WO2009089659A1 - Pyrollidine-based compounds - Google Patents

Pyrollidine-based compounds Download PDF

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Publication number
WO2009089659A1
WO2009089659A1 PCT/CN2008/000137 CN2008000137W WO2009089659A1 WO 2009089659 A1 WO2009089659 A1 WO 2009089659A1 CN 2008000137 W CN2008000137 W CN 2008000137W WO 2009089659 A1 WO2009089659 A1 WO 2009089659A1
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yl
alkyl
selected
2h
group consisting
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PCT/CN2008/000137
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French (fr)
Inventor
Li Chen
Eric Dale Jones
Dawei Ma
Dean Cameron Baylis
Ben Li
Jonathan Alan Victor Coates
Xin Xie
David Ian Rhodes
Renhai Chen
John Joseph Deadman
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Shanghai Targetdrug Co., Ltd.
Avexa Limited
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Priority to PCT/CN2008/000137 priority Critical patent/WO2009089659A1/en
Priority claimed from PCT/CN2009/000067 external-priority patent/WO2009092293A1/en
Publication of WO2009089659A1 publication Critical patent/WO2009089659A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12Oxygen or sulfur atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/06Heterocyclic 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 linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D451/00Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Abstract

The present invention discloses the compounds of formula ( I ) or a pharmaceutically acceptable derivative, salt or prodrug thereof, which can inhibit HIV replication.

Description

PYROLLIDINE-BASED COMPOUNDS

FIELD OF THE INVENTION

The present invention provides compounds of Formula (I) and their use in the treatment or prophylaxis of HIV.

BACKGROUND

The retrovirus designated "human immunodeficiency virus" or "HIV" is the etiological agent of a complex disease that progressively destroys the immune system. This disease is known as acquired immune deficiency syndrome or AIDS. As at December 2005 an estimated 40 million people are living with HIV world wide and over 3 million deaths are occurring annually.

HIV infection follows a path of the virus particle interacting non-specifically with adhesion proteins on the host immune cell surface and then binding to the host cell surface receptor CD4. Binding of the HIV-I gpl20 envelope glycoprotein to CD4 induces conformational changes in gpl20 that create or expose a binding site for a co-receptor that can be the CCR5 receptor (a G-protein coupled receptor also known as C-C chemokine receptor type 5; C-C CKR-5; CC-CKR-5; CCR-5; CCR5; CCR5 chemokine receptor; CD 195 antigen; CHEMRl 3; HIV-I fusion coreceptor; MIP-I alpha receptor) resulting in fusion of the virus particle with the cell. Strains of HIV that utilise the CCR5 receptor are called CCR5-tropic strains or R5 isolates.

The association of gpl20 with CCR5 or the CXCR4 receptor, through receptor sites containing tyrosine residues, then drives additional conformational changes within the entire trimeric gpl20/gp41 complex that eventually lead to the insertion of the gp41 fusion peptide into the host cell membrane, provoking fusion and entry. A cluster of residues in the CCR5 protein N-terminus participates in gpl20-binding and is essential for fusion and entry of both R5 and R5X4 isolates. In contrast, residues dispersed throughout the extracellular domain of CXCR4 are involved in gpl20 docking, viral fusion and entry; each HIV-I isolate uses a slightly different subset of CXCR4 residues in order to gain entry into the target cell. The gpl20 binding sites on CCR5 and CXCR4 comprise negatively charged and tyrosine residues. Certain mutations in CXCR4 even enable it to mediate the entry of R5 isolates. Similarities between CCR5 and CXCR4 gpl20-binding sites are further underscored by the ability of R5X4 isolates to interact with both co-receptors. These similarities may account for the ability of a few residue changes in gpl20 to induce a switch in co-receptor usage. It should be noted that the extracellular loops of CCR5 and CXCR4 also play an indirect role in viral entry by influencing the overall conformation and/or oligomerization of the co-receptor proteins. Similarities between CCR5 and CXCR4 gpl20-binding sites are further underscored by the ability of R5X4 isolates to interact with both co-receptors. These similarities may account for the ability of a few residue changes in gpl20 to induce a switch in co-receptor usage. It should be noted that the extracellular loops of CCR5 and CXCR4 also play an indirect role in viral entry by influencing the overall conformation and/or oligomerization of the co-receptor proteins.

It has been shown that preventing HIV entry into the cell by blocking the use of CCR5 will stop the virus from replicating. People who lack CCR5 receptors are healthy and have a decreased susceptibility to HIV infection. Therefore, blocking CCR5 as a HIV co-receptor for use in entry effectively prevents the infection of human cells by HIV and so effectively halts HIV replication

The contents of the virus are released into the cytoplasm where reverse transcription of the HIV genome occurs. Through a series of steps a double stranded proviral DNA copy is produced. The proviral DNA is transported to the nucleus in a complex known as the pre integration complex (PIC) which contains integrase and other viral and possibly cellular proteins. Once inside the nucleus the proviral DNA is integrated into the host cell genome via the action of integrase. Once integrated, transcription and translation of the viral genome can occur resulting in the production of viral proteins and a new viral RNA genome. These proteins and genome assemble at the cell surface and, depending on cell type, possibly other intracellular membranous compartments. Assembled particles then bud out from the cell and during, or soon after, this process mature into infectious HIV particles through the action of the viral protease.

The integration of the proviral genome into the host cell genome requires the action of an integrase which carries out this process in at least three steps, possibly four. The first step involves the assembly of the viral genome into a stable nucleoprotein complex, secondly, processings of two nucleotides from the 3' termini of the genome to give staggered ends with free 3' OH residues and thirdly the transfer of these ends into the host cell genome. The final step involves the gap filling and repair of the insertion site in the host genome. There is still some conjecture over whether the integrase performs this final step or whether it is carried out by cellular repair enzymes.

Currently HIV infection can be treated with a number of inhibitors on the market which target reverse transcriptase, protease, integrase or entry into the cell. Treatment of HIV infection with these, or a combination of these, drugs is known to be an effective treatment for AIDS and similar diseases. Shortcomings with the current inhibitors include the rapid emergence and increased incidence of resistance and numerous side effects and hence there is a need for new classes of inhibitors.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula ( I )

Figure imgf000004_0001

(I)

wherein:

Z is selected from carbonyl and -CH(CO2H)-;

R1 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, which may be substituted with one or more suitable substituent(s);

R2 is selected from the group consisting of -OH, -O-C1-6alkyl, -OC(O)-C 1-6alkyl, and NR8R9; each of R8 and R9 are independently selected from the group consisting of H, Ci-βalkyl, -0(CO)-Ci -6alkyl, and -S(O)2-RiO; Rio is selected from the group consisting of -C1-6alkyl and aryl; R3 is selected from the group consisting of H, C^alkyl, aryl, and heteroaryl;

R4 is selected from the group consisting of H, C1-4alkyl, alkylene, aryl; cycloalkyl and alkylcycloaklyl; or R4 and Rn, together with the atoms to which they are linked, form an optionally substituted 5- or 7-membered heterocycle;

each of R5 and R5> is selected from the group consisting of H, CH3, and OH, or R5 and Rs> together with the carbon atom to which they are attached form a carbonyl group, provided that both R5 and R5- are not both OH;

R6 is absent or is 1 to 5 substituents selected from the group consisting of CF3, OCF3, NO2, SO2R12, NC(O)OC ^alkyl, CrC3alkyl, C3-C6cycloalkyl, C6aryl, heterocyclyl, heteroaryl, Ci-C3alkylOH, alkylaryl, OH, OC1-3alkyl, halo, CN, CO2H, CO2Ci-3alkyl, CONH2, CONH(C1-3alkyl), CON(C1-3alkyl)2, NH2, NH(C1-3alkyl) and N(C1-3alkyl)2; R12 is selected from the group consisting of d^alkenyl and NR13R14; each of R13 and R14 is independently selected from the group consisting of H, alkyl, and cycloalkyl, or R13 and R14 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle;

each ofR7 and R7' is selected from the group consisting of H, CH3, and OH, or R7 and R7' together with the carbon atom to which they are attached form a carbonyl group, provided that both R7 and R7- are not both OH;

A is absent or is selected from the group consisting of -CH2CH2-, -CH2CH2CH2-, and -CH2OCH2-;

Y is absent or is carbonyl;

L is absent or is selected from alkylene and alkenylene;

C is selected from the group consisting of cycloalkyl, aryl, and heteroaryl;

X is absent or is selected from NR11 and O; R11 is H or R4 and R11, together with the atoms to which they are linked, form an optionally substituted 5- or 7-membered heterocycle;

provided that when X is O, L is alkylene and C is aryl then R6 is selected from the group consisting of SO2R12 and OCF3; or C and R6 together with the atoms to which they are linked, form

Figure imgf000005_0001
or a pharmaceutically acceptable derivative, salt or prodrug thereof.

A further object of present invention is to provide a method of treating or preventing HIV infection in a subject. The method comprises administering to said subject an effective amount of a compound of Formula (I).

A yet further object of present invention is to provide a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula (I)

Figure imgf000006_0001

(I) wherein:

Z is selected from carbonyl and -CH(CO2H)-;

R1 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl , which may be substituted with one or more suitable substituent(s);

R2 is selected from the group consisting of -OH, -O-C1-6alkyl, -OC(O)-C1-6alkyl,and NRgR9; each of R8 and R9 are independently selected from the group consisting of H, C1-6alkyl, -O(CO)-C 1-6alkyl, and -S(O)2-Ri0; Rio is selected from the group consisting of -Ci-6alkyl and aryl;

R3 is selected from the group consisting of H, C1-6alkyl, aryl, and heteroaryl; R4 is selected from the group consisting of H, Ci^alkyl, alkylene, aryl, cycloalkyl and alkylcycloaklyl; or R4 and R11, together with the atoms to which they are linked, form an optionally substituted 5- or 7-membered heterocycle;

each of R5 and R5- is selected from the group consisting of H, CH3, and OH, or R5 and R5- together with the carbon atom to which they are attached form a carbonyl group, provided that both R5 and R5- are not both OH;

Rβ is absent or is 1 to 5 substituents selected from the group consisting of CF3, OCF3, NO2, SO2Ri2, NC(O)OCi-6alkyl, d-C3alkyl, C3-C6cycloalkyl, C6aryl, heterocyclyl, heteroaryl, d-C3alkylOH, alkylaryl, OH, OC1-3alkyl, halo, CN, CO2H, CO2C1-3alkyl, CONH2, CONH(C1-3alkyl), CON(C j.Csalkyl);), NH2, NH(C1-3alkyl) and N(C1-3alkyl)2; R12 is selected from the group consisting of C1-6alkenyl and NR13Ri4, each of R13 and R14 is independently selected from the group consisting of H, alkyl, and cycloalkyl, or Ri3 and R14 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle;

each of R7 and R7- is selected from the group consisting of H, CH3, and OH, or R7 and R7' together with the carbon atom to which they are attached form a carbonyl group, provided that both R7 and R7- are not both OH;

A is absent or is selected from the group consisting of -CH2CH2-, -CH2CH2CH2-, and -CH2OCH2-;

Y is absent or is carbonyl;

L is absent or is selected from alkylene and alkenylene;

C is selected from the group consisting of cycloalkyl, aryl, and heteroaryl;

X is absent or is selected from NR11 and O; R11 is H or R4 and Rn, together with the atoms to which they are linked, form an optionally substituted 5- or 7-membered heterocycle;

provided that when X is O, L is alkylene and C is aryl then R6 is selected from the group consisting of SO2Rj2 and OCF3; or C and R6 , together with the atoms to which they are linked, form

Figure imgf000007_0001
or a pharmaceutically acceptable derivative, salt or prodrug thereof.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein R1 is selected from the group consisting of-OH, C1-6alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl, preferably C3-8cycloalkyl, more preferably cyclopentyl.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein R2 is selected from the group consisting of -O-C1-6alkyl, -OC(O)-C i^alkyl, and NR8Rg.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein R4 is preferably selected from Ci^alkenyl and cycloalkyl, more preferably selected from allyl and -CH2cyclopropyl.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein A is selected from the group consisting Of-CH2CH2-, -CH2CH2CH2-, and -CH2OCH2-.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein L is selected from the group consisting of C1-4alkylene and C1-4alkenylene.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein C is selected from the group consisting of benzodioxazole, /w-methoxyphenyl, phenyl substituted with at least one substituent selected from Sθ2Ci-6alkyl and -OCF3.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein Z is preferably carbonyl.

In certain preferred embodiments, the aboved-mentioned compounds, wherein

provided that when X is NH, C is phenyl and L is absent, then Re is 1 to 5 substituents selected from the group consisting of CF3, OCF3, NO2, SO2R12, NC(O)OC 1-6alkyl, C^alkyl, C3-6cycloalkyl, C6aryl, heterocyclyl, heteroaryl, C^alkylOH, alkylaryl, OH, Od-Csalkyl, halo, CN, CO2H, CO2C,-3alkyl, CONH2, CONH(C1-3alkyl), CON(C1-3alkyl)2, NH2, NH(Ci.3alkyl) , and N(C1-3alkyl)2.

Preferably, the compound of Formula (I) is a compound of any one of the Examples, more preferably:

4- (Methylsulfonyl)benzyl allyl(l -(((3S,4i?)-l -(cyclopentanecarbonyl)-4-hydroxy-4-

phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate;

Benzo[c] [ 1 ,2,5]oxadiazol-5-ylmethyl allyl(l -(((3S,4i?)- 1 -(cyclopentanecarbonyl)-4- hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamat;

N-allyl-N-(l-(((3S',4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)meth yl)piperidin-4-yl)-2-(4-(Ny/V-dimethylsulfamoyl)phenyl)acetainide;

N-allyl-N-( 1 -(((3S,4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyπOlidin-3-yl)meth yl)piperidin-4-yl)-2-(4-(7V-methylsulfamoyl)phenyl)acetamide;

N-allyl-N-(l-(((35',4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)meth yl)piperidin-4-yl)-2-(4-sulfamoylphenyl)acetamide;

1 -Allyl- 1 -( 1 -(((3 S, 4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)meth yl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea;

4-((3 - Allyl-3 -( 1 -(((35,4/?)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)m ethyl)piperidin-4-yl)vιreido)methyl)-iVy/V-diinethylbenzenesulfonamide;

4-((3-Allyl-3-(l-(((3iS',4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)m ethyl)piperidin-4-yl)ureido)methyl)-N-methylbenzenesulfonamide; or

3 -( 1 -(((3S,4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)methyl)piperi din-4-yl)- 1 -(4-(trifluoromethyl)benzyl)-3 ,4-dihydropyrimidin-2( 1 H)-one.

