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; CD195 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.

It has been shown that preventing HIV entry into the cell by blocking the use of CCR.5 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, processing 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 )

(I)

wherein:

Z is selected from carbonyl and -CH(CO ₂ H)-;

R ₁ is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, which may be substituted with one or more suitable substituent(s);

R ₂ is selected from the group consisting of -OH, -O-Ci _-6 alkyl, -OC(O)-Ci _-6 alkyl, and NR ₈ Rg; each of R ₈ and Rg are independently selected from the group consisting of H, C _1-6 alkyl, -O(CO)-C _1-6 alkyl, and -S(O) ₂ -R ₁₀ ; R ₁₀ is selected from the group consisting of -C _1-6 alkyl and aryl;

R ₃ is selected from the group consisting of H, C _1-6 alkyl, aryl, and heteroaryl;

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

each of R ₅ and R _5' is selected from the group consisting of H, CH ₃ , and OH, or R ₅ and R ₅ • together with the carbon atom to which they are attached form a carbonyl group, provided that both R ₅ and R _5' are not both OH;

R ₆ is absent or is 1 to 5 substituents selected from the group consisting of CF ₃ , OCF ₃ , NO ₂ , SO ₂ R ₁₂ , NC(O)OC _1-6 alkyl, CrCsalkyl, C ₃ -C ₆ cycloalkyl, Qaryl, heterocyclyl, heteroaryl, Q-CsalkylOH, alkylaryl, OH, OCrsalkyl, halo, CN ₅ CO ₂ H, CO ₂ C _1-3 alkyl, CONH ₂ , CONH(C _1-3 alkyl), CON(C _1-3 alkyl) ₂ , NH ₂ , NH(C _1-3 alkyl) and N(C _1-3 alkyl) ₂ ; R ₁₂ is selected from the group consisting of Ci _-6 alkenyl and NRi ₃ R _14; each of R ₁₃ and R ₁₄ is independently

selected from the group consisting of H, alkyl, and cycloalkyl, or R ₁₃ and Ri ₄ together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle;

each of R ₇ and R _7' is selected from the group consisting of H, CH ₃ , and OH, or R ₇ and R _7' together with the carbon atom to which they are attached form a carbonyl group, provided that both R ₇ and R ₇ > are not both OH;

A is absent or is selected from the group consisting of -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, and -CH ₂ OCH ₂ -;

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 NR ₁₁ and O; R ₁₁ is H or R ₄ and R ₁₁ , 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 R ₆ is selected from the group consisting of SO ₂ Ri ₂ and OCF ₃ ; or C and R ₆ together with the atoms to which they are linked, form

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)

(I) wherein:

Z is selected from carbonyl and -CH(CO ₂ H)-;

R ₁ is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl , which may be substituted with one or more suitable substituent(s);

R ₂ is selected from the group consisting of -OH, -O-C _1-6 alkyl, -OC(O)-C _1-6 alkyl,and NR ₈ R ₉ ; each of R ₈ and R ₉ are independently selected from the group consisting of H, C _1-6 alkyl, -O(CO)-C _1-6 alkyl, and -S(O) ₂ -R ₁₀ ; R ₁₀ is selected from the group consisting of -C _1-6 alkyl and aryl;

R ₃ is selected from the group consisting of H, C _1-6 alkyl, aryl, and heteroaryl;

R ₄ is selected from the group consisting of H, C _1-4 alkyl, alkylene, aryl, cycloalkyl and alkylcycloaklyl; or R ₄ and R ₁₁ , together with the atoms to which they are linked, form an optionally substituted 5- or 7-membered heterocycle;

each of R ₅ and R ₅ - is selected from the group consisting of H, CH ₃ , and OH, or R ₅ and R ₅ - together with the carbon atom to which they are attached form a carbonyl group, provided that both R ₅ and R ₅ ' are not both OH;

R ₆ is absent or is 1 to 5 substituents selected from the group consisting of CF ₃ , OCF ₃ , NO ₂ , SO ₂ Ri ₂ , NC(O)OC _1-6 alkyl, Q-Csalkyl, C ₃ -C ₆ cycloalkyl, C ₆ aryl, heterocyclyl, heteroaryl, C _r C ₃ alkylOH, alkylaryl, OH, OCr ₃ alkyl, halo, CN, CO ₂ H, CO ₂ C _1-3 alkyl, CONH ₂ , CONH(C _1-3 alkyl), CON(C _1- C ₃ alkyl) ₂ , NH ₂ , NH(C _1-3 alkyl) and N(C _1-3 alkyl) ₂ ; R ₁₂ is selected from the group consisting of C _1-6 alkenyl and NR ₁₃ R ₁₄ ; each of R ₁₃ and R ₁₄ is independently

selected from the group consisting of H, alkyl, and cycloalkyl, or R ₁₃ and R ₁₄ together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle;

each of R ₇ and R ₇ > is selected from the group consisting of H, CH ₃ , and OH, or R ₇ and R ₇ ' together with the carbon atom to which they are attached form a carbonyl group, provided that both R ₇ and R ₇ ' are not both OH;

A is absent or is selected from the group consisting of -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, and -CH ₂ OCH ₂ -;

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 NR ₁₁ and O; R ₁₁ is H or R ₄ and R ₁₁ , 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 R ₆ is selected from the group consisting of SO ₂ R ₁₂ and OCF ₃ ; or C and R ₆ , together with the atoms to which they are linked, form

or a pharmaceutically acceptable derivative, salt or prodrug thereof.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein R ₁ is selected from the group consisting of-OH, C _1-6 alkyl, C _3-8 cycloalkyl, aryl, heteroaryl, and heterocyclyl, preferably C _3-8 cycloalkyl, more preferably cyclopentyl.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein R ₂ is selected from the group consisting of -O-C _1-6 alkyl, -OC(O)-C _1-6 alkyl, and NR ₈ R ₉ .

In certain other preferred embodiments, the aboved-mentioned compounds, wherein R ₄ is preferably selected from C _1-6 alkenyl and cycloalkyl, more preferably selected from allyl and -CH ₂ cyclopropyl.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein A is selected from the group consisting Of-CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, and -CH ₂ OCH ₂ -.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein L is selected from the group consisting of C _1-4 alkylene and C _1-4 alkenylene.

In certain other preferred embodiments, the aboved-mentioned compounds, wherein C is selected from the group consisting of benzodioxazole, m-methoxyphenyl, phenyl substituted with at least one substiruent selected from SO ₂ C _1-6 alkyl and -OCF ₃ .

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 R ₆ is 1 to 5 substituents selected from the group consisting of CF ₃ , OCF ₃ , NO ₂ , SO ₂ R12 ₅ NC(O)OCi _-6 alkyl, C^alkyl, C ₃ - ₆ cycloalkyl, C ₆ aryl, heterocyclyl, heteroaryl, CrsalkylOH, alkylaryl, OH, OC _r C ₃ alkyl, halo, CN, CO ₂ H, CO ₂ C _I-3 alkyl, CONH ₂ , CONH(C _1-3 alkyl), CON(C _I-3 alkyl) ₂ , NH ₂ , NH(C _1-3 alkyl) , and N(C _1-3 alkyl) ₂ .

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

provided that when A is C i _ ₄ alkyl,

Z is carbonyl;

R ₁ is selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclyl;

each ofR ₂ and R ₃ is selected from the group consisting of H, C _1-6 alkyl, aryl, and heteroaryl;

R ₄ is selected from the group consisting of H, Ci _-4 alkyl, alkylene, aryl, cycloalkyl and alkylcycloaklyl; or R ₄ and R ₁₁ , together with the atoms to which they are linked, form an optionally substituted 5- or 7-membered heterocycle;

each ofR ₅ and R ₅ > is H;

R ₆ is absent or is 1 to 5 substituents selected from the group consisting of CF ₃ , OCF ₃ , NO ₂ , SO ₂ R ₁₂ , NC(O)OC _1-6 alkyl, Ci-C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ aryl, heterocyclyl, heteroaryl, Ci-QjalkylOH, alkylaryl, OH, OC^alkyl, halo, CN, CO ₂ H, CO ₂ C _1-3 alkyl, CONH ₂ , CONH(Ci _-3 alkyl), CON(d.C ₃ alkyl)2, NH ₂ , NH(C _1-3 alkyl) and N(C _1-3 alkyl) ₂ ; R ₁₂ is selected from the group consisting of C _1-6 alkenyl and NR ₁₃ Rj _4; each OfRi ₃ and R ₁₄ is independently selected from the group consisting of H, alkyl, and cycloalkyl, or Ri ₃ and R ₁₄ together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle;

each of R ₇ and R ₇ - is H;

Y is carbonyl;

L is alkylene;

C is aryl; the said groups which may be substituted with one or more suitable substituent(s).

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

4- (Methylsulfonyl)benzyl allyl( 1 -(((3S,4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-

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

Benzo[c] [1 ,2,5]oxadiazol-5-ylmethyl allyl(l -(((35,4.K)-I -(cyclopentanecarbonyl)-4-

hydroxy-4-phenylpyrrolidin-3 -yl)methyl)piperidin-4-yl)carbamat;

iV-allyl-JV-( 1 -(((3S, 4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)methyl )piperidin-4-yl)-2-(4-(N,iV-dimethylsulfamoyl)phenyl)acetami de;

7V-allyl-iV-(l-(((3jS',4i?)-l-(cyclopentanecarbonyl)-4-hy droxy-4-phenylpyrrolidm-3-yl)methyl )piperidin-4-yl)-2-(4-(iV-methylsulfamoyl)phenyl)acetamide;

iV-allyl-iV-(l-(((35 ^r ,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin- 3-yl)methyl )piperidin-4-yl)-2-(4-sulfamoylphenyl)acetamide;

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

4-((3 -Allyl-3 -( 1 -(((3S,4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)me thyl)piperidin-4-yl)ureido)methyl)-iV,iV-dimethylbenzenesulf onamide;

4-((3-Allyl-3-(l-(((35,4i?)-l-(cyclopentanecarbonyl)-4-hy droxy-4-phenylpyrrolidin-3-yl)me thyl)piperidin-4-yl)ureido)methyl)-iV-methylbenzenesulfonami de;

3 -( 1 -(((3S, 4R)- 1 -(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)methyl)piperid in-4-yl)- 1 -(4-(trifluoromethyl)benzyl)-3 ,4-dihydropyrimidin-2( 1 H)-one;

Exo- 1 -allyl- 1 -(8-(((3 S,4R)- 1 -(cyclopentanecarbonyl)-4-(3-fluorophenyl)-4-hydroxypyrrolid in-3 -yl)methyl)-8-azabicyclo [3.2.1 ]octan-3 -yl)-3 -(4-(trifluoromethyl)benzyl)urea;

Exo-4-((3 -allyl-3 -(8 -(((3 S ,4R)- 1 -(cyclopentanecarbonyl)-4-(3 -fluorophenyl)-4-hydroxypyrr olidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)met hyl)-N,N-dimethylbenzenesulf onamide;

Eχ _O -4-((3-allyl-3-(8-(((3S,4R)-l-(4,4-difluorocyclohexanecarbon yl)-4-(3-fluorophenyl)-4-h ydroxypyrrolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl) ureido)methyl)-N,N-dimethyl benzenesulfonamide;

Exo-4-((3 -allyl-3 -(8-(((3 S,4R)-4-(3 -fluorophenyl)-4-hydroxy- 1 -( 1 H-pyrrole-2-carbonyl)pyr rolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)me thyl)-N,N-dimethylbenzenesul fonamide;

Exo- 1 -allyl- 1 -(8-(((3 S,4R)- 1 -(cyclopentanecarbonyl)-4-(3 -fluorophenyl)-4-hydroxypyrrolid in-3 -yl)methyl)-8-azabicyclo [3.2.1 ] octan-3 -yl)-3 -(4-fluorobenzyl)urea;

