3-cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors
The instant invention is directed to chemokine receptor modulators, e.g., antagonists, and their use as medicinal agents. The present invention further relates to novel compounds and medical methods of treatment of inflammation, and other disorders especially those associated with lymphocyte or monocyte accumulation such as rheumatoid arthritis, lupus, graft versus host diseases and/or transplant rejection. More particularly, the present invention relates to 3-cycloalkylaminopyrrolidine derivatives and their use as modulators of chemokine receptors. More specifically, the instant invention relates to new anti-inflammatory and immunomodulatory bioactive compounds and pharmaceutical compositions thereof that act via antagonism of the CCR2 receptor, (also known as the MCP-1 receptor), and therefore leading to the inhibition of Monocyte Chemoattractant Protein-1 (MCP-1). The new compounds are 3-cycloalkylaminopyrrolidine derivatives. The invention further relates to novel compounds for use in the compositions, to processes for their preparation, to intermediates useful in their preparation and to their use as therapeutic agents. The chemokine receptor modulators/antagonists of the invention may be effective as therapeutic agents and/or preventive agents for diseases such as atherosclerosis, asthma, pulmonary fibrosis, myocarditis, ulcerative colitis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, lupus, systemic lupus erythematosus, hepatitis, pancreatitis, sarcoidosis, organ transplantation, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis in which tissue infiltration of blood leukocytes, such as monocytes and lymphocytes, play a major role in the initiation, progression or maintenance of the disease. The present invention also provides immunomodulatory bioactive compounds and pharmaceutical compositions thereof that act via antagonism of the CCR5 receptor. The migration and transport of leukocytes from blood vessels into diseased tissues appears to be a critical component to the initiation of normal disease-fighting inflammatory responses. The process, also known as leukocyte recruitment, is also related to the onset and progression of life-threatening inflammatory, as well as debilitating autoimmune diseases. The resulting pathology of these diseases derives from the attack of the body's immune system defenses on normal tissues. Accordingly, preventing and blocking leukocyte recruitment to target tissues in inflammatory and autoimmune disease would be a highly effective approach to therapeutic intervention. The different classes of leukocyte cells that are involved in cellular immune responses include monocytes, lymphocytes, neutrophils, eosinophils and basophils. In most cases, lymphocytes are the leukocyte class that initiates, coordinates, and maintains chronic inflammatory responses, and thus are generally the most important class of cells to block from entering inflammatory sites. Lymphocytes attract monocytes to the tissue sites, which, collectively with lymphocytes, are responsible for most of the actual tissue damage that occurs in inflammatory disease. Infiltration of the lymphocytes and/or monocytes is known to lead to a wide range of chronic, autoimmune diseases, and also organ transplant rejection. These diseases include, but are not limited to, rheumatoid arthritis, chronic contact dermatitis, inflammatory bowel disease, lupus, systemic lupus erythematosus, multiple sclerosis, atherosclerosis, psoriasis, sarcoidosis, idiopathic pulmonary fibrosis, dermatomyositis, skin pemphigoid and related diseases, (e.g., pemphigus vulgaris, p. foliacious, p. erythematosis), glomerulonephritides, vasculitides, hepatitis, diabetes, allograft rejection, and graft-versushost disease. The process, by which leukocytes leave the bloodstream and accumulate at inflammatory sites, and start a disease, has at least three steps which have been described as (1) rolling, (2) activation/firm adhesion and (3) transendothelial migration [ Chemotactic cytokines (leukocyte chemoattractant/activating factors) also known as chemokines, also known as intercrines and SIS cytokines are a group of inflammatory/ immunomodulatory polypeptide factors, of molecular weight 6-15 kDa, that are released by a wide variety of cells such as macrophages, monocytes, eosinophils, neutrophiles, fibroblasts, vascular endotherial cells, smooth muscle cells, and mast cells, at inflammatory sites (reviewed in MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic and activating factor) or JE) is a CC chemokine produced by monocytes/macrophages, smooth muscle cells, fibroblasts, and vascular endothelial cells and causes cell migration and cell adhesion of monocytes (see for example The published literature indicate that chemokines such as MCP-1 and MIP-1α attract monocytes and lymphocytes to disease sites and mediate their activation and thus are thought to be intimately involved in the initiation, progression and maintenance of diseases deeply involving monocytes and lymphocytes, such as atherosclerosis, restenosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, and sepsis (see for example The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Genes encoding receptors of specific chemokines have been cloned, and it is now known that these receptors are G protein-coupled seven-transmembrane receptors present on various leukocyte populations. So far, at least five CXC chemokine receptors (CXCR1-CXCR5) and eight CC chemokine receptors (CCR1-CCR8) have been identified. For example IL-8 is a ligand for CXCR1 and CXCR2, MIP-1α is that for CCR1 and CCR5, and MCP-1 is that for CCR2A and CCR2B (for reference, see for example, Accordingly, drugs which inhibit the binding of chemokines such as MCP-1 and/or MIP-1α to these receptors, e.g., chemokine receptor antagonists, may be useful as pharmaceutical agents which inhibit the action of chemokines such as MCP-1 and/or MIP-1α on the target cells, but the prior art is silent regarding 3-cycloalkylaminopyrrolidine derivatives having such pharmacological effects. The identification of compounds that modulate the function of CCR2 and/or CCR5 represents an excellent drug design approach to the development of pharmacological agents for the treatment of inflammatory conditions and diseases associated with CCR2 and/or CCR5 activation, such as rheumatoid arthritis, lupus and other inflammatory diseases. The present invention provides solutions to a long felt need in the field of chemokine receptor modulators and antagonists. With the foregoing in mind, it is an object of the present invention to provide chemokine receptor antagonists and chemokine receptor modulators for treating rheumatoid arthritits. Another main object of the invention is to provide chemokine receptor antagonists and their use as medicinal agents. An additional object of the invention is to provide chemokine receptor modulators and their use as medicinal agents. A further object of the present invention is to provide 3-cycloalkylaminopyrrolidine derivatives. Another object of the invention relates to novel compounds and medical methods of treatment of inflammation. A still further object of the invention provides new anti-inflammatory and immunomodulatory bioactive compounds and pharmaceutical compositions thereof that act via antagonism of the CCR2 receptor. An additional object of the invention provides 3-cycloalkylaminopyrrolidine derivatives and their use as modulators of chemokine receptors. A still additional object of the invention provides 3-cycloalkylaminopyrrolidine derivatives and their use in treating and preventing atherosclerosis and restenosis. A further object of the invention provides 3-cycloalkylaminopyrrolidine derivatives and their use as modulators of the CCR5 receptor. Another main object of the invention provides 3-cycloalkylaminopyrrolidine bioactive compounds and pharmaceutical compositions thereof that act via antagonism of the CCR5 receptor. Other objects and embodiments of the present invention will be discussed below. In its broadest sense, the invention pertains to subject-matter as defined in the claims. The invention pertains to a compound selected from the group consisting of: The invention also pertains to a compound N-[2-((3 The invention also pertains to compositions comprising said compounds, or their pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier. The invention further pertains to use of said compounds, or their pharmaceutically acceptable salts, for the manufacture of a medicament for treating inflammation, rheumatoid arthritis, atherosclerosis, neuropathic pain, lupus, systemic lupus erythematosus, restenosis, immune disorders, or transplant rejection in a mammal, modulating chemokine receptor activity in a mammal, treating a CCR2-mediated condition or disease in a subject, treating a CCR5-mediated condition or disease in a subject, treating a disease associated with expression or activity of a chemokine receptor in a patient, or treating HIV infection in a patient. The instant disclosure is directed to a compound of the formula 1: including its enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures thereof, prodrugs, crystalline forms, non-crystalline forms, amorphous forms thereof, solvates thereof, metabolites thereof, and pharmaceutically acceptable salts, wherein: In a further embodiment, the disclosure relates to a compound of the formula II: including its enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures thereof, prodrugs, crystalline forms, non-crystalline forms, amorphous forms thereof, solvates thereof, metabolites thereof, and pharmaceutically acceptable salts, wherein constituent variables are provided hereinabove. In some embodiments, X can be selected from aryl, mono or poly substituted aryl, heterocycle, heteroaryl, mono or poly substituted heteroaryl, carbocycle, mono or poly substituted carbocycle, and (CR8R9) In some embodiments, X is a bond, heterocycle, mono or poly substituted heterocycle, heteroaryl, mono or poly substituted heteroaryl, or (CR8R9) In some embodiments, X is a heterocycle, mono or poly substituted heterocycle, heteroaryl, or mono or poly substituted heteroaryl. In some embodiments, X is (CR8R9) In some embodiments, X is CH2. In some embodiments, Y is a bond or -alkyl-O-alkyl-. In some embodiments, -X-Y- is -(CR8R9) In some embodiments, -X-Y- is -CH2-NH-CO-, -CH2-O-CH2-, azetidine, pyrrolidine, piperidine, imidazole, or 4,5-dihydroisoxazole. In some embodiments, -X-Y- is -CH2-NH-CO-. In some embodiments, Z is aryl or heteroaryl, each substituted with 0-3 R10 substituents. In some embodiments, Z is 6-memebered aryl or 6-membered heteroaryl, each substituted with 0-3 R10 substituents. In some embodiments, Z is phenyl, pyridyl or pyrimidinyl, each substituted with 0-3 R10 substituents. In some embodiments, Z is phenyl, pyridyl or pyrimidinyl, each substituted with at least one mono-, di- or tri-haloalkyl. In some embodiments, Z is: In some embodiments, Z is: In some embodiments, the carbocycle substituent of R1 is intended to include, for example, cycloalkyl of 3-10 carbon atoms, and bicyclic and multicyclic bridged systems such as norbornanyl, adamantyl and bicyclo[2.2.2]octyl. The carbocycle of R1 may also be further substituted with a heterocycle or heteroaryl ring such as pyridyl, pyrrolidinyl, and all those defined under X above. Specific examples of R1 substituents include phenyl, pyridin-2-yl, 4-methylphenyl, 3-methyl-phenyl, 2-methylphenyl, 4-bromophenyl, 3-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 3-pyridyl, 4-pyridyl, 2-methoxy-5-pyridyl, 2-ethoxy-5-pyridyl, 3,4-methylenedioxyphenyl, 4-fluorophenyl, 3-trifluoromethyl-1H-pyrazol-1-yl, 3-fluorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, pyridin-4-yl, pyridin-3-yl, 5-methylpyridin-2-yl, 6-methylpyridin-2-yl, quinolin-4-yl, 3-methyl-1H-pyrazol-1-yl, 3,5-dimethyl-1H-pyrazol-1-yl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3,4-methylene-dioxyphenyl, 4-cyanophenyl, 4-(methylaminocarbonyl)phenyl, 1-oxidopyridin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-methylpyridin-2-yl, 5-methyl-pyridin-2-yl, 6-methylpyridin-2-yl, 6-methoxypyridin-2-yl, 6-methoxypyridin-3-yl, 6-methylpyridin-3-yl, 6-ethylpyridin-3-yl, 6-isopropylpyridin-3-yl, 6-cyclopropylpyridin-3-yl, 1-oxidopyridin-3-yl, 1-oxidopyridin-2-yl, 3-cyanophenyl, 3-(methylaminocarbonyl)-phenyl, 4-(morpholin-4-ylcarbonyl)-phenyl, 5-(morpholin-4-ylcarbonyl)pyridin-2-yl, 6-(morpholin-4-ylcarbonyl)pyridin-3-yl, 4-(4-methylpiperazin-1-yl-carbonyl)phenyl, 6-(azetin-1-yl)pyridin-3-yl, 5-cyanopyridin-2-yl, 6-cyanopyridin-3-yl, 5-(methoxy-methyl)pyridin-2-yl, 5-(1-hydroxy-1-methylethyl)pyridin-2-yl, 5-dimethylaminomethyl, 4-ethylaminocarbonylphenyl, 