MODULATORS OF CCR-5 ACTIVITY

FIELD OF THE INVENTION

[0001] The present invention relates to low molecular weight compounds and pharmaceutical compositions thereof, useful, e.g., as modulators of CCR-5 activity. The invention further relates to the preparation and use of such compounds and compositions in treating disorders mediated by CCR-5, such as viral infections and inflammatory diseases.

BACKGROUND OF THE INVENTION

[0002] Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract other cells, such as macrophages, T cells, eosinophils, basophils and neutrophils, to sites of inflammation (reviewed in Schall, Cytokine, 3, 165-183 (1991) and Murphy, Rev. Lnmun., 12, 593-633 (1994)). There are two major classes of chemokines, C-X-C (α) and C-C (β) chemokines, depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C). The α-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA), are chemotactic primarily for neutrophils, whereas the β-chemokines are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature, 381, 661-666 (1996)). The β-chemokines include eotaxin; MIPs (macrophage inflammatory proteins) such as MIP-Ia and MIP-I β; MCPs (monocyte chemoattractant protein) such as MCP-I, MCP-2, and MCP-3; and RANTES (regulation-upon-activation, normal T expressed and secreted).

[0003] The chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. ScL, 15, 159-165 (1994)) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. Several chemokine receptors have

been identified that bind or respond to chemokines with their own characteristic pattern. For example, the following chemokine receptors and naturally occurring ligands (in brackets) have been identified: CCR-I (or "CKR-I" or "CC-CKR-I") [MIP-I α, MJDP-lβ, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem., 270, 22123-22128 (1995); Beote, et al, Cell, 72, 415-425 (1993)); CCR-2A and CCR-2B (or "CKR-2A7"CKR-2B" or "CC-CKR-2A"/"CC-CKR-2B") [MCP-I, MCP-3, MCP- 4]; CCR-3 (or "CKR-3" or "CC-CKR-3") [eotaxin, RANTES, MCP-3] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995); CCR-4 (or "CKR-4" or "CC-CKR4") [MEP-lα, RANTES, MCP-I] (Power, et al., J. Biol. Chem., 270, 19495-19500 (1995)); CCR-5 (or "CKR-5" or "CC-CKR-5") [MlP-lα, RANTES, MlP-lβ] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-group antigen [RANTES, MCP-I] (Chaudhun, et al., J. Biol. Chem., 269, 7835-7838 (1994)).

[0004] Chemokine receptors, such as CCR-I , CCR-2, CCR-2A, CCR-2B,

CCR-3, CCR-4, CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. A review of the role of chemokines in allergic inflammation is provided by Kita, H., et al., J. Exp. Med. 183, 2421-2426 (1996).

[0005] A number of studies have suggested a role for RANTES in rheumatoid arthritis. Both RANTES mRNA and protein appear to be up-regulated in rheumatoid arthritis. Antibodies against RANTES significantly decreased the severity of ongoing clinical disease in a rat adjuvant-induced rheumatoid arthritis model.

[0006] It has been established that a number of chemokines including KC

(murine GRO-α), IP-10, MlP-lα, RANTES, MARC (murine MCP-3), and TCA-3 (murine 1-309) are upregulated during the course of murine experimental allergic encephalitis (EAE), a mouse model of multiple sclerosis (MS). It has also been demonstrated that the chemokines JE (murine MCP-I), RANTES, MP- lα, IP-10, and KC are upregulated in the spinal cord and brain during the acute stages and

chronic relapse of murine EAE. Co-localization studies demonstrated that in EAE, MIP- lα and RANTES are produced exclusively by infiltrating leukocytes.

[0007] The principle chemokines that are elevated during acute rejection are thought to be those that interact with the receptors CCR-I and CCR-5 (i.e., MEP- lα and RANTES) and recruit monocytes and T-cells. This suggests that antagonists that block these receptors might be beneficial for treatment of transplant rejection. Enhanced expression of various chemokines in rejected human allograft tissue has been documented, including RANTES. RANTES has also been shown to be elevated in the bronchoalveolar lavage of lung transplant recipients during rejection, especially in patients diagnosed with cytomegalovirus, a complication associated with accelerated rejection. It has also been reported that RANTES expression in cardiac allograft is linked to rejection in an experimental rat model. In humans, RANTES and MD?- lα have been observed in the arteries of heart-transplant recipients undergoing accelerated atherosclerosis. RANTES has also been identified in asthmatic patients after allergen challenge.

[0008] Ligands for the CCR- 1 receptor (MB?- 1 α and RANTES) have been implicated in a number of chronic inflammatory diseases, including multiple sclerosis and rheumatoid arthritis. CCR-I has also been found to play a significant role in allograft rejection. Chemokine receptors, CCR-I and -5 and their natural ligands, MIP- lα and RANTES are thought to be involved in glomerular and interstitial lesions of human glomerular disease. CCR-I is also found to be a major contributor to the airway remodeling responses that arise from Aspergillus fumigatus-induced allergic airway disease.

[0009] A retrovirus designated human immunodeficiency virus (HIV-I) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. Certain compounds have been demonstrated to inhibit the replication of HIV, including soluble CD4 protein and synthetic derivatives (Smith, et al., Science, 238, 1704-1707 (1987)), dextran sulfate, the dyes Direct Yellow 50, Evans Blue, and certain azo dyes (U.S. Pat. No. 5,468,469). Some of these antiviral agents have been shown to act by blocking the

binding of gpl20, the coat protein of HIV, to its target, the CD4 glycoprotein of the cell.

[0010] Entry of HIV-I into a target cell requires cell-surface CD4 and additional host cell cofactors. It has been recognized that for efficient entry into target cells, human immunodeficiency virus requires chemokine receptors, most probably CCR-5 or CXCR-4, as well as the primary receptor CD4 (Levy, N. Engl. J. Med., 335(20), 1528-1530 (1996)). The CXCR-4 receptor (also known as fusin) has been identified as a cofactor required for infection with virus adapted for growth in transformed T-cells, however, CXCR-4 receptor does not promote entry of macrophage-tropic viruses, which are believed to be the key pathogenic strains of HIV in vivo. The principal cofactor for entry mediated by the envelope glycoproteins of primary macrophage-trophic strains of HIV-I (mHIV-1) is CCR-5, a receptor for the β-chemokines RANTES, MIP-I α and MlP-I β (Deng, et al, Nature, 381, 661-666 (1996)). HIV attaches to the CD4 molecule on cells through a region of its envelope protein, gpl20. It is believed that the CD4 binding site on the gpl20 of HIV interacts with the CD4 molecule on the cell surface, and undergoes conformational changes which allow it to bind to another cell-surface receptor, such as CCR-5 and/or CXCR- 4. This brings the viral envelope closer to the cell surface and allows interaction between gp41 on the viral envelope and a fusion domain on the cell surface, fusion with the cell membrane, and entry of the viral core into the cell. It has been shown that β -chemokine ligands prevent HIV-I from fusing with the cell (Dragic, et al., Nature, 381, 667-673 (1996)). It has further been demonstrated that a complex of gpl20 and soluble CD4 interacts specifically with CCR-5 and inhibits the binding of the natural CCR-5 ligands MIP-I α and MIP-I β (Wu, et al., Nature, 384, 179-183 (1996); Trkola, et al., Nature, 384, 184-187 (1996)).

[0011] Humans who are homozygous for mutant CCR-5 receptors which do not serve as co-receptors for HIV-I in vitro appear to be unusually resistant to mHTV- 1 infection and are not immunocompromised by the presence of this genetic variant (Nature, 382, 722-725 (1996)). Absence of CCR-5 appears to confer substantial protection fromniHIV-1 infection (Nature, 382, 668-669 (1996)). Other chemokine receptors may be used by some strains of HIV-I or may be favored by non-sexual routes of transmission. Although most HIV-I isolates studied to date utilize CCR-5

or rusm, some can use ooin as wen as me related CCR-2B and CCR-3 as co-receptors (Nature Medicine, 2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokine receptors may not be unduly compromised by the genetic diversity of ffiV-1 (Zhang, et al., Nature, 383, 768 (1996)). Accordingly, an agent which could block chemokine receptors in humans who possess normal chemokine receptors should prevent infection in healthy individuals and slow or halt viral progression in infected patients. By focusing on the host's cellular immune response to HIV infection, better therapies towards all subtypes of HIV may be provided.

[0012] Because of the findings above, inhibition of chemokine receptors presents a viable method for the prevention or treatment of infection by HIV and the prevention or treatment of AIDS, and in the prevention and treatment of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies, such as rheumatoid arthritis and atherosclerosis.

SUMMARY OF THE INVENTION

[0013] The present invention provides low molecular weight compounds useful as modulators of CCR-5 activity and compositions thereof. In one aspect, the present invention relates in part to compounds having Formula I or II; to pharmaceutical compositions including such compounds; and to methods for their use in treating conditions mediated by the CCR-5 receptor. More specifically, CCR-5 modulators are provided for use in the treatment of disorders such as HIV infection, inflammation and immunoregulatory disorders and diseases.

[0014] Thus, there are provided compounds having Formula I,

Formula I

wherein

R ¹ is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group; each R ² is independently a halogen or a substituted or unsubstituted C _1-4 alkyl group;

R ³ , R ^3a , R ⁴ , R ^4a , R ⁷ , and R ^7a are each independently H, a halogen, or a substituted or unsubstituted C _1-6 alkyl or C _1-4 alkoxy group;

R ⁵ is a substituted or unsubstituted alkyl, aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group;

R ⁶ is a substituted or unsubstituted aryl, aralkyl, heterocyclyl or heterocyclylalkyl group;

R ⁸ is H, OH, a substituted or unsubstituted alkyl, alkenyl, or alkynyl group; or R ⁸ , together with the carbon to which it is attached, forms a 5-8 membered monocyclic heterocyclyl with -L' -R ⁵ ;

R ⁹ is H and R ¹⁰ is C(O)-R ⁵ ; or R ⁹ and R ¹⁰ together with the nitrogen to which they are attached form a substituted or unsubstituted 5 membered heterocyclyl; each R is independently H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group;

L is -C(X)-, -C(X)NR-, -S(O) ₂ -, or -C(X)O-;

L' is a bond, -NR-, -C(X)NR-, -NRC(X)NR-, -S(O) ₂ NR-, -S(0) _p -, -0-, -NRC(X)O-, or -C(O)O-;

L" is a bond, -C(X)-, -C(X)NR-, -S(O) ₂ -, or -C(X)O-;

each X is independently O, S or NR'; wherein each R' is independently H, a substituted or unsubstituted alkyl, alkenyl, or alkynyl group, -NO ₂ , or -CN; each Y is independently C(O), C(S), C(NR') or CHR;

W is -(CH ₂ )- or -(CH ₂ ) ₂ -; m is O - 4; nis O - 5; p is O - 2; and s is 0 or 1 ; stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof.

[0015] Compounds of the invention include compounds of Formula I having the following structures:

Formula IA Formula IB

Formula IC Formula ID

Formula IE

[0016] In some embodiments of compounds of Formula I, A is

4 T-N v W_/ Y — L'— R ⁵ _or 4 ^τ — N v W_/ N — L"— R ⁶

[0017] In other embodiments, R ¹ is substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group. For example, R ¹ is a substituted or unsubstituted methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, t-butyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group. In others, R ¹ is a substituted or unsubstituted allyl, phenyl, benzyl, methyl-2- furanyl, azetidinyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, moφholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrazolyl, tetrazolyl, thiophenyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydropyranyl, oxazolidin-2-onyl, pyrrolidin-2-onyl, oxazolyl, quinuclidinyl, thiazolyl, isoxazolyl, furanyl, or tetrahydrofuranyl group. In some such embodiments, R ¹ is a substituted or unsubstituted piperazinyl, azetidinyl, pyrrolidinyl, piperidyl, or tetrahydropyranyl group.

[0018] In some embodiments of compounds of Formula I, each R ² is independently F, Cl, Br, or a substituted or unsubstituted methyl group, hi some other embodiments of compounds of Formula I, L is -C(X)-, -C(X)O-, or -C(X)NR-. For example, L is -C(O)-, -OC(O)-, or -C(O)NH-. hi some other embodiments of compounds of Formula I, L' is a bond or -C(X)NR-. For example, L' is -C(O)NH-.

[0019] In yet other embodiments of compounds of Formula I, R ⁵ is a substituted or unsubstituted aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group. In some such embodiments, R ⁵ is a substituted or unsubstituted phenyl, benzyl, phenethyl, dihydronaphthyl, tetrahydronaphthyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyrazolidinonyl, triazolyl, triazolidinonyl, tetrazolyl, oxazolidinonyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, pyridyl, or isoquinolyl group, hi some such embodiments, R ⁵ is a substituted or unsubstituted 1,2,3-triazolyl group, a substituted or unsubstituted 1,2,4-triazolyl

group, a substituted or unsubstituted benzimidazolyl group, a substituted or unsubstituted pyridin-3-yl group, a substituted or unsubstituted 4-isoquinolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-benzimidazolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridyl group, or a substituted or unsubstituted 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl group. For example, R ⁵ is a substituted or unsubstituted l,2,4-triazol-4-yl, as shown below:

\ '

or a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridyl; or benzimidazolyl group.

[0020] In some other embodiments of compounds of Formula I, R ⁵ is

Z and Z are selected from CH ₂ and NR ^Z such that one of Z and Z is CH ₂ and the other is NR ^Z ;

R ^z is H, R ^q , C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , SO ₂ R ^q , or a substituted or unsubstituted aralkyl group;

R ^q is a substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, a 5- or 6-membered heteroaryl, or a 4- to 7- membered heterocyclyl group;

R ^w is H or a substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl group; each R ^y is independently H or a substituted or unsubstituted C _1-6 alkyl group;

or, alternatively, R ^w and R ^y together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 5- to 7-membered heterocyclyl group.

[0021] In some such embodiments, R ⁵ is

_; wherein

Z ¹ and Z ² are selected from CH ₂ and NR ^Z such that one of Z ¹ and Z ² is CH ₂ and the other is NR ^Z ;

R ^z is H _; R ^q , C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , SO ₂ R ^q , or a (C _1-6 alkyl)phenyl group; wherein the (C _1-6 alkyl)ρhenyl group is substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , C(0)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, Ci _-6 alkoxy, or C _1-6 alkoxycarbonyl group;

R ^q is a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-I0 aryl, a 5- or 6-membered heteroaryl, or a 4- to 7-membered heterocyclyl group; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y ; wherein the heteroaryl and heterocyclyl groups contain one to three heteroatoms selected from N, O or S; and the heteroaryl and heterocyclyl groups are substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , C(O)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group,;

R ^w is H or a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl group; wherein the alkyl, alkenyl, alkynyl, cycloalkyL and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, C(O)R ^y , or CO ₂ R ^y ; and the heteroaryl and heterocyclyl groups contain one to three heteroatoms selected from N, O or S; and wherein the heteroaryl and heterocyclyl groups are substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, C(O)R ^y , CO ₂ R ^y , or a substituted or

unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group; each R ^y is independently H or a substituted or unsubstituted C _1-6 alkyl group; or, alternatively, R ^w and R ^y together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 5- to 7-membered heterocyclyl group, containing from 0 to 2 additional heteroatoms selected from O, N, or S.

[0022] m others, R ⁵ is

[0023] In yet others, R ^z is H, substituted or unsubstituted C _1-6 alkyl, C(O)R ^q ,

CO ₂ R ^q , C(O)NR ^w R ^y , SO ₂ R ^q , or (C _1-4 alkyl)phenyl, wherein the (C _1-4 alkyl)phenyl is substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or Ci _-6 alkoxycarbonyl group. For example, R ^z is H, or a substituted or unsubstituted methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, benzyl, or phenethyl group or R ^z is C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , or SO ₂ R ^q .

[0024] In still other embodiments, R ^q is a Ci _-6 alkyl, C _3-7 cycloalkyl, or C _6- io aryl group, wherein the alkyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y . For example, R ^q is a substituted or unsubstituted methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl group.

[0025] In some other embodiments of compounds of Formula I, R ⁵ is

[0026] In some such embodiments, R ^q is a C _1-6 alkyl, C _3-7 cycloalkyl, or C _6-10 aryl group, wherein the alkyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y . For example, R ^q is a substituted or unsubstituted methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl group.

[0027] In some other embodiments of compounds of Formula I, L" is a bond or -C(X)NR-. For example, L" is -C(O)NH-.

[0028] In yet other embodiments, R ⁶ is a substituted or unsubstituted aryl, aralkyl, or heterocyclyl group. For example, R ⁶ is a substituted or unsubstituted phenyl, benzyl, phenethyl, dihydronaphthyl, tetrahydronaphthyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyrazolidinonyl, triazolyl, triazolidinonyl, tetrazolyl, oxazolidinonyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, pyridyl, or isoquinolyl group. For example, R ⁶ is a substituted or unsubstituted 1,2,3- triazolyl group, a substituted or unsubstituted 1,2,4-triazolyl group, a substituted or unsubstituted benzimidazolyl group, a substituted or unsubstituted pyridin-3-yl group, a substituted or unsubstituted 4-isoquinolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-benzimidazolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridyl group, or a substituted or unsubstituted 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl group. In still others, R ⁶ is

a substituted or unsubstituted l,2,4-triazol-4-yl, pyridin-3-yl, or isoquinolin-4-yl group .

[0029] In some embodiments of compounds of Formula I, R ⁶ is

Z ¹ and Z ² are selected from CH ₂ and NR ^Z such that one of Z ¹ and Z ² is CH ₂ and the other is NR ^Z ;

R ^z is H, R ^q , C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , SO ₂ R ^q , or a substituted or unsubstituted aralkyl group;

R ^q is a substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, a 5- or 6-membered heteroaryl, or a 4- to 7- membered heterocyclyl group;

R ^w is H or a substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl group; each R ^y is independently H or a substituted or unsubstituted C _1-6 alkyl group; or, alternatively, R ^w and R ^y together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 5- to 7-membered heterocyclyl group.

[0030] Li some such embodiments, R > 6 . is

Z ¹ and Z ² are selected from CH ₂ and NR ^Z such that one of Z ¹ and Z ² is CH ₂ and the other is NR ^Z ;

R ^z is H, R ^q , C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , SO ₂ R ^q , or a (C _1-6 alkyl)phenyl group, wherein the (C _1-6 alkyl)phenyl group is substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , C(0)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group;

R ^q is a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, a 5- or 6-membered heteroaryl, or a 4- to 7-membered heterocyclyl group; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y ; wherein the heteroaryl and heterocyclyl groups contain one to three heteroatoms selected from N, O or S; and the heteroaryl and heterocyclyl groups are substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , C(O)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group;

R ^w is H or a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl group; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, C(O)R ^y , or CO ₂ R ^y ; and the heteroaryl and heterocyclyl groups contain one to three heteroatoms selected from N, O or S; and wherein the heteroaryl and heterocyclyl groups are substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, C(O)R ^y , C0 ₂ R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group; each R ^y is independently H or a substituted or unsubstituted Ci _-6 alkyl group; or, alternatively, R ^w and R ^y together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 5- to 7-membered heterocyclyl group, containing from 0 to 2 additional heteroatoms selected from O, N, or S.

[0031] In some such embodiments, R ⁶ is

[0032] In others, R ^z is H, substituted or unsubstituted Ci _-6 alkyl, C(O)R ^q ,

CO ₂ R ^q , C(0)NR ^w R ^y , SO ₂ R ^q , or (C _1-4 alkyl)phenyl, wherein the (C _1-4 alkyl)phenyl is substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group. For example, R ^z is H, or a substituted or unsubstituted methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, t-butyl, n-butyl, benzyl, or phenethyl group, hi other embodiments, R ^z is C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , or SO ₂ R ^q . hi yet other embodiments, R ^q is a C _1-6 alkyl, C _3-7 cycloalkyl, or C _6-1O aryl group, wherein the alkyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y . For example, R ^q is a substituted or unsubstituted methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl group.

[0033] hi some embodiments of compounds of Formula I, R ⁶ is

[0034] In some such embodiments, R ^q is a C _1-6 alkyl, C _3-7 cycloalkyl, or C _6-10 aryl group, wherein the alkyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y . For example, R ^q is substituted or unsubstituted methyl, ethyl, n-propyl,

isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl group.

[0035] In some embodiments of compounds of Formula I, s is 1.

[0036] In some embodiments of compounds of Formula I, R ⁹ is H and R ¹⁰ is

C(O)-(aralkyl), wherein the aralkyl group is substituted or unsubstituted. For example, R ¹⁰ is C(O)-(benzyl) wherein the benzyl is substituted or unsubstituted.. In other embodiments, R ⁹ and R ¹⁰ form a substituted or unsubstituted triazolyl group. For example, R ⁹ and R ¹⁰ form a substituted or unsubstituted l,2,4-triazol-4-yl group.

[0037] In some embodiments of compounds of Formula I, wherein A is

L is -C(O)NH-, -OC(O)-, or -C(O)-; L' is a bond; W is -CH ₂ -CH ₂ -; and R ⁵ is a substituted or unsubstituted heterocyclyl group. In some such embodiments, R ⁵ substituted or unsubstituted 1,2,3 -triazolyl group, a substituted or unsubstituted 1,2,4- triazolyl group, a substituted or unsubstituted benzimidazolyl group, a substituted or unsubstituted pyridin-3-yl group, a substituted or unsubstituted 4-isoquinolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-benzimidazolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridyl group, or a substituted or unsubstituted 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl group. In others, R ⁵ is a substituted or unsubstituted l,2,4-triazol-4-yl, 4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridyl, or benzimidazolyl group. In some such embodiments, R ⁵ is

[0038] In some other embodiments of compounds of Formula I, wherein A is

L is -C(O)NH-, -OC(O)-, or -C(O)-; L" is a bond; W is -CH ₂ -CH ₂ -; and R ⁶ is a substituted or unsubstituted heterocyclyl group. In some such embodiments, R ⁶ is a substituted or unsubstituted 1,2,3-triazolyl group, a substituted or unsubstituted 1,2,4- triazolyl group, a substituted or unsubstituted benzimidazolyl group, a substituted or unsubstituted pyridin-3-yl group, a substituted or unsubstituted 4-isoquinolyl group, a substituted or unsubstituted 4,5,6,7 -tetrahydro-lH-benziniidazolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridyl group, or a substituted or unsubstituted 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl group. In others, R is a substituted or unsubstituted l,2,4-triazol-4-yl, 4,5,6 ₅ 7-tetrahydro-lH-imidazo[4,5- c]pyridyl, or benzimidazolyl group, hi some such embodiments, R ⁶ is

[0039] In yet other embodiments of compounds of Formula I, wherein A is

L is -C(O)-, n is 0, 1 or 2, and each R ² is independently selected from F, Cl, Br, or a substituted or unsubstituted methyl group. In some such embodiments, R ¹ is a substituted or unsubstituted heterocyclyl group, for example, R ¹ is a substituted or unsubstituted piperazinyl, azetidinyl, pyrrolidinyl, piperidyl, or tetrahydropyranyl group.

[0040] In still other embodiments of compounds of Formula I wherein A is

L is -C(O)NH-, n is 0, 1 or 2 and each R ² is independently selected from F, Cl, Br, or a substituted or unsubstituted methyl group. In some such embodiments, R ¹ is a substituted or unsubstituted alkyl, aryl, or heterocyclyl group, for example, R ¹ is a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, allyl, phenyl, benzyl, methyl-2-furanyl, azetidinyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrazolyl, tetrazolyl, thiophenyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydropyranyl, oxazolidin-2-onyl, ρyrrolidin-2-onyl, oxazolyl, quinuclidinyl, thiazolyl, isoxazolyl, furanyl, or tetrahydrofuranyl group.

[0041] Where features or aspects of the invention are described in terms of

Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group. By way of illustration and not limitation, Table 1 sets forth various combinations of substituents of Formula I as described herein. Thus, e.g., combination 1083 describes those embodiments in which R ¹ is cyclohexyl and L is -C(O)NH-.

[0042] Table 2 sets forth various combinations of substituents L' and R ⁵ of

Formula I. Thus, e.g., combination 2100 describes those embodiments in which L' is a bond and R ⁵ is 1,2,3-triazolyl. Further, those skilled in the art will understand that a combination of substituents is permissible only if such a combination results in a chemically stable compound, and that any combination from Table 1, describing R and L, may be combined with any combination from Table 2, describing L' and R ⁵ . For example, combination 1083 from Table 1 and combination 2100 from Table 2 describe those embodiments of Formula I in which R ¹ is cyclohexyl, L is -C(O)NH-, L' is a bond, and R ⁵ is 1,2,3-triazolyl. Each R ¹ and R ⁵ in the tables is understood to be optionally substituted as described herein. Moreover, each value of W (-CH ₂ -, - (CH ₂ ) ₂ -) may be combined with any combination from Table 1 or Table 2 or any pair of combinations from the two tables. Thus, e.g., it will be understood that combination 1083 describes those embodiments in which W is - CH ₂ -, R ¹ is cyclohexyl, and L is -C(O)NH-, as well as those where W is -(CH ₂ ) ₂ -, R ¹ is cyclohexyl and L is -C(O)NH-.

[0043] Table 1 : Exemplary combinations of L and R ¹ for Formula I.

[0044] Table 2. Exemplary combinations of L' and R ⁵ for Formula I.

[0045] Similarly, as described above for Table 1 and Table 2, Table 3 sets forth various combinations of substituents L" and R ⁶ of Formula I. Further, it should be understood that any combination from Table 1, describing R ¹ and L, may be combined with any combination from Table 3, describing L" and R ⁶ . Moreover, each

value of W (-CH ₂ -, -(CH ₂ ) ₂ -) may be combined with any combination from Table 1 or Table 3 or any pair of combinations from the two tables.

[0046] Table 3. Exemplary combinations of L" and R ⁶ for Formula I.

