HK1089758A

HK1089758A - Inhibitors of the binding of chemokines i-tac or sdf-1 to the ccxckr2 receptor

Info

Publication number: HK1089758A
Application number: HK06110070.6A
Authority: HK
Inventors: Anita Melikian; Jennifer Burns; Brian E. Mcmaster; Thomas Schall; J. J. Wright
Original assignee: Chemocentryx, Inc.
Priority date: 2002-12-20
Filing date: 2003-12-22
Publication date: 2006-12-08

Description

Inhibitors of chemokine I-TAC or SDF-1 binding to CCXCKR2 receptor

RELATED APPLICATIONS

This application claims priority to U.S. provisional application serial No. 60/434912, filed 12/20/2002 and to U.S. provisional application serial No. 60/516151, filed 10/30/2003. The disclosure of this priority application is incorporated herein by reference in its entirety.

Background

The present invention relates to novel compounds and pharmaceutical compositions that inhibit binding of either SDF-1 chemokine (also known as CXCL12 chemokine) or I-TAC (also known as CXCL11) to the chemokine receptor CCXCKR 2. These compounds are useful for preventing tumor cell proliferation, tumor formation and tumor metastasis.

Chemokines belong to the superfamily of small cytokine-like proteins that induce cytoskeletal rearrangements to attach firmly to epithelial cells and to migrate directionally, and also affect cell activation and proliferation. Chemokines function in a manner consistent with cell surface proteins specifically targeting various subunits of the guide cell to specific anatomical sites.

Early research efforts by several groups have indicated a role for the chemokine receptor CXCR4 in tumor metastasis and tumor growth. Muller et al, "Involvement of ChemokineReceptiors in Breast Cancer Metastasis", Nature, 410: 50-56(2001) demonstrated that breast cancer cells employ chemokine-mediated mechanisms, such as those that regulate leukocyte trafficking during tumor metastasis. Tumor cells express a unique, non-random pattern of functionally active chemokine receptors. Signaling through CXCR4 mediates actin polymerization and lichen formation in breast cancer cells and induces chemotactic and invasive responses. In addition, organs representing the major site of breast cancer metastasis (e.g., lymph nodes, bone marrow, and lungs) are a major rich source of ligands for the CXCR4 receptor.

The metastasis of injected human breast cancer cells was successfully reduced by treatment with antibodies known to bind to CXCR4 using immunodeficient mice, Muller and colleagues. Their findings suggest that breast cancer metastasis can be reduced by treating patients with CXCR4 antagonists.

Bertolini et al, "CXCR 4Neutralization, a Novel therapeutic approach for Non-Hodgkin's Lymphoma", Cancer Research, 62: 3106-. They explain their findings suggesting that tumor volume can be reduced by treating patients with CXCR4 antagonists.

Recent studies suggest that another chemokine receptor, CCXCKR2, may also be a potential candidate in the treatment of cancer. CCXCKR2 is preferentially expressed in transformed cells over normal cells, and expression is detectable in a variety of human cancers. In vitro studies indicate that proliferation of cells expressing CCXCKR2 can be inhibited by CCXCKR2 antagonists. In vivo studies in mice indicate that CCXCKR2 antagonists inhibit tumor formation and tumor growth.

Another explanation of the reduction in tumor volume observed by Bertolini and coworkers illustrates the potential importance of CCXCKR 2. This reduction is clearly a result of antibody-mediated clearance and not a result of anti-CXCR 4 antibodies as previously believed. In antibody-mediated clearance, any antibody that recognizes a cell surface protein of a lymphocyte should have the same effect as that contributed by an anti-CXCR 4 antibody. Unfortunately, the Bertolini and coworkers studies did not determine whether the observed tumor response was due to antibody-mediated clearance or interaction with CXCR 4.

However, it is currently known that lymphoid cancer cells used by Bertolini and coworkers express both CXCR4 and CCXCKR 2. SDF-1 is the only ligand for CXCR 4. Both SDF-1 and I-TAC combine CCXCKR 2. With anti-SDF-1 antibodies, CCXCKR2 antagonists have been shown to be responsible for the reduction of tumor burden and increase survival. Since SDF-1 is the only ligand for CXCR4, one would expect that neutralization of SDF-1 with anti-SDF-1 antibodies would be equivalent to neutralization of CXCR4 with anti-CXCR 4 antibodies. However, experiments with anti-SDF-1 antibodies demonstrated only partial reduction of tumor burden and increased survival. This led to the belief that CCXCKR2 was the actual target, since sustained activity was likely the result of the interaction of the second ligand, I-TAC, with CCXCKR 2.

Until recently, the possible importance of CCXCKR2 in tumor cell proliferation, tumor growth, and tumor metastasis was unknown. Currently, by virtue of the recent facts that indicate the ability of certain CCXCKR2 antagonists to prevent the growth and spread of cancer and the expression patterns that indicate limited tissue distribution of CCXCKR2 receptors, it would be beneficial to provide compounds that are capable of specifically binding to CCXCKR2 receptors on tumor cells with potentially few side effects.

SUMMARY

The present invention relates to novel compounds and compositions comprising small molecule modulators that bind to the CCXCKR2 receptor. Typically the novel compounds have the following structure (I):

wherein R is³、R⁴、R⁵And R⁶Y, Z, m and n are defined below.

In one embodiment, the novel compounds have the following structure (II):

wherein R is³、R⁴、R⁵And R⁷And Y is defined as follows.

In another embodiment, the composition comprises a modulator of the invention and a pharmaceutically acceptable carrier.

In another embodiment, methods of inhibiting binding of SDF-1, I-TAC, or both to the CCXCKR2 receptor are disclosed.

In another embodiment, a method of inhibiting cancer is disclosed.

These and other embodiments are discussed in more detail below.

Detailed Description

The present invention provides compositions comprising a pharmaceutically acceptable carrier and an active compound that modulates SDF-1 and/or I-TAC chemokine binding to CCXCKR2 receptor expressed by cancer cells. Preferably, these active compounds bind to CCXCKR2 receptors on tumor cells, but do not significantly bind to lymphoid-derived cells or myeloid cells. The compounds and compositions of the invention are useful for treating cancer, and in particular for reducing the incidence of breast cancer metastasis.

Definition of

When describing the compounds, compositions, methods, and processes of the present invention, the following terms are defined as follows, unless otherwise indicated.

"alkoxy" refers to the group-OR'. Representative alkoxy groups include, for example, methoxy, ethoxy, isopropoxy, trifluoromethoxy, and difluoromethoxy.

"alkyl" by itself or as part of another substituent means a hydrocarbon group which may be linear, cyclic or branched or a collection thereof having the specified number of carbon atoms (e.g., C)_1-8Meaning 1 to 8 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl) methyl, cyclopropylmethyl, and the like. Examples of substituted alkyls include haloalkyl, thioalkyl, aminoalkyl, and the like.

"alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, e.g. through-CH₂CH₂CH₂CH₂As illustrated. Generally, an alkyl (or alkylene) group having 8 or less carbon atoms is preferred in the present invention. Representative alkylene groups include, for example, methylene, ethylene-1, 2-diyl ("ethylene"), propane-1, 2-diyl, propane-1, 3-diyl, butane-1, 4-diyl, pentane-1, 5-diyl, and the like.

"alkenyl" refers to an unsaturated hydrocarbon group or collection thereof that can be linear, cyclic, or branched. Alkenyl groups having 2 to 10 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3 carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

"alkynyl" refers to a monovalent unsaturated hydrocarbon group that can be linear, cyclic, or branched and has at least 1, and typically 1, 2, or 3 carbon-carbon triple bonds. Unless otherwise indicated, such alkynyl groups typically contain 2-10 carbon atoms. Representative alkynyl groups include, for example, ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

"aryl" refers to a polyunsaturated aromatic hydrocarbon group having a single ring (e.g., phenyl) or multiple rings thereof fused together (e.g., naphthalene) or covalently linked together. Unless otherwise indicated, such aryl groups typically contain from 6 to 10 carbon ring atoms. Representative aryl groups include, for example, phenyl and naphthalen-1-yl, naphthalen-2-yl, biphenyl, and the like.

"arylene" refers to a divalent aromatic hydrocarbon having a single ring (e.g., phenylene) or fused ring (e.g., naphthalenediyl). Unless otherwise indicated, such arylene groups typically contain 6 to 10 carbon ring atoms. Representative arylene groups include, for example, 1, 2-phenylene, 1, 3-phenylene, 1, 4-phenylene, naphthalene-1, 5-diyl, naphthalene-2, 7-diyl, and the like.

"aralkyl" refers to an aryl-substituted alkyl group. Representative aralkyl groups include benzyl.

"Compound" refers to a particular molecule and includes its enantiomers, diastereomers, polymorphs, and salts thereof.

"fused" refers to a reaction in which two or more molecules are covalently linked. Likewise, a fused product is a product formed by a fusion reaction.

"cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group having a single ring or fused rings. Unless otherwise indicated, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Representative cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

"halo" or "halogen" refers to fluoro- (-F), chloro- (-Cl), bromo- (-Br), and iodo- (I).

"heteroatom" means nitrogen, oxygen, silicon or sulfur.

"Heterocyclyl" refers to a saturated or unsaturated non-aromatic group containing at least one heteroatom.

"heteroaryl" refers to an aromatic group containing at least one heteroatom. Each of the heterocyclic and heteroaryl groups may be attached to any available ring carbon or heteroatom. Each of the heterocyclyl and heteroaryl groups may have one or more rings. When multiple rings are present, they can be fused together or covalently linked. Each heterocyclyl and heteroaryl group must contain at least one heteroatom (typically 1-5 heteroatoms) selected from nitrogen, oxygen or sulfur. Preferably, these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Examples of saturated and unsaturated heterocyclic groups include pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1, 4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline, and the like. Examples of unsaturated and aromatic heterocyclic groups include pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, tetrazole, oxadiazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene, benzimidazole, benzopyrazole, benzothiazole, quinoline, isoquinoline, quinazoline, quinoxaline, and the like. Heterocyclyl and heteroaryl groups may be unsubstituted or substituted. For substituted groups, the substitution may occur on carbon or a heteroatom. For example, when the substitution is ═ O, the resulting group may have a carbonyl group (-c (O) -) or an N-oxide (-N (O) -).

Suitable substituents for substituted alkyl, substituted alkenyl, substituted alkynyl and substituted cycloalkyl include-halo, -OR ', -NR ' R ", -SR ', -SiR ' R ', -OC (O) R ', -C (O) R ', -CO₂R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R*、-NR”C(O)₂R’、-S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-NR’S(O)₂R', -CN, oxo (═ O or-O-), and-NO₂The number of substituents is between 0- (2m '+ 1), where m' is the total number of carbon atoms in such a group.

Suitable substituents for substituted aryl and substituted heteroaryl include-halo, unsubstituted OR substituted alkyl, unsubstituted OR substituted alkenyl, unsubstituted OR substituted alkynyl, unsubstituted OR substituted cycloalkyl, -OR ', oxo (═ O OR-O), -oc (O) R ', -NR ' R ", -SR ', -R ', -CN, -NO₂、-CO₂R’、-CONR’R”、-C(O)R’、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)₂R’、-NR’-C(O)NR”R*、-NH-C(NH₂)＝NH、-NR’C(NH₂)＝NH、-NH-C(NH₂)＝NR’、-S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-NR’S(O)₂R”and-N₃The number of substituents is between the total number of open (open) valences on the O-aromatic ring system.

Suitable substituents for substituted heterocyclyl include halogen, unsubstituted OR substituted alkyl, unsubstituted OR substituted alkenyl, unsubstituted OR substituted alkynyl, unsubstituted OR substituted cycloalkyl, -OR ', oxo (═ O OR-O), -OC (O) R ', -NR ' R ", -SR ', -R ', -CN, -NO₂、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)₂R’、-NR’-C(O)NR”R*、-NH-C(NH₂)＝NH、-NR’C(NH₂)＝NH、-NH-C(NH₂)＝NR’、-S(O)R’、-S(O)₂NR’R”、-NR’S(O)₂R' and-N₃The number of substituents is between 0 and the total number of open valences on the aromatic ring system.

As used above, R ', R "and R'" are each independently meant to include hydrogen, halogen, unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_3-6Cycloalkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl. Preferably, R 'and R' independently mean a member selected from the group consisting of hydrogen, unsubstituted C_1-8Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C1-8 alkyl, unsubstituted C_1-8Alkoxy, unsubstituted C_1-8Thioalkoxy or unsubstituted aryl-C_1-4Various groups of alkyl groups. When R 'and R "are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring (e.g., -NR' R" includes 1-pyrrolidinyl and 4-morpholinyl).

Alternatively, two substituents on adjacent atoms of the aryl, heteroaryl or heterocyclyl ring may optionally be of the formula-T-C (O) - (CH)₂)_q-U-wherein T and U are independently-NR' -, -O-, -CH₂-or a single bond, and q is an integer from 0 to 2. Or, of aryl or heteroaryl ringsTwo substituents on adjacent atoms may optionally be of the formula-A- (CH)₂)_r-substituent substitution of B-, wherein A and B are independently-CH₂-、-O-、-NR’-、-S-、-S(O)-、-S(O)₂-、-S(O)₂NR' -or a single bond, and r is an integer of 1 to 3. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with a group of formula- (CH)₂)_s-X-(CH₂)_t-wherein S and t are independently integers from 0 to 3 and X is-O-, -NR' -, -S (O)₂-or-S (O)₂NR'. at-NR' -and-S (O)₂The substituents R 'in NR' are selected from hydrogen or unsubstituted C_1-6An alkyl group.

A "pharmaceutically acceptable" carrier, diluent or excipient is one that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

"pharmaceutically acceptable salt" refers to a salt that is acceptable to a patient, e.g., a mammal, to which it is administered (e.g., a salt that is acceptably safe in mammals for a given dosage regimen). Such salts may be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, depending on the particular substituents found for the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, 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. Salts derived from pharmaceutically acceptable inorganic bases include salts of aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, hexavalent manganese (manganic), manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, tertiary and quaternary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functional groups, 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. Salts derived from pharmaceutically acceptable acids include acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glucuronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic salts and the like.

"salts thereof" refer to compounds formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation. Preferably, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds which are not intended for administration to a patient.

"substituted" refers to a group that is bound to the parent molecule or group. Thus, a benzene ring having a methyl substituent is a methyl-substituted benzene. Similarly, a phenyl ring having 5 hydrogen substituents is unsubstituted phenyl when bound to the parent molecule.

"therapeutically effective amount" refers to an amount of a compound, substance, or composition comprising a compound of the invention effective to produce the desired therapeutic effect in the treatment of cancer when administered to a patient in need thereof.

"therapeutic" or "treatment" refers to the administration of a composition, such as a mammalian (particularly human or companion animal) composition, to a patient, such as a mammal, suffering from a disease or medical condition (e.g., cancer), comprising: (a) relieving the disease or medical condition by preventing the transformation of precancerous cancer cells into their invasive counterparts (counterparts) or causing the regression of the disease or medical condition in the patient; (b) inhibiting a disease or medical condition, i.e., slowing or inhibiting the spread of cancer in a patient; or (c) alleviating a symptom of the disease or medical condition in the patient.

"structure-activity relationship" (SAR) refers to a method in which the molecular structure of a compound is altered to alter its interaction with a receptor.

Conditioning agents

The present invention provides modulators for the treatment of cancer. These compounds are useful as modulators of SDF-1 and I-TAC by binding to the CCXCKR2 receptor. Modulators (I) may also be useful as modulators against other chemokine receptors. The chemokine family of peptides is defined on the basis of sequence homology and in the presence of conserved cysteine sequence changes. Schall (1996) Cytokine 3: 165-183 and Oppenheim et al (1991) Annu.Rev.Immunol.9: 617-648. Chemokines exhibit in vitro and in vivo functions ranging from pro-inflammatory activity to proliferation-regulating activity on a range of cell types. To date, several chemokine receptors have been described. See, e.g., Neote et al (1993) Cell 72: 415-; ponath et al (1996) j.exp.med.183: 2437-2448 and Power et al (1995) J.biol.chem.270: 19495-19500.

In one embodiment, the modulators of the present invention have the following general structure (I):

wherein m is an integer of 1 to 5;

each Y is independently selected from hydrogen, halogen, -CN, -NO₂、-OH、-OR’、-C(O)R’、-CO₂R’、-O(CO)R’、-C(O)NR’R”、-OC(O)NR’R”、-SR’、-SOR’、-SO₂R’、-SO₂NR’R”、-NR’R”、-NR’C(O)R”、-NR’C(O)₂R”、-NR’SO₂R ', -NR' (CO) NR 'R', unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl;

wherein each R ', R ' and R ' is independently hydrogen, halogen, unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl;

n is 0, 1, 2 or 3;

z is-CHR¹R²-、-OR¹or-NR¹R²；

R¹And R²Each independently is alkyl or hydrogen, or Z and R¹And R²Combine to form a substituted or unsubstituted 5-to 8-membered ring comprising at least one nitrogen and 0-3 additional heteroatoms;

R⁶is alkyl, hydrogen or halogen; and

R³、R⁴and R⁵Each independently selected from hydrogen, halogen, -CN, -NO₂、-OH、-OR’、-C(O)R’、-CO₂R’、-O(CO)R’、-C(O)NR’R”、-OC(O)NR’R”、-SR’、-SOR’、-SO₂R’、-SO₂NR’R”、-NR’R”、-NR’C(O)R”、-NR’C(O)₂R”、-NR’SO₂R ", -NR 'C (O) NR" R' ", unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl and unsubstituted or substituted 3-to 10-membered heterocyclyl;

or R³、R⁴And R⁵Any two of which, together with the atoms to which they are substituted, form an unsubstituted or substituted 3-to 10-membered heterocyclyl.

The modulators of the invention are capable of replacing at least 50% of the binding of the chemokines SDF-1 or I-TAC to the CCXCKR2 receptor at a concentration of 1.1 micromolar (. mu.M) or less than 1.1 micromolar (. mu.M) and more preferably at a concentration of 300 nanomolar (nM) or less than 300 nanomolar (nM). At present, particularly preferred compounds are capable of replacing at least 50% of SDF-1 or I-TAC binding to the CCXCKR2 receptor at a concentration of 200 nanomolar or less than 200 nanomolar.

The wavy bond linking the olefin to the substituted benzene ring represents the ring relative to R⁶May be cis or trans. In a preferred embodiment, n is 1, 2 or 3. In another preferred embodiment, n is 2 or 3. In another preferred embodiment, n is 3.

Known compounds

The following compounds are known, but are not CCXCKR2 modulators:

these compounds are excluded from the modulators (I) of the present invention.

Alternatively, modulators (I) of the invention may have one or more of the following limitations:

if Z is-NR¹R²And R is¹And R²Together with Z form morpholinyl, then n is 3 and R³、R⁴And R⁵At least one of which is hydroxyl, alkoxy or aryloxy; or

If n is 1 and Z is-CHR¹R²Then R¹And R²In which the binding is other than-CH₂CH₂NCH₂CH₂-; or

If n is 3 and Z is-NR¹R²Then R¹And R²Does not bind to-CHNCHCH-; or

If R is¹And R²Together are-CH (CH)₃)(CH₂)₄-, then Z is-CH-; or

If R is⁵Is tert-butyl, then R³Is hydrogen; or

If R is⁴And R⁵Together form a 5-membered ring, then at least one of the atoms bonded to the phenyl ring is carbon.

If n ═ 1 and Z are alkyl-CHR¹R²Wherein R is¹And R²Each is methyl, then R³Or R⁵Neither can be alkyl; or R³、R⁴Or R⁵Each cannot be hydrogen at the same time; or R⁴And cannot be methyl.

Preferred substituents

R⁶Preferably hydrogen, halogen or C_1-8Alkyl, more preferably methyl.

R³、R⁴And R⁵Preferably each is independently selected from hydrogen, -OR' and substituted OR unsubstituted C_1-8An alkyl group. More preferably R³、R⁴And R⁵Each independently selected from hydrogen and-OR ', wherein R' is substituted C_1-8An alkyl group.

In another preferred embodiment, R⁴And R⁵Together with the atoms to which they are substituted, may form a ring selected from a substituted or unsubstituted 3-to 10-membered heterocyclic group. More preferably, R⁴And R⁵Together with the atoms to which they are substituted, form a substituted or unsubstituted 5-to 6-membered heterocyclic group containing 1-2 oxygen atoms.