Exo- 1 -allyl- 1 -(8 -(((3 S, 4R)- 1 -(cyclopropanecarbonyl)-4-(3 -fluorophenyl)-4-hydroxypyrrolid in-3 -yl)methyl)-8-azabicyclo [3.2.1 ] octan-3 -yl)-3 -(4-(trifluoromethyl)benzyl)urea;

Exo- 1 -allyl- 1 -(8-(((3 S,4R)- 1 -(4,4-difluorocyclohexanecarbonyl)-4-(3 -fluorophenyl)-4-hydr oxypyrrolidin-3 -yl)methyl)-8-azabicyclo [3.2.1] octan-3 -yl)-3 -(4-(trifluoromethyl)benzyl)ure a;

Exo- 1 -allyl- 1 -(8 -(((3 S,4R)-4-(3 -fluorophenyl)-4-hydroxy- 1 -( 1 H-pyrrole-2-carbonyl)pyrroli din-3 -yl)methyl)-8-azabicyclo [3.2.1 ] octan-3 -yl)-3 -(4-(trifluoromethyl)benzyl)urea;

Exo-4-((3-allyl-3-(8-(((3S,4R)-l-(cyclopropanecarbonyl)-4 -(3-fluorophenyl)-4-hydroxypyrr olidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)met hyl)-N,N-dimethylbenzenesulf onamide;

Eχo-4-((3-allyl-3-(8-(((3S,4R)-l-(cyclopropanecarbonyl)- 4-(3-fluorophenyl)-4-hydroxypyrr olidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)met hyl)benzenesulfonamide;

Exo-4-((3-allyl-3-(8-(((3S,4R)-l-(4,4-difluorocyclohexane carbonyl)-4-(3-fluorophenyl)-4-h ydroxypyrrolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl) ureido)methyl)benzenesulfona mide or

Exo-4-((3-allyl-3-(8-(((3S,4R)-l-(cyclopropanecarbonyl)-4 -(3-fluorophenyl)-4-hydroxypyrr olidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)ureido)met hyl)-N-methylbenzenesulfona mide.

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

H

( II ) wherein R ₃ is selected from the group consisting of H, C _1-6 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 NH(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-methylpentyl.

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 C ₆ -C ₁₀ 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 C _3-6 ,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 CrC ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ aryl, heterocyclyl, heteroaryl, Q-CsalkylOH, alkylaryl, OH, OCi-C ₃ alkyl, halo, CN, NO ₂ , CO ₂ H, CO ₂ Ci.C ₃ alkyl, CONH ₂ , CONH(Ci.C ₃ alkyl), CON(C _1- C ₃ alkyl) ₂ , trifluoromethyl, NH ₂ , NHCCj.Caalkyl), N(Ci-C ₃ alkyl) ₂ , S(O) ₂ NH ₂ , SO ₂ NH(Ci _-3 alkyl), SO ₂ (C _1-3 alkyl) ₂ , and Sθ ₂ C _1-3 alkyl. 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, 1 ^st 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:

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:

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:

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:

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:

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:

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:

THF

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:

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:

Alternatively, a variety of final compounds of formula (I) can be prepared following the procedures described in Scheme 9 (CN101007800; 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 animation 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:

51

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 N^'-dicyclohexylcarbodiimide

HOSu N-hydroxysuccinimide

DMAP 4-dimethylaminopyridine

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

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

Step A

4- (methylsulfonyl) benzyl carbonochloridate

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 ⁰ C 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?,45)-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 0 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.22 g, 71%). ¹ H NMR (CDCl ₃ , 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 allyl(l-(((3iS ^r ,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4 -phenylpyrroIidin-3-yI)methyl)piperidin-4-yl)carbamate

This compound was prepared substantially as described in Example 1 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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] [1,2,5] oxadiazol-5-ylmethyl alIyl(l-(((3S,42?)-l-(cyclopentanecarbonyl)-4-

hydroxy-4-phenylpyrrolidm-3-yl)methyl)piperidin-4-yl)carb amate

Step A

(4-Aminophenyl)methano!

4-Nitrobenzyl alcohol (10.0 g, 65.3 mmol) was hydrogenated over 10% Pd/C (1 g, 50% H ₂ O) in EtOH (150 niL). 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. ¹ H NMR (CDCl ₃ , 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

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 ⁰ C 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (20% EA in PE) afforded the title compound as white solid (3.35 g, 100%). ¹ H NMR (CDCl ₃ , 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-3-nitrobenzyl acetate

Substituted acetanilide (16.2 mmol) was added in portions to a cooled (-4 0 ⁰ C) mixture of 60 % nitric acid (6 mL) and concentrated sulfuric acid (6 mL). The mixture was stirred at 0 ⁰ C 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (15%-20% EA in PE) afforded the title compound as yellow powder (1.25 g, 31%). ¹ H NMR (CDCl ₃ , 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

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 ⁰ C. 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%). ¹ H NMR (CDCl ₃ , 300 MHz): δ 7.48-7.18 (m, 3H), 4.72 (s, 2H), 2.51 (brs, IH).

Step E

Benzofcjfl, 2, 5]oxadiazol-5-ylmethanol

A mixture of the oxide (0.534 g, 3.21 mmol) from step D, Ph ₃ P (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%). ¹ H NMR (CDCl ₃ , 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

Benzoic] [1, 2, 5]oxadiazol-5-ylmethyl allyl(l-(((3S, 4R)-l-(cyclopentanecarbonyl)-4-

hydroxy-4-phenylpyrrolidin-3-yJ)methyl)piperidin-4-yl)car bamate

This compound was prepared substantially as described in Example 1 using the starting materials from step E. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.84-7.81 (d, J = 9.0 Hz, IH), 7.75 (s, IH), 7.52-7.47 (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

N-aIIyl-N-(l-(((35',4i?)-l-(cyclopentanecarbonyl)-4-hydro xy-4-phenyIpyrrolidin-3-yl)m ethyI)piperidin-4-yl)-2-phenylacetamide

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

((3i?,4<S)-4-((4-(allylamino)piperidin- 1 -yl)methyl) -3 -hydroxy-3 -phenylpyrrolidin- 1 -yl)(cycl opentyl)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 mL) at 0 ⁰ C. 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.232 g, 90 %). ¹ H NMR (CDCl ₃ , 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

7V-aIlyl-N-(l-(((3S',4if)-l-(cyclopentanecarbonyl)-4-liyd roxy-4-phenylpyrroIidin-3-yl)m ethyl)piperidin-4-yl)-2-(4-methoxyphenyI)acetamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.51-7.45 (m, 2H), 7.40-7.27 (m, 3H) ₃ 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

λ ^r -aIlyI-iV-(l-(((3iS',4i?)-l-(cycIopentanecarbonyl)-4-hydroxy -4-phenyIpyrroIidin-3-yI)m ethyl)piperidin-4-yI)-2-(4-(methyIsulfonyl)phenyl)acetamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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

A ^r -allyl-N-(l-(((3S,4i?)-l-(cycIopentanecarbonyl)-4-hydroxy-4- phenylpyrrolidin-3-yl)m ethyl)piperidin-4-yl)-2-(4-nitrophenyl)acetamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.19-8.16 (d, J = 8.7 Hz, 2H), 7.51-7.25 (m, 7H) ₅ 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

λ ^r -allyl-λ ^r -(l-(((3S,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpy rroIidin-3-yl)m ethyI)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)acetamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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

λ ^/ -allyl-λ ⁷ -(l-(((3S,4if)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpy rrolidin-3-yl)in ethyl)piperidin-4-yl)-2-(4-fluorophenyl)acetamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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

iV-allyl-A ^r -(l-(((3iS ^r ,4if)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin- 3-yl)m ethyl)piperidin-4-yl)-2-(4-(AVV-dimethyIsulfamoyl)phenyl)ace tamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73-7.61 (m, 2H) ₅ 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 (l-(((3,S ^r ,4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3 -yl)m ethyl)piperidin-4-yl)-2-(4-(7V-methylsulfamoyl)phenyl)acetam ide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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), 4.80 (brs, IH), 4.51-4.48 (m, IH), 3.87-3.65 (m, 8H), 3.05-2.81 (m, IH), 2.81-2.59 (m, 6H), 2.53-2.42 (m, 2H), 2.23-2.13 (m, 2H), 1.87-1.53 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 623.5 (M+H) ⁺ , 645.5 (M+Na) ⁺ .

Example 12

iV-allyl-N-(l-(((35',4R)-l-(cyclopentanecarbonyl)-4-hydro xy-4-phenylpyrrolidin-3-yI)m ethyl)piperidin-4-yl)-2-(4-sulfamoylphenyl)acetamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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), 4.45-4.40 (m, IH), 3.87-3.63 (m, 8H), 3.01-2.95 (m, IH), 2.82-2.52 (m, 3H), 2.52-2.39 (m, 2H), 2.18-2.15 (m, 2H), 1.93-1.45 (m, 12H); MS (ESI, Pos. 1.5 kV) m/z 609.5 (M+H) ⁺ , 631.5 (M+Na) ⁺ .

Example 13

λ ^r -allyl-N-(l-(((35',4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4 -phenylpyrrolidin-3-yl)m ethyl)piperidin-4-yl)benzamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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

λ ^r -allyl-iV-(l-(((3 ₁ S',4J?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrroIidi n-3-yl)in ethyl)piperidin-4-yl)-3-phenylpropanamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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

iV-allyl-λ ^r -(l-(((3S',4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylp yrrolidin-3-yl)m ethyl)piperidin-4-yl)cinnamamide

This compound was prepared substantially as described in Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.12-1.61 (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), 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-(((35,4R)-l-(cyclopentane carbonyl)-4-hydroxy-4-pheny lpyrrolidin-3-yl)methyl)piperidin-4-yl)urea

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)m ethanone (0.2 g, 0.49 mmol) and triethylamine (0.14 mL, 0.98 mmol) in DCM (4 mL) at 0 ⁰ C. 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (l%-2% MeOH in DCM) afforded the title compound as a white foam (0.25 g, 93 %). ¹ H NMR (CDCl ₃ , 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-(((3S ^r ,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-pheny lpyrrolidin-3-yl)methyl)piperidin-4-yl)urea

This compound was prepared substantially as described in Example 16 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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 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-AUyl-l-(l-(((3S,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy -4-phenylpyrrolidiii-3-yl)me thyl)piperidin-4-yl)-3-(4-phenoxyphenyl)urea

This compound was prepared substantially as described in Example 16 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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,4i?)-l-(cyclopentan ecarbonyl)-4-hydroxy-4-phenyl pyrrolidin-3-yl)methyl)piperidin-4-yl)urea

This compound was prepared substantially as described in Example 16 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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 IcV) m/z 573.5 (M+H) ⁺ , 595.4 (M+Na) ⁺ .

Example 20

l-AUyl-l-(l-(((35,4 _J R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-y l)me thyl)piperidin-4-yl)-3-o-tolylurea

This compound was prepared substantially as described in Example 16 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-te^-butylphenyl)-l-(l-(((3S,4i?)-l-(cyclopen tanecarbonyl)-4-hydroxy-4-ph enylpyrrolidin-3-yl)methyl)piperidin-4-yl)urea

This compound was prepared substantially as described in Example 16 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-(((35,4if)-l-(cyclopentanecarbonyl)-4-hydrox y-

4-phenylpyrroIidin-3-yI)methyl)piperidin-4-yl)ureido)benz oate

This compound was prepared substantially as described in Example 16 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.96-7.93 (d, J - 8.7 Hz ₅ 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-(cycIopentanecarbon yl)-4-hydroxy-4-phenylpyrro lidin-3-yl)methyl)piperidin-4-yl)urea

This compound was prepared substantially as described in Example 16 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-(((3S,4R)-l-(cyclopentanecarbonyl)- 4-hydroxy-4-phenylpyrrolidi n-3-yl)methyl)piperidin-4-yl)urea

According to Scheme 4, to a solution of triphosgene (0.06 g, 0.20 mmol) in DCM (2 niL) 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- 1 -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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.17 g, 65%). ¹ H NMR (CDCl ₃ , 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) m/z 545.5 (M+H) ⁺ , 567.5 (M+Na) ⁺ .

