspended phase, which is capable of being inhaled into the bronchioles or nasal passages. Specifically, aerosol includes a gas-borne suspension of droplets, as can be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition suspended in air or other carrier gas, which can be delivered by insufflation from an inhaler device, for example. See Ganderton & Jones, Drug Delivery to the Respiratory Tract, Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313; and Raeburn et al. (1992) J. Pharmacol. Toxicol. Methods 27:143-159. Aerosols of liquid particles can be produced by any suitable means, such as with a pressure-driven aerosol nebulizer or an ultrasonic nebulizer, as is known to those of skill in the art. See, e.g., U.S. Patent No. 4,501,729. Aerosols of solid particles including the compounds described herein can likewise be produced with any solid particulate medicament aerosol generator, by techniques known in the pharmaceutical art. Alternatively, one can administer the compounds described herein in a local rather than systemic manner, for example, in a depot or sustained- release formulation.
In particular embodiments of the invention, administration is by subcutaneous or intradermal administration. Subcutaneous and intradermal administration can be by any method known in the art including, but not limited to, injection, gene gun, powderject device, bioject device, microenhancer array, microneedles, and scarification (i.e., abrading the surface and then applying a solution including the compounds described herein).
In other embodiments, the compounds described herein are administered intramuscularly, for example, by intramuscular injection or by local administration.
Novel Compounds and Compositions
Novel compounds~according to some embodiments of the invention include the compounds of Formula (I)
Figure imgf000031_0001
or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, wherein:
W is null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene or cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, amino, thio, sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with at least one halogen atom;
Ai is a monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene or monocyclic heteroarylene, each optionally substituted with at least one alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy, phosphoramide, phosphoramidealkyl, phosphonate, phosphonatealkyl or -R9Q, wherein R9 is null or alkylene and Q is -NR10R11, -CN1 -CO2R12, -SR13, -SOR14, -SO2Ri5, -SO2NR16R17, - NR18COR19, -NR2oCONR21 R22, -CONR23R24, -NR25SOR26, -R27COR28, or- OR29;
A2 is null, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with at least one of an alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and/or -RgQ, wherein R9 and Q are as defined above;
R-IOJ RI1J RI2> RI3S Ri4» RI5J Ri6» Ri7j Ri8j Ri9j R2O. R2I1 R∑2ι R23) R∑4>
R25, R26, R271 R28 and R29 are each independently hydrogen, alkyl, aryl, ■ heteroaryl, allyl, alkoxy, cycloalkyl, heterocycloalkyl, fluoroalkyl, fluorocycloalkyl, arylalkyl or heteroarylalkyl; or wherein R1O and R11, R16 and R17, R21 and R22 or R23 and R24, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl;
Y is-CO-CO-, -SO2-, -C=NRx-CO-, and -CO-C=NRx-, -O-CO-, or - NR30CO-; wherein Rx is alkyl, fluoroalkyl, alkoxyalkyl, cycloalkyf, heterocycloalkyl, aryl or heteroaryl, optionally substituted with at least one halogen, alkyl, alkoxy, -CF3, -OCF3, and/or -CN;
R1, R2, R3, R4, R5, Re, Rr and R8 are each independently hydrogen or alkyl; and/or at least one of R1, R2, R3, R4 is taken together with at least one of R5, Re, R7 and Re to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with at least one halogen, amino, hydroxyl, -CN, -NO2, alkoxy, -CF3, -OCF3, alkyl, allyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether and/or R31-Q' group, wherein R31 is null or alkylene and Q' is -SO2NR32R33, -NR34COR35, -CONR36R37 or -COOR38;
R3o> R32, R33, R34, R351 R36. R37 and R38 are each hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; or R32 and R33 or R36 and R37, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with at least one hydrogen, halo, alkoxy, CF3, -OCF3 and/or -CN;
Figure imgf000033_0001
R41 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each optionally substituted with at least one alkyl, cycloalkyl, alkoxy, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, halo, -CN, -CF3, alkylthio, hydroxy, alkenyl, alkenoxy, acetyl and/or -RgQ, wherein R9 and Q are defined above;
. R42 is aryl or heteroaryl, optionally substituted with at least one halo, alkoxy, -CF3, -OCF3, -CN, alkyl, -cycloalkyl, -fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, acetyl, alkenyl, alkenoxy and/or -R9Q, wherein R9 and Q are defined above;
R43 is hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with at least one halo, alkyl, alkoxy, -CF3, -OCF3, -CN1 cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and/or -R9Q, wherein R9 and Q are defined above;
R39 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with at least one halogen, alkyl, alkoxy, -CF3, -OCF3, -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, S-alkyl, hydroxy, alkenyl, alkenoxy,. acetyl. and/or -R9Q, wherein R9 and Q are defined above; and R40 is hydrogen, -CN, alkyl, halo, -CF3, cycloalkyl, fluoroalkyl, fluorocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are optionally substituted with at least one halo, alkyl, alkoxy, - CF3, -OCF3, -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl; fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and/or -RgQ, wherein R9 and Q are defined above.
In particular embodiments of the invention, in a compound of Formula
(I),
W is null, C0 - C6alkylene, (Co - C3 alkylene)-O-(Co - C3 alkylene), (C0 - C3 alkylene)-NR'-(C0 - C3 alkylene), (C0 - C3 alkylene)-S-(C0 - C3 alkylene), (C0 - C3 alkylene)-S(=O)-(C0 - C3 alkylene), (C0 - C3 alkylene)-SO2-(C0 - C3 alkylene), (C0 - C3 alkylene)-C(=O)-(C0 - C3 alkylene), (C0 - C3 alkylene)- C(=0)NR'-(Co - C3 alkylene) or (C0 - C6cycloalkylidene), wherein the alkylene and cycloalkylidene groups are optionally substituted with 1 to 3 halogen atoms;
Ai is phenylene or monocyclic heteroarylene, wherein the phenylene and monocyclic heteroarylene are optionally substituted with 1 to 5 functional groups, wherein each functional group may be a Ci-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, hydroxy, halo, Ci-C6 fluoroalkoxy, C2-C6 alkenyl, C2-C6 alkenoxy or -RgQ, wherein R9 is null or C1-C2 alkylene and Q is -NRioRii, -CN, -CO2Ri2, -SRi3, -SOR14, -SO2Ri5, -SO2NR16Ri7, - NRi8CORi9, -NR20CONR21R22, -CONR23R24, -NR25SOR26, -R27COR28, or- OR29;
. A2 is phenyl or heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with 1 to 5 functional groups, wherein each functional group may be a Ci-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, hydroxy, halogen, C1-C6 fluoroalkoxy, C2-C6 alkenyl, C2-C6 alkenoxy or -R9Q, wherein R9 is null or C1-C2 alkylene and Q is defined above; R'j RiO> Ri1) Ri2» Ri3» Ri4> Ri5» Ri6i Ri7> Ri8i Ri9> R20> R21» R22» R23> R24>
R25J R26. R27, R28 and R29 are each independently hydrogen, C1-C6 alkyl, allyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycloalkyl, C1-C6 alkoxy, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroarylmethyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl or heterocycloalkylethyl; or wherein R10 and R11, R16 and R17, R21 and R22, or R23 and R24, taken together with the nitrogen to which they are attached, are part of a ring selected from the group consisting of azetidine, azetidin-2-one, pyrrolidine, pyrrolidin-2-one, pyrrolidin-3-one, piperidine, piperidin-2-one, piperidin-3-one, piperidin-4-one, morpholine, morpholin-2-one, morpholin-3- one and N-alkylpiperazine; wherein the heterocycloalkyl includes 0 to 4 nitrogen atoms; 0 to 2 nitrogen atoms and 0 to 1 oxygen atom;
0 to 2 nitrogen atoms and 0 to 1 sulfur atom; or
0 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulphur atom; and wherein the heteroaryl imidazolyl, pyrazolyl, triazolyl, tetrazolyf, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thtadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; and wherein the phenyl, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, C1-C6 alkoxy, -CF3, -OCF3 or -CN;
Rx is alkyl, fluoroalkyl, alkoxyalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; wherein each heteroaryl ring is optionally substituted with 1 to 5 functional groups wherein each functional group may be halo, C1-C6 alkyl, C1-C6 alkoxy, -CF3, -OCF3 or -CN; R-I, R2, R3, R4, Rs, Re, RΛ and R8 are each independently hydrogen or C1- C6 alkyl, wherein the CrC6 alkyl is optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, amino, hydroxyl, -CN, - NO2, C1-C6 alkoxy, -CF3, -OCF3, C1-C6 alkyl, allyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycloalkyl, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroarylmethyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl, heterocycloalkylethyl, (CRaRb)U-T-(CRcRd)1JRe or R31Q' wherein R31 is null or CrC∑ alkylene and Q' is -SO2NR32R33, - NR34COR35, -CONR36R37 or -COOR38;
R30, R32 , R33, R34, R35, R36, R37, R38, Ra, Rb, Rc, Rd and Reare each independently hydrogen, C1-C6 alkyl, allyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycloalkyl, C1-C6 alkoxy, phenyl-(C0-C2 alkyl), heteroaryl-(Co-C2 alkyl) or heterocycloalkyl-(C0-C2 alkyl); wherein the heterocycloalkyl includes 0 to 4 nitrogen atoms;
0 to 2 nitrogen atoms and 0 to 1 oxygen atom; 0 to 2 nitrogen atoms and 0 to 1 sulfur atom; or 0 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulphur atom; and wherein the heteroaryl group is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, or quinoxalinyl; wherein the phenyl, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, C1-C6 alkoxy, -CF3, -OCF3 or -CN; or wherein R32 and R33 or R36 and R37, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl selected from the group consisting of aziridine, azetidine, pyrrolidine, pyrrolidin-2-one, piperidine, morpholine and N-alkylpiperazine;
U and U' are each independently O, 1 or 2; T is null or oxy;
R41 is phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazoyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl; each of which is optionally substituted with at least one Ci - C3 alkyl, C3 - C6 cycloalkyl, Ci -C3 alkoxy, C1-C6 fluoroalkoxy, C1-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, -CN1 -F, -Cl, -Br, -CF3, Co-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-Ce alkenoxy, acetyl and/or -R9Q, wherein R9 is null or C1-C2 alkylene and Q is defined above;
R42 is phenyl, heteroaryl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, benzothienyl, benzofuryl, benzoindazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, quinoxalinyl, thienopyridine, thienopyrimidine, thienopyridazine, thienopyrazine, furopyridine, furoopyrimidine, furopyrida.zine, furopyrazine, oxazolopyridine, oxazolopyrimidine, oxazolopyridazine.oxazolopyrazine, thiazolopyridine, thiazolopyrimidine, thiazolopyridazine.thiazolopyrazine, napthyridine, pyridopyrimidine, pyridopyridazine orpyridopyrazine; each optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, C1-C6 alkoxy, -CF3, -OCF3 or -CN, Ci - C3 alkyl, C3 - C6 cycloalkyl, C1-Ce fluoroalkoxy, C1-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, Co-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl or -R9Q, wherein R9 is null or Ci-C2 alkylene and Q is defined above;
R43 is hydrogen, -CN, C1-C6 alkoxy, C1-C6 fluoroalkoxy, C1-C6 alkyl, C1-
C6 fluoroalkyl, C3-C7 cycloalkyl or C3-C7 fluorocycloalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyf, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; wherein the aryl or heteroaryl are optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, C1 - C6 alkyl, C1-C6 alkoxy, -CF3, -OCF3 or -CN1 C1 - C3 alkyl, C3 - C6 cycloalkyl, C1-C6 fluoroalkoxy, C1-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, C0-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl or -RgQ, wherein R9 is null or Ci-C2 alkylene and Q is defined above;
R39 is phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyi.isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; each optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, Ci - C6 alkyl, Ci-C6 alkoxy, -CF3, -OCF3, -CN, Ci - C3 alkyl, C3 - C6 cycloalkyl, C1-C6 fluoroalkoxy, Ci-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, S-(Co-C3 alkyl), hydroxy, C2-CΘ alkenyl, C2-C6 alkenoxy, acetyl or — RgQ, wherein R9 is null or C1-C2 alkylene and Q is defined above; and
R40 is hydrogen, -CN, Ci - C6 alkyl, halo, -CF3, C3 - C6 cycloalkyl, Ci-
C6 fluoroalkyl, C3-Cz fluorocycloalkyl, heterocycloalkyl, heterocycloalkylmethyl, heterocycloalkylethyl, R41, -CH2R4I and
Figure imgf000038_0001
wherein the heterocycloalkyl includes 0 to 4 nitrogen atoms; 0 to 2 nitrogen atoms and 0 to 1 oxygen atom;
0 to 2 nitrogen atoms and 0 to 1 sulfur atom; or
0 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulphur atom; and wherein R4I is phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; and is optionally substituted with 1 to 5 functional groups, wherein each functional group may be halogen, Ci - C6 alkyl, C1-C6 alkoxy, -CF3, -OCF3, -CN, hydrogen, Ci - C3 alkyl, C3 - C6 cycloalkyl, 0-(C1-C6 fluoroalkyl), CrC6 fluoroalkyl, C3-C7 fluorocycloalkyl, S- (C0-C3 alkyl), hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl or -R9Q, wherein R9 is null or Ci-C2 alkylene and Q is defined above.
Novel compounds according to embodiments of the invention also include compounds of Formula (II)
Figure imgf000039_0001
or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, wherein:
W is null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene or cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, -amino, thio, sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with 1-3 halogen atoms;
Ai is a monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene and monocyclic heteroarylene, optionally substituted with 1 to 5 functional groups, wherein each functional group may be alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy or -RgQ, wherein Q is -NR10R11, -CN, -CO2Ri2, -SR13, -SORi4, -SO2Ri5, -SO2NR16Ri7, - NR18CORi9, -NR20CONR21R22, -CONR23R24, -NR25SOR2S, ^27COR28 or- OR29;
A2 is null, cycloalkyl, heterocycloalkyl, aryl pr heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 5 functional groups, wherein each functional group may be alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and -RgQ, wherein Rg and Q are as defined above;
Riθs Ri1» Ri2, Ri3» Ri4> Ri5> Ri6> "i7j Ri8> Ri9> R2O1 R2I1 R22J R23» R24» R25, R26, R27, R28 and R29 are hydrogen, alkyl, aryl, heteroaryl, allyl, alkoxy, cycloalkyl, heterocycloalkyl, fluoroalkyl, fluorocycloalkyl, arylalkyl or heteroarylalkyl; or wherein R10 and R11, R16 and Ru, R21 and R22, or R23 or R24, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl;
Y is -CO-CO-, -SO2-, -C=NRx-CO-, and -CO-C=NRx-, -O-CO-, or - NR30CO-; wherein Rx is alkyl, fluoroalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with 1 to 5 functional groups, wherein each functional group may be halogen, alkyl, alkoxy, -CF3, - OCF3 and -CN;
Ri, R2, R3, R4, R5, Re. R7 and R8 are each independently hydrogen or alkyl; and/or at least one of R1, R2, R3, R4 is taken together with at least one of R5, Re, R7 and Re to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with 1 to 3 functional groups, wherein each functional group may be halogen, amino, hydroxyl, -CN, -NO2, alkoxy, -CF3, -OCF3, alkyl, allyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether or R31-Q' wherein Rs1 is null or alkylene and Q' is -SO2NR32R33, - NR34COR35. -CONR36R37 or -COOR3S;
R30, R32, R331 R34. R351 R36, R37 and R38 are each independently hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl or heteroarylalkyl; or wherein R32 and R33 or R36 and R37, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with 1 to 5 functional groups, wherein each functional group may be halo, alkoxy, -CF3, -OCF3 and -CN; and
X is O, S or NR39, wherein R39 is hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, qυinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl; optionally substituted with 1 to 5 functional groups, wherein each s functional group may be halo, alkyl, alkoxy, -CF3, -OCF3 or -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy, acetyl or -RgQ, wherein R9 and Q are defined above.
In particular embodiments of the invention, in the compound of Formula 0 (II),
W is -(CH2)x(CO)y(CH2)z-, wherein x, y and z are each independently 0, ' 1 , 2 or 3;
5 Ai is a cycloalkylidene, heterocycloalkylidene, arylene or heteroarylene, each optionally substituted with 1 to 3 functional groups, - wherein each functional group may be halo, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, hydroxy, amino, alkylamino, dialkylamino or thiol;
0 A2 is a monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocycloalkyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl, each optionally substituted with 1 to 3 functional groups, wherein each functional group may be halo, -CN, alkyl, alkoxy, acetyl, oxo, fluoroalkyl, 5 fluoroalkoxy, hydroxy, amino, methylamino, dimethylamino, -SH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or arylcarbonyl; wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted onto the monocyclic or bicyclic ring is optionally substituted with a halo, alkyl, acetyl or alkoxycarbonyl; 0
Y is
Figure imgf000041_0001
or -SO2-, wherein m and n are each independently 0, 1, 2 or 3;
Ri, R2, R3, R4, R5, Re, R7 and R8 are each independently hydrogen or alkyl; and/or at least one of Ri1 R∑, R3, R4 is taken together with at least one of Rs1 Re, R7 and Re to form an alkylene bridge; and
X is O, -CN or N-O-alkyl.
With regard to the compounds and compositions described herein, according to some embodiments, any of the R groups and/or functional groups represented thereby can be excluded from a particular compound or composition. According to some embodiments of the invention, the compounds of
Formula .(I) and Formula (II) are present as racemic mixtures. However, in some embodiments, compound of Formula (I) and Formula (II) are present substantially as one enantiomer or in the enantiomerically pure (R) form. The term "substantially on enantiomer" as used herein, refers to a %(R) enantiomer or %(S) enantiomer of greater than about 60%, in some embodiments about 90%, and in some embodiments greater than 95%.
Pharmaceutical compositions of embodiments of the invention include a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof; and a pharmaceutically acceptable carrier, excipient or diluent.
Methods
A compound according to the present invention or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or as part of a pharmaceutical composition, may be used in antiviral treatment alone (also known as "monotherapy"), or in combination or in a treatment regimen (e.g., when used simultaneously, or in a cycling on with one drug and cycling off with another) with other therapeutic agents (including antiviral drugs) used for treatment of HIV (e.g., including, but not limited to, other HIV entry inhibitors (e.g., gp41 fusion inhibitors, CCR5 inhibitors, retrocyclin, CD4 inhibitors, gp120 inhibitors, and the like), HIV integrase inhibitors, reverse transcriptase inhibitors (e.g., nucleoside or nonnucleoside), protease inhibitors, viral- specific transcription inhibitors, viral processing inhibitors, HIV maturation inhibitors, inhibitors of uridine phosphorylating enzyme, HIV vaccines, and the like, as well known in the art. One commonly used treatment, involving a combination of antiviral agents, is known as HAART (Highly Active Anti- Retroviral Therapy). HAART typically combines three or more drugs with antiviral activity against HIV, and typically involves more than one class of drug (a "class" referring to the mechanism of action, or viral protein or process targeted by the drug). Thus, a method of treatment, a compound, and a pharmaceutical composition, according to the present invention, may be administered alone (e.g., as monotherapy) or may be administered in a treatment regimen, or co-administered, involving a combination of additional therapeutic agents for the treatment of HIV infection and/or AIDS, as " . described in more detail herein.
For example, in some embodiments, one or more therapeutic agents may be combined in treatment with a compound (by itself, or in a pharmaceutical composition) according to the present invention. Typically, the combination comprises two or more antiviral agents to increase the efficacy of the treatment by, for example, reducing the ability of the virus to become resistant to the antiviral agents used in the treatment (as compared to monotherapy). Such combinations may be prepared from effective amounts of antiviral agents (useful in treating of HIV infection) currently approved or approved in the future, which include, but are not limited to, one or more additional therapeutic agents selected from the following: reverse transcriptase inhibitor, including but not limited to, abacavir, AZT (zidovudine), ddC (zalcitabine), nevirapine, ddl (didanosine), FTC (emtricitabine), (+) and (-) FTC, reverset, 3TC (lamivudine), GS 840, GW-1592, GW-8248, GW-5634, HBY097, delaviridine, efavirenz, d4T (stavudine), FLT, TMC125, adefovir, tenofovir, and alovudine; protease inhibitor, including but not limited to, amprenivir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, PNU- 140690, ritonavir, saquinavir, telinavir, tipranovir, atazanavir, lopinavir; viral entry inhibitor, including but not limited to, fusion inhibitor (enfuvirtide, T-1249, other fusion inhibitor peptides, and small molecules), chemokine receptor antagonist (e.g., CCR5 antagonist, such as ONO-4128, GW-873140, AMD- 887, CMPD-167; CXCR4 antagonist, such as AMD-070), an agent which affects viral binding interactions (e.g., affects gp120 and CD4 receptor interactions, such as BMS806, BMS-488043; and/or PRO 542, PRO140; or lipid and/or cholesterol interactions, such as procaine hydrochloride (SP-01 and SP-01 A)); integrase inhibitor, including but not limited to, L-870, and 810; RNAseH inhibitor;, inhibitor of rev or REV; inhibitor of vif (e.g., vif-derived proline-enriched peptide, HIV-1 protease N-terminal-derived peptide); viral processing inhibitor, including but not limited to betulin, and dihydrobetulin derivatives (e.g., PA-457); and immunomodulator, including but not limited to, AS-101, granulocyte macrophage colony stimulating factor, IL-2, valproic acid, and thymopentin. As appreciated by one skilled in the art of treatment of
HIV infection and/or AIDS, a combination drug treatment may comprise two or more therapeutic agents having the same mechanism of action (viral protein or process as a target), or may comprise two or more therapeutic agents having a different mechanism of action. Thus, according to some embodiments, administration of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, and another therapeutic agent is sequential, and in other embodiments, administration of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, and another therapeutic agent is simultaneous. According to some embodiments, administration of a compound according to the present invention and another therapeutic agent is simultaneous.
According to some embodiments, the administration of at least one of the therapeutic agents is oral, and in some embodiments, administration of at least one of the therapeutic agents is parenteral, such as subcutaneous.
According to some embodiments of the invention, methods of treating HIV infection in a subject include administering an effective amount of a compound according to an embodiment of the invention, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, and an effective amount of at least one therapeutic agent. According to some embodiments of the invention, provided are methods of inhibiting HIV replication including administering to a subject an effective amount of the compound according to an embodiment of the invention, or a pharmaceutically acceptable. prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, and an effective amount of at least one therapeutic agent.
Effective dosages of these illustrative additional therapeutic agents, which may be. used in combinations with a compound, or pharmaceutical composition, according to the present invention, are known in the art. Such combinations may include a number of antiviral agents or therapeutic agents that can be administered by one or more routes, sequentially or simultaneously, depending on the route of administration and desired pharmacological effect, as is apparent to one skilled in the art. Effective dosages of a compound or pharmaceutical composition according to the present invention to be administered may be determined through procedures well known to those in the art; e.g., by determining potency, biological half-life, bioavailability, and toxicity. In a preferred embodiment, an effective amount of a compound according to the present invention and its dosage range are determined by one skilled in the art using data from routine in vitro and in vivo studies well know to those skilled in the art. For example, in vitro infectivity assays of antiviral activity, such as described herein, enables one skilled in the art to determine the mean inhibitory concentration (IC) of the compound, as the sole active ingredient or in combination with other active ingredients, necessary to inhibit a predetermined range of viral infectivity (e.g., 50% inhibition, IC50; or 90% inhibition, ICg0) or viral replication. Appropriate doses can then be selected by one skilled in the art using pharmacokinetic data from one or more standard models, so that a minimum plasma concentration (C[min]) of the active ingredient is obtained which is equal to or exceeds a predetermined value for inhibition of viral infectivity or viral replication. While dosage ranges typically depend on the route of administration chosen and the formulation of the dosage, when administered orally, an exemplary dosage range of a compound according to the present invention, as an active ingredient, may be from about 1 mg/kg body weight to about 100 mg/kg body weight; and more preferably no less thani mg/kg body weight to no more than 10 rng/kg body weight.
