1,4-disubstituted 1,2,3-triazole analogues as CCR8 agonists

Abstract

The invention relates to CCR8 agonists and their use in diseases such as autoimmune diseases.

Description

[0001] 1,4-DISUBSTITUTED 1,2,3-TRIAZOLE ANALOGUES AS CCR8 AGONISTS BACKGROUND OF THE INVENTION

[0002] The human CC chemokine receptor 8, discovered in 1997, is a cell surface receptor that belongs to the G protein-coupled receptor (GPCR) family. The endogenous ligands for the chemokine receptors are called chemokines, which is shorthand for chemoattractant cytokine, a family of small proteins that directs the trafficking of immune cells during normal immune function, but is also involved in many pathological disorders. Various chemokines, such as CCL1, CCL8, CCL16, CCL18, are known to interact with CCR8. However, CCL1 exclusively binds CCR8, and hence the CCL1-CCR8 axis is the most extensively studied one.

[0003] CCR8 is highly expressed in the thymus, and the spleen, is also abundant in some NK and T cell lines and in the subset of T-helper-2 (Th2). CCR8 expression is upregulated on Th2 cells upon activation. Activated Th2 cells produce the cytokines IL-4, IL-5, and IL-13, which are important mediators of inflammation and airway hyper-reactivity in bronchial asthma, and CCR8 deficiency has been shown to ameliorate lung inflammation and airway function in the mouse.

[0004] More recently, it has been demonstrated that CCR8 is also expressed in tumor-resident regulatory T (Treg) cells, but is poorly expressed in tumor-infiltrating effector T-cells or peripheral Tregs. Treg cells promote cancer progression by suppressing antitumor immune responses of cytotoxic T-lymphocytes within the tumor microenvironment. Since Treg cells are endowed with immunosuppressive properties, they are also crucial in the suppression of autoimmunity.

[0005] Overall, these data indicate that CCR8 shows promise as drug target for the treatment of cancer, inflammatory disorders and autoimmune diseases.

[0006] Various anti-human CCR8 antibodies have been developed that show promising activity against a variety of solid cancers. These antibodies induce potent antibody-dependent cellular cytotoxicity (ADCC) and deplete Tregs within the tumor microenvironment leading to tumor growth inhibition. Examples include RO7502175, BAY 3375968 and S-531011. IPG7236 is an example of a potent and selective small molecule CCR8 antagonist (Fig. 1). It shows anti-tumor efficacy when evaluated in a mouse preclinical breast cancer xenograft model and is currently being evaluated in phase I clinical trials. / V-substituted N-substituted-5-aryl-oxazolidinones have also been studied because of their CCR8 antagonistic properties. SB-649701 (Fig. 1) is a potent CCR8 antagonist, lacks activity against other GPCRs (including other chemokine receptors) and does not inhibit CYP isoenzymes or the hERG ion channel. In vivo pharmacokinetic experiments in mice revealed moderate clearance and modest oral bioavailability (18%).ML-604086 (Fig. 1) is an optimized CCR8 antagonist from the naphthalene sulfonamide series. It was evaluated in a primate model of asthma. Although more than >98% target inhibition by ML604086 on peripheral T cells was achieved, this did not result in improvements of lung inflammation and lung function, suggesting a dispensable role of CCR8 in airway inflammation.

[0007] CCR8 agonism has also been studied as therapeutic strategy. Targeting CCR8 through a stabilized CCLl-Ig fusion protein (CCLl-Ig) improved Treg proliferation and suppressed disease in an experimental autoimmune encephalomyelitis (EAE) model, which is a murine model of multiple sclerosis. Similarly, stimulation of the CCL1-CCR8 signaling axis protected the gut from acute intestinal damage in a mouse model of inflammatory bowel disease.

[0008] Various small molecule CCR8 agonists have been developed as well (Fig 2). A series of diazaspiroundecanes was developed as CCR8 agonists. The most attractive congener is AZ-084, showing low nanomolar activity in various CCR8-related assays. In addition, it displays very good selectivity when evaluated against a panel of other chemokine receptors and ion channels. Moreover, AZ-84 has an attractive in vivo pharmacokinetic profile. Phenoxybenzylpiperidine analogues is another chemotype that has been pursued for their CCR8 agonistic properties. The prototype is ZK-756326 that shows moderate activity as CCR8 agonist. Further SAR studies with a focus on structural variation of the ethoxoyethanol side chain yielded various analogues with improved CCR8 agonistic activity. For example, the triazaspiro[4.5]decane analogue LMD-009 and the spiro-pyrrolidine analogue both showed low nM CCR8 agonism.

[0009] SUMMARY OF THE INVENTION

[0010] The present invention relates to novel 1,4-disubstituted 1,2,3-triazole analogues as agonists for the human CCR8 receptor and their use as agents for the treatment of autoimmune diseases. It is based on the unexpected finding that certain 1,4-disubstituted 1,2,3-triazole analogues show unexpected biological properties, in particular having significant human CCR8 agonistic activity.

[0011] The present invention further provides the use of these triazole analogues as a medicine for the treatment of autoimmune diseases. The auto-immune disorders to be treated by compounds from this invention include both systemic auto-immune diseases such as but not limited to lupus erythematosus, psoriasis, vasculitis, polymyositis, scleroderma, multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis and Sjogren syndrome; auto-immune endocrine disorders such as thyroiditis; and organ-specific auto-immune diseases such as but not limited to Addison disease, haemolytic or pernicious anaemia, Goodpasture syndrome, Graves disease, idiopathic thrombocytopenic purpura, insulindependent diabetes mellitus, juvenile diabetes, uveitis, Crohn's disease, ulcerative colitis,pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, glomerulonephritis and spontaneous infertility. Transplant rejections to be prevented or treated by the pharmaceutical compositions or combined preparations of this invention include the rejection of transplanted or grafted organs or cells (both allografts and xenografts), such as but not limited to host-versus-graft reaction disease. Furthermore, autoimmune-like disorders, such as the graft-versus-host disease (GvHD), can be treated by compounds from this invention.

[0012] Numbered statements of the invention are:

[0013] 1. A compound of formula I:

[0014]

[0015] "

[0016] Ari and Ar2are heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo Cl-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, Cl-7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio Cl-7 alkyl, thio C3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamide, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino;

[0017] X is O, NH, S, CH2;

[0018] RI and R2are each independently selected from H or Cl-7 alkyl;

[0019]

[0020] schematically represents a saturated or partly unsaturated heterocyclic ring with at least one nitrogen in said heterocyclic ring;

[0021] R3aand R3bare each independently selected from the group consisting of hydrogen, Cl-7 alkyl or a carbonyl group, or R3aand R3b together form a bridge consisting of -(CH2)m-, wherein m is 1 or 2;

[0022] R4is selected from the group consisting of H, hydroxyl, halogen, Cl-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo Cl-7 alkyl or Cl-7 alkoxy, which is optionally containing one or morefunctions selected from the group consisting of halogen, carbonyl, hydroxyl, cyano, carboxylic acid, carboxylic acid ester or carboxamide;

[0023] Rs is selected from the group consisting of H, Cl-7 alkyl or (CH2)n-Ar3,

[0024] wherein n is 0-2 and

[0025] wherein Ar3is a heteroaryl and aryl group, and wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo Cl-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, Cl-7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio Cl-7 alkyl, thio C3-10 cycloalkyl, thioaryl, thio- heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamide, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino;

[0026] and / or a pharmaceutical acceptable addition salt thereof and / or a stereoisomer thereof and / or a solvate thereof.

[0027] 2. The compound according to statement 1, wherein Ari, Ar2and Ar3are each independently selected from the group consisting of an unsubstituted heteroaryl and an aryl group, wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, Cl-7 alkoxy, hydroxyl, nitro and cyano.

[0028] 3. The compound according to statement 1 or 2, wherein X is O or CH2, preferentially X is O.

[0029] 4. The compound according to any one of statements 1 to 3, wherein Ri and R2are each selected from H or Cl-3 alkyl, preferentially Ri and R2are H or methyl.

[0030] 5. The compound according to any one of statements 1 to 4, wherein

[0031]

[0032] schematically represents a saturated heterocyclic ring with one nitrogen in said heterocyclic ring, preferentially said heterocyclic ring is a six-membered ring with one nitrogen in said heterocyclic ring.

[0033] 6. The compound according to any one of statements 1 to 5, wherein R3aand R3bare each independently selected from the group consisting of a methyl and a carbonyl group, or R3aand R3b together form a bridge consisting of -(CH2)2-.7. The compound according to any one of statements 1 to 6, wherein R4is selected from the group consisting of hydroxyl and Cl-7 alkoxy which is optionally substituted with one or more functions selected from the group consisting of hydroxyl, carboxylic acid, or carboxylic acid ester.

[0034] 8. The compound according to any one of statements 1 to 7, wherein R5is Ar3wherein said Ar3is an unsubstituted heteroaryl or an aryl group, and wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, Cl-7 alkoxy, halo C-l-7 alkyl, nitro, hydroxyl and cyano.