4-isopropylaminocarbonylphenyl, 4- In some embodiments, R1 is aryl or heteroaryl, each substituted with 0-3 R1a. In some embodiments, R1 is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or thiazolyl, each substituted with 0-3 R1a. In some embodiments, R1 is aryl or heteroaryl, each substituted with 0-3 R1a alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, mono- or di-substituted aminoalkyl, aminocarbonyl, mono- or di-substituted aminocarbonyl, cyclic aminocarbonyl, alkylcarbonyl, formyl, carboxylic acid, carbamate, mono- or di-substituted carbamate, R1b-aryl or R1b-heteroaryl. In some embodiments, R1 is aryl or heteroaryl, each substituted with 0-1 R1b-aryl or R1b-heteroaryl. In some embodiments, R1 is aryl or heteroaryl, each substituted with phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, or imidazolyl. In some embodiments, R1 is heteroaryl substituted with phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, or imidazolyl. In some embodiments, the R2 group can be selected from H, amino, mono- or di-substituted amino, OH, carboxyl, esterified carboxyl, carboxamide, N(C1-C5)-monosusbstituted carboxamide, and N(C1-C5), N(C1-C5)-disubstituted carboxamide, cyano, (C1-C8)alkyl, (C2-C8)-alkenyl, (C2-C8)alkynyl, (C5-C7)-cycloalkyl, (C5-C7)-cycloalkenyl, alkoxy, alkoxyalkyl, thioalkyl, mono-, di- or trihaloalkyl, halogen, aryl or heteroaryl. In some embodiments, R2 is H or OH. In some embodiments, R2 is OH. In some embodiments, R1 is aryl or heteroaryl, each substituted with 0-1 R1b-aryl or R1b-heteroaryl; and R2 is OH. In some embodiments, the R3 and R4 group susbtituents can be independently selected form the group consisting of: H, amino, OH, (C1-C8)alkyl, halo(C1-C5)alkyl, dihalo(C1-C3)alkyl, trihalo(C1-C5)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (C1-C5)alkoxy and thio(C1-C5)alkyl. In some embodiments, R3 and R4 are both H. In some embodiments, the R5 substituent can be independently selected from hydrogen, (C1-C8)alkyl, formyl; and when R5 is alkyl, the nitrogen may optionally be in the N-oxide form. In some embodiments, R5 is H. In some embodiments, the R6 and R7 substituents are each independently selected from the group consisting of H, C1-C10 alkyl, optionally C1-C10 alkyl can be interrupted by oxygen, nitrogen or sulfur, carbocycle, heterocycle, alkoxy, mono-, di- or tri-haloalkyl, mono-, di- or tri-haloalkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, arylalkoxyalkyl or heteroarylalkoxyalkyl; aryl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyloxyalkyl, heterocycloalkyloxyalkyl, aminoalkyl, mono- or di-substituted aminoalkyl, arylaminoalkyl, heteroarylaminoalkyl, alkylthioalkyl, cycloalkylthioalkyl, heterocycloalkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkylsulfonylalkyl, cycloalkylsulfonylalkyl, heterocycloalkylsulfonylalkyl, arylsulfonylalkyl, heteroarylsulfonylalkyl, aminocarbonyl, mono- or di-substituted aminocarbonyl, aminocarbonylalkyl, mono- or di-substituted aminocarbonylalkyl, alkylcarbonylalkyl, cycloalkylcarbonylalkyl, heterocycloalkylcarbonylalkyl, alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl, arylsulfonylaminoalkyl, and heteroarylsulfonylaminoalkyl. Specific examples of R6 and R7 substituents are the same as those defined for R1 above. In some embodiments, R6 and R7 are independently selected from H, C1-C10 alkyl, hydroxyalkyl, and alkoxyalkyl. In some embodiments, one of R6 and R7 is H and the other is H, C1-C10 alkyl, hydroxyalkyl, or alkoxyalkyl. In some embodiments, R6 and R7 are both H. In some embodiments, the R8 and R9 substituents are independently selected from the group consisting of H, OH, amino, (C1-C8)-alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, (C1-C8)-alkoxy, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)alkoxyalkyl, mono(C1-C8)- or di(C1-C8)-substituted amino, a carbocycle, and a heterocycle. When R8 and R9 are cyclized to form a 3-7 membered carbocycle or heterocycle, such groups can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclcopentyl, isoxazolyl thiazolyl, dihydrooxazolyl, pyridyl, pyrimidyl, or imidazolyl. In some embodiments, R8 and R9 are both H. In some embodiments, r is 0, 1, 2, or 3. In further embodiments, r is 1. In some embodiments: In some embodiments: In some embodiments: In some embodiments: At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the Markush group defined for R. It is further appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. The term aryl groups is intended to include aromatic carbocylic groups such as phenyl, biphenylyl, indenyl, naphthyl as well as aromatic carbocycles fued to a heterocycle such as benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazole, benzooxazole, benzimidazole, isoquinolinyl, isoindolyl, benzotriazole, indazole, and acridinyl. The term heteroaryl is intended to include mono- and poly-cyclic aromatic rings containing from 3 to 20, preferably from 4 to 10 ring atoms, at least one of which is a heteroatom such as oxygen, sulphur, phosphorus or nitrogen. Examples of such groups include furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, iosquinolinyl, quinoxalinyl, benzthiazolyl, benzoxazolyl, benzothienyl or benzofuryl. The terms "cyclic alkyl," "cycloalkyl," and "carbocycle" are used interchangably herein to refer to non-aromatic, cyclized hydrocarbons (mono and polycyclic) such as cyclized alkyl, alkenyl, or alkynyl groups. In some embodiments, the cycloalkyl group is C314, C3-10, C3-8, C3-7, C3-6, or C3-5. In some embodiments, cycloalkyl moieties each have from 3 to 14, from 3 to 10, or from 3 to 7 ring-forming carbon atoms. In some embodiments, the cycloalkyl group has 0, 1 or 2 double or triple bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, etc. In the present application, cycloalkyl is also intended to include bridged cyclic hydrocarbons such as adamantyl groups and the like. Heterocycles are non-aromatic carbocyclic rings (mono or polycyclic) which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring. In some embodiments, the ring can be three, four, five, six, seven or eight-membered. In some embodiments, the heterocycle contains 1, 2 or 3 heteroatoms. Heterocycles can be saturated or unsaturated. In some embodiments, heterocycles contain 0, 1 or 2 double bonds or triple bonds. Ring-forming carbon atoms and heteroatoms can also bear oxo or sulfide substituents (e.g., CO, CS, SO, SO2, NO, etc.). Examples of heterocycles include tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, thiomorpholino, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyrane, dioxane, and thiazolidinyl. Additionally, when the heteroaryl or heterocyclic groups are nitrogen containing heterocycles, the nitrogen may be modified to exist in the form of the N→O (N oxides) and such oxides are intended to be included within the scope of the instant disclosure. In the cases of sulfur containing heterocycles, the sulfur oxides are also intended to be included within the scope of the present disclosure. Monosubstituted aryl refers to an aryl group having one substituent. Polysubstituted aryl refers to aryl having 2 or more substitutents (such as 2-4 substituents). Monosubstituted heteroaryl refers to a heteroaryl group having one substituent. Polysubstituted heteroaryl refers to heteroaryl having 2 or more substitutents (such as 2-4 substituents). Monosubstituted cycloalkyl (or carbocycle) refers to a cycloalkyl group having one substituent. Polysubstituted cycloalkyl (or carbocycle) refers to cycloalkyl having 2 or more substitutents (such as 2-4 substituents). Monosubstituted heterocycle refers to a heterocycle having one substituent. Polysubstituted heterocycle refers to heterocycle having 2 or more substitutents (such as 2-4 substituents). The substituents on the aryl groups, arylalkyl groups, heteroaryl groups, heteroarylalkyl groups, carbocycle (cycloalkyl) groups and heterocyclic groups of the invention can be selected from the group consisting of halogen, alkyl, alkoxy, monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, thioalkyl and monohaloalkyl, dihaloalkyl, trihaloalkyl, nitro, amino, carboxyl, esterified carboxyl, carboxamide, thiocarboxamido and cyano. More in particular, the substituents can also be selected from the group consisting of trifluoromethyl, C1-4 alkyl, halo, trifluoromethoxy, fluoromethoxy, difluoromethoxy, C1-5 alkoxy, C1-5 alkanoyl, C1-5 alkanoyloxy, C1-5 alkylamino, di(C1-5 alkyl)-amino, C1-5 alkanoylamino, nitro, carboxy, carbamoyl, C1-5 alkoxycarbonyl, thiol, C1-5, sulphon-amido, carbamoyl C1-5 alkyl, N-(C1-5 alkyl)carbamoyl C1-5 alkyl, N-(C1-5 alkyl)2 carbamoyl- C1-5 alkyl, hydroxy C1-5 alkyl, and C1-5 alkoxy C1-4 alkyl. The terms halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine. Similarly, terms such as haloalkyl, are meant to include monohaloalkyl and polyhaloalkyl. For example, the term haloalkyl, such as halo(C1-C4)alkyl, is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term alkyl when used either alone or as a suffix includes straight chain and branched structures such as primary alkyl groups, secondary alkyl groups and tertiary alkyl groups. These groups may contain up to 15, preferably up to 8 and more preferably up to 4 carbon atoms. In some embodiments, the alkyl group is C1-10, C1-8, C1-6, C1-5, C1-4, or C1-3. Examples of alkyl radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, and sec-butyl. Similarly the terms alkenyl and alkynyl refer to unsaturated straight or branched structures containing for example from 2 to 12, preferably from 2 to 6 carbon atoms. In some embodiments, the alkenyl or alkynyl group is C2-10, C2-8, C2-6, C2-5, C2-4, or C2-3. Examples of alkenyl and alkynyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. Aralkyl or arylalkyl is meant to refer to an alkyl group substituted by an aryl group. An example arylalkyl group is benzyl. Arylalkenyl refers to an alkenyl group substituted by aryl. Arylalkynyl refers to an alkynyl group substituted by an aryl group. Heteroarylalkyl is meant to refer to an alkyl group substituted by heteroaryl. Heteroarylalkenyl refers to an akenyl group substituted by a heteroaryl. Heteroarylalkynyl refers to an alkynyl group substituted by heteroaryl. Heterocycloalkyl or heterocyclicalkyl is meant to refer to an alkyl group substituted by a heterocycle. Cycloalkylalkyl or cyclic alkyl alkyl is meant to refer to an alkyl group substituted by a cycloalkyl group. Examples of cycloalkylalkyl groups include (cyclohexyl)methyl, cyclopropylmethyl, and the like. The terms alkoxy, alkylamino and alkylthio (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Therefore, terms such as alkoxy and thioalkyl comprise alkyl moieties as defined above, attached to the appropriate functionality. Other suitable substituents which can be used in the many carbon rings of the present invention such as cycloaliphatic, aromatic, non-aromatic heterocyclic ring or benzyl group include, for example, -OH, halogen (-Br, -Cl, -I and -F) -O(aliphatic, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, aromatic or substituted aromatic group), -CN, -NO2, -COOH, -NH2, -NH(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, aromatic or substituted aromatic group), -N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, aromatic or substituted aromatic group)2, -COO(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, aromatic or substituted aromatic group), -CONH2, -CONH(aliphatic, substituted aliphatic group, benzyl, substituted benzyl, phenyl, substituted phenyl, aromatic or substituted aromatic group)), -SH, -S(aliphatic, substituted aliphatic, benzyl, substituted benzyl, phenyl, substituted phenyl, aromatic or substituted aromatic group) and -NH-C=NH)-NH2. A substituted non-aromatic heterocyclic ring, benzylic group or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent. A substituted alkyl or aliphatic group can also have a non-aromatic heterocyclic ring, benzyl, substituted benzyl, aromatic or substituted aromatic group as a substituent. A substituted non-aromatic heterocyclic ring can also have =O, =S, =NH or =N(aliphatic, aromatic or substituted aromatic group) as a substituent. A substituted aliphatic, substituted aromatic, substituted non-aromatic heterocyclic ring or substituted benzyl group can have more than one substituent. For bivalent moieties such as X and Y, the term "amide bond" refers to -NHCO-; the term "thiamide bond" refers to -NHCS-; the term "sulfonamide" refers to -NHSO2-; the term "ketone" refers to -OC-; the term "oxime" refers to -C(=N-OH)-; and the term "urea" refers to -NHCONH-. "Cyclic alkoxy" refers to -O-(cycloalkyl). "Heterocyclic alkoxy" refers to -O-(heterocycle). "Alkoxyalkyl" refers to alkyl substituted by alkoxy. "Cyclicalkoxyalkyl" refers to alkyl substituted by -O-(cycloalkyl). "Heterocyclic