In another aspect, the invention provides an intermediate of formula II useful of formula I :

Figure imgf000009_0001
( II ) wherein R3 is selected from the group consisting of H, Q^alkyl, aryl, and heteroary.

As used herein, the term "halo" or "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

As used herein, the term "alkyl" either used alone or in compound terms such as ΝH(alkyl) or N(alkyl)2, refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3, 1 to 6, 1 to 10 or 1 to 21 carbon atoms as appropriate. For example, suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4- or 5-methyIpentyl. As used herein, the term "alkenyl" refers to straight chain or branched hydrocarbon groups having one or more double bonds between carbon atoms. Suitable alkenyl groups include, but are not limited to ethenyl, allyl, propenyl, isopropenyl, butenyl, pentenyl and hexenyl.

The term "alkynyl" as used herein, refers to straight chain or branched hydrocarbon groups containing one or more triple bonds. Suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexenyl.

The term "cycloalkyl" as used herein, refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "aryl" as used herein, refers to a C6-CiO aromatic hydrocarbon group, for example phenyl or naphthyl.

The term "arylalkyl" includes, for example, benzyl.

The term "heterocycle" when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C3-6, wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue. The heterocycle may be saturated or unsaturated. Suitable heteroatoms include, O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. Suitable examples of heterocyclic groups may include pyrrolidinyl, piperidinyl, piperazinyl, morpholino, quinolinyl, isoquinolinyl, thiomorpholino, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl etc. The heteroaromatic ring may also be fused to a 5- or 6- aromatic ring eg benzodioxolane.

The term "heteroaryl" includes a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S. Suitable examples of heteroaryl groups include tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazolyl, oxadiazolyl etc. The heteroaromatic ring may be fused to a 5- or 6- aromatic or heteroaromatic ring to form a bicyclic aromatic system eg benzofuran or benzooxadiazole.

Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group may be optionally substituted with one or more of CpCaalkyl, C3-C6cycloalkyl, C6aryl, heterocyclyl, heteroaryl, Q-QalkylOH, alkylaryl, OH, OQ-Csalkyl, halo, CN, NO2, CO2H, CO2C]-C3alkyl, CONH2, CONH(C ^alkyl), CONtQ.Csalkyrh, trifluoromethyl, NH2, NHCd.Csalkyl), NCd.Qalkytø, S(O)2NH2, SO2NH(C1-3alkyl), SO2(Ci-3alkyl)2, and SO2C1-3alkyl. For example, an optionally substituted aryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl. Each optional substituent may also be optionally substituted.

Examples of optional substituents also include suitable nitrogen protecting groups (see "Protective Groups in Organic Synthesis" Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999).

The salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.

The term "pharmaceutically acceptable derivative" may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antibacterially active metabolite or residue thereof.

Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as "Handbook of Pharmaceutical salts" P.H.Stahl, C.G.Wermuth, 1st edition, 2002, Wiley- VCH.

Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. This invention also encompasses prodrugs of compounds of formula I. ' This invention also encompasses methods of treating or preventing disorders in a subject that can be treated or prevented by the inhibition of AIDS and other disorders that can be treated by inhibition of the integrase enzyme by administering prodrugs of compounds of the formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.

Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy and carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.

It will also be recognized that the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.

A further object of the present invention is to provide a method of treating of treatment or prophylaxis of a HIV infection in a subject, the method comprising administering to said subject an effective amunt of a compound of Formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof.

The term "effective amount" means the amount of the subject composition that will elicit the reduction in viral load or inhibition of viral replication that is being sought by the researcher, veterinarian, medical doctor or other clinician.

As would be understood by those skilled in the art of treating viral infections, and particularly HIV infections, the term "treatment" does not necessarily mean that the viral infection is completely cured. The term "treatment" encompasses any level of reduction of the viral load and/or inhibition of replication in the subject being treated.

The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment.

A yet further object of the present invention is to provide a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof and a pharmaceutically acceptable carrier, diluent or excipient.

The compositions of the present invention may contain other therapeutic agents and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

The compounds of the present invention may be administered by any suitable means, for example, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).

Pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, carrier or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).

The subjects treated in the above method are mammals, including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species, and preferably a human being, male or female. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.

When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

In the treatment or prevention of conditions which require HIV inhibition or HIV integrase enzyme inhibition an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound; the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Synthetic Schemes

The compounds of the present invention can be prepared using the methods described in Schemes 1-10.

Scheme 1:

Figure imgf000015_0001
Compound 4 can be synthesized starting from benzyl alcohol 1. Reaction of benzyl alcohol 1 with triphosgene followed by treatment of the resulting chloroformate 2 with the amine 3 provides compound 4.

Scheme 2:

Figure imgf000016_0001

A variety of acid 5 can be coupled with the amine 3 using coupling agents such as EDCI and HOBt to give the amide 6.

Scheme 3:

Figure imgf000016_0002

The urea 8 can be obtained by reaction of a variety of isocyanates 7 with the amine 3 out lined in Scheme 3.

Scheme 4:

Figure imgf000016_0003
The urea 11 can be synthesized starting from benzyl amine 9. Treatment of compound 9 with triphosgene converts the amine to isocyanate 10 and the resulting compound is reacted with the amine 3 to give urea 11.

Scheme 5:

Figure imgf000017_0001

Alternatively, a variety of final compounds 4 can be synthesized using the procedures outlined in Scheme 5. Reductive amination of compound 12 with the ketone 13 using a reducing agent such as sodium triacetoxyborohydride provides the intermediate 3. Treatment of compound 3 with chloroformate 2 provides compound 4 or reaction with an acid provides compound 6.

Scheme 6:

Figure imgf000017_0002
A variety of compounds 17, with rigid configuration can be prepared using the method shown in Scheme 6. Reductive amination amine 14 with ketone 13 using sodium triacetoxyborohydride provides the intermediate ketal 15. Reaction of compound 15 with an isocyanate 10 followed by treating the resulting urea 16 with p-methylbenzenesulfonic acid results in a ring closure to provide compound 17.

Scheme 7:

t THF

Figure imgf000018_0001
Figure imgf000018_0002

Figure imgf000018_0003
24

Alternatively, a variety of final compounds 24 can be synthesized using the sequence shown in Scheme 7. Boc protection of amine 18 followed by oxidation using an oxidant such as DMSO and (COCl)2 affords ketone 20. Reductive amination of an amine with ketone 20 using a reducing agent such as sodium triacetoxyborohydride provides intermediate 21. Treatment of compound 21 with chloroformate 2 or isocyanate 10 provides compound 22. Removal of the Boc by reaction with trifluoroacetic acid followed by coupling with an acid affords the amide 24.

Scheme 8:

Figure imgf000018_0004
Alternatively, a variety of final compounds 24 can be obtained following the procedures described in Scheme 8. Treatment the intermediate 23 with an acid chloride produces the amide 24. Scheme 9:

Figure imgf000019_0001

28 29

Figure imgf000019_0002
Alternatively, a variety of final compounds of formula (I) can be prepared following the procedures described in Scheme 9 (CNl 01007800; D. Ma et α/.ChemMedChem 2007, 2, 187-193). DABCO-catalyzed Baylis - Hillman reaction of methyl acrylate and ketone 25 provides diester 26, which is reacted with (R)- α -methylbenzylamine in methanol to afford the 1,4-addition product 27 as a mixture of four diastereomers. Lactamization of 27 occurred upon refluxing in dioxane and TFA to produce enantiopure pyrrolidone 28 after direct crystallization from the reaction mixture. Hydrolysis of 28 with aqueous NaOH in methanol produces acid 30. After transformation of acid 30 into its activated ester via reaction with DCC, amide formation can be performed with an amine, such as 4-piperidone, to afford diamide 31. LAH-reduction of diamide 31 then provides diamine 32. Hydrogenolysis of the resultant diamine 32 followed by acylation of the liberated secondary amine with a variety of acyl chlorides gives rise to amide 34. Swern oxidation can be carried out to afford ketone 35. Finally, reductive amination of 35 with a variety of amine and subsequent condensation with an isocyanate, chloroformate or aryl acid gives a variety of final compound 39.

Scheme 10:

Figure imgf000020_0001

Alternatively, a variety of final compounds of formula (I) can be synthesized using the sequence shown in Scheme 10. Reduction of intermediate 30 with LAH affords alcohol 40. Hydrogenolysis of alcohol 40 followed by acylation of the liberated secondary amine with a variety of acyl chlorides affords amides 42. Selective TBS protection of the primary hydroxyl of 42, followed by alkylation of the remaining tertiary hydroxyl affords compound 44. Cleavage of the TBS ether using TBAF reveals the primary hydroxyl which can then be oxidized under Swerm conditions to aldehyde 46.

Reductive amination of an amine with ketone 47 using a reducing agent such as sodium triacetoxyborohydride provides intermediate 48. Treatment of compound 48 with chloroformate 2, acid 5 or isocyanate 10 provides compound 49. Removal of the Boc by reaction with trifluoroacetic acid and then reductive amination of amine 50 with aldehyde 46 gives a variety of final compounds 51.

Abbreviations

DCC NjN'-dicyclohexylcarbodiimide

HOSu N-hydroxysuccinimide

DMAP 4-dimethylaminopyridine

EDCI 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide hydrochloride

HOBt 1-hydroxybenzotriazole

DCM dichloromethane

EA ethyl acetate

PE Petroleum ether

DiPEA Diisopropylethylamine

DMSO dimethylsulfoxide

THF Tetrahydrofuran

DABCO Triethylene Diamine

LAH Lithium aluminum hydride

TFA Trifluoroacetic acid

TBDSCl Tert-butyldimethylsilyl chloride

TBAF Tetrabutylammonium fluoride The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.

Example 1

4- (Methylsulfonyl)benzyl ally^l-^-S^^-l^cyclopentanecarbonyl) -4-hydroxy-4-

phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

Figure imgf000022_0001

Step A

4-(methylsulfonyl)benzyl carbonochloridate

Figure imgf000022_0002

According to Scheme 1, to a solution of triphosgene (0.160 g, 0.54 mmol) in DCM (2 mL) was added dropwise a mixture of (4-(methylsulfonyl)phenyl)methanol (0.101 g, 0.54 mmol) and DiPEA (0.10 mL, 0.54 mmol) in DCM (2 mL) at 0 0C over 30 min. After stirring at 0 °C under nitrogen for 2 h, the solution was concentrated under vacuum to provide the crude title compound that was used for next reaction without further purification.

Step B

4- (Methylsulfonyl)benzyl allyl(l-(((3S, 4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenyl

pyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

A solution of the chloroformate from step A (0.54 mmol) in DCM (2 mL) was added dropwise to a mixture of ((3i?,4S)-4-((4-(allylamino)piperidin-l-yl)methyl)-3-hydroxy-3- phenylpyrrolidin-l-yl)(cyclopentyl)methanone (0.2 g, 0.49 mmol) and triethyl amine (0.14 mL, 0.98 mmol) in DCM (4 mL) at O 0C. After being stirred at room temperature overnight, the resulting solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica ( 1 %-3 % MeOH in DCM) afforded the title compound as a white foam (0.22 g, 71 %). 1H NMR (CDCl3, 300MHz) δ 7.95-7.92 (d, J = 8.1 Hz, 2H), 7.54-7.47 (m, 4H), 7.41-7.27 (m, 3H), 5.84-5.74 (m, IH), 5.21-5.09 (m, 4H), 4.04-3.65 (m, 7H), 3.06-2.94 (m, 4H), 2.85-2.61 (m, 3H), 2.52-2.42 (m, 2H), 2.18-2.07 (m, 2H), 1.86-1.50 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 624.5 (M+H)+, 646.5 (M+Na)+.

Example 2

4- (Trifluoromethoxy)benzyl aIIyl(l-(((3»S',4Λ)-l-(cyclopeiitanecarbonyI)-4-hydroxy-4

-phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

Figure imgf000023_0001

This compound was prepared substantially as described in Example 1 using appropriate starting materials. 1H NMR (CDCl3, 300MHz) δ 7.52-7.49 (t, J = 7.5 Hz, 2H), 7.41-7.27 (m, 5H), 7.21-7.18 (d, J = 8.1 Hz, 2H), 5.83-5.74 (m, IH), 5.20-5.09 (m, 4H), 4.10-3.645 (m, 7H), 3.03-2.99 (m, IH), 2.83-2.61 (m, 3H), 2.59-2.39 (m, 2H), 2.20-2.05 (m, 2H), 1.86-1.53 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 630.5 (M+H)+, 652.4 (M+Na)+.

Example 3

Benzo[c][l,2,5]oxadiazol-5-ylmethyl allyl(l-(((3S,4i?)-l-(cyclopentanecarbonyl)-4-

hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

Figure imgf000024_0001

Step A

(4-Aminophenyl)methanol

Figure imgf000024_0002

4-Nitrobenzyl alcohol (10.0 g, 65.3 mmol) was hydrogenated over 10% Pd/C (1 g, 50%

H2O) in EtOH (150 mL). After the absorption of hydrogen was complete, the catalyst was filtered. The solution was concentrated under vacuum to provide the crude title compound that was used for next reaction without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.17 (d, J = 4.2 Hz, 2H), 6.67 (d, J = 4.2 Hz, 2H), 4.53 (s, 2H).