[0035] 9. The compound according to any one of statements 1 to 8, wherein the compound is selected from the group consisting of:

[0036] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidine 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidine l-(3-(2-methoxyphenoxy)benzyl)-4-(lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0037] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-methyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol 4-(l-ethyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol 4-methoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine

[0038] 4-ethoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine

[0039] 1-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)-4- propoxypiperidine

[0040] 4-fluoro-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine

[0041] ethyl 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-yl)oxy)acetate

[0042] 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4- yl)oxy)ethan-l-ol

[0043] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-nitrophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0044] 4-(l-(4-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol

[0045] 4-(l-(3-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol

[0046] 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-oll-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0047] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0048] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0049] 4-(l-(4-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0050] 4-(l-(3-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0051] 4-(l-(2-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0052] 1-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-(trifluoromethyl)phenyl)-lH-l,2,3-triazol- 4-yl)piperidin-4-ol

[0053] 2-(4-(4-hydroxy-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-lH-l,2,3-triazol-l-yl)benzonitrile

[0054] 4-(l-(2,3-difluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0055] 4-(l-(4-chloro-2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0056] 4-(l-(2,6-dimethoxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0057] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3,4,5-trimethoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0058] 4-(l-(furan-3-yl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0059] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(thiophen-2-yl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0060] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(pyridin-2-yl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol

[0061] 5-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-2-(3-(2-methoxyphenoxy)benzyl)-2-azabicyclo[2.2.1]heptan-5-ol

[0062] l-(3-(2-methoxyphenoxy)benzyl)-3-methyl-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0063] l-(3-(2-methoxyphenoxy)benzyl)-3,3-dimethyl-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0064] (8-(3-(2-methoxyphenoxy)benzyl)-3-(l-phenyl-lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3endo-ol1-(3-(2-methoxyphenoxy)benzyl)-2-methyl-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0065] (2S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)- 2-methylpiperidin-4-ol

[0066] (2R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)- 2-methylpiperidin-4-ol

[0067] l-(4-fluoro-3-phenoxybenzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol

[0068] l-(3-(2-fluorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol

[0069] 1-(3-(2-chlorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol

[0070] 2-(3-((4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-4-hydroxypiperidin-l- yl)methyl)phenoxy)benzonitrile

[0071] - 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-phenoxybenzyl)piperidin-4-ol -(S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- methoxyphenoxy)phenyl)ethyl)piperidin-4-ol

[0072] -(R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- methoxyphenoxy)phenyl)ethyl)piperidin-4-ol

[0073] - (S)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0074] - (R)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0075] - (R)-l-(l-(3-(2,4-difluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3- triazol-4-yl)piperidin-4-ol

[0076] - (S)-4-(l-(2-chlorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- fluorophenoxy)phenyl)ethyl)piperidin-4-ol

[0077] - l-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0078] - 8-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol

[0079] - 8-((6-(2-fluorobenzyl)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol

[0080] - 8-((4-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol

[0081] - 8-((5-(2-fluorophenoxy)pyridin-3-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3encfo-ol.

[0082] 0. A compound according to any one of statements 1 to 9, for use as a medicament.11. A compound according to any one of statements 1 to 9, for use in the treatment or prevention of a CCR8 mediated disease.

[0083] 12. The compound for use in the treatment or prevention according to statement 11 wherein the CCR.8 mediated disease is an autoimmune disease.

[0084] 13. The compound for use in the treatment or prevention according to statement 11 wherein the CCR.8 mediated disease is selected from the group consisting of graft-versus-host disease (GVHD), multiple sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, psoriasis and diabetes.

[0085] 14. The compound for use in the treatment or prevention according to any one of statements 11 to 13, wherein the compound is selected from the group consisting of: l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidine 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidine l-(3-(2-methoxyphenoxy)benzyl)-4-(lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0086] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-methyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol 4-(l-ethyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol 4-methoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine

[0087] 4-ethoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine

[0088] 1-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)-4- propoxypiperidine

[0089] 4-fluoro-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine

[0090] ethyl 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-yl)oxy)acetate

[0091] 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4- yl)oxy)ethan-l-ol

[0092] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-nitrophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0093] 4-(l-(4-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol

[0094] 4-(l-(3-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol

[0095] 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-oll-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0096] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0097] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0098] 4-(l-(4-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0099] 4-(l-(3-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0100] 4-(l-(2-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0101] 1-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-(trifluoromethyl)phenyl)-lH-l,2,3-triazol- 4-yl)piperidin-4-ol

[0102] 2-(4-(4-hydroxy-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-lH-l,2,3-triazol-l-yl)benzonitrile

[0103] 4-(l-(2,3-difluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0104] 4-(l-(4-chloro-2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0105] 4-(l-(2,6-dimethoxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0106] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3,4,5-trimethoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0107] 4-(l-(furan-3-yl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol

[0108] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(thiophen-2-yl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0109] l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(pyridin-2-yl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol

[0110] 5-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-2-(3-(2-methoxyphenoxy)benzyl)-2-azabicyclo[2.2.1]heptan-5-ol

[0111] l-(3-(2-methoxyphenoxy)benzyl)-3-methyl-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0112] l-(3-(2-methoxyphenoxy)benzyl)-3,3-dimethyl-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol

[0113] (8-(3-(2-methoxyphenoxy)benzyl)-3-(l-phenyl-lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3endo-ol1-(3-(2-methoxyphenoxy)benzyl)-2-methyl-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0114] (2S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)- 2-methylpiperidin-4-ol

[0115] (2R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)- 2-methylpiperidin-4-ol

[0116] l-(4-fluoro-3-phenoxybenzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol

[0117] l-(3-(2-fluorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol

[0118] 1-(3-(2-chlorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol

[0119] 2-(3-((4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-4-hydroxypiperidin-l- yl)methyl)phenoxy)benzonitrile - 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l- (3-phenoxybenzyl)piperidin-4-ol

[0120] - (S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- methoxyphenoxy)phenyl)ethyl)piperidin-4-ol

[0121] - (R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- methoxyphenoxy)phenyl)ethyl)piperidin-4-ol

[0122] - (S)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0123] - (R)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0124] - (R)-l-(l-(3-(2,4-difluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3- triazol-4-yl)piperidin-4-ol

[0125] - (S)-4-(l-(2-chlorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2-fluorophenoxy) phenyl)ethyl)piperidin-4-ol

[0126] - l-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol

[0127] - 8-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol

[0128] - 8-((6-(2-fluorobenzyl)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol

[0129] - 8-((4-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol

[0130] - 8-((5-(2-fluorophenoxy)pyridin-3-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol.15. A pharmaceutical composition comprising a compound according to any one of the statements 1 to 9, and a pharmaceutically acceptable carrier.

[0131] BRIEF DESCRIPTION OF THE FIGURES

[0132] Figure 1. Small molecule CCR.8 antagonists.

[0133] Figure 2. Small molecule CCR8 agonists.

[0134] Figure 3. CCR8 agonism increases Treg suppressive potential. Expanded human Treg were treated with CCL1 (A) or a compound at indicated doses and evaluated for CD39 and FOXP3 expression. The CCR.8 agonist treatment resulted in an increased levels of both markers.

[0135] Figure 4. Treg preferentially express CCR8 in xGvHD model and increase CCR8 expression upon treatment with compound 17d. NSG mice were transplanted with human PBMC. (A-C) On day 9, Treg, CD4 non-Treg and CD8 T-cells were analyzed for frequency of CCR8+ cells (A) and per cell level of CCR8 (B). (C) Representative data in histogram (n=2). (D) Transplanted mice were treated with indicated doses (dl, d4) of compound 17d or PBS and analyzed at day 9 for frequency of CCR8+ Treg and CD4 non-Treg (left) and CCR8 per cell level (right).

[0136] DETAILED DESCRIPTION OF THE INVENTION

[0137] One embodiment of the present invention concerns a compound of formula I according to

[0138] the invention wherein X, Ri, R2, Rsa, Rsb, R4, Rs and

[0139]

[0140] have any of the values as described herein and wherein Ari and Ar2are heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo Cl-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, Cl-7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio Cl-7 alkyl, thio C3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamide, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; preferably said Ari and Ar2are independently selected from the group consisting of an unsubstituted heteroaryl and an aryl group, wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, Cl-7 alkoxy, hydroxyl and cyano. In certain embodiments thereof, said Ari isselected from the group consisting of an aryl group, wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, Cl-7 alkoxy, hydroxyl and cyano; preferably said aryl is a Ce aryl. In certain embodiments thereof, said Ar2is selected from the group consisting of an aryl group, wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, Cl-7 alkoxy, hydroxyl and cyano; preferably said aryl is a Ce aryl. In certain other embodiments thereof, said Ar2is an unsubstituted heteroaryl, containing one nitrogen; preferably said heteroaryl is a 6-membered heteroaryl.

[0141] Another embodiment of the present invention concerns a compound of formula I according

[0142] to the invention wherein Ari, Ar2, Ri, R2, R3a, R3b, 4, Rs and

[0143]

[0144] have any of the values as described herein and wherein X is O (oxygen) or CH2; preferably said X is O. Another embodiment of the present invention concerns a compound of formula I according

[0145] to the invention wherein Ari, Ar2, X, R3a, R3b, R4, Rs and

[0146]

[0147] have any of the values as described herein and wherein Ri and R2are each selected from H or Cl-7 alkyl, preferentially Ri and R2are H or Cl-3 alkyl. In a more specific embodiment thereof, Ri and R2are each selected from H or methyl.

[0148] Another embodiment of the present invention concerns a compound of formula I according to the invention wherein Ari, R3a, R3b, R4, and Rs have any of the values as

[0149] described herein and wherein

[0150]

[0151] schematically represents a saturated or partly unsaturated heterocyclic ring with at least one nitrogen in said heterocyclic ring; preferentially it is an unsaturated heterocyclic ring with one nitrogen, preferentially it is a 6-membered heterocyclic ring with one nitrogen.

[0152] Another embodiment of the present invention concerns a compound of formula I according

[0153] to the invention wherein Ari, Ar2, X, Ri, R2, R4, Rs and

[0154]

[0155] have any of the values as described herein and wherein R3aand R3b are each independently selected from the group consisting of hydrogen, Cl-7 alkyl or a carbonyl group, or R3aand R3b together form a bridge consisting of -(CH2)m-, wherein m is 1 or 2; preferentially said m is 2. In specific embodiments thereof, said R3aand R3b are each independently selected from the groupconsisting of hydrogen and Cl-3 alkyl, preferentially said R3aand R3bare each H or methyl, or both R3aand R3bare H.