A compound or pharmaceutical composition according to the present invention may be administered to an individual by any means that enables the active ingredient to reach the target cells. Thus, a compound or pharmaceutical composition according to the present invention may be administered by. any suitable technique, including oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, or subcutaneous injection or . infusion, intradermal, or implant), nasal (e.g., inhalation spray), pulmonary, vaginal, rectal, sublingual, or other suitable routes of administration; and can be formulated in dosage forms appropriate for each route of administration. The specific route of administration will depend, e.g., on the medical history of the individual, including any perceived or anticipated side effects from such administration, other factors known to medical practitioners, and the formulation of the compound, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof (by itself or as part of combination treatment) being administered. In particular embodiments, a compound or pharmaceutical composition according to the present invention is administered to an individual orally. Thus, in accordance with the present invention, provided are methods for inhibition of transmission of HIV to a cell, comprising administering a compound or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention in an effective amount to inhibit infection of the cell by HIV. The method may further include administering a compound, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention in combination with other therapeutic agents used to treat HIV infection and/or AIDS to an individual by administering to the individual the combination (simultaneously or sequentially, or a part of a therapeutic regimen) of therapeutic agents which includes an effective amount of the compound, pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention.
Also provided are methods for inhibiting HIV entry comprising administering to an individual in need of treatment a compound or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof or pharmaceutical composition according to the present invention in an effective amount to inhibit viral entry of a target cell. The methods may further include administering a compound, a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention in combination with one or more additional inhibitors of viral entry useful in treating HIV infection, in an effective amount. Embodiments of the present invention provide prophylaxis of the diseases and disorders described herein. In some embodiments, the inventive methods eliminate or reduce the incidence or onset of the disease or disorder, as compared to that which would occur in the absence of the measure taken. Alternatively stated, the present methods slow, delay, control, or decrease the likelihood or probability of the disease or disorder in the subject, as compared to that which would occur in the absence of the measure taken.
Embodiments of the invention further provide kits that can include at least one compound according to embodiments of the present invention or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, or pharmaceutical composition according to the present invention, and optionally instructions for administering the same. Further, the kits can include additional therapeutic agents useful for the treatment of HIV. In some embodiments, the components of the kits may be packaged together in a common container. EXAMPLES EXAMPLE 1
In this example are illustrated experimental procedures for determining biological activity, such as antiviral activity. For determining biological activity, an HIV-1 infection assay was used to determine the antiviral potency for compounds of the present invention. In using an in vitro assay for demonstrating antiviral potency, it is important to note that antiviral effect demonstrated in the in vitro assay has been correlated with antiviral effect in. vivo. For example, one or more antiviral agents known to have an antiviral effect in vivo, were used to demonstrate that such antiviral agents also demonstrated an antiviral effect in this in vitro virus assay.
For determining biological activity, an HIV-1 pseudotyped virus assay was used to determine the respective antiviral potencies of each compound tested in the assay for comparison. The pseudotyped assay scores for a reduction in infection as indicated by decreased signal from the reporter gene encoding a luciferase enzyme ("reporter gene"). The assay employs cell lines expressing CD4 and either of the primary chemokine receptors (CCR5 or CXCR4) that HIV uses as a co-receptor ("target cells"). Pseudotyped virus was prepared by co-traήsfection of 293T cells with: 1) a plasmid construct carrying the HIV-1 envelope of choice, in combination with 2) a pseudotyped virus backbone construct in which (a) envelope expression has been abrogated due to a frameshift in the envelope sequence, and (b) the reporter gene replaces nef. Expression of HIV-1 envelope on 293T packaging ceils results in the production of a pseudotyped virus carrying the reporter gene that is capable of a single cycle of infection.
The compounds of the present invention. being tested for antiviral activity were serially diluted and dose responses determined in duplicate in two separate experiments. The compounds to be tested were added directly to the plated, target cells, followed by the addition of pseudotyped virus described above. The cells were cultured for three days prior harvest. Media and compound were removed, the cell monolayer was washed, lysed by detergent, and then frozen at -80 degrees C for a minimum of 30 minutes. Following thawing and acclimation to room temperature, luciferase production was quatified by injecting 100 Dl of a substrate (of the enzyme encoded by the reporter gene) into each well followed by detecting the signal (light emitted from the interaction between the enzyme and substrate) after 5 seconds. In the pseudotyped assay, a 50% reduction in signal is significant, and provides the primary cutoff value for assessing antiviral activity ("IC50" is defined as the dilution resulting in a 50% reduction in enzymatic activity as interpolated from a titration curve). Representative compounds according to the present invention, and their antiviral activity, are illustrated in Table 3.
EXAMPLE 2 This example, along with the Schemes herein, illustrate the chemistry and general synthetic procedures to produce compounds according to embodiments of the invention, and intermediates useful for their synthesis. It is understood that reaction conditions, methods, and reactions given in specific examples for specific compounds, are broadly applicable to other compounds of the invention, as described herein. It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the synthesis task in the schemes in a different order than described or modify one or more of the transformations, to make the desired compound of Formula (I). It will be still further appreciated by those skilled in the art that, as illustrated in the schemes that follow, it may be necessary or desirable at any stage in the synthesis of compounds of Formula I to protect one or more sensitive groups in the molecules so as to prevent undesirable side reactions. In particular, it may necessary or desirable to protect amino groups, 1 -indole or azaindole. The protecting groups that may be used in the preparation of compounds of Formula (I) are well known in the art, and may used in methods well known in the art.
General procedures to prepare biaryl piperazine derivatives are described in Scheme 1. Scheme 1
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
Typically the sulfonyl chloride 1, acid halide 4, or carboxylic acid 6 is coupled with a cyclic amine of general structure 2 using methods well known in the art. In a variation of this procedure, the cyclic amine may be a monoprotected piperazine derivative or a carbonyl-protected analog of 4-piperidinone. In these cases, the protecting group is then cleaved after the reaction steps illustrated in Scheme 2, and additional synthetic transformations are performed on the liberated amino or keto group to provide the final target compounds or the intermediates. The identity of the deprotecting agent will depend on the identity other groups present in the molecule. If cyclic amine 2 is a monoprotected piperazine derivative, a protecting group such as tert- butoxycarbonyl ("BOC") or benzyloxycarbonyl ("CBZ") may be appropriate. These protecting groups are commonly cleaved with the use of trifluoroacetic acid and hydrogen gas with a palladium catalyst respectively. If 2 is a carbonyl-protected 4-piperϊdinone, dimethylacetal may be a suitable protecting group, and cleavage may be effected with the use of hydrogen chloride in aqueous methanol. Other useful protecting groups, procedures for the introduction and cleavage are found in the text "Protective Groups in Organic Synthesis" by Theodora W. Greene. Peter G. M. Wuts. (1999), John Wiley and Sons, N. Y., N. Y.) In a further embodiment, the acid of formula 6 (activated by suitable reagents such as 3-(diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3H)-one (DEPBT), or HBTU/HATU (HBTU is O-benzotriazoM-yl-N.N.N'.N1- tetramethyluronium hexafluorophosphate; HATU is O-(7-azabenzotriazoI-1- yl)- N,N,N',N',-tetrarnethyl-uroniurn hexafluorophosphate) and HOBt/HOAt (HOBt is 1-hydroxybenzotriazole hydrate; HOAt is 1-Hydroxy-7- azabenzotriazole), the appropriate cyclic amine of formula 2, and excess amount of an acid acceptor such as triethylamine or N1 N-dϋsopropyl-N- ethylamine, are reacted in a solvent such as haloalkane (e. g. dichloromethane), an ether (e. g. tetrahydrofuran, "THF"), or N1N- dimethylformamide ("DMF") at room temperature for approximately 4 to 48 hours. The reaction may conveniently be carried out by reacting the relevant piperazine, 1.0 equivalent of the relevant carboxylic acid, 1.2 to about 2 equivalent of HATU, with 1.2 to about 2 equivalent of HOAT, 2.2 to about 10 • equivalent of triethylamine in DMF at room temperature for 12 hours. In yet a further embodiment the acyl chloride of formula 4, the appropriate cyclic amine of formula 2, and excess amount of an acid acceptor such as triethylamine or N, N-diisopropyl-N-ethylamine or N-methyl morpholine, are reacted in a solvent such as haloalkane (e. g. dichloromethane), an ether (e. g. tetrahydrofuran), or DMF at room temperature for about 4 to 48 hours. The reaction may conveniently be carried out by reacting the relevant piperazine, 1.0 equivalent of the relevant acyl chloride, about 2 to10 equivalent N-methyl morpholine in DCE at room temperature for 12 hours.
In yet a further embodiment the sulfonyl chloride of formula 1, the cyclic amine of formula 2, and excess amount of an acid acceptor such as triethylamine or N, N-diisopropyl-N-ethylamine or N-methyl morpholine or pyridine or the combination of different acid acceptors, are reacted in a solvent such as haloalkane (e. g. dichloromethane), an ether (e. g. tetrahydrofuran), or DMF at room temperature for about 4 to 48 hours. The reaction may conveniently be carried out by reacting the relevant piperazine, 1.0 equivalent of the relevant sulfonyl chloride, about 2 to10 equivalent N- methyl morpholine in DCE at room temperature for 12 hours.
Piperazines with a single unsubstituted ring nitrogen are available commercially, and can also be produced by a variety of procedures that are illustrated in Scheme 2.
Scheme 2.
Figure imgf000052_0001
6 7 8
Figure imgf000052_0002
10
Figure imgf000052_0003
11 12
Figure imgf000053_0001
Piperazines with two unsubstituted ring nitrogens typically react with electrophiles such as acid chlorides, activated carboxylic acids, aryl halides, carboxylic esters, imidate esters, etc. to give a mixture of products arising from substitution of one or both nitrogens. In many cases, it is possible to select reaction conditions in which monosubsituted products predominate, and in such cases the major product is usually that arising from substitution of the less-hindered nitrogen- atom. For example, treatment of piperazine itself with a butyllithium followed by benzoyl chloride provides primarily the monobenzoyl derivative 13 (Wang, T. et al., J. Organic Chemistry 1999, vol
64, 7661), and treatment of 2-methylpiperazine with methyl benzoate and diethylaluminum chloride gives predominantly the product of monoacylation at the less hindered nitrogen, 14 (Wang, T. et al., J. Organic Chem. 2000, vol
65, 4740). Certain monoprotected piperazines that are useful for the synthesis of other piperazines with a single unsubstituted nitrogen atom are commercially available. Others can be prepared by selective functionalization of the less hindered piperazine nitrogen with electrophiles such as di-tert-butyl dicarbonate. Commercially available monoprotected piperazine derivatives include the mono-Boc piperazines 15 - 17.
Figure imgf000054_0001
Figure imgf000054_0002
16 17
Scheme 3 shows a representative synthesis of a monoacylated piperazine using 15 as starting material. In Scheme 3, the monoprotected piperazine 15 is treated with an acid chloride in the presence of triethylamine as an acid acceptor, and the Boc group is removed from the acylation product by the action of trifluoroacetic acid. Scheme 3.
Figure imgf000054_0003
Monoprotected piperazines may be converted into mono amidino derivatives such as 22 in an analogous fashion (Scheme 4). Typically, compounds of formulas 19 are treated with 1 equivalent of an appropriate carboximidoyl chloride in a solvent such as haloalkane (e. g. dichloromethane, "DCM"), or an ether (e. g. tetrahydrofuran) and are treated with excess amount of an acid acceptor such as triethylamine or N, N-diisopropyl-N- ethylamine or N-methyl morpholine at room temperature for approximately 1 to 2 hours. If a carboximidic acid ester or carboximidothioic acid ester is used in place of the caboximidoyl chloride, the addition of a base may not always be necessary. In some cases methanol may be useful as the reaction solvent, depending on the exact nature of the reagent. Published summaries of standard methods of amidine formation include "Chemistry of the Amidines and lmidates (Chemistry of Functional Groups Series)" by S Patai, Saul Patai (Editor), John Wiley and Sons, N.Y., N.Y.; "Amidines and N-Substituted Amidines" Dunn, P. J. Comprehensive Organic Functional Group Transformations Il (2005), 5 655-699, Elsevier Ltd., Oxford, UK.
Scheme 4. :
ion
Figure imgf000055_0001
22
Many N-Aryl and N-Heteroaryl piperazines may be prepared according to Scheme 5. Electron-deficient heteroaryl halides such as haloquinolines will react with substituted piperazines when heated together in the presence of an acid acceptor such as diisopropylethylamine. In some cases, improved yields will be obtained by the use of a solvent such as dimethylpropylene urea. In some cases, improved yields will be obtained by the use of a catalyst, such as copper powder or a copper salt. A variety of other methods are available for the N-substitution of piperazines with heteroaryl groups, including less electron-deficient aryls and heteroaryls (Antilla, J.C. et al, Organic Letters 2001, vol 3, 2077; Chan, D. M. T. et al., Tetrahedron Lett. 1998, 2933; Kunz, K. et al., Synϊett. 2003, 2428; Kwong, F. Y. et al., Organic Letters 2002, vol 4, 581). The method in shown in Scheme 6 is representative. Scheme 5.
n
Figure imgf000056_0001
25
Scheme 6.
n
Figure imgf000056_0002
25
It is apparent to one skilled in the art that in some cases it may be more efficient to change the order of the steps in which the two piperazine nitrogens are functionalized. This approach is outlined in Schemes 7 and 8. In Scheme 7, a monoprotected piperazine is treated with sulfonyl chloride A in the presence of an acid acceptor such as dϋsopropylethylamine to give sulfonamide 26. Removal of the protecting group with a suitable deprotecting agent (TFA if PG = BOC) gives the intermediate 27. Functionalization of the free NH may be performed using an acid chloride to give a compound of general structure 28. Alternatively, the free NH of the piperazine may be . functionalized with an aryl or heteroaryl halide in the presence of an acid acceptor such as diisopropylethylamine. Treating 27 with an appropriate amidatipn reagent gives an amidine such as 30. It is apparent to one skilled in the art that in certain cases the selective acylation, amidination, and arylation of piperazine derivatives can alternatively be performed without the use of protecting groups.
Scheme 7.
3
Figure imgf000057_0001
LG is a leaving group, such as alkoxy, halogen, or alkylthio 1 Ar-LG
PG is a protecting group
Ar is an aryl or heteroaryl group
Figure imgf000057_0002
29 Scheme 8.
Figure imgf000058_0001
19 31
/ deprotectioπ
Figure imgf000058_0002
34
LG is a leaving group, such as alkoxy, halogen, or alkylthio I ^r.i_e
PG is a protecting group ♦
Ar is an aryl or heteroaryl group
Figure imgf000058_0003
35
An alternate route for preparing intermediates 31 is described in Scheme 9. In this approach, a cyanomethylpiperazine derivative is prepared by treating a functionalized piperazine with chloroacetonitrile. The resulting aminonitrile is treated with a strong base and an ester to give an adduct that is oxidized with sodium hypochlorite or MCPBA to give a ketoamide (Yang, Z. et al., Organic Letters 2002, vol 4, 1103).
Scheme 9.
"
Figure imgf000058_0004
19 37
Figure imgf000058_0005
38 31 Scheme 10 shows a method for the synthesis of alkylidene piperidines of general structure 42. In this general scheme, an N-protected piperidinone. is treated with an active methylene compound in the presence of a suitable base to provide protected alkylidene derivatives of general structure 41. Deprotection of 41 gives the free NH derivative 42, which is an example of generic structure 2.
Scheme 10.
n
Figure imgf000059_0001
PG is a protecting group
Ar is an aryl or heteroaryl group
EWG is a group capable of acidifying a hydrogen on an adjacent carbon
Figure imgf000059_0002
42
Other alkylidene piperidines may be prepared according to Scheme 11. In this scheme an arylmethylphosphonium salt is treated with strong base and then added to a protected piperidinone according to well-known literature methods. Treating the intermediate 44 with bromine and potassium carbonate in chloroform followed by treatment with sodium hydroxide in aqueous methanol gives the bromide 50. Using methods well-known in the art (Miyura, N et al., Chemical Reviews 1995, vol 95, 2457. Mitchell, T. N., Synthesis 1992, 803. StHIe, J. K., Angewandte Chemie Int. Ed. English 1986, 508), the bromide 50 can be coupled with aryltin or arylboron compounds in the presence of a palladium catalyst to give the protected alkylidene derivatives 51. Deprotection gives the free NH intermediate 52. Alternatively, the bromide can be subjected to metal halogen exchange with butyllithium, typically in a solvent such as tetrahydrofuran at -78° C, and treated with carbon dioxide to give the carboxylic acid 46. Carboxylic acids are well- known precursors for a variety of heterocyles, and Scheme 10 illustrates the conversion of a carboxylic acid group into oxadiazole substituents by coupling with a carboxylic acid hydrazide followed by dehydration. Deprotection gives the free NH compound 49.
Scheme 11.
PG is a protecting group
Figure imgf000060_0001
Ar is an aryl or heteroaryl group
Q(C=O)NHNH2 is a carboxylic acid hydrazide
Figure imgf000060_0003
Figure imgf000060_0004
Ar2B(OH)2
Figure imgf000060_0002
Figure imgf000060_0005
Figure imgf000060_0006
A variety of literature methods are available for the synthesis of sulfonyl chlorides of general structure 53. These are outlined in Scheme 12. Treating an aromatic compound with chlorosulfonic acid provides sulfonyl chlorides 53. The temperature of the reaction may range between -400C to 120 0C, and a solvent such as dichloromethane may optionally be used. Best results will usually be obtained when at least a five-fold excess of chlorosulfonic acid is used. Treating an aryl thiol, aryl thiocyanate, or certain aryl thioalkyl derivatives with chlorine gas in acetic acid provides sulfonyl chlorides 53. The reaction is normally performed at temperatures of 50C to 15 0C. Treating an aryllithium or aryl Grignard reagent with sulfur dioxide gives an aryl sulfinate salt, which upon treatment with N-chlorosuccinimide provides sulfonyl chlorides of general structure 53. Compounds 53 may be examples of generic structure 1 , or the aryl group may be modified by further synthetic operations at a later point in the synthesis to give the compounds of the invention as shown in Scheme 13.
Scheme 12.
Ar_H HQS°2CI , Ar-SO2C.
53
Ar-SH Cl5
53
I) SO2
Ar-M ! ^ 53
2) NCS
Ar-M is an aryllithium or aryl Grignard reagent Scheme 13.
Figure imgf000061_0001
54
Figure imgf000061_0002
A variety of methods well known in the art are available for the synthesis of aryl ketoacids of generic structure 57. Treating an aryl bromide 55 with magnesium gives an arylmagnesium bromide, which is treated directly with by methyl chlorooxalate and a copper catalyst to give an aryl ketoester 56 (Babudrϊ, F. et al., Tetrahedron 1996, vol 52, 13513). Hydrolysis of the ketoester with sodium hydroxide in a mixture of methanol and water gives a ketoacid of general structure 57. Alternatively, a methyl-substituted arene of general structure 58 is treated with NBS in the presence of light or a free radical initiator to give a bromide of general structure 59. Displacement of the bromine with cyanide gives a nitrile of general structure 60. This reaction may be performed in a variety of solvents, most commonly a polar solvent such as DMSO or DMF. Partial hydrolysis of the nitrile to an ester 61 may be conducted by treating the nitrile with hydrochloric acid in methanol. Oxidation of the resulting ester to a ketoester 56 may be performed in a variety of literature methods, commonly by the use of selenium dioxide. Alternatively, treating an aryl aldehyde of general structure 62 with sodium cyanide in the presence of a buffer acid such as acetic acid gives a cyanohydrin 63 which can be partially hydrolysed to a hydroxyester 64 using hydrochloric acid in methanol. Hydroxyesters 64 can be oxidized to ketoesters 56 using a variety of methods known in the art. Generic structure 57 may be an example of generic structure 6, or it may be a synthetic intermediate that is converted to 6 by further transformations.
Scheme 14.
1) Mg NaOH
Ar-Br Ar-COCOOMe Ar-COCO2H 55 2) CICOCOOMe 56 Cu catalyst 57
NBS NaCN HCI Ar-CH3 *~ Ar-CH2Br *- Ar-CH2CN ^ ArCH2CO2Me
MeOH
58 59 60 61
SeO2
56
Arnt-tn NaCN „„,.„«„ HCI oxidation ArCHO *► Ar-CH(OH)CN » ArCH(OH)CO2Me *- 56
62 63 64
A variety of methods known in the art are available for the synthesis of compounds having an aryl-aryl bond. Most commonly, such compounds are prepared by one of two methods. In the first, a substituted aryl compound is subjected to synthetic transformations in which the substituent is converted into, an aryl ring. This approach is most commonly used when the aryl ring being formed is a heteroaryl ring (See, Heterocyclic Chemistry, Gilchrist, T.L., Prentice Hall; 3rd edition (1997), Comprehensive Heterocyclic Chemistry on CD ROM, KatritzkyA R.; Rees, CW. (Ed.), Elsevier Science (1997)). The examples shown below should be considered as representative, but not limiting. For the synthesis of a thiazole of type 67, a methyl ketone is brominated with bromine, commonly in acetic acid as solvent at room temperature to reflux. Treating this bromoketone with a thioamide in a polar solvent such as DMF at temperatures of 25 0C to reflux provides 67. Treating an aldehyde with hydroxylamine generated in situ from hydroxylamine hydrochloride and base gives an oxime, which can be chlorinated with NCS in warm DMF to give 69. Adding this chloride slowly to a solution of an acetylene and base at room temperature gives an isoxazole of structure 70. Alternatively, adding the chloride 69 slowly to excess methanolic ammonia gives an amideoxime 71, which is cyclized to 72 by adding an acid chloride, optionally in the presence of a tertiary amine base, and heating to temperatures of 700C to 1200C. Alternatively, treating 68 with toluenesulfonyl isocyanate (TOSMIC) gives an oxazole 73. Further examples of this approach are well known in the art of heterocyclic chemistry. Treating a nitrile of structure 74 with hydrogen sulfide in a mixture of pyridine and triethyl amine at temperatures of 250C to 500C gives the thioamide 75, which can be cyclized to a thiazole 76 upon treatment with a bromoketone in DMF at temperatures of 250C to 1000C. Alternatively, treating the nitrile 74 with methanol and hydrogen chloride in ether at temperatures of -100C to 100C gives an imidate hydrochloride of general structure 77. This reaction typically gives best results when only 1.0 to 1.2 equivalents of methanol are used. In some cases, it may be desirable to use diethyl ether as a dilutant for the reaction. Treating the imidate hydrochloride with a carboxylic acid hydrazide in a solvent such as methanol gives an adduct which can be cyclized by heating in toluene or another high boiling solvent at temperatures of 1000C to 180 0C; thus, giving the triazole 78. Treating aryl bromide 79 with trimethylsilylacetylene and a palladium catalyst in an amine solvent followed by treatment with methanolic base gives the aryl acetylene 80. The acetylene 80 upon treatment with an alkyl azide, optionally in the presence of a copper catalyst, gives the triazole 81. Details for the performance of these transformations are well known in the art.
Scheme 15.