Step B

4-Acetamidobenzyl acetate

Figure imgf000024_0003

To a solution of (4-aminophenyl)methanol (2.0 g, 16.2 mmol) from step A and DMAP (0.40 g, 3.2 mmol)in DCM (50 mL) was added dropwise acetic anhydride (7.6 mL, 81.0 mmol) at 0 0C over 30 min. After stirring under nitrogen for 30 min, the solution was concentrated and extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (20% EA in PE) afforded the title compound as white solid (3.35 g, 100%). 1H NMR (CDCl3, 300 MHz): δ 7.51 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.05 (s, 2H), 2.16 (s, 3H), 2.08 (s, 3H). MS (ESI, Pos. 1.5 kV) m/z 230.0 (M+Na)+. Step C

4-Acetamido-S-nitrobenzyl acetate

Figure imgf000025_0001

Substituted acetanilide (16.2 mmol) was added in portions to a cooled (-4 0 0C) mixture of 60 % nitric acid (6 mL) and concentrated sulfuric acid (6 mL). The mixture was stirred at 0

0C for 10 min and then at room temperature for 30 min. The acidic solution was poured onto ice-water, extracted with EA twice. The combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica

(15%-20% EA in PE) afforded the title compound as yellow powder (1.25 g, 31%). 1H NMR (CDCl3, 300 MHz): δ 10.32 (s, IH), 8.78 (d, J = 9.0 Hz, IH), 8.21 (s, IH), 7.64 (d,

J = 9.0 Hz, IH), 5.09 (s, 2H), 2.29 (s, 3H), 2.11 (s, 3H). MS (ESI, Pos. 1.5 kV) m/z 275.0

(M+Na)+.

Step D

6-(Hydroxymethyl)benzo[c] [1 , 2, 5]oxadiazole 1 -oxide

Figure imgf000025_0002

KOH (0.73 g, 13.1 mmol) was dissolved in MeOH (40 mL) with heating. The product (0.94 g, 3.73 mmol) from step C was added to the hot solution and after 10 min the mixture was cooled to 0 0C. Aqueous NaClO (8.2 mL, 1.6 M, 13.1 mmol) was added dropwise and the reaction was stirred for 30 min. The solvent was evaporated in vacuo and the residue was neutralized with aqueous HCl (10%) and extracted with EA twice. After the work-up the organic layer was evaporated in vacuo. Column chromatography on silica (50% EA in PE) afforded the title compound as yellow solid (0.534 g, 86%). 1H NMR (CDCl3, 300 MHz): δ 7.48-7.18 (m, 3H), 4.72 (s, 2H), 2.51 (brs, IH).

Step E

Benzo[c][l, 2, 5]oxadiazol-5-ylmethanol

Figure imgf000026_0001

A mixture of the oxide (0.534 g, 3.21 mmol) from step D, Ph3P (0.843 g, 3.21 g), and EtOH (60 mL) was heated at reflux for 2 h. The EtOH was removed by reduced pressure distillation, and the residue was purified by column chromatography on silica (0%-l% MeOH in DCM). The product was isolated as a yellow oil (0.43 g, 90%). 1H NMR (CDCl3, 300 MHz): δ 7.79 (m, 2H), 7.37 (d, J = 10.5 Hz, IH), 4.82 (d, J = 5.1 Hz, 2H), 2.63 (t, J = 5.1 Hz, IH).

Step F and G

Benzo[c][l,2,5]oxadiazol-5-ylmethyl allyl(l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-

hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

This compound was prepared substantially as described in Example 1 using the starting materials from step E. 1H NMR (CDCl3, 300 MHz) δ 7.84-7.81 (d, J = 9.0 Hz, IH), 7.75 (s, IH), 1.52-1 Al (t, J = 7.5 Hz, 2H), 7.41-7.27 (m, 4H), 5.87-5.77 (m, IH), 5.21-5.14 (m, 4H), 4.11-3.65 (m, 7H), 3.05-3.01 (m, IH), 2.83-2.71 (m, 3H), 2.62-2.40 (m, 2H), 2.19-2.12 (m, 2H), 1.86-1.50 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 588.5 (M+H)+, 610.5 (M+Na)+.

Example 4

iV-allyl-iV-(l-(((35,4if)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl) methyl)piperidin-4-yl)-2-phenylacetamide

Figure imgf000026_0002

Following the procedure in scheme 2, DiPEA (0.26 mL, 1.47 mmol) was added dropwise to a mixture of

((3i?,4S)-4-((4-(allylamino)piperidin-l-yl)methyl) -3-hydroxy-3-phenylpyrrolidin-l-yl)(cyc lopentyl)methanone (0.20 g, 0.49 mmol), phenylacetic acid (0.066 g, 0.49 mmol), EDCI (0.14 g, 0.73 mmol) and HOBt (0.100 g, 0.73 mmol) in DCM (5 niL) at O 0C. After stirring at room temperature overnight, the resulting solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.232 g, 90 %). 1H NMR (CDCl3, 300 MHz) δ 7.51-7.19 (m, 10H), 5.86-5.76 (m, IH), 5.28-5.08 (m, 2H), 4.54-4.50 (m, IH), 3.86-3.59 (m, 8H), 3.02-2.96 (m, IH), 2.81-2.60 (m, 3H), 2.51-2.38 (m, 2H), 2.21-2.05 (m, 2H), 1.83-1.47 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 530.4 (M+H)+, 552.4 (M+Na)+.

Example 5

iV-allyl-TV-Cl-^SS^^-l-^yclopeiitanecarbony^^-hydroxy^-phenylpyrrolidin-S-yl) methyl)piperidiα-4-yl)-2-(4-methoxyphenyl)acetamide

Figure imgf000027_0001

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.51-7.45 (m, 2H), 7.40-7.27 (m, 3H), 7.16-7.11 (m, 2H), 6.87-6.82 (m, 2H), 5.86-5.76 (m, IH), 5.30-5.07 (m, 2H), 4.53-4.49 (m, IH), 3.86-3.58 (m, HH), 3.02-2.97 (m, IH), 2.81-2.60 (m, 3H), 2.52-2.39 (m, 2H), 2.23-2.05 (m, 2H), 1.88-1.53 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 560.4 (M+H)+, 582.4 (M+Na)+.

Example 6

iV-allyl-iV-(l-(((35',4Λ)-l-(cyclopeiitanecarboiiyl)-4-hydroxy-4-phenylpyrrolidin-3-yl) methyl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

Figure imgf000027_0002
This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.90-7.87 (d, J = 8.1 Hz, 2H), 7.51-7.27 (m, 7H), 5.91-5.80 (m, IH), 5.33-5.10 (m, 2H), 4.51-4.47 (m, IH), 3.88-3.64 (m, 8H), 3.05-2.97 (m, 4H), 2.82-2.59 (m, 3H), 2.53-2.42 (m, 2H), 2.19-2.11 (m, 2H), 1.86-1.53 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 608.4 (M+H)+, 630.4 (M+Na)+.

Example 7

Λ'-allyl-Λ'-(l-(((35',4if)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl) methyl)piperidin-4-yl)-2-(4-nitrophenyl)acetamide

Figure imgf000028_0001

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 8.19-8.16 (d, J = 8.7 Hz, 2H), 7.51-7.25 (m, 7H), 5.91-5.82 (m, IH), 5.34-5.11 (m, 2H), 4.52-4.47 (m, IH), 3.88-3.65 (m, 8H), 3.04-2.97 (m, IH), 2.82-2.59 (m, 3H), 2.52-2.39 (m, 2H), 2.21-2.14 (m, 2H), 1.86-1.50 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 575.4 (M+H)+, 597.5 (M+Na)+.

Example 8

iV-allyl-iV-(l-(((3-5,4if)-l-(cyclopeiitanecarbonyl)-4-hydroxy-4-phenylpyrrolidm-3-yl) methyI)piperidin-4-yI)-2-(4-(trifluoromethyI)phenyI)acetamide

Figure imgf000028_0002

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.58-7.27 (m, 9H), 5.89-5.80 (m, IH),

5.32-5.10 (m, 2H), 4.51-4.49 (m, IH), 3.86-3.65 (m, 8H), 3.03-2.99 (m, IH), 2.82-2.61 (m, 3H), 2.53-2.42 (m, 2H), 2.20-2.14 (m, 2H), 1.86-1.55 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 598.4 (M+H)+, 620.4 (M+Na)+.

Example 9

iV-allyl-iV-(l-(((3S,4l?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl) methyl)piperidin-4-yl)-2-(4-fluorophenyl)acetamide

Figure imgf000029_0001

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.51-7.17 (m, 7H), 7.02-6.96 (t, J = 8.7 Hz, 2H), 5.87-5.78 (m, IH), 5.30-5.08 (m, 2H), 4.52-4.49 (m, IH), 3.83-3.56 (m, 8H), 3.02-2.96 (m, IH), 2.81-2.65 (m, 3H), 2.60-2.41 (m, 2H), 2.23-2.13 (m, 2H), 1.92-1.55 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 548.5 (M+H)+, 570.4 (M+Na)+.

Example 10

N-allyl-iV-(l-(((35',4if)-l-(cyclopeiitanecarbonyl)-4-hydroxy-4-phenylpyrrolidiiι-3-yl) methyl)piperidin-4-yl)-2-(4-(Λ'^V-dimethylsulfamoyl)phenyl)acetamide

Figure imgf000029_0002

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.73-7.61 (m, 2H), 7.51-7.27 (m, 7H), 5.90-5.81 (m, IH), 5.33-5.11 (m, 2H), 4.52-4.47 (m, IH), 3.88-3.65 (m, 8H), 3.04-2.94 (m, IH), 2.82-2.59 (m, 9H), 2.53-2.42 (m, 2H), 2.21-2.05 (m, 2H), 1.92-1.54 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 637.5 (M+H)+, 659.4 (M+Na)+.

Example 11 iV-allyl-Λ'-(l-(((35',4/?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenyIpyrrolidin-3-yl) methyl)piperidin-4-yl)-2-(4-(iV-methylsulfamoyl)phenyl)acetainide

Figure imgf000030_0001

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.80-7.70 (m, 2H), 7.51-7.27 (m, 7H), 5.86-5.81 (m, IH), 5.33-5.21 (m, 2H)5 4.80 (brs, IH)5 4.51-4.48 (m, IH), 3.87-3.65 (m, 8H)5 3.05-2.81 (m, IH), 2.81-2.59 (m, 6H)5 2.53-2.42 (m, 2H), 2.23-2.13 (m, 2H)5 1.87-1.53 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 623.5 (M+H)+, 645.5 (M+Na)+.

Example 12

7V-allyl-iV-(l -(((3S,4R)-1 -(cy clopen tan ecarbony l)-4-hy droxy-4-phenylpy rrolidin-3-yl) methyl)piperidin-4-yl)-2-(4-sulfamoylphenyl)acetamide

Figure imgf000030_0002

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.83-7.76 (m, 2H), 7.51-7.27 (m, 7H), 5.89-5.79 (m, IH), 5.50 (brs, IH), 5.32-5.07 (m, 2H)5 4.45-4.40 (m5 IH), 3.87-3.63 (m, 8H), 3.01-2.95 (m, IH)5 2.82-2.52 (m, 3H)5 2.52-2.39 (m, 2H)5 2.18-2.15 (m, 2H)5 1.93-1.45 (m, 12H); MS (ESI5 Pos. 1.5 kV) m/z 609.5 (M+H)+, 631.5 (M+Na)+.

Example 13

iV-allyl-iV-(l-(((3-S',4l?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl) methyI)piperidin-4-yI)benzamide

Figure imgf000031_0001

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.52-7.27 (m, 10H), 5.97-5.64 (m, IH), 5.22-4.99 (m, 2H), 4.52-4.43 (m, IH), 4.07-3.48 (m, 6H), 3.06-2.94 (m, IH), 2.85-2.58 (m, 3H), 2.58-2.39 (m, 2H), 2.30-2.14 (m, 2H), 1.86-1.44 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 516.4 (M+H)+, 538.4 (M+Na)+.

Example 14

iV-aIIyI-iV-(l-(((35',4if)-l-(cycIopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidiii-3-yl) methyl)piperidin-4-yl)-3-phenylpropanamide

Figure imgf000031_0002

This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1R NMR (CDCl3, 300 MHz) δ 7.51-7.17 (m, 10H), 5.77-5.68 (m, IH), 5.19-5.05 (m, 2H), 4.58-4.47 (m, IH), 3.87-3.61 (m, 6H), 3.01-2.84 (m, 3H), 2.84-2.36 (m, 7H), 2.27-2.09 (m, 2H), 1.94-1.48 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 544.4 (M+H)+, 566.4 (M+Na)+.

Example 15

ΛLallyl-Λ'-(l-(((3-Sr,4Λ)-l-(cyclopeιitanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl) methyl)piperidin-4-yl)cinnamamide

Figure imgf000031_0003
This compound was prepared substantially as described in Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.72-7.67 (d, J = 15.0 Hz, IH), 7.53-7.27 (m, 10H), 6.75-7.70 (d, J = 15.0 Hz, IH), 5.95-5.86 (m, IH), 5.30-5.22 (m, 2H), 4.66-4.61 (m, IH), 3.99 (br, 2H), 3.88-3.67 (m, 4H), 3.06-3.02 (m, IH)5 2.86-2.66 (m, 3H), 2.55-2.43 (m, 2H), 2.27-2.19 (m, 2H), 1.87-1.53 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 542.4 (M+H)+, 564.3 (M+Na)+.