[0156] Another embodiment of the present invention concerns a compound of formula I according

[0157] to the invention wherein Ari, Ar2, X, Ri, R2, R3a, R3b, Rs and

[0158]

[0159] have any of the values as described herein and wherein R4is selected from the group consisting of H, hydroxyl, halogen, and Cl-7 alkoxy, which is optionally containing one or more functions selected from the group consisting of halogen, carbonyl, hydroxyl, cyano, carboxylic acid, carboxylic acid ester or carboxamide. In specific embodiments thereof, said R4is OH. In other specific embodiments thereof, said R4is Cl-3 alkoxy optionally containing one or more functions selected from the group consisting of halogen, hydroxyl, carboxylic acid, carboxylic acid ester. In a more specific embodiment thereof, said Cl-7 alkoxy or said Cl- 3 alkoxy contains one function selected from the group consisting of halogen, hydroxyl, carboxylic acid, carboxylic acid ester.

[0160] Another embodiment of the present invention concerns a compound of formula I according

[0161] to the invention wherein Ari, Ar2, X, Ri, R2, R3a, R3b, R4and

[0162]

[0163] have any of the values as described herein and wherein R5is selected from the group consisting of H, Cl- 7 alkyl or (CH2)n-Ar3, wherein n is 0-2 and wherein Ar3is a heteroaryl and aryl group, and wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo Cl-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, Cl-7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio Cl-7 alkyl, thio C3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic- substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamide, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino. In a more specific embodiment thereof said Rs is selected from the group consisting of Cl-3 alkyl or (CH2)n-Ar3, wherein n is 0-2 and wherein Ar3is a heteroaryl and aryl group and wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, amino and Cl-3 alkoxy. In a more specific embodiment thereof said n is 0 and said Ar3is a 5- or 6-membered heteroaryl containing one heteroatom selected from N, S and O orsaid Ar3is a 6-membered aryl optionally substituted with 1 -3 substituents selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, amino and Cl -3 alkoxy.

[0164] Another embodiment of the present invention concerns a compound of formula I according to the invention wherein Ari, Ar2, X, Ri, R2, R3a, R3b, and R4 have any of the values as

[0165] described herein

[0166]

[0167] Another embodiment of the present invention concerns a compound of formula I according to the invention, having structural formula la

[0168]

[0169] wherein Ari, Ar2, X, Ri, R2, R3a, R3b, and R4 have any of the values as described herein. Another embodiment of the present invention concerns a compound of formula I, or la according to the invention, wherein Ari and Ar2are each independently selected from an unsubstituted 6-membered heteroaryl containing one heteroatom selected from N, S and O, or a 6 membered aryl group (i.e. phenyl), wherein said phenyl group is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, Cl-7 alkoxy, hydroxyl and cyano;

[0170] X is -O- or -CH2-; preferably said X is -O-;

[0171] wherein Ri and R2are each independently selected from H or Cl-3 alkyl; preferably Ri and R2are each independently selected from H or methyl; preferably Ri is H or methyl and R2is H;

[0172] wherein R3aand R3b are each independently selected from hydrogen or Cl-7 alkyl, or R3aand R3b together with the carbon atom to which they are attached form a bridge consisting of -(CH2)m-, wherein m is 1 or 2; preferentially said m is 2, preferably R3aand R3bare each independently selected from hydrogen or Cl-3 alkyl, preferentially said R3aand R3b are each H or methyl, or both R3aand R3bare H;

[0173] R4 is selected from the group consisting of H, hydroxyl, halogen, and Cl-7 alkoxy, wherein is said Cl-7 alkoxy is optionally containing one or more functions selected from the group consisting of carbonyl, hydroxyl, carboxylic acid, or carboxylic acid ester;

[0174] R5is selected from the group consisting of H, Cl-7 alkyl or (CH2)n-Ar3, wherein n is an integer selected from 0, 1 or 2, preferably n is 0 or 1; and wherein Ar3is a 5 or 6-membered heteroaryl containing one heteroatom selected from N, S or O or Ar3is a 6 membered aryl group (i.e. phenyl), wherein said 5-6 membered heteroaryl and phenyl are each independently optionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, nitro, hydroxyl, Cl-7 alkoxy, or cyano; preferably Rs is Cl-3 alkyl or (CH2)n-Ar3, wherein n is 0 or 1 and wherein Ar3is a 5-6 membered heteroaryl or phenyl and wherein said heteroaryl or phenyl groups are each independently optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, cyano and Cl-3 alkoxy; preferably Rs is (CH2)n-Ar3, n is 0 and Ar3is a 5-or 6-membered heteroaryl containing one heteroatom selected from N, S and O or Ar3is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, cyano and Cl- 3 alkoxy.

[0175] Another embodiment of the present invention concerns a compound of formula I according to the invention, having structural formula lb

[0176]

[0177] wherein Ari, Ar2, Ri, R2, R3a, R3b, and R4 have any of the values as described herein.

[0178] Another embodiment of the present invention concerns a compound of formula I, la, or lb according to the invention, wherein Ari is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, Cl-7 alkoxy, hydroxyl and cyano;

[0179] Ar2is selected from an unsubstituted 6-membered heteroaryl containing one N heteroatom or phenyl, wherein said phenyl group is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, Cl-7 alkoxy, hydroxyl and cyano;

[0180] wherein Ri is H and R2is selected from H or Cl-3 alkyl; preferably Ri is H or methyl and R2is H;

[0181] wherein R3aand R3bare each independently selected from hydrogen or Cl-7 alkyl, or R3aand R3b together with the carbon atoms to which they are attached form a bridge consisting of -(CH2)m-, wherein m is 1 or 2; preferentially said m is 2, preferably R3aand R3bare each independently selected from hydrogen or Cl-3 alkyl, preferably R3aand R3b are each independently H or methyl, or both R3aand R3bare H;

[0182] R4 is selected from the group consisting of H, hydroxyl, halogen, and Cl-7 alkoxy, wherein is said Cl-7 alkoxy is optionally containing one or more functions selected from the group consisting of carbonyl, hydroxyl, carboxylic acid, or carboxylic acid ester;

[0183] R5is (CH2)n-Ar3or Cl-3 alkyl, wherein n is 0 or 1; and wherein Ar3is a 5 or 6-membered heteroaryl containing one heteroatom selected from N, S or O or Ar3is phenyl optionally substituted with one or more substituents each independently selected from the groupconsisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, nitro, hydroxyl, Cl-7 alkoxy, or cyano; preferably Ar3is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, cyano and Cl-3 alkoxy; preferably Rs is (CH2)n-Ar3, n is 0 and Ar3is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, cyano and Cl-3 alkoxy; or Ar3is a 5- or 6-membered heteroaryl containing one heteroatom selected from N, S and O.

[0184] Another embodiment of the present invention concerns a compound of formula I, la, or lb according to the invention wherein Ari, Ar2, X, Ri, R2, and R4 have any of the values as

[0185] described herein

[0186]

[0187] together with the carbon atom to which they are attached forming a bridge consisting of -(CH2)m-, with m being 1 or 2, is

[0188]

[0189] In some embodiments, X is -O- or -CH2-; preferably X is -O-.

[0190] In some embodiments, Ari is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkoxy, hydroxyl, Cl-3 alkyl, halo Cl-3 alkyl, and cyano; preferably Ari is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkoxy, and hydroxyl.

[0191] In some embodiments, Ar2is phenyl or an unsubstituted 6-membered heteroaryl containing one N heteroatom, wherein said phenyl group is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, Cl-3 alkoxy, hydroxyl and cyano; preferably Ar2is an unsubstituted phenyl or an unsubstituted pyridinyl.In some embodiments, Ri is H and R2is selected from H or Cl-3 alkyl; preferably Ri is H or methyl and R2is H.

[0192] In some embodiments, R3aand Rsbare each independently selected from hydrogen or Cl-7 alkyl, preferably R3aand R3b are each independently selected from hydrogen or Cl-3 alkyl, preferentially R3aand R3b are each independently H or methyl, or both R3aand R3b are H.

[0193] In some embodiments, R4 is selected from the group consisting of H, hydroxyl, halogen, and Cl-7 alkoxy, wherein is said Cl-7 alkoxy is optionally containing one or more functions selected from the group consisting of carbonyl, hydroxyl, carboxylic acid, or carboxylic acid ester; preferably R4 is selected from the group consisting of H, hydroxyl, and Cl-7 alkoxy, wherein is said Cl-7 alkoxy is optionally containing one or more functions selected from the group consisting of hydroxyl, carboxylic acid, or carboxylic acid ester; preferably R4 is selected from the group consisting of H, hydroxyl, Cl-3 alkoxy, hydroxy-Cl-3 alkoxy, Cl-3alkyl-O-CO-Cl-3alkoxy.

[0194] In some embodiments, Rs is (CH2)n-Ar3or Cl-3 alkyl, wherein n is 0 or 1; and wherein Ar3is phenyl or a 5 or 6-membered heteroaryl containing one heteroatom selected from N, S or O, wherein said phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, nitro, hydroxyl, Cl-7 alkoxy, or cyano.

[0195] In some embodiments, Rs is (CH2)n-Ar3, n is 0 and Ar3is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, cyano and Cl-3 alkoxy; preferably Ar3is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, cyano and Cl-3 alkoxy.

[0196] In some embodiments, Rs is (CH2)n-Ar3, n is 0 and Ar3is a 5- or 6-membered heteroaryl containing one heteroatom selected from N, S and O.

[0197] In some embodiments, Rs is (CH2)n-Ar3, n is 1 and Ar3is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, cyano and Cl-3 alkoxy; preferably Ar3is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, nitro, hydroxyl, cyano and Cl-3 alkoxy.