L0047J In another aspect oi me invention, there are also provided compounds having Formula II:

Formula II wherein

R ¹ is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group; each R ² is independently a halogen or a substituted or unsubstituted C _1-4 alkyl group;

R ³ , R ^3a , R ⁴ , and R ^4a are each independently H, a halogen, or a substituted or unsubstituted C _1-6 alkyl or C _1-4 alkoxy group;

R ⁶ is a substituted or unsubstituted aryl, aralkyl, heterocyclyl or heterocyclylalkyl group; each R is independently H or a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group;

L is -C(X)-, -C(X)NR-, -S(O) ₂ -, or -C(X)O-;

L" is a bond, -C(X)-, -C(X)NR-, -S(O) ₂ -, or -C(X)O-; each X is independently O, S or NR'; each Y is independently C(O), C(S), C(NR') or CHR; wherein each R' is independently H, -NO ₂ , -CN, or a substituted or unsubstituted alkyl, alkenyl, or alkynyl group;

W is -(CH ₂ )- or -(CH ₂ ) ₂ -; m is O - 4; and

n is 0 - 5; stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; provided, however, that the compound is not (S)-3-(biphenyl-4- sulfonyl)-thiazolidine-2-carboxylic acid {(S)-3-[4-(2-methoxy-phenyl)-piperazin-l- yl]-l -phenyl-propyl} -amide, N-(3-{4-[2-(3,5-bis-trifluoromethyl-benzyloxy)-l- phenyl-ethyl]-piperazin-l-yl}-l-phenyl-propyl)-acetamide, or N-(3-(4- (benzo[d] [ 1 ,3]dioxol-5-ylmethyl)piperazin-l -yl)- 1 -phenylpropyl)-5-methyl- 1,3- diphenyl- 1 H-pyrazole-4-carboxamide.

[0048] As indicated in Formula II, compounds of the invention include compounds of the following structures:

Formula IIA Formula UB

Formula HC

[0049] In some embodiments of compounds of Formula II, A is

[0050] hi some other embodiments of compounds of Formula II, R ¹ is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, or heterocyclylalkyl group. For example, R ¹ is a substituted or unsubstituted methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group. In still others, R ¹ is a substituted or unsubstituted allyl, phenyl, benzyl, methyl-2-furanyl, azetidinyl,

pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, moφholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrazolyl, tetrazolyl, thiophenyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetraliydropyranyl, oxazolidin-2-onyl, pyrrolidin-2-onyl, oxazolyl, quinuclidinyl, thiazolyl, isoxazolyl, furanyl, or tetrahydrofuranyl group. For example, R ¹ is a substituted or unsubstituted piperazinyl, azetidinyl, pyrrolidinyl, piperidyl, or tetraliydropyranyl group.

[0051 ] In some embodiments of compounds of Formula II, R ² independently is F, Cl, Br, or a substituted or unsubstituted methyl group. In others, L is -C(X)-, -C(X)O-, or -C(X)NR-. For example, L is -C(O)-, -OC(O)-, or -C(O)NH-. In other embodiments of compounds of Formula II, L" is a bond or -C(X)NR-. For example, L" is -C(O)NH-.

[0052] In some embodiments of compounds of Formula II, R ⁶ is substituted or unsubstituted aryl, aralkyl, or heterocyclyl group. For example, R ⁶ is a substituted or unsubstituted phenyl, benzyl, phenethyl, dihydronaphthyl, tetrahydronaphthyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyrazolidinonyl, triazolyl, triazolidinonyl, tetrazolyl, oxazolidinonyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl or tetrahydrotriazolopyridyl, pyridyl, or isoquinolyl group. In some such embodiments, R ⁶ is a substituted or unsubstituted 1,2,3-triazolyl group, a substituted or unsubstituted 1,2,4-triazolyl group, a substituted or unsubstituted benzimidazolyl group, a substituted or unsubstituted pyridin-3-yl group, a substituted or unsubstituted 4- isoquinolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH- benzimidazolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridinyl group, or a substituted or unsubstituted 4,5,6,7-tetrahydro- 3H-imidazo[4,5-c]pyridyl group. For example, R ⁶ is a substituted or unsubstituted l,2,4-triazol-4-yl group, as shown below

or a substituted or unsubstituted pyridin-3-yl, or isoquinolin-4-yl group.

[0053] In some other embodiments of compounds of Formula II, R ⁶ is

Z ¹ and Z ² are selected from CH ₂ and NR ^Z such that one of Z ¹ and Z ² is CH ₂ and the other is NR ^Z ;

R ^z is H, R ^q , C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , SO ₂ R ^q , or a substituted or unsubstituted aralkyl group;

R ^q is a substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, a 5- or 6-membered heteroaryl, or a 4- to 7- membered heterocyclyl group;

R ^w is H or a substituted or unsubstituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl group; each R ^y is independently H or a substituted or unsubstituted C _1-6 alkyl group; or, alternatively, R ^w and R ^y together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 5- to 7-membered heterocyclyl group.

[0054] hi some other embodiments of compounds of Formula II, R ⁶ is

Z ¹ and Z ² are selected from CH ₂ and NR ^Z such that one of Z ¹ and Z ² is CH ₂ and the other is NR ² ;

R ^z is H, R ^q , C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , SO ₂ R ^q , or a (C _1-6 alkyl)phenyl group, wherein the (C _1-6 alkyl)phenyl group is substituted by 0 to 3

groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , C(O)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group;

R ^q is a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, a 5- or 6-membered heteroaryl, or a 4- to 7-membered heterocyclyl group; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y ; wherein the heteroaryl and heterocyclyl groups contain one to three heteroatoms selected from N, O or S; and the heteroaryl and heterocyclyl groups are substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , C(0)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group,;

R ^w is H or a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _6-10 aryl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl group; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, C(O)R ^y , or CO ₂ R ^y ; and the heteroaryl and heterocyclyl groups contain one to three heteroatoms selected from N, O or S; and wherein the heteroaryl and heterocyclyl groups are substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, C(O)R ^y , CO ₂ R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group; each R ^y is independently H or a substituted or unsubstituted C _1-6 alkyl group; or, alternatively, R ^w and R ^y together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted 5- to 7-membered heterocyclyl group, containing from O to 2 additional heteroatoms selected from O, N, or S.

[0055] In some such embodiments, R ⁶ is

[0056] In others, R ^z is H, substituted or unsubstituted C _1-6 alkyl, C(O)R ^q ,

CO ₂ R ^q , C(O)NR ^w R ^y , SO ₂ R ^q , or (C _1-4 alkyl)phenyl, wherein the (C _1-4 alkyl) phenylgroup is substituted by 0 to 3 groups selected from halogen, CF ₃ , OH, CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y , or a substituted or unsubstituted C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy, or C _1-6 alkoxycarbonyl group,. For example, R ^z is H, or a substituted or unsubstituted methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, benzyl, or phenethyl group. In others, R ^z is C(O)R ^q , CO ₂ R ^q , C(O)NR ^w R ^y , or SO ₂ R ^q . hi still others, R ^q is a C _1-6 alkyl, C _3-7 cycloalkyl; or C _6-I0 aryl group, wherein the alkyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y . For example, R ^q is a substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl group.

[0057] In some embodiments, R ⁶ is

[0058] In some such embodiments, R ^q is a C _1-6 alkyl, C _3-7 cycloalkyl, or C _6-10 aryl group, wherein the alkyl, cycloalkyl, and aryl groups are substituted by 0 to 3 groups selected from oxo, halogen, CF ₃ , OR ^y , CN, NR ^w R ^y , C(O)R ^y , CO ₂ R ^y , or C(O)NR ^w R ^y . For example, R ^q is a substituted or unsubstituted methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl group.

[0059] In some embodiments of compounds of Formula II, wherein A is

L is -C(O)- or -C(O)NH-, L" is a bond, and R ⁶ is a substituted or unsubstituted heterocyclyl group. In some such embodiments, R is a substituted or unsubstituted 1,2,3-triazolyl group, a substituted or unsubstituted 1,2,4-triazolyl group, a substituted or unsubstituted benzimidazolyl group, a substituted or unsubstituted pyridin-3-yl group, a substituted or unsubstituted 4-isoquinolyl group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-benzimidazolyl) group, a substituted or unsubstituted 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridyl group, or a substituted or unsubstituted 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl group. For example, R ⁶ is a substituted or unsubstituted l,2,4-triazol-4-yl, 4,5,6,7-tetrahydro-lH-imidazo[4,5- cjpyridyl, or benzimidazolyl group. In other embodiments, R ⁶ is

[0060] In other embodiments of compounds of Formula II, wherein A is

L is -C(O)- or -C(O)NH-, L" is -C(O)NH-, and R ⁶ is a substituted or unsubstituted aralkyl group. For example, R ⁶ is a substituted or unsubstituted benzyl group.

[0061 ] In other embodiments of compounds of Formula II, wherein A is

[0062] L is -C(O)-, n is 0, 1 or 2, and each R ² is independently selected from

F, Cl, Br, or a substituted or unsubstituted methyl group. In some such embodiments, R ¹ is a substituted or unsubstituted heterocyclyl group, for example, R ¹ is a substituted or unsubstituted piperazinyl, azetidinyl, pyrrolidinyl, piperidyl, or tetrahydropyranyl group.In still other embodiments of compounds of Formula II, wherein A is

L is -C(O)NH-, n is 0, 1 or 2 and each R ² is independently selected from F, Cl, Br, or a substituted or unsubstituted methyl group. In some such embodiments, R ¹ is a substituted or unsubstituted alkyl, aryl, or heterocyclyl group, for example, R ¹ is a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, allyl. phenyl, benzyl, methyl-2-furanyl, azetidinyl, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrazolyl, tetrazolyl, thiophenyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydropyranyl, oxazolidin-2-onyl, pyrrolidin-2-onyl, oxazolyl, quiimclidinyl, thiazolyl, isoxazolyl, furanyl, or tetrahydrofuranyl group.

[0063] Similar to Table 1 above, Table 4 illustrates combinations of R ¹ and L for compounds having Formula II, while Table 5 illustrates exemplary combinations of L" and R ⁶ .

[0064] Table 4: Exemplary combinations of R ¹ and L for Formula II.

65] Table 5. Exemplary combinations of L" and R for Formula II.

[0066] In accordance with yet another aspect of the invention there are provided the following compounds, including representative examples of compounds of Formula I and II:

(S)-N-(3 -(4-(2-(4-(methylsulfonyl)phenyl)acetamido)piperazin- 1 -yl)- 1 - phenylpropytycyclopentane-carboxamide;

(S)-N-(3 -(4-(3-isoρroρyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)ρiperazin- 1 -yl)- 1 - phenylpropyTjcyclopentane-carboxamide;

N-((S)-3-((lR,5S)-3-(4-methylρyridin-3-yl)-3,8-diaza-bicycl o[3.2.1]octan-8-yl)-l- phenylpropy^cyclopentane-carboxamide; l-((S)-3-((lR _J 5S)-3-(4-methylρyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octan- 8-yl)-l- ρhenylproρyl)-3-p-tolylurea;

N-((S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8-diaza-bicyclo[ 3.2.1]octan-8-yl)-l- ρhenylpropyl)cyclopentanecarboxamide;

l-((S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3 ₃ 8-diaza-bicyclo[3.2.1]octan-8-yl)-l- phenylpropyl)-3-p-tolylurea; l-(3-((lR,5S)-3-(3-isopropyl-5-methyl-4H-l ₃ 2,4-triazol-4-yl)-3,8-diaza- bicyclo[3.2λ]octan-8-yl)propyl)-l-phenyl-3-p-tolylurea;

N-((S)-3-((lR,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazo l-4-yl)-3,8-diaza- bicyclo[3.2.1]octan-8-yl)-l-phenylpropyl)cyclobutanecarboxam ide; l-(3-((lR,5S)-3-benzyl-8-aza-bicyclo[3.2.1]octan-8-yl)propyl )-l-(3-fluoroρhenyl)-3- p-tolylurea; l-(3-((lR,5S)-3-benzyl-8-aza-bicyclo[3.2.1]octan-8-yl)propyl )-l-ρhenyl-3-p- tolylurea;

1 -(3-((lR,5S)-3-benzyl-8-aza-bicyclo[3.2.1 ]octan-8-yl)ρropyl)- 1 -ρhenyl-3-(4-

(trifluoromethyl)phenyl)urea; l-(3-((lR,5S)-3-benzyl-8-aza-bicyclo[3.2.1]octan-8-yl)propyl )-3-(4-chlorophenyl)-l- phenylurea; l-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)-

S-aza-bicyclofS^.ljoctan-δ-y^propyty-l-phenyl-S-p-tolylu rea; l-(3-((lR,3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methyl-4,5,6,7 -tetrahydroitnidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nyl-3-p-tolylurea; l-(3-((lR,3r,5S)-3-(5-(cyclopropanecarbonyl)-2-methyl-4,5,6, 7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenyl-3 -p-tolylurea; l-(3-((lR,3r,5S)-3-(5-(cycloρentanecarbonyl)-2-methyl-4,5,6 ,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenyl-3 -p-tolylurea; l-(3-((lR,3r,5S)-3-(5-benzoyl-2-methyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenyl-3-p-tolylurea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(4-(tri fluoromethyl)phenyl)urea; methyl 2-methyl- 1 -((lR,3r,5S)-8-(3-(l -phenyl-3-(4-

(trifluoromethyl)phenyl)ureido)propyl)-8-aza-biGyclo[3.2. 1 ]octan-3-yl)-6,7-dihydro-

1 H-imidazo [4, 5 -c]pyridine-5 (4H)-carboxylate;

l-(3-((lR,3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methyl-4,5, 6,7-tetrahydroimidazo[4,5- c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenyl-3 -(4-

(trifluoromethyl)phenyl)urea; l-(3-((lR,3r,5S)-3-(2-methyl-5-(methylsulfonyl)-4,5,6,7-tetr ahydroimidazo[4,5- c]pyridin- 1 -yl)-8-aza-bicyclo[3.2. l]octan-8-yl)propyl)- 1 -phenyl-3-(4-

(trifluoromethyl)phenyl)ui-ea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-fluorophenyl) -l-phenylurea; methyl l-((lR,3r,5S)-8-(3-(3-(4-fluorophenyl)-l-phenylureido)propyl )-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridine-5(4H)- carboxylate; l-(3-((lR,3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methyl-4,5,6,7 -tetrahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4- fluorophenyl)-l- phenylurea;

3-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(methyl sulfonyl)-4,5,6,7- tetrahydroiniidazo[4,5-c]pyridm- 1 -yl)-8-aza-bicyclo[3.2. l]octan-8-yl)propyl)-l - phenylurea;

N,2-dimethyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-ρ-tolylureid o)proρyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]ρyri dine-5(4H)- carboxamide; l-(3-((lR,3r,5S)-3-(2-methyl-5-(methylsulfonyl)-4,5,6,7-tetr ahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nyl-3-p-tolylurea;

1 -(3-((lR,3r,5S)-3-(2-methyl-5-pivaloyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridin- 1 - y^-S-aza-bicyclotS^.lJoctan-δ-y^propy^-l-phenyl-S-p-tolylur ea; l-(3-((lR,3r,5S)-3-(5-(cyclopropanecarbonyl)-2-methyl-4,5,6, 7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1- phenyl-3-(4-(trifluoromethyl)phenyl)urea; l-(3-((lR,3r,5S)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro imidazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenyl-3-(4-

(tήfluoromethyl)ρhenyl)urea; l-(3-((lR,3r,5S)-3-(5-(cycloρentanecarbonyl)-2-methyl-4,5 _J 6 _: ,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenyl-3-(4-(trifluoromethyl)phenyl)urea;

l-(3-((lR,3r,5S)-3-(5-(cyclohexanecarbonyl)-2-methyl-4,5, 6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)ρropyl)-l- phenyl-3-(4-(trifluoromethyl)ρhenyl)urea; l-(3-((lR,3r,5S)-3-(5-(cycloρroρanecarbonyl)-2-methyl-4,5, 6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-3-(4- fluorophenyl)- 1 -phenylurea;

3-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(5-isobutyryl-2-methyl -4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-(3-((lR,3r,5S)-3-(5-(cyclopentanecarbonyl)-2-methyl-4,5,6, 7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-3-(4- fluoroρhenyl)-l -phenylurea; l-(3-((lR,3r,5S)-3-(5-(cyclohexanecarbonyl)-2-methyl-4,5 ₅ 6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-3-(4- fluorophenyl)- 1 -phenylurea;

N,2-dimethyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-(4-

(trifluoromethyl)phenyl)ureido)propyl)-8-aza-bicyclo[3.2. 1]octan-3-yl)-6,7-dihydro-

1 H-imidazo [4,5 -c]pyridine-5 (4H)-carboxamide; l-((lR,3r,5S)-8-(3-(3-(4-fluorophenyl)-l-phenylureido)ρropy l)-8-aza- bicyclo [3.2.1] octan-3 -yl)-N _» 2-dimethyl-6 ,7-dihydro- 1 H-imidazo [4, 5-c]pyridine-

5(4H)-carboxamide; isobutyl 2-methyl-l-((lR ₅ 3r,5S)-8-(3-(l-phenyl-3-(4-

(trifluoromethyl)phenyl)ureido)propyl)-8-aza-bicyclo[3.2. 1 ]octan-3-yl)-6,7-dihydro-

1 H-imidazo [4,5 -c]pyridine-5 (4H)-carboxylate ; cyclopentyl 2-methyl-l-((lR,3r,5S)-8-(3-(l -phenyl-3-(4-

(trifluoromethyl)phenyl)ureido)ρropyl)-8-aza-bicyclo[3.2 .1]octan-3-yl)-6,7-dihydro- lH-imidazo[4,5-c]pyridine-5(4H)-carboxylate; isobutyl l-((lR,3r,5S)-8-(3-(3-(4-fluorophenyl)-l-phenylureido)ρropy l)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]ρyridine-5(4H)- carboxylate; cyclopentyl l-((lR,3r,5S)-8-(3-(3-(4-fluoroρhenyl)-l-phenylureido)propy l)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridine-5(4H)- carboxylate;

l-(3-((lR,3r,5S)-3-(2-methyl-5-propionyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l- yty-δ-aza-bicyclotS^.lJoctan-S-ytypropyty-l-phenyl-S-p-toly lurea; l-(3-((lR,3r,5S)-3-(5-butyryl-2-methyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1] octan-8-yl)propyl)- 1 -phenyl-3 -p-tolylurea; l-(3-((lR3r,5S)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydroi midazo[4,5-c]ρyridin-l- yl)-8-aza-bicyclo[3.2.1] octan-8-yl)propyl)- 1 -phenyl-3 -p-tolylurea; l-(3-((lR,3r,5S)-3-(5-(cyclohexanecarbonyl)-2-methyl-4,5,6,7 - tetrahydroimidazo^ _j S-^pyridin-l-y^-S-aza-bicyclotS^.lJoctan-S-y^propyl)-!- phenyl-3 -p-tolylurea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)- δ-aza-bicyclofS^.lJoctan-S-ytypropyty-l-phenyl-S-p-tolylure a; l-(3-((lR,3r,5S)-3-(2-methyl-5-ρivaloyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(4-

(trifluoromethyl)phenyl)urea;

3-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-pivaloy l-4,5,6,7- tetrahydroimidazo[4,5-c]pyridm-l-yl)-8-aza-bicyclo[3.2.1]oct an-8-yl)propyl)-l- phenylurea; l-(3-((lR,3r,5S)-3-(2-methyl-5-propionyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(4-

(trifluoromethyl)phenyl)urea; l-(3-((lR,3r,5S)-3-(5-butyryl-2-methyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridm-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(4-

(trifluoromethyl)phenyl)urea; l-(3-((lR,3r,5S)-3-(5-benzoyl-2-methyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(4-

(trifluoromethyl)phenyl)urea;

3-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-propion yl-4,5,6,7- tetrahydroimidazo [4,5-c]pyridin- 1 -yl)-8-aza-bicyclo [3.2.1] octan-8-yl)ρropyl)- 1 - phenylurea; l-(3-((lR,3r,5S)-3-(5-butyryl-2-methyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-fluorophenyl )-l-phenylurea; l-(3-((lR,3r,5S)-3-(5-benzoyl-2-methyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-fluorophenyl )-l-phenylurea;

l-acetyl-N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-te trahydroimidazo[4,5- c]ρyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-(3 -chloro-4- niethylph.enyl)ρiperidine-4-carboxamide; l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8-aza -bicyclo[3.2.1]octan-

8 -yl)propyl)- 1 -phenyl-3 -p-tolylurea;

3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[ d]imidazol-l-yl)-8-aza- bicyclo[3.2. l]octan-8-yl)propyl)-l -phenylurea; l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8-aza -bicyclo[3.2.1]octan-

8-yl)propyl)-l-phenyl-3-(4-(trifluoromethyl)phenyl)urea;

N'-(2-((lR,3s,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazo l-4-yl)-8-aza- bicyclo[3.2.1 ]octan-8-yl)ethyl)-N'-phenylcyclohexanecarbohydrazide;

N'-(2-((lR,3s,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazo l-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)ethyl)-N'-phenylcyclopropanecarbohy drazide;

N'-(2-((lR,3s,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazo l-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)ethyl)-N'-phenylcyclobutanecarbohyd razide;

N'-(2-((lR,3s,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazo l-4-yl)-8-aza- bicyclotS^.lJoctan-δ-y^ethy^-N'-phenylbenzohydrazide;

N-(4-(2-(2-(cyclohexanecarbonyl)- 1 -phenylhydrazinyl)ethyl)piperazin- 1 -yl)-2-(4-

(methylsulfonyl)phenyl)acetamide;

N-(2-(4-(2-(4-(methylsulfonyl)phenyl)acetamido)piperazin- l-yl)ethyl)-N- phenylcyclohexanecarboxaniide;

(S)-N-(3-(4-(2-(4-(methylsulfonyl)phenyl)acetamido)pipera zin-l-yl)-l- phenylpropyl)cyclohexanecarboxamide;

(S)-N-(3-(4-(2-(4-(methylsulfonyl)phenyl)acetamido)pipera zin-l-yl)-l- plienylpropyl)cyclobutanecarboxamide;

(S)-N-(3-(4-(2-(4-(methylsulfonyl)phenyl)acetamido)pipera zin-l-yl)-l- ρhenylpropyl)cyclopropanecarboxamide;

(S)-N-(3 -(4-(2-(4-(methylsulfonyl)phenyl)acetamido)piperazin- 1 -yl)- 1 - phenylρropyl)benzamide;

(S)-N-(4-(3-(3-cyclopentylureido)-3-phenylpropyl)piperazi n-l-yl)-2-(4-

(methylsulfonyl)phenyl)acetamide;

(S)-N-(4-(3-(3-cyclohexylureido)-3-phenylpropyl)piperazin -l-yl)-2-(4-

(methylsulfonyl)phenyl)acetamide;

(S)-N-(3 -(4-(34s<ψrøpyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)piperazin- 1 -yl)-l - phenylpropy^cyclohexanecarboxamide;

(S)-N-(3-(4-(3-isopiOpyl-5-methyl-4H-l ₅ 2,4-triazol-4-yl)piperazin-l-yl)-l- phenylpropyl)cyclobutanecarboxamide;

(S)-N-(3-(4-(3-isopropyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)piρerazin- 1 -yl)- 1 - phenylpropytycyclopropanecarboxamide;

(S)-l-cyclohexyl-3-(3-(4-(3-isopropyl-5-methyl-4H-l,2,4-t riazol-4-yl)piperazin-l-yl)-

1 -phenylpropyl)urea;

3-cyclopentyl-l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H -l,2,4-triazol-4-yl)-8-aza- bicyclotS^.lloctan-δ-y^propy^-l-phenylurea;

3-isopropyl-l-(3-((lS,3s,5R)-3-(3-isoproρyl-5-methyl-4H- l,2,4-txiazol-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenylurea;

3-benzyl-l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2, 4-triazol-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenylurea; l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)-8-aza- bicyclofS^.lJoctan-S-y^propy^-l-phenyl-S-m-tolylurea; l-(3-((lS,3s,5R)-3-(3-isoρroρyl-5-methyl-4H-l,2,4-triazol- 4-yl)-8-aza- bicyclo[3.2.1] octan-8-yl)propyl)- 1 -phenyl-3 -o-tolylurea; l-(3-((lS,3s,5R)-3-(3-isoρroρyl-5-methyl-4H-l,2,4-triazol- 4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-3-(2-methoxyphenyl)-l-pheny lurea;

3-(2-chlorophenyl)-l-(3-((lS,3s,5R)-3-(3-isopropyl-5-meth yl-4H-l,2,4-triazol-4-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenylurea; l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)-8-aza- bicyclofS^.ljoctan-S-y^propy^-l-phenyl-S-propylurea;

3-(2,5-di-tert-butylρhenyl)-l-(3-((lS,3s,5R)-3-(3-isopro pyl-5-methyl-4H-l,2,4- triazol-4-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-pheny lurea;

N-(3-((lS,3s,5R)-3-(3-isoproρyl-5-methyl-4H-l,2,4-triazo l-4-yl)-8-aza- bicyclo[3.2.1 ]octan-8-yl)propyl)-N-phenylcyclopiOpanecarboxaniide;

N-(3-((lS,3s,5R)-3-(3-isoρropyl-5-methyl-4H-l,2,4-triazo l-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-N-phenylcyclohexanecarboxam ide; l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)-8-aza- bicyclo[3.2.1] octan-8-yl)propyl)-3-(3 -methoxyphenyl)- 1 -phenylurea;

N-CZ-CllS^s^Rj-S-CS-isopropyl-S-methyl^H-l^^-triazoM-y^-S -aza- bicyclo[3.2.1]octan-8-yl)ethyl)-N-phenylcyclohexanecarboxami de;

N-(2-((lS,3s,5R)-3-(3-isoρroρyl-5-methyl-4H-l,2,4-triaz ol-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)ethyl)-N-phenylcyclopropanecarboxam ide;

N-(2-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol -4-yl)-8-aza- bicyclo[3.2. l]octan-8-yl)ethyl)-N-phenylcyclobutanecarboxamide;

N-(2-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol -4-yl)-8-aza- bicyclo[3.2. l]octan-8-yl)ethyl)-N-phenylbenzamide;

3-cyclohexyl-l -(3-((I S,3s,5R)-3-(3-isoρropyl-5-methyl-4H-l ,2,4-triazol-4-yl)-8-aza- bicyclotS^.ljoctan-δ-y^propy^-l-phenylurea;

3-(4-chlorophenyl)-l-(3-((lS,3s,5R)-3-(3-isoproρyl-5-met hyl-4H-l,2,4-triazol-4-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenylurea; l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)-8-aza- bicyclotS^lJoctan-S-ytypropyty-l^-diphenylurea; l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)-8-aza- bicyclo[3.2.1] octan-8-yl)propyl)-3 -(4-methoxyphenyl)- 1 -phenylurea; l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)-8-aza- bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenyl-3-p-tolylurea;

3-(3-chlorophenyl)-l -(3-((I S,3s,5R)-3-(3-isoρropyl-5-methyl-4H-l ,2,4-triazol-4-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-l -phenylurea;

3-(2,6-dichlorophenyl)-l-(3-((lS,3s,5R)-3-(3-isopropyl-5- methyl-4H-l,2,4-triazol-4- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phenylurea;