Example 16

l-Allyl-3-(4-chlorophenyl)-l-(l-(((3S,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phen ylpyrrolidin-3-yl)methyl)piperidin-4-yl)urea

Figure imgf000032_0001

According to Scheme 3, a solution of 4-chlorophenyl isocyanate (0.09g, 0.58 mmol) in DCM (2 mL) was added dropwise to a mixture of ((3i?,45)-4-((4-(allylamino)piperidin-l -yl)methyl)-3-hydroxy-3-phenylpyrrolidin-l-yl)(cyclopentyl)methanone (0.2 g, 0.49 mmol) and triethylamine (0.14 mL, 0.98 mmol) in DCM (4 mL) at 0 0C. The reaction was stirred at room temperature overnight and the resulting solution was extracted with DCM twice. The combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (l%-2% MeOH in DCM) afforded the title compound as a white foam (0.25 g, 93 %). 1H NMR (CDCl3, 300 MHz) δ 7.53-7.47 (t, J = 9.0 Hz, 2H), 7.42-7.19 (m, 7H), 6.53 (s, IH), 5.96-5.86 (m, IH), 5.45-5.39 (m, 2H), 4.37-4.29 (m, IH), 3.84-3.66 (m, 6H), 3.04-2.99 (m, IH), 2.83-2.64 (m, 3H), 2.55-2.42 (m, 2H), 2.24-2.14 (m, 2H), 1.87-1.54 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 565.4 M+.

Example 17

l-Allyl-3-(3-chlorophenyl)-l-(l-(((35,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phen yIpyrrolidin-3-yl)methyl)piperidin-4-yl)urea

Figure imgf000033_0001

This compound was prepared substantially as described in Example 16 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.46-7.42 (t, J = 6.0 Hz, 2H), 7 '.42-7..27 (m, 4H), 7.20-7.12 (m, 2H), 6.99-6.97 (t, J = 6.0 Hz, IH), 6.56 (s, IH), 5.96-5.87 (m, IH), 5.45-5.39 (m, 2H), 4.37-4.29 (m, IH), 3.87-3.66 (m, 6H), 3.05-2.98 (m, IH), 2.83-2.60 (m, 3H), 2.55-2.42 (m, 2H), 2.26-2.04 (m, 2H), 1.90-1.50 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 565.3 M+.

Example 18

l-Allyl-l-(l-(((3iSf,4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)m ethyl)piperidin-4-yl)-3-(4-phenoxyphenyl)urea

Figure imgf000033_0002

This compound was prepared substantially as described in Example 16 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.53-7.27 (m, 9H), 7.08-6.93 (m, 5H), 6.49 (s, IH), 5.91-5.87 (m, IH), 5.46-5.38 (m, 2H), 4.40-4.32 (m, IH), 3.90-3.67 (m, 6H), 3.06-2.97 (m, IH), 2.85-2.63 (m, 3H), 2.55-2.30 (m, 2H), 2.30-2.14 (m, 2H), 1.86-1.49 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 623.5 (M+H)+, 645.4 (M+Na)+.

Example 19

3-(4-Acetylphenyl)-l-allyl-l-(l-(((3S,4lf)-l-(cyclopentanecarbonyl)-4-hydroxy-4-pheii yIpyrroIidin-3-yI)methyI)piperidin-4-yI)urea

Figure imgf000034_0001

This compound was prepared substantially as described in Example 16 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.90-7.87 (d, J = 8.7 Hz, 2H), 7.53-7.27 (m, 7H), 6.81 (s, IH), 5.98-5.89 (m, IH), 5.48-5.42 (m, 2H), 4.39-4.31 (m, IH), 3.87-3.67 (m, 6H), 3.07-2.97 (m, IH), 2.86-2.63 (m, 3H), 2.55-2.31 (m, 5H), 2.31-2.17 (m, 2H), 1.86-1.55 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 573.5 (M+H)+, 595.4 (M+Na)+.

Example 20

l-AllyI-l-(l-(((3S,4/f)-l-(cyclopentanecarbonyI)-4-hydroxy-4-phenylpyrrolidiii-3-yl)iii ethyl)piperidin-4-yl)-3-o-tolylurea

Figure imgf000034_0002

This compound was prepared substantially as described in Example 16 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.74-7.71 (d, J = 7.8 Hz, IH), 7.53-7.48 (t, J = 7.8 Hz, IH), 7.42-7.27 (m, 4H), 7.16-7.11 (m, 2H), 6.99-6.97 (t, J = 7.8 Hz, IH), 6.31 (s, IH), 5.98-5.89 (m, IH), 5.47-5.35 (m, 2H), 4.41-4.32 (m, IH), 3.90-3.65 (m, 6H), 3.06-2.96 (m, IH), 2.85-2.63 (m, 3H), 2.55-2.31 (m, 2H), 2.31-2.11 (m, 5H), 1.94-1.54 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 545.4 (M+H)+, 567.4 (M+Na)+.

Example 21

l-Allyl-3-(4-/ert-butylphenyl)-l-(l-(((35',4Λ)-l-(cyclopentanecarbonyl)-4-hydroxy-4-p henylpyrroIidin-3-yI)methyI)piperidiii-4-yI)urea

Figure imgf000035_0001

This compound was prepared substantially as described in Example 16 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.53-7.48 (t, J = 7.5 Hz, 2H), 7.42-7.20 (m, 7H), 6.47 (s, IH), 5.95-5.86 (m, IH), 5.44-5.36 (m, 2H), 4.40-4.32 (m, IH), 3.83-3.65 (m, 6H), 3.05-2.98 (m, IH), 2.85-2.62 (m, 3H), 2.54-2.31 (m, 2H), 2.31-2.14 (m, 2H), 1.86-1.49 (m, 12H), 1.29 (s, 9H); MS (ESI, Pos. 1.5 kV) m/z 587.4 (M+H)+, 609.4 (M+Na)+.

Example 22

Ethyl 4-(3-allyl-3-(l-(((35,4/?)-l-(cyclopentanecarbonyl)-4-hydroxy-

4-phenylpy rrolidin-3-yl)methyl)piperidin-4-yl)ureido)benzoate

Figure imgf000035_0002

This compound was prepared substantially as described in Example 16 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.96-7.93 (d, J = 8.7 Hz, 2H), 7.53-7.27 (m, 7H), 6.77 (s, IH), 5.98-5.89 (m, IH), 5.48-5.42 (m, 2H), 4.38-4.31 (m, 3H), 3.87-3.67 (m, 6H), 3.06-2.98 (m, IH), 2.83-2.64 (m, 3H), 2.55-2.26 (m, 2H), 2.26-2.14 (m, 2H), 1.86-1.53 (m, 12H), 1.40-1.35 (t, J = 7.2 Hz, 2H); MS (ESI, Pos. 1.5 kV) m/z 603.5 (M+H)+, 625.5 (M+Na)+.

Example 23

l-AHyl-3-cyclohexyl-l-(l-(((3S,4i?)-l-(cyclopeiitanecarbonyl)-4-hydroxy-4-phenylpyrr olidin-3-yl)methyl)piperidin-4-yl)urea

Figure imgf000036_0001

This compound was prepared substantially as described in Example 16 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.52-7.47 (t, J = 7.2 Hz, 2H), 7.41-7.26 (m, 3H), 5.84-5.74 (m, IH), 5.30-5.22 (m, 2H), 4.36-4.26 (m, 2H), 3.86-3.47 (m, 7H), 3.02-2.98 (m, IH), 2.82-2.61 (m, 3H), 2.54-2.38 (m, 2H), 2.27-2.14 (m, 2H), 1.95-1.01 (m, 22H); MS (ESI, Pos. 1.5 kV) m/z 537.4 (M+H)+, 559.4 (M+Na)+.

Example 24

l-Allyl-3-benzyl-l-(l-(((3-Sr,4/?)-l-(cycIopentanecarbonyl)-4-hydroxy-4-phenyIpyrroIid in-3-yl)methyϊ)piperidin-4-yl)urea

Figure imgf000036_0002

According to Scheme 4, to a solution of triphosgene (0.06 g, 0.20 mmol) in DCM (2 mL) was added dropwise a mixture of benzyl amine (0.06 mL, 0.54 mmol) and DiPEA (0.10 mL, 0.54 mmol) in DCM (2 mL) at room temperature over 30 min. After stirring under nitrogen for 5 min, a mixture of (3i?,4S)-4-((4-(allylamino)piperidin-l-yl)methyl)-3- hydroxy-3-phenylpyrrolidin-l-yl)(cyclopentyl)methanone (0.2 g, 0.49 mmol) and DiPEA (0.10 mL, 0.54 mmol) in DCM (2 mL) was added drop wise over 15 min. After stirring at room temperature for 30 min, the solution was extracted with DCM twice. The combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.17 g, 65%). 1H NMR (CDCl3, 300 MHz) δ 7.52-7.24 (m, 10H), 5.83-5.74 (m, IH), 5.30-5.20 (m, 2H), 4.80-4.77 (m, IH), 4.40-4.30 (m, 3H), 3.86-3.66 (m, 6H), 3.03-2.94 (m, IH), 2.85-2.65 (m, 3H), 2.53-2.37 (m, 2H), 2.28-2.11 (m, 2H), 1.94-1.55 (m, 12H); MS (ESI, Pos. 1.5 kV) πi/z 545.5 (M+H)+, 567.5 (M+Na)+.

Example 25 l-Allyl-l-(l-(((3-S',4/?)-l-(cycIopentanecarbonyl)-4-hydroxy-4-phenylpyrroIidin-3-yl)m ethyl)piperidin-4-yl)-3-(4-fluorobenzyl)urea

Figure imgf000037_0001

This compound was prepared substantially as described in Example 24 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.52-7.47 (m, 2H), 7.40-7.20 (m, 5H), 7.02-6.96 (m, 2H), 5.83-5.72 (m, IH), 5.25-5.20 (m, 2H), 4.80-4.76 (m, IH), 4.38-4.27 (m, 3H), 3.86-3.65 (m, 6H), 3.03-2.95 (m, IH), 2.93-2.63 (m, 3H), 2.55-2.28 (m, 2H), 2.24-2.14 (m, 2H), 1.86-1.49 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 563.4 (M+H)+, 585.4 (M+Na)+.

Example 26

l-Allyl-l-(l-(((3-S',4Jf)-l-(cyclopeiitanecarbonyl)-4-hydroxy-4-phenylpyrrolidiii-3-yl)m ethyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

Figure imgf000037_0002

This compound was prepared substantially as described in Example 24 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.58-7.46 (m, 4H), 7.35-7.27 (m, 5H), 5.86-5.75 (m, IH), 5.30-5.23 (m, 2H), 4.92-4.88 (m, IH), 4.44-4.29 (m, 3H), 3.86-3.65 (m, 6H), 3.03-2.97 (m, IH), 2.93-2.66 (m, 3H), 2.55-2.28 (m, 2H), 2.24-2.15 (m, 2H), 1.86-1.55 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 613.5 (M+H)+, 635.4 (M+Na)+.

Example 27

1-AlIyI-I-(I -(^S^^-l-^ycIopentanecarbonylJ^-Iiydroxy^-phenylpyrroIidin-S-y^m ethyl)piperidin-4-yl)-3-(3,4-difluorobenzyl)urea

Figure imgf000038_0001

This compound was prepared substantially as described in Example 24 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.52-7.47 (t, J = 8.4 Hz, 2H), 7.42-7.29 (m, 3H), 7.13-6.94 (m, 3H), 5.85-5.76 (m, IH), 5.27-5.22 (m, 2H), 4.87-4.84 (m, IH), 4.33-4.28 (m, 3H), 3.85-3.65 (m, 6H), 3.03-2.99 (m, IH), 2.82-2.63 (m, 3H), 2.55-2.24 (m, 2H), 2.24-2.15 (m, 2H), 1.90-1.58 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 581.5 (M+H)+, 603.4 (M+Na)+.

Example 28

l-Allyl-l-(l-(((3-Sr,4jR)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)m ethyl)piperidin-4-yl)-3-(2,4-difluorobenzyI)urea

Figure imgf000038_0002

This compound was prepared substantially as described in Example 24 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.51 -7.46 (t, J = 7.5 Hz, 2H), 7.41 -7.25 (m, 4H), 6.85-6.73 (m, 2H), 5.82-5.72 (m, IH), 5.30-5.19 (m, 2H), 4.92-4.89 (m, IH), 4.37-4.25 (m, 3H), 3.86-3.65 (m, 6H), 3.02-2.98 (m, IH), 2.82-2.62 (m, 3H), 2.54-2.26 (m, 2H), 2.17-2.09 (m, 2H), 1.91-1.48 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 581.5 (M+H)+, 603.5 (M+Na)+.

Example 29

l-Allyl-l-(l-(((35,4J?)-l-(cyclopeiitanecarboiiyl)-4-hydroxy-4-phenylpyrrolidiii-3-yl)in ethyl)piperidin-4-yI)-3-((if)-l-phenylethyl)urea

Figure imgf000039_0001

This compound was prepared substantially as described in Example 24 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.51-7.46 (t, J = 7.5 Hz, 2H), 7.40-7.20 (m, 8H), 5.86-5.77 (m, IH), 5.30-5.24 (m, 2H), 4.96-4.89 (q, J = 1.2 Hz, IH), 4.77-4.74 (d, J = 7.2 Hz, IH), 4.34-4.26 (m, IH), 3.86-3.65 (m, 6H), 3.03-2.98 (m, IH), 2.82-2.60 (m, 3H), 2.52-2.26 (m, 2H), 2.21-2.11 (m, 2H), 1.92-1.52 (m, 12H), 1.43-1.41 (d, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 559.5 (M+H)+, 581.5 (M+Na)+.

Example 30

4-((3-Allyl-3-(l-(((3S,4Jf)-l-(cycloρentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-y I)methyl)piperidin-4-yl)ureido)methyl)-7VvY-dimethylbenzenesulfonamide

Figure imgf000039_0002

This compound was prepared substantially as described in Example 24 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.72-7.69 (d, J = 8.4 Hz, 2H), 1.52-1 Al (d, J = 7.8 Hz, 2H), 7.42-7.28 (m, 5H), 5.87-5.78 (m, IH), 5.30-5.24 (m, 2H), 5.01-4.97 (t, J = 5.7 Hz, IH), 4.48-4.46 (d, J = 5.7 Hz, 2H), 4.35-4.28 (m, IH), 3.86-3.65 (m, 6H), 3.04-2.99 (m, IH), 2.82-2.63 (m, 9H), 2.54-2.23 (m, 2H), 2.23-2.14 (m, 2H), 1.93-1.53 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 652.5 (M+H)+, 674.5 (M+Na)+.