Example 25

l-AUyl-l-(l-(((3iS',4R)-l-(cyclopentanecarbonyl)-4-hydrox y-4-phenylpyrrolidiii-3-yl)me thyl)piperidin-4-yl)-3-(4-fluorobenzyl)urea

This compound was prepared substantially as described in Example 24 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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 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-AUyl-l-(l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-hydroxy- 4-phenylpyrrolidin-3-yl)me thyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyI)urea

This compound was prepared substantially as described in Example 24 using appropriate starting materials. ¹ U NMR (CDCl ₃ , 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

l-AUyl-l-(l-(((3S,4i?)-l-(cyclopentanecarbonyl)-4-hydroxy -4-phenylpyrrolidin-3-yl)ine thyl)piperidin-4-yl)-3-(3,4-difluorobenzyl)urea

This compound was prepared substantially as described in Example 24 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-(((3S,4i?)-l-(cyclopentanecarbonyl)-4-hydrox y-4-phenyIpyrroIidin-3-yI)me thyl)piperidin-4-yI)-3-(2,4-difluorobenzyl)urea

This compound was prepared substantially as described in Example 24 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-AUyI-l-(l-(((3S,4if)-l-(cyclopentanecarbonyl)-4-hydroxy -4-phenyIpyrrolidin-3-yl)me thyl)piperidin-4-yI)-3-((i?)-l-phenylethyl)urea

This compound was prepared substantially as described in Example 24 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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 = 7.2 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-AHyl-3-(l-(((3S,4i?)-l-(cycIopentanecarbonyl)-4-hyd roxy-4-phenylpyrrolidin-3-yl )methyl)piperidin-4-yl)ureido)methyl)-AVV-dimethyIbenzenesuI fonamide

This compound was prepared substantially as described in Example 24 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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 ₅ 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 fcV) m/z 652.5 (M+H) ⁺ , 674.5 (M+Na) ⁺ .

Example 31

4-((3-AlIyl-3-(l-(((3.S',4i?)-l-(cyclopentanecarboiiyI)-4 -hydroxy-4-phenylpyrrolidin-3-yl )methyl)piperidin-4-yl)ureido)methyl)-iV-methylbenzenesulfon amide

This compound was prepared substantially as described in Example 24 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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 ₅ 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 -(((3S,4jR)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenyIpyrro lidin-3-yl) methyl)piperidin-4-yI(cyclopropylmethyl)carbamate

Step A

Cyclopentyl((3R,4S)-4-((4~(cyclopropylmethylamino)piperid in-l-yl)methyl)-3-hydroxy-3-ph enylpyrrolidin-l-yl)methanom

Following the procedure in scheme 5, a mixture of l-(((3S,4i?)-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, NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO ₄ 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-phenylpyrro lidin-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 ⁰ C. 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (l%-2% MeOH in DCM) afforded the title compound as a white foam (0.25 g, 77 %). ¹ H NMR (CDCl ₃ , 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-(((3 ₁ S',4i?)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidi n-3-yl)methyl)

piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-iV-phenylace tamide

This compound was prepared substantially as described in Example 32 step A and Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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

iV-benzyl-iV-(l-(((3ιS ^r ,4if)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin- 3-yl) methyl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide

This compound was prepared substantially as described in Example 33 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-(((3 _* S',4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-phenylpyrrolidin -3-yl)methyl)pip eridin-4-yI)-l-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrimi din-2(lH)-one

Step A

Cyclopentyl((3R,4S)-4-((4-(3,3-diethoxypropylamino)piperi din-l-yl)methyl)-3-hydroxy-3-ph enylpyrrolidin-1 -yl)methanone

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 niL, 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 dry THF (8 mL) was stirred at room temperature overnight. After this time, the mixture was diluted with EA and washed sequentially with NaOH, NaHCCβ 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-(l-(((3SAR)-l-(cyclopentanecarbonyl)-4-hydroxy-4ψhenyl pyrrolidm-3-yl)methyl)piperidi n-4-yl) -l-(3, 3-diethoxypropyl) -3 -(4- (trifluoromethyl)benzyl) urea

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)-1 '-(cyclopentcmecarbonyl)-4-hydroxy-4-phenylpyrrolidin-3-yl)m ethyl)pipeήdi n-4-yl)-l- (4- (trifluoromethyl)benzyl) -3, 4-dihydropyrim idin-2 (IH) -one

To a solution of the crude acetal intermediate (0.065 g, 0.09 mmol) from step B in DCM (20 niL) 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 NaHCO ₃ and brine, dried over Na ₂ SO ₄ , 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 %). ¹ H NMR (CDCl ₃ , 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 (m, 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-Allyl-l-(l-(((3iS',4i?)-l-(furan-2-carbo,nyl)-4-hydroxy -4-phenyIpyrroIidin-3-yI)methyl) piperidin-4-yl)-3-(4-(trifluoromethyl)benzyI)urea

Step A

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

-1-carboxylate

According to Scheme 7, a solution of (Boc) ₂ O (8.7 g, 39.8 mmol) in DCM (20 rnL) was added dropwise to a solution of DMAP (0.44 g, 3.62 mmol), Et ₃ N (10 mL, 72.4 mmol) and l-(((3i?,4i?)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piper idin-4-ol (10.0 g, 36.2 mmol) in DCM (100 mL) at O 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 Na ₂ SO ₄ 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-phenylpyrrolidin e-l

-carboxylate

To a solution of oxalyl chloride (2.0 mL, 22.5 mmol) in DCM (10 mL) at -78 ⁰ C 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 Et ₃ N 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (50%-100% EA in PE) afforded the title compound as a yellow foam (5.0 g, 78 %). ¹ H NMR (CDCl ₃ , 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, HH), 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-phenylp yrrolidine

-1-carboxylate

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, NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO ₄ and concentrated to afford the crude amine which was used without further purification in the next step. ¹ H NMR (CDCl ₃ , 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

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

-3 -hydroxy-3-phenylpyrrolidine- 1-carboxylate

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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.83 g, 70%). ¹ H NMR (CDCl ₃ , 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) ₃ 4.92-4.88 (m, IH), 4.52-4.23 (m, 3H) ₅ 3.82-3.48 (m, 6H) ₃ 3.08-2.62 (m, 3H), 2.52-2.00 (m, 4H) ₅ 1.79-1.55 (m, 4H) ₃ 1.49 (m, 9H); MS (ESI ₅ Pos. 1.5 kV) m/z 617.4 (M+H) ⁺ , 639.4 (M+Na) ⁺ .

Step E

1 -AlIy]-I -(I -(((3R,4R)-4-hydroxy-4-phenylpyrrolidin-3-yl)methyl)piperidi n-4-yl)~3-(4-(tr'iflu oromethyl)benzyl) urea

To a solution of Boc-urea product from step D (0.6 g, 0.97 mmol) in DCM (10 niL) was- added TFA (0.75 niL, 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 ₃ water and brine, dried over Na ₂ SO ₄ and concentrated. This affored the crude product which was used without further purification in the next step.

Step F

l-Allyl-l-(l-(((3S,4R)-l-(furan-2-carbonyl)-4-hydroxy-4-p henylpyrrolidin-3-yl)methyl)piper idin-4-yl)-3-(4-(trtfluoromethyl)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 ⁰ C. 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.050 g, 82 %). ¹ H NMR (CDCl ₃ , 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) ₃ 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 IcV) m/z 611.5 (M+H) ⁺ , 633.5 (M+Na) ⁺ .

Example 37

1-AlIyI-I-(I -(((3S,4R)-l-(4,4-difluorocyclohexanecarbonyl)-4-hydroxy-4-p henylpyrroli din-3-yl)methyl)piperidin-4-yI)-3-(4-(trifluoromethyl)benzyl )urea

This compound was prepared substantially as described in Example 36 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-Allyl-l-(l-(((3S,4i?)-4-hydroxy-4-phenyl-l-((jS)-tetrah ydrofuran-2-carbonyl)pyrrolidi n-3-yl)methyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)u rea

This compound was prepared substantially as described in Example 36 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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

l-AUyl-l-(l-(((35,4 _J R)-4-hydroxy-4-phenyl-l-((i?)-tetrahydrofuran-2-carbonyl)pyr rolidi n-3-yl)methyl)piperidin-4-yI)-3-(4-(trifluoromethyl)benzyI)u rea

This compound was prepared substantially as described in Example 36 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.58-7.48 (m, 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) ₃ 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-AllyI-l-(l-(((3iS',4i?)-4-hydroxy-4-phenyl-l-(lH-pyrrol e-l-carbonyl)pyrroIidin-3-yI)m ethyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyI)urea

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 ⁰ C. After stirring under nitrogen overnight, the solution was extracted with DCM twice. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. Column chromatography on silica (l%-3% MeOH in DCM) afforded the title compound as a white foam (0.044 g, 62%). ¹ H NMR (CDCl ₃ , 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-AHyI-l-(l-(((3S,4R)-4-hydroxy-4-phenyl-l-(pyrroIidine-l -carbonyl)pyrrolidin-3-yI)m ethyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

This compound was prepared substantially as described in Example 40 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-NitrobenzylallyI(l-(((3S,4i?)-l-(cyclopentanecarbonyl)- 4-hydroxy-4- (4-methoxyphenyl)pyrrolidin-3-yl)methyl)piperidin-4-yl)carba mate

Step A

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

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 rnL) and then washed with HCl (2 M, 600 ml) and water (600 ml). The mixture was dried over Na ₂ SO ₄ , filtered and evaporated to afford the crude product (150 g, 75 %), which was used without further purification in the next step. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.55-7.52 (d, J = 9.0 Hz, 2H), 6.92-6.89 (d, J = 9.0 Hz, 2H), 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 IcV) 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

A solution of the alkene from step A (49.0 g, 166 mmol) and (i?)-l-phenylethanamine (23 mL, 183 mmol) in MeOH (200 niL) 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

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 NaHCO ₃ and brine, dried

over Na ₂ SO ₄ , 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). ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.43-7.33 (m, 5H), 7.00-6.95 (d, J = 9.0 Hz, 2H) ₃ 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-phen ylethyl)pyrrolidine-3-carboxyli c acid

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 Na ₂ SO ₄ 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)-l-p henylethyl)pyrrolidine-3-carbo nyl)piperidιn-4-one

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 ⁰ C. After stirring under nitrogen overnight, the reaction mixture was

filtrated and washed with dry THF. Et ₃ N (1.4 mL, 31.2 mmol) and piperidine-4-one hydrochloride (1.55 g, 11.4 mmol) were then added at 0 ⁰ C 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 NaHCO ₃ and brine, dried over Na ₂ SO ₄ , 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%). ¹ H NMR (CDCl ₃ , 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 IcV) m/z 459.3 (M+ Na) ⁺ , 491.3 (M+MeOH+Na) ⁺ .