3-(2,3-dichlorophenyl)-l-(3-((lS,3s,5R)-3-(3-isopropyl-5- methyl-4H-l,2,4-triazol-4- y^-δ-aza-bicyclofS^.lJoctan-δ-y^propy^-l-phenylurea; l-(3-((lS,3s,5R)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(4-(trifluoromet hyl)phenyl)urea;

N-((S)-3-((lR,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazo l-4-yl)-3,8-diaza- bicyclo[3.2. l]octan-8-yl)- 1 -phenylpropytycyclohexanecarboxamide;

N-((S)-3-((lS,5R)-3-(3-isoρropyl-5-methyl-4H-l,2,4-triaz ol-4-yl)-3,8-diaza- bicyclo[3.2.1]octan-8-yl)-l-phenylpropyl)cyclopentanecarboxa mide; l-acetyl-N-((S)-3-((lR,5S)-3-(3-isoρropyl-5-methyl-4H-l,2,4 -triazol-4-yl)-3,8-diaza- bicyclo[3.2.1]octan-8-yl)-l-phenylpropyl)piperidine-4-carbox amide;

4,4-difluoro-N-((S)-3-((lR,5S)-3-(3-isopropyl-5-methyl-4H -l,2,4-triazol-4-yl)-3,8- diaza-bicyclo[3.2.1 ] octan-8-yl)- 1 -phenylpropytycyclohexanecarboxamide;

N-((S)-3-((lR,5S)-3-(3-isopropyl-5-methyl~4H-l _; 2,4-triazol-4-yl)-3,8-diaza- bicyclo[3.2.1]octan-8-yl)-l-phenylpropyl)-tetrahydro-2H-pyra n-4-carboxamide;

2-(4-(methylsulfonyl)phenyl)-N-(4-(3 -( 1 -phenyl-3 -(4-

(trifluoromethyl)phenyl)ureido)propyl)piperazin- 1 -yl)acetamide;

3-(3,4-dichlorophenyl)-l-(3-((lS,5R)-3-(3-isopropyl-5-met hyl-4H-l,2,4-triazol-4-yl)-

3 ,8-diaza-bicyclo[3.2.1 ] octan-8-yl)propyl)- 1 -phenylurea;

3-(4-tert-butylρhenyl)-l-(3-((lS ₅ 5R)-3-(3-isoproρyl-5-methyl-4H-l,2,4-triazol-4-yl)-

3 , 8-diaza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenylurea; l-(3-((lR,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl) -3,8-diaza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(4-(trifluoronie thyl)phenyl)urea; l-(3-((lR,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl) -3,8-diaza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(3-(trifluoromet hyl)phenyl)urea;

3-(4-chlorophenyl)-l-(3-((lR,5S)-3-(3-isoρropyl-5-methyl -4H-l,2,4-triazol-4-yl)-3,8- diaza-bicyclo [3.2.1] octan- 8-yl)propyl)- 1 -phenylurea;

3-(3,4-dimethylphenyl)-l-(3-((lR,5S)-3-(3-isoproρyl-5-me thyl-4H-l,2,4-triazol-4-yl)-

S^-diaza-bicyclofS^.lJoctan-S-ytypropyty-l-phenylurea; l-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5 ₅ 6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-chlorophenyl) -l-(3-fluorophenyl)urea;

3-(4-chlorophenyl)-l-(3-fluoroρhenyl)-l-(3-((lR ₅ 3r,5S)-3-(2-methyl-4,5,6,7- tetrahydroimidazo [4, 5-c]pyridin- 1 -yl)-8 -aza-bicyclo[3.2.1] octan-8-yl)propyl)urea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-chlorophenyl)-l- (3-fluorophenyl)urea; l-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4 ₅ 5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-(3-fluorophenyl) -3-p-tolylurea;

3-(4-chlorophenyl)-l-(3-fluorophenyl)-l-(3-((lR,3r,5S)-3- (2-methyl-lH- benzofdJimidazol-l-y^-S-aza-bicyclotS^.lJoctan-S-y^propy^ure a; l-(3-fluoroρhenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d] imidazol-l-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-3-phenylurea; l-(3-chloro-4-methylphenyl)-3-(4-chlorophenyl)-l-(3-((lS,3r, 5R)-3-(2-methyl-lH- benzotdlimidazol-l-y^-δ-aza-bicyclotS^.lJoctan-S-y^propy^ur ea;

l-(3-chloro-4-methylphenyl)-3-(4-fluorophenyl)-l-(3-((lS,3r, 5R)-3-(2-methyl-lH- benzo [d] imidazol- 1 -yl)- 8-aza-bicyclo [3.2.1 ] octan- 8-yl)propyl)urea; l-(3-chloro-4-methylphenyl)-l-(3-((lS,3r,5R)-3-(2-methyl-lH- benzo[d]imidazol-l- yty-δ-aza-bicyclop.lJJoctan-S-ytypropyty-S-p-tolylurea; l-(3-chloro-4-methylphenyl)-3-(4-isopropylphenyl)-l-(3-((lS, 3r,5R)-3-(2-methyl-lH- benzofdJimidazol-l-yty-S-aza-bicyclop^^octan-S-ytypropytyure a; l-(3-chloro-4-methylρhenyl)-l-(3-((lS,3r ₅ 5R)-3-(2-methyl-lH-benzo[d]imidazol-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-(trifluorome thyl)phenyl)urea; l-(3-chloro-4-methylphenyl)-3-(3,4-dimethylρhenyl)-l-(3-((l S ₃ 3r,5R)-3-(2-methyl- lH-benzofdJimidazol-l-y^-S-aza-bicyclofS^.ljoctan-S-y^propy^ urea; l-(3-chloro-4-methylρhenyl)-3-(3,4-difluoroρhenyl)-l-(3-(( lS,3r,5R)-3-(2-methyl- lH-benzofdJimidazol-l-y^-S-aza-bicyclofS^.lJoctan-S-y^propy^ urea; l-(3-fluoroρhenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-4,5,6,7-tet raliydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-p-t olylurea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]ρyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-(3-fluorophenyl) -3-p-tolylurea; methyl l-((lR,3r,5S)-8-(3-(l-(3-fluorophenyl)-3-p-tolylureido)ρrop yl)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridine-5(4H)- carboxylate;

3-(4-chlorophenyl)-l-(3-((lR ₅ 3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2. l]octan-8-yl)propyl)- 1 -(3- fluorophenyl)urea; l-(3-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-lH-beiizo[d] imidazol-l-yl)-8-aza- bicyclo[3.2.1 ]octan-8-yl)propyl)-3-p-tolylurea;

N-(3-fluorophenyl)-N-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[ d]imidazol-l-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)acetamide; l-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]ρyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-chlorophenyl) -l-ρhenylurea;

5,5-dibenzyl-l-((lR,3r,5S)-8-(3-(3-(4-chloroρhenyl)-l-ρ henylureido)propyl)-8-aza- bicyclo[3.2J]octan-3-yl)-2-methyl-4,5,6,7-tetrahydro-lH-imid azo[4,5-c]pyridin-5- ium; l-(3-chloro-4-methylphenyl)-3-(4-fluorophenyl)-l-(3-((lS,3s, 5R)-3-(3-isoρroρyl-5- methyl-4H- 1 ,2,4-triazol-4-yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)urea;

l-(3-chloro-4-methylphenyl)-3-(4-chlorophenyl)-l-(3-((lS, 3s,5R)-3-(3-isoproρyl-5- methyl-4H-l,2,4-triazol-4-yl)-8-aza-bicyclo[3.2.1]octan-8-yl )propyl)urea; l-(3-chloro-4-methylphenyl)-l-(3-((lS,3s,5R)-3-(3-isopropyl- 5-methyl-4H-l,2,4- triazol-4-yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-3-p-tolylurea; l-(3-chloro-4-methylρhenyl)-l-(3-((lS,3s,5R)-3-(3-isoproρy l-5-methyl-4H-l,2,4- triazol-4-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-

(trifluoromethyl)phenyl)urea; l-(3-chloro-4-methylρhenyl)-3-(3,4-dichlorophenyl)-l-(3-((l S,3s,5R)-3-(3-isopropyl-

5-methyl-4H-l,2,4-triazol-4-yl)-8-aza-bicyclo[3.2.1]octan -8-yl)propyl)urea; l-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetraliydroimi dazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2. l]octan-8-yl)propyl)-3 -methyl- 1-phenylurea; ethyl 2-methyl-l-((lR,3r,5S)-8-(3-(l-ρhenyl-3-ρ-tolylureido)prop yl)-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)-carboxylate; methyl 2-methyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-p-tolylureido)propyl )-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)-carboxylate;

3-allyl-l-(3-chloro-4-methylphenyl)-l-(3-((lS,3r,5R)-3-(2-me thyl-lH- benzotdJimidazol-l-y^-S-aza-bicyclotS^.lJoctan-δ-y^propy^ur ea; l-(3-chloro-4-methylρhenyl)-3-(fiiran-2-ylmethyl)-l-(3-((lS ,3r,5R)-3-(2-methyl-lH- benzotdJimidazol-l-y^-S-aza-bicyclofS^.lJoctan-δ-y^propy^ur ea; l-(3-chloro-4-methylρhenyl)-3-isoρroρyl-l-(3-((lS,3r ₅ 5R)-3-(2-methyl-lH- benzofdJimidazol-l-y^-δ-aza-bicyclofS^.ljoctan-δ-y^propy^u rea; l-(3-chloro-4-methylphenyl)-l-(3-((lS,3r,5R)-3-(2-methyl-lH- benzo[d]imidazol-l- yl)-8 -aza-bicyclo [3.2.1] octan- 8-yl)propyl)-3-propylurea; ethyl 2-(3-(3-chloro-4-methylphenyl)-3-(3-((lS,3r,5R)-3-(2-methyl- lH- benzo[d]imidazol-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)proρy l)ureido)acetate; l-(3-chloro-4-methylphenyl)-3-cyclohexyl-l-(3-((lS,3r,5R)-3- (2-methyl-lH- benzotdJimidazol-l-y^-δ-aza-bicyclotS^.lJoctan-δ-y^propy^u rea; isopropyl 2-methyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-p-tolylureido)propyl )-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)-carboxylate;

3-(4-chlorophenyl)-l-(3-((lS,3s ₅ 5R)-3-(3-ethyl-5-methyl-4H-l,2,4-triazol-4-yl)-8- aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1-phenylurea;

3-(4-chlorophenyl)-l-(3-((lS,3s,5R)-3-(3-ethyl-5-methyl-4 H-l,2,4-triazol-4-yl)-8- aza-bicyclo[3.2.1]octan-8-yl)ρropyl)-l-(3-fluorophenyl)urea ;

l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lS,3r,5R)-3-( 2-methyl-lH- benzo[d]imidazol-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl )piperidine-4- carboxamide; isobutyl 2-methyl-l-((lR,3r,5S)-8-(3-(l-ρhenyl-3-p-tolylureido)proρ yl)-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)-carboxylate;

N-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-phenylpiperidin e-l-carboxamide; cyclohexyl 3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetrahydroimidazo [4,5- c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl(phenyl)carbamate; l-acetyl-N-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-(3- chloro-4- methylphenyl)piperidine-4-carboxamide; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(3-i sopropyl-5-metliyl-4H-

1 ,2,4-triazol-4-yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)piperidine-4-carboxamide; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-( cyclobutanecarbonyl)-

2-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8- yl)propyl)piperidine-4-carboxamide; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(2-m ethyl-5-

(meth.ylsulfonyl)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin -l-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)piperidine-4-carboxamide;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetraliydro imidazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo [3.2.1 ]octan-8-yl)propyl)-N-phenylpiperidine- 1 -carboxamide; methyl 2-methyl-l-((lR,3r,5S)-8-(3-(N-phenylpiperidine-l-carboxamid o)propyl)-8- aza-bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]p yridine-5(4H)- carboxylate; cyclohexyl 3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimidazo [4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl(phenyl )carbamate; methyl l-((lR,3r,5S)-8-(3-((cyclohexyloxycarbonyl)(phenyl)amino)pro pyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridine-5(4H)- carboxylate; methyl 3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetrahydroimidazo [4,5-c]pyridin- l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl(phenyl)carbamate ;

l-acetyl-N-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d]imidazol -l-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-N-phenylpiperidine-4-carbox amide; l-acetyl-N-(3-((lR,3s,5S)-3-(3-isopropyl-5-methyl-4H-l,2,4-t riazol-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-N-phenylpiperidine-4-carbox amide; methyl 3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimidazo [4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)piOpyl(phenyl)carbamate; methyl l-((lR,3r,5S)-8-(3-(methoxycarbonyl(phenyl)amino)propyl)-8-a za- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridine-5(4H)- carboxylate;

3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(2-oxo-octahydroben zo[d]imidazol-l-yl)-8- aza-bicyclotS^.lloctan-δ-y^propy^-l-phenylurea; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3s,5S)-3-(3-e thyl-5-methyl-4H-

1 ,2,4-triazol-4-yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)piperidine-4-carboxamide; l-acetyl-N-(3-((lR,3s,5S)-3-(3-ethyl-5-methyl-4H-l,2,4-triaz ol-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-N-phenylpiperidine-4-carbox amide; l-(3-((lR,3s,5S)-3-(3-ethyl-5-methyl-4H-l,2,4-triazol-4-yl)- 8-aza- bicyclo [3.2.1] octan-8-yl)propyl)- 1 -phenyl-3 -p-tolylurea;

3-cyclopentyl-l-(3-((lR,3s,5S)-3-(3-ethyl-5-methyl-4H-l,2 ,4-triazol-4-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenylurea; l-(3-((lR,3s,5S)-3-(3-ethyl-5-methyl-4H-l,2,4-triazol-4-yl)- 8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(4-(trifluoromet hyl)phenyl)urea;

N-((S)-3-((lR,5S)-3-(4-methylpyridin-3-yl)-3,8-diaza-bicy clo[3.2.1]octan-8-yl)-l- phenylpropyl)cyclobutanecarboxamide;

N-((S)-3-((lR,5S)-3-(4-methylpyridin-3-yl)-3,8-diaza-bicy clo[3.2.1]octan-8-yl)-l- phenylpropyl)cyclohexanecarboxamide;

N-((S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8-diaza-bicyclo[ 3.2.1]octan-8-yl)-l- phenylpropyl)cyclobutanecarboxamide;

N-((S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8-diaza-bicyclo[ 3.2.1]octan-8-yl)-l- phenylpropyl)cyclohexanecarboxamide; l-cyclopentyl-3-((S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8-dia za-bicyclo[3.2.1]octan-8- yl)- 1 -phenylpropyl)urea; l-acetyl-N-((S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8-diaza-bi cyclo[3.2.1]octan-8-yl)- l-phenylpropyl)piperidine-4-carboxamide;

l-acetyl-N-(3-((lR,3r,5S)-3-(5-(cycloproρanecarbonyl)-2-met hyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l -yl)-8-aza-bicyclo[3.2. l]octan-8-yl)propyl)-N- phenylpiperidine-4-carboxamide; l-acetyl-N-(3-((lR,3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methy l-4,5 ₅ 6,7- tetrahydroiinidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]o ctan-8-yl)propyl)-N- phenylpiρeridine-4-carboxamide; l-acetyl-N-(3-((lR,3r,5S)-3-(5-(cyclopentanecarbonyl)-2-meth yl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-N- phenylpiperidine-4-carboxamide;

3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(methyl sulfonyl)-lH- benzotdjimidazol-l-y^-S-aza-bicyclotS^.lJoctan-S-y^propy^-l- phenylurea; l-(3-((lR,3r,5S)-3-(2,5-dimethyl-4,5,6,7-tetrahydroimidazo[4 ,5-c]pyridin-l-yl)-8- aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- l-phenyl-3-p-tolylurea; l-(3-((lR,3r,5S)-3-(2-methyl-lH-imidazo[4,5-c]pyridin-l-yl)- 8-aza- bicyclotS^.lJoctan-S-ytypropyty-l-phenyl-S-p-tolylurea; l-(3-((lS,3r,5R)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-3-(4-chlorophenyl)- 1 -phenylurea;

3-(4-chlorophenyl)-l-(3-((lS,3r,5R)-3-(2-methyl-5-propionyl- 4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-(3-((lS ₅ 3r,5R)-3-(5-butyryl-2-methyl-4,5,6,7-tetrahydroimidazo[4,5-c ]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-chlorophenyl )-l-phenylurea;

3-(4-chlorophenyl)-l-(3-((lS,3r,5R)-3-(5-isobutyryl-2-met hyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 - phenylurea;

3-(4-chlorophenyl)- 1 -(3-((I S,3r,5R)-3-(2-methyl-5-pivaloyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-l - phenylurea;

3-(4-chlorophenyl)- 1 -(3-((I S,3r,5R)-3-(5-(cyclopropanecarbonyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 - phenylurea;

3-(4-chlorophenyl)-l-(3-((lS,3r,5R)-3-(5-(cyclobutanecarb onyl)-2-methyl-4,5,6,7- tetxahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-(3-((lR,3r,5S)-3-(5-(ethylsulfonyl)-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nyl-3-p-tolylurea;

3-(4-chlorophenyl)-l-(3-((lS,3r,5R)-3-(5-(cyclopentanecar bonyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-(3-((lR,3r,5S)-3-(2-methyl-5-(propylsulfonyl)-4,5,6,7-tetr ahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nyl-3-p-tolylurea;

3-(4-chlorophenyl)-l-(3-((lS,3r,5R)-3-(5-(cyclohexanecarb onyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-(3-((lR,3r,5S)-3-(5-(isopropylsulfonyl)-2-methyl-4,5,6,7-t etrahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nyl-3-p-tolylurea; l-(3-((lR,3r,5S)-3-(2-methyl-5-(phenylsulfonyl)-4,5,6,7-tetr ahydroimidazo[4,5- cjpyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenyl-3-p-tolylurea;

2-methyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-p-tolylureido)pro pyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-N-propyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridine-5(4H)- carboxamide; l-(3-((lS,3r,5R)-3-(5-benzoyl-2-methyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridin-l- yl)- 8 -aza-bicyclo [3.2.1] octan- 8-yl)propyl)-3 -(4-chlorophenyl)- 1 -phenylurea;

N-isopropyl-2-methyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-p-tol ylureido)propyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)- carboxamide; l-(3-((lR,3r,5S)-3-(5-(ethylsulfonyl)-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4- fluorophenyl)-l- phenylurea; l-((lS,3r,5R)-8-(3-(3-(4-chloroρhenyl)-l-phenylureido)ρro� �yl)-8-aza- bicyclo[3.2.1]octan-3-yl)-N,2-dimethyl-6,7-dihydro-lH-imidaz o[4,5-c]pyridine-

5(4H)-carboxamide;

3-(4-fluoropnenyl)-l-(J-(( _ι lκ,ir,5ϊ>j-J-(./-methyl-5-(propylsulfonyl)-4,5 ₅ 6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea;

3-(4-fluoroρhenyl)-l-(3-((lR,3r,5S)-3-(5-(isoρropylsulf onyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea;

1 -((1 S,3r,5R)-8-(3-(3-(4-chloroρhenyl)- 1 -phenylureido)ρropyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-N-propyl-6,7-dihydro-lH-i πiidazo[4,5-c]pyridine-

5(4H)-carboxamide;

3-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(phenyl sulfonyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-((lS,3r,5R)-8-(3-(3-(4-chlorophenyl)-l-phenylureido)propyl )-8-aza- bicyclo[3.2.1]octan-3-yl)-N-isopropyl-2-methyl-6,7-dihydro-l H-imidazo[4,5- c]pyridine-5 (4H)-carboxamide; l-((lR,3r,5S)-8-(3-(3-(4-fluorophenyl)-l-ρhenylureido)propy l)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-nietb.yl-N-propyl-6,7-dihydro-lH -imidazo[4,5-c]pyridine-

5 (4H)-carboxamide; l-((lS,3r,5R)-8-(3-(3-(4-chlorophenyl)-l-ρhenylureido)ρrop yl)-8-aza- bicyclo[3.2.1]octan-3-yl)-N-cyclopentyl-2-metb.yl-6,7-dihydr o-lH-imidazo[4,5- c]pyridine-5 (4H)-carboxamide; l-((lR,3r ₅ 5S)-8-(3-(3-(4-fluoroρhenyl)-l-ρhenylureido)propyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-N-isopropyl-2-metb.yl-6,7-dihydro- lH-iniidazo[4,5- c]pyridine-5 (4H)-carboxamide;

3-(4-chlorophenyl)-l-(3-((lS,3r,5R)-3-(2-methyl-5-(methyl sulfonyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l -yl)-8-aza-bicyclo[3.2. l]octan-8-yl)propyl)- 1 - phenylurea;

3-(4-chlorophenyl)-l-(3-((lS,3r,5R)-3-(5-(ethylsulfonyl)- 2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea;

3-(4-chlorophenyl)-l-(3-((lS,3r,5R)-3-(2-methyl-5-(propyl sulfonyl)-4,5,6,7- tetrahydroimidazo[4,5-c]ρyridin-l -yl)-8-aza-bicyclo[3.2. l]octan-8-yl)propyl)- 1 - phenylurea;

methyl l-((lS,3r,5R)-8-(3-(3-(4-chloroρhenyl)-l-phenylureido)ρro� �yl)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]ρyridine-5(4H)- carboxylate; ethyl l-((lS,3r,5R)-8-(3-(3-(4-chloroρhenyl)-l-ρhenylureido)ρro pyl)-8-aza- bicyclo[3.2.1 ]octan-3-yl)-2-methyl-6,7-dihydro- lH-imidazo[4,5-c]pyridine-5(4H)- carboxylate; l-(3-((lR,3r,5S)-3-(5-benzyl-4,5,6,7-tetrahydroimidazo[4,5-c ]pyridin-l-yl)-8-aza- bicycloP^λJoctan-δ-ytypropyty-l-phenyl-S-p-tolylurea; isobutyl l-((lR,3r,5S)-8-(3-(l-phenyl-3-ρ-tolylureido)ρroρyl)-8-az a- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)-carboxylate; l-(3-((lR,3r,5S)-3-(5-(butylsulfonyl)-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nyl-3-p-tolylurea; l-(3-((lR,3r,5S)-3-(5-(ethylsulfonyl)-2-methyl-4 ₅ 5,6,7-tetrahydroimidazo[4,5- cjpyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)proρyl)- 1 -phenyl-3 -(4-

(trifluoromethyl)phenyl)urea; l-(3-((lR,3r,5S)-3-(2-methyl-5-(propylsulfonyl)-4,5,6,7-tetr ahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nyl-3-(4-

(trifluoromethyl)phenyl)urea; l-(3-((lR,3r,5S)-3-(5-(isopropylsulfonyl)-2-methyl-4,5,6,7-t etrahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)proρyl)-l-ph enyl-3-(4-

(trifluoromethyl)ρhenyl)urea;

2-methyl- 1 -((lR,3r,5S)-8-(3-(l -phenyl-3-(4-(trifluoromethyl)phenyl)ureido)ρropyl)-

8-aza-bicyclo[3.2.1]octan-3-yl)-N-propyl-6,7-dihydro-lH-i midazo[4,5-c]pyridine-

5(4H)-carboxamide;

N-isopropyl-2-methyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-(4-

(trifluoromethyl)phenyl)ureido)ρropyl)-8-aza-bicyclo[3.2 .1]octan-3-yl)-6,7-dihydro-

1 H-imidazo [4,5 -c]pyridine-5 (4H)-carboxamide; l-(3-((lR,3r,5S)-3-(5-(butylsulfonyl)-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nyl-3-(4-

(trifluoromethyl)phenyl)urea;

2-(l-((lR,3r,5S)-8-(3-(3-(4-fluorophenyl)-l-phenylureido) proρyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridin-5(4H)- yl)acetic acid;

l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4 ₅ 5-c]ρyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-(4-fluorophenyl)-3- ρ-tolylurea; l-(4-fluorophenyl)-l-(3-((lR,3r ₅ 5S)-3-(2-methyl-5-pivaloyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-3-p- tolylurea; methyl 1 -((lR,3r,5S)-8-(3-(l -(4-fluorophenyl)-3-p-tolylureido)proρyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridine-5(4H)- carboxylate; l-(4-fluorophenyl)-l-(3-((lR ₃ 3r,5S)-3-(2-methyl-5-(methylsulfonyl)-4,5,6,7- tetrahydroiniidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]o ctan-8-yl)propyl)-3-p- tolylurea; l-((lR,3r,5S)-8-(3-(l-(4-fluorophenyl)-3-p-tolylureido)propy l)-8-aza- bicyclo[3.2.1]octan-3-yl)-N,2-dimethyl-6,7-dihydro-lH-imidaz o[4,5-c]pyridine-

5 (4H)-carboxamide; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridm-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l,3-bis(4-fluoroph enyl)urea; l,3-bis(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-metliyl-5-piva loyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2. l]octan-8-yl)propyl)urea; methyl l-((lR,3r,5S)-8-(3-(l,3-bis(4-fluoroρhenyl)ureido)propyl)-8 -aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo[4, 5-c]pyridine-5(4H)- carboxylate; l,3-bis(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(meth ylsulfonyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)urea; l-((lR,3r,5S)-8-(3-(l,3-bis(4-fluorophenyl)ureido)ρropyl)-8 -aza-bicyclo[3.2.1]octan-

3-yl)-N,2-dimethyl-6,7-dihydro-lH-imidazo[4,5-c]pyridine- 5(4H)-carboxamide; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -(4-fluorophenyl)-3-(4-

(trifluoromethyl)phenyl)urea; l-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl~5-ρivaloyl- 4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-3-(4-

(trifluoromethyl)phenyl)urea;

methyl l-((lR,3r,5S)-8-(3-(l-(4-fluorophenyl)-3-(4-

(trifluorom.ethyl)phenyl)ureido)proρyl)-8-aza-bicyclo[3. 2.1]octaα-3-yl)-2-methyl-6,7- dihydro-lH-imidazo[4,5-c]pyridine-5(4H)-carboxylate; l-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(methylsul fonyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-3-(4-

(trifluorometliyl)phenyl)urea; l-((lR,3r,5S)-8-(3-(l-(4-fluorophenyl)-3-(4-(trifluoromethyl )phenyl)ureido)ρropyl)-

8-aza-bicyclo[3.2.1]octan-3-yl)-N,2-dimethyl-6,7-dihydro-lH- imidazo[4,5- c]pyridine-5 (4H)-carboxamide; l-(3-((lR ₅ 3r,5S)-3-(5-acetyl-2-(trifluoromethyl)-4,5,6,7-tetrahydroimi dazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4- fluorophenyl)-l- phenylurea;