Example 31

4-((3-AIIyI-3-(l-(((3S,4/?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-y l)methyl)piperidin-4-yl)ureido)methyl)-7V-methylbenzenesulfonainide

Figure imgf000040_0001

This compound was prepared substantially as described in Example 24 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.80-7.77 (d, J = 8.4 Hz, 2H), 7.52-7. 27 (m, 7H), 5.83-5.77 (m, IH), 5.30-5.24 (m, 2H), 5.01-4.97 (t, J = 5.7 Hz, IH), 4.74-4.72 (q, J = 5.4 Hz, IH), 4.46-4.44 (d, J - 5.7 Hz, 2H), 4.33-4.30 (m, IH), 3.86-3.66 (m, 6H), 3.04-2.99 (m, IH), 2.82-2.66 (m, 3H), 2.64-2.62 (d, J = 5.7 Hz, 3H), 2.53-2.24 (m, 2H), 2.20-2.14 (m, 2H), 1.86-1.53 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 638.5 (M+H)+, 660.5 (M+Na)+.

Example 32

4-Nitrobenzyl -(((35,4Λ)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl )methyl)piperidin-4-yl(cyclopropylmethyl)carbamate

Figure imgf000040_0002

Step A

Cyclopentyl((3R,4S)-4-((4-(cyclopropylmethylamino)piperidin-l-yl)methyl)-3-hydroxy-3-p henylpyrrolidin-l-yl)methanone

Figure imgf000040_0003

Following the procedure in scheme 5, a mixture of l-(((3ιS',4Λ)-l-(cyclopentanecarbonyl)-4 -hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-one (1.0 g, 2.7 mmol), acetic acid (0.16 mL, 2.7 mmol), NaBH(OAc)3 (0.86 g, 4.05 mmol) and cyclopropylmethanamine (0.26 mL, 2.97 mmol) in dry THF (8 mL) was stirred at room temperature overnight. After this time, the mixture was diluted with EA and washed sequentially with NaOH, NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated to yield crude amine which was used without further purification in the next step.

Step B

4-Nitrobenzyl l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)

methyl)piperidin-4-yl(cyclopropylmethyl)carbamate

A solution of 4-nitrobenzyl chloroformate (0.129 g, 0.60 mmol) in DCM (2 mL) was added dropwise to a mixture of the amine from step A (0.2 g, 0.54 mmol) and triethylamine (0.23 mL, 1.62 mmol) in DCM (4 mL) at 0 0C. After stirring at room temperature overnight, the solution was extracted with DCM twice. The combined organinc extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (l%-2% MeOH in DCM) afforded the title compound as a white foam (0.25 g, 77 %). 1H NMR (CDCl3, 300 MHz) δ 8.24-8.21 (d, J = 7.5 Hz, 2H), 7.52-7.27 (m, 7H), 5.23 (s, 2H), 3.87-3.66 (m, 5H), 3.10-2.83 (m, 3H), 2.83-2.65 (m, 3H), 2.65-2.44 (m, 2H), 2.20-2.09 (m, 2H), 1.86-1.54 (m, 12H), 0.95-0.94 (m, IH), 0.54-0.48 (m, 2H), 0.24 (m, 2H); MS (ESI, Pos. 1.5 kV) m/z 605.5 (M+H)+, 627.5 (M+Na)+.

Example 33

iV-(l-(((35,4iϊ)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidiii-3-yl)methyl)

piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-iV-phenylacetamide

Figure imgf000041_0001

This compound was prepared substantially as described in Example 32 step A and Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.82-7.80 (d, J = 7.5 Hz, 2H), 7.48-7.23 (m, 10H), 7.03-7.00 (m, 2H), 4.61-4.53 (m, IH), 3.81-3.48 (m, 4H), 3.37 (s, 2H), 3.03-2.95 (m, 4H), 2.78-2.48 (m, 3H), 2.48-2.23 (m, 2H), 2.17-2.09 (m, 2H), 1.81-1.40 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 644.4 (M+H)+, 666.4 (M+Na)+.

Example 34

N-benzyl-Λr-(l-(((35',4l?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl )methyl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

Figure imgf000042_0001

This compound was prepared substantially as described in Example 33 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.86-7.83 (d, J = 8.1 Hz, 2H), 7.50-7.20 (m, 12H), 4.62-4.52 (m, 3H), 3.90-3.59 (m, 6H), 3.03 (s, 3H), 2.99-2.85 (m, IH), 2.79-2.47 (m, 3H), 2.44-2.38 (m, 2H), 2.21-2.12 (m, 2H), 1.82-1.49 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 658.4 (M+H)+, 680.4 (M+Na)+.

Example 35

3-(l-(((35,4/f)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)pi peridin-4-yl)-l-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrimidiii-2(lH)-one

Figure imgf000042_0002

Step A

Cyclopentyl((3R,4S)-4-((4-(3,3-diethoxypropylamino)piperidin-l-yl)methyl)-3-hydroxy-3-p henylpyrrolidin-l-yl)methanone

Figure imgf000043_0001

Following the procedure in Scheme 6, a mixture of l-(((3S,4R)-l-(cyclopentanecarbonyl) - 4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-one (1.0 g, 2.7 mmol), acetic acid (0.16 mL, 2.7 mmol), NaBH(OAc)3 (0.86 g, 4.05 mmol) and 3,3-diethoxypropan-l-amine (0.48 mL, 2.97 mmol) in diy THF (8 mL) was stirred at room temperature overnight. After this time, the mixture was diluted with EA and washed sequentially with NaOH, NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated to yield crude amine which was used without further purification in the next step. MS (ESI, Pos. 1.5 kV) m/z 502.5 (M+H)+, 524.5 (M+Na)+.

Step B

l-O-tfβS^RJ-l-ζcyclopentanecarbonylJ^-hydroxy^-phenylpyrrolidin^-ylJmethylJpiperi din-4-yl)-l-(3,3-diethoxypropyl)-3-(4-(trifluoromethyl)benzyl)urea

Figure imgf000043_0002

This compound was prepared substantially as described in Example 24 using the starting material from step A, which was used without further purification in the next step.

Step C

3-(l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperi din-4-yl)-l-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrimidin-2(lH)-one

To a solution of the crude acetal intermediate (0.065 g, 0.09 mmol) from step B in DCM (20 mL) was added TsOH (0.032 g). The reaction was heated at reflux for 3 d, during which time EtOH was removed using 4-A molecular sieves. The reaction mixture was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white powder (0.045 g, 70 %). 1H NMR (CDCl3, 300 MHz) δ 7.61-7.20 (m, 10H), 5.75-5.73 (m, 0.5H), 5.26-5.18 (m, 0.5H), 4.92-4.82 (m, 0.5H), 4.50-4.31 (m, 1.5H), 3.89-3.59 (m, 6H), 3.17-2.93 (m5 2H), 2.90-2.62 (m, 4H), 2.54-2.37 (m, 2H), 2.27-2.10 (m, 2H), 1.96-1.56 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 611.5 (M+H)+, 630.7 (M+Na)+.

Example 36

l-AUyl-l-(l-(((3S,4l?)-l-(furan-2-carbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl )piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

Figure imgf000044_0001

Step A

(3R,4S)-tert-butyl 3-hydroxy-4-((4-hydroxypiperidin-l-yl)methyl)-3-phenylpyrrolidine

-l-carboxylate

Figure imgf000044_0002

According to Scheme 7, a solution of (Boc)2O (8.7 g, 39.8 mmol) in DCM (20 mL) was added dropwise to a solution of DMAP (0.44 g, 3.62 mmol), Et3N (10 mL, 72.4 mmol) and l-(((3i?,4i?)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-ol (10.0 g, 36.2 mmol) in DCM (100 mL) at 0°C over 30 min. After stirring under nitrogen overnight, the solution was extracted with DCM twice. The combined organic extracts were washed with 10% HCl and brine, dried over Na2SO4 and concentrated, this afforde the crude title compound which was used without further purification in the next step.

Step B (3R,4S)-tert-butyl 3-hydroxy-4-((4-oxopiperidin-l-yl)methyl)-3-phenylpyrrolidine-l

-carboxylate

Figure imgf000045_0001

To a solution of oxalyl chloride (2.0 mL, 22.5 mmol) in DCM (10 mL) at -78 0C was added dropwise to a solution of dimethylsulfoxide (3.7 mL, 51.9 mmol) in DCM (10 mL). After stirring for 30 min, the alcohol (6.5 g, 17.3 mmol) from step A as a solution in DCM (60 mL) was added dropwise. The resultant slurry was stirred for another 30 min and then Et3N was added. After 5 min, the reaction was allowed to warm to room temperature. The mixture was extracted with DCM twice and the combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (50%-100% EA in PE) afforded the title compound as a yellow foam (5.0 g, 78 %). 1H NMR (CDCl3, 300 MHz) δ 7.52-7.50 (d, J = 7.5 Hz, 2H), 7.40-7.35 (t, J = 7.5 Hz, 2H), 7.30-7.26 (m, IH), 3.78-3.48 (m, 4H), 2.77-2.29 (m, 1 IH), 1.49 (s, 9H); MS (ESI, Pos. 1.5 kV) m/z 375.3 (M+H)+, 407.3 (M+MeOH+H)+.

Step C

(3R,4S)-tert-butyl 4-((4-(allylamino)piperidin-l-yl)methyl)-3-hydroxy-3-phenylpyrrolidine

-1 -carboxylate

Figure imgf000045_0002

A mixture of the ketone (3.0 g, 8.0 mmol) from step B, acetic acid (0.46 mL, 8.0 mmol), NaBH(OAc)3 (2.54 g, 12.0 mmol) and allyl amine (0.66 mL, 8.8 mmol) in dry THF (50 mL) was stirred at room temperature overnight. After this time, the mixture was diluted with EA and washed sequentially with NaOH, NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated to afford the crude amine which was used without further purification in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.50-7.47 (d, J = 7.5 Hz, 2H), 7.33-7.33 (t, J = 7.5 Hz, 2H), 7.31-7.19 (m, IH), 5.95-5.81 (m, IH), 5.18-5.05 (m, 2H), 3.77-3.67 (m, 4H), 3.25-3.23 (d, J = 5.7 Hz, 2H), 2.92-2.88 (m, IH), 2.74-2.51 (m, 2H), 2.51-2.34 (m, 3H), 2.15-2.00 (m, 2H), 1.94-1.53 (m, 4H),1.48 (m, 9H); MS (ESI, Pos. 1.5 kV) m/z 416.4 (M+H)+. Step D

(3 R, 4S) -tert-butyl 4- ((4- (1 -allyl-3- (4- (trifluoromethyl) benzyl) ureido)piperidin-l-yl)methyl) S-hydroxyS-phenylpyrrolidine-l-carboxylate

Figure imgf000046_0001

To a solution of triphosgene (0.234 g, 0.788 mmol) in DCM (5 mL) was added dropwise a mixture of 4-(trifluoromethyl)benzyl amine hydrochloride (0.45 g, 2.13 mmol) and DiPEA (0.76 mL, 4.25 mmol) as a solution in DCM (5 mL) at room temperature over 30 min. After stirring under nitrogen for further 5 min, a mixture of the amine from step C (0.8 g, 1.93 mmol) and DiPEA (0.40 mL, 2.13 mmol) in DCM (5 mL) were added slowly over 15 min. After being stirred at room temperature for 30 min, the solution was extracted with

DCM twice. The combined organic extracts were washed with water and brine, dried over

Na2SO4 and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.83 g, 70%). 1H NMR (CDCl3, 300 MHz) δ 7.58-7.55 (d, J = 7.5 Hz, 2H), 7.51-7.48 (d, J = 7.5 Hz, 2H), 7.42-7.25 (m, 5H), 5.85-5.75 (m, IH), 5.28-5.15 (m, 2H), 4.92-4.88 (m, IH), 4.52-4.23 (m, 3H), 3.82-3.48 (m, 6H), 3.08-2.62 (m, 3H), 2.52-2.00 (m, 4H), 1.79-1.55 (m, 4H), 1.49 (m, 9H); MS (ESI, Pos. 1.5 kV) m/z 617.4 (M+H)+, 639.4 (M+Na)+.

Step E

l-AHyl-l-(l-(((3R,4R)-4-hydroocy-4ψhenylpyrrolidin-3-yl)methyl)piperidin-4-yl)-3-(4-(trifl uoromethyl)benzyl)urea

Figure imgf000046_0002
To a solution of Boc-urea product from step D (0.6 g, 0.97 mmol) in DCM (10 mL) was added TFA (0.75 mL, 9.7 mmol) at room temperature. After stirring under nitrogen for four hours, the solution was concentrated and diluted with DCM, then washed sequentially with 2 N NaOH, water and brine, dried over Na2SO4 and concentrated. This affored the crude product which was used without further purification in the next step.

Step F

l-Allyl-l-(l-(((3SJR)-l-(furarι-2-carbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)τnethyl)pip eridin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

DiPEA (0.05 mL, 0.3 mmol) was added dropwise to a solution of the amine from step E (0.05 g, 0.10 mmol), 2-furoic acid (0.013 g, 0.12 mmol), EDCI (0.029 g, 0.15 mmol) and HOBt (0.020 g, 0.15 mmol) in DCM (2 mL) at 0 0C. After stirring at room temperature overnight, the resulting solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.050 g, 82 %). 1H NMR (CDCl3, 300 MHz) δ 7.58-7.52 (m, 4H), 7.46-7.27 (m, 6H), 7.14-7.08 (m, IH), 6.52-6.47 (m, IH), 5.87-5.75 (m, IH), 5.29-5.23 (m, 2H), 4.92 (m, IH), 4.45-4.28 (m, 3H), 4.20-3.88 (m, 4H), 3.76 (s, 2 H), 3.06-2.98 (m, IH), 2.77-2.60 (m, 2H), 2.58-2.45 (m, 2H), 2.29-2.17 (m, 2H), 1.80-1.52 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 611.5 (MH-H)+, 633.5 (M+Na)+.