Step F

l-(((3S,4R)-4-hydroxy-4-(4-methoxyphenyl)-l-((R)-l-phenyl ethyl)pyrrolidin-3-yl)methyl)pip eridin-4-ol

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 ⁰ C. The reaction mixture was heated at reflux for 24 h, after which time, it was stopped by adding 1 mL H ₂ O, ImL 15% NaOH and ImL H ₂ O. 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

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 H ₂ at 50 ⁰ C 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)py rrolidin-1 -yljmethanone

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 Et ₃ N (2.0 mL, 14.4 mmol) in dry DCM (20 mL) at 0 ⁰ C. After stirring under nitrogen overnight, the reaction mixture was extracted with DCM. The organic layer was washed with saturated aqueous

NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Recrystallization from

PE/EA afforded the title compound as white crystals (1.11 g, 60 % for the three steps). ¹ H NMR (CDCl ₃ , 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

1-(((3S,4R)-1 '-(cyclopentanecarbonyl)-4-hydroxy-4-(4-methoxyphenyl)pyrrol idin-3-yl)methy I)piperidin-4-one

To a solution of oxalyl chloride (0.26 mL, 3.0 mmol) in DCM (5 mL) at -78 ⁰ C 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 niL) was added dropwise. The resultant slurry was stirred for another 30 min and then Et ₃ N (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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (50%- 100% EA in PE) afforded the title compound as a white yellow foam (0.672 g, 73 %). ¹ H NMR (CDCl ₃ , 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-(aπylamino)piperidin-l-yl)methyl)-3-hydro xy-3-(4-methoxyphenyl)pyrrolidin -l-yl)(cyclopentyl)methanone

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, NaHCO ₃ and brine. The organic phase was dried with Na ₂ SO ₄ 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-me thoxy

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 ⁰ C. After stirring at room temperature overnight, the solution was extracted with DCM twice. The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. Column chromatography on silica (1 %-3 % MeOH in DCM) afforded the title compound as a white foam (0.060 g, 75 %). ¹ H NMR

(CDCl ₃ , 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-AUyl-l-(l-(((3 _* S',4i ^l ?)-l-(cyclopentanecarbonyl)-4-(4-fluorophenyl)-4-hydroxypyrr olidi n-3-yl)methyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)u rea

This compound was prepared substantially as described in Example 42 and Example 24 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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

N-allyl-N-(l-(((35 ^f ,4i?)-l-(cyclopentanecarbonyl)-4-(4-fluorophenyl)-4-hydroxyp yrrolid in-3-yl)methyl)piperidin-4-yl)-2-(4-(N,N-dimethylsulfamoyl)p henyl)acetamide

This compound was prepared substantially as described in Example 42 and Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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) ₃ 2.83-2.62 (m, 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',4i?)-l-(cyclopentanecarbonyl)-4-methoxy-4- phenylpyrrolidin-3-yl)methyl)piperidin-4-yl)carbamate

Step A

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

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

3-carboxylic acid (4.0 g, 12.3 mmol) in dry THF (40 mL) at 0 ⁰ C. The reaction mixture was heated at reflux for 4 h after which time, the reaction was stopped by adding 1 mL H ₂ O, ImL 15% NaOH and ImL H ₂ O. Filtration and concentration to give a yellow oil, which was used without further purification in the next step.

Step B

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

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 H ₂ at 50 ⁰ C 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-(liydroxymethyl)-3-phenyl pyrrolidin-l-yl)methanone

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 Et ₃ N (4.8 mL, 34.5 mmol) in dry DCM (30 mL) at 0 ⁰ C. After stirring under nitrogen overnight, the reaction mixture was extracted with DCM. The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Recrystallization from PE/EA afforded the title compound as white crystals (2.0 g, 61 % for the three steps). ¹ H 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

((3RAR)-4-((tert-butyldimethylsilyloxy)methyl)-3-hydroxy- 3-phenylpyrrolidin-l-yl)(cyclope ntyl)methanone

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

((3RAR)-4-((tert-butyldimethylsilyloxy)methyl)-3-methoxy- 3-phenylpyrrolidin-l~yl)(cyclope ntyl)methanone

To a cooled (O °C) solution of the alcohol from step D (0.2 g, 0.5 mmol) in dry THF (5 niL) 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 Et ₂ O and washed with a saturated solution OfNH ₄ Cl and H ₂ O. The organic layer was dried (Na ₂ SO ₄ ) ^' and concentrated, and the residue was purified by flash chromatography to afford the product as a colorless oil (0.15 g, 72 %). ¹ H NMR (CDCl ₃ , 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)meth anone

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 %). ¹ H NMR (CDCl ₃ , 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

(3SAR)-l-(cyclopentanecarbonyl)-4-methoxy-4~phenylpyrroli dine-3-carbaldehyde

To a solution of oxalyl chloride (0.03 mL, 0.343 mmol) in DCM (2 mL) at -78 ⁰ C 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 Et ₃ N (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 Na ₂ SO ₄ 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

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, NaHCO ₃ and brine. The organic phase was dried with Na ₂ SO ₄ and concentrated to yield crude amine which was used without further purification in the next step. ¹ H NMR (CDCl ₃ , 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, HH); MS (ESI, Pos. 1.5 kV) m/z 241.2 (M+H) ⁺ .

Step I

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

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 O 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 Na ₂ SO ₄ and concentrated. Column chromatography on silica (10%-20% EA in PE) afforded the title compound as a colorless oil (0.90 g, 86%). ¹ H NMR (CDCl ₃ , 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

To a solution of Boc-amine (0.8 g, 1.91 mmol) from step I in DCM (10 mL) was added CF ₃ COOH (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 Na ₂ SO ₄ and concentrated, which was used without further purification in the next step. ¹ H NMR (CDCl ₃ , 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

4-nitrobenzylaUyl(l-(((3S,4R)-l-(cyclopentanecarbonyl)-4- methoxy-4~phenylpyrroHdin-3-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 O 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 Na ₂ SO ₄ , 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%). ¹ H NMR (CDCl ₃ , 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) ₅ 2.39-2.28 (m, 2H), 1.90-1.59 (m, 12H). MS (ESI, Pos. 1.5 IcV) m/z 605.7 (M+H) ⁺ , 627.7 (M+Na) ⁺ .

Example 46

endo-N-allyI-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)a cetaniide

This compound was prepared substantially as described in Example 42 and Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 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-hydroxypyrr olidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-2τ(4-(N- methylsulfamoyl)phenyl)acet amide

This compound was prepared substantially as described in Example 42 and Example 4 using appropriate starting materials. ¹ H NMR (CDCl ₃ , 300 MHz) 6 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) ₅ 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

l-allyl-l-(l-(((3S,4R)-4-hydroxy-4-phenyl-l-(lH-pyrrole-2 -carbonyl)pyrrolidm-3-yI)m ethyl)piperidin-4-yI)-3-(4-(trifluoromethyl)benzyl)urea

This compound was prepared substantially as described in Example 36 using appropriate starting materials. ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.78-9.70 (m, 2H) ₃ 7.58-7.27 (m, 9H), 6.98-6.95 (m, IH), 6.68-6.56 (m ₅ IH), 6.30-6.24 (m, IH), 5.86-5.77 (m, IH), 5.29-5.20 (m, 2H), 4.94-4.80 (m, IH), 4.45-4.20 (m, 3H), 4.03-3.76 (m, 6H), 3.30-2.96 (m, IH), 2.88-2.63 (m, 2H), 2.56-2.34 (m, 2H), 2.31-2.10 (m, 2H), 1.99-1.49 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 160.6, 158.1, 143.7, 135.3, 128.5, 127.5, 125.4, 125.2, 121.2, 116.6, 112.4, 110.0, 82.5, 62.3, 55.0, 54.0, 51.3, 48.7, 45.3, 44.5, 43.7, 30.1, 29.6; ESI-MS m/z 632.3 (M + Na) ⁺ ; HRMS calcd. for C ₃₃ H ₃₉ F ₃ N ₅ O ₃ (M + H) ⁺ requires 610.2998, found 610.3000.

Example 49

l-allyl-l-(l-(((3S,4R)-l-(cyclopropanecarbonyl)-4-hydroxy -4-phenylpyrrolidin-3-yl)me thyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

This compound was prepared substantially as described in Example 36 using appropriate starting materials. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64-7.27 (m, 9H), 5.86-5.74 (m, IH), 5.35-5.16 (m, 2H), 4.91-4.85 (m, IH), 4.54-4.17 (m, 4H), 3.95-3.64 (m, 5H), 3.03-2.96 (m, IH), 2.82-2.63 (m, 2H) ₅ 2.52-2.33 (m, 3H), 2.27-2.04 (m, 2H), 1.86-1.38 (m, 8H), 1.06-1.01 (m, 2H), 0.85-0.76 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.7, 158.3, 144.0, 143.6, 135.6, 128.7, 127.6, 125.4, 124.8, 123.0, 117.0, 82.5, 61.6, 60.4, 55.6, 55.2, 54.4, 51.5, 49.2, 46.5, 44.6, 30.3, 29.9, 12.6, 7.8; ESI-MS m/z 585.3 (M + H) ⁺ ; HRMS calcd. for C ₃₂ H ₄₀ F ₃ N ₄ O ₃ (M + H) ⁺ requires 585.3049, found 585.3047.

Example 50 l-allyl-l-(l-(((3S,4R)-l-(cyclobutanecarbonyl)-4-hydroxy-4-p henylpyrrolidin-3-yl)met hyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)urea

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +2.2, (c 0.50, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64-7.27 (m, 9H), 5.86-5.74 (m, IH), 5.35-5.16 (m, 2H), 4.91-4.85 (m, IH), 4.54-4.17 (m, 4H), 3.95-3.64 (m, 5H), 3.03-2.96 (m, IH), 2.82-2.63 (m, 2H), 2.52-2.33 (m, 3H), 2.27-2.04 (m, 2H), 1.86-1.38 (m, 8H), 1.06-1.01 (m, 2H), 0.85-0.76 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 173.6, 158.0, 143.8, 143.3, 135.3, 129.1, 128.3, 127.6, 127.3, 125.3, 124.5, 116.7, 82.2, 60.6, 59.8, 55.7, 54.9, 54.3, 52.0, 51.2, 48.2, 47.5, 46.2, 44.3, 38.0, 30.1, 29.9, 24.5, 17.9;

ESI-MS m/z 621.3 (M + Na) ⁺ ; HRMS calcd. for C ₃₃ H ₄₂ F ₃ N ₄ O ₃ (M + H) ⁺ requires 599.3212, found 599.3204.

Example 51

N-allyl-N-(l-(((3S,4R)-l-(cyclopropanecarbonyl)-4-hydroxy -4-phenylpyrrolidin-3-yl)m ethyl)piperidiu-4-yI)-2-(4-(N-methylsulfamoyl)phenyl)acetami de

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +5.1, (c 0.51, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.70 (m, 2H), 7.54-7.27 (m, 7H), 5.90-5.75 (m, IH), 5.33-5.10 (m, 2H), 4.95-4.71 (m, IH), 4.52-4.49 (m, IH), 3.95-3.52 (m, 8H), 3.04-2.96 (m, IH), 2.81-2.63 (m, 6H), 2.56-2.43 (m, 2H), 2.22-2.11 (m, 2H), 2.03-1.46 (m, 4H), 1.10-0.95 (m, 2H), 0.83-0.75 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.6, 170.7, 143.0, 140.3, 139.0, 137.4, 136.6, 134.7, 133.4, 129.8, 128.4, 125.2, 116.7, 82.2, 61.3, 60.2, 55.1, 54.0, 51.0, 47.8, 46.3, 45.3, 44.4, 40.3, 30.2, 29.3, 12.3, 7.5; ESI-MS m/z 595.2 (M + H) ⁺ ; HRMS calcd. for C ₃₂ H ₄₃ N ₄ O ₅ S (M + H) ⁺ requires 595.2956, found 595.2949.