3-(4-fluoroρhenyl)-l-ρhenyl-l-(3-((lR,3r,5S)-3-(5-pival oyl-2-(trifluoromethyl)-

4,5,6,7 -tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]o ctan-8- yl)propyl)urea;

3-(4-fluoroρhenyl)-l-(3-((lR,3r,5S)-3-(5-(methylsulfonyl )-2-(trifluoromethyl)-

4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyc lo[3.2.1]octan-8-yl)propyl)-

1-phenylurea; l-(3-((lR,3r,5S)-3-(5-(etb.ylsulfonyl)-2-methyl-4,5,6,7-tetr ahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-(4- fluorophenyl)-3-p- tolylurea; l-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(propylsul fonyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-3-p- tolylurea; l-(4-fluoroρhenyl)-l-(3-((lR,3r,5S)-3-(5-(isopropylsulfonyl )-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-3-p- tolylurea; l-(3-((lR,3r,5S)-3-(5-(butylsulfonyl)-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin-l -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -(4-fluorophenyl)-3-p- tolylurea; l-((lR,3r,5S)-8-(3-(l-(4-fluorophenyl)-3-p-tolylureido)propy l)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-N-propyl-6,7-dihydro-lH-i midazo[4,5-c]pyridine-

5 (4H)-carboxamide;

l-(3-((lR,3r,5S)-3-(5-(ethylsulfonyl)-2-methyl-4,5,6,7-te trahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l,3-b is(4-fluorophenyl)urea; l,3-bis(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(prop ylsulfonyl)-4,5,6,7- tetrahydroimidazo [4, 5 -c]pyridin- 1 -yl)-8 -aza-bicyclo [3.2.1] octan- 8-yl)propyl)urea; l,3-bis(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(5-(isopropylsulf onyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)urea; l-(3-((lR,3r,5S)-3-(5-(butylsulfonyl)-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin- 1 -yl)-8-aza-bicyclo [3.2.1 ]octan-8-yl)propyl)- 1 ,3 -bis(4-fluorophenyl)urea; l-((lR,3r,5S)-8-(3-(l,3-bis(4-fluoroρhenyl)ureido)propyl)-8 -aza-bicyclo[3.2.1]octan-

3-yl)-2-methyl-N-propyl-6,7-dihydro-lH-imidazo[4,5-c]pyri dme-5(4H)-carboxamide; l-((lR,3r,5S)-8-(3-(l,3-bis(4-fluorophenyl)ureido)propyl)-8- aza-bicyclo[3.2.1]octan-

3-yl)-N-isopropyl-2-methyl-6,7-dihydro-lH-imidazo[4,5-c]p yridine-5(4H)- carboxamide; l-benzyl-3-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-met hyl-3-phenylurea; ethyl 2-(l-((lR,3r,5S)-8-(3-(3-(4-chlorophenyl)-l-phenylureido)pro pyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-methyl-4,5,6,7-tetrahydro-lH-imi dazo[4,5-c]pyridine-5- carboxamido)acetate; l-((lR,3r,5S)-8-(3-(3-(4-chlorophenyl)-l-phenylureido)propyl )-8-aza- bicyclo[3.2.1]octan-3-yl)-N-cyclohexyl-2-methyl-6,7-dihydro- lH-imidazo[4,5- c]pyridine-5(4H)-carboxamide;

3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(5-(isopropylsulfon yl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo [3.2.1] octan-8-yl)propyl)- 1 - phenylurea;

3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(phenyl sulfonyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetraliydroimi dazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-chlorophenyl) -l-(4-fluorophenyl)urea;

3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(5-(cyclobutanecarb onyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l-(4- fluorophenyl)urea;

3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(5-(cyclopentanecar bonyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l-(4- fluorophenyl)urea;

3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(5-(cyclohexanecarb onyl)-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l-(4- fluorophenyl)urea; l-(3-((lR,3r,5S)-3-(5-benzoyl-2-methyl-4,5,6,7-tetrahydroimi dazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(4-chlorophenyl )-l-(4- fluorophenyl)urea;

3-(4-chlorophenyl)-l-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3- (2-methyl-5-

(methylsulfonyl)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin- l-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)urea; l-((lR,3r,5S)-8-(3-(3-(4-chlorophenyl)-l-(4-fluorophenyl)ure ido)propyl)-8-aza- bicyclo [3.2.1 ] octan-3 -yl)-N,2-dimethyl-6,7-dihydro- 1 H-imidazo [4, 5 -c]pyridine-

5(4H)-carboxamide; l-((lR,3r,5S)-8-(3-(3-(4-chlorophenyl)-l-(4-fluorophenyl)ure ido)propyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-2-niethyl-N-propyl-6,7-diliydro-lH -imidazo[4,5-c]pyridine-

5(4H)-carboxamide; methyl l-((lR,3r,5S)-8-(3-(3-(4-chlorophenyl)-l-(4-fluoroρhenyl)ur eido)propyl)-8- aza-bicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidaz o[4,5-c]pyridine-

5 (4H)-carboxylate; ethyl l-((lR,3r,5S)-8-(3-(3-(4-chlorophenyl)-l-(4-fluorophenyl)ure ido)ρropyl)-8-aza- bicyclo [3.2.1 ] octan-3 -yl)-2-methyl-6,7-dihydro- 1 H-imidazo [4, 5 -c]pyridine-5 (4H)- carboxylate; methyl l-((lR,3r,5S)-8-(3-(l-acetyl-N-(3-chloro-4-methylphenyl)pipe ridine-4- carboxamido)propyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-2-methyl -6,7-dihydro-lH- imidazo [4, 5 -c]pyridine-5 (4H)-carboxylate; l-((lR,3r,5S)-8-(3-(l-acetyl-N-(3-chloro-4-methylphenyl)pipe ridine-4- carboxamido)propyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-N,2-dime thyl-6,7-dihydro-lH- imidazo[4,5-c]pyridine-5(4H)-carboxamide; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-i sobutyryl-2-methyl-

4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyc lo[3.2.1]octan-8- yl)propyl)piperidine-4-carboxamide;

l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-( 5-

(cycloρropanecarbonyl)-2-methyl-4,5,6,7-tetrahydroimidazo[4 ,5-c]pyridin-l-yl)-8- aza-bicyclo[3.2.1]octan-8-yl)propyl)piperidine-4-carboxamide ; l-(3-((lR,3r ₅ 5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyr idin-l-yl)-

8-aza-bicyclo[3.2.1] octan-8-yl)propyl)-3 -(4-cyanophenyl)- 1 -phenylurea;

3-(4-cyanophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-ρivaloy l-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1] octan-8-yl)propyl)- 1 - phenylurea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)- δ-aza-bicyclofS^.lJoctan-δ-y^propyty-S-methyl-l-phenylurea ;

3-methyl-l-(3-((lR,3r,5S)-3-(2-methyl-5-pivaloyl-4,5,6,7- tetrahydroimidazo[4,5- c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenylurea;

3-methyl-l-(3-((lR,3r,5S)-3-(2-methyl-5-(methylsulfonyl)- 4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)ρropyl)-l- phenylurea;

N,2-dimethyl-l-((lR,3r,5S)-8-(3-(3-methyl-l-phenylureido)pro ρyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)- carboxamide; l-(3-((lR,3r,5S)-3-(2-methyl-5-(3,3,3-trifluoroproρanoyl)-4 ,5,6,7- tetrahydroimidazo[4 ₅ 5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l- phenyl-3 -p-tolylurea;

3-(4-fluoroρhenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(3,3,3 -trifluoroproρanoyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-acetyl-N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-N-p-tolylpiperidine-4- carboxamide; l-(3-((lR,3r,5S)-3-(5-acetyl-2-ethyl-4,5,6,7-tetraliydroimid azo[4,5-c]ρyridin-l-yl)-8- aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenyl-3 -p-tolylurea; l-(3-((lR,3r,5S)-3-(2-ethyl-5-ρivaloyl-4,5,6,7-tetrahydroim idazo[4,5-c]pyridin-l-yl)-

S-aza-bicyclotS^.^octan-δ-yOpropy^-l-phenyl-S-p-tolylure a; l-(3-((lR,3r,5S)-3-(2-ethyl-5-(methylsulfonyl)-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1] octan-8-yl)proρyl)- 1 -phenyl-3 -p-tolylurea;

3-(4-cyanophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(methyls ulfonyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-acetyl-N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetra hydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-(3- chloro-4- methylphenyl)azetidine-3-carboxamide; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-e thyl-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8- yl)propyl)piperidine-4-carboxamide; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(2-m etliyl-5-ρropyl-

4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyc lo[3.2.1]octan-8- yl)propyl)piperidine-4-carboxamide; l-acetyl-N-(3-chloro-4-methylρhenyl)-N-(3-((lR,3r,5S)-3-(5- isobutyl-2-methyl-

4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyc lo[3.2.1]octan-8- yl)propyl)piperidine-4-carboxamide; l-(3-((lR,3r,5S)-3-(5-acetyl-2-isopropyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l- y^-S-aza-bicyclofS^.^octan-S-y^propy^-l-phenyl-S-p-tolylurea ; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(2-m ethyl-5-propionyl-

4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyc lo[3.2.1]octan-8- yl)propyl)piperidine-4-carboxamide; l-acetyl-N-(3-((lR,3r,5S)-3-(5-butyryl-2-methyl-4,5,6,7-tetr ahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-(3- chloro-4- methylphenyl)piperidine-4-carboxamide; l-acetyl-N-(3-chloro-4-methylρhenyl)-N-(3-((lR,3r,5S)-3-(2- methyl-5-pivaloyl-

4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyc lo[3.2.1]octan-8- yl)propyl)piperidine-4-carboxamide; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-( cycloρentanecarbonyl)-

2-methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8- aza-bicyclo[3.2.1]octan-8- yl)propyl)piperidine-4-carboxamide; l-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(2-m ethyl-5-(3,3,3- trifluoropropanoyl)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin- l-yl)-8-aza- bicyclo[3.2. l]octan-8-yl)propyl)piperidine-4-carboxamide;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-metliyl-4,5,6,7-tetrahydro imidazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-(3-chloro-4-meth ylphenyl)-tetrahydro-2H- pyran-4-carboxamide;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-N-(3-chloro-4-methylphenyl)-4,4- difluorocyclohexanecarboxamide;

N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-(cyclop ropanecarbonyl)-2- methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-b icyclo[3.2.1]octan-8- yl)propyl)-tetrahydro-2H-pyran-4-carboxamide;

N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-(cycloprop anecarbonyl)-2- methyMjS^jV-tetrahydroimidazo^ _j S-^pyridin-l-y^-S-aza-bicyclotS^.lJoctan-δ- yl)propyl)-4,4-difluorocyclohexanecarboxamide;

N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-isobuty ryl-2-methyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)- tetrahydro-2H-pyran-4-carboxamide;

N-(3-chloro-4-methylphenyl)-4,4-difluoro-N-(3-((lR,3r,5S)-3- (5-isobutyryl-2- methyMjSjβ^-tetrahydroimidazo^ _j S-^pyridin-l-y^-S-aza-bicyclotS^.lJoctan-δ- yl)propyl)cyclohexanecarboxamide; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)- δ-aza-bicyclofS^.ljoctan-S-y^propy^-S-isopropyl-l-plienylur ea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-3-cyclopentyl- 1 -phenylurea; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridm-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-cyclohexyl-l-phe nylurea; l-(3-((lR,3r,5S)-3-(5-(cyclopropanecarbonyl)-2-methyl-4,5,6, 7- tetrahydroimidazo^^-^pyridin-l-y^-δ-aza-bicyclofS^.lJoctan- S-y^propy^-S- isopropyl- 1 -phenylurea;

3-cyclohexyl-l-(3-((lR,3r,5S)-3-(5-(cyclopropanecarbonyl) -2-metliyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l- phenylurea; l-(3-((lR,3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methyl-4,5,6,7 -tetrahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-met hyl-l-phenylurea;

3-isopropyl-l-(3-((lR,3r,5S)-3-(2-methyl-5-pivaloyl-4,5,6 ,7-tetrahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nylurea;

3-cyclohexyl-l-(3-((lR,3r,5S)-3-(2-methyl-5-pivaloyl-4,5, 6,7-tetrahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phe nylurea; l-(3-((lR,3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methyl-4,5,6,7 -tetrahydroimidazo[4,5- cjpyridin- 1 -yl)-8-aza-bicyclo [3.2.1 ] octan-8-yl)propyl)-3 -isopropyl- 1 -phenylurea; l-(3-((lR,3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methyl-4,5,6,7 -tetrahydroimidazo[4,5- c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-cyc lohexyl-l-phenylurea;

2-methyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-p-tolylureido)pro pyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)- carboxamide;

N,N,2-trimethyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-p-tolylure ido)propyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c]pyrid ine-5(4H)- carboxamide; l-(3-((lR,3r,5S)-3-(2-methyl-5-(pyrrolidine-l-carbonyl)-4,5, 6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2. l]octan-8-yl)propyl)- 1 - phenyl-3 -p-tolylurea; l-(3-((lR,3r,5S)-3-(5-(cyclobutanecarbonyl)-2-methyl-4,5,6,7 -tetrahydroimidazo[4,5- c]pyridin-l -yl)-8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 -phenyl-3-(pyridin-3-yl)urea; l-(3-((lR,3r,5S)-3-(2-methyl-5-pivaloyl-4,5,6,7-tetrahydroim idazo[4,5-c]pyridin-l- yl)-8-aza-bicyclo [3.2.1] octan- 8 -yl)propyl)- 1 -phenyl-3 -(pyridin-3 -yl)urea;

N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-(cyclop ropanecarbonyl)-2- methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-b icyclo[3.2.1]octan-8- yl)propyl)- 1 -(methylsulfonyl)piperidine-4-carboxamide;

N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-(cyclob utanecarbonyl)-2-metb.yl-

4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyc lo[3.2.1]octan-8-yl)propyl)- l-(methylsulfonyl)piperidine-4-carboxamide;

N-(3-chloro-4-methylρhenyl)-N-(3-((lR,3r,5S)-3-(5-(cyclo ρentanecarbonyl)-2- methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8- yl)propyl)- 1 -(methylsulfonyl)piperidine-4-carboxamide;

N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(2-methyl- 5-pivaloyl-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-bicyclo[3.2.1]oc tan-8-yl)propyl)-l-

(methylsulfonyl)piperidme-4-carboxamide;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroi midazo[4,5-c]ρyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-(3-chloro-4-meth ylphenyl)-l-

(methylsulfonyl)piperidine~4-carboxamide;

3-benzyl-l-(3-((lR ₅ 3r,5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8-aza- bicyclofS^.lJoctan-δ-ytypropyty-l-phenylurea; l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8-aza -bicyclo[3.2.1]octan-

8-yl)propyl)-3-(2-methylbenzyl)-l-phenylurea; l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8-aza -bicyclo[3.2.1]octan-

8-yl)propyl)-3-(3-methylbenzyl)-l-phenylurea;

3-(3-fluorobenzyl)-l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[ d]imidazol-l-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenylurea;

3-(3,5-bis(trifluoromethyl)benzyl)-l-(3-((lR,3r,5S)-3-(2- methyl-lH- benzotdJimidazol-l-y^-S-aza-bicyclotS^.lJoctan-S-y^propy^-l- phenylurea;

3-(2-methoxybenzyl)-l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo [d]imidazol-l-yl)-8-aza- bicyclofS^.ljoctan-S-y^propy^-l-phenylurea;

3-(2-fluorobenzyl)-l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[ d]imidazol-l-yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-l-phenylurea;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-N-(3 -chloro-4-methylphenyl)- 1 - propionylpiρeridine-4-carboxamide;

N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-(cyclop ropanecarbonyl)-2- methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin- 1 -yl)-8-aza-bicyclo[3.2.1 ]octan-8- yl)ρropyl)- 1 -propionylpiperidine-4-carboxamide;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)proρyl)-l-butyryl-N-(3-ch loro-4- methylphenyl)piperidine-4-carboxamide; l-butyryl-N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-

(cyclopiOpanecarbonyl)-2-methyl-4,5,6,7-tetrahydroinαida zo[4,5-c]pyridin-l-yl)-8- aza-bicyclo[3.2.1]octan-8-yl)propyl)piperidine-4-carboxamide ;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-(3-chloro-4-meth ylphenyl)-l- isobutyrylpiperidine-4-carboxamide;

N-(3-chloro-4-methylphenyl)-N-(3-((lR,3r,5S)-3-(5-(cyclop ropanecarbonyl)-2- methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-l-yl)-8-aza-b icyclo[3.2.1]octan-8- yl)propyl)-l-isobutyrylpiperidine-4-carboxamide;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroi niidazo[4,5-c]ρyridin-l-yl)-

8-aza-bicyclo[3.2.1 ]octan-8-yl)propyl)-N-(3-chloro-4-methylphenyl)- 1 -

(cyclopropanecarbonyl)piperidine-4-carboxamide;

N-(3-chloro-4-methylphenyl)-l-(cyclopropanecarbonyl)-N-(3 -((lR,3r,5S)-3-(5-

(cyclopropanecarbonyl)-2-methyl-4,5,6,7-tetrahydroimidazo [4,5-c]pyridin-l-yl)-8- aza-bicyclo[3.2.1]octan-8-yl)propyl)piperidine-4-carboxamide ;

N-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroi midazo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-N-(3-ch.loro-4-met hylphenyl)-l-

(cyclobutanecarbonyl)piperidine-4-carboxamide; l-(3-((lR,3r,5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydroimid azo[4,5-c]pyridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-3-(6-fluoropyridin-3- yl)-l-phenylurea; l-(3-((lR,3r,5S)-3-(5-(cycloρroρanecarbonyl)-2-methyl-4,5, 6,7- tetraliydroimidazo[4,5-c]ρyridin-l-yl)-8-aza-bicyclo[3.2.1] octan-8-yl)ρropyl)-3-(6- fluoropyridin-3 -yl)- 1 -phenylurea; l-(3-((lR,3r ₅ 5S)-3-(5-acetyl-2-methyl-4,5,6,7-tetrahydiOimidazo[4,5-c]ρy ridin-l-yl)-

8-aza-bicyclo[3.2.1]octan-8-yl)propyl)-l-phenyl-3-(6-(tri fluoromethyl)pyridin-3- yl)urea; or l-(3-((lR,3r,5S)-3-(5-(cycloρroρanecarbonyl)-2-methyl-4,5, 6,7- tetrahydroimidazo[4,5-c]ρyridin-l-yl)-8-aza-bicyclo[3.2.1]o ctan-8-yl)propyl)-l- phenyl-3-(6-(trifluorometliyl)pyridin-3-yl)urea.

[0067] In some embodiments of compounds of the invention (e.g., compounds of Formula I, IA, EB, IC, ID, IE, II, IIA, ID3, and HC), the compound at a concentration of lOμM in the presence of CCR-5 is a CCR-5 modulator. Compounds of the invention may be shown to be modulators of CCR-5 in any suitable assay system such as those described in the Examples herein.

[0068] The invention further provides pharmaceutical compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.

[0069] In a further aspect, the invention provides a method of modulating the

CCR-5 chemokine receptor activity, the method comprising administering an effective amount of a compound of Formula I or II to a subject in need thereof. In some embodiments, the subject suffers from a CCR-5 mediated disease, as described herein.

[0070] In yet a further aspect, the invention also provides a method comprising contacting a CCR-5 receptor with an amount of a compound of Formula I or π effective to inhibit binding of MIP-Io; MIP-1/3, or RANTES to the CCR-5 receptor, for example, by administering the compound of Formula I or II to a subject. In some such embodiments, the subject suffers from a CCR-5 mediated disease, as described herein.

[0071] Also provided is a method comprising administering an amount of a compound of Formula I or II to a subject in need thereof, wherein the amount is effective to treat infection by HIV, to delay the onset of AIDS, or to treat AIDS.. In some such embodiments, the method further comprises administering an antiviral agent to the subject. Examples of antiviral agents include nucleoside reverse transcriptase inhibitors (NRTI), such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, AVX-754, emtricitabine, elvucitabine, amdoxovir, and reverset; nucleotide reverse transcriptase inhibitors (NtRTI), such as adefovir dipivoxil and tenovir; non-nucleoside reverse transcriptase inhibitors (NNRTI), such as nevirapine, delavirdine, efavirenz, rilpivirine, GW-695634, etravirine, capravirine, and (+)-calanolide A; and protease inhibitors (PI), such as saquinavir, ritonavir, indinavir, nelmavir, amprenavir, lopinavir, atazanavir, tipranavir, and fosamprenavir; or a combination of one or more thereof. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL- 12, and pentafuside.

[0072] In yet another aspect of the invention, a method is provided whichcomprises administering to a subject in need thereof an amount of a compound of Formula I or II, wherein the amount of compound is effective to treat a CCR-5 mediated disease. Examples of CCR-5 mediated diseases include HIV, arthritis, rheumatoid arthritis, osteoarthritis, psoriasis, dermatitis, conjunctivitis, multiple sclerosis, gout, acute pseudogout, acute gouty arthritis, allograft rejection, chronic transplant rejection, asthma, atherosclerosis, mononuclear-phagocyte dependent lung

injury, idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute chest syndrome in sickle cell disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, urosepsis, glomerulonephritis, lupus nephritis, thrombosis, graft vs. host reaction, angiogenesis, and cancer.

DETAILED DESCRIPTION OF THE INVENTION

[0073] The following terms are used throughout as defined below.

[0074] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Hence, isotopically labeled compounds are within the scope of the invention.

[0075] hi general, "substituted" refers to a functional group as defined below

(e.g., an alkyl group) in which one or more bonds to a hydrogen atom(s) contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. Examples of substituent groups include, but not limited to: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; thiols; alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl sulfide groups; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; and nitriles.

[0076] Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be

substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0077] Alkyl groups include straight chain and branched alkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Alkyl groups further include cycloalkyl groups as defined. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n- heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

[0078] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 10 or 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like. Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with any of the groups listed above, for example, methyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

[0079] Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkylene brige, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms, if the two hydrogen atoms are located on adjacent carbon atoms, or 2 to

4 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 1

or 2 carbon atoms. Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexane, or tricyclic, such as, for example, adamantyl. Representative bridged cycloalkyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl, noradamantyl, bornyl, or norbornyl groups. Substituted bridged cycloalkyl groups may be substituted one or more times with non- hydrogen and non-carbon groups as defined above. Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted adamantyl groups, which may be substituted with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

[0080] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above. Representative substituted cycloalkylalkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

[0081] Alkenyl groups include straight and branched chain alkyl and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, allyl, -CH=CH(CH ₃ ), -CH=C(CH ₃ ) ₂ , -C(CHs)=CH ₂ , -C(CHs)=CH(CH ₃ ), -C(CH ₂ CH ₃ )=CH ₂ , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

[0082] Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

[0083] Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C≡CH, -CsC(CH ₃ ), -CsC(CH ₂ CH ₃ ), -CH ₂ C≡CH, -CH ₂ C≡C(CH ₃ ), and -CH ₂ C≡C(CH ₂ CH ₃ ), among others. Representative substituted alkynyl groups may be substituted one or more times with any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

[0084] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups include monocyclic, bicyclic and polycyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono- substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, A-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with groups such as those listed above.

[0085] Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Representative substituted aralkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and/or halogen groups.

[0086] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing 3 or more ring members, of which one

or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 10, 12, or 15 ring members. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non- aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups". Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyL benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetraliydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted heterocyclyl groups maybe mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-,

5-, or 6-substituted, or disubstituted with various groups as defined above, including, but not limited to, alkyl, oxo, carbonyl, amino, alkoxy, cyano, and/or halogens.

[0087] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Although the phrase "heteroaryl groups" includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups". Representative substituted heteroaryl groups may be substituted one or more times with various groups as defined above, including, but not limited to, amino, oxo, alkoxy, alkyl, cyano, and/or halogen groups.

[0088] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with various groups as defined above, including, but not limited to, amino, oxo, alkoxy, alkyl, cyano, and/or halogen groups

[0089] Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.

[0090] Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclop entyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with various groups as defined above, including, but not limited to, amino, oxo, alkoxy, alkyl, cyano, and/or halogen groups.

[0091] The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with various groups as defined above, including, but not limited to, amino, oxo, alkoxy, alkyl, cyano, and/or halogen groups.

[0092] The term "carboxylate" as used herein refers to a -COOH group.

[0093] The term "carboxylic ester" as used herein refers to -COOR ³⁰ groups.

R ³⁰ is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.

[0094] The term "amide" (or "amido") includes C- and N-amide groups, i.e.,

-C(O)NR ³¹ R ³² , and -NR ³¹ C(O)R ³² groups, respectively. R ³¹ and R ³² are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH ₂ ) and formamide groups (-NHC(O)H).

[0095] Urethane groups include N- and O-urethane groups, i.e.,

-NR ³³ C(O)OR ³⁴ and -OC(O)NR ³³ R ³⁴ groups, respectively. R ³³ and R ³⁴ are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.

[0096] The term "amine" as used herein refers to -NH ₂ , -NHR ³⁵ and -NR ³⁶ R ³⁷ groups, wherein R ³⁵ , R ³⁶ and R ³⁷ are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.

[0097] The term "sulfonamido" includes S- and N-sulfonamide groups, i.e.,

-SO ₂ NR ³⁸ R ³⁹ and -NR ³⁸ SO ₂ R ³⁹ groups, respectively. R ³⁸ and R ³⁹ are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO ₂ NH ₂ ).

[0098] The term "thiol" refers to -SH groups, while sulfides include -SR ⁴⁰ groups, sulfoxides include -S(O)R ⁴¹ , sulfones include -SO ₂ R ⁴² groups, and sulfonyls include -SO ₂ OR ⁴³ . R ⁴⁰ , R ⁴¹ , R ⁴² , and R ⁴³ are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0099] The term "urea" refers to -NR ⁴⁴ -C(O)-NR ⁴⁵ R ⁴⁶ groups. R ⁴⁴ , R ⁴⁵ , and

R ⁶ groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[00100] The term "amidine" refers to -C(NR ⁴⁷ )NR ⁴⁸ R ⁴⁹ and -NR ⁴⁷ C(NR ⁴⁸ )R ⁴⁹ groups, wherein R ⁴⁷ , R ⁴⁸ , and R ⁴⁹ are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00101] The term "guanidine" refers to -NR ^5O C(NR ⁵¹ )NR ⁵² R ⁵³ groups, wherein R ⁵⁰ , R ⁵¹ , R ⁵² and R ⁵³ are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00102] The term "enamine" refers to -C(R ⁵⁴ )=C(R ⁵⁵ )NR ⁵⁶ R ⁵⁷ and

-NR ⁵⁴ C(R ⁵⁵ )=C(R ⁵⁶ )R ⁵⁷ groups, wherein R ⁵⁴ , R ⁵⁵ , R ⁵⁶ and R ⁵⁷ are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00103] The term "imide" refers to -C(O)NR ⁵⁸ C(O)R ⁵⁹ groups, wherein R ⁵⁸ and R ⁵⁹ are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[00104] The term "imine" refers to -CR ⁶⁰ (NR ⁶¹ ) and -N(CR ⁶⁰ R ⁶¹ ) groups, wherein R ⁶⁰ and R ⁶¹ are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R ⁶⁰ and R ⁶¹ are not both simultaneously hydrogen.