Figure imgf000065_0001
TOSMIC
68 «-β O" 73
Figure imgf000065_0002
A _, TMSCCH RN3 . /N*N Ar-Br »> Ar- Ar- base, Pd° VK
79 80 R
81
A second commonly used approach to the synthesis of compounds 83 containing an aryl-aryl bond is to use a palladium catalyst to couple an aryl halide with an arylzinc, arylboronate or aryltin compound (See, Miyura, N. et al., Chemical Reviews 1995, vol 95, 2457; Mitchell, T. N. Synthesis 1992, 803; Stille, J. K. Angewandte Chemie Int. Ed. English 1986, 508; Negishi, E- I. et al., J. Organic Chemistry 1977 , 1821 ; Erdik, E., Tetrahedron 1992, 9577), This approach is exemplified in Scheme 16. The coupling reaction between an aryl halide 82 and an aryltin compound is commonly performed using PhCH2PdCI(Pr»3P)2 as catalyst in refluxing chloroform. Other solvents and catalysts are occasionally useful for this transformation, and in some cases additives such as lithium chloride or copper salts facilitate the reaction. The coupling between an aryl halide and an aryl boron compound is commonly performed using a two phase mixture of benzene, aqueous sodium carbonate, and ethanol as solvent, and tetrakis(triphenylphosphine) palladium(O) as catalyst. In certain cases, the use of other solvents, catalysts, and bases gives superior results as well known in the art. Coupling between an aryl halide and an arylzinc reagent is usually performed in tetrahydrofuran, dimethylformamide, or a mixture of these two solvents using tetrakis(triρhenylphosphine) palladium(O) as catalyst. In certain cases it may be preferable to use the chloride, bromide or iodide as the aryl halide coupling partner, depending on the nature of the two aryl groups being coupled and whether the coupling partner is a boron reagent, tin reagent, or zinc reagent.
Scheme 16.
, v Ar*-SnMe3, Ar'-B(OH)2, or Af-ZnCl
AΓ-Λ ^. Ar-Ar1
X = l, Br, or CI
83
82
Many aryltin, arylzinc, and arylboronate compounds are commercially available. Others can be prepared by the routes shown in the scheme below. Treating an aryl bromide with butyllithium in tetrahydrofuran at -78 0C gives an aryllithium species that is treated in situ with trimethylborate. Hydrolysis of the resulting borate salt with hydrochloric acid gives the boronic acid 85.
Alternatively, treating the aryllithium species with trimethylstannyl chloride gives an isolate aryltin compound 86. Treating an aryflithium with zinc chloride gives the arylzinc species 87 which is usually used directly in a palladium catalyzed coupling step without isolation. Aryltin compounds may also be formed by treating an aryl bromide or iodide with hexamethylditin and a catalytic PhCH2PdCI(Ph3Pk in dioxane at temperatures of 500C to 1200C (See, Stille, J. K. Angewandte Chemie Int. Ed. English 1986, 508). Arylboronic esters can be formed by treating an aryl bromide or iodide with a palladium catalyst and bis(pinacolborane) in the presence of sodium acetate (See, Baudoin, O. et al., J. Organic Chem. 2000, vol 65, 9268). In palladium- catalyzed coupling reactions, the boronate esters 89 often give results that are equivalent to those obtained with the boronic acids 85.'
Scheme 17.
I) BuLi
Af-Br Ar-B(OH)2 84 - 2) B(OMe)3 3) HCI 85
1) BuLi
Af-Br Ar-SnMe3 84 2) Me3SnCI 86
1) BuLi
Af-Br Ar-ZnCI 84 2) ZnCI2 87
Figure imgf000067_0001
84 palladium catalyst
89
Me3Sn-SnMe3
Af-Br Ar-SnMe3 84 palladium catalyst 86
Diaryl ketones may be prepared by treating an aryl aldehyde with a Gringard or organolithium reagent to give a carbinol 88. Oxidation of the carbinol with a suitable oxidizing agent such as manganese dioxide or pyridinium dichromate gives the ketone 89. Scheme 18.
Ar1Li or Ar1MgBr Oxidation Ar-CHO +- Ar-CH(OH)-Ar" *- Ar-(C=O)-Ar1
87 88 8Θ
Alternatively, dtaryl ketones 91 may be prepared from acid chlorides (Dieter, K. R. Tetrahedron 1999, vol 55, 4177). One method involves treating an acid chloride 90 with an arylzinc or aryltin compound in the presence of a palladium catalyst In the case of the arylzinc reagents, tetrakis(triphenylphosphine)palladium(o) is commonly a useful catalyst and the reaction is performed at 250C to 65 0C in THF. When an aryltin compound is used, the catalyst is commonly PhCH2PdCI(Ph3P)2 and the reaction is performed in refluxing chloroform. Alternatively, the acid chloride can be treated with an aryl Gringard reagent and a copper salt as catalyst.
Scheme 19.
Ar-COCl ; *~ Ar-CO-Ar1
91
90
Conditions: Ar1SnMe3, PhPdCI(Ph3P)2 or ArZnCI, (Ph3P)4Pd or ArMgBr1 CuI
Certain compounds of this invention are prepared by nucleophilic aromatic substitution reactions. Compounds 94 containing a direct aryl-aryl bond, in which one of the aryl rings is bonded through a ring nitrogen, may be formed by treating an aryl halide 92 with a heterocylic amine in the presence of a base such as potassium hydroxide and a copper catalyst such as copper iodide or copper powder. Temperatures for this reaction may vary between 800C to 180 0C, and in some cases the use of a solvent such as DMPU may facilitate the reaction. Likewise, compounds 97 containing two aryl rings linked through a sulfur atom may be prepared by treating a aryl halide 95 with an aromatic thiol 96 in the presence of a base such as potassium carbonate and a copper catalyst such as copper oxide.
Scheme 20.
Figure imgf000069_0001
A(I)1 A(2), A(3), and A(4) 94 are carbon, nitrogen, oxygen or sulfur.
93
base Ar-Br + Ar'-SH ^. Ar-S-Ar1
95 96 SK 97
Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein are further aspects of the • present invention. Examples of novel intermediates are the following:
((R)-4-{Methoxyimino]-phenyl-methyl}-2-methyl-piperazin-1-yl)-acetonitrile;
((R)-3-Methyl-piperazin-1-yl)-phenyl-methanone O-methyl-oxime; (3R)-3-methyl-1-(phenylcarbonothioyl)piperazine;
5-(4-Benzoyl-2-methyl-piperazine-1-sulfonyl)-thiophene-2-carboxylic acid ethyl ester;
[4-(5-Bromo-thiophene-2-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl- methanone; [4-(5-Bromo-thiophene-2-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl- methanone; tert-butyl 3-methyl-4-(thiophen-2-ylsulfonyl)piperazine-1-carboxylate;
[4-(4-Bromo-benzenesulfonyl)-3-methyl-piperazin-1-yl]-phenyl-methanone;
(R)-(4-(4-ethynylphenylsuIfonyl)-3-methylpiperazin-1-y|)(phenyl)methanone; 4-(1-Methyl-1H-pyrazol-3-yl)-benzoic acid methyl ester;
1 -(4-Benzoyl-2-methyl~piperazin-1 -yl)-2-(4-iodo-phenyl)-ethane-1 ,2-dione;
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(4-bromo-phenyl)-ethane-1 ,2- dione; 1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(4-bromo-2-fluoro-phenyl)-ethane-
1 ,2-dione;
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-3-methyl-phenyl)- ethane-1 ,2-dione;
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)~2-(4-bromo-2-methyl-phenyl)- ethane-1 ,2-dione;
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(6-chloro-pyridin-3-yl)-ethane-1 ,2- dione;
4-[2-(<R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-oxo-acetyl]-boronic acid;
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-dimethylamino- phenyl)-ethane-1 ,2-dione; and
1-(2-Amino-4-bromo-phenyl)-2-((R)-4-benzoyl-2-methyl-piperazin-1-yl)- ethane-1 ,2-dione
EXAMPLE 3 This example, along with the Schemes herein, illustrate typical procedures and characterization of selected examples with respect to representative compounds according to embodiments of the invention, and their synthesis.
Purification and Analytical Procedures
Purification:
Compounds requiring HPLC purification were purified on a system using a Sedex 75 ELSD as the fraction-determining detector, the Gilson 215 as autosampler and fraction collector, and Gilson 321 pumps. Mobile phases used were one of the following:
1. Water/Acetonitrile/0.05% Trifluoroacetic Acid
2. 20 mM ammonium formate at pH 4 - 6 and Acetonitrile
3. 0.1% ammonium hydroxide and acetonitrile at pH 9.0. Columns used were either Phenomenex Gemini, 5 μm, 21.2 X 50 mm or Peeke Scientific Ultra 60 C18 5 μm, 20 mm X 50 mm.
Analytical:
Compounds were analyzed on an Applied Biosystems/Sciex 150EX single quad mass spectrometer in positive ion mode using either an ESI (Electrospray Ionization) source or an APCI (Atmospheric Pressure Chemical Ionization) source. Scan range is 100 - 1000 amu. Mobile phase used was one of the above as described in the purification section. Sedex 75 ELSD and Agilent PDA (photodiode array) UV detection was used. The column most commonly used was the Phenomenex Gemini, 5 μm, 4.6 X 50 mm. When necessary to achieve greater separation of close-eluting impurities, other columns were used including the Phenomenex Gemini, 5 um, 4.6 X 100 or 250 mm, the Kromasil 100, C18, 5 μm, 4.6 X 100 or 250, and the DuraGel HS, 5 μm, phenyl 4.6 X 250 mm from Peeke Scientific. Mass ("MS") calculations were made using the monoisotopic mass for the compound.
Example 101: 1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-oxazol-5-yl- phenvθ-ethane-1 ,2-dione
i) NaHMDS ii) aq NaOCI
Figure imgf000071_0001
Figure imgf000071_0002
((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-acetonitrile (182 mg, 0.896 mmol) and 4-oxazol-5-yl-benzoic acid methyl ester (245 mg, 1 mmol) were dissolved in 10 mL of anhydrous THF. N-Sodium hexamethyldisilazane (NaHMDS, 500 mg, 2.7 mmol) was then added directly to the solution in portions while stirring at ambient temperature. The resulting mixture was allowed to stir for 2 to 5 hours. Bleach (10 mL) was then added in one portion and the resulting biphasic emulsion stirred or shaken rapidly for 5 to 10 minutes. 30 mL of EtOAc was added and the resulting organic layer washed once with an equal volume of saturated aqueous sodium sulfite. The organic fraction was then washed with two portions of saturated ammonium chloride and then brine. After drying over MgSO-J, the organic fraction was concentrated in-vacuo to give 265 mg of a brown residue that was subjected to purification by reverse- phase HPLC ultimately affording 49 mg of pure 1-((R)-4-benzoyl-2-methyl- piperazin-1 -yl)-2-(4-oxazol~5-yl-phenyl)-ethane-1 ,2-dione as light yellow syrup (13 %, isolated yield). MS: Calculated for C23H2IN3O4- H+: 403.15. Found: 404.5. 1HNMR (CDCI3): 8.07-8.00 (m, 3H), 7.82 (d, J= 5.7 Hz, 2H), 7.57 (s, 1H)1 7.5-7.35 (br. m, 5H), 5.2-2.9 (br. m, 7H), 1.3 (br. s, 3H).
((R)-4-Benzoyl-2-methyl-piDerazin-1-vπ-acetonitrile
Figure imgf000072_0001
((R)-3-Methyl-piperazin-1-yl)-phenyl-methanone (2g, 10 mmol) was dissolved in 30 ml_ of acetonitrile. Chloroacetonitrile (800 microliters, 12.6 mmol) was then added along with 2 g of anhydrous sodium carbonate. The mixture was refluxed for 3 hours and the insoluble salts removed via vacuum filtration. The solvent was removed under vacuum and the resulting residue partitioned between EtOAc and water. The organic fraction was washed one time with brine, dried over MgSO4, concentrated, and then dried under high vacuum affording 1.25 g of ((R)-4-benzoyl-2-methyl-piperazin-1-yl)-acetonitrile as a colorless syrup (51 %). MS: Calculated for Ci4Hi7N3O H+: 243.31. Found: 244.3. This material was used without further purification for subsequent reactions.
4-Oxazol-5-yl-benzoic acid methyl ester
Figure imgf000072_0002
4-Formyl-benzoic acid methyl ester (2 g, 11.2 mmol), toluenesulphonylmethyl isocyanide (TOSMIC, 2 g, 10.2 mmol) and anhydrous sodium carbonate (2 g, 18.8 mmol) were brought up in 50 ml_ of anhydrous methanol. The mixture was refluxed for 2 hours, allowed to cool to room temperature, then concentrated in-vacuo. The resulting residue was partitioned between EtOAc and saturated aqueous ammonium chloride. The organic fraction was washed one additional time with ammonium chloride and then once with brine. After drying over MgSO4,the organic fraction was concentrated under vacuum to dryness affording 1.48 g of 4-oxazol-5-yl-benzoic acid methyl ester as a yellow solid.
1HNMR (CDCI3): 8.22 (d, J = 8.1 Hz1 2H), 7.97 (s, 1H), 7.74 (d, J = 6 Hz, 2H), 7.48 (s, 1 H), 3.94 (s, 3H).
Example 102: 1-f(R)-4-Benzoyl-2-methyl-pϊperazin-1-vπ-2-r4-f3-methyl- isoxazol-5-vπ-phenvπ-ethane-1,2-dione
i) NaHMDS ii) aq. NaOCI
Figure imgf000073_0001
Figure imgf000073_0002
((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-acetonitrile (315 mg, 1.3 mmol) and 4- (3-Methyl-isoxazol-5-yl)-benzoic acid methyl ester (280 mg, 1.3 mmol) were dissolved in 10 mL of anhydrous THF. N-Sodium hexamethyldisilazane (NaHMDS, 600 mg, 3 mmol) was then added directly to the solution in portions while stirring at ambient temperature. The resulting mixture was allowed to stir for 2 to 5 hours. Bleach (10 mL) was then added in one portion and the resulting biphasic emulsion stirred or shaken rapidly for 5 to 10 minutes. 30 mL of EtOAc was added and the resulting organic layer washed once with an equal volume of saturated aqueous sodium sulfite. The organic fraction was then washed with two portions of saturated ammonium chloride and then brine. After drying over MgSO4, the organic fraction was concentrated in-vacuo to give 200 mg of a brown residue that was subjected to purification by reverse-phase HPLC ultimately affording 407 mg of 1-((R)-4- ben2oyl-2-methyI-pipera2in-1-yl)-2-[4-(3-methyl-isoxazol-5-yl)-phenyl]-ethane- 1 ,2-dione as light yellow foam (75 %). MS: Calculated for C2-IHaIjN3O4-H+: 417.5. Found: 418.4. 1HNMR (CDCI3): 8.03 (m, 2H) 7.91 (d, J = 8.1 Hz, 2H), 7.53-7.32 (m, 5H), 6.54 (s, 1H), 5.24-2.92 (m, 7H), 2.69 (s, 3H), 1.33 (br. s, 3H).
4-(3-Methyl-isoxazol-5-yl)-benzoic acid methyl ester
Figure imgf000074_0001
4-Acetyl-benzoic acid methyl ester (0.5 g, 2.8 mmol) was dissolved in 4 ml_ of DMA dimethyl acetal and heated to 100 0C for 2 hours. Upon cooling to room temperature, 30 mL of EtOAc was added. The sample was concentrated until the crude intermediate eneamine precipitated. The precipitate was isolated by vacuum filtration yielding 412 mg of a brown solid that was immediately dissolved in 10 mL of anhydrous EtOH and combined with 150 mg (2.1 mmol) of hydroxylamine hydrochloride. The resulting mixture was refluxed for three hours and then slowly cooled to 0 0C. The sample was then thawed and the insoluble product collected while the mother liquor was still cool affording 280 mg of tan crystals (78%). 1HNMR (CDCI3): 8.105 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.1 Hz, 2H), 7.07 (s, 1H), 3.89 (s, 3H), 2.31 (s, 3H).
Example 103: 1 -f (R)-4-Benzoyl-2-methyl-piperazin-1 -vO-2-(4-thiazol-2-yl- phenyl)-ethane-1 ,2-dione
i) NaHMDS ii) aq. NaOCI
Figure imgf000074_0002
Figure imgf000074_0003
((R)-4-Benzoyl-2-methyl-piperaziπ-1-yl)-acetonitrile (300 mg, 1.2 mmo]) and 4- thiazol-2-yl-benzoic acid ethyl ester (287 mg, 1.2 mmol) were dissolved in 10 ml_ of anhydrous THF. N-Sodium hexamethyldisilazane (NaHMDS, 600 mg, 3 mmol) was then added directly to the solution in portions while stirring at ambient temperature. The resulting mixture was allowed to stir for 2 to 5 hours. Bleach (10 mL) was then added in one portion and the resulting biphasic emulsion stirred or shaken rapidly for 5 to 10 minutes. 30 mL of EtOAc was added and the resulting organic layer washed once with an equal volume of saturated aqueous sodium sulfite. The organic fraction was then washed with two portions of saturated ammonium chloride and then brine. After drying over MgSO4, the organic fraction was concentrated in-vacuo to give several hundred milligrams of a yellow residue that was subjected to initial purification by preparative TLC (eluting solvent: 95% DCM1 5 % MeOH, 1% TEA) giving 100 mg of off-white semisolid consisting of 60 % 1-((R)-4- benzoyl-2-methyl-piperazin-1-yl)-2-(4-thiazol-2-yl-phenyl)-ethane-1,2-dione and 40 % ((R)-4-benzoyl-2-methyl-piperazin-1-yl)-acetonitrile. This material was further purified by reverse-phase HPLC ultimately giving the product as 11 mg of colorless syrup 2.2%). MS: Calculated for C2SH2IN3O3S H+: 419.13. Found: 420.4. 1HNMR (CDCI3): 8.14 (d, J = 8.1 Hz, 2H), 8.05-8.00 (m, 3H), 7.48 (d, J = 3.3 Hz1 1H)1 7.5-7.3 (m, 5H), 5.24-2.84 (br. m, 7H), 1.3 (br. s, 3H).
4-Thiazol-2-yl-benzoic acid ethyl ester
Figure imgf000075_0001
A mixture of 1.0 grams of ethyl 4-carbamothioylbenzoate, 0.76 mL of bromoacetaldehyde diethyl acetal, and 10 mL of DMF was heated to 95 0C over 3 hours and then maintained at this temperature an additional 2 hours. The mixture was cooled to 25 0C and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, and then the solvent was evaporated at reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane. The partially purified product thus obtained was crystallized from a mixture of ether and hexanes. The title compound was obtained as 0.48 grams of a tan solid. 1HNMR (CDCI3): 8.15 (d, J = 6 Hz1 2H), 8.04 (d, J = 6 Hz, 2H), 7.93 (d, J = 3 Hz, 1H), 7.41 (d, J = 3 Hz, 1H), 4.41 (q, J = 7 Hz, 2H), 1.42 (q, J = 7 Hz, 3H).
Example 104: 1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-r4-(2-methyl- thiazol-4-yl)-phenyl1-ethane-1.2-dione
i) NaHMDS H) aq. NaOCI
Figure imgf000076_0001
Figure imgf000076_0002
((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-acetonitrile (146 mg, 0.6 mmol) and A- (2-methyl-thiazol-4-yl)-benzoic acid methyl ester (140 mg, 0.6 mmol) were dissolved in 10 mL of anhydrous THF. N-Sodium hexamethyldϊsilazane (NaHMDS, 330 mg, 1.8 mmol) was then added directly to the solution in portions while stirring at ambient temperature. The resulting mixture was" allowed to stir for 2 to 5 hours. Bleach (10 mL) was then added in one portion and the resulting biphasic emulsion stirred or shaken rapidly for 5 to 10 minutes. 15 mL of EtOAc was added and the resulting organic layer washed once with an equal volume of saturated aqueous sodium sulfite. The organic fraction was then washed with two portions of saturated ammonium chloride and then brine.' After drying over MgSO4, the organic fraction was concentrated in-vacuo to give ca. 150 mg of a yellow residue that was purified by preparative TLC (eluting solvent: 94% DCM, 5%, MeOH, 1% TEA) affording 95 mg of 90% pure 1-((R)-4-benzoyl-2methylpiperazin-1-yl)-2-[4-(2- rήethyl-thiazol-4-yl)-phenyl]-ethane-1,2-dione (36%) MS: Calculated for C24H23N3O3S H+: 433.15. Found: 433.9. 1HNMR (CDCf3): 8.07-7.94 (m, 4H), 7.52 (s, 1H), 7.48-7.36 (m, 7.5-7.3, 5H), 5.24-2.84 (br. m, 10H), 1.3 (br. s, 3H).
4-(2-Methyl-thiazol-4-vO-benzoic acid methyl ester
Figure imgf000077_0001
4-(2-Methyl-thiazol-4-yl)-benzόic acid (250 mg, 1.1 mmol) was suspended in 2:1 toluene.MeOH. TMS diazomethane (1.5 mL of 2M solution in diethyl ether) was added dropwise at room temperature. Reaction completion was confirmed by TLC (single spot, 1:1 hexanes: EtOAc). The solvent was . removed and remaining yellow solid used without further characterization.
Example 105: 1-((R)-4-Benzoyl-2-methyl-piperazin-1-vO-2-r4-(2-rnethyl- 2H-tetrazol-5-yl)-phenyll-ethane-1,2-dione
i) NaHMDS ii) aq. NaOCI
Figure imgf000077_0002
Figure imgf000077_0003
((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-acetonitrile (178 mg, 0.73 mmol) and 4-(2-methyl-2H-tetrazol-5-yl)-benzoic acid methyl ester (150 mg, 0.73 mmol) were dissolved in 5 mL of anhydrous THF. N-Sodium hexamethyldisilazane (NaHMDS, 300 mg, 1.5 mmol) was then added directly to the solution in portions while stirring at ambient temperature. The resulting mixture was allowed to stir for 2 to 5 hours. Bleach (5 mL) was then added in one portion and the resulting biphasic emulsion stirred or shaken rapidly for 5 to 10 minutes. 10 mL of EtOAc was added and the resulting organic layer washed once with an equal volume of saturated aqueous sodium sulfite. The organic fraction was then washed with two portions of saturated ammonium chloride i and then brine. After drying over MgSO4, the organic fraction was concentrated iή-vacuo to give 72 mg of a tan residue that was subjected to purification by reverse-phase HPLC ultimately affording 21 mg of 1-((R)-4- benzoyl-2-methyl-piperazin'-1-yl)-2-[4-(2-methyl-2H-tetrazol-5-yl)-phenyl]- ethane-1,2-dione as colorless syrup (6.5%). ELSD purity > 95 %. MS: Calculated for C22H22N6O3 H+: 418.18. Found: 419.5.
4-(2-Methyl-2H-tetrazol-5-yl)-benzoic acid methyl ester
Figure imgf000078_0001
4-(2H-Tetrazol-5-yl)-benzoic acid (500 mg, 2.6 mmol) was suspended in 2:1 toluene:MeOH. TMS diazomethane (4 mL of 2M solution in diethyl ether) was added dropwise at room temperature. Reaction completion was confirmed by TLC (1:1 hexanes:EtOAc). The solvent was removed and remaining yellow solid used without further characterization assuming quantitative conversion.