Example 52

N-allyl-N-(l-(((3S,4R)-l-(cyclobutanecarbonyl)-4-hydroxy- 4-phenylpyrrolidin-3-yl)met hyl)piperidin-4-yl)-2-(4-(N-methylsulfamoyl)phenyl)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +9.3, (c 0.69, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96-7.71 (m, 2H), 7.49-7.27 (m, 7H), 5.90-5.80 (m, IH), 5.32-4.96 (m, 3H), 4.50-4.48 (m, IH), 3.87-3.51 (m, 8H), 3.28-3.10 (m, IH), 3.03-2.91 (m, IH), 2.80-2.56 (m, 5H), 2.50-2.29 (m,

4H), 2.19-2.10 (m, 4H), 1.99-1.84 (m, 4H), 1.77-1.57 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 173.6, 170.6, 143.0, 140.1, 138.9, 137.3, 136.5, 134.4, 133.2, 129.7, 129.0, 128.3, 127.3, 125.0, 116.6, 82.0, 60.5, 59.8, 55.2, 54.8, 53.8, 52.6, 51.0, 47.8, 46.1, 45.3, 44.1, 40.3, 37.9, 30.2, 29.5, 24.5, 17.9, 7.7; ESI-MS m/z 609.3 (M + H) ⁺ ; HRMS calcd. for C ₃₃ H ₄₅ N ₄ O ₅ S (M + H) ⁺ requires 609.3119, found 609.3105.

Example 53

N-alIyl-N-(l-(((3S,4R)-l-(2-cyclopropylacetyl)-4-hydroxy- 4-phenylpyrrolidin-3-yl)meth yl)piperidin-4-yl)-2-(4-(N-methyIsuIfamoyl)phenyI)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +7.8, (c 0.70, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.70 (m, 2H), 7.51-7.27 (m, 7H), 5.90-5.81 (m, IH), 5.33-5.10 (m, 2H), 4.64-4.44 (m, 2H), 3.87-3.61 (m, 8H), 3.04-2.91 (m, IH), 2.80-2.58 (m, 5H), 2.52-2.39 (m, 2H), 2.28-2.06 (m, 4H), 1.79-1.53 (m, 4H), 1.15-1.07 (m, IH), 0.60-0.53 (m, 2H), 0.19-0.13 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.8, 170.6, 143.0, 140.4, 137.3, 136.7, 134.7, 133.6, 129.8, 128.5, 127.9, 125.6, 116.8, 82.4, 61.6, 55.6. 55.2, 51.0, 47.4, 46.3, 45.3, 44.4, 40.2, 39.6, 29.9, 29.3, 6.8, 4.5, 1.0; ESI-MS m/z 609.1 (M + H) ⁺ ; HRMS calcd. for C ₃₃ H ₄₅ N ₄ O ₅ S (M + H) ⁺ requires 609.3115, found 609.3105.

Example 54 N-allyl-N-(l-(((3S,4R)-4-hydroxy-l-isobutyryl-4-phenylpyrrol idin-3-yl)methyl)piperidi n-4-yl)-2-(4-(N-methylsulfamoyl)phenyl)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +15.2, (c 0.40, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.70 (m, 2H), 7.51-7.27 (m, 7H), 5.90-5.80 (m, IH), 5.33-5.10 (m, 2H), 4.87-4.70 (m, IH), 4.55-4.44 (m, IH), 3.88-3.66 (m, 8H), 3.04-2.95 (m, IH), 2.77-2.40 (m, 5H), 2.26-2.06 (m, 2H), 1.73-1.58 (m, 4H), 1.18-1.12 (m, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 176.4, 170.9, 143.3, 140.6, 137.7, 136.9, 134.9, 133.7, 129.8, 128.6, 127.6, 125.4, 116.9, 82.5, 61.5, 55.9. 55.3, 54.3, 53.0, 51.3, 48.0, 46.2, 45.6, 44.5, 40.4, 32.2, 29.6, 19.3; ESI-MS m/∑ 597.2 (M + H) ⁺ ; HRMS calcd. for C ₃₂ H ₄₅ N ₄ O ₅ S (M + H) ⁺ requires 597.3116, found 597.3105.

Example 55 N-allyl-N-(l-(((3S,4R)-4-hydroxy-4-phenyl-l-pivaloylpyrrolid in-3-yl)methyl)piperidin- 4-yl)-2-(4-(N-methylsuIfamoyl)phenyl)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +7.6, (c 0.60, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, J= 8.4 Hz, 2H), 7.44-7.20 (m, 7H), 5.83-5.74 (m, IH), 5.26-5.03 (m, 2H), 4.75-4.58 (m, IH), 4.49-4.37 (m, IH), 3.80-3.65 (m, 8H), 2.99-2.88 (m, IH), 2.70-2.57 (m, 5H), 2.53-2.30 (m, 2H), 2.29-2.03 (m, 2H), 1.58-1.57 (m, 4H), 1.20 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 176.8, 170.6, 143.2, 140.1, 138.9, 137.3, 136.4, 134.6, 133.2, 129.6, 128.3, 127.2, 125.0, 116.5, 82.0, 62.0, 55.3, 54.9, 53.7, 51.0, 49.9, 45.2, 44.0, 42.5, 40.2, 38.7, 29.4, 28.3, 27.3; ESI-MS m/z 611.1 (M + H) ⁺ ; HRMS calcd. for C ₃₃ H ₄₇ N ₄ O ₅ S (M + H) ⁺ requires 611.3277, found 611.3262.

Example 56

N-allyl-N-(l-(((3S,4R)-4-hydroxy-4-phenyl-l-(lH-pyrrole-2 -carbonyl)pyrrolidin-3-yl) methyl)piperidin-4-yl)-2-(4-(N-methylsulfamoyl)phenyl)acetam ide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ^2s = +4.4, (c 0.50, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.85-9.75

(m, IH), 7.81-7.71 (m, 2H), 7.53-7.27 (m, 7H), 6.95 (m, IH), 6.63-6.55 (m, IH), 6.29-6.23 (m, IH), 5.90-5.81 (m, IH), 5.32-5.08 (m, 2H), 4.95-4.89 (m, IH), 4.52-4.50 (m, IH),

4.11-3.72 (m, 8H), 3.05-2.95 (m, IH), 2.82-2.47 (m, 7H), 2.43-2.09 (m, 2H), 1.67-1.60 (m,

4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.8, 160.8, 143.0, 140.3, 139.0, 137.4, 136.6, 134.7,

133.4, 129.8, 128.5, 127.8, 125.5, 121.5, 116.7, 112.6, 109.9, 82.5, 67.9, 62.5, 61.0, 55.6,

54.8, 53.9, 51.1, 49.0, 46.5, 45.4, 43.8, 40.4, 30.7, 29.2; ESI-MS m/z 620.3 (M + H) ⁺ ; HRMS calcd. for C ₃₃ H ₄₂ N ₅ O ₅ S (M + H) ⁺ requires 620.2913, found 620.2901.

Example 57

N-allyl-N-(l-(((3S,4R)-4-hydroxy-4-phenyI-l-((R)-tetrahyd rofuran-2-carbonyl)pyrroli din-3-yl)methyl)piperidin-4-yl)-2-(4-(N-methylsulfamoyl)phen yl)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +24.3, (c 0.35, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.70 (m, 2H), 7.52-7.27 (m, 7H), 5.91-5.78 (m, IH), 5.33-5.10 (m, 2H), 4.69-4.47 (m, 3H), 4.03-3.72 (m, 10H), 3.03-2.96 (m, IH), 2.77-2.63 (m, 5H), 2.53-2.30 (m, 2H), 2.24-1.90 (m, 6H), 1.89-1.40 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.1, 170.7, 142.6, 140.3, 137.3, 136.6, 134.7, 133.5, 129.8, 128.5, 127.4, 125.2, 116.8, 82.4, 69.3, 61.1, 55.2. 54.8, 54.2, 51.0, 47.8, 46.4, 45.3, 44.1, 40.4, 29.6, 29.3, 28.7, 25.7; ESI-MS m/z 625.3 (M + H) ⁺ ; HRMS calcd. for C ₃₃ H ₄₅ N ₄ O ₆ S (M + H) ⁺ requires 625.3060, found 625.3054.

Example 58

N-aIlyI-N-(l-(((3S,4R)-4-hydroxy-4-phenyI-l-((S)-tetrahyd rofuran-2-carbonyI)pyrroIid in-3-yl)methyl)piperidin-4-yl)-2-(4-(N-methylsulfamoyl)pheny l)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ =-1.8, (c 0.39, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.70 (m, 2H) ₃ 7.47-7.27 (m, 7H), 5.91-5.75 (m, IH), 5.33-5.10 (m, 2H), 4.60-4.42 (m, 3H), 4.03-3.72 (m, 10H), 3.03-2.92 (m, IH), 2.75-2.64 (m, 5H), 2.52-2.30 (m, 2H), 2.17-1.90 (m, 6H), 1.91-1.39 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.1, 170.6, 143.0, 140.3, 137.3, 136.5, 134.6, 133.4, 129.8, 128.4, 127.4, 125.1, 116.7, 82.2, 69.1, 60.6, 55.2. 54.9, 54.1, 51.0, 48.1, 46.5, 45.3, 43.6, 40.3, 29.6, 29.3, 28.8, 25.6; ESI-MS m/z 625.3 (M + H) ⁺ ; HRMS calcd. for C ₃₃ H ₄₅ N ₄ O ₆ S (M + H) ⁺ requires 625.3071, found 625.3054.

Example 59

N-allyl-N-(l-(((3S,4R)-4-hydroxy-4-phenyl-l-(tetrahydro-2 H-pyran-4-carbonyl)pyrroIi din-3-yl)methyl)piperidin-4-yl)-2-(4-(N-methylsulfamoyl)phen yI)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +11.3, (c 0.68, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.70 (m, 2H), 7.52-7.27 (m, 7H), 5.90-5.81 (m, IH), 5.33-5.10 (m, 2H), 4.78-4.66 (m, IH), 4.53-4.46 (m, IH), 4.07-4.04 (m, 2H), 3.99-3.65 (m, 8H), 3.51-3.34 (m, 2H), 3.03-2.94 (m, IH), 2.68-2.42 (m, 8H), 2.27-2.11 (m, 2H), 2.03-1.87 (m, 4H), 1.68-1.60 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 173.2, 170.6, 142.5, 140.1, 138.9, 137.3, 136.4, 134.5, 133.3, 129.7, 128.4, 127.2, 125.0, 116.6, 82.1, 67.0, 61.2, 54.9, 54.0, 50.9, 47.6, 46.3, 45.3, 44.0, 40.2, 39.4, 29.5, 29.1, 28.3; ESI-MS m/z 639.1 (M + H) ⁺ ; HRMS calcd. for C ₃₄ H ₄₇ N ₄ O ₆ S (M + H) ⁺ requires 639.3225, found 639.3211.

Example 60

N-allyl-N-(l-(((3S,4R)-l-(4,4-difluorocyclohexanecarbonyl )-4-hydroxy-4-phenylpyrroH din-3-yl)methyl)piperidin-4-yl)-2-(4-(N-methylsulfamoyI)phen yl)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +10.3, (c 0.55, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.70 (m, 2H), 7.52-7.27 (m, 7H), 5.90-5.81 (m, IH), 5.33-5.10 (m, 2H), 4.70-4.59 (m, IH), 4.55-4.46 (m, IH) ₃ 3.87-3.55 (m, 8H), 3.03-2.94 (m, IH) ₅ 2.79-2.33 (m, 7H), 2.23-2.09 (m, 5H), 1.89-1.53 (m ₃ 10H); ¹³ C NMR (100 MHz ₅ CDCl ₃ ) δ 173.3, 170.7, 142.6, 140.3, 137.3, 136.6, 134.7, 133.5, 129.9, 128.6, 127.5, 125.1, 116.8, 82.3, 61.6, 55.2. 54.7, 54.3, 51.0, 48.8, 47.6, 45.4, 44.3, 40.2, 39.7, 32.9, 29.8, 29.3, 25.2; ESI-MS m/z 6733 (M + H) ⁺ ; HRMS calcd. for C ₃₅ H ₄₇ F ₂ N ₄ O ₅ S (M + H) ⁺ requires 673.3245, found 673.3230.