Example 37

l-AUyl-l-(l-(((3S,4Λ)-l-(4,4-difluorocyclohexanecarbonyl)-4-hydroxy-4-phenylpyrroli din-3-yl)methyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

Figure imgf000047_0001

This compound was prepared substantially as described in Example 36 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.58-7.42 (m, 4H), 7.40-7.28 (m, 5H), 5.82-5.75 (m, IH), 5.30-5.23 (m, 2H), 4.89-4.86 (m, IH), 4.44-4.28 (m, 3H), 3.88-3.66 (m, 6H), 3.03-2.98 (m, IH), 2.70-2.55 (m, 2H), 2.47-2.28 (m, 3H), 2.24-2.13 (m, 4H), 1.95-1.52 (m, 10H); MS (ESI, Pos. 1.5 kV) m/z 663.5 (M+H)+, 685.5 (M+Na)+. Example 38

l-AUyH-(l-(((3S,4R)-4-hydroxy-4-phenyl-l-((5)-tetrahydrofuran-2-carbonyl)pyrroli din-3-yl)methyl)piperidin-4-yI)-3-(4-(trifluoromethyl)benzyl)urea

Figure imgf000048_0001

This compound was prepared substantially as described in Example 36 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.58-7.46 (m, 4H), 7.41-7.25 (m, 5H), 5.87-5.75 (m, IH), 5.30-5.23 (m, 2H), 4.91-4.88 (m, IH), 4.60-4.28 (m, 4H), 4.03-3.69 (m, 8H), 3.03-2.94 (m, IH), 2.77-2.63 (m, 2H), 2.54-2.39 (m, 2H), 2.30-1.55 (m, 10H); MS (ESI, Pos. 1.5 kV) m/z 615.4 (M+H)+, 637.4 (M+Na)+.

Example 39

1-AlIyI-I-(I -(((3.9,4if)-4-hydroxy-4-phenyI-l-((-?)-tetrahydrofuran-2-carbonyi)pyrroli din-3-yl)methyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

Figure imgf000048_0002

This compound was prepared substantially as described in Example 36 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.58-7.48 (m5 4H), 7.41-7.27 (m, 5H), 5.86-5.75 (m, IH), 5.28-5.23 (m, 2H), 4.93-4.89 (m, IH), 4.61-4.28 (m, 4H), 4.02-3.67 (m, 8H), 3.02-2.95 (m, IH), 2.77-2.60 (m, 2H), 2.58-2.40 (m, 2H), 2.30-1.55 (m, 10H); MS (ESI, Pos. 1.5 kV) m/z 615.4 (M+H)+, 637.4 (M+Na)+.

Example 40

l-Allyl-l-(l-(((3S,4R)-4-hydroxy-4-phenyl-l-(lH-pyrrole-l-carbonyl)pyrrolidin-3-yl) methyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

Figure imgf000049_0001

Following the procedure in scheme 8, a solution of lH-pyrrole-1-carbonyl chloride (0.17 g, 0.128 mmol) in DCM (1 mL) was added dropwise to a solution of the amine from Example 41 step E (0.06 g, 0.116 mmol) in DCM (100 mL) at 0 0C. After stirring under nitrogen overnight, the solution was extracted with DCM twice. The combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.044 g, 62%). 1H NMR (CDCl3, 300 MHz) δ 9.73-9.66 (m, IH), 7.58-7.48 (m, 4H), 7.41-7.27 (m, 5H), 6.94 (s, IH), 6.63-6.56 (m, IH), 6.29-6.24 (m, IH), 5.86-5.75 (m, IH), 5.29-5.23 (m, 2H), 4.93-4.89 (m, IH), 4.45-4.28 (m, 3H), 4.11-3.75 (m, 4H), 3.71 (s, 2H), 3.05-2.97 (m, IH), 2.82-2.66 (m, 2H), 2.56-2.44 (m, 2H), 2.28-2.13 (m, 2H), 1.82-1.52 (m, 4H); MS (ESI, Pos. 1.5 kV) m/z 610.5 (M+H)+, 632.4 (M+Na)+.

Example 41

l-Allyl-l-(l-(((3iS',4if)-4-hydroxy-4-phenyl-l-(pyrrolidine-l-carbonyl)pyrroIidin-3-yl) methyI)piperidin-4-yI)-3-(4-(trifluoromethyI)benzyI)urea

Figure imgf000049_0002

This compound was prepared substantially as described in Example 40 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.58-7.49 (m, 4H), 7.40-7.25 (m, 5H), 5.86-5.75 (m, IH), 5.29-5.23 (m, 2H), 4.92-4.88 (m, IH), 4.45-4.29 (m, 3H), 3.77-3.57 (m, 6H), 3.39-3.33 (m, 4H), 3.03-2.99 (m, IH), 2.80-2.66 (m, 2H), 2.51-2.39 (m, 2H), 2.24-2.06 (m, 2H), 1.85-1.53 (m, 8H); MS (ESI, Pos. 1.5 kV) m/z 614.6 (M+H)+, 636.5 (M+Na)+.

Example 42 4-Nitrobenzylallyl(l-(((35,4Λ)-l-(cyclopentanecarbonyl)-4-hydroxy-4- (4-methoxyphenyl)pyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

Figure imgf000050_0001

Step A

1 -Ethyl 4-methyl 2-hydroxy-2-(4-methqxyphenyl)-3-methylenesuccinate

Figure imgf000050_0002

Following the procedure in Scheme 9, a mixture of methyl acrylate (123 mL, 1369 mmol), ethyl 2-(4-methoxyphenyl)-2-oxoacetate (142 g, 684 mmol) and DABCO (23 g, 205 mmol) was stirred at room temperature. After 10 days the reaction was stopped, and diluted with ether (600 mL) and then washed with HCl (2 M, 600 ml) and water (600 mL). The mixture was dried over Na2SO4, filtered and evaporated to afford the crude product (15O g, 75 %), which was used without further purification in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.55-7.52 (d, J = 9.0 Hz, 2H), 6.92-6.89 (d, J = 9.0 Hz, 2H)5 6.37 (s, IH), 5.42 (s, IH),

4.32-4.25 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 1.31-1.26 (q, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 317.1 (M+Na)+, 349.2 (M+MeOH+Na)+.

StepB

(R)-I -ethyl 4-methyl 2-hydroxy-2-(4-methoxyphenyl)-3-((l -phenylethylamino)methyl)

succinate

Figure imgf000051_0001

A solution of the alkene from step A (49.0 g, 166 mmol) and (i-)-l-phenylethanamine (23 mL, 183 mmol) in MeOH (200 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to give yellow oil, which was used without further purification in the next step. MS (ESI, Pos. 1.5 kV) m/z 416.3 (M+H)+, 438.2 (M+ Na)+.

Step C

(3R,4R)-methyl 4-hydroxy-4-(4-methoxyphenyl)-5-oxo-l -((R)-I -phenylethyl)pyrrolidine-3

-carboxylate

Figure imgf000051_0002

A solution of the crude amine from step B (67 g, 161 mmol) in dioxane (180 mL) and TFA (4.1 mL) was heated at reflux for 24 h. The reaction mixture was concentrated and extracted with EA. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Column chromatography on silica (20%-40% EA in PE) afforded the title compound as a white foam (2.11 g, 22 % for two steps). 1H NMR (CDCl3, 300 MHz) δ 7.43-7.33 (m, 5H), 7.00-6.95 (d, J = 9.0 Hz, 2H), 6.73-6.68 (d, J = 9.0 Hz, 2H), 5.64-5.57 (q, J = 7.2 Hz, IH), 3.74 (s, 3H), 3.58-3.46 (m, 2H), 3.39 (s, 3H), 3.37-3.27 (m, IH), 1.66-1.64 (d, J = 7.2 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 370.2 (M+H)+, 392.2 (M+ Na)+, 424.3 (M+MeOH+Na)+.

Step D

(3S,4R)-4-hydroxy-4-(4-methoxyphenyl)-5-oxo-l-((R)-l-phenylethyl)pyrrolidine-3-carboxy Hc acid

Figure imgf000052_0001

A solution of the ester from step C (5.0 g, 13.5 mmol) in MeOH (25 mL) and 2 N NaOH (15 mL, 30 mmol) was stirred at room temperature for 6 h. The reaction mixture was concentrated and neutralized with 3 N HCl. Then the solution was extracted with EA. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as a white powder (4.0 g, 83%), which was used without further purification in the next step.

Step E

l-((3S,4R)-4-hydroxy-4-(4-methoxyphenyl)-5-oxo-l -((R)-I -phenylethyl)pyrrolidine-3-carb onyl)piperidin-4-one

Figure imgf000052_0002

A solution of DCC (2.58 g, 12.5 mmol) in dry THF (10 mL) was added dropwise to a solution of the acid from step E (3.70 g, 10.4 mmol) and HOSu (1.44 g, 12.5 mmol) in dry THF (50 mL) at 0 0C. After stirring under nitrogen overnight, the reaction mixture was filtrated and washed with dry THF. Et3N (1.4 mL, 31.2 mmol) and piperidine-4,4-diol hydrochloride (1.76 g, 11.4 mmol) were then added at 0 0C and the resulting slurry was stirred at room temperature for 24 h. After this time, the reaction mixture was concentrated and extracted with EA. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Column chromatography on silica (30%-60% EA in PE) afforded the title compound as a white foam (3.27 g, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.33 (m, 5H), 7.19-7.17 (d, J = 8.7 Hz, 2H), 6.85-6.82 (d, J = 8.7 Hz, 2H), 5.58-5.56 (q, J = 6.9 Hz, IH), 4.33-4.28 (m, IH), 3.97-3.89 (m, 2H), 3.78 (s, 3H), 3.72-3.67 (m, IH), 3.52-3.42 (m, 3H), 3.06-3.00 (dd, J = 9.9 Hz, J = 7.2, Hz IH), 2.63-2.28 (m, 4H), 1.75- 1.72 (d, J = 6.9 Hz, 3H); MS (ESI, Pos. 1.5 kV) m/z 459.3 (M+ Na)+, 491.3 (M+MeOH+Na)+.

Step F

l-(((3S,4R)-4-hydroxy-4-(4-methoxyphenyl)-l-((R)-l-phenylethyl)pyrrolidin-3-yl)methyl)pi peridin-4-ol

Figure imgf000053_0001

LAH (1.0 g, 27.5 mmol) was added in portions to a solution of the ketone from step E (2.0 g, 4.6 mmol) in dry THF (50 mL) at 0 0C. The reaction mixture was heated at reflux for 24 h, after which time, it was stopped by adding 1 mL H2O, ImL 15% NaOH and ImL H2O. Filtration and concentration to give a yellow oil, which was used without further purification in the next step.

Step G

l-(((3R,4R)-4-hydroxy-4-(4-methoxyphenyl)pyrrolidin-3-yl)methyl)piperidin-4-ol

Figure imgf000053_0002

A mixture of the alcohol from step F (1.9 g, 4.60 mmol) in MeOH (50 mL) was hydrogenated in the presence of Pd(OH)2/C (0.38 g) under 3.0 Mp of H2 at 50 0C for 6 h. Filtration and concentration to give a white yellow oil, which was used without further purification in the next step.

Step H

Cyclopentyl((3R,4S)-3-hydroxy-4-((4-hydroxypiperidin-l-yl)methyl)-3-(4-methoxyphenyl)p yrrolidin- 1 -yl)methanone

Figure imgf000054_0001

A solution of cyclopentanecarbonyl chloride (0.76 g, 5.70 mmol) in dry DCM (5 mL) was added dropwise to a solution of the amine from step G (4.60 mmol) and Et3N (2.0 mL, 14.4 mmol) in dry DCM (20 mL) at 0 0C. After stirring under nitrogen overnight, the reaction mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. Recrystallization from PE/EA afforded the title compound as white crystals (1.11 g, 60 % for the three steps). 1H NMR (CDCl3, 300 MHz) δ 7.43-7.37 (m, 2H), 6.93-6.88 (m, 2H), 3.82-3.61 (m, 8H), 2.80-2.05 (m, 8H),1.88-1.50 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 403.2 (M+ H)+, 425.3 (M+Na)+.

Step I

l-tfβS^RJ-l-fcyclopentanecarbonylJ^-hydroxy-^ft-methoxyphenylJpyrrolidin-S-ylJmeth yl)piperidin-4-one

Figure imgf000054_0002

To a solution of oxalyl chloride (0.26 mL, 3.0 mmol) in DCM (5 mL) at -78 0C was added dropwise a solution of dimethylsulfoxide (0.49 mL, 6.9 mmol) in DCM (5 mL). After stirring for 30 min, the alcohol from step H (0.92 g, 2.3 mmol) as a solution in DCM (20 mL) was added dropwise. The resultant slurry was stirred for another 30 min and then Et3N (0.96 mL, 6.9 mmol) was added to the solution. After 5 min, the reaction was allowed to warm to room temperature. The mixture was extracted with DCM twice and the combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (50%- 100% EA in PE) afforded the title compound as a white yellow foam (0.672 g, 73 %). 1H NMR (CDCl3, 300 MHz) δ 7.38-7.35 (m, IH),

7.22-7.17 (m, IH), 6.87-6.81 (m, 2H), 3.78-3.68 (m, 7H), 2.74-2.32 (m, 12H), 1.83-1.45 (m, 8H); MS (ESI, Pos. 1.5 kV) m/z 401.2 (M+H)+, 423.2 (M+Na)+, 433.3 (M+MeOH+H)+.