alkoxy alkyl" refers to alkyl substituted by -O-(heterocycle). "Alkylthioalkyl" refers to alkyl substituted by thioalkyl. "Cyclic alkyl thioalkyl" refers to alkyl substituted by -S-(cycloalkyl). "Heterocyclic alkyl thioalkyl" refers to alkyl substituted by -S-(heterocycle). "Mono- or di-substituted amino" refers to -NH2 wherein either one (e.g., mono) or both (e.g., di) hydrogens are replaced with a substituent such as C1-8 alkyl, OH, CO-(C1-4 alkyl), etc. "Mono- or di-substituted aminoalkyl" refers to alkyl substituted by mono or di-substituted amino. "Esterified carboxyl" refers to COOH where the hydrogen atom is replaced by a substituent such as C1-8 alkyl, carbocycle, heterocycle, aryl or heteroaryl. "Carboxamido" refers to -CONH2. "Mono or di-substituted carboxamide" refers to -CONH2 wherein either one (e.g., mono) or both (e.g., di) hydrogens are replaced with a substituent such as C1-8 alkyl, OH, CO-(C1-4 alkyl), etc. "Carbamate" refers to -OCONH2 and "mono or di-substituted carbamate" refers to-OCONH2 where either one (e.g., mono) or both (e.g., di) hydrogens are replaced with a substituent such as C1-8 alkyl, OH, CO-(C1-4 alkyl), etc. "Sulfonamide" refers to -SO2NH2 and "mono or di-substituted sulfonamide" refers to -SO2NH2 wherein either one (e.g., mono) or both (e.g., di) hydrogens are replaced with a substituent such as C1-8 alkyl, OH, CO-(C1-4 alkyl), etc. "Alkylsulfonyl" refers to -SO2-(alkyl). "Cyclic alkylsulfonyl" refers to -SO2-(carbocycle). "Hetercyclic sulfonyl" refers to -SO2-(heterocycle). "Aryl sulfonyl" refers to-SO2-(aryl). "Heteroaryl sulfonyl" refers to -SO2-(heteroaryl). "Alkylcarbonyl" refers to-CO-(alkyl). "Cyclic alkylcarbonyl" refers to -CO-(cycloalkyl). "Heterocyclic alkylcarbonyl" refers to -CO-(heterocycle). "Arylcarbonyl" refers to -CO-(aryl). "Heteroarylcarbonyl" refers to -CO-(heteroaryl). "Thiocarboxamido" refers to -CSNH2. "Arylaminocarbonyl" refers to -CO-NH-(aryl). "Heteroarylaminocarbonyl" refers to -CO-NH-(heteroaryl). "Arylcarboxamido" refers to -CO-NH-(aryl). "Heteroarylcarboxamido" refers to -CO-NH-(heteroaryl). "Arylureido" referst to ureido substituted by aryl. "Heteroarylureido" refers to ureido substituted by heteroaryl. "Aryloxy" refers to -O-(aryl). "Heteroaryloxy" refers to-O-(heteroaryl). "Arylalkoxy" refers to alkoxy substituted by aryl. "Heteroarylalkoxy" refers to alkoxy substituted by heteroaryl. "Arylamino" refers to -NH-(aryl). "Heteroarylamino" refers to -NH-(heteroaryl). "Hydroxylalkyl" refers to alkyl substituted by hydroxyl (OH). "Aminocarbonylalkyl" refers to alkyl substituted by aminocarbonyl. "Mono- or di-substituted aminocarbonlyalkyl" refers to alkyl substituted by mono- or di-substituted aminocarbonyl. "Alkylcarbonlyalkyl" refers to alkyl substituted by alkylcarbonyl. "Cycloalkylcarbonylalkyl" refers to alkyl substituted by -CO-(cycloalkyl). "Heterocycloalkylcarbonylalkyl" refers to alkyl substituted by -CO-(heterocyle). "Alkylcarbonylaminoalkyl" refers to alkyl substituted by -NH-CO-(alkyl). "Cycloalkylcarbonylaminoalkyl" refers to alkyl substituted by -NH-CO-(cycloalkyl). "Heterocycloalkylcarbonylaminoalkyl" refers to alkyl substituted by -NH-CO-(heterocycle). "Arylcarbonylaminoalkyl" refers to alkyl substituted by -NH-CO-(aryl). "Heteroarylcarbonylaminoalkyl" refers to alkyl substituted by -NH-CO-(heteroaryl). "Arylsulfonylaminoalkyl" refers to alkyl substituted by -NH-SO2-(aryl). "Heteroaylsulfonylaminoalkyl" refers to alkyl substituted by -NH-SO2-(heteroaryl). "Spirocycle" refers to a cycloalkyl group sharing one of its ring-forming atoms with another cycloalkyl or heterocyclyl group. "Spiroheterocycle" refers to a heterocycle group sharing one of its ring-forming atoms with another cycloalkyl or heterocyclyl group. The phrase "optionally R3 and R4 can be cyclized to form a bridged bicyclic system having a methylene group or an ethylene group or a heteroatom selected form the group consisting of N, O and S" refers to when R3 and R4, residing on different atoms, together form a divalent bridging moiety such as, for example, methylene, ethylene, NH, O, S, methylene-O, methylene-S, or methylene-NH. Unless otherwise indicated, the compounds provided in the above formula are meant to include pharmaceutically acceptable salts, prodrugs thereof, enantiomers, diastereomers, racemic mixtures thereof, crystalline forms, non-crystalline forms, amorphous forms thereof and solvates thereof. The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present invention may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Lists of suitable salts are found in The neutral forms of the compounds of the present invention may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. As noted above, some of the compounds of the present disclosure possess chiral or asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual optical isomers are all intended to be encompassed within the scope of the present disclosure. Some of the compounds of formula I or II can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are substantially equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. In addition to salt forms, the present invention provides compounds that may be in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an Compounds of the disclosure including salts, hydrates, and solvates thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the disclosure can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. A variety of 4,4-disubstituted cyclohexanone derivatives can be synthesized using the protocols described in Schemes 1. Compounds of formula 1-2 can be prepared by addition of arylMgX or ArX/BuLi to 1,4-cyclohexanedione 1-1. Alternatively, compounds of formula 1-2 can be prepared by treatment of 1,4-cyclohexanedione 4-Arylcyclohexanone derivatives of formula 2-3 can be synthesized following the procedures shown in Scheme 2. The intermediate 1-4 is subjected to a treatment with a dehydrating agent such as thionyl chloride/pyridine followed by reduction of the resulting olefin by hydrogenation using a catalyst such as Pd-C or PtO2. Conversion of the ketal in 2-2 by treatment with an acid provides the ketones of formula 2-3. Alternatively, compounds of formula 2-3 can be synthesized according to Scheme 3. Reduction of ketone 1-3 using a reducing agent such as sodium borohydride produces the alcohol 3-1 which is converted to a mesylate 3-2 by treating with methanesulfonyl chloride. Displacement of the mesylate 3-2 with a heterocycle such as pyrazole, imidazole, triazole or tetrazole provides the intermediate 2-2 which is converted to compounds of formula 2-3 by treatment with an acid such as HCl. Introduction of a substituent on the aromatic ring in ketones of formula 1-2 or 2-3 can be accomplished starting from the ketal intermediate 1-4 or 2-2 using the methods described in Schemes 4-8. When the aromatic ring in 1-4 or 2-2 bears a cyano group, the ketal 4-1 is subjected to a hydrolysis using a base such as sodium or potassium hydroxide to give the carboxylic acid 4-2. Coupling of 4-2 with an amine using a coupling agent such as BOP provides the amide 4-3. Treatment of 4-3 with an acid such as HCl affords the ketones of formula 4-4. When the aromatic ring in the ketal intermediate 1-4 or 2-2 bears a halide such as bromo or iodo, the halide can be transformed to a substitutent using the procedures described in Scheme 5. Treatment of 5-1 with butyl lithium followed by quenching with an electrophile such as alkyl halide, aldehyde, ketone, chloroformate, or carbonate provides the R-substituted ketal 5-2. Suzuki coupling of 5-1 with a boronic acid ArB(OH)2 (Ar=aryl or heteroaryl) or coupling of 5-1 with ArZnCl which can be generated in situ by treating ArX (X=Br, I) with butyl lithium followed by quenching with zinc chloride or treating 5-1 with iPrMgCl followed by coupling with ArX (X-Br, I) in the presence of a catalyst such as Ni(CH3COCH(OH)CH3)2-1,2-bis(diphenylphosphino)ethane provides the Ar-substituted ketal intermediate 5-4. Treatment of 5-2 and 5-4 with an acid affords their corresponding ketones 5-3 and 5-5. Alternatively, ketones of formula 5-5 can be obtained using the protocol depicted in Scheme 6. Following conversion of 5-1 to a boronic acid ester, the resulting boronic acid ester 6-1 is coupled with ArX (X=Br, I) using a palladium catalyst such as Pd(PPh3)4 to give the Ar-substituted ketal 5-4 from which ketones of formula 5-5 are obtained by treatment with an acid such as HCl. When the Ar group in ketones of formula 1-2 or 2-3 is a 2-thiazole residue, introduction of a substituent at the 5-position on the thiazole can be accomplished using the sequence outlined in Scheme 7. Treatment of thiazole 7-1 with butyl lithium followed by quenching with 1,4-cyclohexanedione mono-ethylene ketal 1-3 gives rise to the tertiary alcohol 7-2. Treatment of 7-2 with butyl lithium followed by quenching the anion 7-3 with an electrophile such as alkyl halide, aldehyde, ketone, chloroformate or carbonate produces the ketal 7-4 with an R substituent at the 5-position on thiazole. Alternatively, the anion 7-3 can be quenched with zinc chloride and the resulting intermediate is coupled with ArX (X=Br, I) using a palladium catalyst such as PdCl2(PPh3)2 to give the ketal 7-6 with an Ar residue at the 5-position on thiazole. Ketals 7-4 and 7-6 are then converted to their corresponding ketones of formula 7-5 and 7-7 by treatment with an acid such as HCl. When the Ar group in ketones of formula 1-2 or 2-3 is a 5-thiazole residue, introduction of a substituent at the 2-position on the thiazole can be accomplished using the sequence outlined in Scheme 7. Lithiation of 2-trimethylsilyl protected thiazole 8-1 followed by quenching with 1-3 gives rise to the intermediate 8-2. Following removal of the trimethylsilyl group using TBAF, lithiation of 8-3 followed by quenching with an electrophile such as alkylhalide, aldehyde, ketone, isocyanate, chloroformate or carbonate provides the 5-R-substituted thiazole derivative 8-4. Treatment of 8-4 with an acid such as HCl affords the ketones of formula 8-5. A variety of 3-aminopyrrolidine intermediates can be prepared as shown in Schemes 6-17. Coupling of a carboxylic acid of formula 9-1 with a commercially available pyrrolidine derivative of formula 9-2 using a coupling agent such as BOP gives rise to the amide 9-3. Removal of the protecting group P (P=Boc, benzyl or Cbz) using an acid such as TFA or HCl or by hydrogenation using a palladium catalyst provides the pyrrolidine intermediates of formula 9-4. 4-Amino-2-methylpyrrolidine derivatives of formula 10-8 can be prepared using the sequence described in Scheme 10. Following Boc protection at the amine and TBS protection at the hydroxyl of 4-Aminopyrrolidine derivativess of formula 11-6 can be prepared according to Scheme 11. Alkylation of the intermediate 10-2 with an alkyl halide (RX) using LHMDS provides the R-substituted intermediate 11-1. Following reduction of the ester to an alcohol using diisobutylaluminun hydride (DIBAL), the alcohol is converted to a tosylate and the resulting tosylate is reduced using LiEt3BH to give 11-2. Intermediate 11-2 is then converted to compounds of formula 11-6 in a manner similar to that described in Scheme 10. 4-Aminopyrrolidine derivatives of formula 12-5 can be synthesized using the method shown in Scheme 12. The intermediate 10-2 is reduced to an alcohol using a reducing agent such as DIBAL and the resulting alcohol is alkylated with an alkyl halide (RX) using sodium hydride to give intermediate 12-1. Using procedures similar to those described in Scheme 10, compounds of formula 12-5 are obtained from the intermediate 12-1. 4-Aminopyrrolidine derivatives of formula 13-7 can be generated according to Scheme 13. The intermediate 10-2 is reduced to an alcohol using a reducing agent such as DIBAL and the resulting alcohol is oxidized to an aldehyde using a oxidizing agent such as Swern oxidation. Addition of a Grignard reagent RMgX to the aldehyde 13-1 is followed by alkylation of the resulting alcohol with an alkyl halide (RX) using sodium hydride. After removal of the Boc and TBS protecting groups in 13-2 or 13-3 using an acid such as HCl, the resulting amine 13-4 is condensed with a carboxylic acid of formula 9-1. Mesylation at the 4-hydroxy on the pyrroldine followed by displacement of the resulting mesylate with sodium azide and reduction of the azido by hydrogenation provides compounds of formula 13-7. 