Example 106: 1-((R)-4-friVIethoxyimino1-phenyl-methyl|-2-methyl- piperazin-1 -yl)-2-(4-oxazol-5-yl-phenyl)-ethane-1 ,2-dione
j) NaHMDS ii) aq. NaOCI
Figure imgf000078_0002
Figure imgf000078_0003
((R)-4-Benzoyl-2-methyUpiperazin-1-yI)-acetonitrile (245 mg, 0.9 mmol) and 4- oxazol-5-yl-benzoic acid methyl ester (182 mg, 0.9 mmol) were dissolved in 10 mL of anhydrous THF. N-Sodium hexamethyldisilazane (NaHMDS, 500 mg, 2.7 mmol) was then added directly to the solution in portions while stirring at ambient temperature. The resulting mixture was allowed to stir for 2 to 5 hours. Bleach (10 ml_) was then added in one portion and the resulting biphasic emulsion stirred or shaken rapidly for 5 to 10 minutes. 30 mL of EtOAc was added and the resulting organic layer washed once with an equal
5 volume of saturated aqueous sodium sulfite.. The organic fraction was then washed with two portions of saturated ammonium chloride and then brine. After drying over MgSO4, the organic fraction was concentrated in-vacuo to give 200 mg of a brown residue that was subjected to purification by reverse- phase HPLC ultimately affording 49 mg of 1-((R)-4-{[(E)-methoxyimino]- i o phenyl-methyl}-2-methyl-piperazin-1 -yl)-2-(4-oxazol-5-yl-phenyl)-ethane-1 ,2- dione. MS: Calculated for C24H24N4O4 H+: 432.18. Found: 433.4. 1HNMR (CDCI3): 8.09-7.99 (m, 3H), 7.82-7.65 (m, 2H)1 7.57 (s, 1H), 7.5-7.3 (m, 5H), 5.3-2.8 (m, 10H), 1.42-1.37 (m, 3H).
15 ((R)-4-fMethoxyimino1-phenyl-methyl>-2-methyl-piperazin-1-yl)-acetonitrile
Figure imgf000079_0001
((R)-3-Methyl-piperazin-1-yl)-phenyl-methanone O-methyl-oxime (223 mg, 20 0.957 mmol), chloroacetonitrile (3 mL, solvent), and anhydrous sodium carbonate (500 mg) were combined in an 8 mL vial. The vial was sealed and the sample heated to 100 0C and held for 1 hour (TLC monitoring, solvent = 94% DCM, 5 % MeOH, 1 % TEA). Upon satisfactory completion, the insoluble salts were removed by vacuum filtration and the filtrate concentrated and then 5 dried under high vacuum. LC-MS analysis showed the material to be > 99% pure by ELSD. MS: Calculated for C15H20N4O-H+: 273.1. Found: 273.3. The material was used without further purificiation.
(f R)-3-Methyl-piperazin-1 -vD-phenyl-methanone O-methyl-oxime 0
Figure imgf000080_0001
A solution of 0.7 grams (1.5 mmol) of tert-butyl (2R)-2-methyl-4- (phenylcarbonothioyl)-piperazine-i-carboxylate methiodide salt in 2 mL of methanol was treated with a solution of 0.13 grams (1.6 mmol) of methoxylamine hydrochloride and 0.36 mL (2 mmol) of Hunig's base in 2 mL of methanol. After 15 minutes, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4 and stripped. The oily yellow residue was dissolved in 5 mL of TFA and stirred one hour. The solution was partitioned between ethyl acetate and excess aqueous potassium carbonate. The organic phase was washed with brine and dried over MgSO4. The solvent was evaporated and the residue was crystallized from hexanes. This procedure yielded the product as 170 mg of white solid (49%). MS: calculated for Ci3Hi9N3O • H+: 234.1. Found: 234.1.
tert-Butyl (2R)-2-methyl-4-(phenylcarbonothioyl)piperazine-1-carboxylate methiodide salt
Figure imgf000080_0002
(3R)-3-Methyl-1-(phenylcarbonothioyl)piperazine (0.85 grams, 3.9 mmol) was dissolved in 10 mL of dichloromethane and treated with 0.9 grams (4.1 mmol) of di(tert-butyl)dicarbonate. The mixture was stirred for 18 hours and then the solvent was evaporated. The residue was dissolved in 20 mL of acetone and treated with 1.4 mL of iodomethane. The mixture was refluxed for four hours. • The solvent was evaporated at reduced pressure and the residue was triturated with ethyl acetate. The yellow solid was collected by filtration to give 1.5 grams of product (100%). MS: Calculated for C18H2TN2O2S+: 335.2. Found: 335.5.
(3R)-3-methvM-(phenylcarbonothioyl)piperazine
Figure imgf000081_0001
A mixture of 2.8 grams (28 mmol) of (f?J-2-methylpiperazιne and 6.0 grams (28. mmol) of S-(thiobenzoyl)thioglycolic acid was suspended in a solution of 1.6 g (40 mmol) NaOH in 50 mL of distilled water. The mixture was stirred for 5 minutes at 25 0C, and then for 5 minutes at 60 0C. The mixture was copied to 25 0C, and the ivory precipitate was collected by filtration. It was washed with distilled water, and dried in a stream of air. After further drying under high vacuum overnight there was obtained 5.1 grams of a white solid (80%). 1HNMR (CDCI3): 7.35 - 7.20 (m, 5 H),.6.50 - 5.45 (m. 1 H), 4.80 - 4.65 (m, 1 H), 3.90 - 3.70 (m, 1 H), 3.30 - 2.70 (m, 5H)1 1.20 (d, J = 7 Hz, 1.5 H), 0.95 (d, J = 7 Hz, 1.5H).
Example 107: ■f3-Methyl-4-r5-(3-methyl-ri.2.4Toxadiazol-5-vn-thiophene- 2-sulfonvπ-piperazin-i-ylVphenyl-methanone
Figure imgf000081_0002
A solution of 5-(4-benzoyl-2-methyl-piperazine-1-sulfonyl)-thiophene-2- carboxylic acid (0.215 g, 0.5 mmol), acetamide oxime (0.04 g, 0.5 mmol), BOP-reagent (0.22 g, 0.5 mmol) and DIPEΞA (0.17 mL, 0.1 mmol) in DCM (20 ml_) was kept at room temperature under stirring overnight. The solvent was then evaporated at reduced pressure. The residue was chromatographed on silica gel eluting with 9:1 ethyl acetate/n-hexane. The solvent was evaporated and the residue was dissolved in xylene (5 mL). p-ToluenesuIphonic acid (as catalyst, 0.01 g) was added and the reaction mixture was refluxed under stirring for 12 hours. It was cooled to room temperature, and chromatographed on silica gel eluting with 4:1 ethyl acetate/n-hexane. The solvent was evaporated to afford {3-methyl-4-[5-(3-methyl-[1,2,4Joxadiazol-5- yl)-thiophene-2-sulfonyl]-piperazin-1 -yl}-phenyl-methanone (0.015 g, 11 %). LCMS: Calc'd for C19H20N4O4S2 H+: m/z = 433.5. Found: m/z = 433, 434. 1H NMR (DMSO-de): 8.05 (d, J = 4.2 Hz, 1H); 7.86 (d, J = 4.2 Hz, 1H); 7.45-7.37 (m, 5H); 4.44-3.36 (br signal, 4H); 3.20-2.76 (br signal, 3H); 2.42 (s, 3H); 1.04 (br signal, 3H).
S-^-Benzoyl^-methyl-piperazine-i-sulfoπyO-thiophene^-carboxylic acid ethyl ester
Figure imgf000082_0001
Chlorosulphonic acid (34 mL, 0.512 mol) was added to a solution of thiophene-2-carboxylic acid ethyl ester (20.0 g, 0.128 mol) in DCM (100 mL) at -500C under stirring. The reaction mixture was allowed to warm to room temperature and kept for 12 hours. It was then poured into ice water, extracted with DCM, and the organic phase was dried with sodium sulfate. The solvent was evaporated to give a mixture (5.75 g) of 5-chlorosulfonyl- thiophene-2-carboxylic acid ethyl ester and an isomeric side product which was used in the next step without separation. The crude 5-chlorosulfonyl- thiophene-2-carboxylic acid ethyl ester (5.75 g, 0.023 mol), triethylamine (3.98 mL, 0.028 mol) and (3-methyl-piperazin-1-yl)-phenyl-rnethanone (5.5 g , 0.027 mol) in DCM (150 mL) was kept at room temperature for 12 hours under stirring (TLC monitoring, MeOH/CHCI3 5:95). It was then washed with water, dried with sodium sulfate and the solvent was evaporated. The residue was purified by reverse phase preparative HPLC to afford 5-(4-benzoyl-2- methyl-piperazine-1 -sulfonyl)-thiophene-2-carboxylic acid ethyl ester (1 g, 10%). LCMS: Calc'd for Ci9H22N2O5S2 . H+: m/z = 423.5. Found: m/z = 423, 424.
5-(4-Benzoyl-2-methyl-piperazine-1-sulfonyl)-thiophene-2-carboxylic acid
A solution of 5-(4-benzoyl-2~methyl-piperazine-1-sulfonyl)-thiophene-2- carboxylic acid ethyl ester (0.58 g, 1.4 mmol) and NaOH (0.28 g, 7 mmol) in a methanol-water mixture (20 mL : 3 mL) was kept at room temperature under stirring until starting material disappeared (TLC monitoring, 10 %
MeOHZCHCI3). The solution was then acidified with HCI to pH3, diluted with water (15 mL), and extracted with chloroform. The organic phase was dried , with sodium sulphate, and the solvent was evaporated to afford 5-(4-benzoyl- 2-methyl-piperazine-1-sulfonyl)-thiophene-2-carboxylic acid (0.45 g, 84%). 1H NMR (DMSO-d6): 13.78 (br s, 1 H); 7.74 (d, J = 3.9 Hz, 1 H); 7.70 (d, J = 3.9 Hz, 1H); 7.45-7.36 (m, 5H); 4.47-3.88 (br signal, 2H); 3.80-3.44 (br signal, 2H); 3.22-2.72 (br signal, 3H); 0.99 (br signal, 3H).
Example 108: 5-(4-Benzoyl-2-methyl-piperazine-1-sulfonyl)-thiophene-2- carboxylic acid methoxy-methyl-amide
Figure imgf000083_0002
A solution of 5-(4-benzoyl-2-methyl-piperazine-1-sulfonyl)-thiophene-2- carboxylic acid (0.25 g, 0.6 mmol), 0,Λ/-dimethyl-hydroxyIamine hydrochloride (0.058 g, 0.6 mmol), BOP-reagent (0.26 g, 0.6 mmol) and DIPEA (0.20 mL, 0.12 mmol) in DCM (20 mL) was kept at room temperature under stirring overnight The solvent was evaporated to Vk the original volume and then the mixture was chromatographed on. silica gel eluting with 2:1 ethyl acetate/n- hexane. The solvent was evaporated to afford 5-(4-benzoyl-2-methyl- piperazine-1 -sulfonyl)-thiophene-2-carboxylic acid methoxy-methyl-amide (0.08 g, 36%). LCMS: Calc'd for C19H23N3O5S2- H+: m/z = 438.5. Found: m/z = 438, 439. 1H NMR (DMSO-d6): 7.85 (d, J = 4.2 Hz, 1H); 7.70 (d, J = 4.2 Hz, 1 H); 7.44-7.37 (m, 5H); 4.52-3.91 (br signal, 2H); 3.80 (s, 3H); 3.78-3.46 (br signal, 2H); 3.32 (s, 3H); 3.27-2.70 (br signal, 3H); 0.99 (br signal, 3H).
Example 109: r3-Methyl-4-(5-H .2.41triazol-1 -yl-thiophene-2-sulfonyl)- piperazirt-1-vH-phenyl-mβthanone
Figure imgf000084_0001
Mixture of [4-(5-bromo-thiophene-2-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl- methanone (0.35 g, 0.8 mmol), Cu-powder (0.1 g, 1.6 mmol), 1 ,2,4-triazole (1.65 mL, 24.0 mmol), and powered KOH (0.09 g, 1.6 mmol) was heated to 155 0C and kept under stirring at this temperature for 1 hour (TLC monitoring, 1 :1 EtOAc/n-hexane). The reaction mixture was then cooled to 50 0C, co- evaporated with methanol (50 mL) and silica gel (15 mL), placed onto a silica gel column, eluted with 2% MeOHZCH2CI2 and evaporated. The residue was purified by reverse phase preparative HPLC to afford [3-methyl-4~(5- [1 ,2,4]triazol-1-yl-thiophene-2-sulfonyl)-piperazin-1~yl]-phenyl-methanone (0.09 g, 27%). LCMS: Calc'd for Ci8Hi9N5O3S2- H+: m/z = 418.5. Found: m/z - 418, 419. 1H NMR (DMSO-d6): 9.38 (s, 1H); 8.30 (s, 1 H); 7.72 (d, J = 4.2 Hz, 1H); 7.65 (d, J = 4.2 Hz, 1H); 7.45-7.37 (m, 5H); 4.47-3.87 (br signal, 2H); 3.79-3.37 (br signal, 2H); 3.28-2.72 (br signal, 3H); 1.05 (br signal, 3H). f4-f5-Bromo-thiophene-2-sulfonyl)-3-methyl-piperazin-1-vn-phenyl-methanone
Figure imgf000085_0001
Triethylamine (0.50 mL, 3.6 mmol) was added to a solution of 5-bromo- thiophene-2-sulfonyl chloride (0.94 g, 3.6 mmol) and (3-methyl-piperazin-1-yl)- phenyl-methanone (0.72 g, 3.6 mmol) in DCM (20 mL). The reaction mixture was stirred at 40 0C for 2 hours (TLC monitoring, MeOHZCHCI3 5:95), washed with water, dried over sodium sulfate and filtered. Solvent was evaporated to afford [4-(5-bromo-thiophene-2-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl- methanone (1.4 g, 92%). 1H NMR (DMSO-d6): 7.55 (d, J = 4.2 Hz, 1H); 7.46- 7.36 (m, 6H); 4.45-3.86 (br signal, 2H); 3.76-3.29 (br signal, 2H); 3.22 (m, 1H); 3.15-2.68 (br signal, 2H); 1.01 (br signal, 3H).
Example 110: f4-r5-(Furan-2-carbonyl)-thiophene-2-sulfonvn-3-methyl- piperazin-1-yli-phenylmethaπone (General Procedure B)
Figure imgf000085_0002
To a solution of diisopropylamine (0.17 mL, 1.2 mmol) in anhydrous THF (10 mL) was added by drops 15% solution of butyllithium in THF (0.8 mL, 1.28 mmol) at -700C under stirring and inert atmosphere. The reaction mixture was kept for 15 minutes, then a solution of tert-butyl 3-methyl-4- (thiophen-2-ylsulfonyl)piperazine-1-carboxylate (0.4 g, 1.16 mmol) in anhydrous THF (5 mL) was added. After 30 minutes of stirring at the same temperature a solution of furan-2-carbaldehyde (0.11 g, 1.16 mmol) in anhydrous THF (5 mL) was added. The reaction mixture was stirred at -70 0C for 30 minutes additionally, then heated to room temperature, quenched with water (30 mL), extracted with DCM, washed with water, dried with sodium sulfate and evaporated. To the crude residue, DMF (5 mL) and pyridiπium dichromate (0.47 g, 1.25 mmol) were added. The reaction mixture was kept under stirring at room temperature overnight, then poured into water (30 mL), extracted with EtOAc washed with brine, dried with sodium sulfate and evaporated to give a compound tentatively identified as tert-butyl 4-(5-(furan- 2-carbonyl)thiophen-2-ylsulfonyl)-3-methylpiperazine-1-carboxylate (0.16 g). LCMS: Calc'd for C14Hi6N2O4S2 " H+ (without fe/ϊ-butoxycarbonyl group): m/z = 340.5. Found: m/z - 341. A 4M solution of HCI in dioxane (20 mL) was added to the above material (0.16 g, 0.364 mmol), and the mixture was stirred at room temperature for 1 hour, and evaporated. To the residue a solution of benzoyl chloride (0.058 g, 0.414 mmol) in DCM (10 mL) and then TEA (0.12 mL, 0.83 mmol) were added. The reaction mixture was stirred for 1 hour, and evaporated. The residue was purified by a silica gel column chromatography using EtOAc/n-hexane (2:1) as eluent to afford {4-[5-(furan-2-carbonyl)- thiophene-2-sulfonyl]-3-methyl-piperazin-1-yl}-phenyl-methanone (0.13 g, total 25% yield from tert-butyl 3-methyl-4-(thiophen-2-ylsulfonyl)piperaziπe-1- carboxylate). LCMS: Calc'd for C2IH20N2O5S2 • H+: m/z = 445.5. Found: m/z = 445, 446. 1H NMR (DMSO-d6): 8.19 (m, 2H); 7.82 (d, J - 4.0 Hz, 1H); 7.69 (d, J = 4.0 Hz1 1H); 7.43-7.37 (m, 5H); 6.87 (m, 1H); 4.55-3.87 (br signal, 2H); 3.83-3.36 (br signal, 2H); 3.29-2.80 (br signal, 3H); 1.04 (br signal, 3H). tert-butyl 3-methyl-4-(thiophen-2-ylsulfonvπpiperazine-1-carboxylate
Figure imgf000087_0001
Triethylamine (2.8 mL, 19.5 mmol) was added to a mixture of 2- chlorosulfonyl-thiophene (3.56 g, 19.5 mmol) and 3-methyl-piperazirie-1- carboxylic acid fert-butyl ester (3.90 g, 19.5 mmol) in DCM (50 mL). The reaction mixture was kept at room temperature for 1 hour under stirring (TLC monitoring, MeOH/CHCI3 5:95), washed with water, dried with sodium sulfate, and evaporated. The residue was purified by a silica gel column chromatography using EtOAc/n-hexane (2:1) as eluent to give tert-butyl 3- methyl-4-(thiophen-2-ylsulfonyl)piperazine-1-carboxylate (6.1 g, 90 %). 1H NMR (DMSO-dβ): 7.99 (dd, J = 5.1 Hz, J = 1.2 Hz, 1H); 7.67 (dd, J = 3.9 Hz1 J = 1.2 Hz, 1H); 7.22 (dd, J = 5.1 Hz, J = 3.9 Hz, 1H); 4.03 (mf 1H); 3.86 (br . signal, 1H); .3.67 (dm, J =13.0 Hz, 1H); 3.54 (dm, J = 13.0 Hz, 1H); 3.07 (m, 1H); 2.90 (br signal, 1H); 2.77 (br signal, 1H); 1.37 (s, 9H); 0.93 (d, J = 6.9 Hz, 3H).
Example 111: f4-r5-(3H-lmidazole-4-carbonyl)-thiophene-2-sulfonvπ-3- methy.-p.perazin-1-yll-phenyl-methanone
Figure imgf000088_0001
{4-[5-(3H-lmidazole-4-carbonyl)-thiophene-2-sulfonyl]-3-methyl-piperazin-1- yl}-phenyl-methanone (0.21 g, total 33% yield from tert-butyl 3-methyl-4- (thiophen-2-ylsulfonyl)piperazine-1-carboxylate) was prepared according to general procedure B using δ-formyl-imidazole-i-carboxylic acid te/t-butyl ester instead of furan-2-carbaldehyde. LCMS: Calc'd for C20H20N4O4S2 " H+: m/z = 445.5. Found: m/z = 444, 446. 1H NMR (DMSO-d6): 13.00 (br, s, 1H); 8.36 (d, J = 3.9 Hz1 1H); 8.14 (br s, 1H); 7.96 (s, 1H); 7.75 (d, J = 3.9 Hz, 1H); 7.43-7.37 (m, 5H); 4.51-3.91 (br signal, 2H); 3.85-3.38 (br signal, 2H); 3.27- 2.81 (br signal, 3H); 1.01 (br signal, 3H).
Example 112: (4-r5-(>soxazole-3-carbonyl^-thiophene-2-sulfonvn-3- mβthyl-piperazin-1-yl>-phenyl-methanone
Figure imgf000089_0001
{4-[5-(lsoxazole-3-carbonyl)-thiophene-2-sulfonyl]-3-methy[-piperazin-1-yl}- phenyl-methanone (0.27 g, total 52% yield from tert-butyl 3-methyl-4- (thiophen-2-ylsulfonyl)piperazine-1-carboxylate) was prepared according to General Procedure B, using isoxazole-3-carbaldehyde instead of furan-2- carbaldehyde. LCMS: Calc'd for C2OHi9N3O5S2 H+: m/z - 446.5: Found: m/z = 446, 447..1H NMR (DMSO-d6): 9.26 (s, 1H); 8.33 (d, J = 4.2 Hz, 1H); 7.84 (d, J = 4-2 Hz, 1H); 7.43-7.37 (m, 5H); 7.14 (s, 1H); 4.51-3.95 (br signal, 2H); 3.91-3-30 (br signal, 3H); 3.21-2.74 (br signal, 2H); 1.04 (br signal, 3H).
8S Examples 113: r3-Methyl-4-(3-H ,2,31triazoM -yl-benzenesulfon vD- piperaz'ιn-1-yll-Phenyl-methanone
Figure imgf000090_0001
Mixture of [4-(3-bromo-benzenesulfonyl)-3-methyl-piperazin-1 -yl]- phenyl-methanone (0.30 g, 0.71 mmol), Cu-powder (0.09 g, 1.42 mmole), 1 ,2,3-triazole (1.47 g, 1.23 mL, 21.3 mmole), and powered KOH (0.079 g, 1.42 mmole) was heated to 160 0C and kept under stirring at this temperature for 24 hours (TLC monitoring, 10% MeOH/CHCI3). The reaction mixture was then cooled to room temperature, diluted with CH2CI2 (~2 mL), placed onto a silica gel column and eluted with 2% MeOH/CH2CI2. Fractions containing the product (together with isomeric side product) were collected and evaporated. The residue was purified by reverse phase preparative HPLC to afford [3- methyl-4-(3-[1,2,3]triazol-1-yl-benzenesulfonyl)-piperazin-1-yl]-phenyl- methanone. (0.035 g, 12 %). LCMS: Calc'd for C20H21 N5O3S • H+: m/z = 412.5. Found: m/z = 412, 413. 1H NMR (DMSO-d6): 9.01 (s, 1H); 8.31 (s, 1H); 8.26 (d, J = 8.1 Hz, 1 H); 7.95 (s, 1 H); 7.90 (d, J = 7.8 Hz, 1 H); 7.86 (dd, J = 7.8 Hz, J = 8.1 Hz1 1H); 7.42-7.34 (m, 5H); 4.39-3.94 (br signal, 2H); 3.83-3.46 (br signal, 2H); 3.23 (m, 1H); 3.09-2.78 (br.signal, 2H); 0.98 (br signal, 3H). r4-(3-Bromo-benzenesulfonylV3-methyl-piperazin-1-vπ-Dhenyl-methanone (General Procedure C).
Figure imgf000091_0001
Triethylamine (2.11 g, 2.9 ml_, 21 mmol) was added to a solution of 3- bromo-benzenesulfonyl chloride (5.00 g, 20 mmol) and (3-methyl-piperazin-1- yl)-phenyl-methanone (4.10 g , 20 mmol) in DCM (5OmL). The reaction mixture was stirred at 40 0C for 2 hours (TLC monitoring, MeOH/CHCI3 5:95), washed with water (3x20mL), dried over sodium sulfate and filtered. Solvent was evaporated to give [4-(3-bromo-benzenesulfonyl)-3-methyl-piperazin-1- yl]-phenyl-methanone (7.12 g, 85%). 1H NMR (DMSO-d6): 7.95 (br s, 1H); 7.90 (d, J = 7.8 Hz, 1H); 7.84 (d, J = 8.0 Hz, 1H); 7.58 (m, 1H); 7.42-7.34 (m, 5H); 4.78-4.16 (br signal, 2 H); 3.86-3.29 (br signal, 2H); 3.18 (m, 1H); 3.15- 2.90 (br signal, 2H); 0.94 (br signal, 3H).