Z is preferably-CHR¹R²or-NR¹R²。

In a preferred embodiment, Z is-CHR¹R²Wherein R is¹And R²Together with Z form a substituted or unsubstituted ring having 0-3 substituents selected fromC of radical_3-10Cycloalkyl groups: halogen, -CN, -NO₂、-OH、-OR’、-C(O)R’、-CO₂R’、-O(CO)R’、-C(O)NR’R”、-OC(O)NR’R”、-SR’、-SOR’、-SO₂R’、-SO₂NR’R”、-NR’R”、-NR’C(O)R”、-NR’C(O)₂R”、-NR’SO₂R ", -NR 'C (O) NR" R' ", unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl.

In another preferred embodiment, R¹And R²Together with Z, form a 3-to 10-membered heterocyclyl having 0-3 substituents selected from: halogen, -OR, substituted OR unsubstituted C_1-8Alkyl, substituted or unsubstituted C_1-8Alkenyl, substituted or unsubstituted C_1-8Alkynyl, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 3-to 10-membered heterocyclyl. More preferably, Z and R¹And R²In combination with a substituent selected from the group consisting of substituted or unsubstituted morpholinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, and substituted or unsubstituted piperazinyl.

In another preferred embodiment, Z is a substituted or unsubstituted group of the formula:

more preferably, Z is a substituted or unsubstituted group of the formula:

wherein R is⁷Selected from hydrogen, -C (O) R', -CO₂R’、-C(O)NR’R”、-SO₂R' is unsubstituted or substituted C_1-10Alkyl, unsubstituted or substituted C_1-8Alkoxy (including, for example, C)_1-10Alkoxyalkoxy radicals, e.g. -CH₂-CH₂OCH₂-CH₂-OCH₃) Unsubstituted or substituted C_2-10Alkenyl, unsubstituted or substituted C_2-10Alkynyl, unsubstituted or substituted C_3-10Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl.

R⁷Most preferably substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_1-10Alkoxy or substituted or unsubstituted C_3-10A cycloalkyl group.

n is preferably 1, 2 or 3.

m is preferably 0, 1 or 2.

When present, Y is preferably halogen.

A modulator having structure (II) or a diastereomer, enantiomer or pharmaceutically acceptable salt thereof:

wherein each Y is independently hydrogen or halogen;

^R3、R⁴and R⁵Each is independently selected from hydrogen, halogen and-OR'; or R³、R⁴And R⁵Any two of which, together with the atoms to which they are substituted, form an unsubstituted or substituted 3-to 10-membered heterocyclyl; and R⁷Selected from hydrogen, -C (O) R', -CO₂R’、-C(O)NR’R”、-SO₂R' is unsubstituted or substituted C_1-10Alkyl, unsubstituted or substituted C_1-8Alkoxyalkoxy (including, for example, C)_1-10Alkoxyalkoxy radicals, e.g. -CH₂-OCH₂OCH₃) Unsubstituted or substituted C_2-10Alkenyl, unsubstituted or substituted C_2-10Alkynyl, unsubstituted or substituted C_3-10Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl.

Synthesis method

While a variety of synthetic routes known to those of ordinary skill in the art can be used to synthesize the active compounds of the present invention, a general synthetic approach is given in scheme I below.

Scheme 1

In scheme I, aldehyde (2) undergoes a condensation reaction with primary amine (3) by reductive amination. Suitable primary amines are commercially available, for example, from Aldrich, Milwaukee, Wis, or can be synthesized by chemical routes known to those of ordinary skill in the art.

The amination reaction can be carried out with a reducing agent in any suitable solvent, including but not limited to Tetrahydrofuran (THF), dichloromethane or methanol, to form intermediate (4). Suitable reducing agents for use in the condensation reaction include, but are not limited to, sodium cyanoborohydride (as described in Mattson et al, J.org.chem.1990, 55, 2552 and Barney et al, Tetrahedron Lett.1990, 31, 5547), sodium triacetoxyborohydride (as described in Abdel-magic et al, Tetrahedron Lett.1990, 31, 5595), sodium borohydride (as described in Grible; Nutaitis Synthesis.1987, 709), iron pentacarbonyl and alcoholic KOH solutions (as described in Watabane et al, Tetrahedron Lett.1974, 1879), and BH 9₃Pyridine (as described in Pelter et al, J.chem.Soc., Perkin Trans.1, 1984, 717)

The conversion of intermediate (4) to compound (5) can be carried out using the appropriately substituted acid chloride in the presence of a base in any suitable solvent, such as tetrahydrofuran or dichloromethane. Tertiary amine bases are preferred. Particularly preferred bases include triethylamine and Hunnings base.

Alternatively, conversion of intermediate (4) to compound (5) may also be obtained in the presence of a catalyst such as 4-N, N-dimethylaminopyridine, or in the presence of hydroxybenzotriazole (as described in k.horiki, synth.commu., 7, 251), using a suitable coupling reagent such as propane phosphonic acid cyclic anhydride (propane phosphonic acid cyclic hydride), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate, 1-ethyl-3- (3-dimethylbutylpropyl) carbodiimide, or dicyclohexyl-carbodiimide (as described in BNeises and w.steglich, angelw.chem., int.ed.engl., 17, 522, 1978).

Pharmaceutical composition

Pharmaceutical compositions for the administration of the claimed active compounds (or salts thereof) may be presented in unit dosage form and may be prepared by any of the methods known in the pharmaceutical art. Preferred methods include the step of admixing the active compound, compound or salt thereof with one or more carriers comprising one or more accessory ingredients.

In one embodiment, a pharmaceutical composition is prepared by admixing an active compound or a salt thereof with an associated liquid carrier, finely divided solid carrier, or both. The composition can then be shaped into the desired formulation product, if desired. In a pharmaceutical composition, the active compound is included in a therapeutically effective amount.

Including but not limited to pharmaceutically acceptable salts, pharmaceutical compositions containing the active compounds may be presented in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets and which may include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin or acacia and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time delay materials such as glycerol monostearate or glycerol distearate may be employed. Tablets may also be coated by techniques described in U.S. Pat. nos. 4256108, 4166452 and 4265874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil vehicle, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may also contain the active composition in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are commonly referred to as suspending, dispersing or wetting agents. Preferred suspending agents include, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.

Preferred dispersing or wetting agents may be naturally occurring phosphatides, for example lecithin; condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethoxyhexadecanol (heptadecetyleneoxyethanol); condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by those examples already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be presented as 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, esters and partial esters derived from fatty acids, 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.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain lubricating agents, preservatives, flavoring and coloring agents.

The pharmaceutical compositions of the present invention may also be used in combination with therapies that modulate chemokine receptor activity, thereby preventing and treating inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune diseases such as rheumatoid arthritis, AIDS, atherosclerosis, and the like. For example, in the treatment or prevention of inflammation, the compounds of the present invention may be used in combination with an anti-inflammatory or analgesic agent, e.g., an opioid agonist, a lipoxygenase inhibitor, e.g., a 5-lipoxygenase inhibitor, a cyclooxygenase inhibitor, e.g., a cyclooxygenase-2 inhibitor, an interleukin inhibitor, e.g., an interleukin-1 inhibitor, an NMDA antagonist, a nitric oxide inhibitor or an inhibitor of nitric oxide synthesis, a non-steroidal anti-inflammatory agent, or a cytokine-suppressing anti-inflammatory agent, such as the following compounds, including, for example: acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, steroidal analgesics, sufentanil, sulindac, tenidap, and the like. Similarly, the compounds of the invention may be combined with pain relieving agents. A potentiator such as caffeine, an H2-antagonist, simethicone, aluminum hydroxide, or magnesium hydroxide, a decongestant such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-deoxy-ephedrine, an anti-cough agent such as codeine, hydrocodone, caramiphene, pentoxyverine, or dextromethorphan, a diuretic agent administered with a sedating or non-sedating antihistamine.

The compounds of the present invention may be used in combination with other drugs for the treatment/prevention/inhibition or alleviation of the diseases or conditions for which the compounds of the present invention are useful. Such other agents may be administered by route and in amounts commonly used, either simultaneously or separately with the compounds of the present invention. When the compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The pharmaceutical compositions may be in the form of injectable aqueous or oily suspensions. Such suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, including those mentioned above. The injectable formulations may also be sterile injectable solutions or suspensions in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending vehicle. For this purpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compositions of the invention may be injected directly into a solid tumor, tissue surrounding a solid tumor, or blood vessels that vascularize a solid tumor.

The compounds of the present invention may also be administered in the form of suppositories for rectal administration. 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.

For topical use, patches, creams, ointments, gels, solutions, suspensions and dispersions containing one or more compounds of the invention may be used. Topical application also includes mouth washes and mouth washes. The pharmaceutical compositions and methods of the invention may additionally include other therapeutically active compounds useful for the treatment of cancer.

In the treatment of cancer with modulators of the invention, suitable dosage levels of the antagonist will generally range from about 0.01 to 500mg per kg of patient body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level is from about 0.1 to about 250mg/kg per day, more preferably from about 0.5 to about 100mg/kg per day. Suitable dosage levels may range from about 0.01 to 250mg/kg per day, from about 0.05 to 100mg/kg per day, or from about 0.1 to 50mg/kg per day. Dosages within this range may be 0.05-0.5, 0.5-5, or 5-50mg/kg per day.

For oral administration, the compositions are preferably provided to the patient to be treated in the form of tablets containing 1.0 to 1000mg of the active ingredient, in particular 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 1000.0mg of the active ingredient in a dosage which modulates the systemic symptoms. The compounds may be administered on a regimen comprising 1 to 4 doses per day, preferably 1 or 2 doses per day.

It will be understood, however, that the specific dose level and number of doses for any particular patient will vary depending upon a variety of factors. These factors include the activity of the specific compound employed, the metabolic stability and length of action of the compound, age, body weight, general health, sex, diet, mode and frequency of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Method for blocking CCXCKR2 receptor

While not wishing to be bound by any particular theory, the compositions of the present invention are believed to provide a means of inhibiting the binding of SDF-1 and/or I-TAC to the CCXCKR2 receptor. SDF-1 is known to provide a target that interferes with the development or spread of cancer cells in mammals such as humans. As shown below in examples 24-26, inhibition of I-TAC binding to CCXCKR2 receptor prevented vascularized tumor formation. By contacting the above-described composition with cancer cells expressing the CCXCKR2 receptor, the otherwise initiated invasive response in the cancer cells can be reduced. Thus, the present invention also relates to a method for the prevention and/or treatment of cancer, in particular solid tumor cancer, more particularly breast cancer.

CCXCKR2 is preferentially expressed in human transformed cells as determined by radiolabeled SDF-1 binding and I-TAC displacement. Table 2 includes the data in which CCXCKR2 is expressed (CCXCKR 2)⁺) And wherein CCXCKR2 is not expressed (CCXCKR 2)^-) Those tissue types of (a).

TABLE 2

CCXCKR2⁺	CCXCKR2^-
CCXCKR2⁺	CCXCKR2^-	Human neck adenocarcinoma	Adult progenitor of normal mouse (c-kit +&CD34+ BM derived)
Human adenocarcinoma, mammary gland	Human acute lymphoblastic leukemia, T cells	Human neck adenocarcinoma	Adult progenitor of normal mouse (c-kit +&CD34+ BM derived)
Human adenocarcinoma, mammary gland	Human acute lymphoblastic leukemia, T cells	Human burkitt's lymphoma, B lymphocyte	Normal mouse bone marrow
Human glioblastoma multiforme, brain	Normal mouse thymus	Human burkitt's lymphoma, B lymphocyte	Normal mouse bone marrow
Human glioblastoma multiforme, brain	Normal mouse thymus	Human cancer, prostate	Normal mouse lung
Murine lymphoblastic leukemia, B lymphocytes	Spleen of normal mouse	Human cancer, prostate	Normal mouse lung
Murine lymphoblastic leukemia, B lymphocytes	Spleen of normal mouse	Mammary tumor of mouse	Normal mouse liver
Liver of normal mouse fetus	Normal mouse PBL	Mammary tumor of mouse	Normal mouse liver
Liver of normal mouse fetus	Normal mouse PBL	Normal mouse brain	Normal human PBL
Normal mouse kidney	Normal mouse Heart	Normal mouse brain	Normal human PBL
Normal mouse kidney	Normal mouse Heart		Normal mouse pancreas

In one embodiment, a preferred method of inhibiting the binding of chemokines SDF-1 and/or I-TAC to the CCXCKR2 receptor comprises contacting one or more of the previously mentioned compounds with a cell expressing the CCXCKR2 receptor for a time sufficient to inhibit the binding of these chemokines to the CCXCKR2 receptor.

Methods of treating cancer

The invention also provides methods of treating cancer. A preferred method of treating cancer comprises administering to a cancer patient a therapeutically effective amount of one or more of the previously mentioned compounds (or salts thereof) for a time sufficient to treat the cancer.

For therapeutic purposes, the compositions of the present invention may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), by inhalation spray, nasal, vaginal, rectal, sublingual or topical routes of administration, and may be formulated alone or in suitable dosage units containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

In addition to primates, such as humans, various other mammals can be treated according to the methods of the present invention. For example, mammals can be treated including, but not limited to, cattle, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species. However, the method may also be carried out in other species such as birds (e.g. chickens).

Standard in vivo tests demonstrating the use of the compositions of the present invention for the treatment of cancer include those described in the following literature, Bertolini, F. et al, endothelin, an Antiangiogenic drug, inducing tumor stability following chemotherapy or anti-CD20therapy in the NOD/SCID mouse model of human high grade non-Hodgkin's lymphoma (Endostatin, an anti-angiogenic drug, inductor tumor stabilization after chemotherapy or anti-CD20therapy (endo vascular model of human high-grade non-Hodgkin lymphoma). Blood, No. 1, 96 vol., 282-87 (1 st.7), Pengnian, L., Antiangiogenic gene therapy targeting endothelial specific receptor tyrosine kinase 2 (anticancer targeting peptide kinase type, Nature toxin, 1998. 29. 9. et 35. mu. and Nature gold toxin, Nature 9. Ex. 3. A. Ex. No. 3. Et. Ex. No. 3 The synergistic effect of Class II major histocompatibility Complex and CD80for use in Clinically relevant immunotherapy for developing Spontaneous metastasis in a post-operative mouse Breast Cancer Model (cooperative of Staphylococcus aureus Enterotoxin B superior, MajorHistohistocompatibility Complex Class II, and CD80for immunological approach of diverse distances methods in a clinical Research recent prescription Model.) Cancer Research, 60, 2710-15 (5/15/2000).

The previous description is not intended to limit the scope of the described embodiments of the invention, but rather to enable any person skilled in the art of organic chemistry and pharmacology to make and use the invention. Similarly, the following examples are not to be construed as limiting the scope of the appended claims or their equivalents, and are provided as illustrative examples only. It is understood that various modifications may be made in the following compositions and methods which are within the scope of the appended claims and their equivalents.

Examples

Example 1: synthesis of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine:

0.5g of 2- (1-methyl-pyrrolidin-2-yl) -ethylamine (3.89mmol) and 0.56g of 2-methyl-3-phenyl-acrolein are combined in 20ml of anhydrous dichloromethane. The mixture was stirred over 5g of magnesium sulfate under nitrogen. After two days, Thin Layer Chromatography (TLC) using a 9: 1: 0.1 dichloromethane/methanol/ammonium hydroxide eluent showed no presence of starting material. The reaction mixture was filtered and the collected solid was washed with dichloromethane. The resulting organic layer was then concentrated in vacuo. To the residual mixture was added 10ml of dry methanol under nitrogen and the solution was cooled to 0 ℃. To this mixture was added 0.14g of sodium borohydride. TLC showed no starting material present after about 15 minutes. The reaction was then quenched with acetone (1ml) and the solvent was removed by distillation. The mixture was partitioned between 5ml water-chloroform and the layers were separated. The aqueous layer was then extracted 3 times with 30ml chloroform. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo afforded 0.78g of a pale yellow solid. Yield: 77 percent.

LC-MSD, m/z vs C₁₇H₂₆N₂[M+H]+：259，[M+2H]+：260

¹H NMR(400MHz，CDCl₃)：δ1.4-1.6(m，2H)，1.67-1.82(m，3H)，1.9-2.0(m，3H)，2.02-2.20(m，2H)，2.38(s，3H)，2.58-2.79(m，2，H)，3.02-3.08(m，1H)，3.39(s，2H)，7.16-7.39(m，5H).

Example 2: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -benzamide.

0.48g (2.4mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to 20ml of anhydrous tetrahydrofuran. To this stirred solution was added 0.23ml (2.4mmol) of anhydrous triethylamine. After about 15 minutes, 0.52g (2.4mmol) of 3, 4, 5-trimethoxybenzoic acid was added. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. Then 0.24g (1.76mmol) of 1-hydroxybenzotriazole is added and after a further 30 minutes 0.42g (1.6mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine is added. After stirring at room temperature overnight, the reaction was quenched with 5ml of water and extracted with 20ml of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The mixture was purified by elution from silica gel with 9: 1 dichloromethane/methanol to give 0.38g of a colorless oil. Yield: 53 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₄[M+H]+：453.2，[M+2H]+：454.2。

¹H NMR(400MHz，CDCl₃)：δ1.44-2.22(m，10H)，2.35(s，3H)，2.92-3.18(m，2H)，3.2-3.4(m，2H)，3.60-3.66(m，1H)，3.8-4.02(m，9H)，4.2-4.4(m，2H)，6.45(s，1H)，6.63-6.71(m，2H)，7.21-7.35(m，5H).

Example 3: 3, 4-bis-difluoromethoxy-3-methoxy-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -benzamide

A mixture of 0.1g (0.4mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine and 0.11g (0.44mmol) of 3, 4-bis-difluoromethoxy-benzoic acid was dissolved in 20ml of ethyl acetate. To the mixture was added 0.16ml of triethylamine and stirred at room temperature for 20 minutes. Then 0.25ml (0.44mmol) of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate) was added to the mixture and stirred at room temperature overnight. To the mixture was added 5ml of a saturated sodium bicarbonate solution and stirred for 5 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate and combined with the organic layer. The organic layer was then dried, concentrated and chromatographed on silica gel eluting with dichloromethane 9.5: methanol 0.5 to give the free amine.

The compound was dissolved in dichloromethane under nitrogen and cooled to 0 ℃ and converted to the HCl salt with HCl-ether solution to give 34mg of a white, hygroscopic compound. Yield: 7 percent.

LC-MSD, m/z vs C₂₆H₃₀F₄N₂O₃[M+H]+：495.1

¹H NMR(400MHz，CDCl₃)：δ1.7(s，3H)，1.9-2.5(m，5H)，2.7-3.0(m，3H)，3.1-3.5(m，1H)，3.3-3.5(m，1H)，3.6-4.0(m，6H)，6.2-6.4(m，1H)，6.5-6.8(m，2H)，7.1-7.5(m，8H).

Example 4: 3, 4, 5-triethoxy-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) -ethyl-benzamide.

Similar procedure as discussed in example 2 was used with 0.22g (0.8mmol) of 3, 4, 5-triethoxy carboxylic acid and 0.1g (0.38mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine, 0.11g (0.57mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.05g (0.418mmol) of 1-hydroxybenzotriazole and 0.08ml of triethylamine. The resulting product was purified by preparative high performance liquid chromatography with a mobile phase gradient comprising 20% to 80% acetonitrile and 0.1% trifluoroacetic acid in water. 84.3mg (0.13mmol) of white powder as TFA salt are obtained. Yield: 30 percent.

LC-MSD, m/z vs C₃₀H₄₂N₂O₄[M+H]+：495.3，[M+2H]+：496.3。

Example 5: 4-difluoromethoxy-3-methoxy-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -benzamide

Using experimental conditions similar to example 3, 0.1g (0.4mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine, 0.93g (0.44mmol) of 4-difluoromethoxy-3-methoxy-benzoic acid, 0.25ml (0.4mmol) of 1-propanephosphonic acid cyclic anhydride (50% ethyl acetate) and 0.16ml of triethylamine were used. The free amine formed was converted to 38mg of a white, hygroscopic solid as the HCl salt. Yield: 8 percent.

Within 20 minutesAnalysis C with a gradient of 20-95% acetonitrile¹⁸HPLC, eluting compound at 14.504 min.

LC-MSD, m/z vs C₂₆H₃₂N₂O₃F₂[M+H]+：459.1，[M+2H]+：460.1，[M+3H]：461.2

Example 6: 3, 4-dimethoxy-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) ethyl ] -benzamide

Similar procedure as discussed in example 2 was used using 0.1g (0.38mmol) of 3, 4-dimethoxycarboxylic acid and 0.1g (0.38mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine, 0.11g (0.57mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.05g (0.41mmol) of 1-hydroxybenzotriazole and 0.08ml of triethylamine to yield 179mg of a light yellow oil. Yield: 41 percent.