4-Aminopyrrolidine derivatives of formula 14-6 can be synthesized using a protocol depicted in Scheme 14. After double addition of a Grignard reagent RMgX to the intermediate 10-2, the resulting tertiary alcohol 14-1 is subjected to an alkylation with an alkyl halide (R'X) to give 14-2. Intermediates 14-1 and 14-2 are then converted to compounds of formula 14-6 in a manner similar to that described in Scheme 13. The synthesis of 4-aminopyrrolidine derivatives of formula 15-5 is given in Scheme 15. After dehydration of the intermediate 14-1 followed by reduction of the olefin by hydrogenation, the resulting intermediate 15-1 is converted to compounds of formula 15-5 in a fashion similar to that described in Scheme 10. Compounds of formula I can be obtained by assembling the aminopyrrolidine derivatives of formula 16-1 with a ketone of formula 16-2 by reductive amination using a reducing agent such as sodium triacetoxyborohydride or through hydrogenation followed by treating the resulting secondary amine 16-3 via reductive amination with an aldehyde or by alkylation with an alkyl halide (RX). Alternatively, compounds of formula I can be prepared using a sequence outlined in Scheme 17. Reductive amination of the aminopyrrolidine derivatives of formula 17-1 with a ketone of formula 16-2 gives rise to the secondary amine 17-2. After removal of the protecting group P (P=Boc, benzyl or Cbz) using an acid or through hydrogenation using a catalyst such as Pd-C, the resulting amine 17-3 is condensed with a carboxylic acid of formula 9-1 to provide compounds of formula 17-4. Alternatively, compounds of formula I can be prepared using a sequence outlined in Scheme 18. Reduction of the cyclohexanone 1-2 with a reducing agent such as lithium aluminum hydride produces the Alternatively, compounds of formula I can be synthesized according to Scheme 19. Displacement of the mesylate 18-2 with sodium azide gives rise to the azido intermediate 19-1 which is reduced to an amine by hydrogenation using a catalyst such as Pd-C. Displacement of the mesylate of formula 19-3 with the resulting amine 19-2 or reductive amination of 19-2 with a ketone of formula 19-4 affords compounds of formula 19-5. The compounds of the present disclosure are MCP-1 receptor modulators, e.g., antagonists, and are capable of inhibiting the binding of MCP-1 to its receptor. Surprisingly, the compounds block T cell migration in vitro, and have dramatic effects on the recruitment of inflammatory cells in multiple models of inflammatory diseases. Therefore, the compounds of formula I are useful as agents for the treatment of inflammatory disease, especially those associated with lymphocyte and/or monocyte accumulation, such as arthritis, rheumatoid arthritis, multiple sclerosis, neuropathic pain, atherosclerosis and transplant rejection. In addition, these compounds can be used in the treatment of allergic hypersensitivity disorders such as asthma and allergic rhinitis characterized by basophil activation and eosinophil recruitment, as well as for the treatment of restenosis and chronic or acute immune disorders. Modulation of chemokine receptor activity, as used in the context of the present invention, is intended to encompass antagonism, agonism, partial antagonism and/or partial agonism of the activity associated with a particular chemokine receptor, preferably the CCR2 receptor. The term composition as used herein is intended to include a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The compounds of formula I of the present disclosure, and compositions thereof are useful in the modulation of chemokine receptor activity, particularly CCR2. Accordingly, the compounds of the present invention are those which inhibit at least one function or characteristic of a mammalian CCR2 protein, for example, a human CCR2 protein. The ability of a compound to inhibit such a function can be demonstrated in a binding assay (e.g., ligand binding or promotor binding), a signalling assay (e.g., activation of a mammalian G protein, induction of rapid and transient increase in the concentration of cytosolic free calcium), and/or cellular response function (e.g., stimulation of chemotaxis, exocytosis or inflammatory mediator release by leukocytes). The invention is illustrated by the following examples, which are not intended to be limiting in any way. Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parentheses). In tables, a single m/e value is reported for the M+H (or, as noted, M-H) ion containing the most common atomic isotopes. Isotope patterns correspond to the expected formula in all cases. (3-Trifluoromethyl-benzoylamino)acetic acid. To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0 °C was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0 °C for 30 min. The reaction mixture was acidified with 3 M HCl to pH = 3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL x 3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90%) was afforded. MS (M+H+) = 248.1.1H NMR (DMSO-d6) δ 12.70 (br s, 1 H), 9.17 (m, 1H), 8.20 (dd, 2H), 7.94 (dd, 1H), 7.78 (m, 1H), 3.97 (d, 2H). N-{2-[(3 8-Phenyl-1,4-dioxaspiro[4.5]decan-8-ol. To a solution of 1,4-cyclohexanone 4-Hydroxy-4-phenylcyclohexanone. The above product was dissolved in THF (50 mL). To it was added 10% HCl/H2O (50 mL). The solution was stirred at room temperature overnight and extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4 and concentrated to give the title compound as a white solid. MS (M+H)+ 191. N-(2-{(3 8-Pyridin-2-yl-1,4-dioxaspiro[4.5]decan-8-ol. To a solution of 2-bromopyridine (14 g, 88.6 mmol) in anhydrous ether (300 mL) cooled at -78 °C was slowly added a solution of 2.5 M n-butyl lithium (36 mL). After the addition, stirring was continued at -78 °C for 1 hour. To it was slowly added a solution of 1,4-cyclohexanedione mono-ethylene ketal (15 g, 96 mmol) in anhydrous ether (300 mL). When the addition was complete, the mixture was allowed to warm to 0 °C and stirring was continued for 1 hour. The reaction was quenched by the addition of an aqueous solution (100 mL) of ammonium chloride (4.5 g). The organic phase was separated and the aqueous phase was extracted with methylene chloride 4 times. The combined organic phases were dried over MgSO4 and concentrated. Crystallization from EtOAc provided 7 g of the desired product. The mother liquid was purified on silica gel eluting with 10% MeOH/EtOAc to give 3 g of the desired product. MS (M+H)+ 236.0. 4-Hydroxy-4-(pyridin-2-yl)cyclohexanone. The above product was dissolved in THF (30 mL) and a 3 N solution of HCl in water (30 mL). The mixture was stirred at 50 °C for 3 hours. After cooling to room temperature, NaHCO3 was added to the solution with stirring until no bubbling occurred. The organic phase was separated and the aqueous layer was extracted with EtOAc three times. The combined organic phase was dried over MgSO4 and concentrated. The residue was triturated with EtOAc to give 5.5 g of the title compound. MS (M+H)+ 192. N-(2-{(3 N-(2-{(3 2-Bromo-5-bromomethylpyridine. 2-Bromo-5-methylpyridine (5.00 g, 29.1 mmoles) and N-bromosuccinimide (5.22 g, 29.3 mmoles) were dissolved in carbon tetrachloride (40 mL) under nitrogen. Benzoyl peroxide (0.35 g, 1.4 mmoles) was added and the mixture heated at reflux for four hours. The mixture was cooled to room temperature, filtered, and washed with NaHCO3/H2O. The mixture was adsorbed onto silica gel and then chromatographed eluting with a gradient of hexane to 10% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired mono-brominated product as a pale yellow solid, 3.60 g (49%). LC/MS (M+H)+ m/z = 249.8, 251.8, 253.8. 2-Bromo-5-(methoxymethyl)pyridine. 2-Bromo-5-bromomethyl-pyridine, 4 (3.58 g, 14.3 mmoles) was dissolved in methanol (20 mL) under nitrogen. Sodium methoxide (0.89 g, 15.7 mmoles, 95%) was added and the mixture stirred at room temperature. After 3 hours, the methanol was rotovapped off and the residue dissolved in dichloromethane and washed with water. The organic extract was adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 20% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the title compound as a colorless oil, 2.62 g (90%). LC/MS (M+H)+ m/z = 202.0. 4-Hydroxy-4-[5-(methoxymethyl)pyridin-2-yl]cyclohexanone. A solution of 2-bromo-5-(methoxymethyl)pyridine (2.61 g, 12.9 mmoles) was dissolved in dry THF (40 mL) under nitrogen and cooled to -78 °C. N-{2-[(3 6-Bromo-pyridine-3-carbaldehyde. 2,5-Dibromopyridine 9.48 g (40 mmol) was dissolved in 60 mL of THF and 150 mL of anhydrous ether. After the solution was cooled to - 78 °C, 16 mL of n-butyllithium (2.5 M, 40 mmol) was slowly dropped through a syringe in 30 min. After being stirred at -78 °C for 30 minutes, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 30-40% EtOAc in hexane, 2.80g white solid was obtained (28% yield), MS: (M+H)+ 186.0, 188.0. 1-(6-Bromopyridin-3-yl)-N,N-dimethylmethanamine. To a solution of titanium tetraisopropoxide (6.4g, 22 mmol) and 2.0 M of dimethylamine in methanol (22 mL, 44 mmol), 6-bromo-pyridine-3-carbaldehyde (2.10 g, 11 mmol) in 20 mL of methanol was added. After being stirred at r. t. for 5 hrs, sodium borohydride (0.43g, 11 mmol) was added and the mixture was stirred overnight. The reaction was quenched by addition of 10 mL of water and extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 20-40% methanol in EtOAc and 0.5% NH4OH, 1.15g oil was obtained (47% yield), MS: (M+H)+ 214.0, 216.0. 8-{5-[(Dimethylamino)methyl]pyridin-2-yl}-1,4-dioxaspiro[4,5]decan-8-ol. 1-(6-Bromopyridin-3-yl)-N,N-dimethylmethanamine (1.15 g, 5.4 mmol) was dissolved in 30 mL of THF and 80 mL of anhydrous ether. After the solution was cooled to - 78 °C, 2.60 mL of 4-{5-[(Dimethylamino)methyl]pyridin-2-yl}-4-hydroxycyclohexanone. 8-{5-[(Dimethylamino)methyl]pyridin-2-yl}-1,4-dioxaspiro[4,5]decan-8-ol (0.85 g, 2.9 mmol) was dissolved in 10 mL of THF and 10 mL of 2 N HCl solution was added. After being stirred for two hours, the reaction mixture was neutralized to pH∼8-9 by addition of a saturated NaHCO3 aqueous solution and extracted twice using EtOAc. The combined extracts were dried and concentrated to obtain 0.37 g white solid (51% yield), MS: (M+H)+ 249.2. N-(2-{(3 The following Examples 6-13 were prepared in a fashion similar to the previous 5 examples. 8-(1,3-Thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol. A solution of n-butyllithium (8.1 mL of 1.6 M solution in hexane, 12.92 mmol) was added to thiazole (1.0 g, 11.75 mmol) in THF (10 mL) at -78 ° C with stirring under N2. After being stirred at -78 °C for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (1.84 g, 11.75 mmol)in THF (10 mL) was added to the lithiated compound solution via syringe and stirred for 3 h at -78 ° C. Water (5 mL) was added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3 ×). The combined organic layers were dried (MgSO4), filtered, concentrated 8-(5-Methyl-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol. A solution of 4-Hydroxy-4-(5-methyl-1,3-thiazol-2-yl)cyclohexanone. A solution of 8-(5-Methyl-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.0 g, 4.14 mmol) in 20 mL of THF/3 N HCl (1:1) was stirred for 1 h at 50 °C. After cooling to room temperature, the mixture was treated with Na2CO3 to pH 8 and extracted with EtOAc (3 ×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.82 g of 4-hydroxy-4-(5-methyl-1,3-thiazol-2-yl)cyclohexanone in 99% yield. MS (EI) (M+H)+= 212.2. 3-(Trifluoromethyl)-N-[2-((3 The following Examples 15-16 were prepared in a fashion similar to Example 14. 2-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole-4-carboxylic acid. A solution of n-butyllithium (17.1 mL of 1.6 M solution in hexane, 27.35 mmol) was added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.00 g, 12.43 mmol) in THF (50 mL) at-78 ° C with stirring under N2. After being stirred at -78 ° C for 1 h, dry ice (10 g, 227 mmol) was added to the lithiated compound solution and stirred for 2 h at -78 ° C. Water was added and the solution was warmed to room temperature. The mixture was then treated with 1N HCl to pH 3 to 4 and extracted with EtOAc (3 x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated and chromatographed (EtOAc to 1% AcOH/EtOAc) to give 3.23 g of 2-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole-4-carboxylic acid. MS (EI) (M+H)+ = 286.0. 2-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-N-methyl-1,3-thiazole-4-carboxamide. To a stirred solution of 2-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole-4-carboxylic acid (0.30 g, 1.05 mmol) and methylamine (2M in THF, 2 mL, 4 mmol)in CH2Cl2 (10 mL) was added Et3N (0.5 mL, 3.6 mmol) followed by EDC (0.242 g, 1.262 mmol) and HOBt (0.193 g, 1.26 mmol). The mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3 and brine. The organic layer was dried (MgSO4), concentrated and flash chromatographed (50% EtOAc/hexanes) to give 0.16 g of the title compound in 50% yield. MS (EI) (M+H)+ = 299.0. 2-(1-Hydroxy-4-oxocyclohexyl)-N-methyl-1,3-thiazole-4-carboxamide. The title compound was prepared by conversion of the ketal of step B to a ketone using a procedure similar to that described in step C of Example 14. MS (EI) (M+H)+ = 255.0. 