[00105] The term "protected" with respect to hydroxyl groups, amine groups, carboxy groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups. Protecting groups are known to those skilled in the art and can be added or removed using well- known procedures such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.

[00106] N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloro acetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,

2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-

dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)- 1 -methylethoxycarbonyl, c^α-dimethyl-3 ,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl- 9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethylsilyl, and the like. Typical N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[00107] Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.

[00108] Representative carboxy protecting groups are C ₁ to C ₈ alkyl (e.g., methyl, ethyl or tertiary butyl, and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl, and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylniethyl, and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups, and the like; arylalkenyl, for example, phenylethenyl, and the like; aryl and substituted derivatives thereof, for example, 5-indanyl, and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl, and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valerytoxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1 -(propionyloxy)- 1 -ethyl, 1 -(pivaloyloxyl)- 1 -ethyl, 1 -methyl- 1 -(propionyloxy)- 1 - ethyl, pivaloyloxymethyl, propionyloxymethyl, and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl, and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2- benzylcarbonyloxyethyl, and the like; alkoxycarbonylalkyl, such as

methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-l -ethyl,, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1 -ethoxycarbonyloxy- 1 -ethyl, l-cyclohexyloxycarbonyloxy-l -ethyl, and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl, and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl, and the like; alkanoylaminoalkyl, such as acetylaminomethyl, and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl, and the like; dialkylaminocarbonylalkyl, such as diniethylaminocarbonyhnethyl, diethylaminocarbonylmethyl, and the like; (5- (alkyl)-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-l,3-dioxolen-4- yl)methyl, and the like; and (5-phenyl-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5- ρhenyl-2-oxo-l,3-dioxolen-4-yl)methyl, and the like.

[00109] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

Similarly, triazoles may exhibit the following tautomers:

[00110] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of compounds of the invention (e.g., compounds of Formulas I, IA, EB, IC, ID, IE, II, ILA, and HB) are within the scope of the present invention.

[00111] Stereoisomers of compounds include all chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure, unless the specific

stereochemistry or isomeric form is specifically indicated. Thus, compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.

[00112] Pharmaceutically acceptable salts of the invention compounds are within the scope of the present invention. When the compound of the invention has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g. formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the invention has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and alkaline earth metals (e.g., Na ⁺ , Li ⁺ , K ⁺ , Ca ²⁺ , Mg ²⁺ , Zn ²⁺ ), ammonia, organic amines (e.g. trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine), or basic amino acids (e.g., arginine, lysine and ornithine).

[00113] Certain compounds within the scope of Formulas I and II are derivatives referred to as prodrugs. The expression "prodrug" denotes a derivative of a known direct acting drug, e.g. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the active drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology 112:309- 323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future «5:165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible- Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, hit. Ed. 1992.

[00114] In one aspect the invention is directed to CCR-5 modulators. As used herein, the term "CCR-5 modulator" is intended to refer to compounds that modulate

the activity of naturally occurring CCR-5 chemokine receptor, as determined by a suitable CCR-5 receptor bioassay. Such compounds may act by modulating one or more properties of the CCR-5 receptor with which they interact, by e.g. inhibiting viral infection, causing receptor down-regulation, causing receptor internalization, modulating calcium flux, initiating or inhibiting chemotaxis, and the like. Thus, the CCR-5 receptor modulators of the present invention can act as antagonists (including inverse agonists), or as agonists (including partial agonists), or combinations of both. CCR-5 modulators which are useful, e.g., in inhibiting viral infection, typically exhibit at least one of these properties. CCR-5 modulators which are useful, e.g., for treating inflammatory conditions typically act as antagonists of CCR-5 receptors. CCR-5 receptor modulators may act in a variety of ways, e.g., by binding to or engaging, but not activating, the receptor, or may mediate their action by other means.

[00115] Compounds that modulate chemokine receptor activity and function, and in particular CCR-5 activity and function, may be used for the treatment of a variety of diseases. For example they may be used to treat diseases that are associated with inflammation, including but not limited to, inflammatory or allergic diseases such as arthritis, rheumatoid arthritis, osteoarthritis, psoriasis, dermatitis, conjunctivitis, multiple sclerosis, gout, acute pseudogout, acute gouty arthritis, allograft rejection, chronic transplant rejection, asthma, atherosclerosis, mononuclear- phagocyte dependent lung injury, idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute chest syndrome in sickle cell disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, urosepsis, glomerulonephritis, lupus nephritis, thrombosis, graft vs. host reaction, angiogenesis, or cancer. In addition, agents which modulate the CCR-5 chemokine receptor would also be useful in infectious diseases such as by blocking infection of CCR-5 expressing cells by HIV.

[00116] "Treating" within the context of the instant invention means an alleviation of symptoms associated with a disorder or disease, or a slowing, halting, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. For example, in the context of HTV infection, successful treatment may include an alleviation of symptoms or a slowing or halting of the progression of the disease as measured by a reduction of HIV-I RNA plasma levels, increased survival rate or other clinical benefit.

[00117] As used herein, a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or disease, or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result by modulation of CCR- 5 activity. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects. In the context of HTV specifically, a therapeutically effective amount of a CCR-5 modulator or antagonist is an amount sufficient to lower HIV-I-RNA plasma levels.

[00118] Compounds of the invention can be used in the methods of the invention alone, or together with additional treatments or active ingredients or a combination thereof. For example, for the treatment of HIV, compounds of the invention can be administered in combination with anti-HIV therapy. One or more, typically one to four, antiviral agents useful in anti-HIV- 1 therapy may be used in combination with at least one CCR-5 modulator of the present invention. A variety of antiviral agents are contemplated for use in combination with the compounds of the present invention, e.g., nucleoside reverse transcriptase inhibitors (NRTI), nucleotide reverse transcriptase inhibitors (NtRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), and the like, including other antiviral drugs listed below not falling within these classifications. In particular, the combinations known as HAART (Highly Active Anti-Retroviral Therapy) are contemplated for use in combination with compounds of this invention.

[00119] The term "anti-HIV- 1 therapy" as used herein means any anti-HIV- 1 drug found useful for treating HIV-I infections alone, or as part of multidrug combination therapies, especially the HAART triple and quadruple combination therapies. Typical suitable known anti-HIV- 1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HIV- 1 drugs selected from NRTIs, NtRTIs, PIs and/or NNRTIs; and (ii) at least two anti-HIV- 1 drugs selected from NNRTIs and/or PIs. Typical suitable HAART-multidrug combination therapies include: (a) triple combination therapies such as two NRTIs and one PI; or

(b) two NRTIs and one NNRTI; and (c) quadruple combination therapies such as two

NRTIs, one PI, and a second PI or an NNRTI. In treatment of naive patients, it is typical to start anti-HIV-1 treatment with the triple combination therapy; the use of two NRTIs and one PI is typical unless there is intolerance to PIs. Drug compliance is essential. The CD4 ⁺ and HIV-I-RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug, e.g., one PI or one NNRTI could be added.

[00120] The term "nucleoside reverse transcriptase inhibitors" ("NRTIs") and

"nucleotide reverse transcriptase inhibitors" ("NtRTIs") as used herein means compounds of which the chemical structure constitutes a modified version of a natural nucleoside or nucleotide. The compounds suppress replication of retroviruses by interfering with the reverse transcriptase enzyme, which catalyzes the conversion of viral genomic HIV-I RNA into pro viral HIV-I DNA. The nucleoside and nucleotide analogs cause premature termination of the pro viral (viral precursor) DNA chain and thereby inhibit the activity of HIV-I reverse transcriptase. Typical suitable NRTIs include zidovudine (AZT) (tradename Retrovir); didanosine (ddl) (tradename Videx); zalcitabine (ddC) (tradename Hivid); stavudine (d4T) (tradename Zerit); lamivudine (3TC) (tradename Epivir); abacavir (tradename Ziagen); AVX-754 (Shire Pharmaceuticals Group); emtricitabine (Triangle Pharmaceuticals); elvucitabine (Vion Pharmaceuticals); amdoxovir (DAPD, (-)-beta-D-2,6,-diamino-purine dioxolane); and reverset (Pharmaset). Typical NtRTIs include adefovir dipivoxil (tradename Preveon) and tenovir (tradename Viread).

[00121] The term "non-nucleoside reverse transcriptase inhibitors" ("NNRTFs) as used herein means a group of structurally diverse compounds that bind to the catalytic site of HIV-I ¹ S reverse transcriptase and thereby inhibit the activity of HIV-I reverse transcriptase. Typical suitable NNRTIs include nevirapine (tradename Viramune); delavirdine (tradename Rescriptor); efavirenz (tradename Sustiva); rilpivirine (Johnson & Johnson); GW-695634 (GSK); etravirine (Johnson & Johnson); capravirine (Shionogi); and (+)-calanolide A (NIH).

[00122] The term "protease inhibitor" ("PI") as used herein means inhibitors of the HIV-I protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-I. HIV protease inhibitors

include compounds having a peptidomimetic structure, high molecular weight (e.g., 7600 daltons) and substantial peptide character, e.g. Crixivan (Merck) as well as non- peptide protease inhibitors e.g., Viracept (Agouron). Typical suitable PIs include saquinavir (tradename Invirase and Fortovase); ritonavir (tradename Norvir); indinavir (tradename Crixivan); nelfhavir (tradename Viracept); amprenavir (tradename Agenerase); lopinavir (tradename Kaletra); atazanavir (tradename Reyataz); tipranavir (Pharmacia); and fosamprenavir (tradenames Lexiva and Telzir).

[00123] Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, and pentafuside.

[00124] Administration of the compounds of the invention and the additional active agents to a mammal can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. A typical route of administration for both compounds of the invention and the additional active agents is oral. Typical routes of administration for the additional active agents or ingredients of the invention are known to those of ordinary skill in the art [See, e.g., Physicians' Desk Reference (57* ed., 2003)]. Alternatively, the compound and the additional active agents are administrated simultaneously by coformulation.

[00125] The additional active agent can be administered in a variety of ways, e.g., orally, intravenously, intramuscularly, subcutaneously, mucosally, or transdermally and once, twice or more daily in an amount of from about 1 to about 3,500 mg, from about 5 to about 2,500 mg, from about 10 to about 500 mg, or from about 25 to about 250 mg.

[00126] The specific amount of the additional active agent(s) will depend on the specific agent(s) used, the type of condition being treated or managed, the severity and stage of the condition, and the amount(s) of compounds and any optional additional active agents concurrently administered to the mammal.

[00127] In some embodiments of the invention, one or more compounds of the invention and an additional active agent are administered to a mammal, more

typically a human, in a sequence and within a time interval such that the compound can act together with the other agent to provide an enhanced benefit relative to the benefits obtained if they were administered otherwise. For example, the additional active agents can be coadminstered by coformulation, administered at the same time or administered sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In some embodiments, the compound and the additional active agents exert their effects at times which overlap. Each additional active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the compound is administered before, concurrently or after administration of the additional active agents.

[00128] In various examples, the compound and the additional active agents are administered less than about 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In other examples, the compound and the additional active agents are administered concurrently. Li yet other examples, the compound and the additional active agents are administered concurrently by coformulation.

[00129] In other examples, the compound and the additional active agents are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.

[00130] In certain examples, the inventive compound and optionally the additional active agents are cyclically administered to a mammal. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and/or third agent for a period of time and repeating this sequential administration. Cycling therapy can provide a variety of benefits, e.g., reduce the development of resistance to one or more of the therapies, avoid or reduce

the side effects of one or more of the therapies, and/or improve the efficacy of the treatment.

[00131 ] In other examples, the inventive compound and optionally the additional active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of an inventive compound and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle, about 30 minutes every cycle or about 15 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.

[00132] Courses of treatment can be administered concurrently to a mammal, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the inventive compound can work together with the additional active agents. For example, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.

[00133] The additional active agents can act additively or, more typically, synergistically with the inventive compound. In one example, the inventive compound is administered concurrently with one or more second active agents in the same pharmaceutical composition. In another example, the inventive compound is administered concurrently with one or more second active agents in separate pharmaceutical compositions. In still another example, the inventive compound is administered prior to or subsequent to administration of a second active agent. The invention contemplates administration of an inventive compound and a second active agent by the same or different routes of administration, e.g., oral and parenteral. In certain embodiments, when the inventive compound is administered concurrently with a second active agent that potentially produces adverse side effects including, but not

limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that elicits the adverse side effect.

[00134] The invention also provides for pharmaceutical compositions which may be prepared by mixing one or more compounds of Formula I and/or II, and optionally additional active ingredients, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like. The inventive compositions are useful for a variety of applications, e.g., to treat or prevent CCR-5 mediated diseases. Inventive compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injections. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.

[00135] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.

[00136] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.

[00137] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.

[00138] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non- volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[00139] For inj ection, the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.

[00140] For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a

cream for release of active agent(s) in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.

[00141 ] Compounds used in the invention may be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other components such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate. Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation.

[00142] Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. A nonaqueous suspension (e.g., in a fluorocarbon propellant) can also be used to deliver compounds used in the invention.

[00143] Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a

nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Delivery of aerosols of the present invention using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound.

[00144] For nasal administration, the pharmaceutical formulations and medicaments may be a spray, nasal drops or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. For administration in the form of nasal drops, the compounds may be formulated in oily solutions or as a gel. For administration of nasal aerosol, any suitable propellant may be used including compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.

[00145] Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds used in the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches. The active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required. Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of any two or more thereof.

[00146] Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the active agent(s) across the skin. The rate of

such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[00147] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention. The compounds used in this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye. The compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the invention compound in a hydrophilic base prepared in combination with, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can be optionally incorporated.

[00148] Intrathecal administration, via bolus dosage or constant infusion, allows the local administration of a compound to a region of the spinal cord, such as the dorsal horn regions, delivering the compound directly to the subarachnoid space containing the CSF (cerebrospinal fluid).

[00149] Central delivery to the spinal cord regions can also be performed by epidural injection to a region of the spinal cord exterior to the arachnoid membrane. Enhancing permeation of the active compound through meningeal membranes may be

achieved by using hypertonic dosing solutions that increase permeability of meningeal membranes, or by addition of permeation enhancers, such as, but not limited to, liposomal encapsulation, surfactants, or ion-pairing agents.

[00150] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[00151 ] The formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.

[00152] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.

[00153] Specific dosages may be adjusted depending on stage of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.

[00154] A therapeutically effective amount of a compound of the present invention may vary depending upon the route of administration and dosage form. The typical compound or compounds of the instant invention is administered as a part of a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD ₅₀ and ED ₅₀ . The LD ₅₀ is the dose lethal to 50% of the population and the

ED ₅₀ is the dose therapeutically effective in 50% of the population. The LD ₅₀ and

ED ₅₀ are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.

[00155] Compounds of the invention can generally be prepared by methods known in the art. The following schemes describe alternate routes by which the compounds of the invention can be synthesized. All substituents are as defined herein, unless otherwise specified. Compounds of Formula I (wherein the compound is substituted by R ³ , R ^3a , R ⁴ , R ^4a , R ⁷ and R ^7a as described above), may be prepared as shown in Scheme 1, which illustrates, but is not limited to, the synthesis of compounds of Formula I, wherein R ³ , R ^3a , R ⁴ , R ^4a , R ⁷ , and R ^7a are H.

Scheme 1

Vl

[00156] In a first step, a 2-phenylamino-ethanol (Formula III, s = 0) or

3-phenylainino-propan-l-ol (Formula III, s = 1) is derivatized by reaction with an acid halide R ¹ C(O)HaI, an acid R ¹ C(O)OH (under coupling conditions), an iso(thio)cyanate R ¹ NC(X), a sulfonyl chloride R ¹ S(O) ₂ Cl or a haloformate R ¹ OC(O)HaI (wherein Hal is a halogen, such as Cl, or Br), to give a compound of Formula IV, wherein L is -C(O)-, -NHC(X)-, -S(O) ₂ - or -OC(O)-, respectively. Typical reaction conditions use DCM or DMF as a solvent at room temperature, optionally elevated temperature, in the presence of a base. Typical bases include but are not limited to triethylamine, diisopropylethylamine, or pyridine. In the case of reaction with R ¹ COOH, an activation reagent, such as for example PyBOP, BOP, DCC or others, is used.

[00157] A compound of Formula IV can be converted to an aldehyde of

Formula V using an oxidizing agent such as PDC in a solvent, typically DCM, at room temperature. Other useful oxidants include PCC or Dess-Martin periodane. Alternatively, Swern, Corey-Kim, or Moffat conditions can be used to oxidize IV to V. Reductive animation of the aldehyde V with A, for example a derivatized 8-aza- bicyclo[3.2.1]octane (tropane) or 6-aza-bicyclo[3.1.1]heptane, leads to compounds of the Formula I. Compounds such as derivatized tropanes are well known in the art (see for example WO 00/38680, WO 01/90106, WO 2005/033107, US 6,586,430, US 6,667,314). The reaction may be carried out in the presence of an excess of a suitable reducing agent, such as sodium triacetoxyborohydride or sodium cyanoborohydride, in a protic solvent system, such as acetic acid in DCM or MeOH, at room temperature or at elevated temperature.

[00158] An alternative synthesis of compounds of Formula I is also shown in

Scheme 1. The hydroxyl group of compounds of Formula IV can be converted to a leaving group, Lx, to provide intermediates of Formula VI. For example, compounds of Formula IV can be reacted with thionyl chloride in a suitable solvent such as DCM or chloroform to give compounds of Formula VI, in which the leaving group L _x is Cl. Compounds of Formula IV can also be reacted with tosylchloride (para-toluene sulfonyl chloride) or triflic anhydride (trifluoromethane sulfonic anhydride), in DCM at room temperature in the presence of a base, to form other suitable leaving groups L _x in Formula VI. Typical bases include, but are not limited to, pyridine, triethylamine, DBU, or diisopropylethylamine. Compounds of Formula VI are reacted, as before, with A, to form compounds of Formula I. Suitable solvents for the displacement reactions include DCM, DMF, DMSO, THF, 1,4-dioxane, acetonitrile, or acetone, while suitable temperatures include room temperature or elevated temperatures. The reactions are typically carried out in the presence of a suitable base, such as pyridine, triethylamine, DBU, or diisopropylethylamine, or an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, or sodium bicarbonate. With inorganic bases, a phase transfer reagent such as 18-crown-6 can be used. The conversion of VI to I can be facilitated, if deemed necessary, by the addition of sodium iodide or potassium iodide to the reaction.

[00159] Compounds of the Formula I , L' is a bond, R ^x is H, and R ⁵ is an optionally substituted or unsubstituted benzyl group can be synthesized using methods well known in the art (e.g., Bioorg. Med. Chem. Lett. 2003, 13, 3597-3600).

[00160] Synthesis of compounds of Formula IA wherein L' is -NR-, -C(X)NR-,

-NRC(X)NR-, -NRS(O) ₂ -, or -NRC(X)O-, is exemplified in Scheme 2.

Scheme 2 Error! Objects cannot be created from editing field codes.

[00161] Similarly to the procedure of Scheme I, compounds of Formula V or

VI are derivatized to produce compounds of Formula VII by reductive animation or displacement reaction, respectively, with P^ protected 8-aza-bicyclo[3.2.1]oct-3- ylamine or 6-aza-bicyclo[3.1.1]hept-3-ylamine. Non-limiting examples of amine protecting groups P _N include Boc, benzyl or Fmoc groups. Removal of the protecting group of compounds of Formula VII to produce compounds of Formula VIII can be accomplished using conventional conditions, well-known in the art. Where P _N is a Boc group, deprotection is achieved using TFA or aqueous HCl, optionally in a co- solvent such as DCM or methanol, respectively. Where P _N is benzyl, deprotection is performed by catalytic hydrogenation, for example, by using palladium (II) hydroxide as the catalyst in a suitable solvent, such as ethanol, in the presence of ammonium formate at elevated temperature. Alternatively, the benzyl deprotection may be performed by catalytic hydrogenation using palladium on charcoal as the catalyst, in a suitable solvent such as methanol. An acid such as PTSA can be added to facilitate the deprotection. Where PN is Fmoc, deprotection is achieved using a base such as piperidine or morpholine in a suitable solvent such as DCM, DMF, or methanol at room temperature.

[00162] Conversion of compounds of Formula VIII to the target compounds can be accomplished by reacting the free amine group, under conditions described above, with an acid halide R ⁵ C(O)HaI, an acid R ⁵ C(O)OH (under coupling conditions), an iso(thio)cyanate R ⁵ NC(X), a sulfonyl chloride R ⁵ S(O) ₂ Cl or a halo formate R ⁵ OC(O)HaI, to give a compound of Formula IA, wherein L' is

-NRC(O)-, -NRC(X)NH-, -NRS(O) ₂ - or -NRC(O)O-, respectively. Alkylation of the amine in Formula VIII with halides R ⁵ -Hal affords compounds of Formula IA, wherein L' is -NR-. Suitable solvents for the displacement reactions include DCM, DMF, DMSO, THF, 1,4-dioxane, acetonitrile, or acetone, while suitable temperatures include room temperature or elevated temperatures. The reactions are typically carried out in the presence of a suitable base, such as pyridine, triethylamine, DBU (diazabicyclo[5.4.0]undec-7-ene), or diisopropylethylamine, or an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, or sodium bicarbonate. With inorganic bases, a phase transfer reagent such as 18-crown-6 can be used. The conversion of compounds VIIA to I can be facilitated, if deemed necessary, by the addition of sodium iodide or potassium iodide to the reaction. Alternatively, the amine of VIII can be reductively alkylated by reaction with aldehydes R ⁵ CHO, using reductive animation conditions as described above.

Scheme 3

[00163] Additional compounds of Formula I, wherein L' is a bond, and R ⁵ is a

N-containing heterocycle, can generally be synthesized from compounds of Formula VIIIA. Scheme 3 exemplifies the case wherein R ⁵ is a triazolyl group. Cyclizations to form triazole derivatives are well known in the art (WO 01/90109). Generally, treatment of a compound of Formula IX (formed as before by acylation of compound VIII with R ^5> C(O)Hal or R ^5' C(O)OH in the presence of coupling agents) with phosphorous oxychloride in a solvent, such as chloroform, in the presence of a base, such as pyridine, followed by treatment with R ⁵ C(O)NHNH ₂ in a suitable solvent, such as chloroform, at elevated temperature, results in the formation of compounds of Formula X, wherein R ⁵ and R ⁵ represent substituents on the heterocyclyl, as defined herein. The reaction may be driven to completion in the presence of an acid, such as

PTSA, in a suitable solvent such as toluene under reflux. Similarly, other

neterocycies tnai can oe synmesizeα as R ⁵ include, but are not limited to, substituted or unsubstituted pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyrazolidinonyl, triazolyl, triazolidinonyl, tetrazolyl, oxazolidinonyl, tetrahydrobenzimidazolyl, or tetrahydroimidazopyridyl groups, using methods well known in the art (Heterocyclic Chemistry 2 ^nd Ed., T. L. Gilchrist, 1992, Wiley and Sons, Inc., NY, NY; US 6586430; WO2005/033107; US 2004/0014742).

[00164] Additional compounds of Formula I, wherein A is

, or can be synthesized using methods known in the art (WO2005/02380; WO 2005/007656; J. Am. Chem. Soc. 1997, 119, 11807- 11816).

[00165] As will be understood by those of skill in the art, the synthesis sequence as described above can be modified to use alternate starting materials, or perform the derivatization steps in different order. For example, the amino group of the starting phenylaminoalcohol can be protected with an amine protecting group P _N , the alcohol group can then be elaborated as before (via the aldehyde and reductive amination or via introduction of a leaving group and subsequent displacement), and finally deprotection of the phenyl amino group allows for the final modification with R^L, via methods described above.

[00166] Compounds of Formula I (s = 0 or s = 1), wherein L is -C(X)NR-

(hydrazide derivatives) (illustrated for but not limited to R ³ , R ^3a , R ⁴ , R ^4a , R ⁷ and R ^7a as H) can be prepared as shown in Scheme 4.

Scheme A

[00167] A compound of Formula XI can be prepared by reacting a phenylhydrazine with 2-bromo-l,l-dimethoxyethane (s = 0) or 3-bromo-l, 1- dimethoxypropane (s = 1), in a suitable solvent such as THF, 1, 4-dioxane, or DMF at room temperature, in the presence of a base. Typical bases that can be used include sodium hydride, potassium tert-butoxide, sodium tert-butoxide, or lithium diisopropylamide. Hydrazine XI can then be reacted with an acid halide R ¹ C(O)HaI, or an acid R ¹ C(O)OH under coupling conditions to give a compound of Formula XII. Typical reaction conditions use DCM or DMF as a solvent at room temperature, in the presence of a base. Typical bases include triethylamine, diisopropylethylamine, or pyridine, hi the case of reaction with R ¹ C(O)OH, an activation reagent would be used such as, for example, PyBOP or BOP. Deprotection of acetal XII is accomplished using TFA, acetic acid, or HCl in a solvent such as DCM, 1, 4-dioxane, or methanol at room temperature to produce aldehyde XIII. As before, reductive animation conditions of the aldehyde of Formula XIII with A leads to target compounds of the Formula I, wherein L is -C(O)NH-.

[00168] As shown in Scheme 5, additional compounds of Formula IA wherein

L is -C(O)NR- can be obtained by similar methods as described above for Scheme 1.

Scheme 5

IA

[00169] Scheme 6 illustrates the synthesis of compounds of Formula II, e.g. wherein A is piperazine and L" is -C(X)-, -C(X)NR-, -S(O) ₂ -, or -C(X)O-.