LC-MSD, m/z vs C₂₈H₃₂N₂O[M+H]+：423.2.2，[M+2H]+：424.2。

Example 7: 3, 5-dimethoxy-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) ethyl ] -benzamide

Using a similar method to that discussed in example 2, using 0.1g (0.38mmol) of 3, 5-dimethoxycarboxylic acid and 0.1g (0.38mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine, 0.11g (0.57mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.05g (0.41mmol) of 1-hydroxybenzotriazole and 0.08ml of triethylamine gives 140mg of a light yellow oil. Yield: 33 percent.

LC-MSD, m/z vs C₂₆H₃₄N₂O₃[M+H]+：423.2.2，[M+2H]+：424.2。

¹H NMR(400MHz，CDCl₃)：δ1.44-2.00(m，14H)，2.25(s，3H)，2.92-3.08(m，1H)，3.2(m，1H)，3.6(m，1H)，3.7(s，3H)，3.8(s，2H)，6.3-6.5(m，3H)，7.1-7.4(m，5H)

Example 8: 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amide

Similar procedure as discussed in example 2 was used using 0.07g (0.3mmol) of 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid and 0.05g (0.2mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine, 0.56g (0.28mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.05g (0.2mmol) of 1-hydroxybenzotriazole and 0.04ml of triethylamine. The resulting product was purified by preparative high performance liquid chromatography with a mobile phase gradient comprising 20% to 70% acetonitrile in 0.1% trifluoroacetic acid in water. 16.3mg (0.13mmol) of HCl salt are obtained as a white powder. Yield: 4 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 15.196 min.

LC-MSD, m/z vs C₂₈H₃₆N₂O₄[M+H]+：465.2，[M+2H]+：466.2。

Example 9: 3, 5-dibromo-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -benzamide

In a similar manner to example 2, 0.16g (0.38mmol) of 3, 5-dibromo-benzoic acid and 0.1g (0.38mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine, 0.11g (0.57mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.05g (0.41mmol) of 1-hydroxybenzotriazole and 0.08ml of triethylamine were used. Reverse phase preparative HPLC was performed with a gradient of 20% to 80% acetonitrile to give 153mg of TFA salt. Yield: and 63 percent.

LC-MSD, m/z vs C₂₄H₂₈N₂OBr₂[M+H]+：519.3，[M+2H]+：520.3，[M+3H]+：521.3，[M+4H]+：522.3，[M+5H]+：523.3，[M+6H]+：524.3。

Example 10: 3, 5-dimethyl-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -benzamide

In a similar manner to example 2, 0.16g (0.38mmol) of 3, 5-dimethyl-benzoic acid and 0.1g (0.38mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine, 0.11g (0.57mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.05g (0.41mmol) of 1-hydroxybenzotriazole and 0.08ml of triethylamine were used. Reverse phase preparative HPLC was performed on a 20-80% acetonitrile phase containing 0.1% trifluoroacetic acid to give 60mg of the TFA salt. Yield: 32 percent.

LC-MSD, m/z vs C₂₆H₃₄N₂O[M+H]+：391.5，[M+2H]+：392.4。

Example 11: 4-methoxy-3, 5-dimethyl-N- (2-methyl-3-phenyl-allyl) -N- [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -benzamide

In a similar manner to example 2, 0.108g (0.58mmol) of 4-methoxy-3, 5-dimethyl-benzoic acid and 0.1g (0.38mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine, 0.11g (0.57mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.05g (0.41mmol) of 1-hydroxybenzotriazole and 0.08ml of triethylamine were used. Reverse phase preparative HPLC was performed on a gradient of 20% to 80% acetonitrile containing 0.1% trifluoroacetic acid to give 45.4mg of the TFA salt. Yield: 22 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₂[M+H]+：421.2，[M+2H]+：422.2。

Example 12: 3, 4-dihydro-2H-benzo [ b ] [1, 4] dioxaheptine (dioxine) -7-carboxylic acid (2-methyl-3-phenyl-allyl) -2[ - (1-methyl-pyrrolidin-2-yl) -ethyl ] -amide

A mixture of 0.1g (0.38mmol) of (2-methyl-3-phenyl-allyl) - [2- (1-methyl-pyrrolidin-2-yl) -ethyl ] -amine and 0.08ml (0.58mmol) triethylamine is stirred in 5ml of anhydrous dichloromethane at 0 ℃ under nitrogen. To this mixture was added 0.098g (0.456mmol) of 3, 4-dihydro-2H-benzo [ b ] [1, 4] dioxaheptin-7-carbonyl chloride. To the reaction mixture were added 25ml of ethyl acetate and 5ml of water. The organic layer was separated from water and then dried over sodium sulfate. The organic layer was filtered and evaporated in vacuo. Purification using flash chromatography eluting with ethyl acetate 9.5, methanol 0.5 and ammonium hydroxide 0.05 gave a brown oil.

LC-MSD, m/z vs C₂₇H₃₄N₂O₃[M+H]+：435.2，[M+2H]+：436.2。

Example 13: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (2-pyrrolidin-2-yl-ethyl) -benzamide

a: BOC-anhydride, NaOH, acetonitrile, 3 hours, room temperature

b: borane dimethylsulfide, tetrahydrofuran, 14 hours, room temperature

c: methanesulfonyl chloride, triethylamine, dichloromethane, 4 hours at room temperature

d: sodium cyanide, dimethylformamide, 5 hours, room temperature

e: raney nickel, ammonia in methanol, H₂2.5kg pressure, 14 hours

f: 1/1-methylcinnamaldehyde, dichloromethane, 16 hours, room temperature, N₂2/sodium borohydride, methanol, at 0 ℃ for 30 minutes

Scheme 1: preparation of 2- [2- (2-methyl-3-phenyl-allylamino) -ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of compound 2- [2- (2-methyl-3-phenyl-allylamino) -ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared from racemic proline according to scheme 1) 0.6g (2mmol) and 3, 4, 5-trimethoxybenzoic acid 0.513g (2.4mmol) in 10ml of dry dichloromethane was added triethylamine 0.2ml and stirred at room temperature for 20 min. O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (1.3 g, 4mmol) was then added at 0 ℃. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and then 10% NaHCO₃The solution was washed with water and brine, dried, concentrated and chromatographed on silica gel using CHCl₃MeOH as eluent, 1g of 2- {2- [ (2-methyl-3-phenyl-allyl) -3, 4, 5-trimethoxy-benzoyl) -amino]-ethyl } -pyrrolidine-1-carboxylic acid tert-butyl ester.

This compound was dissolved in 10ml dioxane and 6N HCl 10ml was added thereto. The reaction mixture was stirred at room temperature for 14 hours, basified with 10% NaOH solution, and extracted twice with ethyl acetate (15 ml). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give 0.35g of free amine. 100mg of the free amine was converted to its hydrochloride salt using dry HCl in ether to give 88mg of a white solid. Yield: 39 percent.

LC-MSD, m/z vs C₂₆H₃₄N₂O₄[M+H]+：439.3

¹H NMR(300MHz，MeOD/D2O)：δ1.6-1.8(m，4H)，1.9-2.1(m，4H)，2.25(m，1H)，3.2(m，3H)，3.5-3.8(m，12H)，4.1(s，2H)，6.5(s，1H)，6.7-6.9(m，2H)，7.2-7.5(m，5H)

Example 14: n- [2- (1-benzyl-pyrrolidin-2-yl) -ethyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (2-pyrrolidin-2-yl-ethyl) -benzamide 0.11g (2.5mmol) and freshly distilled benzaldehyde 0.026g (2.5mmol) were treated in 10ml dry methanol. 0.022ml (3.7mmol) of acetic acid was added thereto at 0 ℃. The reaction mixture was stirred at room temperature for 30 minutes and 0.023g (3.7mmol) of sodium cyanoborohydride was added at 0 ℃. The reaction mixture was gradually warmed to room temperature and stirred for 14 hours. The reaction mixture was concentrated, the residue diluted with water and extracted with chloroform (3X 20 ml). Successively with 10% NaHCO₃The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated and the residue was purified by silica gel column chromatography to give the pure desired compound. It was converted to its hydrochloride salt using dry HCl in ether to give 90mg of the product. Yield: and 63 percent.

LC-MSD, m/z vs C₃₃H₄₀N₂O₄[M+H]+：529.3

¹H NMR(300MHz，MeOD/D2O)：δ1.8-2.2(m，10H)，2.5(m，1H)，3.4-3.6(m，4H)，3.7(m，1H)，3.8(m，9H)，4.0(s，3H)，4.2-4.5(m，2H)，4.7(d，1H)，6.25(s，1H)，6.8(s，2H)，7.2-7.6(m，10H).

Example 15: n- [2- (1-ethyl-pyrrolidin-2-yl) -ethyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

To a solution of 0.1g (2.28mmol) of 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (2-pyrrolidin-2-yl-ethyl) -benzamide in 5ml of dry dichloromethane was added 0.01g (2.7mmol) of sodium bicarbonate followed by 0.037g (3.4mmol) of ethyl bromide at 0 ℃. The reaction mixture was stirred at room temperature for 14 hours. The inorganic material was filtered off and the filtrate was concentrated. The crude material was subjected to column chromatography on silica gel eluting with chloroform-methanol to give the desired compound as the free amine. It was converted to 42mg of hydrochloride as a yellow semi-solid.

LC-MSD, m/z vs C₂₈H₃₈N₂O₄[M+H]+：467.4

¹H NMR(300MHz，MeOD)：δ1.1-2.4(m，4H)，2.7(s，3H)，1.7-2.1(m，4H)，2.4-2.5(m，2H)，3.0-3.2(m，2H)，3.4-3.6(m，2H)，3.6-3.9(m，10H)，4.1-4.2(m，2H)，6.4-7.5(m，8H).

Example 16: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (2- (S) -pyrrolidin-2-yl-ethyl) -benzamide

a: borane dimethylsulfide, tetrahydrofuran, 14 hours, room temperature

b: methanesulfonyl chloride, triethylamine, dichloromethane, 4 hours at room temperature

c: sodium cyanide, dimethylformamide, 5 hours, room temperature

d: raney nickel, ammonia in methanol, H₂2.5kg pressure, 14 hours

e: 1/1-methylcinnamaldehyde, dichloromethane, 16 hours, room temperature, N₂2/sodium borohydride, methanol, at 0 ℃ for 30 minutes

And (2) a flow scheme: preparation of 2- [2- (2-methyl-3-phenyl-allylamino) -ethyl- (S) -pyrrolidine-1-carboxylic acid tert-butyl ester

To the compound tert-butyl 2- [2- (2-methyl-3-phenyl-allylamino) -ethyl- (S) -pyrrolidine-1-carboxylate (prepared from (S) -pyrrolidine-1, 2-dicarboxylic acid-1-tert-butyl ester according to scheme 2) 0.47g (1.3mmol) and 0.3g (1.6mmol) of 3, 4, 5-trimethoxybenzoic acid in 10ml of dry dichloromethane was added triethylamine 0.1ml and stirred at room temperature for 20 min. Then 0.3g (2mmol) of 1-dimethylaminopropyl-3-ethylcarbodiimide and 0.018g (0.13mmol) of 1-hydroxybenzotriazole were added at 0 ℃. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then with 10% NaHCO₃The solution is washed with water and brine, dried, concentrated and subjected to column chromatography (silica gel, n-hexane: ethyl acetate as eluent) to give 0.57g of 2- {2- [ (2-methyl-3-phenyl-allyl) -3, 4, 5-trimethoxy-benzoyl) -amino]-ethyl } - (S) -pyrrolidine-1-carboxylic acid tert-butyl ester (yield: 76%). 0.22g (0.4mmol) of the compound is dissolved in 5ml of dry diethyl ether and 5ml of dry diethyl ether saturated with HCl is added at 0 ℃. The reaction mixture was stirred at room temperature for 10 hours. The ether was concentrated and the residue was washed 3-4 times with dry ether to give 0.12g of a white solid. Yield: 30 percent.

LC-MSD, m/z vs C₂₆H₃₄N₂O₄[M+H]+：439.3

¹H NMR(300MHz，MeOD)：δ1.6-1.8(m，4H)，2.0-2.25(m，6H)，3.3-3.5(m，3H)，3.2(m，3H)，3.5-4.0(m，12H)，4.1(s，1H)，6.5(s，1H)，6.8-7.0(m，2H)，7.2-7.5(m，5H).

Example 17: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (2- (R) -pyrrolidin-2-yl-ethyl) -benzamide

a: borane dimethylsulfide, tetrahydrofuran, 14 hours, room temperature

c: sodium cyanide, dimethylformamide, 5 hours, room temperature

d: raney nickel, ammonia in methanol, H₂2.5kg pressure, 14 hours

And (3) a flow path: preparation of 2- [2- (2-methyl-3-phenyl-allylamino) -ethyl- (R) -pyrrolidine-1-carboxylic acid tert-butyl ester

Using experimental conditions similar to example 13, 0.6g (2mmol) of tert-butyl 2- [2- (2-methyl-3-phenyl-allylamino) ] -ethyl- (R) -pyrrolidine-1-carboxylate (prepared from (R) -pyrrolidine-1, 2-dicarboxylic acid-1-tert-butyl ester according to scheme 3), 0.51g (2.4mmol) of 3, 4, 5-trimethoxybenzoic acid, 1.3g (4mmol) of O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate and 0.2ml of triethylamine were used. The intermediate 2- {2- [ (2-methyl-3-phenyl-allyl) - (3, 4, 5-trimethoxy-benzoyl) -amino ] -ethyl } -pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 10ml dioxane and 5ml 6N HCl, after base treatment and purification 0.35g of compound was obtained. Yield: 39 percent.

LC-MSD, m/z vs C₂₆H₃₄N₂O₄[M+H]+：439.3

¹H NMR(300MHz，MeOD/D2O)：δ1.8(s，4H)，1.9-2.25(m，6H)，3.2(m，3H)，3.5-4.0(m，12H)，4.1(s，1H)，6.5(s，1H)，6.8-7.0(m，2H)，7.2-7.5(m，5H).

Example 18: 3, 4, 5-trimethoxy-N [2- (S) -methoxymethyl-pyrrolidin-1-yl) -propyl ] -N- (2-methyl-3-phenyl-allyl) -benzamide

a: acrylonitrile, 70 ℃, 14 hours

b: raney nickel, ammonia, methanol, H₂Pressure of 3kg

c: 1/alpha-methyl cinnamic aldehyde, methylene chloride, N₂18 hours, room temperature 2/sodium borohydride, methanol, 0 ℃, 15 minutes

And (4) a flow chart: preparation of [2- (2- (S) -methoxymethyl-pyrrolidin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine

0.335g (1.58mmol) of 3, 4, 5-trimethoxybenzoic acid and 0.35ml (2.64mmol) of thionyl chloride are refluxed at 80 ℃ for 3 hours. The reaction mixture was concentrated to give the corresponding acid chloride. 0.4g (1.32mmol) of [2- (2- (S) -methoxymethyl-pyrrolidin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine (prepared from 3- (S) -2-methoxy-ethylpyrrolidine according to scheme 4) was treated with 20ml of dry dichloromethane. To this was added 0.1ml of triethylamine at room temperature, followed by addition of a solution of 3, 4, 5-trimethoxybenzoyl chloride in 15ml of dry dichloromethane at 0 ℃. The reaction mixture was gradually warmed to room temperature, stirred for 2 hours and treated with dichloromethane. Purification by column chromatography on silica gel afforded the pure product which was converted to the corresponding hydrochloride salt using HCl in ether to afford the desired compound as a white solid, 90 mg. Yield: 13 percent.

LC-MSD, m/z vs C₂₉H₄₀N₂O₅[M+H]+：497.3

¹H NMR(300MHz，MeOD)：δ1.75(m，4H)，2.01.9-2.25(m，5H)，3.0(m，1H)，3.4(s，3H)，3.6-4(m，17H)，4.1(s，1H)，6.4(s，1H)，6.8(s，2H)，7.2-7.5(m，5H).

Example 19: n- [3- (R) - (2-ethoxy-pyrrolidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

a: acrylonitrile, 70 ℃, 14 hours

b: raney nickel, ammonia, methanol, H₂Pressure of 3kg

And (5) a flow chart: preparation of [2- (2- (R) -methoxymethyl-pyrrolidin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine

Using experimental conditions similar to example 13, [3- (R) - (ethoxy-pyrrolidin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine (preparation of (R) -2- (methoxymethyl) pyrrolidine as described in scheme 5) 0.7g (2.3mmol) and 0.611g (2.89mmol) of 3, 4, 5-trimethoxybenzoic acid, 0.5ml of triethylamine and 0.893g (2.78mmol) of O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate were used. The reaction yielded the free amine, which was converted to the hydrochloride salt using dry HCl in ether to yield 50mg of solid compound. Yield: 4 percent.

LC-MSD, m/z vs C₂₉H₄₀N₂O₅[M+H]+：497.3

Example 20: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N [3- (3-methyl-piperidin-1-yl) -propyl ] -benzamide

a: acrylonitrile, 70 ℃, 14 hours

b: raney nickel, ammonia, methanol, H₂Pressure of 3kg

And (6) a flow path: preparation of (2-methyl-3-phenyl-allyl) - [3- (3-methyl-piperidin-1-yl) -propyl ] -amine

Using experimental conditions similar to example 13, (2-methyl-3-phenyl-allyl) - [3- (3-methyl-piperidin-1-yl) -propyl ] -amine (prepared from 3-methyl-piperidine as described in scheme 6) 1g (3.5mmol), 3, 4, 5-trimethoxybenzoic acid 0.89g (4.2mmol), triethylamine 0.5ml and O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate 1.68g (5.7mmol) were used. The reaction yielded the free amine, which was converted to 0.9g of hydrochloride as a white solid (using dry HCl in ether). Yield: 49 percent.

LC-MSD, m/z vs C₂₉H₄₀N₂O₄[M+H]+：481.2，[M+2H]+：482.2。

¹H NMR(300MHz，MeOD)：δ0.8-1.1(m，4H)，1.1-1.3(m，1H)，1.3-1.4(s，1H)，1.6-2.0(m，3H)，2.1-2.3(m，2H)，2.4-2.5(m，1H)，2.5-2.7(m，1H)，3.0-.3.1(m，2H)，3.3-3.5(m，2H)，3.5-3.7(m，2H)，3.7-3.9(m，10H)，4.0-4.4(m，2H)，6.5(s，1H)，6.7-7.0(m，2H)，7.2-7.5(m，5H).

Example 21: 1- {3- [ (2-methyl-3-phenyl-allyl) - (3, 4, 5-trimethoxy-benzoyl) -amino ] -propyl } -pyrrolidine-2 (S) -carboxylic acid dimethylamide

a: acrylonitrile, 70 ℃, 14 hours

b: raney nickel, ammonia, methanol, H₂Pressure of 3kg

Scheme 7: preparation of 1- [3- (S) -2-methyl-3-phenyl-allylamino) -propyl ] -pyrrolidine-2-carboxylic acid dimethylamide

Similar experimental conditions to example 3 were used using 0.15g (0.455mmol) of 1- [3- (S) - (2-methyl-3-phenyl-allylamino) -propyl ] -pyrrolidine-2-carboxylic acid dimethylamide (prepared from (S) -pyrrolidine-2-carboxylic acid dimethylamide as described in scheme 7), 0.125g (0.58mmol) of 3, 4, 5-trimethoxybenzoic acid, 0.3ml of triethylamine and 1-propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate). The reaction yielded 55mg of free amine.

The compound was dissolved in dry ether under nitrogen and cooled to 0 ℃ to give the HCl salt as a white precipitate. The ether layer was decanted and dried in vacuo to give 55mg of HCl salt as a white foam.

LC-MSD, m/z vs C₃₀H₄₁N₃O₅[M+H]+：524.3

¹H NMR(300MHz，MeOD)：δ1.1-1.3(m，1H)，1.75(m，3H)，1.75-2.2(m，6H)，2.5-2.75(m，1H)，2.9-3.1(m，7H)，3.2-3.4(m，1H)，3.5-3.6(m，1H)，3.7-3.9(m，9H)，4.0-4.1(m，3H)，4.6-4.89(m，1H)，6.4(s，1H)，6.8(s，2H)，7.1-7.4(m，5H).