[0198] In some embodiments, Rs is (CH2)n-Ar3, n is 0 and Ar3is selected from the group consisting of phenyl, pyridinyl, thiophenyl and furanyl; wherein said phenyl is optionally substituted with one or more substituents each independently selected from the group consisting ofhalogen, halo Cl-3 alkyl, hydroxyl, cyano and Cl-3 alkoxy; preferably Ar3is phenyl, pyridinyl, or thiophenyl; wherein said phenyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, hydroxyl, and Cl-3 alkoxy; preferably Ar3is phenyl, or pyridinyl; wherein said phenyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxyl, and Cl-3 alkoxy.

[0199] Another embodiment of the present invention concerns a compound of formula I according

[0200]

[0201] X is -O- or -CH2-; preferably X is -O-;

[0202] Ari is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkoxy, hydroxyl, Cl-3 alkyl, halo Cl-3 alkyl, and cyano; preferably Ari is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkoxy, and hydroxyl;

[0203] Ar2is phenyl or an unsubstituted 6-membered heteroaryl containing one N heteroatom, wherein said phenyl group is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, Cl-3 alkoxy, hydroxyl and cyano; preferably Ar2is an unsubstituted phenyl or an unsubstituted pyridinyl;

[0204] Ri is H and R2is selected from H or Cl-3 alkyl; preferably Ri is H or methyl and R2is H; R3aand R3b are each independently selected from hydrogen or Cl-7 alkyl, preferably R3aand R3b are each independently selected from hydrogen or Cl-3 alkyl, preferentially R3aand R3b are each independently H or methyl, or both R3aand R3bare H;

[0205] R4 is selected from the group consisting of H, hydroxyl, halogen, and Cl-7 alkoxy, wherein is said Cl-7 alkoxy is optionally containing one or more functions selected from the group consisting of carbonyl, hydroxyl, carboxylic acid, or carboxylic acid ester; preferably R4 is selected from the group consisting of H, hydroxyl, and Cl-7 alkoxy, wherein is said Cl-7 alkoxy is optionally containing one or more functions selected from the group consisting of hydroxyl, carboxylic acid, or carboxylic acid ester; preferably R4 is selected from the group consisting of H, hydroxyl, Cl-3 alkoxy, hydroxy-Cl-3 alkoxy, Cl-3alkyl-O-CO-Cl-3alkoxy;Rs is (CH2)n-Ar3or Cl-3 alkyl, wherein n is 0 or 1; and wherein Ar3is phenyl or a 5 or 6-membered heteroaryl containing one heteroatom selected from N, S or O, wherein said phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, nitro, hydroxyl, Cl-7 alkoxy, or cyano; preferably Rs is (CH2)n-Ar3, n is 0 and Ar3is selected from the group consisting of phenyl, pyridinyl, thiophenyl and furanyl; wherein said phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, halo Cl-3 alkyl, hydroxyl, cyano and Cl-3 alkoxy; preferably Ar3is phenyl, pyridinyl, or thiophenyl; wherein said phenyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, hydroxyl, and Cl-3 alkoxy; preferably Ar3is phenyl, or pyridinyl; wherein said phenyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxyl, and Cl-3 alkoxy.

[0206] The present invention also concerns a compound of formula I, any subgroup thereof, and / or a pharmaceutical acceptable addition salt thereof and / or a stereoisomer thereof and / or a solvate thereof, for use as a medicine.

[0207] The present invention also concerns a compound of formula I, any subgroup thereof, and / or a pharmaceutical acceptable addition salt thereof and / or a stereoisomer thereof and / or a solvate thereof, for use as a medicine for the prevention or treatment of a CCR8 mediated disease in an animal. In a specific embodiment thereof said CCR8 mediated disease is an autoimmune disease, more specifically said autoimmune disease is selected from the group consisting of graft-versus-host disease (GVHD), multiple sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, psoriasis and diabetes. The present invention also concerns a compound of formula I, any subgroup thereof, and / or a pharmaceutical acceptable addition salt thereof and / or a stereoisomer thereof and / or a solvate thereof, for the manufacture of a medicament for the prevention or treatment of an autoimmune disease in an animal. In an embodiment, said animal is a mammal, preferably said mammal is a human being.

[0208] The present invention also concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, any subgroup thereof, and / or a pharmaceutical acceptable addition salt thereof and / or a stereoisomer thereof and / or a solvate thereof, and one or more pharmaceutically acceptable excipients. In an embodiment, said pharmaceutical composition further comprises one or more biologically active drugs being selected from the group consisting of immunosuppressant and / or immunomodulator drugs.The present invention also concerns a method of prevention or treatment of an immune disorder in a mammal, comprising the administration of a therapeutically effective amount of a compound of formula I, any subgroup thereof, and / or a pharmaceutical acceptable addition salt thereof and / or a stereoisomer thereof and / or a solvate thereof, optionally in combination with one or more pharmaceutically acceptable excipients. In an embodiment, said immune disorder is an autoimmune disorder.

[0209] An Ullmann-type of nucleophilic aromatic substitution of 3-bromobenzyl alcohol 1 with 2- methoxyphenol using CuCI as catalyst yielded intermediate 2 [1]. Chlorination of the primary hydroxyl group by thionyl chloride afforded the benzyl chloride 3. Reaction with 4-ethynylpiperidine hydrochloride, followed by a copper(I)-catalyzed cycloaddition "click" reaction with azidobenzene and (azidomethyl)benzene yielded target compounds 5a-b, respectively.

[0210] Alternatively, reaction of benzyl chloride 3 with 4-piperidone hydrochloride afforded intermediate 6. A nucleophilic attack by ethynylmagnesium bromide yielded tertiary alcohol 7. A click reaction with azidotrimethylsilane (a safer azide source when compared to sodium azide) formed the 1,2,3-triazole intermediate 8. Alkylation with iodomethane and iodoethane yielded as regioisomeric mixtures from which the final compounds 9a-b, respectively, could not be isolated in pure form (Scheme 1).

[0211]

[0212] Scheme 1. Reagents and conditions, a) 2-methoxyphenol, NaH, CuCI, DMF, 140 °C, 83%; b) SOCI2, DCM, 0 °C - RT, 89%; c) 4-ethynylpiperidine hydrochloride, K2CO3, DMF, RT, 72%; d) azidobenzene or (azidomethyl)benzene, Cui, DMF / MeOH, RT, 78-84%; e) 4- Piperidon hydrochloride, K2CO3, DMF, RT, 92%; f) ethynylmagnesium bromide, THF, 0 °C, crude; g) azidotrimethylsilane, Cui, DMF / MeOH, RT, 52%; h) iodomethane or iodoethane, K2CO3, DMF, 50 °C, 34-56%;

[0213] The copper-catalyzed 1,3-dipolar cycloaddition between alkyne 7 and phenylazide or (azidomethyl)benzene yielded triazole analogue 10a and 10b, respectively. The hydroxyl group of compound 10a was alkylated by treatment with various alkylhalides to get final compounds lla-c. Moreover, fluorination of the hydroxyl group of compound 10a bytreatment with diethylaminosulfur trifluoride (DAST) afforded compound 12. Alternatively, reaction of compound 10a with ethyl 2-diazoacetate yielded compound 13. Reduction of the ester moiety by treatment with lithium aluminium hydride, affords the primary alcohol derivative 14.

[0214] Azides 16a-p were prepared in situ by diazotation of commercially available anilines 15a-p, using tert-butyl nitrite followed by reaction with trimethylsilyl azide [2]. A click reaction between key intermediate 7 and the various substituted phenylazides 16a-p furnished final compounds 17a-p.

[0215] A slightly different strategy was used for the synthesis of 1,2,3-triazole analogues carrying a heteroaromatic ring instead of the phenyl moiety. A one-pot, two-step sequence, whereby the heteroaromatic azide was generated in situ from a corresponding heteroaromatic halide using sodium azide, cupric sulfate, sodium ascorbate, and N,N'-dimethylethylenediamine (DMEDA) as the ligand was applied [3]. The heteroaromatic azide was immediately subjected to the click reaction with the acetylene derivative 7 yielding final compounds 19 and 21. To access the pyridine derivative 22, a similar approach using tetrazolo[l,5-a]pyridine as the ligand.

[0216]

[0217] Scheme 2. Reagents and conditions, a) azidobenzene, Cui, DMF / MeOH, RT, 70%; b) iodomethane, iodoethane or 1-iodopropane, NaH, DMF, 50 °C, 10-40%; c) DAST, DCM, -78 °C - RT, 82%; d) ethyl 2-diazoacetate, rhodium(II) acetate, DCM, RT, 22%; e) LiAIH4, THF, 0°C - RT, 66%; f) tert-butyl nitrite, trimethylsilyl azide, MeCN, 0 °C - RT, crude; g) Cui, DMF / MeOH, RT, 37-85%; h) sodium azide, 1,2-dimethylethylenediamine, sodium ascorbate, Cui, EtOH / H2O, 50 °C, 43-49%; i) tetrazolo[l,5-a]pyridine, sodium ascorbate, copper(II) sulfate, DMF / H2O, 85 °C, 33%.

[0218] The synthesis of derivatives containing a substituted piperidinyl moiety or an azabicyclic system is depicted in Scheme 3. The nucleophilic addition of ethynylmagnesium bromide to the ketone 23 in a Grignard reaction yielded the alkyne analogue 24. A click reaction formed intermediate 25. Afterwards, the Boc group was removed under acidic conditions, followed by alkylation of the secondary piperidinyl nitrogen with l-(3-(chloromethyl)phenoxy)-2-methoxybenzene, yielding the final compound 26.