Scheme 6

XIV XV

[00170] A mono-protected piperazine is derivatized by reaction with an acid halide R ⁶ C(O)HaI, an acid R ⁶ C(O)OH (under coupling conditions), an iso(thio)cyanate R ⁶ NC(X), a sulfonyl chloride R ⁶ S(O) ₂ Cl or a haloformate R ⁶ OC(O)HaI (wherein Hal is a halogen, such as Cl), to give a compound of Formula XrV, wherein L" is -C(X)-, -C(X)NR-, -S(O) ₂ -, or -C(O)O-, respectively. Typical reaction conditions use DCM or DMF as a solvent at room temperature, optionally elevated temperature, in the presence of a base. Typical bases include but are not limited to triethylamine, diisopropylethylamine, or pyridine. In the case of reaction with R ⁶ COOH, an activation reagent, such as for example PyBOP or BOP, is used. As before, removal of the protecting group PN (defined as before) of compounds of

Formula XIV to produce compounds of Formula XV can be accomplished using conventional conditions. Similarly as above, compounds of Formula XV can then be derivatized with compounds of Formula XVII (see Scheme 7) by reductive animation or a displacement reaction, respectively. Removal of the protecting group of compounds of Formula XVI can be accomplished as before.

[00171] Also, as described above, conversion of compounds of Formula XVI to the target compounds of Formula IIA can be accomplished by reaction with an acid halide R ¹ C(O)HaI, an acid R ¹ C(O)OH (under coupling conditions), an iso(thio)cyanate R ¹ NC(X) ₅ a sulfonyl chloride R ¹ S(O) ₂ Cl or a haloformate R ¹ OC(O)HaI (wherein Hal is a halogen, such as Cl), to give a compound of Formula IV, wherein L is -C(O)-, -NHC(X)-, -S(O) ₂ - or -OC(O)-, respectively.

[00172] Intermediates of Formula XVII are prepared as shown in Scheme 7. A compound of Formula XVIII is reacted with diazomethane in a suitable solvent such as DCM at 0°C to yield the methyl ester of Formula XIX. Reduction to a compound of Formula XVII is accomplished using a suitable reducing agent such as diisobutylalurninum hydride in DCM at reduced temperature.

Scheme 7

XVIII XIX XVlI

[00173] Scheme 8 illustrates the synthesis of additional compounds of Formula

II, wherein L" is a bond, and R is an N-containing heterocycle, starting from 4- protected-piperazin- 1 -ylamine.

Scheme 8

[00174] Shown in Scheme 8, and similarly as before, the synthesis of compounds wherein R ⁶ is a triazolyl group is exemplified. Generally, treatment of a compound of Formula XX (formed as before by acylation of the precursor with R ⁶ C(O)HaI or R ⁶ C(O)OH in the presence of coupling agents) with phosphorous oxychloride in a solvent, such as chloroform, in the presence of a base, such as pyridine, followed by treatment with R C(O)NHNH ₂ in a suitable solvent, such as chloroform, at elevated temperature, results in the formation of compounds of Formula XXI, wherein R ^6' and R ⁶ represent substituents on the heterocyclyl, as defined in the Detailed Description of the Invention section of this application. The reaction may be driven to completion in the presence of an acid, such as PTSA, in a suitable solvent such as toluene under reflux.

[00175] Similarly, other heterocycles that can be synthesized as R ⁶ include, but are not limited to, substituted or unsubstituted pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolyl, imidazolinonyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyrazolidinonyl, triazolyl, triazolidinonyl, tetrazolyl, oxazolidinonyl, tetrahydrobenzimidazolyl, or tetrahydroimidazopyridyl groups using methods well known in the art (Heterocyclic Chemistry 2 ^nd Ed., T. L. Gilchrist, 1992, Wiley and Sons, Inc., NY, NY; US 6586430; WO2005/033107; US 2004/0014742).

[00176] Additional compounds of Formula II, wherein A is ^R can be synthesized using methods known in the art (WO2005/02380; WO 2005/007656; J. Am. Chem. Soc. 1997, 119,11807-11816).

[00177] The activity of compounds of the present invention can be assessed using any suitable assay, such as receptor binding assays or chemotaxis assays (see, for example, WO 99/37651; Hesselgesser et al., J. Biol. Chem. 273(25):15687-15692 (1998) and WO 98/02151). For example, inhibitors of chemokine (e.g., RANTES, MIP- lα and/or MIP-I β) binding to CCR-5 can be identified utilizing suitable cells which express CCR-5 (e.g., Ll.2 cells transfected with a recombinant construct encoding CCR-5, human recombinant CHO-Kl cells) and undergo chemotaxis in response to binding of chemokine (e.g., RANTES, MIP-Ia and/or MlP-lβ) to receptor. Agonists of chemokine receptor (e.g., CCR-5) function can be identified

using suitable cells which express CCR-5. For example, such a cell can be contacted with a test compound under conditions suitable for cellular chemotaxis upon binding of the compound to the chemokine receptor and chemotaxis can be monitored. The activity of the compounds described herein can be assessed in a high through-put receptor binding assay, which monitors the binding of ligand (e.g., ¹²⁵ I-RANTES, ¹²⁵ I- MIP- lα, 1251-MEP-lβ, CDAfBW GP120) to cells expressing chemokine receptor (e.g. CCR-5) or membranes prepared from such cells. Compounds of the present invention can also be identified by virtue of their ability to inhibit the activation steps triggered by binding of a chemokine to its receptor, such as chemotaxis, integrin activation and granule mediator release.

[00178] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

[00179] AU publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[00180] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

[00181] The following abbreviations are used throughout the application with respect to chemical terminology:

AcN: Acetonitrile

AcOH or HOAc: Acetic acid aq.: Aqueous

9-BBN: 9-Borobicyclo[3.3.1 ]nonane

Boc: N-tert-Butoxycarbonyl

Bu: Butyl

BzI: Benzyl

DIEA: N,N-Diisopropylethylamme

DCM: Dichloromethane

DMF: N, λf-Dimethylformamide

DMSO: Dimethylsulfoxide

EDC or EDCI: 1 -(3 -Dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride

Eq.: Equivalent

Et ₂ O: Diethylether

EtOAc: Ethyl acetate

EtOH: Ethanol

Fmoc: 9-Fluorenymiethoxycarbonyl

FmocONSu: N-(9-fluorenyhnethoxycarbonyl)-succinimide

Hex: Hexanes

HOBt: hydroxybenzotriazole

HPLC: High Pressure Liquid Chromatography

HV: High vacuum

IC ₅₀ value: The concentration of an inhibitor that causes a 50 % reduction in a measured activity

LC-MS: Liquid chromatography- mass spectroscopy

o.n.: Overnight

Me: Methyl

MeOH: Methanol

NMM: N-methyhnorpholine

Pd ₂ dba ₃ : Tris-(dibenzylideneacetone)dipalladium

Pent: Pentyl

Ph: Phenyl

Pr: Propyl

PyBOP: Benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate r.t: Room temperature sat.: Saturated soln.: Solution

TFA: Trifluoroacetic acid

TFAA: Trifluoroacetic anhydride

THF: Tetrahydrofuran

TLC: Thin layer chromatography

ToI: Tolyl

General synthetic methods towards intermediates

[00182] Aldehyde intermediates.

[00183] Step 1. Cyclohexyl phenylcarbamate (R=H, XR'= OcHex) (IA-I).

Phenyl isocyanate (2.5 ml, 22.9 mmol) was mixed slowly with cyclohexanol (2.30 g, 22.96 mmol, 1.03 eq), keeping the speed of the addition slow enough to keep the exothermic reaction from boiling the starting material. After cooling to room temperature, the reaction mixture solidified to afford pure product, which was dried overnight at high vacuum. ¹ H-NMR in CDCl ₃ : δ (ppm) 7.39, (d, 2H, Ph), 7.31 (t, 2H, Ph), 7.06 (t, IH, Ph), 6.58 (bs,lH, NH), 4.77 (h,lH), 1.20-2.00 (m, 10 H).

[00184] With R=H, the following compounds were similarly prepared: cyclopentyl phenylcarbamate (XR'= O-cPent, from cyclop entanol), N- phenylpiperidine-1-carboxamide (X ⁵ R= piperidine, from piperidine), methyl phenylcarbamate (XR'= OMe, from MeOH), and 1 -benzyl- l-methyl-3-phenylurea (XR'= NMeBzI, from N-methylbenzylamine).

[00185] Step 2. Cyclohexyl allyl(phenyl)carbamate (R=H, XR'=OcHex).

Cyclohexyl phenylcarbamate (obtained in the previous reaction, 22.9 mmol) was dissolved in THF (80 ml), NaH was added at once (650 mg, 27 mmol, 1.18 eq), followed by allyl bromide (2.35 ml, 27 mmol). After completion of the reaction (4 to 14 hr), the THF was evaporated and the residue partitioned between water and DCM. The organic layer was washed twice more with water, dried with magnesium sulfate and evaporated, yielding 5.77 g (97 %) of the desired product. ¹ H-NMR in CDCl ₃ : δ (ppm) 7.15-7.35 (m, 5H, Ph), 5.93 (m,lH), 5.10-5.20 (m, 2H), 4.76 (h,lH, CH-O), 4.27 (dt, 2H), 1.20-1.85 (m, 10 H).

[00186] Additional compounds were similarly synthesized, using either THF,

DMF or mixtures thereof as reaction solvents. For example (R=H in all cases): cyclopentyl allyl(phenyl)carbamate (XR'= OcPent), methyl allyl(phenyl)carbamate (XR' = OMe), and l-allyl-3-benzyl-3 -methyl- 1-phenylurea (XR'= NMeBzI ).

[00187] Step 3. Cyclohexyl 3-hydroxypropyl(phenyI)carbamate (R=H,

XR'=OcHex) (IB-I). Cyclohexyl allyl(phenyl)carbamate (5.77 g, 22.3 mmol) was dissolved in THF (150 ml) and 9-BBN (3 g, 24.6 mmol) was added. The reaction mixture was stirred overnight and additional 9-BBN was added if necessary to obtain reaction completion. Aqueous hydrogen peroxide (30% solution, 8 ml) was added drop wise and the reaction mixture was stirred for 45 minutes. Solid NaOH (1 g, 25 mmol) was added and the reaction mixture was stirred for an additional 30 minutes. The solvent was evaporated, and the residue partitioned between water and DCM. The organic layer was washed twice more with saturated aqueous sodium bicarbonate, dried with magnesium sulfate and evaporated. The residue was purified by silica gel chromatography, using a gradient of 0-3% of MeOH in DCM. ¹ H-NMR in CDCl ₃ : δ (ppm) 6.85-7.10 (m, 5H, Ph), 4.44 (bs,lH, CH-O), 3.57 (t,2H), 3.42 (t,2H), 2.03 (bs,2H), 0.85-1.55 (m, 10 H).

[00188] Step 4. Method A: Dess-Martin oxidation. Cyclohexyl 3- oxopropyl(phenyl)carbamate (R=H, XR'=OcHex) (IC-I). Cyclohexyl 3- hydroxypropyl(phenyl)carbamate (520 mg, 1.88 mmol) was dissolved in DCM and Dess-Martin periodinane (800 mg, 1.88 mmol) was added. After 2 hr of stirring at r.t, the reaction was complete as evaluated by TLC. The reaction mixture was diluted with DCM and washed with a mixture OfNa ₂ S ₂ O ₃ (1 M) and Na ₂ CO ₃ (10 % aq.) (1 : 1), followed by saturated NaHCO ₃ (2 times), and brine (once). The DCM solution was dried with magnesium sulfate and evaporated to give sufficiently pure product to be used in the next reaction without purification. ¹ H-NMR in CDCl ₃ : δ (ppm) 9.69 (s, IH), 7.07-7.32 (m, 5H, Ph), 4.66 (bs,lH, CH-O), 3.96 (t,2H), 2.65 (t,2H), 1.05-1.85 (m, 10 H).

[00189] Method B: Swern oxidation. tert-Butyl 3- oxopropyl(phenyl)carbamate (R=H, XR'= OtBu) (lC-2). DMSO (711 μl, 10.0 mmol) was added dropwise to a cooled (-78 ⁰ C) soln. of oxalyl chloride (437 μl, 5.0 mmol) in DCM (5.0 ml) and the mixture was stirred at -78°C for 10 min. Then a soln. of tert-butyl 3-hydroxypropyl(phenyl)carbamate (R=H, prepared as described in Synth. Commun. 1995, 25(14), 2135) (968 mg, 3.85 mmol) in DCM (6 ml) was added dropwise and the mixture was stirred at -78 ⁰ C for 30 min. Then DIEA (3.36 ml, 19.25 mmol) was added dropwise and the mixture was stirred at -78 ⁰ C for 5 min. After the mixture was allowed to warm up to r.t. for 2 hr, it was diluted with DCM (50 ml), washed with 5% aq. KHSO ₄ soln. (2 x 50 ml), and water (50 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give pure lC-2 (914.8 mg, yield 95%) as a pale yellow oil after drying in HV. ¹ H-NMR in CDCl ₃ : δ (ppm) 9.69 (s, IH), 7.26-7.29 (m, 2H), 7.14-7.17 (m, IH), 7.08-7.10 (m, 2H), 3.93 (t, 2H), 2.61-2.64 (m, 2H), 1.34 (s, 9H).

[00190] tert-Butyl 3-fluorophenyl(3-oxopropyl)carbamate (lC-3) (R= 3-F,

XR'= OtBu) was similarly prepared. ¹ H-NMR in CDCl ₃ : δ (ppm) 9.70 (s, IH), 7.19- 7.25 (m, 2H), 6.81-6.90 (m, 2H), 3.92 (t, 2H), 2.63-2.66 (m, 2H), 1.34 (s, 9H).

[00191] Step 1. l-Acetyl-iV-(3-chloro-4-methyIphenyl)-iV-(3- oxopropyI)piperidine-4-carboxamide (IE). To a solution of 3-chloro-4- methylaniline (1.0 g, 7.0 mmol) and l-acetylpiperidine-4-carboxylic acid (1.2 g, 7.0 mmol) in DCM (20 ml) at r.t. was added EDC (2.1 g, 11.0 mmol), and the solution was stirred for 4hr. The mixture was extracted with DCM and dried (Mg ₂ SO ₄ ), filtered and concentrated to yield intermediate ID (1.4 g). To an ice-cold solution of this intermediate (0.50 g, 1.70 mmol) in DMF was added NaH (3 mmol). After stirring for lhr at r.t., 2-(2-bromoethyl)-l,3-dioxolane (0.32 g, 1.80 mmol) was added and the solution was stirred at 8O ⁰ C for 20hr. After cooling, the mixture was diluted with water, extracted with EtOAc, dried (MgSO ₄ ) and concentrated. The product was suspended in IM HCl and stirred 18hr at r.t.. This solution was extracted with DCM and the organic layer was washed with water and brine, dried (Mg ₂ SO ₄ ) and concentrated to yield the title compound IE as a yellow solid (0.46 g). (LC-MS: calc. mass: 350, obs.: 351).

[00192] Piperazine intermediates.

[00193] tert-Butyl 4-aminopiperazine-l-carboxyIate (2A). To a solution of tert-butyl piperazine- 1-carboxylate (1.86 g, 10.0 mmol) in water (20 ml) at r.t. was added acetic acid (10 ml) and sodium nitrite (1.03 g, 15.0 mmol). After stirring this solution at r.t. for 6.5 hr, zinc (2.0 g, 30.7 mmol) was added in one portion and the resulting suspension was stirred at 4O ⁰ C for 2hr. The reaction was quenched with IM NaOH and extracted with DCM. The organic layer was washed with brine, dried over MgSO ₄ , and concentrated to yield 2A (1.84g) as a clear syrup which was used without further purification. (LC-MS: calc. mass: 201, obs.: 202).

[00194] te^-Butyl 4-(2-(4-(methylsulfonyl)phenyl)acetamido)piperazine-l- carboxylate (2B). To a solution of 2A (0.25 mmol) in DMF (5 ml) at r.t. was added 2-(4-(methylsulfonyl)phenyl)acetic acid (64 mg, 0.30 mmol), PyBOP (0.26 g, 0.50 mmol), and DIEA (0.13 ml, 0.75 mmol). The mixture was stirred at r.t. for 20 hr, diluted with water and extracted with DCM (20 ml). The organic layer was washed with water and brine and concentrated. Flash chromatography (EtOAc/Hexanes) gave 2B as a yellow solid. (LC-MS: calc. mass: 397, obs.: 398).

[00195] tert-butyl 4-isobutyramidopiperazine-l-carboxylate (2C). To a solution of 2A (0.50 mmol) in DCM (5 ml) containing DIEA (0.17 ml, 1.0 mmol) was added isobutyryl chloride (53 mg, 0.50 mmol) and the mixture was stirred at r.t. for 5 hours, poured into DCM (20 ml), washed with water and brine, dried over MgSO ₄ and concentrated to give crude 2B. The product was used without further purification. (LC-MS: calc. mass: 271, obs.: 272).

[00196] l-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)piperazine (2D). To a solution of 2C (0.25 mmol, ) in DCM (5 ml) at r.t. was added pyridine (1 ml). The solution was cooled to O ⁰ C, and phosporus oxychloride (76 mg, 0.50 mmol) was added after stirring for 2 hr at r.t.. The solvent and excess reagent were removed via evaporation and a chloroform (5 ml) solution of acetic hydrazide (41 mg, 0.40 mmol) was added and stirred at 5O ⁰ C for 20 hr. The chloroform was evaporated and 2D was recovered via reverse-phase chromatography as a clear syrup. (LC-MS: calc. mass: 209, obs.: 210).

[00197] Tropane intermediates.

[uuiyδj δ-βenzyi-j-Denzyiiαene-δ-azabicyclop.I.lloctane (3A). A mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (prepared as described in WO01/90106) (3.229 g, 15.0 mmol), diethyl benzylphosphonate (6.983 g, 30.6 mmol), potassium tert-butoxide (3.367 g, 30.0 mmol), and toluene (120 ml) was stirred at r.t. for 10 min and then heated to 13O ⁰ C for 17 hr in a closed vial. After cooling, the toluene solution was separated from a dark viscous oil. The toluene solution was washed with sat. aq. NaHCO ₃ solution (2 x 100 ml), sat. aq. NaCl soln. (100 ml), was dried over Na ₂ SO ₄ , concentrated and the resulting amber oil was dried in HV to give 3A (4.60 g, 92% pure by LC-MS, contains traces of diethyl benzylphosphonate). (LC-MS: calc. mass: 289.4, obs.: 289).

[00199] 3-Benzyl-8-azabicyclo[3.2.1]octane (3B). Palladium on active carbon (10% Pd/C, 50% water, 1.0 g) was added to a degassed soln. of 3A (4.6 g, 15.0 mmol) in MeOH (100 ml) and the mixture was stirred under H ₂ balloon at 50 ⁰ C for 17 hr. Then another portion of the Pd/C (1.0 g) was added and the mixture was stirred under H ₂ balloon at 50 ⁰ C for another 2 hr. After cooling the mixture was filtered through celite, the filtrate was concentrated and the crude product was dissolved in Et ₂ O (100 ml) and extracted with cold 6 M aq. HCl (2 x 200 ml). The combined aq. layers were washed with Et ₂ O (100 ml), cooled, and carefully neutralized with solid NaOH to pH 14. The aq. soln. was extracted with DCM (4 x 100 ml), the combined organic layers were dried over Na ₂ SO ₄ , concentrated, and the resulting amber oil was dried in HV to give the relatively volatile 3B (2.60 g, 86% yield for 2 steps, 90% pure by LC-MS). (LC-MS: calc. mass: 201.31, obs.: 201/242).

[00200] l-((lR,3r,5S)-3-(2-methyl-lH-imidazo[4,5-c]pyridin-l-yl)-8- azabicyclo[3.2.1]octane (3C). l-((lR,3r,5S)-3-(2-memyl-lH-imidazo[4,5-c]pyridin- l-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone (obtained as described in WO03/084954) (50 mg, 0.2 mmol) was dissolved in 5 M aq. HCl and heated at 8O ⁰ C for 22 hr. The solvent was evaporated and 10% Na ₂ CO ₃ was added. The aqueous layer was extracted with DCM, and the organic layer was dried (MgSO ₄ ), and evaporated to afford the target product 3C. (LC-MS: calc. mass: 284.2, obs.: 285).

[00201] l-αiR^r^SVδ-azabicyclo^.l.lloctan-S-yO-l^-dimethyl^.S.ό,? - tetrahydro-lH-imidazo [4,5-c] pyridine (3D). 1 -((1 R,3r,5 S)-3 -(2-methyl- 1 H- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)et hanone (110 mg, 0.4 mmol) was dissolved in EtOH and MeI (1.1 eq) was added. After a week, the reaction mixture was cooled to -7O ⁰ C, and NaBH ₄ (2.1 eq) was added. The temperature was allowed to rise to -30 ⁰ C, (lhr), then recooled to -70 ⁰ C, water (1 ml) was added, and then the reaction mixture was allowed to warm to r.t. The solvent was evaporated, water was added and the product was extracted into DCM. The organic layer was dried over MgSO ₄ and evaporated to afford the target acetyl derivative. (LC-MS: calcd: 302.2; found: 303). This intermediate was dissolved in 5 M aq. HCl and heated at 80 ⁰ C for 22 hr. The solvent was evaporated and 10% Na ₂ CO ₃ was added. The product was into DCM, the organic layer was dried over MgSO ₄ and evaporated to give the target compound (3D). (LC-MS: calc. mass: 260.2; obs: 261).

[00202] (lR,3r,5S)-tert-butyI 3-(3-aminopyridin-4-ylamino)-8- azabicyclo[3.2.1]octane-8-carboxyIate (3E). (lR,3r,5S)-tert-butyl 3-(3-nitropyridin-

4-ylamino)-8-azabicyclo[3.2.1]octane-8-cafboxylate (obtained as described in WO2005033107) (200 mg, 0.57 mmol) was dissolved in MeOH. A spatula tip of Raney nickel (washed with water and MeOH) was added and the solution was stirred under hydrogen atmosphere for 2 days providing the desired product, which was used after evaporation in the next reaction. (LC-MS: calc. mass: 319.2; obs.: 319.1).

[00203] (lR,3r,SS)-tert-butyl 3-(lH-imidazo [4,5-c]pyridin-l-yl)-8- azabicyclo[3.2.1]octane-8-carboxyIate (R ^y = H) (3F-1). The product of the previous reaction (181 mg, 0.57 mmol) was dissolved in trimethylorthoformate (5 ml), and a catalytic amount of formic acid (35 μl) was added. The reaction mixture was heated at 80 ⁰ C for one day and then evaporated to afford the target compound. (LC-MS: calcd. mass: 329.2; obs.: 329.1).

[00204] (lR,3r,5S)-tert-butyl 3-(5-benzyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octane-8-carb oxylate (R ^y = H) (3G-1). The product of the previous reaction (187 mg, 0.57 mmol) was dissolved in EtOH (5 ml), benzylbromide (80 μl, 0.67mmol) was added, and the reaction mixture was left at room temperature for two days. After cooling the mixture to -70 ⁰ C, NaBH ₄ (30 mg, 0.79mmol) was added, and the temperature was allowed to rise to -20°C over 3 hr. The mixture was re-cooled to -70 ⁰ C, additional NaBH ₄ (20 mg, 0.53 mmol) was added, and after 1 hr at -70 ⁰ C water (2 ml) was added. The mixture was allowed to warm to r.t. The ethanol was removed by evaporation, water was added and the product was extracted into DCM. The organic layer was dried over MgSO ₄ and evaporated to yield the target compound. (LC-MS calcd. mass: 423.2, obs.: 423.4).

[00205] 5-benzyl-l-((lR,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-4,5,6, 7- tetrahydro-lH-imidazo[4,5-c]pyridine (R ^y = H) QHrVj. Compound 3G-1 (0.57 mmol) was dissolved in DCM (2 ml) and TFA (3 ml) was added. After 20 minutes the solvent was evaporated to yield the target compound, which was used without further purification. (LC-MS: calcd. mass: 323.2; obs.: 323.2).

[00206] 2,2,2-trifluoro-l-((lR,3r,5S)-3-(2-(trifluoromethyI)-lH-imid azo[4,5- c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone (R ^y = CF ₃ ) (3F-2).

Compound 3E (300 mg, 0.86 mmol) was dissolved in DCM (4 ml), and TFAA (530 μl) was added. The reaction mixture was kept at r.t for 3 hr, then at 60 ⁰ C to evaporate the DCM. The solvent was completely evaporated, and the residue was dissolved in EtOH (3 ml) and heated in a closed vial at 110 ⁰ C for 100 min. The solvent was evaporated to afford the target compound. (LC-MS: calcd. mass: 393.1; obs.: 393.2).

[00207] 5-benzyl-l-((lR,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2- (trifluoromethyI)-4,5,6.7-tetrahydro-lH-imidazor4,5-c1pvridi ne (3G-2). The product of the previous reaction 3F-2 (0.86 mmol)) was dissolved in DCM, the organic layer was washed 3 times with aq. sat. NaHCO ₃ , dried over MgSO ₄ and evaporated. The residue (275 mg) was dissolved in EtOH (10 ml), benzylbromide (95 μl, 0.82mmol) was added. The mixture was left at room temperature for 12 days, after which it was cooled to -60°C. NaBH ₄ (100 mg, 2.63 mmol) was added and the temperature was allowed to rise to -3O ⁰ C over 3hr and then re-cooled to -70 ⁰ C. Water (4 ml) was added, and the mixture was allowed to warm to r.t. The ethanol layer was evaporated, water was added, and the product was extracted into DCM. The organic layer was dried over MgSO ₄ and evaporated. Since incomplete reduction was observed, the residue was dissolved in MeOH and an excess OfNaBH ₄ was added at r.t. The MeOH layer was evaporated, water was added and the product was extracted into DCM. The organic layer was dried over MgSO ₄ and evaporated to yield 300 mg of the crude product (LC-MS: calcd. mass: 390.2; obs.: 391.3).

[00208] Azatropane intermediates

[00209] tert-butyl 3-amino-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (4A). hi a 125ml Erlenmeyer flask was placed 8-Boc-3,8-diaza-bicyclo[3.2.1]octane

(488 mg, 2.30 mmol) dissolved in acetic acid (2 ml) and water (6 ml). To this homogeneous solution was added sodium nitrite (238 mg, 3.45 mmol) in portions. The solution turned cloudy within one minute. After 3.5 hr at room temperature, zinc (748 mg, 11.5 mmol) was added in portions and the suspension was stirred at 40 ⁰ C for 2.5 hr during which time bubbles evolved slowly. The reaction mixture was quenched with 2N NaOH (100ml) and the white suspension gently extracted with DCM (3x50ml). The combined organic layers were dried over sodium sulfate and the solvent removed to afford 492 mg of the target product as a mixture with starting material which was used further without purification.