Example 22: n- [3- (R) - (3-hydroxy-pyrrolidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

a: acrylonitrile, 70 ℃, 14 hours

b: raney nickel, ammonia, methanol, H₂Pressure of 3kg

And (3) a process 8: preparation of 1- (R) - [3- (2-methyl-3-phenyl-allylamino) -propyl ] -pyrrolidin-3-ol

Similar experimental conditions to example 3 were used with 0.5g (1.845mmol), 0.46g (2.1mmol) of 3, 4, 5-trimethoxybenzoic acid, 0.3ml of triethylamine and 0.34g of 1-propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate) in 20ml of ethyl acetate (prepared from (R) -pyrrolidin-3-ol as described in scheme 8). The reaction yielded 28mg of free amine. The compound was dissolved in dry ether and converted to the HCl salt to give 30mg of a white solid. Yield: 3 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₅[M+H]+：469.4

Example 23: n- [3- (2-benzyl-piperidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

a: acrylonitrile, 70 ℃, 14 hours

b: raney nickel, ammonia, methanol, H₂Pressure of 3kg

And (3) a process 9: preparation of [3- (2-benzyl-piperidin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine

Using experimental conditions analogous to example 3, 0.2g (0.5mmol) of [3- (2-benzyl-piperidin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine (prepared from 2-benzylpiperidine as described in scheme 9) in 20ml of ethyl acetate, 0.139g (0.65mmol) of 3, 4, 5-trimethoxybenzoic acid, 0.6ml of triethylamine and 0.5g of a solution of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate) were used. The free amine was converted to the HCl salt in diethyl ether to give 90mg of an off-white solid. Yield: 30 percent.

LC-MSD, m/z vs C₃₅H₄₄N₂O₄[M+H]+：557.5

¹H NMR(300MHz，MeOD)：δ1.05(t，1H)，1.3-1.8(m，10H)，2.0-2.2(m，2H)，2.7-2.8(m，1H)，2.8-3.9(m，20H)，4.4.2(m，2H)，6.4(s，1H)，6.8(s，2H)，7.1-7.4(m，5H).

Example 24: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- [3- (2-methyl-pyrrolidin-1-yl) -propyl ] -benzamide

a: acrylonitrile, 70 ℃, 14 hours

b: raney nickel, ammonia, methanol, H₂Pressure of 3kg

A process 10: preparation of (2-methyl-3-phenyl-allyl) - [3- (2-methyl-pyrrolidin-1-yl) -propyl ] -amine

Using experimental conditions similar to example 3, 0.14g (0.5mmol), (2-methyl-3-phenyl-allyl) - [3- (2-methyl-pyrrolidin-1-yl) -propyl ] -amine (prepared from 2-methyl-pyrrolidine as described in scheme 10) in 10ml ethyl acetate, 0.130g (0.65mmol) 3, 4, 5-trimethoxybenzoic acid, 0.1ml triethylamine and 0.7g propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate) were used. The free amine was converted to the HCl salt in ether to give 40mg of a brown semisolid. Yield: 15 percent.

LC-MSD, m/z vs C₂₈H₃₈N₂O₄[M+H]+：467.2

¹H NMR(300MHz，MeOD)：δ1.0(m，1H)1.2(t，2H)，1.3-1.5(m，2H)，1.7-1.8(m，4H)，2.1-2.5(m，5H)，3.0-3.2(m，2H)，3.5-3.6(m，2H)，3.6-3.9(m，9H)，4.2(m，2H)，6.5(s，1H)，6.9(s，2H)，7.2-7.5(m，5H).

Example 25: n- (3-hydroxy-propyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

6.1g (28mmol) of 3, 4, 5-trimethoxybenzoic acid and 5.22g of thionyl chloride were refluxed together under nitrogen for 4.5 hours. The excess thionyl chloride is then evaporated in vacuo and dried under a high vacuum pump. The dried acid chloride was then dissolved in 5ml of anhydrous THF and added with stirring to an ice-cold 10% NaOH solution of 3- (2-methyl-3-phenyl-allylamino) -propan-1-ol. The reaction mixture was then gradually brought back to room temperature. After 2 hours, the reaction was complete. The mixture was then extracted with dichloromethane and the solvent was evaporated, followed by drying over sodium sulfate. Then by column chromatography on silica gel (9/1: CHCl)₃MeOH) to give pure alcohol as a white solid8g of alcohol (c). Yield: 71 percent.

¹H NMR(300MHz，CDCl₃)：δ1.8-2.0(m，5H)，3.5-4.0(m，16H)，6.5(s，1H)，6.9(s，2H)，7.2-7.5(m，5H).

Example 26: n- [3- (4-benzyl-piperazin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

1g (2.5mmol) of N- (3-hydroxy-propyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide is dissolved in 20ml of dry ether under nitrogen. The solution was then cooled to 0 ℃ and 0.34g of phosphorus tribromide was added in portions with stirring. The mixture was gradually warmed to room temperature and stirred at room temperature for 1 hour. Crushed ice was then added to the reaction mixture. The organic layer was washed with 10% sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated to give the intermediate N- (3-hydroxy-propyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide. To a mixture of 0.26g (1.4mmol) of 1-benzylpiperazine and 0.3g (1.5mmol) of potassium carbonate in 5ml of DMF was added 0.6g (1.3mmol) of the bromo intermediate in 5ml of dimethylformamide. The reaction mixture was warmed at room temperature and stirred for 17 hours. To this mixture was added 30ml of water and extracted with chloroform (3X 30 ml). The organic layer was dried over sodium sulfate and evaporated to give a mixture of compounds. Purification using a silica gel column, eluting with 5% methanol in chloroform, gave 80mg of the free amine. Yield: 11 percent. The free amine was then converted to the HCl salt to give 40mg of a white powder.

LC-MSD, m/z vs C₃₄H₄₃N₃O₄[M+H]+：558.3

¹H NMR(300MHz，MeOD)：δ1.0(m，1H)，1.2(t，2H)，1.3-1.5(m，2H)，1.7-1.8(m，2H)，2.1-2.5(m，2H)，3.2(s，4H)，3.4-3.5(m，3H)，3.6-4.0(m，9H)，4.1(m，2H)，4.5(m，2H)，6.5(s，1H)，6.9(s，2H)，7.2-7.6(m，10H).

Example 27: n- [3- (4-benzyl-piperidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions analogous to example 26, using N- (3-hydroxy-propyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide intermediate (prepared from N- (3-hydroxy-propyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide) 0.4g (0.8mmol), 0.13g (0.74mmol) of 4-benzylpiperidine and 0.4g of potassium carbonate gives 80mg of the free amine. This compound was converted to the HCl salt to yield 87mg of a brown solid. Yield: 19 percent.

LC-MSD, m/z vs C₃₅H₄₄N₂O₄[M+H]+：557.3

Example 28: n- [3- (S) - (3-benzyl-piperazin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

a: acrylonitrile, 70 ℃, 14 hours

b: raney nickel, ammonia, methanol, H₂Pressure of 3kg

Scheme 11: preparation of [3- (S) - (3-benzyl-piperazin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine

Using experimental conditions similar to example 18, [3- (S) - (3-benzyl-piperazin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine (prepared from (S) -2-benzylpiperazine as described in scheme 11) 0.08g (0.24mmol), 3, 4, 5-trimethoxybenzoic acid 0.05g (0.24mmol), thionyl chloride 0.02ml (0.46mmol) and triethylamine were used. After purification the free amine was converted to the HCl salt to give 45mg of a brown semi-solid salt. Yield: 7 percent.

LC-MSD, m/z vs C₃₄H₄₃N₃O₄[M+H]+：558.3

¹H NMR(300MHz，MeOD)：δ1.2(t，2H)，1.7-1.9(m，3H)，2.3-1.4(m，1H)，3.0-4.2(m，24H)，6.5(s，1H)，6.8(s，2H)，7.1-7.4(m，10H).

Example 29: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (S) -pyrrolidin-2-yl-methyl-benzamide

And (3) a process 12: preparation of tert-butyl 2- (S) - [ (2-methyl-3-phenyl-allylamino) -methyl ] -pyrrolidine-1-carboxylate

Similar experimental conditions as in example 3 were used with 0.6g (1.8mmol), 0.46g (2.1mmol) of 3, 4, 5-trimethoxybenzoic acid, 0.1ml of triethylamine and 1.15g (3.63mmol) of a solution of propane phosphonic acid cyclic anhydride (50% in ethyl acetate) in 20ml of ethyl acetate tert-butyl 2- [ (2-methyl-3-phenyl-allylamino) -methyl ] -pyrrolidine-1-carboxylate (prepared according to scheme 12 from tert-butyl 2- (S) -aminomethyl-pyrrolidine-1-carboxylate). The reaction yielded 0.13g of the compound.

0.1g (0.24mmol) of tert-butyl 2- (S) - [ 2-methyl-3-phenyl-allyl) - (3, 4, 5-trimethoxy-benzoyl) -amino ] -methyl-pyrrolidine-1-carboxylate was dissolved in 5ml of dioxane. To this mixture was added 4ml of 6N HCl. The mixture was stirred at room temperature overnight. To this mixture was added 10% sodium hydroxide solution. The mixture was extracted with chloroform, and the organic layer was washed with brine, dried over sodium sulfate, and then concentrated. The free amine was converted to the hydrochloride salt to give 80mg (0.18mmol) of a white powder.

LC-MSD, m/z vs C₂₅H₃₂N₂O₄[M+H]+：425.3

¹H NMR(300MHz，MeOD/D₂O)：δ1.2(s，1H)，1.7-1.9(m，4H)，2.0-2.2(m，2H)，2.2-2.3(m，1H)，3.2-3.5(m，3H)，3.5-4.0(m，10H)，4.1(s，1H)，(6.5(s，1H)，7.0(s，2H)，7.2-7.4(m，5H).

Example 30: (S) -N- (1-benzyl-pyrrolidin-2-ylmethyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide.

Using experimental conditions similar to example 14, using 0.2g (0.4mmol) of 3, 4, 5-trimethoxy- (S) -N- (2-methyl-3-phenyl-allyl-N-pyrrolidin-2-ylmethyl) -benzamide, 0.14ml (1.4mmol) of benzaldehyde and 0.04ml (0.7mmol) of acetic acid and 0.04g (0.7mmol) of sodium cyanoborohydride gives 120mg of a white powder. Yield: 50 percent.

LC-MSD, m/z vs C₃₂H₃₈N₂O₄[M+H]+：515.5

¹H NMR(300MHz，MeOD)：δ1.1(t，1H)，1.5-1.7(s，3H)，1.9-2.2(m，3H)，2.2-2.4(m，1H)，3.3-3.7(m，2H)，3.8(s，10H)，4.0-4.1(m，3H)，4.4(d，1H)，4.6(d，1H)，6.4(s，1H)，6.8(s，2H)，7.2-7.4(m，5H)，7.5(s，3H)，7.7(s，2H)

Example 31: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (S) - (1-methyl-pyrrolidin-2-yl-methyl) -benzamide

Using experimental conditions analogous to example 14, 0.1g (0.23mmol) of 3, 4, 5-trimethoxy- (S) -N- (2-methyl-3-phenyl-allyl-N-pyrrolidin-2-ylmethyl) -benzamide, 0.035g (0.11mmol) of paraformaldehyde, 0.021ml (0.35mmol) of acetic acid and 0.02g (0.35mmol) of sodium cyanoborohydride are used. After conversion of the free base to the HCl salt, 65mg of a white solid was obtained. Yield: 54 percent.

LC-MSD, m/z vs C₂₆H₃₄N₂O₄[M+H]+：439.4

¹H NMR(300MHz，MeOD)：δ1.7(s，3H)，1.9-2.2(m，3H)，2.2-2.4(m，1H)，3.0(s，3H)，3.1-3.3(m，1H)，3.6-3.8(m，11H)，3.8-4.1(m，2H)，4.1-4.3(m，2H)，4.6(d，1H)，6.4(s，1H)，6.8(s，2H)，7.1-7.4(m，5H).

Example 32: n- (S) - (1-ethyl-pyrrolidin-2-ylmethyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions analogous to example 14, 0.2g (0.23mmol) of 3, 4, 5-trimethoxy- (S) -N- (2-methyl-3-phenyl-allyl-N-pyrrolidin-2-ylmethyl) -benzamide, 0.1g (2.3mmol) of acetaldehyde, 0.04ml (0.7mmol) of acetic acid and 0.043g (0.7mmol) of sodium cyanoborohydride are used. After conversion of the free base to the HCl salt, 40mg of a white solid was obtained. Yield: 35 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₄[M+H]+：453.4

¹H NMR(300MHz，MeOD/D₂O)：δ1.3-1.5(m，3H)，1.5-1.7(s，3H)，1.9-2.2(m，4H)，2.4-2.5(m，1H)，3.1-3.4(m，3H)，3.5-3.6(s，1H)，3.7-3.8(m，9H)，3.7-4.0(m，2H)，4.0-4.2(m，1H)，4.2(s，2H)，6.5(s，1H)，6.9(s，2H)，7.2-7.5(m，5H).

Example 33: n- (S) - [1- (4-fluoro-benzyl) -pyrrolidin-2-ylmethyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 30, 0.2g (0.47mmol) of 3, 4, 5-trimethoxy- (S) -N- (2-methyl-3-phenyl-allyl-N-pyrrolidin-2-ylmethyl) -benzamide, 0.17g (1.41mmol) of 4-fluorobenzaldehyde, 0.04ml (0.7mmol) of acetic acid and 0.044g (0.7mmol) of sodium cyanoborohydride were used. After conversion of the free base to the HCl salt, 80mg of a white solid was obtained. Yield: 35 percent.

LC-MSD, m/z vs C₃₂H₃₇N₂O₄F[M+H]+：533.3

¹H NMR(300MHz，MeOD/D₂O)：δ1.6-1.8(s，3H)，2.0-2.3(m，3H)，2.4-2.6(m，1H)，3.1-3.4(m，3H)，3.4-3.5(m，1H)，3.5-3.6(m，1H)，3.7(s，9H)，4.0-4.2(m，4H)，4.5(dd，3H)，6.5(s，1H)，6.9(s，2H)，7.1-7.5(m，7H)，7.7(s，2H).

Example 34: n- (S) - (1-isopropyl-pyrrolidin-2-ylmethyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions analogous to example 14, 0.15g (0.3mmol) of 3, 4, 5-trimethoxy- (S) -N- (2-methyl-3-phenyl-allyl-N-pyrrolidin-2-ylmethyl) -benzamide, 0.07g (1mmol) of dry acetone, 0.03ml (0.5mmol) of acetic acid and 0.033g (0.5mmol) of sodium cyanoborohydride are used. After conversion of the free base to the HCl salt, 90mg of an off-white solid was obtained. Yield: 58 percent.

LC-MSD, m/z vs C₂₈H₃₈N₂O₄[M+H]+：467.4

¹H NMR(300MHz，MeOD)：δ1.4-1.6(m，5H)，1.9(s，3H)，2.0-2.2(m，3H)，2.4-2.5(m，1H)，3.3-3.5(m，1H)，3.5-3.6(m，1H)，3.7-3.9(m，12H)，4.0-4.2(m，2H)，4.4(s，2H)，6.5(s，1H)，7.0(s，2H)，7.2-7.5(m，5H).

Example 34: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 30, 0.1g (0.23mmol) of 3, 4, 5-trimethoxy- (S) -N- (2-methyl-3-phenyl-allyl-N-pyrrolidin-2-ylmethyl) -benzamide, 0.037g (0.28mmol) of cyclohexanecarboxaldehyde, 0.02ml (0.35mmol) of acetic acid and 0.022g (0.35mmol) of sodium cyanoborohydride were used. After conversion of the free base to the HCl salt, 60mg of a pale yellow solid was obtained. Yield: 46 percent.

LC-MSD, m/z vs C₃₂H₄₄N₂O₄[M+H]+：521.5

¹H NMR(300MHz，MeOD)：δ1.0-1.5(m，6H)，1.6-1.9(m，8H)，2.0-2.1(m，2H)，2.1-2.3(m，2H)，2.4-2.5(m，1H)，3.0-3.1-3.6(m，1H)，3.6-3.9(m，12H)，3.9-4.1(m，2H)，4.1-4.4(q，2H)，6.5(s，1H)，7.0(s，2H)，7.2-7.5(m，5H).

Example 35: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (R) -pyrrolidin-2-ylmethyl-benzamide

Scheme 13: preparation of tert-butyl 2- (R) - [ (2-methyl-3-phenyl-allylamino) -methyl ] -pyrrolidine-1-carboxylate

Similar experimental conditions to example 22 were used with tert-butyl 2- (R) - [ (2-methyl-3-phenyl-allylamino) -methyl ] -pyrrolidine-1-carboxylate (prepared according to scheme 13) in 10ml DCM and with 0.5g (1.51mmol) of tert-butyl 2- (R) -carboxymethyl-pyrrolidine-1-carboxylate, 0.38g (1.8mmol) of 3, 4, 5-trimethoxybenzoic acid, 0.1ml of triethylamine, 0.43g (2.2mmol) of 1- (dimethylaminopropyl) -3-ethylcarbodiimide and 0.2g (1.5mmol) of 1-hydroxybenzotriazole. The reaction yielded 0.46g of tert-butyl 2- (R) { [ 2-methyl-3-phenyl-allyl ] -3, 4, 5-trimethoxy-benzoyl } -amino } -methyl } -pyrrolidine-1-carboxylate. After BOC deprotection in analogy to example 13, the compound was converted into the HCl salt to yield 0.35g of a white solid. Yield: 50 percent.

LC-MSD, m/z vs C₂₅H₃₂N₂O₄[M+H]+：425.4

¹H NMR(300MHz，MeOD)：δ1.1-1.4(m，1H)，1.6-1.9(m，3H)，2.0-2.2(m，2H)，2.2-2.3(m，1H)，3.2-3.5(m，3H)，3.5-3.7(m，1H)，3.7-3.10(m，10H)，4.1(s，3H)，6.5(s，1H)，7.0(m，2H)，7.2-7.5(m，5H).

Example 36: n- [3- (4-fluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide

The process 14: preparation of 3- (4-fluoro-phenyl) -2-methyl-propenal

Using experimental conditions similar to example 2, using tert-butyl 2- (S) - { [3- (4-fluoro-phenyl) -2-methyl-allylamino ] -methyl } -pyrrolidine-1-carboxylate in 10ml DCM and using tert-butyl 2- (S) -carboxymethyl-pyrrolidine-1-carboxylate and 3- (4-fluoro-phenyl) -2-methyl-acrolein as described in scheme 14) 0.36g (1.03mmol), 0.26g (1.2mmol) of 3, 4, 5-trimethoxybenzoic acid, triethylamine 0.2ml, 1- (dimethylaminopropyl) -3-ethylcarbodiimide 0.29g (1.55mmol) and 1-hydroxybenzotriazole 0.014g (0.1 mmol). The reaction yielded 0.32g of tert-butyl 2- (S) - { [3- (4-fluoro-phenyl) -2-methyl-allylamino ] -methyl } -pyrrolidine-1-carboxylate. BOC deprotection was carried out in analogy to example 13, converting the compound into the HCl salt to yield 69mg of a white solid. Yield: 14 percent.

LC-MSD, m/z vs C₂₅H₃₁FN₂O₄[M+H]+：443.4

¹H NMR(300MHz，MeOD)：δ1.6-2.0(m，5H)，2.0-2.3(m，3H)，2.3-2.5(m，1H)，3.2-3.6(m，2H)，3.6-4.0(m，10H)，4.1-4.3(m，4H)，6.5(s，1H)，7.0(m，2H)，7.2-7.4(m，4H).

Example 38: n- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide

Using experimental conditions similar to example 2, tert-butyl 2- (S) - { [3- (2, 4-difluoro-phenyl) -2-methyl-allylamino ] -methyl } -pyrrolidine-1-carboxylate in 10ml DCM was used for tert-butyl 2- (S) -carboxymethyl-pyrrolidine-1-carboxylate and 3- (2, 4-difluoro-phenyl) -2-methyl-propenal as described in scheme 15) 0.4g (1mmol), 0.27g (1.3mmol) of 3, 4, 5-trimethoxybenzoic acid, triethylamine 0.1ml, 1- (dimethylaminopropyl) -3-ethylcarbodiimide 0.31g (1.63mmol) and 1-hydroxybenzotriazole 0.014g (0.1 mmol). The reaction yielded 0.49g of tert-butyl 2- (S) - { [3- (2, 4-difluoro-phenyl) -2-methyl-allylamino ] -methyl } -pyrrolidine-1-carboxylate. The compound was converted to the HCl salt to give 45mg of a white solid. Yield: 14 percent.

LC-MSD, m/z vs C₂₅H₃₀F₂N₂O₄[M+H]+：443.4

¹H NMR(300MHz，MeOD)：δ1.6(s，2H)，1.7-2.0(m，1H)，2.0-2.2(m，2H)，2.2-2.5(m，1H)，3.2-3.5(m，3H)，3.5-4.0(m，10H)，4.1-4.3(m，4H)6.4(s，1H)，6.9-7.5(m，5H).