2-(1-Hydroxy-4-{[(3 The following Examples 18-19 were prepared in fashion similar to Example 17. N-{2-[(3S)-3-({4-Hydroxy-4-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]cyclohexyl}-amino)pyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide. MS (EI): (M+H)+ 594.1. 8-(1,3-Thiazol-5-yl)-1,4-dioxaspiro[4,5]decan-8-ol. 2-TMS-thiazole (2.5 g, 15.89 mmol) was added to a solution of n-butyllithium (11.9 mL of 1.6 M solution in hexane, 19.07 mmol) in THF (20 mL) at -78 ° C with stirring under N2. After being stirred at -78 ° C for 0.5 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (2.48 g, 15.89 mmol) in THF (20 mL) was added to the lithiated compound solution via syringe and stirred for 1 h at -78 ° C. Water (5 mL) and EtOAc were added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3 x). The combined organic layers were dried (MgSO4), filtered, and crystallized from EtOAc to yield 3.4 g of 8-(1,3-thiazol-5-yl)-1,4-dioxaspiro[4,5]decan-8-ol in 90% yield. MS (EI) (M+H)+ = 242.1. A solution of 3-(Trifluoromethyl)-N-{2-[(3 The following Examples 21-23 were prepared in fashion similar to Example 20. 8-(5-Pyridin-3-yl-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol. A solution of N-[2-(3 N-[2-({(3 8-Pyridazin-3-yl-1,4-dioxaspiro[4.5]decan-8-ol. To a solution of pyridazine (17.7 mmol), 1.28 mL) in THF (60 mL) was added lithium 2,2,6,6-tetramethylpiperidine (71 mmol, 10 g) at -78 °C. The reaction was then stirred for 6 min and 1,4-dioxa-spiro[4.5]decan-8-one (71 mmol, 11 g) was added. The reaction was stirred for 5 h at -78 °C at which point the reaction was quenched using a solution of ethanol, hydrochloric acid and THF (30 mL, 1:1:1). The resulting solution was extracted using EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified using flash chromatography to afford the desired alcohol (44%, 1.84 g). MS (M+H)+ 237.1. 4-Hydroxy-4-pyridazin-3-ylcyclohexanone. To the product from step A (7.79 mmol, 1.84 g) in THF (15 mL) was added HCl (45 mmoi, 15 mL). The reaction was stirred overnight and subsequently quenched using Na2CO3. The solution was then extracted using EtOAc (3 x 100 mL). The organic layers were combined, dried and concentrated N-(2-{(3 N-(2-{(3 8-Pyrimidin-2-yl-1,4-dioxa-spiro[4. 5]decan-8-ol (1a). To a solution of 2-bromopyrimidine (0.20 g, 1.258 mmol) in dry methylene chloride (3.0 mL) was dropwise added 1.6 M of n-butyllithium in hexane (0.86 mL) at -78 °C. The reaction mixture was stirred for 29 min at -78 °C and 1,4-dioxa-spiro[4.5]decan-8-one (0.196 g, 1.26 mmol) in CH2Cl2 (3 mL) was added dropwise. The reaction was stirred at -78 °C for 50 min and quenched with an aqueous solution of NH4Cl. After being warmed to room temperature, the mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4, filtered and concentrated 4-Hydroxy-4-pyrimidin-2-ylcyclohexanone. To the product from step A (190 mmol, 44 g) in THF (200 mL) was added HCl solution (300 mmol, 100 mL). The reaction was stirred over 2 days after which the reaction was washed using diethyl ether. The aqueous layer was then quenched using NaOH (50%) to obtain a pH of 11. The aqueous layer was extracted using EtOAc (6 x 300 mL). The organic layers were combined and dried over MgSO4 and concentrated N-(2-{(3 6-Bromonicotinonitrile. 6-Chloronicotinonitrile (13.8 g, 100 mmol) was heated at 145 °C in phosphorus tribromide (150 mL) for 32 h. After cooling, the mixture was concentrated 6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)nicotinonitrile. A solution of 6-bromonicotinonitrile (2 g, 11 mmol) in 50 mL of dry THF and 15 mL of dry hexane under argon was cooled to -100 °C in a liquid nitrogen-Et2O bath. 6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)nicotinic acid. A mixture of 6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)nicotinonitrile (1.9g, 7. 3 mmol) in 50 mL of 2-methoxyethanol and 50 mL of 2.5 N NaOH was heated on a steam bath for 15 h. The solution was cooled in an ice bath, adjusted to pH 7-8 with concentrated HCl, and evaporated to driness. Water (375mL) was added, and the pH was adjusted to 2 with HCl. The tan solid was filtered off and washed with water to give 1.92 g (6. 9 mmol, 94% yield) of 6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)nicotinic acid: MS: (M+H)+ 280. 6-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-N-methylnicotinamide. 6-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)nicotinic acid (560 mg, 2 mmol), methylamine (1.2 mL, 2.0 M THF solution), BOP reagent (1.07 g, 2.4 mmol) and 0.8 mL (6 mmol) of triethylamine were dissolved in 15 mL of DMF at room temperature. The reaction mixture was stirred at room temperature overnight. Direct chromatography on silica gel (flash chromatography grade) with 50% ethyl acetate-hexane gave 410 mg (70%) of the desired product, 6-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-N-methylnicotinamide: MS: (M+H)+ 293. 6-(1-Hydroxy-4-oxocyclohexyl)-N-methylnicotinamide. 6-(8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-N-methylnicotinamide (410 mg, 1.4 mmol) was dissolved in the mixture solvent of 7 mL of THF and 7 mL of 1 N HCl aqueous solution at room temperature. The reaction mixture was then stirred at 60 °C for 1 h. The solution was cooled down to room temperature, adjusted to pH 7-8 with saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted twice with EA (20 ml × 2). The combined organic extracts were dried over MgSO4 and evaporated to give an oil residue. Chromatography on silica gel (flash chromatography grade) with 40% ethyl acetate-hexane gave 410 mg (90%) of the desired product, 6-(1-hydroxy-4-oxocyclohexyl)-N-methylnicotinamide: MS: (M+H)+ 249. 6-(1-Hydroxy-4-{[(3 The following Examples 30-31 were prepared in fashion similar to Example 29. N-{2-[(3 8-(5-Bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol. To a solution of 2,5-dibromopyridine (4.10 g, 17 mmol) in anhydrous toluene (250 mL) at -78 °C was dropwise added n-BuLi (1.6 M, 12 mL). After stirred at -78 °C for 2.5 hours, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (2.73 g, 17 mmol) in methylene chloride (25 mL) was added into the reaction mixture, and the resulting mixture was stirred for additional one hour and allowed to warm up to room temperature slowly. The reaction mixture was poured into aqueous NaHCO3 (200 mL) and then extracted with EtOAc (2 × 50 mL). The organic extracts were combined, washed with saline solution (2 × 50 mL), dried over MgSO4, and concentrated in 4-(5-Bromopyridin-2-yl)-4-hydroxycyclohexanone. The title compound was prepared by treating the ketal of step A with HCl in water following the procedure described in step B of Example 2. MS (M+H)+ 271. N-[2-((3 N-{2-[(3 N-(2-(3 8-(4-Iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol. To a solution of 1,4-diiodobenzene (16.5 g, 50 mmol) in THF (350 mL) at -78 °C was added n-BuLi (2.5 M, 24 mL) over I hour. After being stirred additional 30 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (7.8 g, 50 mmol) in THF (30 mL) was added in and the resulting mixture was stirred for 3 hours. To the mixture was added TMSCl (5.4 g, 50 mmol) and the resulting mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The reaction mixture was neutralized to pH 6.0, and extracted with ethyl acetate (3 × 50 mL). The organic extracts were combined, washed with saline solution (2 × 50 mL), dried over sodium sulfate, and concentrated 8-(4-pyrimidin-2-ylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol. To a solution of 8-(4-iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (450.0 mg, 1.249 mmol) in THF (1.0 mL) at room temperature was added dropwise isopropylmagnesium chloride (2.0 M in THF, 1.37 mL) and the reaction mixture was stirred at room temperature for 30 mins. To another flask charged with nickel acetylacetonate (20 mg, 0.06 mmol) and 1,3-bis(diphenylphosphino)-propane (26 mg, 0.062 mmol) suspended in THF (3 mL) under N2 was added 2-bromopyrimidine (199 mg, 1.25 mmol). The resulting mixture was stirred at room temperature until it is clear. This mixture was transferred into the degassed Grignard solution prepared above. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, quenched with water, washed with brine, dried over Na2SO4, and concentrated. The residue was columned on silica gel, eluting with hexane/EtOAc (2/1), to gave the desired compound (270 mg, 69%) as a white solid. LCMS: 313.1, (M+H, 100%).1H NMR (CDCl3): 8 8.86 (d, 2H), 8.46 (dd, 2H), 7.71 (dd, 2H), 7.24 (t, 1H), 4.05 (d, 4H), 2.30 (dt, 2H), 2.18 (dt, 2H), 1.90 (m, 2H), 1.78 (m, 2H). 4-Hydroxy-4-(4-pyrimidin-2-ylphenyl)cyclohexanone. The title compound was prepared by treating the ketal of step B with HCl in water following the procedure described in step B of Example 2. MS (M+H)+ 269. N-[2-((3S)-3-[4-hydroxy-4-(4-pyrimidin-2-ylphenyl)cyclohexyl]aminopyrrolidin-1-yl)-2-oxoethyl]-3-(trifluoromethyl)benzamide bis(trifluoroacetate) (salt). To a 1-neck round-bottom flask charged with methylene chloride (1 mL) was added 4-hydroxy-4-(4-pyrimidin-2-ylphenyl)cyclohexanone (50.0 mg, 0.186 mmol), N-2-[(3S)-3-aminopyrrolidin-1-yl]-2-oxoethyl-3-(trifluoromethyl)benzamide hydrochloride (65.5 mg, 0.186 mmol), and triethylamine (85.7 uL, 0.615 mmol). The resulting mixture was stirred at 25 °C for 30 minutes, and to it was added sodium triacetoxyborohydride (62.4 mg, 0.28 mmol) in portion. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was chromatographed on SiO2, eluting with acetone/methanol (100% to 90%/10%) to give two fractions, which were further purified on prep-LCMS separately to afford F1 (24.2 mg) and F2 (25.9 mg) as white powder in a total of 34% yield. LCMS: 568.2 (M+H, 100%) for both isomers. The following Examples 36-37 were prepared in a similar manner. A solution of 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (168.5 g, 0.5363 mol) in THF (2000 mL) was degassed with nitrogen for 30 minutes. A 2.0 M solution of isopropylmagnesium chloride in THF (563 mL) was added dropwise over 70 mins at room temperature to the above solution. The reaction mixture(light brownish color) was stirred for 180 minutes at 25 °C. Into another flask was charged with THF (500 mL) that was degassed with nitrogen for 10 min. To it were added Nickel acetylacetonate (6.9 g, 0.027 mol) and 1,2-bis(diphenylphosphino)-ethane (11 g, 0.027 mol) under nitrogen flush, and 10 minutes later 2-iodopyrimidine (113 g, 0.536 mol). After being stirred for 30 minutes at 25 °C, the resulting light green suspension was transfered to the above solution. The reaction mixture was stirred at room temperature overnight and the reaction was found to be complete by HPLC. LC-MS: found (M+H) 314.20 for desired product. The reaction mixture was directly used for next reaction. About half of the THF in the reaction mixture from step A was removed by evaporation under reduced pressure. To the remaining reaction mixture was added a 4.00 M solution of HCl in water (900 mL), After being stirred for 1 hour, the mixture was diluted with 1000 mL water and neutralized with solid Na2CO3 to pH 8∼9. Large ammount of yellow solid precipitated out. The solid was filtered off and washed with ethyl aceate containing 1% aqueous NH4OH (about 2000 mL) untill no desired product was detected byTLC. The filtrate was partitioned and the aqueous layer was extracted with ethyl acetate (1200mL × 3). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to half of the volume. The soild precipitating out was filtered and dissolved in dichloromethane (600 mL). The resulting solution was heated to reflux for 30 minutes and filtered. The filtrate was cooled in an ice bath. The solid precipitating out was collected by filtration to give 30 g of pure product. The mother liquids from the two crystallizations were combined and evaporated. The residue was taken into acetonitrile (500 mL). The resulting solution was heated to reflux until all solid was dissolved. Once insolubles were filtered off, the filtrate was allowed to stand at room temperature and solid was precipitated out. The solid was filtered and suspended in dichloromethane (700 mL). After being heated to reflux, the solution was filtered, evaporated to half of the volume, and cooled in an ice bath. The light brownish solid precipitating out was collected by filtration to give the second batch of solid (58 g). MS (M+H) 270.2. To a solution of N-{2-[(3 The following examples were prepared in a similar manner. N-{2-[(3 3-(Trifluoromethyl)benzaldehyde oxime. To a flask containing 3-trifluorobenzaldehyde (1.74 g, 10 mmol) and hydroxylamine hydrochloride (0.76 g, 11 mmol) in methanol (25 mL) was added TEA (0.65 g, 11 mmol). The reaction mixture was heated to reflux for 3 h, neutralized to pH 6.0, and extracted with ethyl acetate (3 × 20 mL). The organic extracts were combined, washed with saline solution (20 mL), dried over sodium sulfate, concentrated 3-(Trifluoromethyl)benzaldehyde oxime. To a dried flask containing 3-(trifluoromethyl)benzaldehyde oxime (1.89 g, 10 mmol) in methylene chloride (100 mL) was added N-chlorosuccinimide (1.40 g, 10.5 mmol) slowly at 0 °C. The reaction mixture was warmed to 45 °C for 2 h, poured over ice, diluted with H2O (20 mL), and extracted with EtOAc (100 mL). The organic phase was washed with H2O (2 × 25 mL) and saline solution (25 mL), dried over sodium sulfate, concentrated Methyl 3-[3-(Trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate. To a flask containing N-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride (2.0 g, 8.9 mmol) and methyl acrylate (0.7 g, 8 mmol) in methylene chloride (100 mL) at 0 °C under an inert atmosphere was added TEA (0.90 g, 8.8 mmol). The reaction mixture was slowly warmed to ambient temperature, stirred for 20 h, quenched with water (30 mL), and extracted with methylene chloride (2 × 50 mL). The organic extracts were combined, washed with saline solution (50 mL), dried over sodium sulfate, concentrated 3-[3-(Trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylic Acid. To a solution of methyl 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate (2.3 g, 8.4 mmol) in THF (10 mL) was added a 2 M solution of sodium hydroxide in water (10 mL) at 0 °C. The reaction mixture was slowly warmed to ambient temperature, stirred for 2 h, neutralized with 2 N HCl to pH 7, and extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined, washed with saline solution (50 mL), dried over sodium sulfate, and concentrated (3 1-Pyridin-2-yl-4-[(3 The following Examples 56-58 were prepared in a fashion similar to Example 55. Methyl (2 1- (3 N-{2-[(2 (3 N-{2-[(2 N-{2-[(2 N-(2-{(2 N-{2-[(2 N-(2-{(2 Lower Rf isomer: LCMS (M+H)+ m/z = 549.1;1H NMR (CDCl3) δ 8.52 (m, 1H), 8.11 (m, 1H), 8.00 (m, 1H), 7.73 (m, 2H), 7.55 (m, 1H), 7.39 (m, 2H), 7.20 (m, 1H), 4.11-4.48 (m, 3H), 3.46-3.88 (m, 5H), 3.21 (m, 1H), 2.63 (m, 1H), 2.38 (m, 1H), 1.55-1.98 (m, 10H), 1.20 (m, 3H). N-(2-{(2 N-(2-{(2 N-{2-[(2 N-(2-{(2 1- N-(2-{(4 1-Benzyl 2-Methyl (2 1-Benzyl 2-Methyl (2 Benzyl (2 Benzyl (2 (2 LC/MS (M+H)+ m/z = 220.2;1H NMR (CDCl3) δ 7.33 (m, 5H), 4.49 (m, 2H), 4.12 (m, 1H), 3.19 (dd, 1H), 3.00 (m, 2H), 2.05 (m, 1H), 1.96 (bs, 1H), 1.49 (m, 2H), 1.00 (d, 3H), 0.91 (d, 3H). N-{2-[(2 N-{2-[(2 N-(2-{(2 The following Examples 68-71 were prepared in a manner similar to Example 67. N-{2-[(2 N-(2-{(3 N-(2-{(3 Methyl 1-[3-(Trifluoromethyl)phenyl]piperidine-4-carboxylate. Methyl piperidine-4-carboxylate (2.0 g, 14 mmol), 1-bromo-3-(trifluoromethyl)benzene (1.5 g, 6.8 mmol), and potassium tert-butoxide (0.76 g, 6.8 mmol) in a mixed solvent of toluene (20 mL) and DMF (4 m L) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (0.3 g, 0.4 mmol) under nitrogen. The mixture was heated at 130 °C in an oil bath overnight. After cooling to room temperature, the mixture was filtered through celite and diluted with EtOAc. The resulting solution was washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried (MgSO4), concentrated and flash chromatographed with EtOAc/hexanes (20% to 40%) to give 0.90 g of product. MS (M+H) 288.2. 1-[3-(Trifluoromethyl)phenyl]piperidine-4-carboxylic Acid. Methyl 1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxylate (0.9 g, 3 mmol) was treated with the mixture of 2 M of sodium hydroxide in water (10 mL), THF (10 mL) and methanol (10 mL) at 50 °C for 1h. After being neutralized with concentrated HCl (pH=3), the solution was concentrated. The resulting residue was azeotropically treated with benzene for 3 times to give the title compound which was used for the next reaction without purification. MS (M+H) 274.1. (3 1-Pyridin-2-yl-4-{[(3 1-(5-pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-[(Benzyloxy)carbonyl]piperidine-4-carboxylic acid. Triethylamine (8.1 mL, 58 mmol) was added to a solution of piperidine-4-carboxylic acid (5 g, 40 mmol) and benzyl chloroformate (7.9 g, 46 mmol) in dichloromethane (100 mL) in an ice-water bath. After being stirred overnight, the solution was washed with concentrated HCl and brine, dried over Na2SO4 and concentrated. Chromatography on silica gel gave the title compound (10 g) as an oil. MS (M+H) 264.2. Benzyl 4-({(3 tert-Butyl [(3 tert-Butyl [(3 (3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 The following examples were prepared in a manner analogous to that for Example 78. Ethyl 1-[4-(Trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylate. To a solution of methyl 1H-imidazole-4-carboxylate (417 mg, 3.3 mmol) in DMF (10 mL) was added sodium hydride (130 mg, 3.3 mmol). After being stir for 1 h at room temperature, 2-chloro-4-(trifluoromethyl)pyridine (500 mg, 2.8 mmol) was added. The mixture was stirred at 80 °C overnight. After being cooled to room temperature, ethyl acetate was added. The solution was washed with brine several times, dried (MgSO4) and concentrated. Chromatography on silica gel eluting with EtOAc/hexanes (1:1) afforded the title compound (120 mg). MS (M+H) 272.1. 1-[4-(Trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylic Acid. To a solution of methyl 1-[4-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylate (120 mg, 0.44 mmol) in methanol (2.5 mL) was added a 5 M solution of sodium hydroxide in water (2.5 mL) and the mixture was stirred at room temperature for I h. After removal of methanol under vacuum, the resulting solution was acidified with concentrated HCl (pH=5) and concentrated. The residue was taken up in acetone and insolubles were filtered off. The filtrate was evaporated to give the title compound (120 mg). MS (M+H) 258.2. tert-Butyl [(3 1-({(3 1-(6-Pyrimidin-2-ylpyridin-3-yl)-4-{[(3 2-Methyl-4-(trifluoromethyl)pyridine 1-Oxide. To a solution of 2-methyl-4-(trifluoromethyl)pyridine (3.9 g, 24 mmol) in methylene chloride (50 mL) was added m-chloroperbenzoic acid (7.0 g, 31 mmol). After being stirred at room temperature overnight, the solution was washed with 50 mL of 1 N NaOH. The water phase was back-extracted with methylene chloride. The combined organic phases were dried over Na2SO4 and concentrated under vacuum to give the title compound. MS (M+H) 178.1. [4-(Trifluoromethyl)pyridin-2-yl]methyl Acetate. 2-Methyl-4-(trifluoromethyl)pyridine 1-oxide (4.0 g, 22 mmol) was added to acetic anhydride (12 mL) at 120 °C. The mixture was refluxed for 1 h. To it was carefully added 10 mL of ethanol. Reflux was continued for 10 min. The mixture was poured into ice, neutralized with NaHCO3, and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated. Chromatography on silica gel (5:2 hexanes/EtOAc) provided the product (3.4 g) as a brown oil. MS (M+H) 220.1. [4-(Trifluoromethyl)pyridin-2-yl]methanol. To a solution of [4-(trifluoromethyl)pyridin-2-yl]methyl acetate (1.0 g, 3.2 mmol) in methanol (10 mL) was added a 1.0 M solution of sodium hydroxide in water (10 mL). After being stirred at room temperature overnight, the solution was diluted with 20 mL) of water and extracted with EtOAc twice. The combined organic layers were dried (MgSO4) and concentrated under vacuum. Chromatography on silica gel eluting with hexanes/EtOAc (1:1) afforded the title compound (0.34 g) as a clear oil. MS (M+H) 178.1. {[4-(Trifluoromethyl)pyridin-2-yl]methoxy}acetic Acid. To a solution of [4-(trifluoromethyl)pyridin-2-yl]methanol (340 mg, 1.9 mmol) in DMF (10 mL) was added sodium hydride (150 mg, 3.8 mmol). After being stirred at room temperature for 5 min. 1,1-dimethylethyl bromoacetate (0.28 mL, 1.9 mmol) was added. Stirring was continued at room temperature for 1 h. Water (20 mL) was added and the resulting solution was extracted with EtOAc. The water layer was neutralized to pH=5 with HCl and extracted with EtOAc twice. The combined organic layers were dried (MgSO4) and concentrated under vacuum to give the title compound which was used for the next reaction without purification. MS (M+H) 292.2. tert-Butyl [(3 1-({[4-(Trifluoromethyl)pyridin-2-yl]methoxy}acetyl)pyrrolidin-3-amine. To a solution of tert-butyl [(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 The capacity of the novel compounds of the invention to antagonize CCR2 function can be determined using a suitable screen (e.g., high through-put assay). For example, an agent can be tested in an extracellular acidification assay, calcium flux assay, ligand binding assay or chemotaxis assay (see, for example, In a practical assay, a CCR2 protein which can be isolated or recombinantly derived is used which has at least one property, activity or functional charateristic of a mammalian CCR2 protein. The specific property can be a binding property (to, for example, a ligand or inhibitor), a signalling activity (e.g., activation of a mammalian G protein, induction of rapid and transient increase in the concentration of cytosolic free calcium [Ca++]i, cellular response function (e.g., stimulation of chemotaxis or inflammatory mediator release by leukocytes), and the like. In one embodiment, a composition containing a CCR2 protein or variant thereof is maintained under conditions suitable for binding. The CCR2 receptor is contacted with a compound to be tested, and binding is detected or measured. In alternate embodiments, the assay is a cell-based assay and cells are used which are stably or transiently transfected with a vector or expression cassette having a nucleic acid sequence which encodes the CCR2 receptor. The cells are maintained under conditions appropriate for expression of the receptor and are contacted with an agent under conditions appropriate for binding to occur. Binding can be detected using standard techniques. For example, the extent of binding can be determined relative to a suitable control. Also, a cellular fraction, such as a membrane fraction, containing the receptor can be used in lieu of whole cells. Detection of binding or complex formation can be detected directly or indirectly. For example, the agent can be labeled with a suitable label (e.g., fluorescent label, label, isotope label, enzyme label, and the like) and binding can be determined by detection of the label. Specific and/or competitive binding can be assessed by competition or displacement studies, using unlabeled agent or a ligand as a competitor. The CCR2 antagonist activity of test agents (e.g., the 3-cycloakylaminopyrrolidine compounds of formula I or II of the invention) can be reported as the inhibitor concentration required for 50% inhibition (IC50 values) of specific binding in receptor binding assays using125I-labeled MCP-1, as ligand, and Peripheral Blood Mononuclear Cells (PBMCs) prepared from normal human whole blood via density gradient centrifugation. Specific binding is preferably defined as the total binding (e.g., total cpm on filters) minus the non-specific binding. Non-specific binding is defined as the amount of cpm still detected in the presence of excess unlabeled competitor (e.g., MCP-1). The human PBMCs described above can be used in a suitable binding assay. For example, 200,000 to 500,000 cells can be incubated with 0.1 to 0.2 nM125I-labeled MCP-1, with or without unlabeled competitor (10nM MCP-1) or various concentrations of compounds to be tested.125I-labeled MCP-1, can be prepared by suitable methods or purchased from commercial vendors (Perkin Elmer, Boston MA), The binding reactions can be performed in 50 to 250 µl of a binding buffer consisting of 1M HEPES pH 7.2, and 0.1 % BSA (bovine serum albumin), for 30 min at room temperature. The binding reactions can be terminated by harvesting the membranes by rapid filtration through glass fiber filters (Perkin Elmer) which can be presoaked in 0.3% polyethyleneimine or Phosphate Buffered Saline (PBS). The filters can be rinsed with approximately 600 µl of binding buffer containing 0.5 M NaCl or PBS, then dried, and the amount of bound radioactivity can be determined by counting on a Gamma Counter (Perkin Elmer). The capacity of compounds to antagonize CCR2 function can also be determined in a leukocyte chemotaxis assay using suitable cells. Suitable cells include, for example, cell lines, recombinant cells or isolated cells which express CCR2 and undergo CCR2 ligand-induced (e.g., MCP-1) chemotaxis. The assay in use, utilizes human peripheral blood mononuclear cells, in a modified Boyden Chamber (Neuro Probe). 500,000 cells in serum free DMEM media (In Vitrogen) are incubated with or without the inhibitors and warmed to 37°C. The chemotaxis chamber (Neuro Probe) is also prewarmed. 