Example 114: r3-Methyl-4-(3-H,2,41triazol-1-yl-benzeπesulfonyl)- piperazin-i-yli-phenyl-methanone
Figure imgf000091_0002
Mixture of [4-(3-bromo-benzenesulfonyl)-3-methyl-piperazin-1 -yl]- phenyl-methanone (0.30 g, 0.71 mmol), Cu-powder (0.09 g, 1.42 mmole), 1,2,4-triazole (1.23 mL, 21.3 mmole), and powered KOH (0.079 g, 1.42 mmole) was heated to.160 0C and kept under stirring at this temperature for 24 hours (TLC monitoring, 10% MeOH/CHCI3). The reaction mixture was then cooled to room temperature, diluted with CH2CI2 (~2 mL), placed onto a silica gel column and eluted with CH2CI2, then 2% MeOH/CH2Cfe and evaporated to afford [3-methyl-4-(3-[1,2,4]triazol-1-yl-benzenesulfonyl)-piperazin-1-yl]- phenyl-methanone (0.15 g, 52 %). LCMS: Calc'd for C2OH2IN5O3S" H+: m/z = 412.5. Found: m/z = 412, 413. 1H NMR (DMSO-d6): 9.46 (s, 1H); 8.29 (s, 1H); 8.25 (S, 1H); 7.95 (d, J = 7.8 Hz1 1H); 7.83 (m, 2H); 7.42-7.34 (m, 5H); 4.39- 3.94 (br signal, 2H); 3.83-3.46 (br signal, 2H); 3.23 (m, 1 H); 3.09-2.78 (br signal, 2H); 0.98 (br signal, 3H).
Example 115. r3-Methyl-4-(3-pyrazol-1-yl-benzenesulfonyl)-piperazirt-1- vH-phenyl-methanone
Figure imgf000092_0001
[3-Methyl-4-(3-pyrazol-1-yl-beπzenesu!fonyl)-piperazin-1-yl]-phenyl- methanone (0.17 g, 59 %) was prepared according to Example 114 above, using pyrazole instead of 1 ,2,4-triazole. LCMS: Calc'd for C21H22N4O3S ■ H+: m/z = 411.5. Found: m/z = 411 , 412. 1H NMR (DMSO-d6): 8.68 (s, 1H); 8.24 (s, 1H); 8.16 (br s, 1H); 7.82 (s, 1H); 7.74 (m, 2H); 7.42-7.34 (m, 5H); 6.60 (br s, 1 H); 4.42-3.90 (br signal, 2H); 3.85-3.46 (br signal, 2H); 3.23 (m, 1 H); 3.10- 2.75 (br signal, 2H); 0.97 (br signal, 3H). Examples 116 and 117: r3-Methyl-4-(4-M .2.31triazol-1 -yl- benzenesulfonyl)-piDerazin-1-vn-phenyl-methanone and r3-methyl-4-(4- n.2.31triazol-2-vl-benzenesulfonvn-piperazin-1-vn-phenvl-methanone
Figure imgf000093_0001
Mixture of [4-(4-bromo-benzenesulfonyl)-3-methyl-piperazin-1 -yl]- phenyl-methanone (0.30 g, 0.71 mmol), Cu-powder (0.09 g, 1.42 mmole), 1 ,2,3-triazole (1.47 g, 1.23 mL, 21.3 mmole), and powered KOH (0.08 g, 1.42 mmole) was heated to 160 0C and kept under stirring at this temperature for 24 hours (TLC monitoring, 10% MeOH/CHCfe). The reaction mixture was then cooled to room temperature, diluted with MeOH (~5 mL), filtered and evaporated. The residue was purified by a silica gel column chromatography using ethylacetate as eluent to give [3-methyl-4-(4-[1 ,2,3]triazol-1-yl- benzenesulfonyl)-piperazin-1-yl]-phehyl-methanone (0.11 g, 38 %) and [3- methyl-4-(4-[1 ,2,3]triazol-2-yl-benzenesulfonyl)-piperazin-1 -yl]-phenyl- methanone (0.09 g, 31 %).
[3-methyM-(4-[1,2,3]triazoM-yl-benzenesulfonyl)-piperaziri-1-yl]-phenyl- methanone LCMS: Calc'd for C2OH2IN5O3S - H+: m/z = 412.5. Found: m/z = 412, 413. 1H NMR (DMSO-d6): 8.99 (d, J = 1.0 Hz, 1H); 8.19 (d, J = 8.8 Hz, 2H); 8.04 (d, J = 8.8 Hz, 2H); 8.04 (d, J = 1.0 Hz, 1H); 7.42 (m, 3H); 7.35 (m, 2H); 4.46-3.86 (br signal, 2H); 3.84-3.38 (br signal, 2H); 3.21 (m, 1 H); 3.14- 2.70 (br signal, 2H); 0.98 (br signal, 3H). [3-methyl-4-(4-[1,2,3]triazol-2-yl-benzenesulfonyl)-piperazin-1-yl]-phenyl- methanone LCMS: Calc'd for C20H21N5O3S • H+: m/z = 412.5. Found: m/z = 412, 413. 1H NMR (DMSOd6): 8.24 (d, J = 8.5 Hz, 2H); 8.23 (s, 2H); 8.01 (d, J = 8.5 Hz, 2H); 7.41 (m, 3H); 7.35 (m, 2H); 4.39-3.84 (br signal, 2H); 3.82- 3.37 (br signal, 2H); 3.20 (m, 1H); 3.09-2.70 (br signal, 2H); 0.97 (br signal, 3H).
f4-(4-Bromo-benzenesulfonyl)-3-methyl-piperazin-1-vn-phenyl-methanone
Figure imgf000094_0001
[4-(4-Bromo-benzenesulfonyl)-3-rnethyl-piperazin-1-yl]-phenyl- methanone (6.70 g, 80%) was prepared according to General procedure C using 4-bromo-benzenesulfonyl chloride in place of 3-bromo-benzenesuϊfonyl chloride. 1H NMR (DMSOd6): 7.82 (d, J = 8.6 Hz, 2H); 7.75 (d, J = 8.6 Hz, 2H); 7.45-7.35 (m, 5H); 4.44-3.85 (br signal, 2 H); 3.79-3.40 (br signal, 2H); 3.16 (m, 1H); 3.08-2.65 (br signal, 2H); 0.94 (br signal, 3H).
Example 118: r3-Methyl-4-(4-π .2,41triazol-1 -yl-benzenesulfonyl)- piperazin-1-vn-phenvl-methanone
Figure imgf000095_0001
[3-Methyl-4-(4-[1,2,4]triazol-1-yl-benzenesulfonyl)-piperazin-1-yl]- phenyl-methanone (0.15 g, 51 %) was prepared according to the procedure in Examples116 and 117, using 1 ,2,4-triazole instead of 1,2,3-triazole. LCMS: Calc'd for C20H21N5O3S H+: m/z ~ 412.5. Found: m/z = 412, 413. 1H NMR (DMSO-de): 9.47 (s, 1H); 8.32 (s, 1 H); 8.12 (d, J = 8.8 Hz, 2H); 8.00 (d, J = 8.8 Hz, 2H); 7.42 (m, 3H); 7.35 (m, 2H); 4.40-3.86 (br signal, 2H); 3.82-3.38 (br signal, 2H); 3.20 (m, 1H); 3.11-2.60 (br signal, 2H); 0.98 (br signal, 3H).
Example 119: r3-Methyl-4-(4-pyrazo|-1 -yl-benzenesulfonvU-piperaziivi ■ yli-phenyl-methanone
Figure imgf000096_0001
[3-Methyl-4-(4-py razol-1 -yl-benzenesulfonyl)-piperazin-1 -yl]-phenyl- methanone (0.09 g, 29 %) was prepared according to the procedure in Examples 116 and 117, using pyrazole instead of 1 ,2,4-triazole. LCMS: Calc'd for C2IH22N4O3S - H+: m/z = 411.5. Found: m/z = 411 , 412. 1H NMR (DMSO- d6): 8.67 (d, J = 2.7 Hz, 1H); 8.09 (d, J = 8.8 Hz, 2H); 8.00 (d, J = 8.8 Hz, 2H); 7.84 (d, J = 1.5 Hz, 1 H); 7.42-7.34 (m, 5H); 6.63 (m, 1H); 4.43-3.96 (br signal, 2H); 3.78-3.41. (br signal, 2H); 3.18 (m, 1H); 3.08-2.67 (br signal, 2H); 0.96 (br signal, 3H).
Figure imgf000097_0001
General procedure A for the 1 ,3-di polar reactions of azides with [(R)-4-(4- ethynyl-benzenesulfonyl)-3-methyl-piperazin-1-yl]-phenyl-methanone
Figure imgf000097_0002
To a mixture of [(R)-4-(4-etrtynyl-benzenesulfonyl)-3-methyl-piperazin- 1-yl]-phenyl-methanone (40 mg, 0.13 mmol) and azide (0.13 mmol) in 1:1 1BuOHhH2O (2 mL) containing 100 uL of DMF was added freshly prepared aqueous solutions (1 mM) of sodium ascorbate (11 uL) and copper sulfate (1 uL) and the resulting suspension was stirred at ambient temperatures (250C to 80 0C) until all the starting material is consumed (8 to 24 hours). If necessary, additional reagents were added. Solvents were evaporated under high vacuum and the products were purified by HPLC. Example 120: f(Ri-3-Methyl-4-r4-( 1 H-M .2.31triazol-4-v»)-benzenesulfonyl1- piperazin-1-yl)-pheπyl-methanone
Figure imgf000098_0001
Prepared according to General Procedure A using trimethylsily azide. LCMS: m/e 412 (M+H). 1H NMR (CDCI3, .300 MHz): δ 8.00 (s, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.45-7.33 (m, 5H), 4.20-3.01 (m, 7H), 4.2-3.01 (m, 7H), 1.03 (br s, 3H).
f(R)-4-(4-bromo-benzenesulfonyl)-3-methyl-piperazin-1-vn-phenyl-methanone
Figure imgf000098_0002
To a solution of ((R)-3-methyl-piperazine-1-yl)-phenyl-methanone hydrochloride (720 mg, 3 mmol) in 15 % triethylamine/tetrahydrofuran (20 mL) was added 4-bromo-benzenesulfonyl chloride (712 mg, 3.3 mmol) and mixture was stirred at 45 0C for 3 hours. Solvent was evaporated and the residue was partitioned between ethyl acetate and water. Separate organic layer and the aqueous layer was extracted with ethyl acetate (2x20 mL). Combined extract was dried (MgSCU), filtered and concentrated to afford [(R)- 4-(4-bromo-benzenesulfonyl)-3-methyl-piperazin-1-yl]-phenyl-methanone as light brown solid (1.27 g, 100%) which was used in next reactions without further purification. LCMS: m/e 424 (M+H). 1H NMR (CDCI3, 300 MHz): δ 7.71-7.62(m, 4H), 7.48-7.29(m, 5H), 4.6-3.16(m, 7H), 1.03 (br s, 3H). (R)-(3-methyl-4-(4-((trimethylsilyl)ethvnyl>phenylsulfonyl^piperazin-1- yl)(phenvl)methanone
Figure imgf000099_0001
A heterogeneous mixture containing [(R)-4-(4-bromo-benzenesulfonyl)- 3-methyl-piperazin-1-yl]-phenyl-methanone (800 mg, 1.9 mmol), trimethyisilylacetylene (222 mg, 2.2 mmol), palladium dichloride bis(triphenyl)phosphene (67 mg, 5 mol%), copper iodide (5 mol%) and diisopropyl ethylamine (575 mg, 5.7 mmol) in anhydrous tetrahydrofuran (20 ml_) was heated at 50 0C for 12 hours. The reaction mixture was cooled and the diluted with ethyl acetate (20 ml_) and filtered though a Celite bed. The filtrate was concentrated and the crude mixture was purified by a silica gel column chromatography using 20% ethyl aceate in hexanes to afford [(R)-3- methyl-4-(4-trimethylsilanylethynyl-benzenesulfonyl)- piperazin-1-yl]-phenyl- methanone as half white solid (607 mg, 73 %). LCMS: m/e 441 (M+); 1H NMR (CDCI3, 300 MHz): δ 7.73 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 7.46T7.31 (m, 5H), 4.16-2.95(m, 7H), 0.94 (s, 3H), 0.27 (s, 9H).
(R)-(4-f4-ethvnylphenylsulfonyl)-3-methylpiperazin-1-yl)(phenyl)methanone
Figure imgf000099_0002
(R)-(3-methyl-4-(4-((trimethylsilyl)ethynyl)phenylsulfonyl)piperazin-1- yl)(phenyl)methanone was dissolved in methanol (10 mL) and was added K2CO3 (300 mg, 2.17 mmol). The mixture was stirred at room temperature for 1h. Solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate and water (20 mL). Aqueous layer was extracted with ethyl acetate (2x10 mL). Combined organic extract was dried (MgSO4), filtered and concentrated to dryness to afford [(R)-4-(4-ethynyl- benzenesulfonyl)-3-methyl-piperazin-1-yl]-phenyl-methanone which was used in next step without further purification. LCMS: m/e 369 (M+H). 1H NMR (CDCI3, 300 MHz): δ 7.76 (d, J=9 Hz, 2H), 7.62 (d, J=9 Hz, 2H), 7.50-7.33(m, 5H), 3.26 (S1 1H), 4.62-2.85(m, 7H), 1.00 (br s, 3H).
Example 121 : «R)-4-f4-(1-teobutyl-1H-ri.2.3ltriazol-4-yl)- benzenesulfonvn-3-methyl-piperazin-1-yll-phenyl-methanone
Figure imgf000100_0001
Prepared according to General Procedure A using isobutyl azide, which was prepared in situ using isobutyl bromide and sodium azide in DMF solvent. LCMS: m/e 468 (M+H). 1H NMR (CDCI3, 300 MHz): δ 7.99 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 7.66 (s, 1 H), 7.41-7.37(m, 5H), 4.24 (d, J=7.17 Hz, 2H), 4.65-2.65(m, 7H)1 2.28 (m, 1H), 1.03 (m, 9H). 0
Example 122: KRM-M-d-BenzvH H-M .2.31tnazol-4-yl)-benzenesulfonyll- 3-methyl-piperazine-1-vl}-phenvl-methanone
Figure imgf000101_0001
Prepared according to General Procedure A using benzyl azide. LCMS: m/e 502 (M+H). 1H NMR (CDCI3, 300 MHz): δ 7.99 (d, J=9 Hz, 2H), 7.82 (d, J=9 Hz, 2H), 7.77 (s, 1H)1 7.41-7.31(m, 10H)1 5.60 (s, 2H), 4.59- 3.14(m, 7H), 1.01 (m, 3H).
Example 123: 1-(4-f4-r4(fR)-4-Benzoyl-2-methyl-pϊperazine-1-sulfonyl)- phenyli-n .2.31triazol-1 -ylV-phenyl-ethanone
Figure imgf000101_0002
Prepared according to General Procedure A using 4-acetylphenylazide. LCMS: m/e 530 (M+H). 1H NMR (CDCI3, 300 MHz): δ 8.45 (s, 1H), 8.18 (d, J=8.5 Hz, 2H), 7.08 (d, J=8.5 Hz, 2H), 7.96-7.89(m, 4H), 7.41-7.35(m, 5H), 4.26-2.89(m, 7H), 2.68 (s, 3H), 1.03 (m, 3H).
ioo Example 124: l(Rl-3-Methyl-4-r4-(3-phenyl-isoxazol-5-yl)- benzenesulfonyll-piperazin-yli-phenyl-methanone
Figure imgf000102_0001
To solution of [(R)-4-(4-ethynyl-benzenesulfonyl)-3-methyl-piperazin-1- yl]-phenyl-methanone (40 mg, 0.1 mmol ) in anhydrous dichloromethane (2 mL) was added phenylcarbomoyl chloride (18.5 mg, 0.11 mmol) and triethylamine (48 mg, 0.48 mmol). Reaction was allowed stir at room temperature for 24 minutes. Solvent was evaporated and the product was purified by HPLC. LCMS: m/e 488 (M+H). 1H NMR (CDCI3, 300 MHz): δ 7.91- 7.86(m, 6H), 7.51-7.49(m, 3H), 7.41-7.32(m, 5H), 6.98 (s, 1H), 4.30-2.94(m, 7H)1 1.00 (br s, 3H).
General procedure D for the 1,3-dipolar reactions of azides with [(R)-4- (5-ethynyl-thiophene-2-sulfonyll)-3-methyl-piperaziπ-1-yl]-phenyl- methanone
Figure imgf000102_0002
To a mixture of [(R)-4-(5-ethynyl-thiophene-2-sulfonyll)-3-methyl- piperazin-1-yl]-phenyl-methanone (40 mg, 0.1 mmol) and azide (0:1 mmol) in 1 :1 1BuOH--H2O (2 mL) containing 100 uL of DMF was added freshly prepared aqueous solutions (1 mM) of sodium ascorate (11 uL) and copper sulfate (1 uL) and the suspension was stirred at ambient temperatures (25 0C to 80 0C) until all the starting material is consumed (8 to 24 hours). If necessary, additional reagents were added. Solvents were evaporated under high vacuum and the products were purified by preparative TLC or HPLC.
ffR)-4-f5-bromo-thiophene-2-sulfonyl)-3-methyl-piperazin-1-yll-phenyl- methanone
Figure imgf000103_0001
To a solution of ((R)-3-methyl-piperazine-1-yl)-phenyl-methanone hydrochloride (720 mg, 3 mmol) in 15 % triethylamine/tetrahydrofuran (20 mL) was added 5-bromo-thiophenesulfonyl chloride (860 mg, 3.3 mmol) and the mixture was stirred at 45 0C for 3 hours. Solvent was evaporated and the residue was partitioned between ethyl acetate and water. Separate organic layer and the aqueous layer was extracted with ethyl acetate (2x20 mL).Combined extract was dried (MgSO4), filtered and concentrated to afford [(R)-4-(5-bromo-thioρhene-2-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl- methanone as light brown solid (1.27 g, 100%) which was used in next reactions without further purification. LCMS: m/e 430 (M+H).
(R)-(3-methyl-4-f5-((trimethylsilyl)ethynyl)thiophen-2-ylsulfonyl)piperazin-1- . • yl)(pheπyl)methanone
Figure imgf000104_0001
A heterogeneous mixture containing afford [(R)-4-(5-bromo-thiophene- 2-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl-methanone (1 g, 2.3 mmol), trimethyl- silylacetyleπe (270 mg, 2.76 mmol), palladium dichloride bis(triphenyl)phosphine (80 mg, 5 mol%), copper iodide (21.5 mg, 5 mol%) and diisopropyl ethylamine (696 mg, 6.9 mmol) in anhydrous tetrahydrofuran (20 mL) was heated at 450C until all the starting material has been consumed (24 to 36 hours). The reaction mixture was cooled and then diluted with ethyl acetate (20 mL), filtered though a Celite bed. The filtrate was concentrated and the crude product was purified by a silica gel column chromatography using 5% ethyl acetate in dichloromethane to afford [(R)-3-methyl-4-(4- trimethyl-silanylethynyl-benzenesulfonyl)- piperazin-1-yl]-phenyl-methanone as half white solid (678 mg, 45 %). LCMS: m/e 447 (M+H); 1H NMR (CDCI3, 300 MHz): δ 7.43-7.36(m, 6H), 7.14 (d, J=3 Hz1 1H), 4.16-3.15(m, 7H), 1.09 (S, 3H), 0.25 (s, 9H).
(R)-f4-(5-ethvnylthiophen-2-ylsulfonyl)-3-methylpiperazin-1- vDfohenvDmethanone
Figure imgf000105_0001
Above silyl derivative was dissolved in methanol (10 ml_) and was added K2CO3 (800 mg, 5.7 rήmol). The mixture was stirred at room temperature for 30 minutes. Solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate and water (20 ml_). Aqueous layer was extracted with ethyl acetate (2x10 ml_). Combined organic extract was dried (MgSO4), filtered and concentrated to dryness to afford [(R)-4-(5- ethynyl-thiophene-2-sulfonyll)-3-methyl-piperazin-1-yl]-phenyl-methanone. LCMS: m/e 375 (M+H). LCMS: m/e 447 (M+H); 1H NMR (CDCI3, 300 MHz): δ 7.43-7.36(m, 6H), 7.13 (d, J=3 Hz, 1H), 3.53(s, 1H), 4.76-3.10(m, 7H), 0.91 (s, 3H).
Example 125: I i R)-3-Methvt-4-r5-f 1 H-M ,2,3ttriazol-4-vM-thiophene-2- sulfonvIl-piperazin-i-vD-phenyl-methanone
Figure imgf000105_0002
Prepared according to General Procedure D using trimethyl silylazide. LCMS: m/e 412 (M+H). 1H NMR (CDCI3, 300 MHz): δ 8.00 (s, 1H), 7.97 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.!5 Hz, 2H), 7.45-7.33(m, 5H), 4.2-3.01 (m, 7H), 1.03 (br s, 3H), 3.01-4.2 (m, 7H), 7.33-7.45 (m, 5H). Example 126: f I RM-M-d -lsobutyl-1 H-M .2.31triazol-4-yl)- benzenesulfonvH-3-methvl-piperazin-1 -yl)-phenyl-methanone
Figure imgf000106_0001
Prepared according to General Procedure D from isobutyl azide, which was prepared in situ using isobutyl bromide and sodium azide in DMF solvent. LCMS: m/e 468 (M+H). 1H NMR (CDCI3, 300 MHz): δ 7.99 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 7.66 (s, 1H)1 7.41-7.37(m, 5H), 4.24 (d, J=7.17 Hz, 2H)1 4.65-2.65(m, 7H), 2.28 (m, 1H), 1.03 (m, 9H).
Example 127: f (R)-4-r5-(1 -Benzyl-1 H-M .2.31triazol-4-viy-thiophene-2- sulfonvπ-3-methyl-piperazin-1-yl>-phenyl-methanone
Figure imgf000106_0002
Prepared according to General Procedure D using benzyl azide. LCMS: m/e 508 (M+H); 1H NMR (CDCI3, 300 MHz): δ 7.65 (d, 1H)1 7.50 (d, J=3.7 Hz, 1H), 7.42-7.24 (m, 11H)1 5.58 (s, 2H), 4.49-3.06(m, 7H), 1.09 (m, 3H). Example 128: 1 -(4-f4-r5-( (RΪ-4-Benzoyl-2-methyl-piperazine-1 -sulfon vθ- thiophen-2-vn-ri.2.31triazol-1-yl|-phenyl-ethanoπe
Figure imgf000107_0001
Prepared according to General Procedure D using 4- acetylphenylazide. LCMS: m/e 536 (M+H); 1H NMR (DMSOd6, 300 MHz): δ 8.10 <dd, J!=8.1 Hz, J2=3.4 Hz, 4H), 7.77 (d, J=3.7 Hz1 1H), 7.61 (d, J=3.7 Hz, 1H), 7.44-7.42(m, 6H), 4.21-2.89(m7 7H)1 2.66 (s, 3H), 1.03 (br s, 3H).