Example 39: n- (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-benzamide

Using experimental conditions analogous to example 14, 0.15g (0.32mmol) of N- (S) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.027g (0.39mmol) of cyclobutanone, 0.027ml (0.48mmol) of acetic acid and 0.024g (0.48mmol) of sodium cyanoborohydride are used. After conversion of the free base to the HCl salt, 90mg of a white solid was obtained. Yield: 46 percent.

LC-MSD, m/z vs C₂₉H₃₆F₂N₂O₄[M+H]+：515.5

Example 40: n- (S) - (1-cyclopentyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-benzamide

Using experimental conditions analogous to example 14, 0.12g (0.26mmol) of N- (S) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.026g (0.313mmol) of cyclopentanone, 0.023ml (0.39mmol) of acetic acid and 0.025g (0.391mmol) of sodium cyanoborohydride are used. After conversion of the free base to the HCl salt, 90mg of a colorless semisolid were obtained. Yield: 61 percent.

LC-MSD, m/z vs C₃₀H₃₈F₂N₂O₄[M+H]+：529.5

¹H NMR(300MHz，MeOD)：δ1.5-2.0(m，9H)，2.0-2.5(m，6H)，3.2-3.5(m，1H)，3.7-4.0(m，13H)，4.1-4.4(m，3H)6.4(s，1H)，6.8-7.4(m，5H).

Example 41: n- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N- (S) - [1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-2-ylmethyl ] -benzamide

Using experimental conditions analogous to example 14, 0.1g (0.2mmol) of N- (S) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.029g (0.26mmol) of pyran-4-carbaldehyde, 0.018ml (0.32mmol) of acetic acid and 0.029g (0.32mmol) of sodium cyanoborohydride are used. The free base was converted to the HCl salt to give 40mg of a pale yellow solid. Yield: 33 percent.

LC-MSD, m/z vs C₃₁H₄₀F₂N₂O₅[M+H]+：559.5

¹H NMR(300MHz，MeOD)：δ1.3-1.5(m，2H)，1.5-1.7(m，4H)，2.0-2.5(m，7H)，3.2-3.5(m，3H)，3.6-4.0(m，16H)，4.0-4.4(q，1H)，6.4(s，1H)，6.8-7.4(m，5H).

Example 42: n- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N- (S) - [1- (tetrahydro-pyran-4-yl) -pyrrolidin-2-ylmethyl ] -benzamide

Using experimental conditions analogous to example 14, 0.13g (0.28mmol) of N- (S) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.034g (0.33mmol) of tetrahydro-4H-pyran-4-one, 0.026ml (0.42mmol) of acetic acid and 0.027g (0.43mmol) of sodium cyanoborohydride are used. The free base was converted to the HCl salt to give 70mg of a colorless semi-solid. Yield: and 43 percent.

LC-MSD, m/z vs C₃₀H₃₈F₂N₂O₅[M+H]+：545.6

¹H NMR(300MHz，MeOD)：δ1.5-1.8(m，3H)，1.8-2.0(m，2H)，2.0-2.5(m，6H)，3.4-3.6(m，3H)，3.5-4.0(m，13H)，4.0-4.2(m，3H)，4.2-4.4(m，2H)，6.4(s，1H)，6.8-7.4(m，5H).

Example 43: n- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N- (S) -1-pyridin-4-ylmethyl-pyrrolidin-2-ylmethyl) -benzamide

Using experimental conditions analogous to example 14, 0.15g (0.32mmol) of N- (S) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.041g (0.39mmol) of pyridine-4-carbaldehyde, 0.029ml (0.48mmol) of acetic acid and 0.03g (0.48mmol) of sodium cyanoborohydride are used. The free base was converted to the HCl salt to give 90mg of a white solid. Yield: and 47 percent.

LC-MSD, m/z vs C₃₁H₃₅F₂N₃O₅[M+H]+：552.4

Example 44: n- (S) - (1-cyclopentylmethyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-benzamide

To a solution of 0.09g (0.19mmol) of N- (S) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 10ml of dry acetonitrile, was added 0.07g (0.5mmol) of anhydrous potassium carbonate, 0.0032g (0.019mmol) of potassium iodide and 0.1g (0.56mmol) of cyclopentylmethyl methanesulfonate at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 70 ℃ for 40 hours, then poured into ice-cold water 20ml and extracted with chloroform (2X 15 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column (60-120, chloroform: methanol elution) to give the free amine. It was converted to its hydrochloride salt to give 15mg of a yellow solid.

LC-MSD, m/z vs C₃₁H₄₀F₂N₂O₄[M+H]+：543.60

¹H NMR(300MHz，MeOD)：δ1.2-1.5(m，3H)，1.5-1.8(m，8H)，1.8-2.0(m，3H)，2.0-2.1(m，2H)，2.3-2.5(m，2H)，3.1-3.4(m，3H)，3.5-4.0(m，11H)，4.0-4.4(m，2H)，6.4(s，1H)，6.8-7.4(m，5H).

Example 45: n- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N- (R) - (1-piperidin-4-ylmethyl) -benzamide

Using experimental conditions analogous to example 14, 0.1g (0.21mmol) of N- (R) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.051g (0.26mmol) of tert-butyl 4-oxo-piperidine-1-carboxylate, 0.018ml (0.32mmol) of acetic acid and 0.016g (0.32mmol) of sodium cyanoborohydride are used. The reaction yielded 120mg of 4- (2- (R) - { [ [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] - (3, 4, 5-trimethoxy-benzoyl) -amino ] -methyl } -pyrrolidin-1-yl) -piperidine-1-carboxylic acid tert-butyl ester. The compound is dissolved in 5ml of dry ether and 5ml of dry ether saturated with HCl are added at 0 ℃. The reaction mixture was stirred at room temperature for 10 hours. The ether was concentrated and the residue was washed 3-4 times with dry ether to give 80mg of a yellow solid.

LC-MSD, m/z vs C₃₀H₃₉F₂N₂O₅[M+H]+：544.6

¹H NMR(300MHz，MeOD)：δ1.1(t，1H)，1.6(s，1H)，1.7(s，2H)，2.0-2.4(m，4H)，2.4-2.5(m，2H)，2.5-2.6(m，1H)，3.0-3.1(m，1H)，3.2(s，2H)，3.4-3.7(m，6H)，3.7-3.8(3s，9H)，3.9-4.4(m，4H)，6.4(s，1H)，6.8-7.4(m，5H).

Example 46: n- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N- (R) - (1-pyridin-4-ylmethyl-pyrrolidin-2-ylmethyl) -benzamide

Using experimental conditions analogous to example 14, 0.1g (0.21mmol) of N- (R) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.027g (0.26mmol) of pyridine-4-carbaldehyde, 0.018ml (0.32mmol) of acetic acid and 0.016g (0.32mmol) of sodium cyanoborohydride are used. The free base was converted to the HCl salt to give 80mg of a white solid. Yield: and 47 percent.

LC-MSD, m/z vs C₃₁H₃₅F₂N₃O₅[M+H]+：552.4

¹H NMR(300MHz，MeOD)：δ1.6(s，3H)，2.1-2.4(s，3H)，2，5-2.6(s，1H)，3.2-3.5(m，1H)，3.6-3.9(m，10H)，4.1-4.4(m，5H)，5.4(d，1H)，6.4(s，1H)，7.0(s，5H)，7.4(m，1H)，8.5(s，2.H)，9.0(s，2H).

Example 47: n- (R) - (1-cyclohexyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-benzamide

Using experimental conditions analogous to example 14, 0.1g (0.21mmol) of N- (R) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.026g (0.26mmol) of cyclohexanone, 0.018ml (0.32mmol) of acetic acid and 0.016g (0.32mmol) of sodium cyanoborohydride are used. The free base was converted to the HCl salt to give 100mg of a white solid. Yield: and 47 percent.

LC-MSD, m/z vs C₃₁H₄₀F₂N₂O₄[M+H]+：543.5

¹H NMR(300MHz，MeOD)：δ1.2-2.4(m，18H)，3.2-3.5(m，2H)，3.5-3.6(m，1H)，3.6-3.9(m，10H)，4.1-4.4(m，3H)，6.4(s，1H)，6.9(s，2H)，6.9-7.1(m，2H)，7.4-7.5(m，1H).

Example 48: n- (1-cyclobutyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-benzamide

Using experimental conditions analogous to example 14, 0.1g (0.21mmol) of N- (R) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.019g (0.26mmol) of cyclobutanone, 0.018ml (0.32mmol) of acetic acid and 0.016g (0.32mmol) of sodium cyanoborohydride are used. The free base was converted to the HCl salt to give 110mg of a white solid. Yield: and 47 percent.

LC-MSD, m/z vs C₂₉H₃₆F₂N₂O₄[M+H]+：515.5

¹H NMR(300MHz，MeOD)：δ1.5(s，3H)，1.9-2.1(m，2H)，2.1-2.4(m，4H)，2.4-2.5(m，5H)，3.1-3.6(m，2H)，3.6-4.1(m，11H)，4.3(s，3H)，6.4(s，1H)，6.9(s，2H)，6.9-7.1(m，2H)，7.4-7.5(m，1H).

Example 49: 3, 5-dimethoxy-N- (S) - (2-methyl-3-phenyl-allyl) -N-pyrrolidin-2-ylmethyl-benzamide

Using experimental conditions similar to example 2, 0.09g (0.27mmol) of tert-butyl 2- [ (2-methyl-3-phenyl-allylamino) -methyl ] - (S) -pyrrolidine-1-carboxylate in 3ml of tetrahydrofuran, 0.075g (0.4mmol) of 3, 5-dimethoxybenzoic acid, 0.078g (0.4mmol) of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride, 0.04g (0.4mmol) of 1-hydroxybenzotriazole and 0.05ml of triethylamine were used. The reaction yielded 88mg of a yellow oil. The oil was dissolved in 1ml dichloromethane and 0.14ml trifluoroacetic acid. The mixture was purified using reverse phase HPLC eluting with a gradient of acetonitrile 20-80% over 40 minutes. The compound was converted to the HCl salt to give 48mg of a pale yellow oil.

LC-MSD, m/z vs C₂₄H₃₀N₂O₃[M+H]+：395.2

¹H NMR(400MHz，CDCl₃)：δ1.6-1.8(m，3H)，2.0-2.6(m，7H)，3.2-3.4(m，3H)，3.8(s，6H)，4.0-4.4(s，4H)，6.18(s，1H)，6.25(s，1H)，6.6-6.7(m，2H)，7.0-7.2(m，5H).

Example 50: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3, 5-dimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

A mixture of 0.04g (0.1mmol) of 3, 5-dimethoxy-N- (S) - (2-methyl-3-phenyl-allyl) -N-pyrrolidin-2-ylmethyl-benzamide, 0.012g (0.11mmol) of cyclohexanecarboxaldehyde and 0.04mg (0.2mmol) of sodium triacetoxyborohydride in 1ml of dichloromethane is stirred at room temperature under nitrogen. Similar process conditions as in example 14 were used.

The mixture was purified using reverse phase HPLC eluting with a gradient of acetonitrile 20-80% over 40 minutes. The compound was converted to the HCl salt to give 22mg of a white powder.

LC-MSD, m/z vs C₃₁H₄₂N₂O₃[M+H]+：491.3，[M+2H]：492.3，[M+3H]：493.3

Example 51: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -N- [3- (4-fluoro-phenyl) -2-methyl-allyl ] -3, 5-dimethoxy-benzamide

Using experimental conditions analogous to example 51, 0.032g (0.07mmol) of N- [3- (4-fluoro-phenyl) -2-methyl-allyl ] -3, 5-dimethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.008g (0.077mmol) of cyclohexanecarboxaldehyde, 0.033mg (0.14mmol) of sodium triacetoxyborohydride are used. The reaction yielded 25.5mg of hygroscopic white compound as the TFA salt. Yield: 58 percent.

LC-MSD, m/z vs C₃₁H₄₁N₂O₃F[M+H]+：509.2，[M+2H]：510.2，[M+3H]：511.2

¹H NMR(400MHz，CDCl₃)：δ1.0-1.4(m，5H)，1.6-1.8(m，5H)，1.9-2.6(m，8H)，2.8-3.3(m，5H)，3.8(s，6H)，3.9-4.2(m，4H)，6.22(s，1H)，6.4-6.6(m，2H)，6.9-7.1(m，2H)，7.15-7.25(m，3H).

Example 52: n- (R) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 5-dimethoxy-benzamide

Scheme 15: preparation of N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 5-dimethoxy-N- (R) -pyrrolidin-2-ylmethyl-benzamide

Using experimental conditions similar to example 51, 0.13g (0.32mmol) of N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 5-dimethoxy-N- (R) -pyrrolidin-2-ylmethyl-benzamide (prepared according to scheme 15), 0.039g (0.35mmol) of cyclohexanecarboxaldehyde and 0.1g (0.48mmol) of sodium triacetoxyborohydride were used. Compounds were purified using reverse phase HPLC eluting with a gradient of 20-80% acetonitrile. The purified compound was converted to the HCl salt to give 80mg of a white powder. Yield: 44 percent.

LC-MSD, m/z vs C₃₁H₄₀N₂O₃F₂[M+H]+：527.2，[M+2H]：528.2，[M+3H]：529.2

Example 53: n- (R) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 5-diethoxybenzamide

Using experimental conditions analogous to example 51, 0.13g (0.29mmol) of N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 5-diethoxy-N- (R) -pyrrolidin-2-ylmethyl-benzamide, 0.037g (0.31mmol) of cyclohexanecarboxaldehyde and 0.09g (0.43mmol) of sodium triacetoxyborohydride are used. Compounds were purified using reverse phase HPLC eluting with a gradient of 20-80% acetonitrile. The purified compound was converted to the HCl salt to give 30mg of a white powder. Yield: 16 percent.

LC-MSD, m/z vs C₃₃H₄₄N₂O₃F₂[M+H]+：555.2，[M+2H]：556.3.2，[M+3H]：557.2

Example 54: n- (R) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxybenzamide

Using experimental conditions analogous to example 51, 0.16g (0.35mmol) of N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N- (R) -pyrrolidin-2-ylmethyl-benzamide, 0.041g (0.38mmol) of cyclohexanecarboxaldehyde and 0.11g (0.52mmol) of sodium triacetoxyborohydride are used. Compounds were purified using reverse phase HPLC eluting with a gradient of 20-80% acetonitrile. The purified compound was converted to the HCl salt to give 100mg of a white powder. Yield: 48 percent.

LC-MSD, m/z vs C₃₂H₄₂N₂O₄F₂[M+H]+：557.2，[M+2H]：558.2，[M+3H]：559.2

¹H NMR(400MHz，CDCl₃)：δ1.0-1.4(m，7H)，1.5-2.0(m，7H)，2.0-2.6(m，8H)，3.6-3.9(s，9H)，4.0-4.5(m，4H)，6.22-6.7(m，6H)

Example 55: n- (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 5-diethoxybenzamide

Using experimental conditions analogous to example 51, 0.15g (0.35mmol) of N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 5-diethoxy-N-pyrrolidin-2-ylmethyl-benzamide, 0.043g (0.38mmol) of cyclohexanecarboxaldehyde and 0.11g (0.52mmol) of sodium triacetoxyborohydride are used. Compounds were purified using reverse phase HPLC eluting with a gradient of 20-80% acetonitrile. The purified compound was converted to the HCl salt to give 50mg of a white powder. Yield: 24 percent.

LC-MSD, m/z vs C₃₃H₄₄N₂O₃F₂[M+H]+：555.2，[M+2H]：556.2，[M+3H]：557.2

Example 57: n- [1- (S) - (1-cyclohexyl-ethyl) -pyrrolidin-2-ylmethyl ] -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-benzamide

a: benzyl chloroformate, sodium carbonate, tetrahydrofuran, 3 hours at room temperature

b: 6N HCl, dioxane, 14 hours, room temperature

c: cyclohexyl methyl ketone, methanol, acetic acid, sodium cyanoborohydride, 0-room temperature

d: 10% Pd/charcoal, methanol, H₂2.5kg pressure for 5 hours

e: 1/3- (3, 5-dimethyl-phenyl) -acrolein 2/sodium borohydride methanol at 0 deg.C for 15 min

And (3) a process 16: preparation of [1- (S) - (1-cyclohexyl-ethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine

Using experimental conditions similar to example 18, [1- (S) - (1-cyclohexyl-ethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine (prepared according to scheme 16) 0.25g (0.66mmol), 3, 4, 5-trimethoxybenzoic acid 0.16g (0.79mmol), thionyl chloride 0.1ml (1.3mmol) and triethylamine 0.1ml were used. The reaction was purified to give the free base which was then converted to 22mg of HCl salt as a white semi-solid.

LC-MSD, m/z vs C₃₃H₄₄N₂O₄F₂[M+H]+：571.5

¹H NMR(300MHz，MeOD)：δ1.33(s，9H)，1.39-1.46(m，4H)，1.76-1.88(m，8H)，2.19(s，4H)，2.1-2.2(m，1H)，3.84-3.86(m，9H)，4.0-4.1(m，1H)，4.277(m，2H)6.2(s，1H)，6.95(s，2H)，7.03(m，2H)，7.2-7.5(m，1H).

Example 57: n- [1- (S) - (1-cyclohexyl-ethyl) -pyrrolidin-2-ylmethyl ] -4-difluoromethoxy-N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3-methoxy-benzamide

Similar experimental conditions to example 3 were used with 0.13g (0.37mmol) of [1- (S) - (1-cyclohexyl-ethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine, 0.10g (0.40mmol) of 4-difluoromethoxy-3-methoxy-benzoic acid, 0.07ml of triethylamine and 0.49ml of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate). After purification, the reaction yielded the free amine which was then converted to 21mg of HCl salt as a white solid. Yield: 10 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 18.00 min.

LC-MSD, m/z vs C₃₂H₄₀N₂O₃F₄[M+H]+：577.2，[M+2H]：578.2，[M+3H]：579.2

¹H NMR(400MHz，MeOD)：δ0.8-0.9(m，1H)，1.0-1.4(m，8H)，1.5-2.4(m，11H)，3.2-3.4(m，4H)，3.6-4.0(m，5H)，4.0-4.4(m，3H)，6.4(s，1H)，6.6-7.4(m，7H)

Example 58: 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid [1- (1-cyclohexyl-ethyl) -pyrrolidin-2-ylmethyl ] - [3-2, 4-difluoro-phenyl ] -2-methyl-allyl ] -amide

Using experimental conditions analogous to example 3, 0.13g (0.37mmol) of [1- (S) - (1-cyclohexyl-ethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine, 0.10g (0.40mmol) of 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid, 0.07ml of triethylamine and 0.49ml of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate) were used. After purification, the reaction yielded the free amine, which was then converted to 92mg of HCl salt as a white solid. Yield: 40 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, elution at 18.92 min.

LC-MSD, m/z vs C₃₄H₄₄N₂O₄F₄[M+H]+：583.2，[M+2H]：584.2，[M+3H]：585.2

¹H NMR(400MHz，MeOD)：δ1.05-1.45(m，7H)，1.6-2.4(m，15H)，3.2-3.5(m m，8H)，3.6-4.0(m，4H)，4.2-4.4(m，2H)，6.4(s，1H)，6.7-7.4(m，7H)，6.8(d，2H)，6.9-7.2(m，2H)，7.3-7.4(m，1H).

Example 59: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-benzamide

b: 6N HCl, dioxane, 14 hours, room temperature

c: cyclohexyl formaldehyde, methanol, acetic acid, sodium cyanoborohydride, 0-room temperature

d: 10% Pd/charcoal, methanol, H₂2.5kg pressure for 5 hours

e: 1/3- (3, 5-dimethyl-phenyl) -acrolein 2/sodium borohydride, methanol, at 0 ℃ for 15 minutes

Scheme 17: preparation of [1- (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine

Using experimental conditions similar to example 12, [1- (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine (prepared according to scheme 17) 0.18g (0.52mmol), 3, 4, 5-trimethoxy-benzoyl chloride 0.14g (0.8mmol), triethylamine 0.13ml were used. After purification, the reaction yielded the free amine, which was then converted to 110mg of HCl salt as a white semi-solid. Yield: 36 percent.

Example 60: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4-dimethoxy-benzamide

Using experimental conditions analogous to example 2, [1- (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine 0.05g (0.14mmol) and 3, 4, 5-trimethoxybenzoic acid 0.037g (0.21mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.039g (0.21mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The reaction yielded 40mg of a colorless oil, which was then converted to the HCl salt, yielding 22.8mg of a white powder. Yield: 27 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 17.535 min.