400ul of warmed 10nM MCP-1 is added to the bottom chamber in all wells expect the negative control which has DMEM added. An 8 micron membrane filter (Neuro Probe) is place on top and the chamber lid is closed. Cells are then added to the holes in the chamber lid which are associated with the chamber wells below the filter membrane. The whole chamber is incubated at 37°C, 5% CO2 for 30 minutes. The cells are then aspirated off, the chanber lid opened, and the filter gently removed. The top of the filter is washed 3 times with PBS and the bottom is left untouched. The filter is air dried and stained with Wright Geimsa stain (Sigma). Filters are counted by microscopy. The negative control wells serve as background and are subtracted from all values. Antagonist potency can be determined by comparing the number of cell that migrate to the bottom chamber in wells which contain antagonist, to the number of cells which migrate to the bottom chamber in MCP-1 control wells. When the binding assay protocol is used, the compounds of the present invention have IC50 in the range of about 0.01 to about 500 (nM). In chemotaxis assays the compounds of the invention have IC50's in the range of about 1 to about 3000 (nM). A method of modulating activity of a chemokine receptor comprising contacting said chemokine receptor with a compound of claim. Chemokine receptors to which the present compounds bind and/or modulate include any chemokine receptor. In some embodiments, the chemokine receptor belongs to the CC family of chemokine receptors including, for example, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8. In some embodiments, the chemokine receptor is CCR2. In some embodiments, the chemokine receptor is CCR5. In some embodiments, the chemokine receptor binds and/or modulates both CCR2 and CCR5. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an The compounds of the invention can be selective. By "selective" is meant that a compound binds to or inhibits a chemokine receptor with greater affinity or potency, respectively, compared to at least one other chemokine receptor, or preferably compared to all other chemokine receptors of the same class (e.g., all othe CC-type receptors). In some embodiments, the compounds of the invention have binding or inhibition selectivity for CCR2 or CCR5 over any other chemokine receptor. Selectivity can be at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 200-fold, at least about 500-fold or at least about 1000-fold. Binding affinity and inhibitor potency can be measured according to routine methods in the art, such as according to the assays provided herein. The present disclosure further provides methods of treating a chemokine receptor-associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. A chemokine receptor-associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the chemokine receptor. A chemokine receptor-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating chemokine receptor activity. A chemokine receptor-associated disease can further include any disease, disorder or condition that is characterized by binding of an infectious agent such as a virus or viral protein with a chemokine receptor. In some embodiments, the chemokine receptor-associated disease is a CCR5-associated disease such as HIV infection. As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the invention can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The mammal treated in the methods of the invention is a mammal, male or female, in whom modulation of chemokine receptor activity is desired. The term modulation is intended to encompass antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism. In some embodiments, compounds of the present invention are antagonists (e.g., inhibitors) of chemokine receptors. In the present specification, the term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the invention can be administered in therapeuticly effective amounts to treat a disease for example such as rheumatoid arthritis. A therapeutically effective amount of a compound is that amount which results in the inhibition of one or more of the processes mediated by the binding of a chemokine to a receptor such as CCR2 in a subject with a disease associated with aberrant leukocyte recruitment and/or activation. Typical examples of such processes include leukocyte migration, integrin activation, transient increases in the concentration of intracellular free calcium [Ca2+]i and granule release of proinflammatory mediators. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with aberrant leukocyte recruitment and/or activation. Additional diseases or conditions of human or other species which can be treated with the inhibitors or modulators of chemokine receptor function of the invention, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-type hypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome due to the ingestion of contaminated tryptophan, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dennatoses such as an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, restenosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis. In some embodiments, the chemokine receptor-associated diseases, disorders and conditions include inflammation and inflammatory diseases, immune disorders, cancer, and viral infections. Example inflammatory diseases include diseases having an inflammatory component such as asthma, allergic rhinitis, restenosis, atherosclerosis, multiple sclerosis, Crohn's disease, ulcerative colitis, hypersensitivity lung diseases, neuropathic pain, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, asthma, interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis), eye disorders (e.g., retinal neurodegeneration, choroidal neovascularization, etc.), obesity, and the like. Example immune disorders include rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myastenia gravis, diabetes (e.g., juvenile onset diabetes), insulin resistance; glomerulonephritis, autoimmune throiditis, organ transplant rejection including allograft rejection and graft-versus-host disease. Example cancers include cancers such as breast cancer, ovarian cancer, multiple myeloma and the like that are characterized by infiltration of macrophages (e.g., tumor associated macrophages, TAMs) into tumors or diseased tissues. Example viral infections include HIV infection. One or more additional pharmaceutical agents such as, for example, antibodies, anti-inflammatory agents, immunosuppressants, chemotherapeutics can be used in combination with the compounds of the present invention for treatment of chemokine receptor-associated diseases, disorders or conditions. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. One or more additional pharmaceutical agents such as, for example, anti-viral agents, antibodies, anti-inflammatory agents, and/or immunosuppressants can be used in combination with the compounds of the present invention for treatment of chemokine receptor-associated diseases, disorders or conditions. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. Suitable antiviral agents contemplated for use in combination with the compounds of the present invention can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs. Example suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2', 3'-dicleoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-901.52); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidi nedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141 W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607. In some embodiments, anti-inflammatory or analgesic agents contemplated for use in combination with the compounds of the present invention can comprise, for example, an opiate agonist, a lipoxygenase inhibitor such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor such as an interleukin-I inhibitor, an NNMA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example, such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds can be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedfine, or levo-desoxyephedrine; an antfitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. In some embodiments, pharmaceutical agents contemplated for use in combination with the compounds of the present invention can comprise (a) VLA-4 antagonists such as those described in Rheumatoid arthritis (RA) patients, treated aggressively with disease modifying agents (methotrexate, antimalarials, gold, penicillamine, sulfasalazine, dapsone, leflunamide, or biologicals), can achieve varying degrees of disease control, including complete remissions. These clinical responses are associated with improvement in standardized scores of disease activity, specifically the ACR criteria which includes: pain, function, number of tender joints, number of swollen joints, patient global assessment, physician global assessment, laboratory measures of inflammation (CRP and ESR), and radiologic assessment of joint structural damage. Current disease-modifying drugs (DMARDs) require continued administration to maintain optimal benefit. Chronic dosing of these agents is associated with significant toxicity and host defense compromise. Additionally, patients often become refractory to a particular therapy and require an alternative regimen. For these reasons, a novel, effective therapy which allows withdrawal of standard DMARDs would be a clinically important advance. Patients with significant response to anti-TNF therapies (infliximab, etanercept, adalimumab), anti- IL-1 therapy (kinaret) or other disease modifying anti-rheumatic drugs (DMARDs) including but not limited to methotrexate, cyclosporine, gold salts, antimalarials, penicillamine or leflunamide, who have achieved clinical remission of disease can be treated with a substance that inhibits expression and/or activity of CCR2 including, for example, nucleic acids (e.g., antisense or siRNA molecules), proteins (e.g., anti-CCR2 antibodies), small molecule inhibitors (e.g., the compounds disclosed herein and other chemokine receptor inhibitors known in the art). In some embodiments, the substance that inhibits expression and/or activity of CCR2 is a small molecule CCR2 inhibitor (or antagonist). The CCR2 antagonist can be dosed orally q.d. or b.i.d at a dose not to exceed about 500 mgs a day. The patients can be withdrawn from or have a decrease in the dosage of their current therapy and would be maintained on treatment with the CCR2 antagonist. Treating patients with a combination of CCR2 antagonist and their current therapy can be carried out for, for example, about one to about two days, before discontinuing or dose reducing the DMARD and continuing on CCR2 antagonist. Advantages of substituting traditional DMARDS with CCR2 antagonists are numerous. Traditional DMARDs have serious cumulative dose-limiting side effects, the most common being damage to the liver, as well as immunosuppressive actions. CCR2 antagonism is expected to have an improved long-term safety profile and will not have similar immunosuppressive liabilities associated with traditional DMARDs. Additionally, the half-life of the biologicals is typically days or weeks, which is an issue when dealing with adverse reactions. The half-life of an orally bioavailable CCR2 antagonist is expected to be on the order of hours so the risk of continued exposure to the drug after an adverse event is very minimal as compared to biological agents. Also, the current biologic agents (infliximab, etanercept, adalimumab, kinaret) are typically given either i.v. or s.c., requiring doctor's administration or patient self-injection. This leads to the possibility of infusion reaction or injection site reactions. These are avoidable using an orally administered CCR2 antagonist. The compounds of the invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the metabolic stability, rate of excretion, drug combination, and length of action of that compound the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the specific route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the specific disorder for which treatment is necessary. Generally, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.0001 to 1000 mg/kg of body weight, preferably between about 0.001 to 100 mg/kg of body weight per day, and most preferably between about 0.1 to 20 mg/kg/day. For intravenous use, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. The compounds of the instant invention can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, e.g., by using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. The compounds of the invention can typically be administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Additionally, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds of the present invention can also be provided to a patient in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or poly-ethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, and crosslinked or amphipathic block copolymers of hydrogels. Dosage forms for the compounds of the invention suitable for administration may contain from about 0.1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Gelatin capsules can also be used as dosage forms and may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. When using liquid dosage forms for oral administration they can contain coloring and flavoring to increase patient acceptance. Generally, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. As used herein, topical application is also meant to include the use of mouth washes and gargles. The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions. Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 50 milligrams of powdered active ingredient, 100 milligrams of lactose, 25 milligrams of cellulose, and 3 milligrams magnesium stearate. A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 75 milligrams of the active ingredient. The capsules should be washed and dried. Tablets may be prepared by conventional procedures so that the dosage unit is 75 milligrams of active ingredient, 0.15 milligrams of colloidal silicon dioxide, 4 milligrams of magnesium stearate, 250 milligrams of microcrystalline cellulose, 9 milligrams of starch and 75 milligrams of lactose. Appropriate coatings well known to one skilled in the art may be applied to increase palatability or delay absorption. A parenteral composition suitable for administration by injection may be prepared by stirring 1.0% by weight of active ingredient in 8% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized. An aqueous suspension can be prepared for oral administration so that each 5 mL contain 75 mg of finely divided active ingredient, 150 mg of sodium carboxymethyl cellulose, 3.75 mg of sodium benzoate, 0.75 g of sorbitol solution, U.S.P., and 0.015 mL of vanillin. This example describes a procedure to evaluate the efficacy of CCR2 antagonists for treatment of rheumatoid arthritis. An animal model of rheumatoid arthritis can be induced in rodents by injecting them with type II collagen in selected adjuvants. Three series of rodent groups consisting 15 genetically-susceptible mice or rats per group are injected sub-cutaneously or intra-dermally with type II collagen emulsified in Complete Freund's Adjuvant at days 0 and 21. One series of rodents additionally receives phosphate buffered saline (PBS) and Tween 0.5% i.p. at the initial sensitization, and at different dosing schedules thereafter. A second series consists of groups of rodents receiving different doses of the CCR2 antagonist(s) given either intraperitoneally, intravenously, sub-cutaneously, intra-muscularly, orally, or via any other mode of administration at the initial sensitization, and at different dosing schedules thereafter. A third series of rodents, serving as positive control, consists of groups treated with either mouse IL-10 i.p., or anti-TNF antibodies i.p.at the initial sensitization, and at different dosing schedules thereafter. Animals are monitored from weeks 3 til 8 for the development of swollen joints or paws, and graded on a standard disease severity scale. Disease severity is confirmed by histological analysis of joints. Another aspect of the present invention relates to radio-labeled compounds of the invention that would be useful not only in radio-imaging but also in assays, both The present invention further includes isotopically-labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),11C,13C,14C,13N,15N,15O,17O,18O,18F,35S,36Cl,82Br,75Br,76Br,77Br,123I,124I,125I and131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for It is understood that a "radio-labeled " or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of3H,14C,125I,35S and82Br. Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art. A radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the chemokine receptor. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the chemokine receptor directly correlates to its binding affinity. The present disclosure also includes pharmaceutical kits useful, for example, in the treatment or prevention of chemokine-associated diseases which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. The present invention relates to 3-cycloalkylaminopyrrolidine derivatives of the formula I: (wherein R1, R2, R3, R4, R5, R6, R7, X, Y and Z are as defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors and more specifically as modulators of the CCR2 and/or CCR5 receptor. The compounds and compositions of the invention may bind to chemokine receptors, e.g., the CCR2 and/or CCR5 chemokine receptors, and are useful for treating diseases associated with chemokine, e.g., CCR2 and/or CCR5, activity, such as atherosclerosis, restenosis, lupus, organ transplant rejection and rheumatoid arthritis. A compound selected from the group consisting of:
N-(2-{(3 N-(2-{(3 N-(2-{(3 N-{2-[(3 N-(2-{(3 N-[2-((3 N-(2-{(3 N-(2-{(3 N-[2-((3 N-[2-((3 N-[2-((3 N-[2-((3 N-[2-((3 3-(Trifluoromethyl)-N-[2-((3 3-(Trifluoromethyl)-N-{2-[(3 3-(Trifluoromethyl)-N-{2-[(3 2-(1-Hydroxy-4-{[(3 N-Ethyl-2-(1-hydroxy-4-{[(3 N-{2-[(3 3-(Trifluoromethyl)-N-{2-[(3 3-(Trifluoromethyl)-N-[2-((3 3-(Trifluoromethyl)-N-[2-((3 N-[2-((3 N-[2-(3 N-[2-({(3 N-(2-{(3 N-(2-{(3 N-(2-{(3 6-(1-Hydroxy-4-{[(3 6-(1-Hydroxy-4-{[(3 N-{2-[(3 N-[2-((3 N-{2-[(3 N-(2-(3 N-[2-((3 N-[2-((3 N-{2-[(3 N-[2-((3 N-(2-{(3 N-(2-{(3 N-{2-[(3 3-[6-(1-Hydroxy-4-{[(3 N-(2-{(3 N-[2-((3 N-[2-((3 N-[2-((3 N-[2-((3 N-[2-((3 N-{2-[(3 4'-(1-Hydroxy-4-{[(3 N-[2-((3 N-{2-[(3 N-{2-[(3 N-{2-[(3 1-Pyridin-2-yl-4-[(3 1-[5-(1,3-Oxazol-2-yl)pyridin-2-yl]-4-{[(3 1-{5-[(Dimethylamino)methyl]pyridin-2-yl}-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 N-(2-{(2 N-{2-[(2 N-(2-{(2 N-(2-{(2 N-(2-{(2 N-{2-[(2 N-(2-{(2 N-(2-{(4 N-(2-{(2 N-{2-[(2 N-{2-[(2 N-{2-[(2 A compound selected from:
N-{2-[(2 N-(2-{(3 N-(2-{(3 1-Pyridin-2-yl-4-{[(3 1-(5-pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-Pyridin-2-yl-4-{[(3 1-(6-Pyrimidin-2-ylpyridin-3-yl)-4-{[(3 1-Pyridin-2-yl-4-{[(3 1-Pyridin-2-yl-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-[5-(1,3-Oxazol-2-yl)pyridin-2-yl]-4-{[(3 1-(5-Pyrazin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Methylpyridin-2-yl)-4-{[(3 1-(3,3'-Bipyridin-6-yl)-4-{[(3 1-(3,4'-Bipyridin-6-yl)-4-{[(3 1-(5-Methoxypyridin-2-yl)-4-{[(3 1-[5-(Methoxymethyl)pyridin-2-yl]-4-{[(3 6-(1-Hydroxy-4-{[(3 6-(1-Hydroxy-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(6-Pyrimidin-2-ylpyridin-3-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3 A compound
N-[2-((3 A composition comprising a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound of any one of claims 1 to 3, or a Pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating inflammation, rheumatoid arthritis, atherosclerosis, neuropathic pain, lupus, systemic lupus erythematosus, restenosis, immune disorders, or transplant rejection in a mammal. Use of a compound of any one of claims 1 to 3. or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for modulating chemokine receptor activity in a mammal Use of a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a CCR2-mediated condition or disease in a subject. Use of a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a CCR5-mediated condition or disease in a subject. Use of a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for modulating activity of a chemokine receptor. Use of claim 9 wherein said chemokine receptor is CCR2 or CCR5. Use of claim 9 wherein said modulating is inhibiting. Use of a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease associated with expression or activity of a chemokines receptor in a patient. Use of claim 12 wherein said chemokine receptor is CCR2 or CCR5. Use of claim 12 wherein said disease is an inflammatory disease. Use of claim 12 wherein said disease is an immune disorder. Use of claim 12 wherein said disease is rheumatoid arthritis, atherosclerosis, lupus, multiple sclerosis, neuropathic pain, transplant rejection, diabetes, or obesity. Use of claim 12 wherein said disease is cancer. Use of claim 17 wherein said cancer is characterized by tumor associated macrophages. Use of claim 17 wherein said cancer is breast cancer, ovarian cancer or multiple myeloma. Use of claim 12 wherein said disease or condition is a viral infection. Use of claim 20 wherein said viral infection is HIV infection. Use of a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating HIV infection in a patient. Use of claim 22 further comprising simultaneously or sequentially administering at least one anti-viral agent.FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
OBJECTS OF THE INVENTION
SUMMARY OF THE INVENTION
or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTION
EXAMPLES
Example 1
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Example 2
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Example 3
Example 4
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Example 5
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Example 6
N-[2-((3
Example 7
N-(2-{(3
Example 8
N-(2-{(3
Example 9
N-[2-((3
Example 10
N-[2-((3
Example 11
N-[2-((3
Example 12
N-[2-((3
Example 13
N-[2-((3
Example 14
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Step B
Step C
Step D
Example 15
3-(Trifluoromethyl)-N-{2-[(3
Example 16
3-(Trifluoromethyl)-N-{2-[(3
Example 17
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Step B
Step C
Step D
Example 18
N-Ethyl-2-(1-hydroxy-4-{[(3
Example 19
Example 20
Step A
Step B
4-Hydroxy-4-[2-(morpholin-4-ylcarbonyl)-1,3-thiazol-5-yl]cyclohexanone.
Step C
Example 21
3-(Trifluoromethyl)-N-[2-((3
Example 22
3-(Trifluoromethyl)-N-[2-((3
Example 23
N-[2-((3
Example 24
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Step B
Example 25
Example 26
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Example 27
Example 28
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Example 29
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Example 30
6-(1-Hydroxy-4-{[(3
Example 31
Example 32
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Example 33
Example 34
Example 35
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Step B
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Step D
Example 36
N-[2-((3
Example 37
N-{2-[(3
Example 38
Step A
8-(5-Pyrimidin-2-ylpyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol.
Step B
4-Hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone.
Step C
N-[2-((3
Example 39
N-(2-{(3
Example 40
N-(2-{(3
Example 41
N-{2-[(3
Example 42
3-[6-(1-Hydroxy-4-{[(3
Example 43
N-(2-{(3
Example 44
N-[2-((3
Example 45
N-[2-((3
Example 46
N-[2-((3
Example 47
N-[2-((3
Example 48
N-[2-((3
Example 49
N-{2-[(3
Example 50
4'-(1-Hydroxy-4-{[(3
Example 51
N-[2-((3
Example 52
N-{2-[(3
Example 53
Example 54
N-{2-[(3
Example 55
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Step B
Step C
Step D
Step E
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Step G
Example 56
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 57
1-{5-[(Dimethylamino)methyl]pyridin-2-yl}-4-{[(3
Example 58
1-[5-(1,3-Oxazol-2-yl)pyridin-2-yl]-4-{[(3
Example 59
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Step K
Example 60
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Example 61
Example 62
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Example 63
Example 64
Example 65
Example 66
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Step B
Example 67
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Example 68
Example 69
N-{2-[(2
Example 70
N-{2-[(2
Example 71
N-{2-[(2
Example 72
Example 73
Example 74
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Example 75
Example 76
Example 77
Example 78
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Step F
Example 79
1-Pyridin-2-yl-4-{[(3
Example 80
1-(6-Pyrimidin-2-ylpyridin-3-yl)-4-{[(3
Example 81
1-Pyridin-2-yl-4-{[(3
Example 82
1-Pyridin-2-yl-4-{[(3
Example 83
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 84
1-[5-(1,3-Oxazol-2-yl)pyridin-2-yl]-4-{[(3
Example 85
1-(5-Pyrazin-2-ylpyridin-2-yl)-4-{[(3
Example 86
1-(5-Methylpyridin-2-yl)-4-{[(3
Example 87
1-(3,3'-Bipyridin-6-yl)-4-{[(3
Example 88
1-(3,4'-Bipyridin-6-yl)-4-{[(3
Example 89
1-(5-Methoxypyridin-2-yl)-4-{[(3
Example 90
1-[5-(Methoxymethyl)pyridin-2-yl]-4-{[(3
Example 91
6-(1-Hydroxy-4-{[(3
Example 92
6-(1-Hydroxy-4-{[(3
Example 93
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 94
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 95
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 96
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 97
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 98
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 99
1-(5-Pyrimidin-2-ylpyridin-2-yl)-4-{[(3
Example 100
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Example 101
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Example 102
PHARMACEUTICAL APPLICATIONS OF THE COMPOUNDS OF THE INVENTION
Example A