[00210] (9H-fluoren-9-yl)methyl 3-isobutyramido-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (4B). In a 50 ml round-bottomed flask were placed the compound obtained in the previous reaction (246mg, 1.08 mmol) and DCM (25 ml). To this solution was added 2-methylpropionyl chloride (213 μl, 2.0 mmol) and triethylamine (306 μl, 2.2 mmol). After sitting for 30 min at room temperature, the solvent was removed in vacuo. The residue was partitioned between DCM (50 ml) and water and the organic layer dried over sodium sulfate. The solution was filtered and treated with TFA (6 ml). The solvent was removed in vacuo after 45 min and stripped from dichloromethane. The residue was diluted in water (3 ml), and 2M sodium carbonate (3 ml) in a 100 ml round-bottomed flask. The pH was between 11-12. To this magnetically stirred solution was added FmocONSu (607 mg, 1.8 mmol) in THF (6 ml). After Ih 15min the organic solvent was removed in vacuo and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and the solvent removed in vacuo. The residue was purified on silica gel, eluting with EtO Ac/Hex to afford 205 mg of the target product 4B (45% yield). (LC-MS: calc. mass: 419.2, obs.: 420).

[00211] (9H-fluoren-9-yl)methyl 3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxyIate (4C). In a 50 ml round-bottomed flask were placed compound 4B (125 mg, 0.30 mmol) and DCM (3 ml). Pyridine (145 μl, 1.79 mmol) was added followed by phosphorous oxychloride (81 μl, 0.89 mmol). After 3hr the solvent was removed and the residue dried under vacuum. The residue was dissolved in DCM (3 ml) and treated with acetic hydrazide (132 mg, 1.78 mmol)

in DCM, resulting in a cloudy solution. After 30 min a second portion of acetic hydrazide (132 mg, 1.78 mmol) was added, resulting in further cloudiness, followed by a third portion (132 mg, 1.78 mmol), which did not result in precipitate formation. After 1.5 hr at r.t. acetic acid (2 ml) and chloroform (20 ml) were added and the reaction was refluxed for 60 hr. The solvent was removed and the residue was suspended in MeOH/DCM and loaded onto a silica gel column. The residue was purified via silica gel chromatography, eluting with a gradient of MeOH/DCM to afford 110 mg (80% yield) of the product. (LC-MS: calc. mass: 457.2, obs.: 458).

[00212] tert-butyl 3-(3-isopropyl-5-methyl-4H-l ,2,4-triazol-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (4D). In a 50 ml round-bottomed flask were placed tert-butyl 3-isobutyramido-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 0.57 mmol) and DCM (3 ml). Pyridine (294 μl, 3.42 mmol) was added followed by phosphorous oxychloride (157μl, 1.72 mmol). After 6hr the solvent was removed and the residue stripped from DCM/toluene. The residue was suspended in DCM (10 ml) and THF (5 ml) and treated with acetic hydrazide (127 mg, 1.72 mmol) in DCM (5 ml), resulting in a cloudy solution. The reaction was refluxed for 18 hr. The solvent was removed and the residue suspended in MeOH/DCM and loaded onto a silica gel column. The residue was purified via silica gel chromatography, eluting with a gradient of MeOH/DCM to afford 163 mg (85% yield) of target compound 4D as a mixture with the uncyclized intermediate. (LC-MS: calc. mass: 335.2, obs.: 336).

[00213] (lR,5S)-tert-butyl 3-(4-methyIpyridin-3-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (4E). In a 2 dram vial were placed Pd ₂ dba ₃ (10.8mg, 0.0118mmol), tBuONa (68mg, 0.71mmol), 8-Boc-3,8-diaza- bicyclo[3.2.1]octane (lOOmg, 0.47mmol), 2-(dicyclohexylphosphino)-2'- methylbiphenyl (17 mg, 0.05 mmol), 3-bromo-4-methylpyridine (105 mg, 0.61 mmol) and a magnetic stirbar. The vial was flushed with nitrogen, dioxane (0.5 ml) was added and the vial was capped tightly. The reaction was heated to 100 ⁰ C overnight, then loaded directly onto silica gel. The dioxane was evaporated under vacuum and the compound eluted with a gradient of EtO Ac/Hex to afford 69 mg (0.23mmol, 49% yield) of the product as an oil. Rf (l:lEtOAc/Hex) = 0.2. (LC-MS: calc.mass: 303.2, obs. 304.0).

[00214] (lR,5S)-tert-butyl 3-(isoquinolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (4F). In a 2 dram vial were placed Pd ₂ dba ₃ (10.8mg, 0.0118mmol), tBuONa (68mg, 0.71mmol), 8-boc-3,8-diaza- bicyclo[3.2.1]octane (lOOmg, 0.47mmol), 2-(dicyclohexylphosphino)-2'- methylbiphenyl (17 mg, 0.05 mmol), 4-bromoisoquinoline (127 mg, 0.61 mmol) and a magnetic stirbar. The vial was flushed with nitrogen, dioxane (0.5 ml) was added and the vial was capped tightly. The reaction was heated to 100 ⁰ C overnight, then loaded directly onto silica gel. The dioxane was evaporated under vacuum and the compound eluted with a gradient of EtO Ac/Hex to afford 159 mg (0.47mmol, 100% yield) of the product as an oil. Rf (1:1 EtO Ac/Hex) = 0.25 (LC-MS: calc. mass 339.2, obs. 340.1).

Example 1: Synthesis of piperazine derivatives.

[00215] (S)-tert-Butyl 3-(4-(2-(4- (methylsulfonyl)phenyl)acetamido)piperaziii-l-yl)-l-phenylpr opylcarbamate. To a solution of 2B (60 mg, 0.15 mmol) in DCM (5 ml) at r.t. was added TFA (1 ml). The mixture was stirred at r.t. for 1.5 hr. The solvent was removed under vacuum, and the compound was placed under vacuum to remove any remaining TFA. The residue was suspended in DCM (10 ml) containing 1% acetic acid. (S)-tert-Butyl 3- oxo-1-phenylpropylcarbamate (prepared as described in US6,586,430) (37 mg, 0.15 mmol) was added at r.t. and the solution was stirred for 10 min. Sodium triacetoxyborohydride (0.30 mmol) was added in one portion and the resulting solution was stirred at r.t. for 20hr. The reaction mixture was poured into saturated sodium bicarbonate solution and the organic layer was concentrated to give the title compound as a yellow oil. (LC-MS: calc. mass: 530, obs.: 531).

[00216] (S)-iV-(3-(4-(2-(4-(Methylsulfonyl)phenyl)acetamido)piperazi n-l-yl)- l-phenylpropyl)cyclopentanecarboxamide (1). The crude product obtained above (20 mg) was suspended in DCM (5 ml) containing TFA (1 ml) and stirred at r.t. for 2hr. The TFA and DCM were evaporated completely and the product was suspended in DCM (5 ml) containing 0.25 ml DIEA. In a separate vessel, at O ⁰ C, cyclopentanecarbonyl chloride (30 mg) was added to a solution of HOBt (50 mg) and DIEA (0.08 ml). After stirring for lOmin at r.t., this solution was added to the solution containing deprotected compound above and stirred for an additional hr. Evaporation and reverse-phase LC purification furnished product 1 as a white solid. (LC-MS: calc. mass: 526, obs.: 527).

[00217] (S)-ført-Butyl 3-(4-(3-isopropyl-5-methyl-4H-l ,2,4-triazol-4- yl)piperazin-l-yl)-l-phenylpropylcarbamate. Intermediate 2D (25 mg crude product, 0.12 mmol) was suspended in DCM (5 ml) containing 1% acetic acid. (S)- tert-Butyl 3-oxo-l-phenylpropylcarbamate (prepared as described in US6,586,430) (37 mg, 0.15 mmol) was added at r.t. and the solution was stirred for 10 min. Sodium triacetoxyborohydride (0.30 mmol) was added in one portion and the resulting solution was stirred at r.t. for 20hr. The reaction mixture was poured into saturated sodium bicarbonate solution and the organic layer was concentrated to give the crude product as a yellow oil. Reverse-phase chromatography yielded 33mg of the title compound. (LC-MS: calc. mass: 442, obs.: 443).

[00218] (S)-N-(3-(4-(3-Isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)pipe razin-l- yl)-l-phenylpropyl)cyclopentanecarboxamide (2). The compound obtained above (25 mg, 0.06 mmol) was suspended in DCM (5 ml) containing 20% TFA and stirred for lhr at r.t.. The solvent and excess TFA were removed via vacuum. The residue was suspended in DCM (5 ml) containing 0.25 ml DIEA. In a separate vessel, at O ⁰ C, cyclopentanecarbonyl chloride (30 mg) was added to a solution of HOBt (50 mg) and DIEA (0.08 ml). After stirring for lOmin at r.t., this solution was added to the solution containing deprotected compound above and stirred for an additional hr. Evaporation and reverse-phase LC purification furnished product 2 as a white solid. (LC-MS: calc. mass: 438, obs.: 439).

Example 2: Synthesis of azatropane derivatives.

[00219] tert-butyl (S)-3-((lR,5S)-3-(4-methylpyridin-3-yl)-3,8- diazabicyclo[3.2.1]octan-8-yI)-l-phenylpropylcarbamate. In a 25 ml conical flask were placed 8-boc-3,8-diaza-3-N-(4-methylpyrid-3-yl)bicyclo[3.2.1]octane 4E (69 mg, 0.23 mmol) and DCM (8 ml). To this solution was added TFA (4 ml). After 20 min the solvent was removed in vacuo. To this residue was added DCM (3 ml), (S)- fert-Butyl 3-oxo-l-phenylpropylcarbamate (prepared as described in US 6,586,430) (115 mg, 0.46 mmol), acetic acid (50 μL) and sodium acetoxyborohydride (97 mg, 0.46 mmol). After stirring overnight, the solvent was removed in vacuo and the residue loaded onto silica gel, eluting with MeOH/DCM to afford 67 mg (67% yield) of the product as an oil. (Rf (1:9 MeOH/DCM = 0.4, LC-MS calc. mass: 436.3, obs.437.2).

[00220] (S)-3-((lR,5S)-3-(4-methylpyridin-3-yl)-3,8- diazabicyclo[3.2 J]octan-8-yl)-l-phenyIpropan-l-amine (3a) (R= H). In a 50 ml round-bottomed flask were placed the compound obtained in the previous reaction (65 mg, 0.16 mmol) and DCM (5 ml). To this solution was added TFA (1 ml). After 40 min at room temperature the solvent was removed in vacuo. The residue was stripped from DCM twice. The residue was dissolved in DCM (5 ml) and DMF (50μL) and treated with acylating reagents and isocyanates, as described below.

[00221] N-((S)-3-((lR,5S)-3-(4-methylpyridin-3-yI)-3,8- diazabicyclo[3.2.1]octan-8-yl)-l-phenylpropyl)cyclopentaneca rboxamide (3bJ (R= cPent). To the above solution was added 0.1 mmol of a solution prepared from DCM, cyclopentyl carbonyl chloride (66 mg), HOBt (108 mg) and DIEA (87μL). Additional 0.2 mmol DIEA was added and the reaction allowed to sit overnight. The

solvent was removed and the residue purified on HPLC to afford the target compounds. (LC-MS: calc. mass: 432.3, obs. 433.4).

[00222] l-((S)-3-((lR,5S)-3-(4-methyIpyridin-3-yl)-3,8- diazabicyclotS.l.lloctan-δ-yO-l-phenylpropy^-S-p-tolylurea (3c) (R= NH-ToI).

To the above solution was added 0.1 mmol of a solution prepared from DCM, and p- toluylisocyanate. Additional 0.2 mmol DIEA was added and the reaction allowed to sit overnight. The solvent was removed and the residue purified on HPLC. (LC-MS: calc. mass: 469.3, obs. 470.5).

[00223] tert-butyl (S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-l-phenylpropyIcarbamate. In a 25 ml conical flask were placed intermediate 4F (159 mg, 0.47 mmol) and DCM (8 ml). To this solution was added TFA (4 ml). After 20 min the solvent was removed in vacuo. To this residue was added DCM (3 ml), (S)-fert-Butyl 3-oxo-l-phenylpropylcarbamate (prepared as described in US6,586,430) (234 mg, 0.94 mmol), acetic acid (50 μL) and sodium acetoxyborohydride (199 mg, 0.94 mmol). After stirring overnight, additional sodium acetoxyborohydride (45 mg, 0.21 mmol) was added. After stirring for 3 hr, the solvent was removed in vacuo and the residue loaded onto silica gel, eluting with MeOH/DCM to afford 211 mg (95% yield) of the product as an oil. (Rf 1 :9 MeOH/DCM = 0.6, LC-MS: calc. mass: 472.3, obs. 473.5).

[00224] (S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8-diazabicyclo[3.2.1]o ctan-8- yl)-l-phenylpropan-l-amine (4a) (R=H). In a 50 ml round-bottomed flask were placed the compound obtained in the previous reaction (65 mg, 0.16 mmol) and DCM

(5 ml). To this solution was added TFA (1 ml). After 40 min at room temperature the solvent was removed in vacuo. The residue was stripped from DCM twice. The residue was dissolved in DCM (5 ml) and DMF (50μL) and treated with acylating reagents and isocyanates, as described below.

[00225] N-((S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8-diazabicyclo[3.2. 1]octan- 8-yl)-l-phenylpropyI)cyclopentanecarboxamide (4b) (R=cPent). To the above solution was added 0.1 mmol of a solution prepared from DCM, cyclopentyl carbonyl chloride (66 mg), HOBt (108 mg) and DIEA (87μL). Additional 0.2 mmol DIEA was added and the reaction allowed to sit overnight. The solvent was removed and the residue purified on HPLC. (LC-MS: calc. mass: 468.3, obs.: 469.5).

[00226] l-((S)-3-((lR,5S)-3-(isoquinolin-4-yl)-3,8-diazabicydo[3.2.1 ]octan-8- yl)-l-phenyIpropyI)-3-p-tolyIurea (4c) (R=NH-ToI). To the above solution was added 0.1 mmol of a solution prepared from DCM, and p-toluylisocyanate. Additional 0.2 mmol DIEA was added and the reaction allowed to sit overnight. The solvent was removed and the residue purified on HPLC. (LC-MS: calc. mass: 505.3, obs.: 506.5).

[00227] tert-butyI 3-(3-(3-isopropyl-5-methyI-4H-l,2,4-triazoI-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)propyl(phenyl)carbamate. In a 50 ml conical flask were placed the Fmoc amine 4C (110 mg, 0.26 mmol) in dioxane (5.2 ml) and MeOH (1.6 ml). 3M NaOH (173μl, 0.52 mmol) was added and the reaction was stirred at room temperature for 50 min. Acetic acid (30 μl, 0.52 mmol) was added and the solvent removed in vacuo. To this residue was added DCM (3 ml), acetic acid (30 μl, 0.52 mmol), aldehyde lC-2 (139 mg, 0.54 mmol) and sodium triacetoxyborohydride (110 mg, 0.52 mmol) and the reaction stirred overnight. The residue was loaded onto

silica gel and eluted with a gradient from 0-10% MeOH/DCM to afford 79 mg (65% yield) of the the target compound. LC-MS: calc. mass: 46S.3, obs. 468.8).

[00228] l-(3-(3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yi)-3,8- diazabicyclo[3 JJloctan-δ-ytypropylH-phenyl-S-p-toIylurea (5). The compound obtained in the previous reaction (11 mg, 24 μmol) was treated with DCM (1 ml) and TFA (0.2 ml). After 20 min the solvent was removed. The residue was dissolved in DMF (0.5 ml) and treated with p-toluylisocyanate (6 μl) and N-methyhnorpholine (5.3 μl). An additional p-tolylisocyanate (12 μl) was added and the reaction allowed to sit for Ihr _* The reaction was purified directly on HPLC to afford 6.7 mg of the 1- (3-(3-(3-isoρroρyl-5-rαethyl-4H-l,2,4-triazol-4-yl)-3,8-d iazabicyclo[3.2.1]octan-8- yl)proρyl)-l-ρhenyl-3-ρ-tolylurea 5. (LC-MS: calc. mass: 501.3, obs.: 501.8).

[00229] tert-b«tyl (lS)-3-(3-(3-isopropyi-S-methyl-4H-l,2,4-triazol-4-yI)-3,8- diazabicyclo[3.2.1]octan-8-yl)-l-phenyIpropylcarbamate. Intermediate 4D as a mixture containing uncyclized triazole was refiuxed in chloroform (50 ml) and acetic acid (1 ml) for 21 hr, after which time the solvent was removed in vacuo. The residue was diluted in DCM (6 ml) and treated with TFA (2 ml). After 20 min the solvent was removed in vacuo and the residue stripped from DCM. The residue was placed in a 2 dram vial and treated with acetic acid (55 μl, 0.96 mmol), DCM (5 ml), (S)-tert-Butyl 3-oxo-l-phenylpropylcarbamate (prepared as described in US6,586,430) (155 mg, 0.62 mmol), and sodium triacetoxyborohydride (131 nag, 0.62 mmol) and the reaction stirred overnight. The reaction was quenched with IN sodium hydroxide and the organic layer separated and dried over sodium sulfate. The residue was purified on silica gel and eluted with a gradient from 0-10% MeOH/DCM to afford 62 mg (28% yield) of the target material. (LC-MS: calc. mass: 468.3, obs.: 468.8)

[00230] N-((lS)-3-(3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-3, 8- diazabicyclo[3.2.1]octan-8-yl)-l-phenyIpropyl)cyclobutanecar boxamide (6). The compound obtained in the previous step (42 mg, 90 μmol) in DCM (3 ml) was treated with TFA (1.5 ml). The solvent was removed and the residue stripped from 4N HCl in dioxane. The residue was dissolved in DMF (1.5ml) and 0.5 ml of this solution placed in a 2 ml HPLC sample vial. HOBt (13.7 mg, 90 μmol) was placed in a 13mm test tube followed by cyclobutyryl chloride (7.1 mg, 60 μmol) and DCM (0.5 ml). The reaction was treated with N-methylmorpholine (7.2 μl, 66μmol) and the test tube agitated until the solution was homogeneous. The solvent was removed in vacuo and the residue was dissolved in DMF (0.5 ml) and added to the amine hydrochloride solution. The solution was allowed to sit at room temperature for 30 min and then purified by LC-MS to afford 13.9 mg (82% yield) of the N-((lS)-3-(3-(3-isopropyl-5- methyl^H-l^^-triazol^-yO-S^-diazabicyclotS^.lJoctan-δ-yl)-! - phenylpropyl)cyclobutanecarboxamide 6. (LC-MS: calc. mass: 450.3, obs.: 450.7).

Example 3: Synthesis of tropane derivatives.

[00231] tert-Butyl S-p-benzyl-S-azabicyclop.l.lloctan-S-yOpropyip- fluorophenyl)carbamate. A solution of 3B (503 mg, 2.5 mmol), aldehyde lC-3 (524 mg, 2.0 mmol), and HOAc (0.240 ml, 4.0 mmol) in DCM (5.0 ml) was stirred at r.t. for 10 min. NaBH(OAc) ₃ (848 mg, 4.0 mmol) was then added and the mixture was stirred at r.t. for 17 hr. The mixture was diluted with DCM (50 ml), washed with sat. aq. NaHCO ₃ solution (100 ml), the organic layer was dried over Na ₂ SO ₄ , concentrated and the resulting amber oil was dried in HV. The material was used without purification for the next step.

[00232] N-(3-(3-Benzyl-8-azabicyclo[3.2.1]octan-8-yl)propyl)-3- fluoroaniline. TFA (5 ml) was added dropwise to a soln. of the crude compound obtained in the previous reaction in DCM (5 ml). After stirring at r.t. for 1 hr, the mixture was concentrated and the crude product was purified using preparative reverse phase HPLC (20-60% AcN in H ₂ O). The concentrated fractions were neutralized with 2 M aq. K ₂ CO ₃ (50 ml) and the DCM extraction provided the free base of the target product (18.3 mg, 90% pure by LC-MS). (LC-MS: calc. mass: 352.5, obs.: mass: 352).

[00233] l-(3-(3-Benzyl-8-azabicyclo[3.2.1]octan-8-yl)propyl)-l-(3- fluorophenyl)-3-p-toIylurea (7). A soln. of the compound obtained above (18.3 mg) in p-tolylisocyanate (0.5 ml) was stirred at r.t. for 3 hr, the mixture was diluted with MeOH (3 ml), and the precipitated solid was removed by filtration. The filtrate was purified using preparative reverse phase LC-MS (10-90% AcN in H ₂ O) followed by normal phase chromatography (SiO ₂ , 0-10% MeOH in DCM) to give product 7 (6.5 mg, 95% pure by LC-MS). (LC-MS: calc. mass: 485.6, obs.: 485).

[00234] tert-Butyl 3-(3-benzyl-8-azabicyclo[3.2.1]octan-8- yl)propyl(phenyl)carbamate. NaBH(OAc) ₃ (933 mg, 4.4 mmol) was added to a soln. of 3-benzyl-8-azabicyclo[3.2.1]octane 3B (441 mg, 2.19 mmol), aldehyde lC-2 (546 mg, 2.19 mmol), and HOAc (0.381 ml, 6.6 mmol) in DCM (8.0 ml). The mixture was stirred at r.t. for 17 hr. The mixture was diluted with DCM (50 ml), washed with sat. aq. NaHCO ₃ solution (100 ml), the organic layer was dried over Na ₂ SO ₄ , concentrated and the resulting yellow oil was dried in HV. The crude product obtained (960 mg) was used without purification for the next step.

[00235] N-(3-(3-Benzyl-8-azabicyclo[3.2.1]octan-8-yl)propyl)aniline. TFA (5 ml) was added dropwise to a soln. of the crude product obtained above (960 mg) in DCM (5 ml). After stirring at r.t. for 2 hr, the mixture was concentrated, and dried in HV. 2 M aq. K ₂ CO ₃ (50 ml) was added and the DCM extraction (3 x 30 ml) provided the free base of the product as an amber oil (732 mg). (LC-MS: calc. mass: 334.50, obs.: 335).

[00236] l-Acetyl-N-(3-(3-benzyl-8-azabicyclo[3.2.1]octan-8-yl)propyl )-N- phenylpiperidine-4-carboxamide (8). Oxalyl chloride (87 μl, 1.0 mmol) was added dropwise to a mixture of l-acetylpiperidine-4-carboxylic acid (34 mg, 0.2 mmol) and DCM (100 μl). The mixture was stirred at r.t. for 10 min, concentrated and the crude l-acetylρiperidine-4-carbonyl chloride was dried in HV. A soln. of the compound obtained in the previous step (67 mg, 0.2 mmol) and DIEA (70 μl, 0.4 mmol) in DCM (1.0 ml) was added to the crude l-acetylpiperidine-4-carbonyl chloride. The mixture was stirred at r.t. for 1 hr, concentrated, and the residue was dried in HV. Purification using preparative reverse phase LC-MS (30-50% AcN in H ₂ O) gave pure product 8 as a white powder (14.6 mg, 99% pure by LC-MS). (LC-MS: calc. mass: 487.68, obs.: 488).

[00237] General synthesis of l-(3-(3-Benzyl-8-azabicyclo[3.2.1]octan-8- yl)propyl)-3-aryl-l-phenylureas (9). An aryl isocyanate (0.6 mmol, a: 4-CH ₃ - C ₆ H ₄ NCO, b: 4-CF ₃ -C ₆ H ₄ NCO, c: 4-Cl-C ₆ H ₄ NCO ) was added to a soln. of the compound obtained as described above (100 mg, 0.3 mmol) in DCM (1.0 ml) and the mixture was stirred at r.t. for 17 hr. Column chromatography (3 x 12 g SiO ₂ , 0-10% MeOH in DCM) followed by preparative reverse phase LC-MS (30-80% AcN in H ₂ O) gave pure products 9a-9c as white powders (9a: 36.6 mg, 9b: 47.3 mg, 9c: 32.2 mg)- (2ϋ ^: calc mass: 467.64, obs.: 468; 9b: calc. mass: 521.62, obs.: 522; JJc: calc. mass: 488.06, obs.: 488).

Example 2: Synthesis of nortropane imidazopiperidines

[00238] tert-Butyl 3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetrahydro- 1 H-imidazo [4,5-c] py ridin-1 -yl)-8-azabicy clo [3.2.1 ] octan-8- yl)propyl(phenyl)carbamate. A mixture of aldehyde lC-2 (354 mg, 1.42 mmol), 5- benzyl-l-((lR,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl -4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine 3H (prepared as described in WO2005/033107) (477 mg, 1.42 mmol), HOAc (164 μl, 2.84 mmol) and DCM (5.0 ml) was stirred at r.t. for 10 min. Then NaBH(OAc) ₃ (451 mg, 2.13 mmol) was added and the mixture was stirred at r.t. for 4 hr followed by another addition OfNaBH(OAc) ₃ (300 mg) and HOAc (100 μl). After stirring at r.t. for 18 hr, sat. aq. NaHCO ₃ solution (50 ml) was added, and the mixture was extracted with DCM (3 x 50 ml). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated, and dried in HV to give crude target product (958 mg) as a white foam. The product was purified using column chromatography (3 x 12 g SiO ₂ , 0-10% MeOH in DCM) to give 332 mg pure compound. (LC-MS: calc. mass: 569.78, obs.: 570).

[00239] N-(3-((lR,3r,5S)-3-(5-Benzyl-2-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)pr opyl)aniline. TFA (5 ml) was added dropwise to a soln. of the compound obtained above (321 mg, 0.56 mmol) in DCM (5 ml). After stirring at r.t. for 35 min, the mixture was concentrated,

and dried in HV. 2 M aq. K ₂ CO ₃ (50 ml) was added and the DCM extraction (3 x 30 ml) provided the free base of the product as a white foam (298 mg). (LC-MS: calc. mass: 469.66, obs.: 470).

[00240] l-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)pr opyl)-l-phenyI-3-p- tolylurea (10). p-Tolylisocyanate (161 μl, 1.27 mmol) was added dropwise to a soln. of the compound above (298 mg, 0.56 mmol) in DCM (2.0 ml), the mixture was stirred at r.t. for 17 lir, and concentrated. The crude product 10 was dried in HV and used for the next step without purification. (LC-MS: calc. mass: 602.81, obs.: 603).