LC-MSD, m/z vs C₃₂H₄₂N₂O₄F₂[M+H]+：527.2，[M+2H]：528.2，[M+3H]：529.2

¹H NMR(400MHz，CDCl₃)：δ0.5-2.1(m，20H)，2.4-2.6(m，1H)，2.7-3.7(m，4H)，3.8-4.5(m，4H)，6.2-6.5(m，1H)，6.4-6.9(m，2H)，7.0-7.5(m，4H).

Example 61: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3, 4-bis-difluoromethoxy-N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -benzamide

Using experimental conditions similar to example 2, [1- (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine 0.05g (0.14mmol) and 3, 4-bis-difluoromethoxy-benzoic acid 0.053g (0.21mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.039g (0.21mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The reaction yielded 8.3mg of a colorless oil, which was then converted to the HCl salt, yielding 4.8mg of a white powder. Yield: 5 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 16.969 min.

LC-MSD, m/z vs C₃₁H₃₆N₂O₃F₆[M+H]+：599.2，[M+2H]：600.2，[M+3H]：601.2

Example 62: 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amide

Using experimental conditions similar to example 2, [1- (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine 0.05g (0.14mmol) and 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid 0.049g (0.21mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.039g (0.21mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The product was converted to the HCl salt to yield 27.4mg of a white powder. Yield: 32 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 18.69 min.

LC-MSD, m/z vs C₃₃H₄₂N₂O₄F₂[M+H]+：569.2，[M+2H]：570.2，[M+3H]：571.2

Example 63: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3-difluoromethoxy-N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -4-methoxy-benzamide

Using experimental conditions similar to example 2, [1- (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine 0.055g (0.15mmol), 3-difluoromethoxy-4-methoxy-benzoic acid 0.05g (0.22mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.044g (0.22mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The resulting free amine was converted to the HCl salt to give 21mg of a very hygroscopic white powder. Yield: 41 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 17.99 min.

LC-MSD, m/z vs C₃₁H₃₈N₂O₃F₄[M+H]+：563.2，[M+2H]：564.2，[M+3H]：565.2

Example 64: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -4-difluoromethoxy-N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -4-methoxy-benzamide

Using experimental conditions similar to example 2, [1- (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl ] - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -amine 0.055g (0.15mmol), 4-difluoromethoxy-3-methoxy-benzoic acid 0.05g (0.22mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.044g (0.22mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The free amine was converted to the HCl salt to give 21mg of a very hygroscopic white powder. Yield: 41 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 17.81 min.

Example 65: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -N- (2-methyl-3-phenyl-allyl) -3, 4-bis- (2, 2, 2-trifluoro-ethoxy) -benzamide

b: 6N HCl, dioxane, 14 hours, room temperature

c: cyclohexanone, methanol, acetic acid, sodium cyanoborohydride, 0-room temperature

d: 10% Pd/charcoal, methanol, H₂2.5kg pressure for 5 hours

e: 1/alpha-cinnamic aldehyde, DCM 2/sodium borohydride, methanol at 0 ℃ for 15 min

The process 18: preparation of (S) - (1-cyclohexyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine

Using experimental conditions similar to example 2, 0.050g (0.15mmol) of (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine (prepared according to scheme 18), 0.073g (0.22mmol) of 3, 4-bis- (2, 2, 2-trifluoro-ethoxy) -benzoic acid, 0.03ml of triethylamine, 0.044g (0.22mmol) of 1-dimethylaminopropyl-3-ethylcarbodiimide and 0.02g (0.16mmol) of 1-hydroxybenzotriazole were used. The reaction yielded 50mg of colorless free amine, which was converted to the HCl salt as a white powder. Yield: 50 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 18.06 min.

LC-MSD, m/z vs C₃₃H₄₀N₂O₃F₆[M+H]+：627.2，[M+2H]：628.2，[M+3H]：629.2

¹H NMR(400MHz，CDCl₃)：δ0.8-2.0(m，16H)，2.0-2.4(m，4H)，2.6-3.0(m，2H)，3.2-3.4(m，1H)，3.8-4.5(m，8H)，6.4(s，1H)，6.9-7.4(m，8H)

Example 67: 2, 3-dihydro-benzo [1, 4] dioxane-6-carboxylic acid (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amide

Using experimental conditions similar to example 2, (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine 0.050g (0.15mmol), 2, 3-dihydro-benzo [1, 4] dioxane-6-carboxylic acid 0.073g (0.22mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.044g (0.22mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The reaction yielded 45mg of colorless free amine, which was converted to the HCl salt as a white powder. Yield: 60 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 16.71 min.

LC-MSD, m/z vs C₃₁H₄₀N₂O₃[M+H]+：489.2，[M+2H]：490.2，[M+3H]：491.2

¹H NMR(400MHz，CDCl₃)：δ0.8-2.0(m，17H)，2.1-2.4(m，3H)，2.6-3.0(m，2H)，3.5(s，1H)，3.8-4.5(m，8H)，6.4(s，1H)，6.8-7.0(m，2H)，7.0-7.4(m，5H).

Example 68: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3, 4-dimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 2, (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine 0.050g (0.15mmol), 3, 4-dimethoxybenzoic acid 0.042g (0.22mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.044g (0.22mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The reaction yielded 34.7mg of the free amine as a colorless oil, which was converted to the HCl salt as a white powder. Yield: and 47 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 16.33 min.

LC-MSD, m/z vs C₃₁H₄₂N₂O₃[M+H]+：491.2，[M+2H]：492.2，[M+3H]：493.2

¹H NMR(400MHz，CDCl₃)：δ0.8-2.0(m，21H)，2.7-3.0(m，2H)，3.2-3.4(m，1H)，3.8(s，3H)，3.9(s，3H)，4.0-4.5(m，3H)，6.4(s，1H)，6.9-7.4(m，8H).

Example 69: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3, 4-diethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 2, (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine 0.050g (0.15mmol), 3, 4-diethoxybenzoic acid 0.048g (0.22mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.044g (0.22mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The reaction yielded 40mg of the free amine as a colorless oil, which was converted to the HCl salt as a white powder. Yield: 51 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 17.91 min.

LC-MSD, m/z vs C₃₃H₄₆N₂O₃[M+H]+：519.3，[M+2H]：520.3，[M+3H]：521.3

¹H NMR(400MHz，CDCl₃)：δ0.8-2.0(m，22H)，2.0-2.4(m，4H)，2.7-3.0(m，2H)，3.3(s，1H)，3.8-4.3(m，7H)，4.2(d，1H)，6.4(s，1H)，6.8-7.4(m，8H).

Example 70: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3, 4-diisopropoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 2, (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine 0.050g (0.15mmol), 3, 4-diisopropoxybenzoic acid 0.055g (0.22mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.044g (0.22mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The reaction gave the free amine as a colourless oil, which was converted into 22.3mg of HCl salt as a white powder. Yield: 25 percent.

LC-MSD, m/z vs C₃₅H₅₀N₂O₃[M+H]+：547.3，[M+2H]：548.3，[M+3H]：549.3

¹H NMR(400MHz，CDCl₃)：δ1.0-1.4(m，12H)，1.4-2.4(m，19H)，2.7-3.4(m，4H)，3.9-4.6(m，6H)，3.8-4.3(m，7H)，6.4(s，1H)，6.8-7.1(m，2H)，7.2-7.4(m，6H).

Example 71: 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amide

Using experimental conditions similar to example 2, (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine 0.050g (0.15mmol), 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid 0.055g (0.22mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.044g (0.22mmol) and 1-hydroxybenzotriazole 0.02g (0.16mmol) were used. The reaction yielded 50mg of the free amine as a colorless oil, which was converted to the HCl salt as a white powder. Yield: 62 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 20.89 min.

LC-MSD, m/z vs C₃₃H₄₄N₂O₃[M+H]+：533.3，[M+2H]：534.3，[M+3H]：535.3

¹H NMR(400MHz，CDCl₃)：δ0.9-1.4(m，6H)，1.4-1.9(m，15H)，2.0-2.2(m，4H)，2.6-3.0(m，2H)，3.1-3.2(m，1H)，3.8(s，3H)，3.9-4.1(m，2H)，4.15-4.24(m，2H)，4.4-4.5(m，1H)，6.4(s，1H)，6.5-6.7(d，2H)，7.1-7.4(m，5H).

Example 72: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3-difluoromethoxy-4-methoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 2, 0.05g (0.15mmol) of (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine, 0.05g (0.22mmol) of 3-difluoromethoxy-4-methoxy-benzoic acid, 0.03ml of triethylamine, 0.044g (0.22mmol) of 1-dimethylaminopropyl-3-ethylcarbodiimide and 0.02g (0.16mmol) of 1-hydroxybenzotriazole were used. The reaction yielded the free amine, which was converted to the HCl salt as a yellow powder, 20.7 mg. Yield: 25 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 17.62 min.

LC-MSD, m/z vs C₃₃H₄₀N₂O₃F₂[M+H]+：527.2，[M+2H]：528.2，[M+3H]：529.2

¹H NMR(400MHz，CDCl₃)：δ0.5-2.2(m，19H)，2.4-2.6(m，1H)，2.8-3.2(m，2H)，3.3-3.7(m，2H)，3.8(s，3H)，3.9(s，1H)，4.15-4.24(m，2H)，4.4-4.5(m，1H)，6.3(s，1H)，6.4-7.4(m，8H).

Example 73: n- (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -4-difluoromethoxy-methoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 2, 0.05g (0.15mmol) of (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine, 0.05g (0.22mmol) of 3-methoxy-4-difluoromethoxy-benzoic acid, 0.03ml of triethylamine, 0.044g (0.22mmol) of 1-dimethylaminopropyl-3-ethylcarbodiimide and 0.02g (0.16mmol) of 1-hydroxybenzotriazole were used. The reaction yielded the free amine, which was converted to the HCl salt as a white solid, 20.7 mg. Yield: 25 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 17.42 min.

Example 74: 7-difluoromethoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid (S) - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amide

Using experimental conditions similar to example 2, 0.05g (0.15mmol) of (S) - (1-cyclohexylmethyl) -pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine, 0.06g (0.22mmol) of 7-difluoromethoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid, 0.03ml of triethylamine, 0.044g (0.22mmol) of 1-dimethylaminopropyl-3-ethylcarbodiimide and 0.02g (0.16mmol) of 1-hydroxybenzotriazole were used. The reaction yielded the free amine, which was converted to 25mg of HCl salt as a white powder. Yield: 27 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 18.62 min.

¹H NMR(400MHz，CDCl₃)：δ0.9-1.4(m，6H)，1.8(s，6H)，1.5-1.9(m，4H)，1.9-2.4(m，3H)，2.6-3.3(m，6H)，3.8-4.4(m，5H)，6.4(s，1H)，6.6-7.4(m，7H).

Example 75: 2, 2-difluoro-benzo [1, 3] dioxole-5-carboxylic acid (S) - (1-cyclohexyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amide

b: 6NHCl, dioxane, 14 hours, room temperature

d: 10% Pd/charcoal, methanol, H₂2.5Kg of pressure for 5 hours

Scheme 19: preparation of (S) - (1-cyclohexyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine

Using experimental conditions similar to example 2, 0.050g (0.16mmol) of (S) - (1-cyclohexyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine (prepared according to scheme 19), 0.042g (0.20mmol) of 2, 2-difluoro-benzo [1, 3] dioxole-5-carboxylic acid, 0.03ml of triethylamine, 0.037g (0.24mmol) of 1-dimethylaminopropyl-3-ethylcarbodiimide and 0.02g (0.19mmol) of 1-hydroxybenzotriazole and 1ml of THF were used. The reaction gave the free amine as a colorless oil, which was converted to 32mg of HCl salt as a yellow powder. Yield: 37 percent.

Used within 20 minutesAnalysis with 20-95% acetonitrile gradient C¹⁸HPLC, eluting compound at 20.25 min.

LC-MSD, m/z vs C₂₉H₃₄N₂O₃F₂[M+H]+：497.2，[M+2H]：498.2，[M+3H]：499.2

¹H NMR(400MHz，MeOD)：δ1.0-2.4(m，15H)，3.2-3.6(m，4H)，3.9(s，1H)，4.2(m，2H)，4.9(s，4H)，6.4(s，1H)，7.0-7.8(m，8H).

Example 76: n- (S) - (1-cyclohexyl-pyrrolidin-2-ylmethyl) -3, 4-dimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 2, (S) - (1-cyclohexyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine 0.050g (0.16mmol), 3, 4-dichlorobenzoic acid 0.037g (0.20mmol), triethylamine 0.03ml, 1-dimethylaminopropyl-3-ethylcarbodiimide 0.037g (0.24mmol) and 1-hydroxybenzotriazole 0.02g (0.19mmol) were used. The reaction yielded the free amine as a colorless oil, which was converted to 20mg of HCl salt as a white powder. Yield: 38 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, eluting compound at 17.76 min.

LC-MSD, m/z vs C₃₀H₄₀N₂O₃[M+H]+：477.2，[M+2H]：478.2，[M+3H]：479.2

Example 77: 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amide

b: 6N HCl, dioxane, 14 hours, room temperature

c: cyclobutanone, methanol, acetic acid, sodium cyanoborohydride, 0-room temperature

d: 10% Pd/charcoal, methanol, H₂2.5Kg of pressure for 5 hours

A process 20: preparation of (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine

Using experimental conditions similar to example 3, using 0.1g (0.37mmol) of 1- (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine (prepared according to scheme 20), 0.08g (0.40mmol) of 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid, 0.07ml of triethylamine and 0.49ml of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate), purification gave the free amine which was then converted to 28.2mg of the HCl salt as a white solid. Yield: 15 percent.

LC-MSD, m/z vs C₃₀H₃₈N₂O₄[M+H]+：491.2，[M+2H]：492.2，[M+3H]：493.2

¹H NMR(400MHz，CDCl₃)：δ1.4-2.2(m，15H)，2.2-2.5(m，1H)，2.6-3.5(m m，5H)，3.8(s，3H)，4.2-4.4(m，2H)，6.4(s，1H)，6.6(d，2H)，7.3-7.5(m，5H).

Example 77: n- (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) -4-difluoromethoxy-3-methoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions analogous to example 3, using 0.1g (0.37mmol) of 1- (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine, 0.08g (0.40mmol) of 4-difluoromethoxy-3-methoxy-benzoic acid, 0.07ml of triethylamine and 0.49ml of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate), the free amine was obtained after purification which it was converted into 26.2mg of HCl salt as a white solid. Yield: 13 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, elution at 17.90 min.

LC-MSD, m/z vs C₂₈H₃₄N₂O₃F₂[M+H]+：485.2，[M+2H]：486.2，[M+3H]：487.2

¹H NMR(400MHz，CDCl₃)：δ1.4-2.2(m，13H)，2.2-2.5(m，1H)，2.5-3.4(m，4H)，3.5(s，1H)，3.8(m，3H)，4.0-4.6(m，2H)，6.4(s，1H)，6.5-7.4(m，9H).

Example 78: n- (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) -3, 4-dimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions analogous to example 12, using 0.1g (0.37mmol) of 1- (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amine, 0.089g (0.44mmol) of 3, 4-dimethoxybenzoyl chloride and 0.07ml of triethylamine, the free amine was obtained after purification and was then converted into 51mg of the HCl salt as a white solid. Yield: 28 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, elution at 16.55 min.

LC-MSD, m/z vs C₂₈H₃₆N₂O₃[M+H]+：449.2，[M+2H]：450.2，[M+3H]：451.2

¹H NMR(400MHz，CDCl₃)：δ1.4-2.4(m，13H)，2.3-2.5(m，1H)，2.7-3.6(m，5H)，3.8-4.0(m，6H)，4.2(m，2H)，6.4(s，1H)，6.8-7.4(m，8H).

Example 79: n- (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) -4-difluoromethoxy-N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3-methoxy-benzamide

Using experimental conditions analogous to example 3, using 0.11g (0.37mmol) of 1- (S) - (1-cyclobutyl-pyrrolidin-2-ylmethyl) - [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -aminomethyl-3-phenyl-allyl) -amine, 0.08g (0.40mmol) of 4-difluoromethoxy-3-methoxy-benzoic acid, 0.07ml of triethylamine and 0.49ml of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate) in 5ml of dichloromethane, the free amine was obtained after purification and was then converted to 44mg of HCl salt as a white solid. Yield: 13 percent.

Analysis C was performed over 20 min using a 20-95% acetonitrile gradient¹⁸HPLC, elution at 16.79 min.

LC-MSD, m/z vs C₂₈H₃₂N₂O₃F₄[M+H]+：527.2，[M+2H]：528.2，[M+3H]：529.2

¹H NMR(400MHz，CDCl₃)：δ0.8-1.0(m，2H)，1.4-1.6(m，2H)，1.8-2.0(m，3H)，2.0-2.4(m，7H)，3.5-4.0(m，8H)，4.2(s，2H)，6.4(s，1H)，6.6-6.4(m，7H).

Example 80: n- (1-ethyl-piperidin-3-yl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

a: acetic anhydride, room temperature, then 50 ℃, for 4 hours

b: iodoethane, dimethylformamide, 65 ℃ for 3 hours

c: sodium borohydride, tetrahydrofuran, 0 deg.C-room temperature, 14 hours

d: 10% Pd/C, methanol, H₂3Kg of pressure for 14 hours

e: HCl, 100 ℃ for 14 hours

f: 1/alpha-methyl cinnamic aldehyde, dichloromethane 2/sodium borohydride, methanol

Scheme 21: preparation of (1-ethyl-piperidin-3-yl) - (2-methyl-3-phenyl-allyl) -amine

Using experimental conditions analogous to example 18, (1-ethyl-piperidin-3-yl) - (2-methyl-3-phenyl-allyl) -amine 0.35g (1.3mmol), 3, 4, 5-trimethoxybenzoic acid 0.18g (0.86mmol), thionyl chloride 0.39g and triethylamine 0.19ml in 10ml dichloromethane were used. The reaction yielded 35mg of the free amine, which was converted to the HCl salt as an off-white solid. Yield: 9 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₄[M+H]+：453.3

₁H NMR(300MHz，MeOD)：δ1.2-1.5(m，3H)，1.7-2.4(m，7H)，3.0(t，1H)，3.3-3.4(m，2H)，3.6(d，2H)，3.6-3.9(m，10H)，4.1-4.3(m，2H)，4.3-4.4(m，1H)，6.4(s，1H)，6.8(s，2H)，7.2-7.5(m，5H).

Example 81: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- [3- (3-phenoxy-piperidin-1-yl) -propyl ] -benzamide

To a solution of 0.2g (0.41mmol) of N- [3- (3-hydroxy-piperidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide and 0.058g (0.62mmol) of phenol in 10ml of anhydrous dichloromethane were added 0.16g (0.6mmol) of triphenylphosphine and 0.16g (0.6mmol) of diethyl azodicarboxylate at 0 ℃. The reaction mixture was stirred at room temperature for 18 h, concentrated and purified by column chromatography on silica gel eluting with chloroform and methanol to give the free amine which was then converted to the HCl salt to give 39mg of a brown semisolid. Yield: 17 percent.

LC-MSD, m/z vs C₃₄H₄₂N₂O₅[M+H]+：559.3

¹H NMR(300MHz，MeOD)：δ1.8-1.9(m，3H)，2.0-2.5(m，6H)，3.4(m，2H)，3.5-4.0(m，13H)，4.0-4.2(m，3H)，4.3-4.5(m，2H)，6.4(s，1H)，6.8(s，2H)，7.0-7.2(m，3H)，7.2-7.5(m，7H).

Example 82: n- [3- (3-benzylamino-piperidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

0.2ml of anhydrous dichloromethane triethylamine was added to a solution of 0.5g (1.0mmol) of N- [3- (3-hydroxy-piperidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide. Thereafter, methanesulfonyl chloride 0.14g (1.2mmol) was added at 0 ℃. The reaction mixture was stirred for 6 hours, diluted with dichloromethane, washed with water and brine to give 0.4g (0.8mmol) of the intermediate chloride as a brown solid.

To 0.15g (0.29mmol) of this intermediate chloride in acetonitrile was added 0.12g (0.8mmol) of potassium carbonate and stirred at room temperature for 40 minutes. To this mixture was added 0.03g (0.29mmol) of benzylamine and the mixture was refluxed at 80 ℃ for 14 hours. The potassium carbonate was filtered off and the filtrate was concentrated. The residue was diluted with chloroform and washed with 1.5N HCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel eluting with chloroform 9 and methanol 1 gave the free amine which was converted to the HCl salt 36mg as a yellow solid. Yield: 5.9 percent.