Step J

((3R,4S)-4-((4-(allylamino)piperidin-l-yl)methyl)-3-hydroxy-3-(4-methoxyphenyl)pyrrolidi n-l-yl) (cyclopentyl)methanone

Figure imgf000055_0001

A mixture of the ketone from step I (0.052 g, 0.13 mmol), acetic acid (0.075 mL, 0.13 mmol), NaBH(OAc)3 (0.041 g, 0.195 mmol) and allyl amine (0.011 mL, 0.143 mmol) in dry THF (5 mL) was stirred at room temperature overnight. The mixture was diluted with EA and washed sequentially with NaOH, NaHCO3 and brine. The organic phase was dried with Na2SO4 and concentrated to yield crude amine which was used without further purification in the next step.

Step K

4-Nitrobenzyl allyl(l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-(4-methoxy

phenyl)pyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

A solution of 4-nitrobenzyl chloroformate (0.034 g, 0.16 mmol) in DCM (1 mL) was added dropwise to a mixture of the amine from step J (0.057 g, 0.13 mmol) and triethyl amine (0.54 mL, 0.39 mmol) in DCM (2 mL) at 0 0C. After stirring at room temperature overnight, the solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (1 %-3 % MeOH in DCM) afforded the title compound as a white foam (0.060 g, 75 %). 1H NMR (CDCl3, 300 MHz) δ 7.51 -7.25 (m, 6H), 6.93-6.88 (d, J = 8.7 Hz, 2H), 5.88-5.74 (m, IH), 5.22-5.09 (m, 4H), 4.11-3.55 (m, 10H), 3.02-2.97 (m, IH), 2.85-2.66 (m, 3H), 2.65-2.39 (m, 2H), 2.22-2.03 (m, 2H), 1.92-1.49 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 621.5 (M+H)+, 643.5 (M+Na)+. Example 43

l-AUyI-l-(l-(((3-S',4Jf)-l-(cyclopentanecarbonyl)-4-(4-fluorophenyl)-4-hydroxypyrroli din-3-yI)methyI)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

Figure imgf000056_0001

This compound was prepared substantially as described in Example 42 and Example 24 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.57-7.23 (m, 7H), 7.08-7.01 (m, 5H), 5.85-5.75 (m, IH), 5.30-5.22 (m, 2H), 4.92-4.89 (m, IH), 4.43-4.28 (m, 3H), 3.85-3.62 (m, 6H), 3.06-2.92 (m, IH), 2.83-2.56 (m, 3H), 2.53-2.32 (m, 2H), 2.27-2.03 (m, 2H), 1.92-1.44 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 631.5 (M+H)+, 653.5 (M+Na)+.

Example 44

iV-allyl-iV-(l-(((35',4R)-l-(cyclopentanecarbonyl)-4-(4-fluoroplienyl)-4-hydroxypyrroli din-3-yl)methyl)piperidin-4-yl)-2-(4-(7V,7V-dimethylsulfamoyl)phenyl)acetaniide

Figure imgf000056_0002

This compound was prepared substantially as described in Example 42 and Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.73-7.61 (m, 2H), 7.53-7.27 (m, 4H), 7.10-7.02 (m, 2H), 5.90-5.79 (m, IH), 5.33-5.10 (m, 2H), 4.52-4.49 (m, IH), 3.88-3.63 (m, 8H), 3.06-2.93 (m, IH), 2.83-2.62 (m5 9H), 2.54-2.35 (m, 2H), 2.26-2.14 (m, 2H), 1.88-1.49 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 655.5 (M+H)+, 677.5 (M+Na)+. Example 45

4-Nitrobenzyl allyl(l-(((35,4R)-l-(cyclopentanecarbonyl)-4-methoxy-4-

phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

Figure imgf000057_0001

Step A

(3R,4R)-4-(hydroxymethyl)-3-phenyl-l-((R)-l-phenylethyl)pyrrolidin-3-ol

Figure imgf000057_0002

Following the procedure in Scheme 10, LAH (1.4 g, 36.9 mmol) was added portionwise to a solution of (3iS',4i?)-4-hydroxy-5-oxo-4-phenyl- 1 -((R)- 1 -phenylethyl)pyrrolidine-

3-carboxylic acid (4.0 g, 12.3 mmol) in dry THF (40 mL) at 0 0C. The reaction mixture was heated at reflux for 4 h after which time, the reaction was stopped by adding 1 mL H2O, ImL 15% NaOH and ImL H2O. Filtration and concentration to give a yellow oil, which was used without further purification in the next step.

Step B

(3 R, 4R) ~4- (hydroxymethyl) -3-phenylpyrrolidin-3-ol

Figure imgf000057_0003

A mixture of the alcohol from step A (3.65 g, 12.3 mmol) in MeOH (30 mL) was hydrogenated in the presence of Pd(OH)2/C (0.73 g) under 5.0 Mp of H2 at 50 0C for 6 h. Filtration and concentration to give a white yellow oil, which was used without further purification in the next step.

Step C

Cyclopentyl((3R,4R)-3-hydroxy-4-(hydroxymethyl)-3-phenylpyrrolidin-l-yl)methanone

Figure imgf000058_0001

A solution of cyclopentanecarbonyl chloride (1.7 mL, 13.8 mmol) in dry DCM (5 mL) was added dropwise to a solution of the amine from step B (2.22 g, 11.5 mmol) and Et3N (4.8 mL, 34.5 mmol) in dry DCM (30 mL) at 0 0C. After stirring under nitrogen overnight, the reaction mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. Recrystallization from PE/EA afforded the title compound as white crystals (2.0 g, 61 % for the three steps). 1H NMR (DMSO-^6, 300 MHz) δ 7.57-7.51 (m, 2H), 7.38-7.23 (m, 3H), 5.44-5.40 (d, J = 13.5 Hz, 2H), 4.98-4.45 (m, IH), 3.95-3.41 (m, 5H), 2.93-2.88 (m, 0.5H), 2.76-2.62 (m, 0.5H), 2.60-2.54 (m, IH), 1.78-1.47 (m, 8H); MS (ESI, Pos. 1.5 kV) m/z 290.2 (M+ H)+, 312.2 (M+Na)+.

Step D

((3R,4R)-4-((tert-butyldimethylsilyloxy)methyl)-3-hydroxy-3-phenylpyrrolιdin-l-yl)(cyclop entyl)methanone

TBSOH2C,HQ Ph

To the alcohol from step C (0.5 g, 1.73 mmol) as a solution in DMF (6 mL) were added TBDMSCl (0.286 g, 1.9 mmol) and imidazole (0.294 g, 4.325 mmol) and the mixture was stirred for 18 h at room temperature. After dilution with water and extraction with EA, the organic phases were washed, dried, and evaporated, affording the title product (0.65 g, 92 %) as pale yellow foam, which was used without further purification in the next step. Step E

((3R,4R)-4-((tert-butyldimethylsilyloxy)methyl)-3-methoxy-3-phenylpyrrolidin-l-yl)(cyclop entyl)methanone

Figure imgf000059_0001

To a cooled (0 °C) solution of the alcohol from step D (0.2 g, 0.5 mmol) in dry THF (5 mL) was added NaH (60% in paraffin oil, 0.060 g, 1.5 mmol) and MeI (0.093 mL, 1.5 mmol). The reaction was stirred under an argon atmosphere overnight. After this time, the mixture was diluted with Et2O and washed with a saturated solution of NH4Cl and H2O. The organic layer was dried (Na2SO4) and concentrated, and the residue was purified by flash chromatography to afford the product as a colorless oil (0.15 g, 72 %). 1H NMR (CDCl3, 300 MHz) δ 7.38-7.26 (m, 5H), 4.10-3.95 (m, 2H), 3.82-3.59 (m, 4H), 3.10 (s, 0.5H), 3.14 (s, 2.5H), 2.86-2.77 (m, IH), 2.44-2.38 (m, IH), 1.90-1.47 (m, 8H), 0.83 (s, 9H), -0.01 (s, 6H); MS (ESI, Pos. 1.5 kV) m/z 418.3 (M+ H)+, 440.4 (M+Na)+.

Step F

Cyclopentyl((3R, 4R)-4-(hydroxymethyl)-3-methoxy-3-phenylpyrrolidin-l-yl)methanone

Figure imgf000059_0002

Tetrabutylammonium fluoride (0.5 mL, 0.5 mmol, 1 N in THF) was added to a solution of the silyl ether from step E (0.14 g, 0.335 mmol) in THF (2 mL) and stirred at room temperature overnight in the dark. The reaction mixture was filtered over silica gel and purified by chromatography (eluant: PE/EA, 1/1) to afford the product as white crystals (0.095 g, 98 %). 1H NMR (CDCl3, 300 MHz) δ 7.45-7.27 (m, 5H), 4.21-4.00 (m, 2H), 3.85-3.54 (m, 4H), 3.20 (s, 0.5H), 3.17 (s, 2.5H), 3.10-3.06 (m, 0.75H), 3.01-2.87 (m, 0.25H), 2.85-2.79 (m, IH), 2.40-2.32 (m, IH), 1.96-1.58 (m, 8H); MS (ESI, Pos. 1.5 kV) m/z 304.2 (M+ H)+, 326.2 (M+Na)+.

Step G (3S,4R)-l-(cyclopentanecarbonyl)-4-methoxy-4-phenylpyrrolidine-3-carbaldehyde

Figure imgf000060_0001

To a solution of oxalyl chloride (0.03 mL, 0.343 mmol) in DCM (2 mL) at -78 0C was added a solution of dimethylsulfoxide (0.056 mL, 0.792 mmol) in DCM (1 mL) dropwise. After stirring for 30 min, the alcohol from step F (0.080 g, 0.264 mmol) as a solution in DCM (3 mL) was added dropwise. The resultant slurry was stirred for another 30 min and then Et3N (0.11 mL, 0.792 mmol) was added to the solution. After 5 min, the reaction was allowed to warm to room temperature. The mixture was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated to afford the title compound as a yellow powder, which was used without further purification in the next step. MS (ESI, Pos. 1.5 kV) m/z 302.2 (M+H)+, 324.2 (M+Na)+, 356.2 (M+MeOH+Na)+.

Step H

tert-butyl 4-(allylamino)piperidine-l-carboxylate

Figure imgf000060_0002

A mixture of N-Boc 4-piperidinone (5.0 g, 25.1 mmol), acetic acid (1.4 mL, 25.1 mmol), NaBH(OAc)3 (8.0 g, 37.65 mmol) and allyl amine (2.1 mL, 27.6 mmol) in dry THF (50 mL) was stirred at room temperature overnight. The mixture was diluted with EA and washed with NaOH, NaHCO3 and brine. The organic phase was dried with Na2SO4 and concentrated to yield crude amine which was used without further purification in the next step. 1H NMR (CDCl3, 300MHz) δ 5.97-5.84 (m, IH), 5.22-5.07 (m, 2H), 4.05-4.03 (m, 2H), 3.30-3.28 (d, J = 6.0 Hz, 2H), 2.82-2.74 (m, 2H), 2.68-2.61 (m, IH), 1.87-1.83 (m, 2H), 1.50-1.31 (m, 1 IH); MS (ESI, Pos. 1.5 kV) m/z 241.2 (M+H)+.

Step I

tert-butyl 4-(allyl((4-nitrobenzyloxy)carbonyl)amino)piperidine-l-carboxylate

Figure imgf000061_0001

A solution of the 4-nitrobenzyl chloroformate (0.65 g, 3.0 mmol) in DCM (2 mL) was added dropwise to a mixture of the amine (0.60 g, 2.5 mmol) from step H and triethyl amine(1.04 mL, 7.5 mmol) in DCM (8 mL) at 0°C. After being stirred at room temperature overnight, the resulting solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica (10%-20% EA in PE) afforded the title compound as a colorless oil (0.90 g, 86%). 1H NMR (CDCl3, 300MHz) δ 8.23-8.21 (d, J = 8.4 Hz, 2H), 7.52-7.49

(d, J = 8.4 Hz, 2H), 5.85-5.74 (m, IH), 5.24-5.19 (m, 4H)5 4.17-4.09 (m, 3H), 3.84 (br, 2H), 2.73-2.69 (m, 2H), 1.73-1.51 (m, 4H), 1.46 (s, 9H).

Step J

4-nitrobenzyl allyl(piperidin-4-yl)carbamate

Figure imgf000061_0002

To a solution of Boc-amine (0.8 g, 1.91 mmol) from step I in DCM (10 mL) was added CF3COOH (0.71 mL, 9.55 mmol) at room temperature. After stirring under nitrogen for another 2 h, the resulting solution was concentrated and then diluted with DCM, washed with 2 N NaOH, water and brine, dried over Na2SO4 and concentrated, which was used without further purification in the next step. 1H NMR (CDCl3, 300MHz) δ 8.23-8.21 (d, J

= 8.4 Hz, 2H), 7.52-7.49 (d, J = 8.4 Hz, 2H), 5.86-5.75 (m, IH), 5.23-5.10 (m, 4H), 4.13-3.87 (m, 3H), 2.79-2.67 (m, 4H), 1.73 (br, 4H).

Step K ^nitrobenzylallylfl-tfβSJRJ-l-fcyclopentanecarbonylJ-^methoxy-^phenylpyrrolidin-S- yl)methyl)piperidin-4-yl) carbamate

The piperidine intermediate (0.106 g, 0.332 mmol) from step J was dissolved in DCM (5 mL) and treated with the aldehyde (0.100 g, 0.332 mmol) from step G. The reaction was stirred for 30 min, then cooled to 0°C in an ice bath and treated with NaBH(OAc)3 (0.106 g, 0.498 mmol). The reaction was allowed to warm to room temperature as the ice melted and stirred for 12 h at room temperature. The reaction was diluted with EA, then washed with saturated bicarbonate and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel (50%- 100% EA in PE) to give the title compound as a white foam (0.12 g, 60%). 1H NMR (CDCl3, 300MHz) δ 8.22-8.19 (d, J = 8.4 Hz, 2H), 7.49-7.23 (m, 7H), 5.83-5.73 (m, IH), 5.20-5.09 (m, 4H), 4.65-4.58 (m, 0.5H), 4.50-4.44 (m, 0.5H), 4.27-3.49 (m, 7H), 3.19 (s, 0.5H), 3.16 (s, 2.5H), 2.98-2.62 (m, 4H), 2.60-2.51 (m, IH), 2.39-2.28 (m, 2H), 1.90-1.59 (m, 12H). MS (ESI, Pos. 1.5 kV) m/z 605.7 (M+H)+, 627.7 (M+Na)+.