[0219] Alternatively, various commercially available piperidine based starting materials 27a-f reacted with l-(3-(chloromethyl)phenoxy)-2-methoxybenzene yielding the corresponding intermediates 28a-f. Then, the ketone moieties were attacked by a Grignard reagent furnishing alcohols 29a-f. Finally, click reaction was performed to furnish the final compounds 30a-f in yields ranging from 47% to 81% (Scheme 3).

[0220]

[0221] Scheme 3. Reagents and conditions, a) ethynylmagnesium bromide, THF, 0 °C, crude; b) l-azido-2-fluorobenzene, Cui, DMF / MeOH, RT, 38%; c) HCI, dioxane, RT, crude; d) l-(3-(chloromethyl)phenoxy)-2-methoxybenzene, K2CO3, DMF, RT, 76-98%; e) azidobenzene, Cui, DMF / MeOH, RT, 47-81%.

[0222] A Grignard reaction between l-Fmoc-4-piperidone 31 and ethynylmagnesium bromide yielded intermediate 32. Reaction with l-azido-2-fluorobenzene using Cui as catalyst allowed to isolate intermediate 33. The Fmoc group was removed by treatment with morpholine as a base yielding intermediate 34. A reductive amination with 4-fluoro-3-phenoxybenzaldehyde furnished final compound 35.

[0223] Intermediates 37a-b were prepared via an Ullman ether type of coupling of (3-bromophenyl)methanol with phenols 36a-b using CuCI as catalyst. Alternatively, intermediate 39 was obtained by a nucleophilic substitution^], using 2-fluorobenzonitrile 38 as starting material. Chlorination of the primary hydroxyl group of intermediates 37a-b and 39 by treatment with thionyl chloride, yielded alkylating reagents 40a-c, whereas benzyl chloride 40d is commercially available. Finally, alkylation of the piperidinyl moietyof compound 36 by treatment with benzyl chlorides 40a-d reacted afforded final compounds 41a-d in yields ranging from 33% to 35% (Scheme 4).

[0224]

[0225] Scheme 4. Reagents and conditions, a) ethynylmagnesium bromide, THF, 0 °C, crude; b) l-azido-2-fluorobenzene, Cui, DMF / MeOH, RT, 58%; c) morpholine, DCM, RT, crude; d) NaBH(OAc)s, 4-fluoro-3-phenoxybenzaldehyde, DCM, RT, 20%; e) (3-bromophenyl)methanol, NaH, CuCI, DMF, 120 °C, 32-38%; f) 3-(hydroxymethyl)phenol, K2CO3, DMF, 110 °C, 72%; g) SOCI2, DCM, 0 °C - RT, 81-95%; h) K2CO3, DMF, RT, 33-35%.

[0226] The synthesis of analogues carrying a methyl group at the benzylic position is shown in Scheme s. Coupling of 3-(l-aminoethyl)phenol (either the 1-(S) enantiomer 42a or the 1-(R) enantiomer 42b) with 2-methoxyphenol using CuCI as catalyst and NaH as base afforded compounds 43a-b, that were used as such for further reaction without purification. To access the fluorinated phenoxybenzenemethanamine analogues, the Boc-protected benzylamines 45c-e were first prepared from the fluorine containing phenols 44c-e, using Cui as catalyst, 2-picolinic acid as the ligand and K3PO4 as base. Acidic removal of the Boc group yielded intermediates 46c-e. Then, l-ethyl-l-methyl-4-oxopiperidin-l-ium iodide reacted with compounds 43a-b and 46c-e, furnishing intermediates 47a-e via a two-step, one-pot approach. N-ethyl-N-methyl-4-oxopiperidinium iodide undergoes a base-catalyzed Hofmann elimination to form a transient Michael acceptor. The amine nucleophiles 43a-b and 46c-e add in a Michael type fashion, and the resulting secondary amine displace ethylmethylamine to give the desired products 47a-e[5].

[0227] Finally, a nucleophilic addition to the ketone moiety of compounds 47a-e, followed by click reaction on intermediates 48a-e, compounds 49a-f were obtained (Scheme 5).

[0228]

[0229] Scheme 5. Reagents and conditions, a) 2-methoxyphenol, NaH, CuCI, DMF, 120 °C, crude; b) 2-fluorophenol or 2,4-difluorophenol, K3PO4, 2-picolinic acid, Cui, DMSO, 90 °C, 30-33%; c) HCI, dioxane, RT, crude; d) l-ethyl-l-methyl-4-oxopiperidin-l-ium iodide, K2CO3, EtOH / H2O, 100 °C, 40-52%; e) ethynylmagnesium bromide, THF, 0 °C, crude; f) 1-azido-2-fluorobenzene or l-azido-2-chlorobenzene, Cui, DMF / MeOH, RT, 60-63%.

[0230] The synthesis of a series of analogues in which one of the phenyl rings is replaced by a pyridinyl moiety is shown in Scheme 6. A nucleophilic substitution on the starting material 2,6-dibromopyridine 50 with 2-fluorophenol using sodium hydride as a strong base afforded intermediate 51[6]. Treatment with n-butyllithium and DMF, allowed to isolate aldehyde 52 [7]. A reductive amination between intermediate 52 and the piperazine based building block furnished final compound 53. The 3-bromopyridine analogue 54 was subjected to a nucleophilic substitution reaction with 2-fluorophenol forming intermediate 55. Upon reduction of the cyano group with diisobutylaluminium hydride, the aldehyde 56 was formed.

[0231] Intermediate 58[8] was obtained from methyl 4-bromopicolinate 57 applying similar reaction condition as for the synthesis of intermediate 51. DIBAL-mediated reduction of the ester group was followed by chlorination of the alcohol group yielding intermediate 60.

[0232] A Suzuki coupling between 2,6-bis(bromomethyl)pyridine 62 and 2-fluorophenylboronic acid yielded compound 62 [9]. Nucleophilic addition of ethynylmagnesium bromide on piperidin-4-one 63, followed by a click reaction furnished intermediate 65. Acidic cleavageof the Boc protecting group yielded crude 66. Finally, target compounds 67a-d were prepared, either by reductive amination (for compounds 67a-d) or by a nucleophilic substitution reaction (compound 67b-c) (Scheme 6).

[0233]

[0234] Scheme 6. Reagents and conditions, a) 2-fluorophenol, NaH, DMF, 100 °C, 21-84%; b) n-butyllithium, DMF, THF, -40 °C, 65%; c) NaBH(OAc)3, DCM, RT, 27%; d) 2-fluorophenol, Cs2CO3, DMF, 130 °C, 84%; e) DIBAL-H, toluene, -78°C, 20%; f) LiAIH4, THF, 0 °C, 67%; g) SOCI2, DCM, 50 °C, crude; h) (2-fluorophenyl)boronic acid, dichlorobis(triphenylphosphine)palladium(II), K2CO3, THF / H2O, 40 °C, 13%; i) n- butyllithium solution, trimethylsilylethyne, K2CO3, THF and MeOH, -78 °C - RT, crude; j) l-azido-2-fluorobenzene, Cui, DMF / MeOH, RT, 46%; k) HCI, dioxane, RT, crude; I) NaBH(OAc)3, NaHCO3, MeOH, RT, 43%; m) K2CO3, DMF, RT, 30%.

[0235] DEFINITIONS

[0236] When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.

[0237] As used herein with respect to a substituting radical, and unless otherwise stated, the term " C1-7 alkyl " means straight and branched chain saturated acyclic hydrocarbon monovalent radicals having from 1 to 7 carbon atoms such as, for example, methyl, ethyl, propyl, n- butyl, 1-methylethyl (isopropyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (ter-butyl), 2-methylbutyl, n-pentyl, dimethylpropyl, n- hexyl, 2-methylpentyl, 3-methylpentyl, n- heptyl and the like. By analogy, the term " C1-3 alkyl " refers to such radicals having from 1 to 3 carbon atoms, i.e. up to and including propyl.

[0238] As used herein with respect to a substituting radical, and unless otherwise stated, the term " aryl " designate any mono- or polycyclic aromatic monovalent hydrocarbon radical having from 6 up to 30 carbon atoms such as but not limited to phenyl, naphthyl, anthracenyl, phenantracyl, fluoranthenyl, chrysenyl, pyrenyl, biphenylyl, terphenyl, picenyl, indenyl,biphenyl, indacenyl, benzocyclobutenyl, benzocyclooctenyl and the like, including fused benzo-C4-P cycloalkyl radicals (the latter being as defined above) such as, for instance, indanyl, tetrahydronaphthyl, fluorenyl and the like, all of the said radicals being optionally substituted with one or more substituents independently selected from the group consisting of halogen, Cl-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo Cl-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, Cl-7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio Cl-7 alkyl, thio C3-10 cycloalkyl, thioaryl, thio- heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamide, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino and the like.

[0239] As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C1-7 alkoxy ", " C3-10 cycloalkoxy ", " aryloxy ", " arylalkyloxy ", " oxyheterocyclic ", " thio C1-7 alkyl ", " thio C3-10 cycloalkyl ", " arylthio ", " arylalkylthio " and " thioheterocyclic" refer to substituents wherein a carbon atom of a C1-7 alkyl, respectively a C3-10 cycloalkyl, aryl, arylalkyl or heterocyclic radical (each of them such as defined herein), is attached to an oxygen atom or a divalent sulfur atom through a single bond such as, but not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropoxy, sec-butoxy, tertbutoxy, isopentoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiocyclopropyl, thiocyclobutyl, thiocyclopentyl, thiophenyl, phenyloxy, benzyloxy, mercaptobenzyl, cresoxy, and the like.

[0240] As used herein with respect to a substituting atom, and unless otherwise stated, the term "halogen" or "halo" means any atom selected from the group consisting of fluorine, chlorine, bromine and iodine.