LC-MSD, m/z vs C₃₅H₄₅N₃O₄[M+H]+：572.4

¹H NMR(300MHz，MeOD)：δ1.5-1.7(m，3H)，2.0-2.5(m，6H)，3.2-3.7(m，5H)，3.5-4.0(m，12H)，4.0-4.2(m，4H)，4.3-4.5(m，2H)，6.4(s，1H)，6.8(s，2H)，7.2-7.6(m，10H).

Example 83: n- [3- (3-isopropylamino-piperidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 82, 0.1g (0.19mmol) of the chloride intermediate, 0.1g (0.79mmol) of potassium carbonate and 0.23g (3.9mmol) of isopropylamine in anhydrous acetonitrile were used. The reaction yielded 45mg of the HCl salt as a brown solid.

LC-MSD, m/z vs C₃₁H₄₅N₃O₄[M+H]+：524.5

¹H NMR(300MHz，MeOD)：δ1.3-1.5(m，7H)，1.7-2.0(m，4H)，2.0-2.5(m，6H)，2.5-2.7(m，1H)，3.4-3.6(m，3H)，3.7-4.0(m，12H)，4.0-4.3(m，4H)，6.4(s，1H)，6.8(m，2H)，7.2-7.6(m，5H).

Example 84: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (2-piperidin-1-yl-ethyl) -benzamide

Using experimental conditions similar to example 13, (2-methyl-3-phenyl-allyl) - (2-piperidin-1-yl-ethyl) -amine 0.5g (1.9mmol), 3, 4, 5-trimethoxybenzoic acid 0.49g (2.3mmol), 0.2ml triethylamine, O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate 1.2g (3.8mmol) were used. The reaction yielded 102mg of the HCl salt as an off-white solid. Yield: 12 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₄[M+H]+：453.3

¹H NMR(300MHz，MeOD)：δ1.5-1.6(m，3H)，1.7-2.0(m，6H)，3.0-3.2(m，2H)，3.3-3.5(m，3H)，3.6-3.9(m，9H)，3.9-4.0(m，3H)，4.2(m，2H)，6.5(s，1H)，6.8(m，2H)，7.3-7.5(m，5H).

Example 85: n- [3- (3-benzyl-piperidin-1-yl) -propyl ] -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions analogous to example 18, 0.4g (1mmol) of [3- (3-benzyl-piperidin-1-yl) -propyl ] - (2-methyl-3-phenyl-allyl) -amine, 1ml of triethylamine, 0.25g (1.2mmol) of 3, 4, 5-trimethoxybenzoic acid in dichloromethane (conversion to the acid chloride with 0.24g (2.2mmol) of thionyl chloride) were used. The reaction gave the free amine, which was converted to the HCl salt to give 0.3g of a white powder. Yield: 50 percent.

LC-MSD, m/z vs C₃₅H₄₄N₂O₄[M+H]+：557.7

¹H NMR(300MHz，MeOD)：δ1.6-1.9(m，5H)，1.9-2.2(m，5H)，2.5-2.7(m，2H)，2.7-2.9(m，2H)，3.1-3.3(m，2H)，3.4-3.5(m，2H)，3.5-3.7(m，2H)，3.7-3.9(m，9H)，4.0-4.2(m，2H)，6.5(s，1H)，6.6-6.8(m，2H)，7.1-7.4(m，10H).

Example 86: n- (3-dimethylamino-propyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

Using experimental conditions similar to example 13, using 0.65g (3mmol) of 3, 4, 5-trimethoxybenzoic acid and 0.6g (2.5mmol) of N, N-dimethyl-N ' - (2-methyl-3-phenyl-allyl) -propane-1, 3-diamine and 1.5g (5mmol) of O- (benzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium tetrafluoroborate, 130mg of the HCl salt was obtained as a white solid. Yield: 13 percent.

LC-MSD, m/z vs C₂₅H₃₄N₂O₄[M+H]+：427.2

¹H NMR(300MHz，MeOD)：δ1.6(s，3H)，2.1-2.3(m，3H)，2.7(m，1H)，3.8(s，6H)，3.2-3.4(m，2H)，3.5-3.7(m，2H)，3.4-3.8(m，9H)，4.1(s，2H)，6.5(s，1H)，6.8(m，2H)，7.1-7.4(m，5H).

Example 87: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (3-pyrrolidin-1-yl-propyl) -benzamide

Using experimental conditions similar to example 2, 0.4g (1.9mmol), (2-methyl-3-phenyl-allyl) - (3-pyrrolidin-1-yl-propyl) -amine 3, 4, 5-trimethoxybenzoic acid 0.25g (1.9mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.44g (2.3mmol), 1-hydroxybenzotriazole 0.26g (0.19mmol) and triethylamine 0.3ml were used. The reaction yielded 187mg of the HCl salt as a white solid. Yield: 20 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₄[M+H]+：452.27

¹H NMR(300MHz，MeOD)：δ1.6-1.7(s，3H)，2.0-2.3(m，7H)，3.0-3.2(m，2H)，3.2-3.4(m，6H)，3.6-3.8(m，12H)，4.1-4.3(m，2H)，6.5(s，1H)，6.8(m，2H)，7.1-7.4(m，5H).

Example 88: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- [3- (4-phenyl-piperidin-1-yl) -propyl ] -benzamide

Using experimental conditions analogous to example 18, (2-methyl-3-phenyl-allyl) - [3- (4-phenyl-piperidin-1-yl) -propyl-amine 0.47g (1.5mmol), 3, 4, 5-trimethoxybenzoic acid 0.31g (1.48mmol), thionyl chloride 0.32g (2.7mmol) and triethylamine were used. The reaction yielded the free amine, which was converted to the HCl salt to yield 106mg of an off-white solid. Yield: 12 percent.

LC-MSD, m/z vs C₃₄H₄₂N₂O₄[M+H]+：542.31

¹H NMR(300MHz，MeOD)：δ1.6-1.7(s，3H)，1.9-2.2(m，7H)，2.9-3.0(m，1H)，3.0-3.2(m，6H)，3.6-3.8(m，10H)，4.1-4.3(s，2H)，6.5(s，1H)，6.9(s，2H)，7.1-7.5(m，10H).

Example 89: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (3-piperidin-1-yl-propyl) -benzamide

Using experimental conditions similar to example 18, (2-methyl-3-phenyl-allyl) - (3-piperidin-1-yl-propyl) -amine 0.65g (2.3mmol), 3, 4, 5-trimethoxybenzoic acid 0.6g (2.87mmol), thionyl chloride 0.5g (4.7mmol) and triethylamine 0.93ml were used. The reaction yielded the free amine, which was converted to the HCl salt to yield 110mg of a pale yellow hygroscopic solid. Yield: 12 percent.

¹H NMR(300MHz，MeOD)：δ1.4-1.5(m，2H)，1.7-2.0(m，5H)，2.1-2.3(m，2H)，2.9-3.0(m，2H)，3.1-3.3(m，2H)，3.5-3.7(m，5H)，3.7-3.9(m，10H)，4.0-4.1(s，2H)，6.5(s，1H)，6.8(s，2H)，7.1-7.4(m，5H).

Example 90: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (3-morpholin-4-yl-propyl) -benzamide

Using experimental conditions similar to example 18, (2-methyl-3-phenyl-allyl) - (3-morpholino-4-yl-propyl) -amine 0.72g (2.6mmol), 3, 4, 5-trimethoxybenzoic acid 0.6g (2.87mmol), thionyl chloride 0.6g (5.2mmol) and triethylamine 0.93ml were used. The reaction yielded the free amine, which was converted to the HCl salt, yielding 80mg of a light brown hygroscopic solid. Yield: 6.5 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₅[M+H]+：469

¹H NMR(300MHz，MeOD)：δ1.7(s，3H)，2.1-2.4(m，2H)，3.4-3.5(m，2H)，3.5-3.6(m，2H)，3.7-4.0(m，14H)，4.0-4.1(m，2H)，6.5(s，1H)，6.8(s，2H)，7.2-7.5(m，5H).

Example 91: n- (1-butyl-piperidin-4-ylmethyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

a: 1/alpha-methyl cinnamic aldehyde, dichloromethane 2 sodium borohydride, methanol

b: 3, 4, 5-Trimethoxybenzoic acid, TBTU

c: HCl/dioxane

d: bromobutane, potassium carbonate, dimethylformamide

The process 22: preparation of N- (1-butyl-piperidin-4-ylmethyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

0.15g (1.1mmol) of bromobutane is added to a mixture of 0.25g (0.5mmol) of 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N-piperidin-4-ylmethyl-benzamide (prepared according to scheme 22) and 0.19g (1.4mmol) of potassium carbonate in 5ml of dimethylformamide at 0 ℃. The reaction was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated and purified by flash chromatography eluting with chloroform/methanol 9: 1 to give the free amine. This amine was converted to the HCl salt to give 72mg of an off-white solid. Yield: 13 percent.

LC-MSD, m/z vs C₃₀H₄₂N₂O₄[M+H]+：495.4

Example 92: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (2-thiomorpholin-4-yl-ethyl) -benzamide

Using experimental conditions similar to example 13, (2-methyl-3-phenyl-allyl) - (2-thiomorpholin-4-yl-ethyl) -amine 0.5g (1.8mmol), 3, 4, 5-trimethoxybenzoic acid 0.42g (1.7mmol), O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate 1.16g (3.6mmol) and triethylamine 0.2ml were used. The reaction yielded the free amine, which was converted to the HCl salt to yield 157mg of a pink solid. Yield: 19 percent.

LC-MSD, m/z vs C₂₆H₃₄N₂O₅S[M+H]+：471.2

¹H NMR(300MHz，MeOD)：δ1.7(m，3H)，2.7-3.0(m，2H)，3.1-3.4(m，3H)，3.5-3.6(m，3H)，2.7-3.1(m，2H)，3.7-3.8(m，10H)，3.9-4.0(m，4H)，4.0-4.4(m，2H)，6.5(s，1H)，6.8-6.9(m，2H)，7.2-7.4(m，5H).

Example 93: n- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-piperidin-3-yl-benzamide

Similar experimental conditions to example 18 were used using 0.35g (0.94mmol) of tert-butyl 3- [3- (2, 4-difluoro-phenyl) -2-methyl-allylamino ] -piperidine-1-carboxylate, 0.24g (1.13mmol) of 3, 4, 5-trimethoxybenzoic acid, 0.15g (0.94mmol) of thionyl chloride and 0.1ml of triethylamine. The reaction yielded 380mg of BOC protected intermediate. This intermediate 0.36g (0.64mmol) was dissolved in 5ml dioxane, 6N HCl was added and the mixture was stirred at room temperature for 14 hours. Base treatment gave 319mg of free amine. It was converted to the HCl salt to give 100mg of a yellow solid. Yield: 33 percent.

LC-MSD, m/z vs C₂₅H₃₀N₂O₄F₂[M+H]+：461.4

¹H NMR(300MHz，MeOD)：δ1.0-1.3(m，2H)，1.6-2.0(m，5H)，2.0-2.2(m，2H)，2.4-2.6(m，1H)，2.7-3.1(m，2H)，3.7-4.0(m，10H)，4.0-4.4(m，2H)，6.5(s，1H)，6.7(s，2H)，6.8-7.0(m，2H)，7.3-7.5(m，1H).

Example 94: n- (1-cyclohexylmethyl-piperidin-3-yl) -N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-benzamide

Using experimental conditions analogous to example 14, 0.15g (0.22mmol) of N- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4, 5-trimethoxy-N-piperidin-3-yl-benzamide, 0.029g (0.26mmol) of cyclohexylformaldehyde, 0.021ml (0.35mmol) of acetic acid and 0.02g (0.35mmol) of sodium cyanoborohydride are used. The free base was converted to the HCl salt to give 180mg of a white solid. Yield: 99 percent.

LC-MSD, m/z vs C₃₂H₄₂N₂O₄F₂[M+H]+：557.4

¹H NMR(300MHz，MeOD/D₂O)：δ1.0-1.4(m，5H)，1.5-1.9(m，10H)，2.0-2.3(m，3H)，2.9-3.0(m，3H)，3.4-3.6(m，2H)，3.7-4.0(m，10H)，4.0-4.2(m，2H)，4.9-4.6(m，1H)，6.5(s，1H)，6.7(s，2H)，6.8-7.0(m，2H)，7.2-7.5(m，1H).

Example 95: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N-pyrrolidin-3-ylmethyl-benzamide

a: 1/alpha-methyl cinnamic aldehyde, Et₃N, dichloromethane 2/sodium borohydride, methanol

b: 3, 4, 5-Trimethoxybenzoic acid, Et₃N，EDC，HOBT

c: malonic acid dimethyl ester, sodium hydride, (Ph)₃)₄Pd

Flow 23: preparation of 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N-pyrrolidin-3-ylmethyl-benzamide

A mixture of 0.12g (0.24mmol) of allyl 3- { [ (2-methyl-3-phenyl-allyl) - (3, 4, 5-trimethoxy-benzoyl) -amino ] -methyl } -pyrrolidine-1-carboxylate (prepared according to scheme 23), 0.09g (0.73mmol) of dimethyl malonate, 5mg of sodium hydride and 5mg of palladium tetrakis triphenylphosphine in 3ml of anhydrous THF was stirred at room temperature under nitrogen for 1 hour.

The reaction mixture was concentrated and flash chromatographed on silica gel with chloroform 9-methanol 1 as eluent to give the free amine. The free amine was converted to its HCl salt to give 34mg of a pale yellow solid. Yield: 30 percent.

LC-MSD, m/z vs C₂₅H₃₂N₂O₄[M+H]+：425.4

¹H NMR(300MHz，MeOD)：δ1.7-2.0(m，2H)，2.5-2.7(m，1H)，2.8-3.0(m，1H)，3.1-3.3(m，1H)，3.2-3.4(m，3H)，3.5-3.7(m，3H)，3.7-4.0(m，11H)，4.0-4.4(s，2H)，6.5(s，1H)，6.7(s，2H)，7.1-7.5(m，5H).

Example 96: 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxole-5-carboxylic acid [ 4-hydroxy-1- (tetrahydro-pyran-4-yl) -pyrrolidin-2-ylmethyl ] - (2-methyl-3-phenyl-allyl) -amide

Using experimental conditions analogous to example 14, 0.16g (0.35mmol) of 7-methoxy-2, 2-dimethyl-benzo [1, 3] dioxol-5-carboxylic acid (4-hydroxy-pyrrolidin-2-ylmethyl) - (2-methyl-3-phenyl-allyl) -amide, 0.042g (0.42mmol) of tetrahydro-4H-pyran-4-one, 0.03ml (0.53mmol) of acetic acid and 0.026g (0.42mmol) of sodium cyanoborohydride were used. After conversion of the free base to the HCl salt, 130mg of a white solid was obtained. Yield: 65 percent.

LC-MSD, m/z vs C₃₁H₄₀N₂O₆[M+H]+：537.2，[M+2H]+：538.2

¹H NMR(300MHz，MeOD)：δ1.5-2.0(m，12H)，2.0-2.4(m，4H)，2.4-2.5(m，1H)，3.2-3.5(m，3H)，3.5-3.9(m，4H)，3.9-4.1(m，4H)，4.2(s，2H)，4.4-4.5(s，1H)，4.6(s，1H)6.5(s，1H)，6.7(s，1H)，6.9(s，1H)，7.2-7.5(m，5H).

Example 97: n- (1-cyclohex-3-enylmethyl-pyrrolidin-2-ylmethyl) -3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -benzamide

To a solution mixture of 70ml dichloromethane and 30ml trifluoroacetic acid was added 1.2g (2.45mmol) of tert-butyl 2- { [ (2-methyl-3-phenyl-allyl) - (3, 4, 5-trimethoxy-benzoyl) -amino ] -methyl } -pyrrolidine-1-carboxylate at room temperature and the mixture was stirred for 1 hour. To this mixture was added a saturated sodium bicarbonate solution until basic pH and extracted three times with dichloromethane. The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. The intermediate free amine was dissolved in 20ml dichloromethane containing a spatula of molecular sieve. To this mixture were added 0.29g (2.7mmol) of 1, 2, 3, 6-tetrahydro-benzaldehyde and 0.77g (3.67mmol) of sodium triacetoxyborohydride. The molecular sieve was filtered and a saturated solution of sodium bicarbonate was added and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the free amine, which was converted to the HCl salt. 500mg of a slightly pink powder are obtained. Yield: 36 percent.

Analysis C was performed over 20 min using a gradient of 20-80% acetonitrile¹⁸HPLC, eluting compound at 18.11 min.

LC-MSD, m/z vs C₃₂H₄₂N₂O₄[M+H]+：519.2，[M+2H]：520.2，[M+3H]：521.2

Example 98: n- [3- (2, 4-difluoro-phenyl) -2-methyl-allyl ] -3, 4-dimethoxy-N-pyrrolidin-3-yl-benzamide

Using experimental conditions similar to example 18, 0.12g (0.68mmol) of 3, 4-dimethoxybenzoic acid and 2ml (1.68mmol) of thionyl chloride were used. The resulting acid chloride was reacted with 0.2g (0.56mmol) of tert-butyl 3- [3- (2, 4-difluoro-phenyl) -2-methyl-allylamino ] -pyrrolidine-1-carboxylate and 0.2ml of triethylamine. The reaction yielded the free amine, which was converted to the HCl salt as an off-white solid 90 mg: yield: 35 percent.

LC-MSD, m/z vs C₂₃H₂₆N₂O₃F₂[M+H]+：417.6

¹H NMR(300MHz，MeOD)：δ1.7(s，3H)，2.4-2.6(m，2H)，3.2-3.6(m，3H)，3.6-4.0(m，8H)，4.1(s，2H)，4.4-4.5(s，1H)，6.5(s，1H)，6.9-7.5(m，6H)

Example 99: n- [ 2-bromo-3- (4-fluoro-phenyl) -allyl ] -N- (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -3, 4, 5-trimethoxybenzamide

Using experimental conditions analogous to example 12, 0.15g (0.36mmol) of [ 2-bromo-3- (4-fluoro-phenyl) -allyl ] - (1-cyclohexylmethyl-pyrrolidin-2-ylmethyl) -amine, 0.1g (0.47mmol) of 3, 4, 5-trimethoxy-benzoyl chloride and 0.08ml of triethylamine were used. Reversed-phase high performance liquid chromatography with a 20-80% acetonitrile phase gradient afforded 120mg of white powder as the TFA salt.

LC-MSD, m/z vs C₃₁H₄₀N₂O₄FBr[M+2H]+：605.1

¹H NMR(400MHz，CDCl₃)：δ1.0-2.2(m，14H)，2.4-2.6(m，2H)，2.8-3.1(m，2H)，3.4-3.6(m，2H)，3.6-4.0(3s，9H)，4.3-4.5(m，4H)，6.5(s，2H)，6.9-7.1(m，2H)，7.2(s，1H)，7.4-7.6(m，2H)

Example 102: 3, 4, 5-trimethoxy-N- (2-methyl-3-phenyl-allyl) -N- (2-piperidin-1-yl-ethyl) -benzamide

0.5g (1.9mmol) of (2-methyl-3-phenyl-allyl) - (2-piperidin-1-yl-ethyl) -amine is dissolved in 10ml of anhydrous methanol under nitrogen. The solution was cooled to 0 ℃. To this mixture were added 0.49g (2.3mmol) of 3, 4, 5-trimethoxybenzoic acid, 0.2ml of triethylamine and 1.2g (3.8mmol) of TBTU. The reaction was stirred at room temperature for 18 hours. The reaction mixture was then diluted with chloroform, extracted with 2X 10ml of water, 2X 10ml of sodium bicarbonate and washed with 2X 10ml of brine. The organic layer was dried over sodium sulfate and concentrated. The compound was then purified on silica gel eluting with 1.2% methanol in chloroform to give 102mg of the product as an off-white HCl salt. Yield: 12 percent.

LC-MSD, m/z vs C₂₇H₃₆N₂O₄[M+H]+：453.3

Experiment of

To demonstrate that the above-described compounds are useful modulators of SDF-1 and I-TAC chemokines, the compounds were screened in vitro to determine their ability to bind to CCXCKR2 receptor in place of SDF-1 and/or I-TAC at various concentrations. E.g., in the Determination of IC₅₀As described in detail in values, Reagents and Cells (see below), compounds bind to CCXCKR2 receptor expressed by breast Cells in the presence of 125I-labeled chemokines. Screening methods were then used to determine the ability of the compound to bind to the CCXCKR2 receptor site at various concentrations in place of the labeled chemokine.

Compounds considered to be potent modulators are capable of replacing at least 50% of the binding of the chemokines SDF-1 or I-TAC to the CCXCKR2 receptor at concentrations at or below 1.1 micromolar (. mu.M) and more preferably at or below 300 nanomolar (nM). At present, especially preferred compounds are capable of replacing at least 50% of SDF-1 or I-TAC binding to the CCXCKR2 receptor at concentrations at or below 200 nanomolar. Illustrative compounds that meet these criteria are listed in table 1 below.