Example 129: U R)-3-Methyl-4-{ 5-M -(4-meth yl-1 H-imidazol-2-vn-1 H- ri,2,31triazol-4-yll-thioprιene-2-sulfonyl>-piperazin-1-yl)-phenyl- methanone
Figure imgf000107_0002
Prepared according to General Procedure D using 2-azido-4-methyl- 1H-imidazole. LCMS: m/e 499 (M+H); 1H NMR (CDCI3, 300 MHz): δ 8.55 (s, 1H), 7.57 (d, J=3.8 Hz, 1H), 7.43-7.31 (m, 7H), 4.16-3.16(m, 7H), 2.62 (s, 3H), 1.15 (m, 3H). Example 130: 4-C4-r5-((R>-4-Benzoyl-2-nnethyl-piperazine-1-sulfonvπ- thiophen-2-vn-M,2.3Ttriazo[-1-yl>-2-methvtsulfanyl-thiazo[e-5-carboxylic acid ethyl ester
Figure imgf000108_0001
Prepared according to General Procedure D using 4-azido-2- methylsulfanyl-thiozole-5-carboxylic acid ethyl ester. LCMS: m/e 619 (M+H); 1H NMR (CDCI3, 300 MHz): δ 8.39 (s, 1H), 7.56 (d, J=4 Hz, 1H), 7.43-7.32(m, 6H), 4.29 (q, J=7.17 Hz, 2H), 4.16-3.11(m, 7H), 2.76 (s, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.13 (s, 3H).
Example 131: f(R)-3-Methyl-4-r5-(3-phenyl-sioxazol-5-vD-thiophene-2- sulfonyll-piperazin-i-vIV-phenyl-methanone
Figure imgf000108_0002
To a solution of [(R)-4-(5-ethynyl-thiphene-2-sulfonyl)-3-methyl- piperazin-1-yl]-phenyl-methanone (50 mg, 0.133 mmol ) in anhydrous dichloromethane (2 mL) was added phenylcarbomoyl chloride (22.7 mg, 0.14 mmol) and triethylamine (48 mg, 0.48 mmol). Reaction was allowed stir at room temperature for 24 minutes. Solvent was evaporated and the product was purified by HPLC. LCMS: m/e 494 (M+H). 1H NMR (CDCI3, 300 MHz): δ 7.83 (m, 2H), 7.58-7,35(In, 10H), 6.82 (s, 1H), 4.70-3.22(m, 7H)1 1.13 (br s, 3H).
Example 132: (fR>-4-f5-r3-(4-Chloro-benzoyl)-isoxazo[-5-v»-thiophene-2- sulfonviy-3-methvl-piperazin-1-yl)-phenvl-methaπone
Figure imgf000109_0001
Prepared as described in the procedure of Example 131 above, and purified by HPLC. LCMS: m/e 556 (M+). 1H NMR (CDCI3, 300 MHz): δ 8.30 (d, J=8.5 Hz, 2H), 7.60-7.39(m, 9H), 7.04 (s, 1H)1 4.68-3.07(m, 7H), 1.13 (br s, 3H).
Example 133: r(R)-3-methyl -4-(4-p yrazole-1 -yl -benzen es u lfon vD- piperazin-1-vπ-phenyl-methanone
Figure imgf000109_0002
To a solution of phenyt-piperazine-1-yl-methanone hydrochloride (40 mg, 0.166 mmoi) in 30 % triethylamine/tetrahydrofuran (3 mL) was added 4- pyrazol-1-yl-benzenesulfonyl chloride (48 mg, 0.2 mmol) and mixture was stirred at 45 0C for 8 hours. Resulting white suspension was concentrated and the crude reaction mixture was purified by HPLC purification to afford [(R)-3- methyl-4-(4-pyrazole-1-yl-benzenesulfonyl)-piperazin-1-y|]-ρhenyl-methanone. LCMS: m/e 411 (M+H). 1H NMR (CDCI3, 300.MHz): 57.91-7.85 (m, 4H), 7.75 (d, J=1.5 Hz, 1H), 7.43-7.32(m, 5H), 7.13(d, J=2Hz, 1H), 6.54 (t, 1.9 Hz, 1H), 3.6-3.16(m, 7H), 1.03 (br s, 3H).
Example 134: r(Rl-3-methvM-(441.2.31thiadiazol^-yl-penzenesulfonyl)- piperazin-1-vπ-phenvl-methanone
Figure imgf000110_0001
To a solution of phenyl-piperazine-1-yl-methanone hydrochloride (40 mg, 0.166 mmol) in 30 % triethylamine/tetrahydrofuran (3 mL) was added 4- [1,2,3]thiadiazol-4-yl-benzenesulfonyl chloride(52 mg, 0.2 mmol) and mixture was stirred at 450C for 8 hours. Resulting white suspension was concentrated and the crude reaction mixture was purified by HPLC purification to afford [(R)-3-methyl-4-(4-[1,2,3]thiadiazol-4-yl-benzenesuIfonyl)-piperazin-1-yl]- phenyl-methanone. LCMS: m/e 429 (M+H). 1H NMR (CDCI3, 300 MHz): d
8.80 (s, 1H), 8.22 (d, J=8.1 Hz, 2H), 7.95 (d, J=8.1 Hz1 2H), 7.43-7.32(m, 5H), 4.6-2.69(m, 7H), 1.05 (br s, 3H).
General Procedure E for Coupling Reactions Between Aryl Halides and 5-(4-benzoyl-2-methylpiperazin-1-ylsulfonyl)thiophen-2-ylboronic acid
Ar-(Halogen)
Figure imgf000110_0003
Figure imgf000110_0002
A solution of 100 mg of 5-(4-benzoyl-2-methylpiρerazin-1- ylsulfόnyl)thiophen-2-ylboronic acid, 63 mg of sodium bicarbonate, 7 mg of palladium acetate, 0.32 mmol of aryl halide and 25 mg of 2'- (dicyclohexylphosphino)-N,N-dirnethylbiphenyl-2-amine in 2 mL of 4 :1 ethylene glycol dimethyl ether/distilled water was heated to 400C under nitrogen. After stirring for 18 hours the mixture was diluted with 5 mL of ethyl acetate and 1 mL of water. The mixture was filtered and then the phases were separated. The solvent was evaporated from the organic phase at reduced pressure. The products geberated by General Procedure E, as listed in Table 1 , were purified by reverse phase HPLC and, if necessary, further purified by silica gel chromatography. Typical yields of purified products were 5 to15 mg.
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
δ^-benzovt-Z-methylpiperazin-i-ylsulfonvOthiophen^-ylboronic acid
Figure imgf000113_0002
(3-Methyl-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)(phenyl)methanone was prepared by the same procedure used in Example 133, and was used in this preparation without characterization. A -78 0C solution of 6.3 ml_ of diisopropylamine in 50 mL of THF was treated with 16 mL of 2.5 M butyllithium in hexanes over 5 minutes. The mixture was allowed to warm'to room temperature, and 24 mL of the resulting solution was immediately added dropwise to a -78 0C solution of 4.0 grams of (3-methyl-4-(thiophen-2- ylsulfonyl)piperazin-1-yl)(phenyl)methanone and 8.0 mL of triisopropyl borate in 100 mL of THF. After stirring for 2 hours at -78 0C, an addition 5 mL of the lithium diisopropylamine solution was added dropwise. The mixture was stirred 2 more hours. A solution prepared by mixture 25 ml_ of 3 N hydrochloric acid and 150 mL of methanol was then added to the cold solution. The mixture was warmed to 25 0C and then it was partitioned between ethyl acetate and dilute aqueous sodium chloride solution. The aqueous phase was washed with ethyl acetate three times and the solvent was evaporated from the combined organic extracts at reduced pressure. The procedure yielded 4.3 g of a white foam. MS: calc'd for C16H19BN2O5S2 H+: m/z = 395.1. Found: 395.4.
General Procedure F for Coupling Reactions Between Acyl Chlorides and (3-methyl-4-(4-(trirnethylstannvQphenylsulfonyl)piperazin-1- yl)(phenyl)methanone
Figure imgf000114_0001
A mixture of 75 mg of (3-methyl-4-(4-
(trimethylstannyl)phenylsulfonyl)piperazin-1-yl)(phenyl)methanone, 3.8 mg of (Ph3P)2PhCH2Pd Cl, and 0.17 mmol of acid chloride in 1 mL of chloroform was heated to 85 0C in a sealed vial for 12 hours. The mixture was filtered. The solvent was evaporated and the residue was dissolved in 3 mL of THF. The resulting solution was treated with 0.2 mL of 3 N aqueous NaOH solution and stirred for 1 hour. The solvent was evaporated at reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, and filtered. The solvent was evaporated at reduced pressure and the residue was purified by reverse- phase chromatography. Products generated by General Procedure F are listed in Table 2.
Figure imgf000115_0001
(R)-(4-(4-iodophenylsulfonyl)-3-methylpiperazin-1-yl)(phenvπmethanone
Figure imgf000115_0002
A 0 0C solution of 9.5 grams of (R)-1 -benzoyl-2-methylpiperazine hydrochloride and 22 ml_ of Hunig's base in 300 mL of dichloromethane was treated with 12 grams of 4-iodobenzenesulfonyl chloride. The mixture was allowed to warm to 25 °.C and stirred overnight. The mixture was washed with excess aqueous sodium carbonate and dried over magnesium sulfate. The solvent was evaporated and the residue was dissolved in a minimum volume of ethyl acetate. Several volumes of ethyl ether was added and the resulting precipitate was collected by filtration. 1H NMR (CDCI3, 300 MHz): δ 7.9 (d, J = 7 Hz, 2H), 7.5 (d, J = 7 Hz, 2H)1 7.5 - 7.3 (m, 5H), , 4.8 - 2.7 (broad m, 7H), 1.2 - 0.8 (broad multiplet, 3H).
(3-methyl-4-(4-(trimethylstanny0phenylsulfonyl)piperazin-1- ylHphenvPmethanone
Figure imgf000116_0001
A mixture of 1.4 g (3. 0 mmo)l of (R)-(4-(4-iodophenylsulfonyl)-3- methylpiperazin-1-yl)(phenyl)methanone, 2.6 grams (4.5 mmol) of hexamethylditin, and 0.22 grams of PhPdCI(Ph3P^ in 15 ml_ of dioxane was heated at 600C for 4 days. The solvent was evaporated and the residue was chromatographed on silica gel eluting with a mixture of dichlormethane and hexanes. The product was obtained as a colorless oil. 1H NMR (CDCI3, 300 MHz): δ 7.7 (d, J = 7 Hz, 2H), 7.6 (d, J = 7 Hz, 2H)1 7.5 - 7.3 (m, 5H), 4.8 - 2.7 (broad m, 7H), 1.2 - 0.8 (broad multiplet, 3H), 0.35 (s, 9H). Side peaks of about 10% intensity are visible on either side of the 0.35 ppm singlet due to ■ proton-tin coupling with minor isotopes of tin. Example 164: r4-(5-lsoxazol-3-vNthiophene-2-sulfonyl)-3-methyl- piperazin-1-vπ-phenyl-methanone
Figure imgf000117_0001
(3-methyl-piperazin-1-yl)-phenyl-methanone (20 mg, O.immol) and 5- isoxazol-3-yl-thiophene-2-sulfonyl chloride (25 mg, O.immol) were each dissolved in 1 ml_ of a solvent consisting of 30 % triethylamine in anhydrous THF. The two solutions were combined and the resulting mixture stirred overnight at room temperature. The volatiles were removed under vacuum and the remaining crude product was purified by reverse-phase HPLC. Yield: 5.1 mg (12%). The purified material was characterized by LC-MS (95 % purity by ELSD). MS: Calculated for C19H19N3O4S2 H+: 418.08. Found: 417.9.
Example 165: r(R)-3-Methyl-4-(5-ri.2.31thiadiazol-4-yl-thiophene-2- sulfonyl)-piperazin-1-vπ-phenyl-methanone
Figure imgf000117_0002
((R)-3-Methyl-piperazin-1-yl)-phenyl-methanone (75 mg, 0.375 mmol) was dissolved in 5 mL of 30% triethylamine in THF. 5-[1,2,3]thiadiazol-4-yl- thiophene-2-sulfonyl chloride
(100 mg, 0.375 mmol) was then added directly with stirring. The mixture was stirred for 2 to 3 hours at room temperature. Precipitated salts were removed via vacuum filtration and the filtrate concentrated under vacuum. The remaining residue was partitioned between EtOAc and aqueous ammonium chloride. The organic phase was washed once additionally with ammonium chloride, once with brine, dried over MgSO4, and then concentrated to afford 155 mg of a brown residue that was further purified by HPLC. Isolated yield: 27 mg (17 %) The purified material was characterized by LC- MS (98.6 % purity by ELSD). MS: Calculated for Ci8H18N4O3S3 H+: 435.05. Found: 435.4. 1HNMR (CDCI3): 8.67 (s, 1H), 7.61 (d, J = 3.8 Hz, 1H), 7.58 (d, J ~ 3.9 Hz, 1 H) 7.43 - 7.31 (m, 5 H), 4.8 - 2.9 (br. m, 7H), 1.21 (br. s, 3H).
Example 166: f3-Methyl-4-(4-oxazol-5-yl-benzenesulfonyl)-piperazin-1-vπ- phenyl methanone
TEATTHF
Figure imgf000118_0001
Figure imgf000118_0002
(3-methyl-piperazin-1-yl)-phenyl-methanone (20 mg, O.immol) and 4-oxazol- 5-yl-benzenesulfonyl chloride (24 mg, O.immol) were each dissolved in 1 mL of a solvent consisting of 30 % triethylamine in anhydrous THF. The two solutions were combined and the resulting mixture stirred overnight at room temperature. The volatiles were removed under vacuum and the remaining crude product was purified by reverse-phase HPLC. Yield: 9 mg (22%). The purified material was characterized by LC-MS (100 % purity by ELSD). MS: Calculated for C2IH2IN3O4S H+: 412.1. Found: 412.5. Example 167: r(R)-3-Methyl-4-(5-K5-irifluoromethvn-isoxazol-3-vπ- thiophene-2-sulfonyl>-piperazin-1-vn-Phenyl-methanone
Figure imgf000119_0001
R-(3-methyl-piperazin-1-yl)-phenyl-methanone (51 mg, 0.25mmol) was dissolved in 2ml pyridine and 5-[(5-trifluoromethyl)-3-oxazol]-2-yl- thiophenesulfonyl chloride (79.47 mg, Q.25mmol) was dissolved in 4 ml of THF. The two solutions were combined and the resulting mixture was added 2.5mmol of triethylamine and then stirred overnight at room temperature. The volatiles were removed under vacuum and the remaining crude product was purified by reverse-phase HPLC. Yield: 18 mg (15%). The purified material was characterized by LC-MS MS: Calculated for C2IH18N3F3O4S2: 485.07. Found: 485.00. purity via HPLC 99.2%.
Example 168: r(R)-3-Methyl-4-(5-pyridinyl-2-yi-thiophene-2-sulfon vD- piperazin-1-vπ-phenyl-methanone
Figure imgf000119_0002
R-(3-methyl-piperazin-1-yl)-phenyl-methanone (51 mg, 0.25mmol) was dissolved in 2ml pyridine and 5-(pyridinyl-2-yl)-2-yl-thiophenesulfonyl chloride (65 mg, 0.25mmol) was dissolved in 4 ml of THF. The two solutions were combined and the resulting mixture was added 2.5mmol of triethylamine and then stirred overnight at room temperature. The volatiles were removed under vacuum and the remaining crude product was purified by reverse-phase HPLC. Yield: 21 mg (20%). The purified material was characterized by LC-MS MS: Calculated for C2i H2IN3O3S2: 427.10. Found: 427.06. purity via HPLC 98.8%.
Example 168: 1-(4-Benzoyl-2-methyl-piperazin-1-V-)-2-r4-(2H-pyrazσl-3- yl)-phen yli-ethaπe-1.2-dioπe
Figure imgf000120_0001
To a solution of 4-(2/-/-pyrazol-3-yl)-benzoic acid methyl ether (0.2 g, 1 mmol) and (4-benzoyl-2-methyl-piperazin-1-yl)-acetonitrile (0.24 g, 1 mmol) in anhydrous THF (2 mL) was added by drops 1.06 M solution LiHMDS in THF (4 mL, 4 mmol). The reaction mixture was stirred for 1 hour, and m-CPBA was added (0.67 g, 4 mmol). The mixture was stirred for 1 hour additionally, quenched with water, extracted with EtOAc, dried over sodium sulfate, filtered and evaporated. The residue was purified by SiO2 chromatography using 10% MeOH/ethyl acetate as eluent to obtain 1-(4-benzoyl-2-methyl-piperazin-1-yl)- 2-[4-(2H-pyrazol-3-yl)-phenyl]-ethane-1,2-dione (0.09 g, 22%). LCMS: CaICd for C23H22N4O3 • H+: m/z = 403.5. Found: m/z = 403, 404. 1H NMR (DMSO- d6): 13.59 and 13.16 (two br s, 1H, NH-pyrazole); 8.06 (m, 2H); 7.95-7.86 (m, 3H); 7.45-7.40 (m, 5H); 6.89 (br s, 1 H); 4.68-4.30 (br signal, 2 H); 3.29-3.43 (br signal, 2H); 3.16 (m, 1H); 3.08-2.85 (br signal, 2H); 1.20 (br signal,.3H).
4-(2H-Pyrazol-3-yl)-benzoic acid methyl ester
Figure imgf000121_0001
Mixture of 4-(2H-pyrazol-3-yl)-benzoic acid (0.30 g, 1.6 mmol), K2CO3 (0.66 g, 7.78 mmol) and methyl iodide (0.34 g, 2.4 mmole) in DMF (8 ml_) was kept under stirring at RT temperature for 1 h (TLC monitoring, 10% MeOH/CHCU). The reaction mixture was diluted with water (30 ml_), extracted with EtOAc (2x30 mL), organic layers combined, washed with water, brine, dried over sodium sulfate, filtered and evaporated to afford 4-(2H-pyrazol-3- yl)-benzoic acid methyl ether (0.31 g, 96 %). 1H NMR (DMSO-d6): 13.10 (br s, 1 H); 7.98 (m, 4H); 7.80 (br signal, 1H); 6.83 (d, J = 2.2 Hz1 1H); 3.86 (s, 3H).
4-(1-Methyl-1f/-pyrazol-3-yl)-benzoic acid methyl ester
Figure imgf000121_0002
Mixture of 4-(2H-pyrazol-3-yl)-benzoic acid (0.30 g, 1.6 mmol), K2CO3 (0.66 g, 7.78 mmol) and methyl iodide (0.68 g, 4.8 mmole) in DMF (8 mL) was kept under stirring at RT temperature for 24 h (LC/MS monitoring). The reaction mixture was diluted with water (30 mL), extracted with EtOAc (2x30 mL), organic layers combined, washed with water, brine, dried over sodium sulfate, filtered and evaporated to afford 4-(1-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ether (0.28 g, 80 %). LCMS: CaICd for Ci2Hi2N2O2 • H+: m/z 217.24. Found: m/z = 217, 218.
Example 170: 1 -(4-Benzoyl-2-metriyl-piperazin-1 -yl)-2-(4-ri .2,41triazol-1 - yl-phenyl)-ethane-1 ,2-dione
Figure imgf000122_0001
Mixture of 1-(4-benzoyl-2-methyl-piperazin-1 -yl)-2-(4-iodo-phenyl)- ethane-1 ,2-dione (0.33 g, 0.71 mmol), Cu-powder (0.09 g,.1.42 mmole), 1 ,2,4- triazole (1.47 ml_, 21.3 mmole), and powdered KOH (0.08 g, 1.42 mmole) was heated to 1600C and kept under stirring at this temperature for 24 h (TLC monitoring, 10% MeOH/CHCI3). The reaction mixture was then cooled to RT, diluted with EtOAc (~2 mL), placed onto a silica gel column and eluted with EtOAc, and evaporated to afford 1-(4-benzoyl-2-methyl-piperazin-1-yl)-2-(4-
[1 ,2,4]triazol-1-yl-phenyl)-ethane-1,2-dione (0.17 g, 59 %). LCMS: Calc'd for
C22H2IN5O3 • H+: m/z = 404.5. Found: m/z = 404, 405. 1H NMR (DMSO-d6):
9.50 (d, J = 3.1 Hz, 1 H); 8.34 (s, 1H); 8.14-7.98 (m, 4H); 7.45-7.42 (m, 5H);
4.90-4.10 (br signal, 2H); 3.95-3.35 (br signal, 3H); 3.23-2.80 (br signal, 2H); 1.20 (br signal, 3H).
1-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-iodo-phenyl)-ethane-1,2-dione
Figure imgf000123_0001
1-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-iodo-phenyl)-ethane-1 ,2-dione (35%) was prepared according to the procedure above, using 4-iodo-benzoic acid methyl ester. 1H NMR (DMSO-d6): 8.03 (m, 2H); 7.46 (m, 2H); 7.46-7.42 (m, 5H); 4.84-4.03 (br signal, 2H); 3.99-3.34 (br signal, 3H); 3.23-2.79 (broad signal, 2H); 1.21 (br signal, 3H).
Example 171 : 1-(4-Benzovt-2-methyl-piperazin-1-vO-2-(4-furan-2-yl- phenvπ-etharte-1 ,2-dione
Figure imgf000123_0002
1-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-furan-2-yl-pheπyl)-ethane- 1,2-dione (0.02 g, 20%) was prepared according to the procedure above, using 4-furan-2-yl-benzoic acid methyl ester. The product was purified by reverse phase preparative HPLC. LCMS: Calc'd for C24H22N2O4 ; H+: m/z = . 403.5. Found: m/z = 403, 404. 1H NMR (DMSOd6): 7.95-7.89 (m, 5H); 7.45- 7.40 (m, 5H); 7.25 (m, 1H); 6.69 (m, 1H); 4.82-4.18 (br signal, 2H); 4.15-3.40 (br signal, 3H); 3.19-2.86 (broad signal, 2H); 1.22 (br signal, 3H).
Example 172: 1-(4-Benzoyl-2-methyl-piperazin-1-vD-2-r4-(1-methyl-1f/- pyrazol-3-yl)-phenvπ-ethane-1.2-dione
Figure imgf000124_0001
1-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-[4-(1-methyl-1W-pyrazol-3-yl)- phenyl]-ethane-1,2-dione (37%) was prepared according to the procedure above, using 4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid methyl ester.. LCMS: Calc'd for C24H24N4O3 ' H+: m/z = 417.5. Found: m/z = 417, 418. 1H NMR (DMSOd6): 8.02 (m, 2H); 7.94-7.88 (m, 2H); 7.81 (m, 1H); 7.45-7.40 (m, 5H); 6.87 (m, 1H); 4.84-4.18 (br signal, 2H); 3.92 (s, 3H); 3.90-2.85 (br signal, 5H); 1.20 (br signal, 3H).
Example 173: 1 -(4-Benzoyl-2-methyl-piperazin-1 -yl)-2-r4-f 5-methyl-furan- 2-yl>-phenvπ-ethane-1.2-dione
Figure imgf000125_0001
1-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-[4-(5-methyl-furan-2-yl)- phenyl]-ethane-1, 2-dione (19%) was prepared according to the procedure above, using 4-(5-methyl-furaπ-2-yl)-benzoic acid methyl ester. The product was purified by reverse phase preparative HPLC. LCMS: Calc'd for C25H24N2O4 ■ H+: m/z = 417.5. Found: m/z - 417, 418. 1H NMR (DMSO-d6): 7.93-7.83 (m, 4H); 7.45-7.40 (m, 5H); 7.13 (m, 1 H); 6.31 (m, 1H); 4.80-4.18 (br signal, 2 H); 4.15-3.39 (br signal, 3H); 3.19-2.97 (broad signal, 2H); 2.88 (s, 3H); 1.22 (br signal, 3H).
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-phenyl)-ethane-1,2- dione
Figure imgf000125_0002
• 1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(4-bromo-phenyl)-ethane- 1,2-dione (31%) was prepared according to the procedure above, using A- bromo-benzoic acid methyl ester and ((R)-4-benzoyl-2-methyl-piperazin-1 -yl)- acetonitrile. 1H NMR (QMSO-d6): 7.85 (m, 4H); 7.46-7.42 (m, 5H); 4.88-4.09 (br signal, 2H); 3.97-3.35 (br signal, 3H); 3.20-2.77 (broad signal, 2H); 1.18 (br signal, 3H).