Example 61

N-alIyl-N-(l-(((3S,4R)-l-(2-chlorobenzoyl)-4-hydroxy-4-ph enylpyrroIidin-3-yl)methyl) piperidin-4-yl)-2-(4-(N-methyIsulfamoyl)phenyl)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +20.1, (c 0.30, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82-7.70 (m, 2H), 7.55-7.27 (m, HH), 5.90-5.80 (m, IH), 5.33-5.10 (m, 2H), 4.64-4.59 (m, IH), 4.55-4.41 (m, IH), 4.10-3.93 (m, IH), 3.93-3.78 (m, 3H), 3.72-3.55 (m, 3H), 3.43-3.35 (m, IH), 3.10-3.03 (m, IH), 2.94-2.44 (m, 6H), 2.30-2.08 (m, 4H), 1.71-1.43 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.6, 167.3, 142.6, 140.3, 139.0, 137.4, 136.5, 134.5, 133.4, 130.3, 129.9, 129.1, 128.4, 127.6, 127.3, 125.6, 125.1, 116.7, 81.9, 62.1, 59.5, 55.1. 54.1, 53.6,

51.0, 47.7, 45.3, 44.6, 41.9, 40.4, 29.6, 29.2; ESI-MS m/z 665.3 (M + H) ⁺ ; HRMS calcd. for C ₃₅ H ₄₂ ClN ₄ O ₅ S (M + H) ⁺ requires 665.2560, found 665.2559.

Example 62

N-allyl-N-(l-(((3S,4R)-l-(4-fluorobenzoyl)-4-hydroxy-4-ph enylpyrrolidin-3-yl)methyl) piperidin-4-yI)-2-(4-(N-methylsulfamoyl)phenyI)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +21.8, (c 0.50, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.80-7.70 (m, 2H), 7.63-7.27 (m, 9H), 7.15-7.01 (m, 2H), 5.90-5.81 (m, IH), 5.33-5.10 (m, 2H), 4.69-4.60 (m, IH), 4.58-4.41 (m, IH), 4.06-3.58 (m, 8H), 3.10-3.05 (m, IH), 2.94-2.44 (m, 7H), 2.30-2.05 (m, 3H), 1.71-1.41 (m, 4H); ESI-MS m/z 649.2 (M + H) ⁺ ; Anal. Calcd. for C ₃₅ H ₄₁ FN ₄ O ₅ S: C, 64.79; H, 6.37; N, 8.64; Found: C, 64.36; H, 6.24; N, 8.44.

Example 63

N-allyl-N-(l-(((3S,4R)-4-hydroxy-l-isonicotinoyl-4-phenyl pyrrolidin-3-yl)methyI)piper idin-4-yl)-2-(4-(N-methylsuIfamoyl)phenyl)acetamide

This compound was prepared substantially as described in Example 36 using appropriate starting materials. [α] _D ²⁵ = +24.6, (c 0.40, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.74, 8.67 (d, J= 5.7 Hz, 2H), 7.82-7.70 (m, 2H), 7.54-7.27 (m, 9H), 5.90-5.80 (m, IH), 5.33-5.09 (m, 2H), 4.94-4.87 (m, IH), 4.53-4.45 (m, IH), 4.03-3.51 (m, 8H), 3.15-3.03 (m, IH), 2.74-2.47 (m, 7H), 2.26-2.09 (m, 2H), 1.74-1.53 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.8, 167.5, 150.0, 143.7, 140.1, 139.0, 137.4, 136.5, 134.5, 133.3, 129.7, 129.0, 128.5, 127.6, 127.3, 125.5, 125.1, 121.3, 116.7, 81.7, 63.5, 60.3, 54.8. 54.0, 51.9, 50.6, 46.7, 45.8, 44.3, 40.3,

29.6, 29.1; ESI-MS m/z 632.3 (M + H) ⁺ ; HRMS calcd. for C ₃₄ H ₄₂ N ₅ O ₅ S (M + H) ⁺ requires 632.2911, found 632.2901.

Example 64 l-allyl-l-(l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-(3-fluorop henyl)-4-hydroxypyrrolidi n-3-yl)methyl)piperidin-4-yl)-3-(4-(trifluoromethyl)benzyl)u rea

This compound was prepared substantially as described in Example 43 using appropriate starting materials. [α] _D ²⁵ = +12.7, (c 0.50, CHCl ₃ ); ¹ H NMR (300 MHz ₅ CDCl ₃ ) δ 7.58 (d, J = 8.4 Hz, 2H), 7.38-7.18 (m, 5H), 7.02-6.94 (m, IH), 5.88-5.77 (m, IH), 5.30-5.24 (m, 2H), 4.93-4.89 (m, IH), 4.45 (d, J = 6.0 Hz, 2H), 4.39-4.28 (m, IH), 3.85-3.64 (m, 6H), 3.03-2.93 (m, IH), 2.90-2.64 (m, 3H), 2.54-2.28 (m, 2H), 2.16-2.12 (m, 2H), 1.88-1.54 (m, 12H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.4, 158.1, 146.6, 143.8, 135.3, 130.0, 129.1, 127.5, 125.4, 122.8, 120.6, 116.8, 114.1, 112.6, 82.0, 61.2, 60.0, 55.4, 54.1, 51.4, 48.7, 47.6, 46.2, 44.3, 42.8, 30.0, 29.8, 26.0; ESI-MS m/z 631.3 (M + H) ⁺ ; HRMS calcd. for C ₃₄ H ₄₃ F ₄ N ₄ O ₃ (M + H) ⁺ requires 631.3259, found 631.3266.

Example 65

4-((3-(l-(((3S,4R)-l-(cyclopentanecarbonyl)-4-hydroxy-4-p henylpyrrolidin-3-yl)methyl

)piperidin-4-yI)-2-oxo-3,4-dihydropyrimidin-l(2H)-yl)meth yl)-N-methylbenzenesulfon amide

This compound was prepared substantially as described in Example 35 using appropriate starting materials. [α] _D ²⁵ = +13.0, (c 0.16, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.73-7.20 (m, 10H), 5.74-5.65 (m, 0.5H) ₅ 5.60-5.43 (m, 0.5H), 5.20-4.78 (m, 0.5H), 4.60-4.21 (m, 2.5H), 3.89-3.59 (m, 6H), 3.20-2.93 (m, 2H), 2.80-2.37 (m, 9H), 2.20-2.00 (m, 2H),

1.96-1.50 (m, 12H); ¹³ C NMR (IOO MHZ, CDCl ₃ ) δ 175.7, 153.8, 143.3, 142.5, 142.0, 128.8, 128.3, 127.7, 127.6, 125.4, 121.2, 108.8, 82.6, 61.5, 56.3, 55.3, 54.2, 52.3, 51.5, 48.0, 46.4, 44.4, 42.8, 34.5, 30.0, 29.5, 26.3; ^' ESI-MS m/z 636.8 (M + H) ⁺ ; HRMS calcd. for C ₃₄ H ₄₆ N ₅ O ₅ S (M + H) ⁺ requires 636.3243, found 636.3214.

Example 66 l-(l-(((3S,4R)-l-(cycIopentanecarbonyI)-4-(3-fluorophenyI)-4 -hydroxypyrroIidin-3-yI) methyl)piperidin-4-yI)-5-methylene-3-(4-(trifluoromethyl)ben zyl)tetrahydropyrimidin-

2(lH)-one

This compound was prepared substantially as described in Example 45 using appropriate amine and aldehyde. [α] _D ²⁵ = +7.9, (c 0.60, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.59 (d, J = 7.8 Hz, 2H), 7.40 (d, J= 7.8 Hz, 2H) ₅ 7.35-7.19 (m, 3H), 7.03-6.95 (m, IH), 5.06 (s, IH), 4.98 (s, IH), 4.60 (s, 2H), 4.39-4.34 (m, IH), 3.87-3.68 (m, 8H), 3.07-2.96 (m, IH), 2.85-2.66 (m, 3H), 2.56-2.37 (m, 2H), 2.33-2.19 (m, 2H), 1.87-1.50 (m, 12H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.4, 164.3, 161.8, 156.4, 146.5, 142.1, 135.6, 130.1, 129.6, 129.3, 128.0, 125.5, 122.8, 120.6, 114.1, 112.8, 111.1, 82.0, 61.2, 60.0, 55.7, 55.3, 54.1, 51.0, 50.6, 47.6, 45.5, 44.1, 42.8, 30.0, 29.7, 29.4, 26.0; ESI-MS m/z 643.3 (M + H) ⁺ ; HRMS calcd. for C ₃₅ H ₄₃ F ₄ N ₄ O ₃ (M + H) ⁺ requires 643.3271, found 643.3266.

Example 61

cyclopentyl((3R,4S)-3-(3-fluorophenyl)-3-hydroxy-4-((4-(4 -phenyl-lH-l,2,3-triazol-l-yI )piperidin-l-yl)methyl)pyrrolidin-l-yl)methanone

This compound was prepared substantially as described in Example 45 using appropriate amine and aldehyde. [α] _D ²⁵ = +5.9, (c 1.8, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.79-7.60 (m, 3H), 7.44-7.27 (m, 6H), 7.01-6.95 (m, IH), 4.52 (m, IH), 4.00-3.60 (m, 4H), 3.15-3.10

(m, IH) ₃ 2.88-2.00 (m, 10H), 1.98-1.50 (m, 10H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.4, 164.2, 161.7, 147.6, 146.2, 130.4, 130.0, 128.8, 128.1, 125.6, 121.0, 120.5, 117.2, 114.2, 112.9, 112.5, 82.0, 61.2, 60.4, 57.2, 55.3, 53.8, 52.8, 49.4, 47.8, 46.8, 44.2, 42.7, 42.5, 32.6, 30.2, 30.0, 26.0; ESI-MS m/z 518.2 (M + H) ⁺ ; HRMS calcd. for C ₃₀ H ₃₇ FN ₅ O ₂ (M + H) ⁺ requires 518.2931, found 518.2926.

Example 68

Exo-l-alIyl-l-(8-(((3S,4R)-l-(cycIopentanecarbonyl)-4-(3- fluorophenyI)-4-hydroxypyrr olidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-(4-(tri fluoromethyI)benzyl)urea

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +18.1, (c 0.80, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58 (d, J = 7.8 Hz, 2H), 7.40-7.22<m, 5H), 7.03-6.98 (m, IH), 5.88-5.79 (m, IH), 5.31-5.23 (m, 2H), 4.94 (t, J = 5.4 Hz, IH), 4.72-4.65 (m, IH), 4.44 (d, J = 5.4 Hz, 2H), 3.92-3.68 (m, 6H), 3.27-3.20 (m, IH), 3.02-2.90 (m, IH), 2.84-2.60 (m, 2H), 2.40-2.28 (m, 2H), 2.00-1.54 (m, 14H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.6, 164.3, 161.8, 158.3, 146.0, 143.7, 135.4, 130.0, 127.4, 125.5, 120.7, 116.9, 114.3, 112.9, 82.4, 62.0, 60.9, 50.9, 48.0, 47.2, 45.2, 44.3, 42.8, 35.6, 30.1, 29.7, 26.1, 25.3; ESI-MS m/z 657.3 (M + H) ⁺ ; HRMS calcd. for C ₃₆ H ₄₅ F ₄ N ₄ O ₃ (M + H) ⁺ requires 657.3427, found 657.3422.