[0241] As used herein with respect to a substituting radical, and unless otherwise stated, the term ” halo Cl-7 alkyl ” means a Cl-7 alkyl radical (such as above defined) in which one or more hydrogen atoms are each independently replaced by one or more halogens (preferably fluorine, chlorine or bromine), such as but not limited to difluoromethyl, trifluoromethyl, trifluoroethyl, octafluoropentyl, dodecafluoroheptyl, dichloromethyl and the like.

[0242] As used herein with respect to a substituting radical, and unless otherwise stated, the term ” heterocyclic ” means a mono- or polycyclic, saturated or mono-unsaturated or polyunsaturated monovalent hydrocarbon radical having from 2 up to 15 carbon atoms and including one or more heteroatoms in one or more heterocyclic rings, each of said rings1

[0243] having from 3 to 10 atoms (and optionally further including one or more heteroatoms attached to one or more carbon atoms of said ring, for instance in the form of a carbonyl or thiocarbonyl or selenocarbonyl group, and / or to one or more heteroatoms of said ring, for instance in the form of a sulfone, sulfoxide, N-oxide, phosphate, phosphonate or selenium oxide group), each of said heteroatoms being independently selected from the group consisting of nitrogen, oxygen, sulfur, selenium and phosphorus, also including radicals wherein a heterocyclic ring is fused to one or more aromatic hydrocarbon rings for instance in the form of benzo-fused, dibenzo-fused and naphtho-fused heterocyclic radicals; within this definition are included heterocyclic radicals such as, but not limited to, diazepinyl, oxadiazinyl, thiadiazinyl, dithiazinyl, triazolonyl, diazepinonyl, triazepinyl, triazepinonyl, tetrazepinonyl, benzoquinolinyl, benzothiazinyl, benzothiazinonyl, benzoxa-thiinyl, benzodioxinyl, benzodithiinyl, benzoxazepinyl, benzothiazepinyl, benzodiazepine, benzodioxepinyl, benzodithiepinyl, benzoxazocinyl, benzothiazocinyl, benzodiazocinyl, benzoxathiocinyl, benzodioxocinyl, benzotrioxepinyl, benzoxathiazepinyl, benzoxadiazepinyl, benzothia-diazepinyl, benzotriazepinyl, benzoxathiepinyl, benzotriazinonyl, benzoxazolinonyl, azetidinonyl, azaspiroundecyl, dithiaspirodecyl, selenazinyl, selenazolyl, selenophenyl, hypoxanthinyl, azahypoxanthinyl, bipyrazinyl, bipyridinyl, oxazolidinyl, diselenopyrimidinyl, benzodioxocinyl, benzopyrenyl, benzopyranonyl, benzophenazinyl, benzoquinolizinyl, dibenzocarbazolyl, dibenzoacridinyl, dibenzophenazinyl, dibenzothiepinyl, dibenzoxepinyl, dibenzopyranonyl, dibenzoquinoxalinyl, dibenzothiazepinyl, dibenzisoquinolinyl, tetraazaadamantyl, thiatetraazaadamantyl, oxauracil, oxazinyl, dibenzothiophenyl, dibenzofuranyl, oxazolinyl, oxazolonyl, azaindolyl, azolonyl, thiazolinyl, thiazolonyl, thiazolidinyl, thiazanyl, pyrimidonyl, thiopyrimidonyl, thiamorpholinyl, azlactonyl, naphtindazolyl, naphtindolyl, naphtothiazolyl, naphtothioxolyl, naphtoxindolyl, naphto-triazolyl, naphtopyranyl, oxabicycloheptyl, azabenzimidazolyl, azacycloheptyl, azacyclooctyl, azacyclononyl, azabicyclononyl, tetra hydrofury I, tetrahydropyranyl, tetrahydro-pyronyl, tetrahydroquinoleinyl, tetrahydrothienyl and dioxide thereof, dihydrothienyl dioxide, dioxindolyl, dioxinyl, dioxenyl, dioxazinyl, thioxanyl, thioxolyl, thiourazolyl, thiotriazolyl, thiopyranyl, thiopyronyl, coumarinyl, quinoleinyl, oxyquinoleinyl, quinuclidinyl, xanthinyl, dihydropyranyl, benzodihydrofuryl, benzothiopyronyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzodioxolyl, benzodioxanyl, benzothiadiazolyl, benzotriazinyl, benzothiazolyl, benzoxazolyl, phenothioxinyl, phenothiazolyl, phenothienyl (benzothiofuranyl), phenopyronyl, phenoxazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, benzotriazolyl, tetrazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrrolyl, furyl, dihydrofutyl, furoyl, hydantoinyl, dioxolanyl, dioxolyl, dithianyl, dithienyl, dithiinyl, thienyl, indolyl,indazolyl, benzofutyl, quinolyl, quinazolinyl, quinoxalinyl, carbazolyl, phenoxazinyl, phenothiazinyl, xanthenyl, purinyl, benzothienyl, naphtothienyl, thianthrenyl, pyranyl, pyronyl, benzopyronyl, isobenzofuranyl, chromenyl, phenoxathiinyl, indolizinyl, quinolizinyl, isoquinolyl, phthalazinyl, naphthiridinyl, cinnolinyl, pteridinyl, carbolinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, imidazolinyl, imidazolidinyl, benzimidazolyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, piperazinyl, uridinyl, thymidinyl, cytidinyl, azirinyl, aziridinyl, diazirinyl, diaziridinyl, oxiranyl, oxaziridinyl, dioxiranyl, thiiranyl, azetyl, dihydroazetyl, azetidinyl, oxetyl, oxetanyl, oxetanonyl, homopiperazinyl, homopiperidinyl, thietyl, thietanyl, diazabicyclooctyl, diazetyl, diaziridinonyl, diaziridinethionyl, chromanyl, chromanonyl, thiochromanyl, thiochromanonyl, thiochromenyl, benzofuranyl, benzisothiazolyl, benzocarbazolyl, benzochromonyl, benzisoalloxazinyl, benzocoumarinyl, thiocoumarinyl, pheno- metoxazinyl, phenoparoxazinyl, phentriazinyl, thiodiazinyl, thiodiazolyl, indoxyl, thioindoxyl, benzodiazinyl (e.g. phtalazinyl), phtalidyl, phtalimidinyl, phtalazonyl, alloxazinyl, dibenzopyronyl (i.e. xanthonyl), xanthionyl, isatyl, isopyrazolyl, isopyrazolonyl, urazolyl, urazinyl, uretinyl, uretidinyl, succinyl, succinimido, benzylsultimyl, benzylsultamyl and the like, including all possible isomeric forms thereof, wherein each carbon atom of said heterocyclic ring may furthermore be independently substituted with a substituent selected from the group consisting of halogen, nitro, C1-7 alkyl (optionally containing one or more functions or radicals selected from the group consisting of carbonyl (oxo), alcohol (hydroxyl), ether (alkoxy), acetal, amino, imino, oximino, alkyloximino, amino-acid, cyano, carboxylic acid ester or amide, nitro, thio C1-7 alkyl, thio C3-10 cycloalkyl, C1-7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxylalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfonamido and halogen), C3-7 alkenyl, C2-7 alkynyl, halo C1-7 alkyl, C3-10 cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, hydroxyl, amino, C1-7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic- substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfhydryl, C1-7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1-7 alkyl, thio C3-10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, carboxylic acid or esters or thioesters or amides thereof, tricarboxylic acid or esters or thioesters or amides thereof; depending upon the number of unsaturations in the 3 to 10 atoms ring, heterocyclic radicals may be sub-divided into heteroaromatic (or " heteroaryl ") radicals and non- aromatic heterocyclic radicals.Experimental section

[0244] General information

[0245] Chemistry

[0246] Acros Organics (Geel, Belgium), Merck (Darmstadt, Germany), BLD (Germany), Fluorochem (Hadfield, UK), and TCI Europe (Zwijndrecht, Belgium) provided all chemicals, and chemicals were used as received. Moisture sensitive reactions were carried out under argon atmosphere. Reaction mixtures were stirred magnetically and were run in roundbottom flasks when cooling or room temperature reactions were required. Reactions that were run at elevated temperature (higher than 20 - 30°C) were carried out in sealed screwcapped reaction tubes. The process of the various reactions was monitored byTLC analysis using MilliporeSigma™ Silica Gel 60 F254 Coated Aluminum-Backed TLC Sheets or Macherey-Nagel SILPre-coated ALUGRAM® Xtra SIL G / UV254 TLC sheets. UV irradiation (254 nm), iodine coated silica or ninhydrin-staining were used to visualize compounds. Compound purification was performed via standard column chromatography. For column chromatography, 70 - 230 mesh silica 60 (Acros, Geel, Belgium) was used as the stationary phase. Solvents were evaporated with a rotary evaporator at 50°C. Samples were dissolved in de-DMSO, CDCIsor CD3OD.XH NMR spectra were recorded on a Bruker Avance 400 (400 MHz working frequency). Proton-decoupled13C NMR spectra were recorded on a Bruker Avance 400 (101 MHz working frequency). Chemical shifts (6) were reported in parts per million (ppm) referenced to tetramethylsilane (XH), or the internal (NMR) solvent signal (XH and13C) as internal standards. High-resolution mass spectra were acquired on a quadrupole orthogonal acceleration time-of-flight mass spectrometer (Synapt G2 HDMS, Waters, Milford, MA, USA). Samples were infused at 3 pL / min and spectra were obtained in positive ionization mode with a resolution of 15,000 (FWHM— full width at half maximum) using leucine enkephalin as a lock mass. Melting points were determined using a Reichert Thermovar apparatus.