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-fluoro-phenyl)- ethane-1,2-dione
Figure imgf000126_0001
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-flϋoro-phenyl)- ethane-1 ,2-dione (25%) was prepared according to the procedure above, using 4-bromo-2-fluoro-benzoic acid methyl ester and ((R)-4-benzoyl-2- methyl-piperazin-1-yl)-acetonitrile. 1H NMR (DMSO-d6): 7.86-7.81 (m, 2H); 7.68 (m, 1H); 7.46-7.42 (m, 5H); 4.74-3.41 (br signal, 5H); 3.19-2.80 (broad signal, 2H); 1.18 (br signal, 3H).
Example 174: 1-(4-Benzovi-2-methyl-piperazin-1 -vn-2-(4-li .2.31triazol-2- yl-phenvD-ethane-1.2-dione
Figure imgf000127_0001
1-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-[1 ,2,3]triazol-2-yl-phenyI)- ethane-1, 2-dione (0.17 g, 59 %) was prepared according to the procedure above, using 1 ,2,3-triazole instead of 1,2,4-triazole and 2% MeOH/CH2CI2 as eluent. LCMS: Calc'd for C22H2IN5O3 H+: m/z = 404.5. Found: m/z = 404, 405. 1H NMR (DMSO-de): 8.25 (m + s, 2H+2H); 8.10 (m, 2H); 7.45 (m, 5H); 4.80-4.10 (br signal, 2H); 3.90-3.30 (br signal, 3H); 3.23-2.82 (br signal, 2H); 1.19 (br signal, 3H).
Example 181 : 1-(fR)-4-Benzoyl-2-methvI-piperazin-1-yl)-2-r2-methyl-4- (1 //-pvrazol-3-vπ-pheπvπ-ethane-1.2-dione
Figure imgf000127_0002
Toluene (10 mL), EtOH (10 mL) and 2M Na2CO3 (1.15 ml_) were added to a mixture of 1-((R)-4-benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-methyl- phenyl)-ethane-1 ,2-dione (0.3 g, 0.7 mmol), pyrazoleboronic acid (of -88% purity from stock, 0.117 g, 1.05 mmol) and NBu4Br (0.02 g). Argon was bubbled within reaction mixture for ~20 min. Then Pd(PPh3J4 was added (0.042 g, 0.036 mmol). The reaction mixture was stirring under reflux (20 min; TLC-monitoring, CHCI3ZMeOH 9:1), then cooled to RT and diluted with water (2O mL). The product was extracted, with ethylacetate (2x50 ml_). Organic solution was dried with Na2SO.*, evaporated, and the residue was purified by chromatography (silica gel, 10% MeOH/CHCI3). Solvent was evaporated to give product 1 -((R)-4-benzoyl-2~methyl-piperazin-1 -yl)-2-[2-methyl-4-(1 H- pyrazol-3-yl)-phenyl]-ethane-1 ,2-dione (0.20 g, 68%). LCMS: Calc'd for C24H24N4O3 • H+: m/z = 417.5. Found: m/z = 417, 418. 1H NMR (DMSO-d6): 13.58, 13.12 (two broad signals, 1H, NH-pyrazole); 7.87 (m, 3H); 7.78-7.69 (m, 1H); 7.45 (m, 5H); 6.88 (m, 1H); 4.88-4.10 (br signal, 2H); 4.06-3.34 (br signal, 3H); 3.19-2.82 (br signal, 2H); 2.64 (m, 3H); 1.22 (br signal, 3H).
Example 184: 1-((R)-4-Benzoyl-2-methyl-piperazin-1-vπ-2-r3-methyl-4- (1 /-/-pyrazol-3-yl)-phen vπ-ethane-1 ,2-dione
Figure imgf000128_0001
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-[3-methyl-4-(1H- pyrazol-3-yl)-phenyl]-ethane-1 ,2-dione (55 %) was prepared according to the procedure above (2h 30 min^TLC-monitoring, CHCI3ZMeOH 9:1), using 1-((R)- 4-benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-3-methyl-phenyl)-ethane-1 ,2- dione. LCMS: Calc'd for C24H24N4O3 H+: m/z = 417.5. Found: m/z = 417, 418. 1H NMR (DMSO-d6): 1.3.26, 13.16 (two broad signals, 1 H, NH-pyrazole); 7.87-7.72 (rri, 4H); 7.45 (m, 5H); 6.70, 6.61 (two m, 1H); 4.88-4.07 (br signal, 2H); 4.03-3.34 (br signal, 3H); 3.21-2.82 (br signal, 2H); 2.59 (s, 3H); 1.21 (br signal, 3H).
1-((R)-4-Benzoyl-2-methyl-pϊperazin-1-yl)-2-(4-bromo-3-methyl-phenyl)- ethane-1 ,2-dione
Figure imgf000129_0001
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-3-methyl-phenyl)~ ethane-1 ,2-dione (49%) was prepared according to the procedure above, using 4-brόmo-3-methyl-benzoic acid methyl ester and ((R)-4-benzoyl-2- rnethyl-piperazin-1-yl)-acetonitrile. 1H NMR (DMSO-d6): 7.86-7.82 <m, 2H); 7.66-7.58 (m, 1H); 7.45 (m, 5H); 4.86-4.01 (br signal, 2H); 3.98-3.36 (br signal, 3H); 3.21-2.78 (broad signal, 2H); 2.45 (m, 3H); 1.20 (br signal, 3H).
Example 18S: 1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-r6-(1H-pyrazol- 3-yl)-pyridin-3-vn-ethane-1,2-dione
Figure imgf000129_0002
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-[6-(1 H-pyrazol-3-yl)- pyridin-3-yl]-ethane-1 ,2-dione (20 %) was prepared according to the procedure above (3 h; LC/MS-monitoring), using ϊ-((R)-4-benzoyl-2-methyl- piperazin-1-yl)-2-(6-chloro-pyridin-3-yl)-ethane-1 ,2-dione and CHCI3ZMeOH 20:1 (1st column), then EtOAc (2nd column) as eluents. LCMS: Calc'd for C22H21N5O3 H+: m/z = 404.5. Found: m/z = 404, 405. 1H NMR (DMSO-d6): 13.83, 13.34 (two broad signals, 1H, NH-pyrazole); 9.03 (m, 1 H); 8.30 (m, 1 H); 8.20 (m, 1H); 7.90 (s, 1 H); 7.45 (m, 5H); 7.07, 7.97 (two m, 1 H); 4.86- 4.09 (br signal, 2H); 4.03-3.37 (br signal, 3H); 3.22-2.86 (br signal, 2H); 1.22 (br signal, 3H).
Example 193: 1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -vQ-2-(4-pyrazol-1 -y|- phenvπ-ethane-1.2-dione
Figure imgf000130_0001
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(4-pyrazol-1 -yl-phenyl)- ethane-1,2-dione (43%) was prepared according to the procedure above, using 4-pyrazol-1-yl-benzoic acid methyl ester and ((R)-4-benzoyl-2-methyl- ρiperazin-1-yl)-acetonitrile. LCMS: Calc'd for C23H22N4O3 H+: m/z = 403.5. Found: m/z = 403, 404. 1H NMR (DMSO-d6): 8.69 (m, 1H); 8.11-7.98 (m, 4H); 7.87 (m, 1H); 7.45-7.40 (m, 5H); 6.65 (m, 1H); 4.86-4.10 (br signal, 2H); 3.96- 3.41 (br signal, 3H); 3.18 (m, 1H); 3.08-2.85 (br signal, 1H); 1.20 (br signal, 3H).
Example 195: 1-((RM-Benzoyl-2-methyl-piperazin-1-yl)-2-(2-methyl-4- pyrazol-1 -yl-pheπvD-ethane-1 ,2-dione
Figure imgf000131_0001
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(2-methyl-4-pyrazol-1 -yl- phenyl)-ethane-1 ,2-dione (22 %) was prepared according to the procedure above (reaction time 2 h), using 1-((R)-4-beήzoyl-2-methyl-piperazin-1-yl)-2- (4-bromo-2-methyl-phenyl)-ethane-1 ,2-dione and pyrazole, and CHCI3ZMeOH 50:1 (1st column), then EtOAc/n-hexane 2:1 (2nd column) as eluents. LCMS: Calc'd for C24H24N4O3 ■ H+: m/z = 417.5. Found: m/∑ = 417, 418. 1H NMR (DMSO-ds): 8.66 (m, 1H); 7.95-7.78 (m, 4H); 7.45 (m, 5H); 6.63 (m, 1H); 4.83- 4.03 (br signal, 2H); 3.93-3.33 (br signal, 3H); 3.19-2.90 (br signal, 2H); 2.67 (m, 3H); 1.24 (br signal, 3H).
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromp-2-methyl-phenyl)- ethane-1,2-dione
Figure imgf000132_0001
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-methyl-phenyl)- ethane-1 ,2-dione (57%) was prepared according to the procedure above, using 4-bromo-2-methyl-benzoic acid methyl ester and ((R)-4-benzoyl-2- methyl-piperazin-1-yl)-acetonitrile. 1H NMR (DMSO-d6): 7.71-7.59 (m, 3H); 7.45 (m, 5H); 4.83-4.09 (br signal, 2H); 3.93-3.35 (br signal, 3H); 3.19-2.78 (broad signal, 2H); 2.56 (m, 3H); 1.20 (br signal, 3H).
Example 213: 1-((R)-4-Benzoyl-2-methyl-piperazin-1-vD-2-(3-methyl-4- pyrazol-1-yl-phenyl)-ethane-1 ,2-dione
Figure imgf000132_0002
1 -((R)-4-BenzoyI-2-methyl-piperazin-1 -yl)-2-(3-methyl-4-pyrazol-1 -y I- phenyl)-ethane-1 ,2-dione (31 %) was prepared according to the procedure above (reaction time 2 h), using 1-((R)-4-benzoyl-3-methyl-piperazin:1-yl)-2- (4-bromo-2-methyl-phenyl)-ethane-1 ,2-dione and pyrazole, and CHCI3ZMeOH 20:1 (1st column), then EtOAc/n-hexane 2:1 (2nd column) as eluents. LCMS: Calc'd for C24H24N4O3 H+: m/z = 417.5. Found: m/z = 417, 418. 1H NMR (DMSO-de): 8.21 (m, 1H); 7.94-7.81 (m, 3H); 7.64 (m, 1H); 7.45 (m, 5H); 6.58 (m, 1H); 4.84-4.08 (br signal, 2H); 4.03-3.39 (br signal, 3H); 3.22-2.80 (br signal, 2H); 2.40 (m, 3H); 1.22 (br signal, 3H).
Example 214: 1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(6-pyrazol-1-yl- pyridin-3-yl)-ethane-1 ,2-dione
Figure imgf000133_0001
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(6-pyrazol-1 -yl-pyridin-3- yl)-ethane-1 ,2-dione (19 %) was prepared according to the procedure above (reaction time 30 min), using 1-((R)-4-benzoyl-2-methyl-piperazin-1-yl)-2-(6- chloro-pyridin-3-yl)-ethane-1 ,2-dione and pyrazole, and Et20/MeOH 9:1 as eluent. LCMS: Calc'd for C22H2iN5O3 • H+: m/z = 404.5. Found: m/z = 404, 405. 1H NMR (DMSO-dβ): 8.94 (m, 1H); 8.72 (m, 1H); 8.45 (m, 1H); 8.12 (d, J= 8.8 Hz, 1H); 7.96 (s, 1 H); 7.45 (m, 5H); 6.68 (m, 1 H); 4.84-4.12 (br signal, 2H); 4.09-3.41 (br signal, 3H); 3.20-2.82 (br signal, 2H); 1.19 (br signal, 3H). 1-((R)-4-Ben2oyl-2-methyl-piperazin-1-yl)-2-(6-chloro-pyridin-3-yl)- etha ne-1 ,2-dione
Figure imgf000134_0001
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(6-chloro-pyridin-3-yl)- ethane-1 ,2-dione (28%) was prepared according to the procedure above, using 6-chloro-nicotinic acid methyl ester and ((R)-4-benzoyl-2-methyl- piperazin-1-y!)-acetonitrile. LCMS: Calc'd for C19Hi8CIN3O3 - H+: m/z = 372.8. Found: m/z = 373, 374.
Example 215: 1 -((R)-4-Benzoyl-2-meth yl-piperazin-1 -yl)-2-(4-imidazol-1 - yl-2-methyl-phenyl)-ethane-1 ,2-dione
Figure imgf000134_0002
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(4-imidazol-1 -yl-2-methyI- phenyl)-ethane-1 ,2-dione (14 %) was prepared according to the procedure above (reaction time 1 h 30 min), using 1-((R)-4-benzqyl-3-methyl-piperazin-1- yl)-2-(4-bromo-2-methyl-phenyf)-ethane-1,2-dione and imidazole, and , CHCI3ZMeOH 20:1 as eluent The product was additionally purified by HPLC. LCMS: Calc'd for C24H24N4O3 H+: m/z = 41.7.5. Found: m/z = 417, 418. 1H NMR (DMSO-dβ): 7.96-7.82 (m, 3H); 7.57-7.43 (m, 7H); 7.15 (s, 1H); 4.89- 4.05 (br signal, 2H); 4.01-3.37 (br signal, 3H); 3.22-2.81 (br signal, 2H); 2.30 (m, 3H); 1.21 (br signal, 3H).
Example 211:1-((R)-4-Senzoyl-2-methyl-piperazin-1-yl)-2-f4-Dyrrolidin-1- yl-phen vD-ethane-1 ,2-dione
Figure imgf000135_0001
Mixture of boronic acid (0.20 g, 0.53 mmol), pyrrolidine (0.04 g, 0.56 mmol), Et3N (0.16 mL, 1.11 mmol) and anhydrous Cu(OAc)2 (0.10 g, 0.55 mmol) in CH2CI2 (5 mL) was stirring for 1 h under RT. Then H2O (10 mL) and CH2Cb (20 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by SiO2 chromatography using ethyl acetate as eluent to obtain 1-((R)-4-benzoyl-2-methyl-piperazin-1-yl)-2-(4-pyrrolidin-1-yI-phenyl)-ethane- 1 ,2-dione (0.12 g, 56%). LCMS: Calc'd for C24H27N3O3 • H+: m/z = 406.5. Found: m/z = 406, 407. 1H NMR (DMSO-d6): 7.65 (m, 2H); 7.45 (m, 5H); 6.63 (m, 2H); 4.81-4,03 (br signal, 2H); 3.99-3,49 (br signal, 2H); 3.36 (m, 4H); 3.21-2.77 (br signal, 3H); 1.98 (m, 4H); 1.18 (br signal, 3H). 4-[2-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-oxo-acetyl]-boronic acid
Figure imgf000136_0001
Figure imgf000136_0002
Anhydrous DMF (100 ml_) was added to a mixture of 1 -(4-benzoyl-2- methyl-piperazin-1-yl)-2-(4-iodo-phenyl)-ethane-1 ,2-dione (3.75 g, 8.1 mmol), 4,4,5,5,4l >4'15l,5I-octamethyl-[2,2l]bi[[1,3>2]dioxaborolanyl] (2.68 g, 10 mmol) and anhydrous KOAc (2.38 g, 24 mmof). Argon was bubbled within reaction mixture for -20 min. Then PdCI2dppf (0.18 g, 0.24 mmol) was added. The reaction mixture was stirring under 750C for 1.5 h (LCMS-monitoring,), then cooled to RT, diluted with benzene (300 ml_) and washed with water (3x200 mL). Organic layer was evaporated, the residue was extracted with Et2O and filtered. Mother solution was evaporated to give crude 1-((R)-4-benzoyI-2- methyl-piperazin-1-yl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- phenyl]-ethane-1,2-dione which was used for the next step without additional purification. LCMS: Calc'd for C26H32BN2O5 ■ H+: m/z - 463.4. Found: m/z = 463, 464.
NaIO4 (6.5 g, 30 mmol) and NH4OAc (2.42 g, 31 mmol) were added to acetone -water (1 :1, 200 mL) solution of crude 1-((R)-4-benzoyl-2-methyl- piperazin-1-yl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2Idioxaborolan-2-yl)-phenyl]- ethane-1,2-dione from previous step. The reaction mixture was kept under stirring for 24 h at RT, diluted with water (200 mL), and precipitate was filtered off. Solution was extracted with EtOAc (2x200 mL), organic phase was dried with Na2SOu, and evaporated to afford 4-[2-((R)-4-benzoyl-2-methyI- piperazin-1-yl)-2-oxo-acetyl]-boronic acid (2.3 g, 74% per two steps). LCMS: Calc'd for C20H2I BN2O5 • H+: m/z = 381.2. Found: m/z = 381 , 382.
Example 212: 1-((RM-Benzoyl-2-methyl-piperazin-1-yl)-2-r4-(2-oxo- oxazolidin-3-vπ-phenvn-ethane-1.2-dione
Figure imgf000137_0001
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-[4-(2-oxo-oxazolidin-3-yl)- phenyl]-ethane-1 ,2-dione (36 %) was prepared according to the procedure above, using oxazolidin-2-one. The product was additionally purified by HPLC. LCMS: Calc'd for C23H23N3O5 ■ H+: m/z = 422.5. Found: m/z = 422, 423. 1H NMR (DMSO-d6): 7.96-7.90 (m, 2H); 7.80 (m, 2H); 7.45 (m, 5H); 4.87-4.53 (br signal, 1 H); 4.50 (m, 2H); 4.43-4.19 (br signal, 1H); 4.14 (m, 2H); 3.90-3.34 (br signal, 3H); 3.19-2.77 (br signal, 2H); 1.20 (br signal, 3H).
Example 21β:1-f(R)-4-Benzoyl-2-methyl-piperazin-1-vπ-2-f2- d8methylamino-4-(1 H-pyrazol-3-yl)-phenvn-ethane-1.2-dione
Figure imgf000137_0002
1 -((R)-4-Benzoyf-2-methyl-piperazin-1 -yl)-2-[2-dimethyfamino-4-(1 H- pyrazol-3-yl)-phenyl]-ethane-1 ,2-dione (86 %) was prepared according to the procedure above (30 min; TLC-monitoring, CHCI3ZMeOH 20:1), using 1-((R)- 4-benzoyl-2-methyl-piperazin-1-yl)-2~(4-bromo-2-dimethylamino-phenyl)- ethane-1,2-dione, and CHWMeOH 20:1 (1st column), then CHCI3ZMeOH 9:1 (2nd column) as eluents. LCMS: Calc'd for C25H27N5O3 • H+: m/z - 446.5. Found: m/z = 446, 447. 1H NMR (DMSO-d6): 13.51, 13.07 (two broad signals, 1 H1 NH-pyrazole); 7.83-7.46 (m, 9H); 6.86 (m, 1H); 4.81-4.11 (br signal, 2H); 4.07-3.35 (br signal, 3H); 3.15-2.91 (br signal, 2H); 2.84 (s, 3H); 2.78 (s, 3H); 1.19 (br signal, 3H).
1-((R)-4-Benzoyl-2-methyl-piperaziπ-1-yl)-2-(4-bromo-2-dimethylamino- phenyf )-ethane-1 ,2-dione
Figure imgf000138_0001
To a solution of 1-((R)-4-benzoyl-2-rnethyl-piperazin-1-yl)-2-(4-bromo- 2-fluo.ro-phenyl)-ethane-1 ,2-dione (0.5 g, 1.15 mmol) in DMSO (5mL), 40% aqueos solution of dimethylamine (3 ml_) was added. The reation mxture was heated to 800C and kept under stirring at this temperature for 1 h (TLC monitoring, EtOAc/n-hexane 3:1), cooled to RT, poured into ice water (50 mL), and extracted with EtOAc (~2 mL). Organic phase was washed with water (3x30mL), dried over sodium sulfate, and then concentrated. The crude product was purified by silica-gel chromatography using EtOAc/n-hexane 3:1 as eluent to afford 1-((R)-4-benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2- dimethylamino-phenyl)-ethane-1 ,2-dione (0.35 g, 66 %). LCMS: Calc'd for C22H24BrN3O3 H+: m/z = 459. Found: m/z = 459, 460. Example aigzi-ffR^-A-BenzovI-a-methyl-pipcrazin-i-vπ-Σ-r∑-amino^-d-hf- pyrazol-3-vπ-pheπvπ-ethane-1.2-dione
Figure imgf000139_0001
1 -((R)-4-Benzoyl-2-methyl-pϊperazin-1 -yl)-2-[2-dimethylamino-4-( 1 H- pyrazol-3-yl)-phenyl]-ethaήe-1 ,2-dione (52 %) was prepared according to the procedure above (40 min; TLC-monitoring, CHCI3ZMeOH 20:1), using 1-((R)- 4-benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-amino-phenyl)-ethane-1 ,2- dione, and EtOAc as eluent. LCMS: Calc'd for C2SH23N5O3 - H+: m/z = 418.5. Found: m/z = 418, 419. 1H NMR (DMSO-d6): 13.14 (broad signal, 1H, NH- pyrazole); 7.78 (m, 1H); 7.45-7.30 (m, 9H); 7.05 (m, 1 H); 6.68 (m, 1 H); 4.85- 3.36 (br signal, 5H); 3.15-2.84 (br signal, 2H); 1.19 (br signal, 3H).
1-(2-Amino-4-bromo-phenyl)-2-((R)-4-benzoyl-2-methyI-piperazin-1-yl)- ethane-1,2-dione
Figure imgf000139_0002
1-(2-Amino-4-bromo-phenyl)-2-((R)-4-benzoyl-2-methyl-piperazin-1-yl)- ethane-1 ,2-dione was prepared according to the procedure above, using aqueos solution of NH3. LCMS: Calc'd for C2oH2oBrN3O3 • H+: m/z = 431. Found: m/z = 432, 433, 434.
EXAMPLE 4 In this example, illustrated are compounds of Formula (I) according to some embodiments of the present invention. Measurements for antiviral activity, performed according to the methods described in Example 1 herein, are noted by reference to a range in Table 3, with "A" denoting antiviral activity represented by an IC50 less than 5μm; and "B" denoting antiviral activity represented by an IC50 greater than 5 μm. Where the stereochemistry is depicted, the activity of the compound was assayed using an enaπtiomerically purified compound.