TABLE 1

IC₅₀Determination of value

Reagents and cells.¹²⁵I-labeled SDF-1 was purchased from Perkin-Elmer Life Sciences, Inc. (Boston, MA). The MCF-7 (adenocarcinoma, mammary gland) cell line was obtained from the American Type Culture Collection (Manassas, Va.) and was cultured at 37 ℃ in 5% CO₂In a humidified incubator with air mixture, cultures were grown in DMEM (Mediatech, Herndon, VA) supplemented with 10% bovine serum (FBS) (HyClone Logan, UT) and bovine insulin (0.01mg/mL) (Sigma, st.

And (4) performing binding analysis. The compounds of interest were tested to determine their ability to bind to the CCXCKR2 site on MCF-7 cells. The method is carried out by using HHV8-encodedvMIP-I selectedvIgages chemoreceptors CCR5.Agonist and dantagonist profiles of viral chemokiness, J.biol.chem.1999Jul 30; 274(31): 21569-74 and Gosling J et al, Cutting edge: identification of a novel receptor that will bind a critical cell-and T cell-active chemical binding ELC, SLC, and TECK, J.Immunol.2000Mar 15; 164(6): 2851-6, using the most potent radioligand binding.

In these assays, MCF-7 cells were combined with the compound of interest and the ability of these compounds to displace radiolabeled SDF-1 was evaluated using the methods described in Dairaghi and Gosling. Target compounds were added to the plates to reach the indicated concentrations, then in the following binding medium (25mM HEPES, 140mM NaCl, 1mM CaCl)₂，5mM MgCl₂And 0.2% bovine serum albumin, adjusted to pH 7.1) by adding a radiolabelled chemokine: (¹²⁵I SDF-1) was incubated with cells at 4 ℃ for 3 hours. All assays were then incubated at 4 ℃ for 3 hours with gentle stirring. After incubation of all binding assays, the reaction was vortexed and washed twice (25mM HEPES, 500mM NaCl, 1mM CaCl) on PEI-treated GF/B glass filters using a cell harvester (Packard)₂，5mM MgCl₂Adjusted to pH 7.1). Mixed scintillant (MicroScint 10, Packard) was added to the wells and the filters were counted on a Packard Topcount science counter. Data were analyzed and plotted using Prism (GraphPad Prism version 3.0a by Macintosh, GraphPad software, www.graphpad.com).

Inhibition of in vitro cell proliferation

Antagonism of CCXCKR2 expressed on breast cancer by small molecular weight compounds inhibits cell proliferation in vitro. The in vitro treated cells exhibited reduced cell growth over time compared to untreated controls.

Inhibition of cell adhesion in vitro

In vitro quiescent adhesion assays are used to model the migratory activity of leukocytes, including cell adhesion and subsequent infiltration into a given tissue. A monolayer of vascular endothelial cells was grown on the surface and cells expressing CCXCKR2 were labeled with a fluorescent dye to enable visualization. Experiments have shown that the presence of cells expressing CCXCKR2 adhering to the endothelial layer promotes adhesion of cells otherwise expressing CCXCKR2, compared to a control group in which CCXCKR2 is not expressed. In addition, the addition of CCXCKR2 modulator inhibited adhesion compared to vehicle-treated controls.

Inhibition of in vivo tumor formation

Immunodeficient mice were injected with human B-cell lymphoma cells expressing CCXCKR 2. Those mice were treated with CCXCKR2 modulators that inhibit vascularized tumor formation. In one study, only 1 of 17 mice treated with CCXCKR2 antagonist developed cystic, vascularized tumors, while 11 of 17 mice in the vehicle placebo group developed cystic, vascularized tumors.

Reduction of tumor volume in vivo

Immunodeficient mice were given injections of human breast cancer. Tumors were measured three times per week and tumor volumes were determined. Mice treated with CCXCKR2 modulators exhibit reduced tumor volume compared to vehicle control group treated mice.

Those of ordinary skill in the art of organic chemistry will recognize from the provided specification, figures and examples that modifications and variations can be made to the preferred embodiments of the present invention without departing from the scope of the invention as defined by the following claims and their equivalents.

Claims

(modification according to article 19 of the treaty)

1. A modulator of the following structure (I):

wherein m is an integer of 1 to 5;

each Y is independently selected from hydrogen, halogen, -CN, -NO₂、-OH、-OR’、-C(O)R’、-CO₂R’、-O(CO)R’、-C(O)NR’R”、-OC(O)NR’R”、-SR’、-SOR’、-SO₂R’、-SO₂NR’R”、-NR’R”、-NR’C(O)R”、-NR’C(O)₂R”、-NR’SO₂R ", -NR '-C (O) NR" R' ", unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl;

n is 0, 1, 2 or 3;

z is-CHR¹R²-、-OR¹or-NR¹R²；

R¹And R²Each independently is substituted or unsubstituted alkyl or hydrogen, or Z and R¹And R²Combine to form a substituted or unsubstituted 5-to 8-membered ring comprising at least 1 nitrogen and 0-3 additional heteroatoms;

R⁶is alkyl, hydrogenOr halogen; and

R³and R⁵Each independently selected from hydrogen, halogen, -CN, -NO₂、-OH、-OR’、-C(O)R’、-CO₂R’、-O(CO)R’、-C(O)NR’R”、-OC(O)NR’R”、-SR’、-SOR’、-SO₂R’、-SO₂NR’R”、-NR’R”、-NR’C(O)R”、-NR’C(O)₂R”、-NR’SO₂R ", -NR 'C (O) NR" R' ", unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl, and

R⁴independently selected from halogen, -CN, -NO₂、-OH、-OR’、-C(O)R’、-CO₂R’、-O(CO)R’、-C(O)NR’R”、-OC(O)NR’R”、-SR’、-SOR’、-SO₂R’、-SO₂NR’R”、-NR’R”、-NR’C(O)R”、-NR’C(O)₂R”、-NR’SO₂R ", -NR 'C (O) NR" R' ", unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl, or

Wherein R is³、R⁴Or R⁵Any two of which, together with the atoms to which they are substituted, form a substituted or unsubstituted 3-to 10-membered heterocyclyl.

2. The modulator of claim 1, wherein R⁶Is hydrogen.

3. The modulator of claim 1, wherein R⁶Is substituted or unsubstituted C_1-8An alkyl group.

4. The modulator of claim 1, wherein R⁶Is halogen.

5. The modulator of claim 1, wherein R³And R⁵Each is independently selected from hydrogen, -OR' and substituted OR unsubstituted C_1-8Alkyl, and R⁴Independently selected from-OR' and substituted OR unsubstituted C_1-8An alkyl group.

6. The modulator of claim 1, wherein R³And R⁵Each independently selected from-OR' and hydrogen, and R⁴is-OR'.

7. The modulator of claim 1, wherein R³、R⁴And R⁵Each is-OR ', wherein R' is substituted C_1-8An alkyl group.

8. The modulator of claim 1, wherein R⁴And R⁵Together with the atoms to which they are substituted, form a substituted or unsubstituted 5-to 6-membered heterocyclic group containing 1-2 oxygen atoms.

9. The modulator of claim 1, where Z is CHR¹R²And wherein R¹And R²Together with Z form C having 0-3 substituents selected from_3-10Cycloalkyl groups: halogen, -CN, -NO₂、-OH、-OR’、-C(O)R’、-CO₂R’、-O(CO)R’、-C(O)NR’R”、-OC(O)NR’R”、-SR’、-SOR’、-SO₂R’、-SO₂NR’R”、-NR’R”、-NR’C(O)R”、-NR’C(O)₂R”、-NR’SO₂R ', -NR' (CO) NR 'R', unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl.

10. The modulator of claim 1, wherein R¹And R²Together with Z, form a 3-to 10-membered heterocyclyl having 0-3 substituents selected from: halogen, -OR, substituted OR unsubstituted C_1-8Alkyl, substituted or unsubstituted C_1-8Alkenyl, substituted or unsubstituted C_1-8Alkynyl, substituted or unsubstituted C_6-10Aryl, substituted or unsubstituted 5-to 10-membered heteroaryl.

11. The modulator of claim 1, where Z is-CHR¹R²-。

12. The modulator of claim 1, where Z is-NR¹R²-。

13. The modulator of claim 1, wherein Z and R¹And R²Is selected from the group consisting of substituted or unsubstituted morpholinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, and substituted or unsubstituted piperazinyl.

14. The modulator of claim 1, wherein Z is a substituted or unsubstituted group of the formula:

15. the modulator of claim 1, wherein Z is a substituted or unsubstituted group of the formula:

16. the modulator of claim 1, wherein Z is a substituted or unsubstituted group of the formula:

17. the modulator of claim 1, wherein Z is a substituted or unsubstituted group of the formula:

18. the modulator of claim 1, wherein Z is a substituted or unsubstituted group of the formula:

19. the modulator of claim 16, wherein Z is a substituted or unsubstituted group of the formula:

wherein R is⁷Selected from hydrogen, -C (O) R', -CO₂R’、-C(O)NR’R”、-SO₂R' is unsubstituted or substituted C_1-10Alkyl, unsubstituted or substituted C_1-8Alkoxy, unsubstituted or substituted C_2-10Alkenyl, unsubstituted or substituted C_2-10Alkynyl, unsubstituted or substituted C_3-10Cycloalkyl, unsubstituted or substituted C_6-10Aryl radical, C_6-10Aryloxy, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl.

20. The modulator of claim 1, wherein R⁷Is substituted or unsubstituted C_1-10Alkyl, substituted or unsubstituted C_1-10Alkoxy, substituted or unsubstituted aryloxy or substituted or unsubstituted C_3-10A cycloalkyl group.

21. The modulator of claim 1, wherein n is 1, 2, or 3.

22. The modulator of claim 1, wherein m is 1 or 2 and each Y is halogen.

23. The modulator of claim 1, wherein m is 0.

24. The modulator of claim 1 wherein substituted alkyl, substituted alkenyl, substituted alkynyl and substituted cycloalkyl may each be independently substituted with halo, -OR ', -NR' R ', -SR', -SiR 'R' ", -OC (O) R ', -C (O) R', -CO₂R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R*、-NR”C(O)₂R’、-S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-NR’S(O)₂R', -CN, oxo (═ O or-O-) or-NO₂1-3 times, wherein R ', R ' and R ' are each independently hydrogen, halogen, unsubstituted C_1-8Alkyl, unsubstituted C_3-6Cycloalkyl, unsubstituted C_2-8Alkenyl, unsubstituted C_2-8Alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted or substituted heterocyclyl.

25. The modulator of claim 1, wherein the substituted aryl and substituted heteroaryl may each be independently substituted 1-3 times with: halogen, unsubstituted OR substituted alkyl, unsubstituted OR substituted alkenyl, unsubstituted OR substituted alkynyl, unsubstituted OR substituted cycloalkyl, -OR ', oxo (═ O OR-O), -OC (O) R', -NR 'R ", -SR', -R ', -CN, -NO' R", -CN₂、-CO₂R’、-CONR’R”、-C(O)R’、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)₂R’、-NR’-C(O)NR”R*、-NH-C(NH₂)＝NH、-NR’C(NH₂)＝NH、-NH-C(NH₂)＝NR’、-S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-NR’S(O)₂R' and-N₃Wherein R ', R ' and R ' are each independently hydrogen, halogen, unsubstituted C_1-8Alkyl, unsubstituted C_3-6Cycloalkyl, unsubstituted C_2-8Alkenyl, unsubstituted C_2-8Alkynyl, unsubstituted or substituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclyl.

26. The modulator of claim 1, where substituted heterocyclyl may be substituted with halo, unsubstituted OR substituted alkyl, unsubstituted OR substituted alkenyl, unsubstituted OR substituted alkynyl, unsubstituted OR substituted cycloalkyl, -OR ', oxo (═ O OR-O), -OC (O) R ', -NR ' R ", -SR ', -R ', -CN, -NO₂、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)₂R’、-NR’-C(O)NR”R*、-NH-C(NH₂)＝NH、-NR’C(NH₂)＝NH、-NH-C(NH₂)＝NR’、-S(O)R’、-S(O)₂NR’R”、-NR’S(O)₂R' and-N₃1-3 times, wherein R ', R ' and R ' are each independently hydrogen, halogen, unsubstituted C_1-8Alkyl, unsubstituted C_3-6Cycloalkyl, unsubstituted C_2-8Alkenyl, unsubstituted C_2-8Alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclyl.

27. A modulator having the following structure (II):

wherein n is 0-4

Wherein each Y is independently hydrogen or halogen;

R³and R⁵Each is independently selected from hydrogen, halogen and-OR'; and R⁴Independently selected from halogen and-OR';

or R³、R⁴And R⁵Any two of which, together with the atoms to which they are substituted, form an unsubstituted or substituted 3-to 10-membered heterocyclyl; and

R⁷selected from hydrogen, -C (O) R', -CO₂R’、-C(O)NR’R”、-SO₂R' is unsubstituted or substituted C_1-8Alkyl (optionally C)_1-8Alkoxyalkoxy, CH2CH2OCH2CH2OMe), unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl.

28. The modulator of claim 27, wherein R⁷Is C_1-8An alkoxyalkoxy group.

29. The modulator of claim 27, wherein n is 1.

30. A modulator comprising one of the following structural formulae:

31. a pharmaceutical composition comprising the modulator of claim 1 and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising the modulator of claim 27 and a pharmaceutically acceptable carrier.

33. A pharmaceutical composition comprising the modulator of any one of claims 28-30 and a pharmaceutically acceptable carrier.

34. A pharmaceutical composition comprising a compound of the formula:

or

And a pharmaceutically acceptable carrier.

35. A method of inhibiting the binding of chemokines I-TAC and/or SDF-1 to the CCXCKR2 receptor comprising contacting the composition of any one of claims 32-34 with a cell expressing the CCXCKR2 receptor for a time sufficient to inhibit the binding of chemokines to the CCXCKR2 receptor.

36. A method of inhibiting the binding of chemokines I-TAC and/or SDF-1 to the CCXCKR2 receptor comprising contacting the modulator of claim 1 with a cell expressing the CCXCKR2 receptor for a time sufficient to inhibit the binding of chemokines to the CCXCKR2 receptor.

37. A method of treating cancer comprising administering to a cancer patient a therapeutically effective amount of the composition of any one of claims 32-34 for a time sufficient to treat the cancer.

38. A method of treating cancer comprising administering to a cancer patient a therapeutically effective amount of the modulator of claim 1 for a time sufficient to treat the cancer.

Claims

1. A modulator of the following structure (I):

wherein m is an integer of 1 to 5;

n is 0, 1, 2 or 3;

z is-CHR¹R²-、-OR¹or-NR¹R²；

R⁶is alkyl, hydrogen or halogen; and

R³、R⁴and R⁵Each independently selected from hydrogen, halogen, -CN, -NO₂、-OH、-OR’、-C(O)R’、-CO₂R’、-O(CO)R’、-C(O)NR’R”、-OC(O)NR’R”、-SR’、-SOR’、-SO₂R’、-SO₂NR’R”、-NR’R”、-NR’C(O)R”、-NR’C(O)₂R”、-NR’SO₂R ", -NR 'C (O) NR" R' ", unsubstituted or substituted C_1-8Alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl, or wherein R is³、R⁴Or R⁵Any two of which, together with the atom to which they are substituted, form a substituted or unsubstituted3-to 10-membered heterocyclic group.

2. The modulator of claim 1, wherein R⁶Is hydrogen.

4. The modulator of claim 1, wherein R⁶Is halogen.

5. The modulator of claim 1, wherein R³、R⁴And R⁵Each is independently selected from hydrogen, -OR' and substituted OR unsubstituted C_1-8An alkyl group.

6. The modulator of claim 1, wherein R³、R⁴And R⁵Each independently selected from-OR' and hydrogen.

11. The modulator of claim 1, where Z is-CHR¹R²-。

12. The modulator of claim 1, where Z is-NR¹R²-。

wherein R is⁷Selected from hydrogen, -C (O) R', -CO₂R’、-C(O)NR’R”、-SO₂R' is unsubstituted or substituted C_1-10Alkyl, unsubstituted or substituted C_1-8Alkoxy, unsubstituted or substituted C_2-10Alkenyl, unsubstituted or substituted C_2-10Alkynyl, unsubstituted or substituted C_3-10Cycloalkyl, unsubstituted or substituted C_6-10Aryl radical, C_6-10Aryloxy, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl。

21. The modulator of claim 1, wherein n is 1, 2, or 3.

22. The modulator of claim 1, wherein m is 1 or 2 and each Y is halogen.

23. The modulator of claim 1, wherein m is 0.

24. The modulator of claim 1 wherein substituted alkyl, substituted alkenyl, substituted alkynyl and substituted cycloalkyl may each be independently substituted with halo, -OR ', -NR' R ', -SR', -SiR 'R' ", -OC (O) R ', -C (O) R', -CO₂R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、-NR’-C(O)NR”R*、-NR”C(O)₂R’、S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-NR’S(O)₂R', -CN, oxo (═ O or-O-) or-NO₂1-3 times, wherein R ', R ' and R ' are each independently hydrogen, halogen, unsubstituted C_1-8Alkyl, unsubstituted C_3-6Cycloalkyl, unsubstituted C_2-8Alkenyl, unsubstituted C_2-8Alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted or substituted heterocyclyl.

25. The modulator of claim 1, wherein the substituted aryl and substituted heteroaryl may each be independently substituted 1-3 times with: halogen, unsubstituted OR substituted alkyl, unsubstituted OR substituted alkenyl, unsubstituted OR substituted alkynyl, unsubstituted OR substituted cycloalkyl, -OR', oxo(═ O or-O), -OC (O) R ', -NR' R ", -SR ', -R', -CN, -NO₂、-CO₂R’、-CONR’R”、-C(O)R’、-OC(O)NR’R”、-NR”C(O)R’、-NR”C(O)₂R’、-NR’-C(O)NR”R*、-NH-C(NH₂)＝NH、-NR’C(NH₂)＝NH、-NH-C(NH₂)＝NR’、-S(O)R’、-S(O)₂R’、-S(O)₂NR’R”、-NR’S(O)₂R' and-N₃Wherein R ', R ' and R ' are each independently hydrogen, halogen, unsubstituted C_1-8Alkyl, unsubstituted C_3-6Cycloalkyl, unsubstituted C_2-8Alkenyl, unsubstituted C_2-8Alkynyl, unsubstituted or substituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclyl.

26. The modulator of claim 1, where substituted heterocyclyl may be substituted with halo, unsubstituted OR substituted alkyl, unsubstituted OR substituted alkenyl, unsubstituted OR substituted alkynyl, unsubstituted OR substituted cycloalkyl, -OR ', oxo (═ O OR-O), -OC (O) R ', -NR ' R ", -SR ', -R ', -CN, -NO₂、-OC(O)HR’R”、-NR”C(O)R’、-NR”C(O)₂R’、-NR’-C(O)NR”R*、-NH-C(NH₂)＝NH、-NR’C(NH₂)＝NH、-NH-C(NH₂)＝NR’、-S(O)R’、-S(O)₂NR’R”、-NR’S(O)₂R' and-N₃1-3 times, wherein R ', R ' and R ' are each independently hydrogen, halogen, unsubstituted C_1-8Alkyl, unsubstituted C_3-6Cycloalkyl, unsubstituted C_2-8Alkenyl, unsubstituted C_2-8Alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclyl.

27. A modulator having the following structure (II):

wherein n is 0-4

Wherein each Y is independently hydrogen or halogen;

R³、R⁴and R⁵Each is independently selected from hydrogen, halogen and-OR';

R⁷selected from hydrogen, -C (O) R', -CO₂R’、-C(O)NR’R”、-SO₂R' is unsubstituted or substituted C_1-8Alkyl (optionally C)_1-8Alkoxyalkoxy, CH2CH2OCH2CH2OMe) alkyl, unsubstituted or substituted C_2-8Alkenyl, unsubstituted or substituted C_2-8Alkynyl, unsubstituted or substituted C_3-8Cycloalkyl, unsubstituted or substituted C_6-10Aryl, unsubstituted or substituted 5-to 10-membered heteroaryl and unsubstituted or substituted 3-to 10-membered heterocyclyl.

28. The modulator of claim 27, wherein R⁷Is C_1-8An alkoxyalkoxy group.

29. The modulator of claim 27, wherein n is 1.

30. A modulator comprising one of the following structural formulae:

34. A pharmaceutical composition comprising a compound of the formula:

or

And a pharmaceutically acceptable carrier.