[00241] l-(3-((lR,3r,5S)-3-(2-Methyl-4,5,6,7-tetrahydro-lH-imidazo[4 ,5- c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)propyl)-l-phen yl-3-p-tolyIurea (ll).

Palladium on active carbon (10% Pd/C, 50% water, 300 mg) was added to a soln. of crude 10 (0.56 mmol) in MeOH (5.0 ml), the mixture was stirred under H ₂ balloon at r.t. for 3 hr, and filtered through celite. The filtrate was concentrated and the crude product was purified using preparative reverse phase HPLC (20-50% AcN in H ₂ O). The concentrated fractions were neutralized with 2 M aq. K ₂ CO ₃ (50 ml) and the DCM extraction provided the free base of the product 13 as a white foam (137 mg, 98% pure by LC-MS, 47% yield for 3 steps including HPLC purification). (LC-MS: calc. mass: 512.69, obs.: 513).

[00242] General synthesis of l-(3-((lR,3r,5S)-3-(5-Acyl-2-methyl-4,5,6,7- tetrahydro-lH-imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1 ]octan-8-yl)propyl)- l-phenyl-3-p-tolylureas (12). An acid chloride (0.078 mmol; a: cBuCOCl, 8.9 μl; b: cPrCOCl, 7.1 μl; c: cPentCOCl, 9.5 μl; d: PhCOCl, 9.1 μl) was added to a soln. of HOBt (15.8 mg, 0.117 mmol), and NMM (25.8 μl, 0.234 mmol) in DCM (1.0 ml), and the mixture was stirred at r.t. for 15 min. Then solid 11 (20.0 mg, 0.039 mmol) or its soln. in DCM (1.0 ml) was added and the stirring at r.t. was continued for another 15 min. The solutions were concentrated and crude products were purified using preparative reverse phase LC-MS (10-60% AcN in H ₂ O) to give pure 12a-d as white powders after lyophilization from 1,4-dioxane.

[00243] l-(3-((lR,3r,5S)-3-(5-Benzyl-2-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicycIo[3.2.1]octan-8-yl)pr opyl)-l-phenyl-3-(4- (trifluoromethyl)phenyl)urea (13). 4-(Trifluoromethyl)phenylisocyanate (59 mg, 0.315 mmol) was added to a soln. of N-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7- tetrahydro- lH-miidazo[4,5-c]pyridin- 1 -yl)-8-azabicyclo[3.2.1 ]octan-8- yl)propyl)aniline (obtained as before) (74 mg, 0.158 mmol) in DCM (250 μl) and the mixture was stirred at r.t. for 2.5 hr, and concentrated. The crude product was dried in HV and used for the next step without purification. (LC-MS: calc. mass: 656.78, obs.: 657).

[00244] l-(3-((lR ₅ 3r,5S)-3-(2-Methyl-4,5,6,7-tetrahydro-lH-imidazo[4,5- c]pyridin-l-yl)-8-azabicycIo[3.2.1]octan-8-yl)propyl)-l-phen yl-3-(4- (trifluoromethyl)phenyl)urea (14). Palladium on active carbon (10% Pd/C, 50% water, 300 mg) was added to a soln. of crude 15 (0.158 mmol) in MeOH (3.0 ml), the mixture was stirred under H ₂ balloon at r.t. for 3-19 hr, and filtered through celite.

The filtrate was concentrated and the crude product 16 (88.3 mg) was used for the next step without purification or was purified using preparative reverse phase HPLC (10-40% AcN in H ₂ O). The concentrated fractions were neutralized with 2 M aq. K ₂ CO ₃ (50 ml) and the DCM extraction provided the free base of the product 16 as a white foam. (LC-MS: calc. mass: 566.66, obs.: 567).

[00245] l-(3-((lR,3r,5S)-3-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yI)pr opyI)-l-phenyl-3-(4- (trifluoromethyl)phenyl)urea (15). Acetanhydride (1.0 ml) was added to a soln. of crude 14 (88.3 mg, 0.155 mmol) in DCM (1.5 ml) and the mixture was stirred at r.t. for 4 hr. The soln. was concentrated and the crude product was purified using preparative reverse phase LC-MS (10-60% AcN in H ₂ O) to give 15 (22.0 mg, 99% pure by LC-MS) as a white powder after lyophilization from 1,4-dioxane. (LC-MS: calc. mass: 608.70, obs.: 609).

[00246] Methyl 2-methyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-(4- (trifluoromethyI)phenyl)ureido)propyl)-8-azabicyclo[3.2.1]oc tan-3-yl)-6,7- dihydro-lH-imidazo[4,5-c]pyridine-5(4H)-carboxylate (16a) (XR = COOMe).

Dimethyl dicarbonate (3.2 μl, 0.030 mmol) was added to a soln. of 14 (17 mg, 0.030 mmol) in DCM (2.0 ml) and the mixture was stirred at r.t. for 2 hr.

[00247] l-(3-((lR,3r,5S)-3-(5-(CycIobutanecarbonyl)-2-methyl-4,5,6,7 - tetr ahy dro-1 H-imidazo [4,5-c] pyridin-1 -y I)-8-azabicy do [3.2.1] octan-8-yl)propyl)- l-phenyl-3-(4-(trifluoromethyl)phenyl)urea (16b) (XR = COcBu).

Cyclobutanecarbonyl chloride (3.4 μl, 0.030 mmol) was added to a soln. of 14 (17 mg, 0.030 mmol) and NMM (5.0 μl, 0.045 mmol) in DCM (2.0 ml) and the mixture was stirred at r.t. for 2 hr.

[00248] l-(3-((lR,3r,5S)-3-(2-Methyl-5-(methylsulfonyl)-4,5,6,7-tetr ahydro- lH-imidazo[4,5-c]pyridin-l-yI)-8-azabicyclo[3.2.1]octan-8-yl )propyI)-l-phenyl-3- (4-(trifluoromethyl)phenyI)urea (16c) (XR = SO ₂ Me). Methanesulfonyl chloride (2.3 μl, 0.030 mmol) was added to a soln. of 16 (17 mg, 0.030 mmol) and NMM (5.0 μl, 0.045 mmol) in DCM (2.0 ml) and the mixture was stirred at r.t. for 2 hr.

[00249] Workup for 16a-c: The soln. was concentrated, dried in HV, and the crude product was purified using preparative reverse phase HPLC or LC-MS (10-60% AcN in H ₂ O) to give 16a-c (99% pure by LC-MS) as a white powders after lyophilization from 1,4-dioxane.

[00250] 3-(4-FIuorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-4,5,6,7-tetr ahydro- 1 H-imidazo [4,5-c] py ridin-1 -yl)-8-azabicy do [3.2.1 ] octan-8-yI)propyl)-l - phenylurea (17) was prepared according to the above method for synthesis 14. (LC- MS: calc. mass: 516.65, obs.: 517).

[00251] l-(3-((lR,3r,5S)-3-(5-AcetyI-2-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8~yl)pr opyl)-3-(4- fluorophenyl)-l-phenylurea (18a) (XR = COMe). Acetic anhydride (4.3 μl, 0.045 mmol) was added to a soln. of 17 (15.5 mg, 0.030 mmol) in DCM (2.0 ml) and the mixture was stirred at r.t. for 2 hr. The compound 18a was purified according to the above workup method for 16a-c.

[00252] Methyl l-((lR,3r,5S)-8-(3-(3-(4-fluorophenyl)-l- phenylureido)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl -6,7-dihydro-lH- imidazo[4,5-c]pyridine-5(4H)-carboxylate (18b) (XR = COOMe) was prepared according to the above method for compound 16a.

[00253] l-(3-((lR,3r,5S)-3-(5-(Cyclobutanecarbonyl)-2-methyl-4,5,6,7 - tetrahydro-lH-imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1 ]octan-8-yl)propyl)- 3-(4-fluorophenyl)-l-phenylurea (18c) (XR = COcPr) was prepared according to the above method for compound 16b.

[00254] 3-(4-FIuorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-5-(methylsuI fonyl)- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridin-l-yl)-8-azabicyc lo[3.2.1]octan-8- yl)propyl)-l-phenylurea (18d) (XR = SO ₂ Me)was prepared according to the above method for synthesis 16c.

[00255] N,2-Dimethyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-p-tolylureido)pr opyI)- 8-azabicyclo[3.2.1]octan-3-yl)-6,7-dihydro-lH-imidazo[4,5-c] pyridine-5(4H)- carboxamide (19a) (XR = C(O)NHMe). Methyl isocyanate (5.0 μl, 0.078 mmol) was added to a soln. of 11 (20 mg, 0.039 mmol) in DCM (1.0 ml) and the mixture was stirred at r.t. for 2.5 hr. The compound 19a was purified according to the above workup method for 16a-c.

[00256] l-(3-((lR,3r,5S)-3-(2-MethyI-5-pivaloyl-4,5,6,7-tetrahydro-l H- imidazo[4,5-c]pyridin-l-yl)-8-azabicycIo[3.2.1]octan-8-yl)pr opyl)-l-phenyI-3-p- tolylurea (19b) (XR= COtBu). Pivaloyl chloride (5.0 μl, 0.041 mmol) was added to a soln. of 11 (21 mg, 0.041 mmol) in DCM (2.0 ml) and the mixture was stirred at r.t. for 4 hr. The compound 19b was purified according to the above workup method for 16a-c.

[00257] l-(3-((lR,3r,5S)-3-(2-MethyI-5-(methylsulfonyl)-4,5,6,7-tetr ahydro- lH-imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl )propyl)-l-phenyl-3- p-tolylurea (19c) (XR = SO ₂ Me) was prepared according to the above method for synthesis 16c starting from 11 (17 mg, 0.033 mmol).

[00258] l-(3-((lR,3r,5S)-3-(5-AcyI-2-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)pr opyl)-l-phenyI-3-(4- (trifluoromethyl)phenyl)ureas (20a-d) and l-(3-((lR,3r,5S)-3-(5-acyI-2-niethyl- 4,5,6,7-tetrahy dro-1 H-imidazo [4,5-c] py ridin-1 -yl)-8-azabicy do [3.2.1] octan-8- yl)propyl)-3-(4-fluorophenyl)-l-phenylureas (21a-d) were prepared according to the method for synthesis 12a-d starting from 14 or 17 (0.030 mmol), respectively.

[00259] N,2-Dimethyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3-(4- (trifluoromethyl)phenyl)ureido)propyl)-8-azabicyclo[3.2.1]oc tan-3-yl)-6,7- dihydro-lH-imidazo[4,5-c]pyridine-5(4H)-carboxamide (22) and l-((lR,3r,5S)-8- (3-(3-(4-Fluorophenyl)-l-phenylureido)propyl)-8-azabicycIo[3 .2.1]octan-3-yl)- N,2-dimethyl-6,7-dihydro-lH-imidazo[4,5-c]pyridine-5(4H)-car boxamide (23) were prepared according to the method for synthesis 19a starting from 14 or 17 (0.030 mmol), respectively.

[00260] General synthesis of alkyl-2-methyl-l-((lR,3r,5S)-8-(3-(l-phenyl-3- (4-(trifluoromethyl)phenyl)ureido)propyl)-8-azabicyclo[3.2.1 ]octan-3-yl)-6,7- dihydro-lH-imidazo[4,5-c]pyridine-5(4H)-carboxylates (24a-b) and alkyl-l- ((lR,3r,5S)-8-(3-(3-(4-fluorophenyl)-l-phenylureido)propyl)- 8- azabicyclo[3.2.1]octan-3-yl)-2-methyl-6,7-dihydro-lH-imidazo [4,5-c]pyridine- 5(4H)-carboxylates (25a-b). Isobutyl N-succinimidyl carbonate (R ₂ = iBu) (a, 9.7 mg, 0.045 mmol) or cyclopentyl 4-nitrophenyl carbonate (R ₂ = cPent) (b, 11.3 mg, 0.045 mmol) was added to a soln. of 14 (17.0 mg, 0.030 mmol) or 17 (15.5 mg, 0.030 mmol) in DCM (2.0 ml) and the mixture was stirred at r.t. for 17 hr. The compounds 24a-b and 25a-b were purified according to the workup method for 16a-c.

[00261] l-(3-((lR,3r,5S)-3-(5-Acyl-2-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yI)pr opyl)-l-phenyl-3-p-

tolylureas (26a-d) were prepared according to the method for synthesis 12a-d starting from 11.

l-(3-((lR,3r,5S)-3-(5-Acetyl-2-methyl-4,5,6,7-tetrahydro-lH- imidazo[4,5- c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)propyl)-l-phen yI-3-p-toIylurea (27) was prepared according to the method for synthesis 18a starting from 11. (LC-MS: calc. mass: 554.73, obs.: 555).

[00262] l-(3-((lR,3r,5S)-3-(2-Methyl-5-pivaloyI-4,5,6,7-tetrahydro-l H- imidazo[4,5-c]pyridin-l-yl)-8-azabicycIo[3.2.1]octan-8-yl)pr opyl)-l-phenyl-3-(4- (trifluoromethyl)phenyl)urea QS) and 3-(4-fluorophenyl)-l-(3-((lR,3r,5S)-3-(2- methyl-5-pivaIoyl-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridi n-l-yl)-8- azabicyclop^.lloctan-δ-y^propy^-l-phenylurea (29) were prepared according to the method for synthesis 19b starting from 14 (0.025 mmol) or 17 (0.030 mmol), respectively.

[00263] l-(3-((lR ₅ 3r,5S)-3-(5-AcyI-2-methyI-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)pr opyl)-l-phenyl-3-(4- (trifluoromethyl)phenyl)ureas (30a-c) and l-(3-((lR,3r,5S)-3-(5-acyl-2-methyI- 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridin-l-yl)-8-azabicyc lo[3.2.1]octan-8- yl)propyl)-3-(4-fluorophenyl)-l-phenylureas (31a-c) were prepared according to the method for synthesis 12a-d starting from 14 (0.025 mmol) or 17 (0.030 mmol), respectively.

* starting from 0.048 mmol 17

[00264] l-acetyI-iV-(3-((lR,3r,5S)-3-(5-benzyl-2-methyl-4,5,6,7-tetr ahydro- lfi ^r -imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-yI)p ropyl)-iV-(3- chloro-4-methylphenyl)piperidine-4-carboxamide. To a solution containing IE (0.10 g, 0.28 mmol) and 5-benzyl-l-((lR,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2- methyl-4 ₅ 5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridine 3H (see above) (96 mg, 0.28 mmol) in DCM containing 1% AcOH at r.t. was added sodium triacetoxyborohydride (0.21 g, 1.0 mmol). The mixture was stirred at r.t. for 6 hours, poured into a saturated bicarbonate solution (20 ml), washed with water and brine, and concentrated. Flash chromatography (EtOAc/Hexanes) gave the target product as an off-white solid (0.12 g). (LC-MS: calc. mass: 670, obs.: 671).

[00265] l-acetyl-iV-(3-((lR,3r,5S)-3-(5-acetyl-2-inethyl-4,5,6,7-tet rahydro- lJ9-imidazo[4,5-c]pyridin-l-yl)-8-azabicyclo[3.2.1]octan-8-y l)propyl)-iV-(3- chloro-4-methylphenyl)piperidine-4-carboxamide (32). To a solution of the compound obtained above (60 mg, 0.10 mmol) in EtOH (5 ml) at r.t. was added 10 % Pd on Carbon (20 mg). The mixture was placed under 1 atm H ₂ and stirred at r.t. for 15 hours. The mixture was filtered and concentrated to yield the debenzylated compound as a clear syrup. This product was suspended in DCM (5 ml) with DIEA (0.2 ml) and 1.5 eq Ac ₂ O was added. After stirring for 2br, the solvent was removed and the product 32 was isolated via reverse-phase chromatography. (LC-MS: calc. mass: 622, obs.: 623).

[00266] tert-butyI 3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8- azabicyclo[3.2.1]octan-8-yl)propyI(phenyl)carbamate. To a mixture of aldehyde C2 (320 mg, 1.28 mmol), l-((lR,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-lH- benzo[d]imidazole (prepared as described in WOOO/38680) (309 mg, 1.28 mmol), and HOAc (0.5 ml) and DCM (10.0 ml), NaBH(OAc) ₃ (300 mg, 1.41 mmol) was added. After stirring at r.t. for 2 hr, the mixture was added to aq. Na ₂ CO ₃ , and the resulting mixture was extracted with DCM. The combined organic layers were dried (MgSO ₄ ), concentrated, and dried in HV to give crude target product, which was used in the next step without further purification. (LC-MS: calc. mass: 474, obs.:474).

[00267] N-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8- azabicyclo[3.2.1]octan-8-yl)propyl)aniline. The compound obtained above was deprotected by treatment with TFA/DCM (1/2) (100 ml) for 2 hr. The mixture was concentrated, and dried in HV, to yield 210 mg of target compound.

[00268] General synthesis of l-(3-((lR,3r,5S)-3-(2-methyl-lH- benzo[d]imidazoM-yl)-8-azabicyclo[3.2.1]octan-8-yI)propyI)-l ,3-diphenylurea derivatives (33). To a solution of compound obtained above (50 mg, 0.134 mmol) in DMR (2 ml) and DIEA (0.1 ml), isocyanate (0.134 mmol) was added. The mixture was stirred at r.t. for 5 hr. Pure compound was obtained after purification via RP- HPLC, using a gradient of AcN in H ₂ O.

[00269] l-(3-((lR,3r,5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8- azabicyclotS^.ηoctan-δ-y^propy^-l-phenyl-S-p-tolylurea (33a) (R = Me). (LC-MS: calc. mass: 507, obs.:507).

[00270] 3-(4-chlorophenyl)-l-(3-((lR,3r,5S)-3-(2-methyl-lH- benzo[d]imidazol-l-yl)-8-azabicyclo[3.2.1]octan-8-yl)propyl) -l-phenylurea (33_b) (R = Cl). LC-MS: calc. mass: 527, obs.:527).

[00271] l-(3-((lR,3r ₅ 5S)-3-(2-methyl-lH-benzo[d]imidazol-l-yl)-8- azabicyclo[3.2.1] octan-8-yl)propyl)- 1 -ρhenyl-3 -(4-(trifluoromethyl)phenyl)urea (33 c) (R= CF ₃ ). LC-MS: calc. mass: 561, obs.:561).

Example 4: In vitro assays

[00272] CCR-5 Receptor Binding Assay. Method A. The compounds of the present invention can be evaluated using the following CCR-5 receptor binding assay. The ¹²⁵ I-MIP-I β/CCR-5 binding assay is carried out similarly as described in Samson M, LaRosa G, et al. (1997) [ "The second extracellular loop of CCR-5 is the major determinant of ligand specificity" in J.Biol Chem. 272: 24934-24941]. Briefly, compounds are assessed for displacement of binding of 0.1 nM ¹²⁵ I-MIP- lβ to human recombinant CHO-Kl cells. Whole cells are collected from plates in a Ca ²⁺ and Mg ²⁺ -free phosphate-buffered saline supplemented with 5 mM EDTA, gently pelleted for 3 min at 1500 x g, and resuspended in binding buffer. Saturation binding assays are performed in minisorb tubes (Nunc), in a final volume of 0.1 ml of 50 mM Hepes pH 7.4, 1 mM CaCl ₂ , 5 mM MgCl ₂ , 0.5% bovine serum albumin, containing 25,000 cells and 50OpM ¹²⁵ I-MIP-I β. Competition binding experiments are performed in the same conditions, using 500 pM ¹²⁵ I-MIP-I β, and variable concentrations of competitors. Nonspecific binding is determined following the addition of a 200-fold excess of the unlabeled ligand. Samples are incubated for 120 min at25°C, and bound and free tracer are separated by filtration through GF/B filters presoaked in 0.3% polyethyleneimine. Filters are counted by liquid scintillation. IC ₅₀ values are determined by a non-linear, least squares regression analysis using Data Analysis Toolbox (MDL Information Systems, San Leandro, CA, USA).

[00273] Method B. The ¹²⁵ I-gpl20/sCD4/CCR-5 binding assay is carried out similarly as described in Wu et al., Nature, 1996;384:179-183. Briefly, the envelope gpl20 protein derived from HIV-I JR-FL (Trkola et al., Nature, 1996; 384:184-186), an M-tropic strain, is iodinated using solid phase lactoperoxidase to a specific activity of 20 μCi/μg. For each binding reaction (in a final volume of 100 μL binding buffer [50 mM HEPES, pH 7.5, 1 mM CaCl ₂ , 5 mM MgCl ₂ , and 0.5% BSA]), 25 μL (2.5 μg) of membranes prepared from CCR- 5/L 1.2 cells are mixed with 25 μL (3 nM) sCD4, followed by 25 μL (0.1 nM) radio-labeled gpl20 in the presence or absence of 25 μL compound dissolved in DMSO (final concentration of DMSO 0.5%). The reactions are incubated at room temperature for 45 to 60 minutes and stopped by transferring the mixture to GFB filter plates, which are then washed 3 to 4 times with binding buffer containing 0.5 M NaCl. The plates are dried and MicroScint scintillation fluid is added before counting.

[00274] Assay for inhibition of HIV replication. The ability of representative compounds of the present invention to inhibit a single HIV-I infection cycle is determined using a CCR-5 expressing HeLa Magi cell line in the manner described in Hazuda et al., Science 2000, 287: 646-650.

[00275] Inhibition of viral entry using HIV-I luciferase reporter virus. The antiviral activity of compounds was assessed against Env-recombinant pseudotyped viruses using a single-round luciferase reporter assay. The panel of virus envelopes included JR-CSF, ASM80, Ba-L, 97-ZA-003 and RU570. Recombinant virus stocks expressing these viral envelope proteins were prepared by contransfecting HEK-293 cells with the appropriate envelope expression vector and a replication-defective HIV- 1 genomic viral vector, in which a region of the HIV-I envelope gene was replaced with a luciferase expression cassette. The recombinant virus particles were harvested from the co-transfection supernatant and titered using a p24 ELISA. The recombinant virus was incubated in the presence or absence of various test compound and a cell line expressing CD4/CCR5. Successful virus entry followed by a single round of viral replication resulted in the production of large amounts of luciferase activity in the infected cells. Susceptibility to compound was measured by comparing the amount of luciferase activity produced in the presence of compound to the amount of activity produced in the absence of compound.

Example 5: Table of compounds

[00276] Table 6 lists compounds of the invention prepared using the methods and intermediates described herein. Each compound was analyzed by LC-MS and displayed the expected molecular ion. Each of the compounds in Table 1 can be assayed by one or more of the above methods and has or is expected to have activity in one or more of the above assays. Compounds are named according to standard IUPAC nomenclature using the naming program Autonom2000 (Elsevier MDL, San Leandro, CA) or the naming functionality in Chemdraw Ultra 9.0.3 (CambridgeSoft, Cambridge, MA).

Table 6.

-

-

-

-

-

o. Compound Structure MW Cmpd. Name

2-(4-(methylsulfonyl)phenyl)-N-(4-

(3-(l-phenyl-3-(4-

80 618 (trifluoromethyl)phenyl)ureido)prop yl)piperazin- 1 -yl)acetamide

3-(3,4-dichlorophenyl)-l -(3-

((lS,5R)-3-(3-isopropyl-5-methyl-

81 557 4H-l,2,4-triazol-4-yl)-3,8-diaza- bicyclo[3.2.1 ]octan-8-yl)propyl)-l ^■ phenylurea

3-(4-tert-butylphenyl)-l -(3-

((lS,5R)-3-(3-isopropyl-5-methyI-

82 544 4H-l,2,4-triazol-4-yl)-3,8-diaza- bicyclo[3.2. l]octan-8-yl)propyl)-l - phenylurea

l-(3-((lR,5S)-3-(3-isopropyl-5- methyl-4H-l,2,4-triazol-4-yl)-3,8-

83 556 diaza-bicyclo[3.2.1]octan-8- yl)ρropyl)- 1 -phenyl -3 -(4- (trifluoromethyl)phenyl)urea

l-(3-((lR,5S)-3-(3-isopropyl-5- methyl-4H- 1 ,2,4-triazol-4-yl)-3 ,8-

84 556 diaza-bicyclo[3.2.1]octan-8- yl)propyl)- 1 -phenyl-3 -(3 - (trifluoromethyl)phenyl)urea

3-(4-chlorophenyl)-l-(3-((lR,5S)-3- (3-isopropyl-5-methyl-4H-l,2,4-

85 522 triazol-4-yl)-3 , 8-diaza- bicyclo[3.2.1 ]octan-8-yl)propyl)- 1 - phenylurea

3-(3,4-dimethylphenyl)-l -(3-

((lR,5S)-3-(3-isoρropyl-5-methyl-

86 516 4H-1 ,2,4-triazol-4-yl)-3,8-diaza- bicyclo[3.2.1 ]octan-8-yl)proρyl)- 1 ^■ phenylurea

-

-

ound Structure MW Cmpd. Name

1 -(3 -chloro-4-methylphenyl)-3 -(4- chlorophenyl)-l -(3-((I S,3r,5R)-3-(2-

577 methyl-lH-benzo[d]imidazol-l-yl)-

8-aza-bicyclo[3.2.1]octan-8- yl)propyl)urea

1 -(3 -chloro~4-methylphenyl)-3 -(4- fluorophenyl)-l -(3-((I S,3r,5R)-3-(2-

560 methyl- 1 H-benzo [d]imidazol- 1 -yl)-

8-aza-bicyclo[3.2.1]octan-8- yl)propyl)urea

1 -(3 -chloro-4-methylphenyl)- 1 -(3 -

((I S,3r,5R)-3-(2-methyl-lH-

556 benzo[d]imidazol- 1 -yl)-8-aza- bicyclo[3.2.1]octan-8-yl)propyl)-3- p-tolylurea

1 -(3 -chloro-4-methylphenyl)-3 -(4- isopropylphenyl)-l -(3-((I S,3r,5R)-

584 3 -(2-methyl- 1 H-benzo[d]imidazol- l-yl)-8-aza-bicyclo[3.2.1]octan-8- yl)propyl)urea

1 -(3 -chloro-4-methylphenyl)- 1 -(3 - ((lS,3r,5R)-3-(2-methyl-lH-

610 benzo[d]imidazol- 1 -yl)-8-aza- bicyclo[3.2.1 ]octan-8-yl)propyl)-3-

(4-(trifluoromethyl)phenyl)urea

1 -(3-chloro-4-methylphenyl)-3 -(3,4- dimethylρhenyl)-l -(3-((I S,3r,5R)-3-

570 (2-methyl-lH-benzo[d]iniidazol-l- yl)-8-aza-bicyclo[3.2.1 ]octan-8- yl)propyl)urea

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

■

[00277] While typical embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.