Table 3
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
J56
Figure imgf000158_0001

Claims

What is claimed is:
1. A compound of Formula (I)
Figure imgf000159_0001
or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, wherein:
W is selected from the group consisting of null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene and cycloalkytidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, amino, thio, sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with at least one halogen atom;
A1 is a monocyclic ring selected from the group consisting of monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene and monocyclic heteroarylene, wherein the monocyclic ring is optionally substituted with at least one functional group selected from the group consisting of alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy, phosphoramide, phosphoramidralkyl, phosphonate, phosphonatealkyl and -RgQ, wherein R9 is null or aikylene and Q is selected from the group consisting of -NR10R11, -CN, -CO2R12, -SR13, - SOR14, -SO2Ri5> -SO2NR16R17, -NRi8CORi9, -NR20CONR21R22, -CONR23R24, ■ NR25SOR26, -R27COR28, and -OR29;
A2 is selected from the group consisting of null, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one functional group selected from the group consisting of alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and -RgQ, wherein Rg and Q are as defined above;
RiO, Ri1, Ri2» Ri3» Ri4» R-15. Ri6> Ri7» Ri8s Ri9j R20J R21> R22j R23» R24»
R25, R26, R27, R28 and R29 are each independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, allyl, alkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, fluorocycloalkyl, arylalkyl, and heteroarylalkyl; or wherein R10 and R-π, R-ie and R17, R2i and R22 or R23 and R24, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl;
Y is selected from the group consisting of -CO-CO-, -SO2-, -C=NRx-CO-, and -CO-C=NRx-, -O-CO-, and -NR30CO-; wherein Rx is selected from the group consisting of hydrogen, cyano, alkyl, fluoroalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted with at least one functional group selected from the group consisting of halo, alkyl, alkoxy, -CF3, -OCF3, and -CN;
Ri, R2, R3, R4, Rs, Re, R7 and Re are each independently hydrogen, halo, or alkyl; at least one of R-i, R2. R3, R4 is taken together with at least one of R5, Re, R7 and Re to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with at least one functional group selected from the group consisting of halogen, amino, hydroxyl, -CN, -NO2, alkoxy, -CF3, -OCF3, alkyl, allyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether and R31-Q1 wherein R3i is null or alkylene and Q' is selected from the group consisting of -SO2NR32R33, -NR34COR35, -CONR36R37
Figure imgf000160_0001
R30, R32, R33, R34, R35, R36, R37 and R3B are each independently selected from the group consisting of hydrogen, alkyl, allyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl; or wherein R32 and R33 or R36 and R37, taken together with .the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with at least one functional group selected from the group consisting of halo, alkoxy, -CF3, -OCF3 and -CN;
Figure imgf000161_0001
Z is selected from the group consisting Of-COR41, -C^=NR43)R4I and
R41 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; each optionally substituted with one or more functional groups selected from the group consisting of alkyl, cycloalkyl, alkoxy, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, halo, -CN, -CF3, alkylthio, hydroxy, alkenyl, alkenoxy, acetyl and -RgQ, wherein Rg and Q are defined above;
R42 is selected from the group consisting of aryl and heteroaryl, optionally substituted at least one functional group selected from the group consisting of halo, alkoxy, -CF3, -OCF3, -CN, alkyl, -cycloalkyl, -fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, acetyl, alkenyl, alkenoxy and -RgQ, wherein Rg and Q are defined above;
R43 is selected from the group consisting of hydrogen, alkoxy, cyano, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, aryl, heteroaryl or heterocycloalkyl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with at least one functional group selected from the group consisting of halo, alkyl, alkoxy, -CF3, -OCF3, -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and -RgQ, wherein Rg and Q are defined above;
• R39 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each optionally substituted with at least one functional group selected from the group consisting of halogen, alkyl, alkoxy, -CF3, - OCF3, -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, S-alkyl, hydroxy, alkenyl, alkenoxy, acetyl and -R9Q, wherein Rg and Q are defined above; and
R40 is selected from the group consisting of hydrogen, -CN, alkyl, halo, -CF3, cycloalkyl, fluoroalkyl, fluorocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and heterocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl are optionally substituted with at least one functional group selected from the group consisting of halo, alkyl, alkoxy, -CF3, -OCF3, -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy and -RgQ, wherein Rg and Q are defined above.
2. The compound of claim 1 , wherein
W is selected from the group consisting of null, C0 - C6 alkylene, (C0 - C3 alkylene)-O-(C0 - C3 alkylene), (C0 - C3 alkylene)-NR'-(C0 - C3 alkylene), (C0 - C3alkylene)-S-(C0 - C3 alkylene), (C0 - C3 alkylene)-S(=O)-(C0 - C3 alkylene), (C0 - C3 alkylene)-SO2-(C0 - C3 alkylene), (C0 - C3 alkylene)-C(=O)- (C0 - C3 alkylene), (C0 - C3 alkylene)-C(=O)NR'-(C0 - C3 alkylene) and (C0 - Cβcycloalkylidene), wherein the alkylene and cycloalkylidene groups are optionally substituted at least one halogen atom;
A1 is phenylene or monocyclic heteroarylene, wherein the phenylene and monocyclic heteroarylene are optionally substituted with at least one functional group selected from the group consisting of Ci-C6 alkyl, Ci-C6 aikoxy, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, hydroxy, halo, C1-C6 fluoroalkoxy, C2-C6 alkenyl, C2-C6 alkenoxy and -RgQ, wherein Rg is null or Ci-C2 alkylene and Q is selected from the group consisting of -NR10R11, -CN, -CO2R121 -SR13, -SOR14, -SO2RiS, -SO2NR16R17, -NR18COR19, -NR20CONR21 R22, -CONR23R24, -NR25SOR26, -R27COR28, and -OR2g;
A2 is phenyl or heteroaryl, wherein the phenyl and heteroaryl are optionally substituted with at least one functional group selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, hydroxy, halogen, C1-C6 fluoroalkoxy, C2-C6 alkenyl, C2-C6 alkenoxy and -RgQ, wherein R9 is null or C1-C2 alkylene and Q is defined above;
R', R10, R11, Ri2» Ri3j Ri4« Ri5> Ri6j Ri75 Ri8j Ri9, R∑OJ R21> R∑2> R23» ^24»
R25, R26, R27, R28 and R29 are each independently selected from the group consisting of hydrogen, Ci-C6 alkyl, allyl, C1-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycloalkyl, C1-C6 alkoxy, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroarylmethyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl and heterocycloalkylethyl; or wherein R10 and R11, Ri6 and R17, R21 and R22, or R23 and R24, taken together with the nitrogen to which they are attached, are part of a ring selected from the group consisting of azetidine, azetidin-2-one, pyrrolidine, pyrroHdin-2-one, pyrrolidin-3-one, piperidine, piperidin-2-one, piperidin-3-one, piperidin-4-one, morpholine, morpholin-2-one, morpholin-3-one and N-alkylpiperazine; wherein the heterocycloalkyl comprises
O to 4 nitrogen atoms;
O to 2 nitrogen atoms and O to 1 oxygen atom;
O to 2 nitrogen atoms and O to 1 sulfur atom; or
O to 2 nitrogen atoms, O to 1 oxygen atom and O to 1 sulphur atom; and wherein the heteroaryl is selected from the group consisting of imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl; and wherein the phenyl, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 5 functional groups selected from the group consisting of hydrogen, halo, d-Cβ alkoxy, -CF3, -OCF3 and -CN;
Rx is selected from the group consisting of alkyl, fluoroalkyl, alkoxyalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl; wherein each heteroaryl ring is optionally substituted with at least one functional group selected from the group consisting of halo, Ci-C6 alkyl, Ci-C6 alkoxy, -CF3, -OCF3 and -CN;
Ri1 R2, R3, R4, R5, Re, R7, and RB are each independently hydrogen or Ci- C6 alkyl, wherein the Ci-C6 alkyl is optionally substituted with at least one functional group selected from the group consisting of hydrogen, halo, amino, hydroxyl, -CN, -NO2, Ci-C6 alkoxy, -CF3, -OCF3, Ci-C6 alkyl, allyl, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycloalkyl, phenyl, phenylmethyl, phenylethyl, heteroaryl, heteroarylmethyl, heteroarylethyl, heterocycloalkyl, heterocycloalkylmethyl, heterocycloalkylethyl, (CRaRb)U-T-(CR0Rd)U1Re and R3iQ' wherein R3i is null or Ci-C2 alkylene and Q' is selected from the group consisting Of -SO2NR32R33, -NR34COR35, -CONR36R37 and -COOR38;
R3OJ R32 j R33J R34> R35J R36J R37J R3Bs Ra, Rb, Rc, Rd and Re are each independently selected from the group consisting of hydrogen, CrC6 alkyl, allyl, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, C3-C7 fluorocycloalkyl, Ci-C6 alkoxy, phenyl-(Co-C2 alkyl), heteroaryl-(C0-C2 alkyl) and heterocycloalkyl-(Co-C2 alkyl); wherein the heterocycloalkyl comprises
O to 4 nitrogen atoms;
O to 2 nitrogen atoms and O to 1 oxygen atom;
O to 2 nitrogen atoms and O to 1 sulfur atom; or 0 to 2 nitrogen atoms, 0 to 1 oxygen atom and.O to 1 sulphur atom; and wherein the heteroaryl group is selected from the group consisting of imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinoliπyl, isoquinolinyl, benzimidazolyl, azabenzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, and quinoxalinyl; wherein the phenyl, heteroaryl or heterocycloalkyl is optionally substituted with 1 to 5 functional groups selected from group consisting of halo, Ci-C6 alkoxy, -CF3, -OCF3 and -CN; or wherein R32 and R33 or R3s and R37, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl selected from the group consisting of aziridine, azetidine, pyrrolidine, pyrrolidin-2-one, piperidine, morpholine and N-alkylpiperazine;
U and U' are each independently 0, 1 or 2;
T is null or oxy;
R41 is selected from the group consisting of phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazoyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl; each of which is optionally substituted with one or more C1 - C3 alkyl, C3 - C6 cycloalkyl, Ci -C3 alkoxy, C1-C6 fluoroalkoxy, C1-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, -CN, -F, -Cl, -Br, -CF3, C0-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl and -R9Q, wherein R9 is null or C1-C2 alkylene and Q is defined above;
R42 is selected from the group consisting of phenyl, heteroaryl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, benzothienyl, benzofuryl, benzoindazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, quinoxalinyl, thienopyridine, thienopyrimidine, thienopyridazine, thienopyrazine, furopyridine, furoopyrimidine, furopyridazine, furopyrazine, oxazolopyridine, oxazolopyrimidine, oxazolopyridazine.oxazolopyrazine, thiazolopyridine, thiazolopyrimidine, thiazolopyridazine.thiazolopyrazine, napthyridine, pyridopyrimidine, pyridopyridazine and pyridopyrazine; each optionally substituted with at least one functional group selected from the group consisting of halo, Ci-C6 alkoxy, -CF3, -OCF3 or -CN, Ci - C3 alkyl, C3 - C6 cycloalkyl, Ci-C6 fluoroalkoxy, Ci-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, C0-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl and -RgQ, wherein Rg is null or Ci-C2 alkylene and Q is defined above;
R43 is selected from the group consisting of hydrogen, -CN, Ci-C6 alkoxy, Ci-C6 fluoroalkoxy, Ci-C6 alkyl, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl or C3-C7 fluorocycloalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, and quinoxalinyl; wherein the aryl or heteroaryl are optionally substituted with at least one functional group selected from the group consisting of halo, Ci - C6 alkyl, C1-C6 alkoxy, -CF3, -OCF3 or -CN, C1 - C3 alkyl, C3 - C6 cycloalkyl, C1-C6 fluoroalkoxy, C1-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, Co-C3 alkylthio, hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl and -R9Q, wherein R9 is null or C1-C2 alkylene and Q is defined above;
R39 is selected from the group consisting of phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, and quinoxalinyl; each optionally substituted with at least one functional group selected from the group consisting of halo, C1 — C6 alkyl, C1-C6 alkoxy, -CF3, -OCF3, - CN, C1 - C3 alkyl, C3 - C6 cycloalkyl, Ci-C6 fluoroalkoxy, C1-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, S-(C0-C3 alkyl), hydroxy, C2-C6 alkenyl, C2-C6 alkenoxy, acetyl and -R9Q, wherein R9 is null or Ci-C2 alkylene and Q is defined above; and
R40 is selected from the group consisting of hydrogen, -CN, Ci - C6 alkyl, halo, -CF3, C3 - C6 cycloalkyl, Ci-C6 fluoroalkyl, C3-C7 fluorocycloalkyl, and heterocycloalkyl, heterocycloalkylmethyl, heterocycloalkylethyl, R41, R4imethyl and R41 ethyl; wherein the heterocycloalkyl comprises
0 to 4 nitrogen atoms;
0 to 2 nitrogen atoms and 0 to 1 oxygen atom;
0 to 2 nitrogen atoms and 0 to 1 sulfur atom; or
0 to 2 nitrogen atoms, 0 to 1 oxygen atom and 0 to 1 sulphur atom; and wherein R41 is selected from the group consisting of phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, azabenimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl, and quinoxalinyl; and is optionally substituted with at least one functional group selected from the group consisting of halogen, Ci - Ce alkyl, Ci-C6 alkoxy, -CF3, -OCF3, -CN1 hydrogen, Ci - C3 alkyl,. C3 - C6 cycloalkyl, O-(Ci-C6 fluoroalkyl), CrC6 fluoroalkyl, C3-C7 fluorocycloalkyl, S-(Co-C3 alkyl), hydroxy, C2-C6 alkenyl, C2- C6 alkenoxy, acetyl and -RgQ, wherein Rg is null or C1-C2 alkylene and Q is defined above.
3. A compound of Formula (II)
Figure imgf000167_0001
or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, wherein:
W is selected from the group consisting of null, oxy, amino, thio, sulfinyl, sulfonyl, carbonyl, amide, alkylene and cycloalkylidene, wherein at least one carbon atom of the alkylene or cycloalkylidene is optionally substituted with an oxy, amino, thio, sulfinyl, sulfonyl, carbonyl or amide group, and wherein the alkylene or cycloalkylidene is optionally substituted with 1 to 3 halogen atoms;
Ai is a monocyclic ring selected from the group consisting of monocyclic cycloalkylidene, monocyclic heterocycloalkylidene, monocyclic arylene and monocyclic heteroarylene, wherein the monocyclic ring is optionally substituted with 1 to 5 functional groups, each independently selected from the group consisting of alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and -RgQ, wherein Q is selected from the group consisting of ~NRi0Rii, -CN, -CO2R12, -SRi3, -SORi4, -SO2R15, -SO2NR16Ri7, -NR1J3COR19, -NR20CONR21R22, -CONR23R24, -NR25SOR26, - R27COR28 and -OR29;
A2 is selected from the group consisting of null, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 5 functional groups, each independently selected from the group consisting of alkyl, alkoxy, fluoroalkyl, cycloalkyl, hydroxy, halo, fluoroalkoxy, alkenyl, alkenoxy and -RgQ, wherein Rg and Q are as defined above;
R-IO, R-11, Ri2> Ri3» Ri4> R15. Ri6» Ri7» Ri8» Ri9» R20J R21» R22J R23» R∑4>
R25, R26, R27, R28 and R29 are each independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, allyl, alkoxy, cycloalkyl, heterocycloalkyl, fluoroalkyl, fluorocycloalkyl, arylalkyl, and heteroarylalkyl; or wherein R10 and Rn, R16 and R17, R21 and R22, or R23 or R24, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl;
Y is selected from the group consisting of -CO-CO-, -SO2-, -C=NRx-CO-, and -CO-C=NRx-, -O-CO-, and -NR30CO-; wherein Rx Is selected from the group consisting alkyl, fluoroalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted with 1 to 5 functional groups selected from the group consisting of halogen, alkyl, alkoxy, -CF3, -OCF3 and -CN;
Ri1 R2, R3, R-i, R5, Re, R? and R8 are each independently hydrogen or • alkyl; and/or at least one of R-i, R2, R3, R4 is taken together with at least one of R5, Re, R7 and Rs to form an alkylene bridge, wherein the alkyl or alkylene bridge is optionally substituted with 1 to 3 functional groups, each independently selected from the group consisting of halogen, amino, hydroxyl, -CN, -NO2, alkoxy, -CF3, -OCF3, alkyl, allyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, polyether and R31-Q" wherein R3i is null or alkylene and Q' is selected from the group consisting of -SO2NR32R33, -NR34COR35, - CONR3SR37 and -COOR38;
R30, R32, R33, R34. R35, R36, R37 and R3B are each independently selected from the group consisting of hydrogen, alkyl, allyl, fluoroalkyl, • cycloalkyl, heterocycloalkyl, fluorocycloalkyl, alkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl; or wherein R32 and R33 or R36 and R37, taken together with the nitrogen to which they are attached, are part of a heterocycloalkyl or heteroaryl; and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with 1 to 5 functional groups selected from the group consisting of halo, alkoxy, -CF3, -OCF3 and -CN; and
X is O, S or NR39, wherein R39 is selected from the group consisting of hydrogen, -CN, alkoxy, fluoroalkoxy, alkyl, fluoroalkyl, cycloalkyl, fluorocycloalkyl, phenyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthaiazinyl, benzoxazolyl and quinoxalinyl; optionally substituted with 1 to 5 functional groups selected from the group consisting of halo, alkyl, alkoxy, -CF3, -OCF3 or -CN, cycloalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, alkylthio, hydroxy, alkenyl, alkenoxy, acetyl and -R9Q, wherein R9 and Q are defined above.
4. The compound of claim 3, wherein
W is -(CH2)x(CO)y(CH2)z-, wherein x, y and z are each independently 0, 1 , 2 or 3;
Ai is a monocyclic ring selected from the group consisting of a cycloalkylidene, heterocycloalkylidene, arylene and heteroarylene, each optionally substituted with 1 to 3 functional groups selected from the group consisting of halo, alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, hydroxy, amino, alkylarnino, dialkylamino and thiol;
A2 is a monocyclic or bicyclic ring selected from the group consisting of monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocycloalkyl, monocyclic or bicyclic aryl and monocyclic or bicyclic heteroaryl, each optionally substituted with 1 to 3 functional groups selected from the group consisting of halo, -CN, alkyl, alkoxy, acetyl, oxo, fluoroalkyl, fluoroalkoxy, hydroxy, amino, methylamino, dimethylamino, -SH1 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and arylcarboπyl; wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl substituted onto the monocyclic or bicyclic ring is optionally substituted with a halo, alkyl, acetyl or alkoxycarbonyl;
Y is -(CH2)m(C=O)n- or -SO2-, wherein m and n are each independently 0, 1, 2 or 3;
Ri, R2, R3, R4, Rs, Re, R7 and R8 are each independently hydrogen or alkyl; and/or at least one of Ri, R2, R3, R4 is taken together with at least one of R5, Re, R7 and R8 to form an alkylene bridge; and
X is O1 -CN or N-O-alkyl.
5. • The compound of claim 1 ,. wherein the compound is selected from the group consisting of:
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000183_0002
Figure imgf000183_0003
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
6. The compound of claim 1, selected from the group consisting of the compounds 101 , 102, 103, 105, 106, 108, 120, 141, 142, 144, 147, 164, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 189, 190, 191, 192, 193, 197, 198, 199,
7. The compound of claim 1, wherein the compound is present as a racemic mixture.
8. The compound of claim 1, wherein the compound is present substantially as the (R) enantiomer.
9. A pharmaceutical composition comprising: a compound of Formula I of claim 1, or ^a pharmaceutically acceptable, prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof; and a pharmaceutically acceptable carrier, excipient or diluent.
10. A pharmaceutical composition comprising: a compound of Formula Il of claim 3, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof; and a pharmaceutically acceptable carrier, excipient or diluent.
11. A method for the inhibition of transmission of an HIV virus to a cell, comprising contacting the cell with an effective concentration of the compound of claim 1 under conditions sufficient wherein fusion of the virus is inhibited.
12. A method of treating HIV infection in a subject, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof.
13. The method of claim 12, wherein the method further comprises administering an effective amount of at least one other therapeutic agent.
14. The method of claim 13, wherein the therapeutic agent is a reverse transcriptase inhibitor, a viral protease inhibitor, a cytokine, a cytokine inhibitor, a glycosylation inhibitor or a viral mRNA processing inhibitor.
15. The method of claim 13, wherein the therapeutic agent is a nucleoside analogue.
16. The method of claim 15, wherein the nucleoside analogue is azidothymidine (AZT), ddl, ddC, ddA, d4T or 3TC.
17. The method of claim 13 wherein the therapeutic agent is interferon-α', interferon-β or interferon-γ.
18. The method of claim 14, wherein the protease inhibitor is an inhibitor of HIV-1 protease.
19. The method of claim 18, wherein the inhibitor of HIV-1 protease is indinavir.
20. The method of claim 13, wherein the administration is sequential.
21. The method of claim 20, wherein the sequential administration is a cycling therapy.
22. The method of claim 21 , wherein the sequential administration of each agent comprising the cycling therapy is repeated one or more times in fixed order.
23. The method of claim 21 , wherein the cycling therapy comprises administration of the compound of claim 1 or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof, in alternation with at least one therapeutic agent selected from the group consisting of a reverse transcriptase inhibitor, a viral protease inhibitor, a cytokine, a cytokine inhibitor, a glycosylation inhibitor or a viral mRNA processing inhibitor.
24. The method of claim 13, wherein the administration is simultaneous.
25. The method of claim 13, wherein the compound of claim 1 or or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof is administered before the other therapeutic agent.
26. The method of claim 13, wherein the compound of claim 1 or or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or derivative thereof is administered after the therapeutic agent.
27. The method of claim 13, wherein the administration of at least one therapeutic agent is oral.
28. The method of claim 13, wherein the administration is parenteral.
29. The method of claim 28, wherein the parenteral administration is subcutaneous.
30. A method of treating HIV infection in a subject comprising administering an effective amount of a compound of claim 3, or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or a derivative thereof.
31. The method of claim 30, wherein the method further comprises administering an effective amount of at least one other therapeutic agent.
32. A method of inhibiting HIV replication comprising administering to a subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof.
33. The method of claim 32, wherein the method further comprises administering an effective amount of at least one other therapeutic agent.
34. A method for the inhibition of transmission of an HIV retrovirus to a cell, comprising contacting the cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or a derivative therof.
35. The method of claim 34, wherein the method further comprises administering an effective amount of at least one other therapeutic agent.
36. A kit comprising the compound of formula (I) of claim 1 , or a pharmaceutically acceptable prodrug, salt, polymorph, solvate, enantiomer, diastereomer, racemate, mixture of stereoisomers thereof, or a derivative therof.
37. The kit of claim 36, wherein the kit further includes instructions for administration for the treatment of HIV infection and AIDS.
38. A compound selected from the group consisting of:
((RJ^^Mβthoxy^'πol-phβπy'-n^βthyl^-methyl-piperazin-i-yO-acetonitrile;
((R)-3-Methyl-piperazin-1 -yl)-phenyl-methanone O-methyl-oxime;
(3R)-3-methyl-1-(phenylcarbonothioyl)piperazine; δ-^-Benzoyl^-methyl-piperazine-i-sulfonylJ-thiophene^-carboxylic acid ethyl ester;
[4-(5-Bromo-thiophene-2-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl- methanone;
[4-(5-Bromo-thiophene-2-sulfonyl)-3-methyl-piperazin-1-yl]-phenyl- methanone; tert-butyl 3-methylτ4-(thiophen-2-ylsulfonyl)piperazine-1-carboxylate;
[4-(4-Bromo-benzenesulfonyl)-3-methyl-piperazin-1-yl]-phenyl-methanone;
(R)-(4-(4-ethynylphenylsulfonyl)-3-methylpiperazin-1-yl)(phenyl)methanone;
4-(1-Methyl-1W-pyrazol-3-yl)-benzoic acid methyl ester;
1-(4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-iodo-phenyl)-ethane-1 ,2-dione;
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(4-bromo-ρhenyl)-ethane-1 ,2- dione; 1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-fluoro-phenyl)-ethane-
1,2-dione;
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2~(4-bromo-3-methyl-phenyl)- ethane-1 ,2-dione;
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-methyl-phenyl)- ethane-1 ,2-dione;
1 -((R)-4-Benzoyl-2-methyl-piperazin-1 -yl)-2-(6-chloro-pyridin-3-yl)-ethane-1 ,2- dioπe;
4-[2-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-oxo-acetyl]-boronic acid;
1-((R)-4-Benzoyl-2-methyl-piperazin-1-yl)-2-(4-bromo-2-dimethylamino- phenyl)-ethane-1 ,2-dione; and
1-(2-Amino-4-bromo-phenyl)-2-((R)-4-benzoyl-2-methyl-piperazin-1-yl)- ethane-1 ,2-dione.
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