[0247] General procedure 1 (with compound 3 as a representative example)

[0248] Compound 2 (4.5 g, 19.54 mmol, 1.00 eq) was dissolved in dichloromethane (30.0 mL) and the reaction mixture was stirred for 5 minutes at 0 °C before the addition of thionyl chloride (4.65 g, 39.09 mmol, 2.00 eq). The mixture was stirred at room temperature for 2 h. Then, the reaction mixture was washed with brine (20.0 mL) and extracted with dichloromethane (40.0 mL). The organic layer was collected and dried over magnesium sulfate. Then, it was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (10% of ethyl acetate in petroleum ether) to give compound 3 as a white solid (4.15 g, 85% yield).

[0249] General procedure 2 (with compound 6 as a representative example)4-Piperidone hydrochloride (0.75 g, 5.50 mmol, 1.10 eq) and K2CO3 (1.52 g, 11.00 mmol, 2.20 eq) were dissolved in DMF (20.0 mL) and the reaction mixture was stirred for 5 minutes at room temperature before the addition of the compound 3 (1.24 g, 5.00 mmol, 1.00 eq). The mixture was stirred at room temperature for 8 h. Then, the reaction mixture was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (40% of ethyl acetate in petroleum ether) to give compound 6 as a yellow oil (1.43 g, 92% yield).

[0250] General procedure 3 (with compound 17b a representative example)

[0251] To an oven-dried screw cap test tube was added a magnetic stir-bar. The tube was then vacuum evacuated and back-filled with argon. This evacuation / backfill sequence was repeated two additional times. Under a counterflow of argon, ethynylmagnesium bromide (5.8 mL of 0.5 M solution in THF) was added dropwise by a syringe. The reaction mixture was placed at 0 °C. Then, a THF solution (2 mL) containing compound 6 (816.0 mg, 2.62 mmol, 1.00 eq) was added slowly and the reaction mixture was stirred at 0 °C for 1.5 h. Afterwards, a saturated aqueous ammonium chloride solution (0.5 mL) was added. At last, the reaction mixture was washed with brine (20.0 mL) and extracted with dichloromethane (40.0 mL). The organic layer was collected and dried over magnesium sulfate, followed by evaporation of solvent under reduced pressure to give the crude compound 7 which was used for the next step without further purification. Compound 15b (44.4 mg, 0.40 mmol, 1.00 eq) was dissolved in CH3CN (0.5 mL). It was placed at 0 °C for 5 minutes before the addition of tert-butyl nitrite (45.4 mg, 0.44 mmol, 1.10 eq). Then, it was stirred at 0 °C for 10 minutes before adding azidotrimethylsilane (50.7 mg, 0.44 mmol, 1.10 eq). Afterwards, the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure affording the crude compound 16b which was used for next step without further purification. Crude compound 7 (30.0 mg, 0.09 mmol, 1.00 eq), crude compound 16b (30.5 mg, 0.22 mmol, 2.50 eq) and Cui (8.5 mg, 0.05 mmol, 0.50 eq) were dissolved in DMF (1.0 mL) and methanol (0.5 mL). The reaction mixture was stirred at room temperature for 10 h. Then, the reaction mixture was washed with brine (5.0 mL) and extracted with ethyl acetate (10.0 mL). The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (8% of methanol in dichloromethane) to give compound 17b as a yellow solid (15.8 mg, 37% yield).

[0252] General procedure 4 (with compound 26 as a representative example)

[0253] Compound 25 (130.0 mg, 0.35 mmol, 1.00 eq) was dissolved in 1,4-dioxane (2.0 mL) prior to the addition of a hydrogen chloride solution (2.0 mL of a 4.0 M solution in dioxane). The reaction mixture was stirred at room temperature for 6 h. Afterwards, it wasconcentrated under reduced pressure to give the crude compound 5-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-2-azabicyclo[2.2.1]heptan-5-ol hydrochloride which was used for the next step without further purification. Crude 5-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-2-azabicyclo[2.2.1]heptan-5-ol hydrochloride (31.1 mg, 0.10 mmol, 1.00 eq) and K2CO3 (30.4 mg, 0.22 mmol, 2.20 eq) were dissolved in DMF (2.0 mL) and the reaction mixture was stirred for 5 minutes at room temperature before the addition of 1-(chloromethyl)-3-(2-methoxyphenoxy)benzene 3 (27.4 mg, 0.11 mmol, 1.10 eq). The mixture was stirred at room temperature for 8 h. At last, the reaction mixture was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (10% of methanol in dichloromethane) to give compound 26 as a yellow solid (37.1 mg, 76% yield).

[0254] General procedure 5 (with compound 35 as a representative example)

[0255] To a solution of compound 33 (380.0 mg, 0.78 mmol, 1.00 eq) in DCM (2.0 mL) was added morpholine (2.0 mL). The reaction mixture was stirred at room temperature for 6 h. Afterwards, it was concentrated under reduced pressure to give crude compound 34 which was used for the next step without further purification. 4-Fluoro-3-phenoxybenzaldehyde (28.5 mg, 0.13 mmol, 1.10 eq) and crude compound 34 (31.5 mg, 0.12 mmol, 1.00 eq) were dissolved in dichloromethane (3.0 mL) and the reaction mixture was stirred for 10 minutes at 0 °C before the addition of the NaBH(OAc)s (63.6 g, 0.30 mmol, 2.50 eq). The mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (5% methanol in dichloromethane) to give compound 35 as a yellow oil (11.2 mg, 20% yield).

[0256] General procedure 6 (with compound 47c as a representative example)

[0257] Compound 46c (107.1 mg, 0.40 mmol, 1.00 eq), l-ethyl-l-methyl-4-oxopiperidin-l-ium iodide (118.4 mg, 0.44 mmol, 1.10 eq) and K2CO3 (182.4 mg, 1.32 mmol, 3.30 eq) were dissolved in ethanol (2.4 mL) and H2O (1.2 mL). The resulting reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (25% of ethyl acetate in petroleum ether) to give compound 47c as a yellow oil (60.1 mg, 48% yield).

[0258] The preparation of (3-(2-methoxyphenoxy)phenyl)methanol (compound 2)

[0259] An oven-dried screw cap test tube was added with a magnetic stir-bar, CuCI (4.95 g, 50.00 mmol, 1.00 eq), and sodium hydride (2.67 g, 0.10 mol, 2.00 eq). The tube was then evacuated and back-filled with argon. The evacuation / backfill sequence was repeated with two additional times. The reaction tube was evacuated and backfilled with argon three times. Under counterflow of argon, the solvent anhydrous DMF (60.0 mL) was added,followed by 2-methoxyphenol (12.41 g, 0.10 mol, 2.00 eq) by syringe. After that, the reaction mixture was stirred for 5 minutes at 0 °C. A needle was used to release the gas which the reaction generated before the addition of the compound 1 (9.35 g, 50.00 mmol, 1.00 eq). Afterwards, the reaction mixture was placed into heating block at 140 °C for 48 h. The reaction mixture was cooled to room temperature. Then, the reaction mixture was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (25% of ethyl acetate in petroleum ether) to give compound 2 as a yellow oil (9.60 g, 83% yield).

[0260] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.25 (t, J = 7.9 Hz, 1H), 7.15-7.10 (m, 1H), 7.02-6.96 (m, 3H), 6.93-6.89 (m, 2H), 6.84 (dd, J = 2.2, 8.1 Hz, 1H), 4.59 (s, 2H), 3.80 (s, 3H), 2.04 (s, 1H).

[0261] The preparation of l-(3-(chloromethyl)phenoxy)-2-methoxybenzene (compound 3) This compound was synthesized via general procedure 1 affording compound 3 as a white solid, in 85% yield.

[0262] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.26 (t, J = 7.9 Hz, 1H), 7.18-7.14 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.03-6.99 (m, 2H), 6.93-6.89 (m, 2H), 6.87 (dd, J = 2.2, 8.2 Hz 1H), 4.52 (s, 2H), 3.82 (s, 3H).

[0263] The preparation of 4-ethynyl-l-(3-(2-methoxyphenoxy)benzyl)piperidine (compound 4) This compound was synthesized via general procedure 2 affording compound 4 as a colorless oil, in 72% yield.

[0264] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.22 (t, J = 7.8 Hz, 1H), 7.14-7.10 (m, 1H), 7.00 (d, J = 8.1 Hz, 2H), 6.97-6.89 (m, 3H), 6.81 (dd, J = 2.0, 8.0 Hz, 1H), 3.84 (s, 3H), 3.45 (s, 2H), 2.71-2.68 (m, 2H), 2.39-2.36 (m, 1H), 2.17-2.11 (m, 2H), 2.06 (d, J = 2.4 Hz, 1H), 1.85-1.82 (m, 2H), 1.71-1.62 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.77, 151.33, 145.28, 140.35, 129.19, 124.57, 123.22, 121.06, 120.73, 118.08, 115.84, 112.75, 87.64, 68.69, 63.02, 55.95, 52.08, 31.68, 26.81.

[0265] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidine (compound 5a)

[0266] This compound was synthesized via general procedure 3 affording compound 5a as a yellow solid, in 78% yield.

[0267] Mp: 106.6-108.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.73-7.70 (m, 3H), 7.51 (t, J =7.8 Hz, 2H), 7.41 (t, J =7.4 Hz, 1H), 7.24 (t, J =8.2 Hz, 1H), 7.14-7.10 (m, 1H), 7.06 (d, J =7.6 Hz, 1H), 7.02-6.96 (m, 3H), 6.94-6.90 (m, 1H), 6.82 (dd, J = 2.1, 7.9 Hz, 1H), 3.84 (s, 3H), 3.54 (s, 2H), 3.01-2.98 (m, 2H), 2.92-2.84 (m, 1H), 2.20-2.14 (m, 2H), 2.11-2.08 (m, 2H), 1.86-1.76 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.81, 153.17, 151.33, 145.23, 139.97, 137.26, 129.67, 129.27, 128.47, 124.62, 123.38, 121.08, 120.77, 120.44, 118.24, 117.70, 115.92, 112.77, 62.99, 55.95, 53.44, 33.40, 32.00; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C27H28N4O2: 441.22848; found: 441.2289.