Example 69

Exo-l-allyl-l-(8-(((3S,4R)-l-(cyclopentanecarbonyl)-4-(3- fluorophenyl)-4-hydroxypyrr olidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yI)-3-(4-fluo robenzyl)urea

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +17.7, (c 1.35, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40-7.18 (m, 5H), 7.02-6.96 (m, 3H), 5.84-5.75 (m, IH), 5.24-5.19 (m, 2H), 4.83 (t, J= 5.1 Hz, IH), 4.71-4.62 (m, IH), 4.34 (d, J = 5.4 Hz, 2H), 4.04-3.64 (m, 8H), 3.25-3.19 (m, IH), 3.02-2.96 (m, IH), 2.88-2.62 (m, 2H), 2.45-2.28 (m, 2H), 1.95-1.53 (m, 14H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.5, 163.1, 161.8, 158.2, 146.0, 135.3, 129.9, 128.9, 120.8, 116.7, 115.3, 114.2, 112.9, 82.3, 62.6, 60.8, 50.7, 48.0, 47.0, 45.2, 44.0, 42.7, 35.6, 30.0, 29.7, 26.1, 25.2; ESI-MS m/z 607.3 (M + H) ⁺ ; HRMS calcd. for C ₃₅ H ₄₅ F ₂ N ₄ O ₃ (M + H) ⁺ requires 607.3437, found 607.3454.

Example 70

Exo-4-((3-alIyl-3-(8-(((3S,4R)-l-(cyclopentanecarbonyI)-4 -(3-fluorophenyI)-4-hydroxyp yrrolidin-3-yl)methyl)-8-azabicycIo[3.2.1]octan-3-yl)ureido) methyl)-N,N-dimethylbenz enesulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +15.3, (c 0.42, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.73 (d, J = 8.1 Hz, 2H), 7.41 (d, J= 8.1 Hz, 2H), 7.38-7.22 (m, 3H), 7.03-6.98 (m, IH), 5.90-5.80 (m, IH), 5.30-5.24 (m, 2H), 4.98 (t, J= 5.7 Hz, IH), 4.73-4.64 (m, IH), 4.48 (d, J= 5.7 Hz, 2H), 4.05-3.66 (m, 8H), 3.27-3.21 (m, IH), 3.06-2.98 (m, IH), 2.84-2.63 (m, 8H), 2.46-2.28 (m, 2H), 1.95-1.49 (m, 14H); ¹³ C NMR (IOO MHz, CDCl ₃ ) δ 175.6, 158.2, 145.8, 145.1, 135.3, 133.9, 130.0, 127.9, 127.4, 120.7, 116.7, 114.3, 112.9, 82.3, 62.5, 61.8, 53.6, 47.2, 45.4,

44.8, 44.0, 42.7, 41.9, 37.8, 35.4, 30.0, 29.7, 26.0, 25.2; ESI-MS m/z 696.1 (M + H) ⁺ ; HRMS calcd. for C ₃₇ H ₅₁ FN ₅ O ₅ S (M + H) ⁺ requires 696.3590, found 696.3590.

Example 71

Endo- l-allyl-l-(8-(((3S,4R)-l-(cycIopentanecarbonyl)-4-(3-fluorop henyl)-4-hydroxypyrrolidi n-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-(4-(trifluor omethyl)benzyl)urea

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +13.2, (c 0.50, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58 (d, J = 8.1 Hz, 2H), 7.38 (d, J= 8.1 Hz, 2H), 7.35-7.23 (m, 3H), 7.01-6.94 (m, IH), 5.85-5.75 (m, IH), 5.31-5.21 (m, 2H), 4.85-4.80 (m, IH), 4.51-4.38 (m, 2H), 4.33-4.20 (m, IH), 3.92-3.67 (m, 6H), 3.28-3.17 (m, IH), 3.10-3.05 (m, IH), 2.87-2.26 (m, 6H), 2.12-1.25 (m, 14H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.4, 164.2, 161.8, 157.8, 146.1, 143.8, 134.9, 130.0, 127.5, 125.3, 120.8, 116.6, 114.1, 112.9, 82.4, 61.8, 60.9, 59.7, 59.2, 58.9, 50.4, 46.8, 46.7, 45.2, 44.1, 42.7, 35.1, 30.1, 29.7, 26.1; ESI-MS m/z 657.3 (M + H) ⁺ ; HRMS calcd. for C ₃₆ H ₄₅ F ₄ N ₄ O ₃ (M + H) ⁺ requires 657.3431, found 657.3422.

Example 72

Exo-N-allyl-N-(8-(((3S,4R)-l-(cyclopentanecarbonyl)-4-hyd roxy-4-phenylpyrrolidin-3- yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(4-(N-methylsulf amoyl)phenyI)acetamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +14.1, (c 0.23, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86-7.70 (m, 2H), 7.55-7.27 (m, 7H), 5.93-5.82 (m, IH), 5.34-5.14 (m, 2H), 4.90-4.80 (m, 2H), 3.92-3.70 (m, 8H), 3.27-3.20 (m, IH), 3.03-2.99 (m, IH), 2.87-2.58 (m, 5H), 2.40-2.30 (m, 2H), 1.99-1.45 (m, 16H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.6, 170.9, 142.6, 134.7, 133.6, 130.0, 129.1, 128.5, 127.9, 127.4, 125.3, 116.7, 82.6, 62.5, 60.4, 47.2, 45.3, 42.8, 40.4, 29.9, 29.3, 26.1, 25.3; ESI-MS m/z 649.3 (M + H) ⁺ ; HRMS calcd. for C ₃₆ H ₄₉ N ₄ O ₅ S (M + H) ⁺ requires 649.3426, found 649.3418.

Example 73

Endo-N-allyl-N-(8-(((3S,4R)-l-(cyclopentanecarbonyI)-4-hy droxy-4-phenylpyrroIidin-3 -yI)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(4-(N-methyIsul famoyl)phenyl)acetamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = -7.7, (c 0.20, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83-7.27 (m, 9H), 6.57 (t, J= 4.8 Hz, IH), 5.87-5.74 (m, IH), 5.30-5.03 (m, 2H), 4.14-3.52 (m, 9H), 3.06-2.58 (m, 7H), 2.40-2.19 (m, 4H), 2.01-1.11 (m, 14H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 176.5, 170.1, 141.8, 139.9, 137.8, 134.4, 129.8, 129.4, 128.6, 127.6, 125.3, 116.0, 82.9, 62.4, 60.7, 59.4, 50.4, 48.8, 46.8, 45.6, 44.6, 43.0, 42.6, 36.2, 35.1, 29.9, 29.2, 26.0; ESI-MS m/z 649.3 (M + H) ⁺ ; HRMS calcd. for C ₃₆ H ₄₉ N ₄ O ₅ S (M + H) ⁺ requires 649.3421, found 649.3418.

Example 74

Exo-l-allyl-l-(8-(((3S,4R)-l-(cyclopropanecarbonyl)-4-(3- fluorophenyl)-4-hydroxypyrr olidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-(4-(tri fluoromethyl)benzyl)urea

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +18.5, (c 0.35, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.59 (d, J = 8.1 Hz ₅ 2H), 7.37-7.22 (m, 5H), 7.04-6.98 (m, IH), 5.89-5.77 (m, IH), 5.29-5.23 (m, 2H), 4.95 (t, J = 5.7 Hz, IH), 4.72-4.66 (m, IH), 4.44 (d, J = 5.7 Hz, 2H), 4.03-3.68 (m, 6H), 3.26-3.24 (m, IH), 3.02-3.01 (m, IH), 2.67-2.63 (m, IH), 2.44-2.26 (m, 2H), 2.00-1.52 (m, 9H), 1.08-0.99 (m, 2H), 0.82-0.75 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.6, 164.3, 161.9, 158.2, 146.0, 143.7, 135.4, 130.0, 127.4, 125.4, 120.7, 116.7, 114.1, 112.9, 82.4, 62.7, 61.9, 60.8, 50.8, 48.1, 47.2, 45.3, 44.8, 44.3, 35.6, 26.3, 25.3, 12.3, 7.5; ESI-MS m/z 629.2 (M + H) ⁺ ; HRMS calcd. for C ₃₄ H ₄₁ F ₄ N ₄ O ₃ (M + H) ⁺ requires 629.3097, found 629.3109.

Example 75

Exo-l-allyl-l-(8-(((3S,4R)-l-(4,4-difluorocyclohexanecarb onyl)-4-(3-fluorophenyl)-4-hy droxypyrrolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)- 3-(4-(trifluoromethyl)benz yl)urea

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ^2S = +15.3, (c 0.31, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58 (d, J

= 7.8 Hz, 2H), 7.39-7.22 (m, 5H), 7.04-6.99 (m, IH), 5.88-5.79 (m, IH), 5.29-5.23 (m, 2H),

4.97 (t, J = 5.4 Hz, IH), 4.71-4.64 (m, IH), 4.44 (d, J = 5.4 Hz, 2H) ₅ 3.92-3.56 (m, 6H), 3.25-3.23 (m, IH), 3.03-2.95 (m, IH), 2.67-2.63 (m, IH), 2.44-2.17 (m, 5H), 2.00-1.50 (m, 12H), 1.49-1.35 (m, 2H); ¹³ C NMR (IOO MHz, CDCl ₃ ) δ 173.4, 164.3, 161.9, 158.2, 145.5, 143.7, 135.3, 130.1, 127.4, 125.4, 122.6, 120.7, 116.7, 114.4, 112.9, 82.3, 62.9, 61.9, 60.9, 50.8, 47.3, 45.3, 44.8, 44.3, 39.9, 35.6, 32.9, 32.6, 28.4, 26.3, 25.2; ESI-MS m/z 707.3 (M + H) ⁺ ; HRMS calcd. for C ₃₇ H ₄₅ F ₆ N ₄ O ₃ (M + H) ⁺ requires 707.3389, found 707.3390.

Example 76

Exo-l-aIlyl-l-(8-(((3S,4R)-4-(3-fluorophenyl)-4-hydroxy-l -(lH-pyrrole-2-carbonyl)pyr rolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-(4-(tr ifluoromethyl)benzyl)urea

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +14.9, (c 0.66, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.81-9.67 (m, IH), 9.10-8.81 (m, IH), 7.58 (d, J- 7.8 Hz, 2H), 7.39-7.27 (m, 5H), 7.05-6.95 (m, 2H), 6.66-6.53 (m, IH), 6.31-6.22 (m, IH), 5.88-5.71 (m, IH), 5.27-5.22 (m, 2H), 4.95 (t, J= 5.7 Hz, IH), 4.70-4.65 (m, IH), 4.43 (d, J = 5.7 Hz, 2H), 4.15-3.93 (m, 4H), 3.72 (s, 2H), 3.30-3.28 (m, IH), 3.05-3.04 (m, IH), 2.72-2.68 (m, IH), 2.46-2.34 (m, 2H), 2.00-1.65 (m, 8H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.3, 161.9, 160.9, 158.2, 146.0, 143.7, 135.3, 130.1, 127.4, 125.4, 121.1, 120.8, 116.7, 114.4, 113.0, 112.8, 112.4, 109.9, 82.7, 63.2, 62.5, 61.9, 50.7, 49.5, 48.2, 47.4, 45.3, 44.8, 44.3, 43.7, 35.6, 26.4, 25.3; ESI-MS m/z 654.2 (M + H) ⁺ ; HRMS calcd. for C ₃₅ H ₄₀ F ₄ N ₅ O ₃ (M + H) ⁺ requires 654.3071 , found 654.3062.

Example 77

Exo-4-((3-aIlyϊ-3-(8-(((3S,4R)-l-(cyclopropanecarbonyl)- 4-(3-fluorophenyl)-4-hydroxy pyrrolidin-3-yI)methyI)-8-azabicyclo[3.2.1]octan-3-yl)ureido )methyl)-N,N-dimethylben zenesulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +6.6, (c (J>87, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72 (d, J= 8.1 Hz, 2H), 7.41-7.23 (m, 5H), 7.03-6.98 (m, IH), 5.89-5.79 (m, IH), 5.29-5.21 (m, 2H), 5.08-5.03 (m, IH), 4.73-4.66 (m, IH), 4.48-4.46 (m, 2H), 3.99-3.67 (m, 6H), 3.33-3.27 (m, 2H), 2.91-2.86 (m, IH), 2.69-2.59 (m, 7H), 2.44-2.28 (m, IH), 2.10-1.55 (m, 9H), 0.94-0.92 (m, 2H), 0.80-0.77 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 172.6, 164.2, 161.8, 158.2, 154.8, 145.0, 135.2, 134.0, 130.0, 127.9, 127.4, 120.7, 116.7, 114.1, 113.0, 82.3, 62.5, 61.8, 60.9, 54.9, 49.0, 47.4, 45.3, 44.8, 44.0, 37.8, 35.2, 26.2, 25.7, 12.3, 7.7; ESI-MS m/z 668.2 (M + H) ⁺ ; HRMS calcd. for C ₃₅ H ₄₇ FN ₅ O ₅ S (M + H) ⁺ requires 668.3286, found 668.3277.