Example 46

endo-N-allyl-N-(8-(((3S,4R)-l-(cyclopentanecarbonyl)-4-(3-fluorophenyl)-4-hydroxyp y rrolidin-3-y l)methy I)-8-azabicyclo [3.2.1 ] octan-3-y l)-2-(4-(N-methy lsulfamoy l)pheny 1 )acetamide

Figure imgf000062_0001

This compound was prepared substantially as described in Example 42 and Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.83-7.60 (m, 3H), 7.47-7.27 (m, 4H), 7.07-6.95 (m, IH), 6.51-6.46 (s, J = 5.1 Hz, IH), 5.86-5.74 (m, IH), 5.32-5.03 (m, 2H), 4.13-3.52 (m, 9H), 3.26-2.58 (m, 7H), 2.43-2.25 (m, 4H), 2.01-2.11 (m, 14H); MS (ESI, Pos. 1.5 kV) m/z 667.4 (M+H)+, 689.4 (M+Na)+.

Example 47 exo-N-allyl-N-(8-(((3S,4R)-l-(cyclopentanecarbonyl)-4-(3-fluorophenyl)-4-hydroxypy rrolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(4-(N-methylsulfamoyl)phenyl) acetamide

Figure imgf000063_0001

This compound was prepared substantially as described in Example 42 and Example 4 using appropriate starting materials. 1H NMR (CDCl3, 300 MHz) δ 7.85-7.68 (m, 2H), 7.53-7.22 (m, 5H), 7.03-6.95 (m, IH), 5.94-5.84 (m, IH), 5.34-5.08 (m, 2H), 4.90-4.83 (m, IH), 4.74-4.58 (m, IH), 3.91-3.71 (m, 8H), 3.25-3.18 (m, IH), 3.03-2.99 (m, IH), 2.87-2.58 (m, 5H), 2.40-2.29 (m, 2H), 2.00-1.47 (m, 16H); MS (ESI, Pos. 1.5 kV) m/z 667.4 (M+H)+, 689.3 (M+Na)+.

Example 48

Inhibition of HIV replication in PBMC

PBMC were isolated from buffy coats (obtained from the Australian Red Cross Blood Service, South Melbourne) from HIV-I and hepatitis B virus-seronegative donors, using a

Ficoll gradient. PBMC were pooled from two donors and incubated at a density of 2x106 cells/ml for 3 days in culture medium containing PHA (5ug/ml). Cells were seeded into

96 well microtitre plates at 200,000 cells per 50μl per well in RF- 10 containing 10U/mL

IL-2 (RF-10/IL2). Compounds were prepared to 4 x final concentration in RF-10/IL2, and 30 μL added to cells. Virus (40 μL in RF-10/IL2 containing 1400 pfu) was added to each well or 40 μL RF-10/IL2 for negative controls and for assaying compound cytotoxicity. After 24 hrs, an additional 90 μL of media or media containing 1 x compound was added to each well. At 4 days post infection, 100 μL of media was removed from each well and replaced with 100 μl of fresh media with or without compound. Forty eight hours later supernatants were harvested and levels of extracellular p24 determined.

Supernatants were diluted 1 in 10,000 and p24 levels assayed using the Vironostika p24 assay kit. EC50 was calculated as the concentration required to inhibit HIV p24 production to 50% that of no drug controls.

Example 49

Selected Compounds and the Inhibition of HIV replication in PBMC

Example Activity Example Activity Example Activity Example Activity

10 24 + 31 ++++

+ 11 + 25 32

+ 12 26 35 +

7 14 + 27 +++ 36 8 16 + 30 ++++ 37

Compound Structure Activity

Compound 34 from Wu et al,

Figure imgf000064_0001

Example 3

Figure imgf000064_0002

EC50 <5 nM; +++ ECS0 6 to 50 nM; ++ ECS0 51 to 99 nM; + EC50 >100 nM Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia or elsewhere before the priority date of each claim of this application.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. A compound of formula (I)
Figure imgf000066_0001
wherein
Z is selected from carbonyl and -CH(CO2H)-;
R1 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl , which may be substituted with one or more suitable substituent(s);
R2 is selected from the group consisting of -OH, -O-C1-6alkyl, -OC(O)-C i^alky^and NR8R9; each of R8 and R9 are independently selected from the group consisting of H, C1-6alkyl, -0(CO)-C 1-6alkyl, and -S(O)2-R10; Rio is selected from the group consisting of -Ci-δalkyl and aryl;
R3 is selected from the group consisting of H, C^alkyl, aryl, and heteroaryl;
R4 is selected from the group consisting of H, C^alkyl, alkylene, aryl, cycloalkyl and alkylcycloaklyl; or R4 and Rn, together with the atoms to which they are linked, form an optionally substituted 5- or 7-membered heterocycle;
each of R5 and R5> is selected from the group consisting of H, CH3, and OH, or R5 and R5' together with the carbon atom to which they are attached form a carbonyl group, provided that both R5 and R5- are not both OH; R6 is absent or is 1 to 5 substituents selected from the group consisting of CF3, OCF3, NO2, SO2R12, NC(O)OC 1-6alkyl, C1-C3EIlCyI, C3-C6cycloalkyl, C6aryl, heterocyclyl, heteroaryl, C1-C3alkylOH, alkylaryl, OH, OCi-3alkyl, halo, CN, CO2H, CO2C1-3alkyl, CONH2, CONH(C1 -3alkyl), CON(C j.Csalkyl);,, NH2, NH(C1-3alkyl) and N(C1-3alkyl)2; R12 is selected from the group consisting of Ci-6alkenyl and NR13R14, each of R]3 and R14 is independently selected from the group consisting of H, alkyl, and cycloalkyl, or R13 and R14 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle;
each of R7 and R7' is selected from the group consisting of H, CH3, and OH, or R7 and R7- together with the carbon atom to which they are attached form a carbonyl group, provided that both R7 and R7- are not both OH;
A is absent or is selected from the group consisting of -CH2CH2-, -CH2CH2CHa-, and -CH2OCH2-;
Y is absent or is carbonyl;
L is absent or is selected from alkylene and alkenylene;
C is selected from the group consisting of cycloalkyl, aryl, and heteroaryl;
X is absent or is selected from NR11 and O; R11 is H or R4 and R11, together with the atoms to which they are linked, form an optionally substituted 5- or 7-membered heterocycle;
provided that when X is O, L is alkylene and C is aryl then R6 is selected from the group consisting of SO2R12 and OCF3; or C and R^ , together with the atoms to which they are linked, form
Figure imgf000067_0001
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
2. The compound of claim 1, wherein
R1 is selected from the group consisting of-OH,
Figure imgf000067_0002
aryl, heteroaryl, and heterocyclyl,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
3. The compound of claim 2, wherein
R1 is C3-8cycloalkyl,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
4. The compound of claim 3, wherein
Ri is cyclopentyl,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
5. The compound of claim 1, wherein
R2 is selected from the group consisting of -O-Ci-όalkyl, -OC(O)-C ^alkyl, and NR8R9, each of R8 and R9 are independently selected from the group consisting of H, Ci^alkyl, -O(CO)-C ^alkyl, and -S(O)2-RiO; Rio is selected from the group consisting of -C1-6alkyl and aryl,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
6. The compound of claim 1, wherein
R4 is selected from C^alkenyl and cycloalkyl,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
7. The compound of claim 6, wherein
R4 is selected from allyl and -CH2cyclopropyl,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
8. The compound of claim 1, wherein
A is selected from the group consisting Of-CH2CH2-, -CH2CH2CH2-, and -CH2OCH2-,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
9. The compound of claim 1, wherein
Figure imgf000068_0001
L is selected from d^alkylene and Ci^alkenylene,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
10. The compound of claim 1, wherein C is selected from the group consisting of benzodioxazole, m-methoxyphenyl, and phenyl substituted with at least one substituent selected from SO2C1-6alkyl and -OCF3,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
11. The compound of claim 1, wherein
Z is carbonyl,
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
12. The compound of claim 1, wherein
X is absent or is NR^; provided that when X is NH, C is phenyl and L is absent, then R6 is 1 to 5 substituents selected from the group consisting of CF3, OCF3, NO2, SO2Rl 2, NC(O)OC i-6alkyl, C^alkyl, C3-6cycloalkyl, C6aryl, heterocyclyl, heteroaryl, d-3alkyl0H, alkylaryl, OH, OCpQalkyl, halo, CN, CO2H, CO2C1-3alkyl, CONH2, CONH(C 1-3alkyl), CON(C1-3alkyl)2, NH2, NH(C1-3alkyl) , and N(C1-3alkyl)2;
or a pharmaceutically acceptable derivative, salt or prodrug thereof.
13. The compound of claim 1, which is indepentedly selected from
4- (Methylsulfonyl)benzyl allyl( 1 -(((35,4/J)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-
phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate;
Benzo[c][l,2,5]oxadiazol-5-ylmethyl allyl(l-(((35',4i?)-l-(cyclopentanecarbonyl)-4-
hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamat;
N-allyl-iV-(l-(((3iSr,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)meth yl)piperidin-4-yl)-2-(4-(N,Λ'-dimethylsulfamoyl)phenyl)acetamide;
7V-allyl-iV-( 1 -(((3S,4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)meth yl)piperidin-4-yl)-2-(4-(N-methylsulfamoyl)phenyl)acetamide;
iV-allyl-iV-( 1 -(((35,47?)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)meth yl)piperidin-4-yl)-2-(4-sulfamoylphenyl)acetamide;
1 - Allyl- 1 -( 1 -(((3S,4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)meth yl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea; 4-((3 -Ally 1-3 -( 1 -(((3 S, 4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)m ethyl)piperidin-4-yl)ureido)methyl)-Λf,N-dimethylberizenesulfonamide;
4-((3-Allyl-3-(l-(((35',47?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)m ethyl)piperidin-4-yl)ureido)methyl)-N-methylbenzenesulfonamide; or
3 -( 1 -(((3S, AR)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)methyl)piperi din-4-yl)- 1 -(4-(trifluoromethyl)benzyl)-3 ,4-dihydropyrimidin-2( 1 H)-one.
14. An intermediate of formula ( II) useful of formula ( I ),
Figure imgf000070_0001
II wherein R3 is selected from the group consisting of H, C^alkyl, aryl, heteroary.
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
16. A method of treating of treatment or prophylaxis of a HIV infection in a subject, which comprises administering an effective amount of the compound of claim 1 to a human being or an animal.
PCT/CN2008/000137 2008-01-18 2008-01-18 Pyrollidine-based compounds WO2009089659A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8658797B2 (en) 2011-02-25 2014-02-25 Helsinn Healthcare Sa Asymmetric ureas and medical uses thereof
JP2016128431A (en) * 2010-09-24 2016-07-14 株式会社Wave Life Sciences Japan Asymmetric auxiliary group
US9982257B2 (en) 2012-07-13 2018-05-29 Wave Life Sciences Ltd. Chiral control
US10144933B2 (en) 2014-01-15 2018-12-04 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator
US10149905B2 (en) 2014-01-15 2018-12-11 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having antitumor effect and antitumor agent
US10160969B2 (en) 2014-01-16 2018-12-25 Wave Life Sciences Ltd. Chiral design
US10167309B2 (en) 2012-07-13 2019-01-01 Wave Life Sciences Ltd. Asymmetric auxiliary group
US10280192B2 (en) 2011-07-19 2019-05-07 Wave Life Sciences Ltd. Methods for the synthesis of functionalized nucleic acids

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1706824A (en) * 2004-06-09 2005-12-14 上海靶点药物有限公司 Compound as CCR5 agonist
CN1939916A (en) * 2005-09-05 2007-04-04 上海靶点药物有限公司 Compound for treating AIDS
CN101007800A (en) * 2006-01-26 2007-08-01 上海靶点药物有限公司 Compound for preparing nifeviroc and its preparing process

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1706824A (en) * 2004-06-09 2005-12-14 上海靶点药物有限公司 Compound as CCR5 agonist
CN1939916A (en) * 2005-09-05 2007-04-04 上海靶点药物有限公司 Compound for treating AIDS
CN101007800A (en) * 2006-01-26 2007-08-01 上海靶点药物有限公司 Compound for preparing nifeviroc and its preparing process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MA, DAWEI ET AL.: "Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent.", CHEMMEDCHEM, vol. 2, no. 2, 2007, pages 187 - 193 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016128431A (en) * 2010-09-24 2016-07-14 株式会社Wave Life Sciences Japan Asymmetric auxiliary group
US8658797B2 (en) 2011-02-25 2014-02-25 Helsinn Healthcare Sa Asymmetric ureas and medical uses thereof
US9751836B2 (en) 2011-02-25 2017-09-05 Helsinn Healthcare Sa Asymmetric ureas and medical uses thereof
US10280192B2 (en) 2011-07-19 2019-05-07 Wave Life Sciences Ltd. Methods for the synthesis of functionalized nucleic acids
US9982257B2 (en) 2012-07-13 2018-05-29 Wave Life Sciences Ltd. Chiral control
US10167309B2 (en) 2012-07-13 2019-01-01 Wave Life Sciences Ltd. Asymmetric auxiliary group
US10144933B2 (en) 2014-01-15 2018-12-04 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator
US10149905B2 (en) 2014-01-15 2018-12-11 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having antitumor effect and antitumor agent
US10160969B2 (en) 2014-01-16 2018-12-25 Wave Life Sciences Ltd. Chiral design

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