Example 78

Exo-4-((3-allyl-3-(8-(((3S,4R)-l-(4,4-difluorocyclohexane carbonyl)-4-(3-fluorophenyl)- 4-hydroxypyrrolidin-3-yI)methyl)-8-azabicyclo[3.2.1]octan-3- yl)ureido)methyI)-N,N-di methylbenzenesulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +14.3, (c 0.40, CHCl ₃ ); ¹ H NMR (300 MHz ₅ CDCl ₃ ) δ 7.73 (d, J = 7.8 Hz, 2H), 7.41-7.22 (m, 5H), 7.04-6.99 (m, IH), 5.89-5.80 (m, IH), 5.30-5.25 (m, 2H) ₅ 4.98 (t, J = 5.4 Hz ₅ IH), 4.69-4.65 (m, IH), 4.48 (U ₃ J = 5.4 Hz, 2H), 3.92-3.62 (m, 6H) ₅ 3.26-3.23 (m, IH) ₅ 3.01-2.99 (m, IH), 2.70-2.62 (m, 7H), 2.46-2.36 (m, 3H) ₅ 2.22-2.04 (m, 2H), 2.00-1.56 (m, 14H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 173.4, 164.3, 161.9, 158.2, 145.5, 145.0, 135.3, 134.0, 130.I ₅ 127.9, 127.4, 125.0, 122.6, 120.7, 116.8, 114.4, 112.9, 82.3, 62.8,

61.9, 60.9, 47.3, 46.0, 45.3, 44.9, 44.1, 39.9, 37.8, 35.6, 32.9, 29.6, 28.4, 26.3, 25.2; ESI-MS m/z 7463 (M + H) ⁺ ; HRMS calcd. for C ₃₈ H ₅₁ F ₃ N ₅ O ₅ S (M + H) ⁺ requires 746.3561, found ^• 746.3558.

Example 79

Exo-4-((3-allyl-3-(8-(((3S,4R)-4-(3-fluorophenyl)-4-hydro xy-l-(lH-pyrrole-2-carbonyl) pyrroIidin-3-yl)methyI)-8-azabicycIo[3.2.1]octan-3-yI)ureido )methyI)-N,N-dimethyIben zenesulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +8.5, (c 0.22, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.76-9.65 (m, IH), 9.09-8.70 (m, IH), 7.73 (d, J= 8.4 Hz, 2H), 7.41-7.27 (m, 5H), 7.05-6.94 (m, 2H), 6.67-6.53 (m, IH), 6.31-6.23 (m, IH), 5.89-5.79 (m, IH), 5.29-5.23 (m, 2H), 4.99 (t, J= 5.7 Hz, IH), 4.70-4.65 (m, IH), 4.48 (d, J = 5.7 Hz, 2H), 4.15-3.94 (m, 4H), 3.74 (s, 2H), 3.32-3.27 (m, IH), 3.06-3.02 (m, IH) ₅ 2.69-2.50 (m, 7H), 2.46-2.32 (m, 2H), 2.00-1.57 (m, 8H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.3, 161.9, 160.8, 158.2, 145.0, 135.3, 134.1, 130.0, 128.0, 127.5, 125.4, 121.0, 120.8, 116.8, 114.3, 113.0, 112.8, 112.3, 110.0, 82.7, 63.2, 62.6, 61.9, 50.7, 48.2, 47.4, 44.8, 44.1, 37.9, 35.6, 29.6, 28.5, 26.4, 25.3; ESI-MS m/z 693.3 (M + H) ⁺ ; HRMS calcd. for C ₃₆ H ₄₆ FN ₆ O ₅ S (M + H) ⁺ requires 693.3231, found 693.3229.

Example 80

Exo-4-((3-aIlyl-3-(8-(((3S,4R)-4-(3-fluorophenyl)-4-hydro xy-l-(tetrahydro-2H-pyran-4- carbonyl)py rrolidin-3-yl)methyl)-8-azabicy clo [3.2.1] octan-3-yl)ureido)methyl)-N,N-di methylbenzenesulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. [α] _D ²⁵ = +5.4, (c 1.40, CHCl ₃ ); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72 (d, J= 7.8 Hz, 2H), 7.41-7.25 (m, 5H), 7.03-6.98 (m, IH), 5.89-5.80 (m, IH), 5.29-5.19 (m, 2H), 5.02 (t, J = 5.7 Hz, IH), 4.71-4.66 (m, IH), 4.47 (d, J = 5.7 Hz, 2H), 4.03-3.92 (m, 2H), 3.89-3.56 (m, 6H), 3.53-3.34 (m, 2H), 3.24-3.20 (m, IH), 3.07-3.01 (m, IH), 2.69-2.35 (m, 10H), 2.08-1.60 (m, 12H); ¹³ C NMR (IOO MHz, CDCl ₃ ) δ 173.4, 158.2, 145.0, 135.3, 134.0, 130.0, 127.9, 127.4, 120.7, 118.6, 116.8, 114.2, 112.9, 82.3, 66.8, 61.8, 55.8, 47.1, 46.0, 45.3, 44.9, 44.1, 39.4, 38.7, 37.8, 35.5, 30.9, 29.6, 28.4, 26.3, 25.2; ESI-MS m/z 712.4 (M + H) ⁺ ; HRMS calcd. for C ₃₇ H ₅₁ FN ₅ O ₆ S (M + H) ⁺ requires 712.3522, found 712.3539.

Example 81

Exo-4-((3-aIlyl-3-(8-(((3S,4R)-l-(cyclopropanecarbonyI)-4 -(3-fluorophenyl)-4-hydroxy pyrrolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yI)ureido )methyI)benzenesulfonami de

This compound was prepared substantially as described in Example 46 using appropriate starting materials. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83-7.56 (m, 2H), 7.42-7.22 (m, 5H), 7.03-6.95 (m, IH), 5.87-5.76 (m, IH), 5.27-5.22 (m, 2H), 5.12-5.05 (m, IH), 4.67-4.57 (m, IH), 4.40-4.38 (m, 2H), 4.01-3.62 (m, 6H), 3.24-3.23 (m, IH), 3.01-2.82 (m, IH), 2.67-2.63 (m, IH), 2.43-2.30 (m, 2H), 1.95-1.71 (m, 8H), 1.08-0.95 (m, 2H), 0.81-0.74 (m, 2H); ESI-MS m/z 649.2 (M + H) ⁺ .

Example 82

Exo-4-((3-allyl-3-(8-(((3S,4R)-l-(4,4-difluorocyclohexane carbonyl)-4-(3-fluorophenyl)-

4-hydroxypyrrolidin-3-yI)methyl)-8-azabicyclo[3.2.1]octan -3-yl)ureido)methyl)benzene sulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83-7.75 (m, 2H), 7.42-7.22 (m, 5H) ₅ 7.04-6.96 (m, IH), 5.88-5.76 (m, IH), 5.30-5.22 (m, 2H), 5.12-5.04 (m, IH), 4.63-4.53 (m, IH), 4.40 (d, J = 5.7 Hz, 2H), 3.90-3.62 (m, 6H), 3.23-3.22 (m, IH), 2.99-2.96 (m, IH) ₅ 2.67-2.63 (m, IH), 2.52-2.29 (m, 3H), 2.22-2.16 (m, 2H), 1.98-1.61 (m, 14H); ESI-MS m/z 727.3 (M + H) ⁺ .

Example 83

Exo-4-((3-allyl-3-(8-(((3S,4R)-4-(3-fluorophenyl)-4-hydro xy-l-(tetrahydro-2H-pyran-4- carbonyl)pyrrolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3- yl)ureido)methyl)benzene sulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.84-7.78 (m, 2H), 7.42-7.22 (m, 5H), 7.03-6.98 (m, IH), 5.86-5.77 (m, IH), 5.30-5.22 (m, 2H), 5.10-5.05 (m, IH), 4.64-4.54 (m, IH), 4.40 (d, J = 4.5 Hz, 2H), 4.04-3.98 (m, 2H), 3.97-3.62 (m, 6H) ₅ 3.51-3.23 (m, 2H),

3.21-3.18 (m, IH), 3.05-2.99 (m, IH), 2.67-2.51 (m, 2H), 2.42-2.31 (m, 2H), 1.95-1.60 (m, 12H); ESI-MS m/z 684.4 (M + H) ⁺ .

Example 84

Exo-4-((3-aIlyl-3-(8-(((3S,4R)-l-(cyclopropanecarbonyl)-4 -(3-fluorophenyl)-4-hydroxy pyrrolidin-3-yl)methyl)-8-azabicycIo[3.2.1]octan-3-yl)ureido )methyI)-N-methyIbenzene sulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81-7.76 (m, 2H), 7.39-7.25 (m, 5H), 7.03-6.98 (m, IH), 5.92-5.76 (m, IH), 5.29-5.18 (m, 2H), 5.01-4.97 (m, IH), 4.85-4.64 (m, 2H), 4.46 (d, J = 5.7 Hz, 2H), 3.97-3.66 (m, 6H), 3.27-3.20 (m, IH), 3.03-3.02 (m, IH), 2.70-2.63 (m, 4H), 2.44-2.26 (m, 2H), 1.97-1.52 (m, 8H), 1.05-0.95 (m, 2H), 0.83-0.71 (m, 2H); ESI-MS m/z 654.2 (M + H) ⁺ .

Example 85

Exo-4-((3-allyl-3-(8-(((3S,4R)-l-(4,4-difluorocyclohexane carbonyl)-4-(3-fluorophenyl)- 4-hydroxypyrrolidin-3-yl)methyl)-8-azabicyclo[3.2.1]octan-3- yl)ureido)methyl)-N-met hylbenzenesulfonamide

This compound was prepared substantially as described in Example 46 using appropriate starting materials. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.80-7.73 (m, 2H), 7.41-7.22 (m, 5H),

7.04-6.98 (m, IH) ₅ 5.90-5.78 (m, IH), 5.30-5.18 (m, 2H), 5.00-4.98 (m, IH), 4.78-4.66 (m, 2H), 4.45 (d, J = 5.7 Hz, 2H), 3.91-3.66 (m, 6H), 3.26-3.21 (m, IH), 3.01-2.98 (m, IH), 2.70-2.63 (m, 4H), 2.41-2.25 (m, 3H), 2.25-2.13 (m, 2H), 2.00-1.57 (m, 14H); ESI-MS m/z 732.3 (M + H) ⁺ .

Example 86

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 2x10 ⁶ 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. EC ₅₀ was calculated as the concentration required to inhibit HIV p24 production to 50% that of no drug controls.

Example 87

Selected Compounds and the Inhibition of HIV replication in PBMC

Example Activity Example Activity Example Activity Example Activity

1 ++++ 12 ++++ 30 ++++ 70 ++++

3 ++++ 14 + 31 ++++ 78 ++++

6 + 16 + 32 +++ 79 ++++

7 24 + 35 + 81 ++

8 ++ 25 +++ 36 +

10 26 ++++ 37 +++

11 ++++ 27 +++ 68 ++++

Compound Structure Activity

+

Example 3 ++++

++++ EC ₅₀ <5 nM; +++ EC ₅₀ 6 to 50 nM; ++ EC ₅₀ 51 to 99 nM; + EC ₅₀ >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.

AU 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.