[0268] The preparation of 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl) piperidine (compound 5b)This compound was synthesized via general procedure 2 affording compound 5b as a white solid, in 84% yield.

[0269] Mp: 83.4-85.1 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.38-7.34 (m, 3H), 7.26-7.20 (m, 3H), 7.17 (s, 1H), 7.13-7.09 (m, 1H), 7.04 (d, J =7.6 Hz, 1H), 7.00-6.94 (m, 3H), 6.92-6.88 (m, 1H), 6.81 (dd, J = 2.1, 8.1 Hz, 1H), 5.48 (s, 2H), 3.82 (s, 3H), 3.52 (s, 2H), 2.96-2.94 (m, 2H), 2.83-2.76 (m, 1H), 2.17-2.11 (m, 2H), 2.02-1.99 (m, 2H), 1.75-1.65 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.80, 152.84, 151.32, 145.16, 139.62, 134.81, 129.28, 129.07, 128.65, 128.02, 124.64, 123.42, 121.08, 120.79, 119.39, 118.24, 115.95, 112.77, 62.86, 55.94, 54.07, 53.35, 33.27, 31.85; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C28H30N4O2: 455.24413; found: 455.2439.

[0270] The preparation of l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-one (compound 6) This compound was synthesized via general procedure 2 affording compound 6 as a yellow oil, in 92% yield.

[0271] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.25 (t, J = 7.7 Hz, 1H), 7.16-7.11 (m, 1H), 7.04-6.97 (m, 4H), 6.94-6.90 (m, 1H), 6.83 (dd, J = 1.9, 8.1 Hz, 1H), 3.84 (s, 3H), 3.59 (s, 2H), 2.73 (t, J = 6.0 Hz, 4H), 2.44 (t, J = 6.1 Hz, 4H);13C NMR (101 MHz,

[0272] CDCI3) 5 (ppm) 209.28, 158.04, 151.39, 145.08, 140.08, 129.40, 124.78, 122.90, 121.10, 120.89, 117.70, 116.01, 112.79, 61.62, 55.95, 52.88, 41.33.

[0273] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 8)

[0274] Compound 7 (400.0 mg, 1.19 mmol, 1.00 eq) and Cui (112.9 mg, 0.59 mmol, 0.50 eq) were dissolved in DMF (3.0 mL) and methanol (1.0 mL). The reaction mixture was stirred for 2 minutes at room temperature before the addition of trimethylsilyl azide (163.9 mg, 1.42 mmol, 1.20 eq). The mixture was stirred at room temperature for 10 h. Then, the reaction mixture was washed with brine (10.0 mL) and extracted with ethyl acetate (20.0 mL). The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (15% of methanol in dichloromethane) to give compound 8 as a white solid (235.3 mg, 52% yield).

[0275] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.96 (br, 1H), 7.52 (s, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.10-6.88 (m, 6H), 6.80 (dd, J = 2.0, 7.6 Hz 1H), 3.79 (s, 3H), 3.60 (s, 2H), 2.72-2.61 (m, 4H), 2.18-2.11 (m, 2H), 1.95-1.92 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.88, 152.18, 151.29, 144.94, 138.38, 129.49, 127.18, 124.82, 123.73, 121.14, 120.90, 118.54, 116.19, 112.81, 67.02, 62.37, 55.92, 48.83, 37.10; HRMS (ESI-Q-TOF): m / z [M+H]+calcd. for C21H24N4O3: 381.19210; found: 381.1923.

[0276] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-methyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 9a)

[0277] This compound was synthesized via general procedure 2 at 50 °C affording compound 9a as a colorless oil, in 34% yield.

[0278] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.48 (s, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.15-7.10 (m, 1H), 7.07 (d, J = 7.4 Hz, 1H), 7.03-6.96 (m, 3H), 6.94-6.89 (m, 1H), 6.82 (dd, J = 2.0, 8.0 Hz, 1H), 4.15 (s, 3H), 3.84 (s, 3H), 3.57 (s, 2H), 2.72-2.69 (m, 2H), 2.60-2.54 (m, 2H), 2.20-2.13 (m, 2H), 1.91-1.88 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.87,154.66, 151.34, 145.16, 145.09, 130.46, 129.37, 124.68, 123.40, 121.09, 120.81, 118.24, 116.04, 112.78, 67.46, 62.55, 55.95, 48.99, 41.62, 37.64; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C22H26N4O3: 395.20775; found: 395.2073.

[0279] The preparation of 4-(l-ethyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl) piperidin-4-ol (compound 9b)

[0280] This compound was synthesized via general procedure 2 at 50 °C affording compound 9b as a colorless oil, in 56% yield.

[0281] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.48 (s, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.15-7.10 (m, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.03-6.96 (m, 3H), 6.93-6.89 (m, 1H), 6.82 (dd, J = 2.4, 8.1 Hz, 1H), 4.42 (q, J = 7.3 Hz, 2H), 3.83 (s, 3H), 3.57 (s, 2H), 2.72-2.70 (m, 2H), 2.60-2.55 (m, 2H), 2.21-2.14 (m, 2H), 1.92-1.88 (m, 2H), 1.54 (t, J = 7.3 Hz, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.86, 154.30, 151.33, 145.15, 139.48, 130.16, 129.36, 124.68, 123.41, 121.09, 120.81, 118.24, 116.03, 112.78, 67.47, 62.55, 55.94, 49.94, 49.01, 37.65, 14.75; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C23H28N4O3:

[0282] 409.22340; found: 409.2226.

[0283] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 10a)

[0284] This compound was synthesized via general procedure 3 affording compound 10a as a white solid, in 70% yield.

[0285] Mp: 154.6-155.7 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.87 (s, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.14-7.10 (m, 1H), 7.07 (d, J = 7.5 Hz, 1H), 7.02-6.96 (m, 3H), 6.94-6.92 (m, 1H), 6.82 (dd, J = 1.9, 8.1 Hz, 1H), 3.84 (s, 3H), 3.57(s, 2H), 2.75-2.72 (m, 2H), 2.61-2.56 (m, 2H), 2.29-2.22 (m, 2H), 2.01-1.98 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.86, 155.38, 151.35, 145.21, 140.07, 137.08, 129.76, 129.31, 128.78, 124.65, 123.33, 121.09, 120.80, 120.59, 118.16, 117.79, 115.95, 112.79, 67.54, 62.69, 55.97, 49.09, 37.76; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C27H28N4O3: 457.22340; found: 457.2227.

[0286] The preparation of 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl) piperidin-4-ol (compound 10b)

[0287] This compound was synthesized via general procedure 3 affording compound 10b as a white solid, in 77% yield.

[0288] Mp: 97.2-98.3 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.38-7.35 (m, 4H), 7.26-7.20 (m, 3H), 7.13-7.06 (m, 2H), 7.00-6.95 (m, 3H), 6.92-6.88 (m, 1H), 6.81 (dd, J = 2.3, 8.1 Hz, 1H), 5.48 (s, 2H), 3.81 (s, 3H), 3.58 (s, 2H), 2.73-2.71 (m, 2H), 2.63-2.57 (m, 2H), 2.17-2.11 (m, 2H), 1.95-1.92 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.87, 151.33, 145.06, 139.12, 134.46, 129.39, 129.13, 128.90, 128.79, 128.13, 124.72, 123.48, 121.10, 120.87, 119.43, 118.26, 116.07, 112.80, 67.06, 62.46, 55.93, 54.21, 48.97, 37.41; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C28H30N4O3: 471.23905; found: 471.2386.

[0289] The preparation of 4-methoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidine (compound Ila)

[0290] Using NaH as base, this compound was synthesized via general procedure 2 at 50 °C affording compound Ila as a white solid, in 40% yield.Mp: 38.5-40.1 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.89 (s, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.53 (t, J = 7.8 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.14-7.10 (m, 1H), 7.04 (d, J = 7.5 Hz, 1H), 7.01-6.95 (m, 3H), 6.93-6.89 (m, 1H), 6.82 (dd, J = 2.0, 8.0 Hz, 1H), 3.84 (s, 3H), 3.51(s, 2H), 3.13 (s, 3H), 2.61-2.50 (m, 4H), 2.27-2.17 (m, 4H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.81, 151.76, 151.33, 145.26, 140.48, 137.10, 129.74, 129.24, 128.70, 124.59, 123.24, 121.07, 120.75, 120.45, 119.27, 118.06, 115.88, 112.77, 72.07, 62.70, 55.96, 49.98, 49.19, 34.17; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C28H30N4O3: 471.23905; found: 471.2383.

[0291] The preparation of 4-ethoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidine (compound 11b)

[0292] Using NaH as base, this compound was synthesized via general procedure 2 at 50 °C affording compound 11b as a yellow solid, in 36% yield.

[0293] Mp: 41.0-42.8 °C.XH NMR (600 MHz, CDCI3): 6 (ppm) 7.87 (s, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.13-7.10 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.01-6.95 (m, 3H), 6.93-6.90 (m, 1H), 6.82 (dd, J = 2.2, 8.0 Hz, 1H), 3.84 (s, 3H), 3.50 (s, 2H), 3.30 (q, J = 7.0 Hz, 2H), 2.60-2.55 (m, 4H), 2.23-2.18 (m, 4H), 1.13 (t, J = 7.0 Hz, 3H);13C NMR (151 MHz, CDCI3) 6 (ppm) 157.80, 152.47, 151.33, 145.28, 140.51, 137.12, 129.74, 129.23, 128.67, 124.58, 123.28, 121.09, 120.75, 120.44, 119.05, 118.08, 115.90, 112.79, 71.76, 62.71, 57.41, 55.97, 49.31, 34.66, 15.73; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C29H32N4O3: 485.25470; found: 485.2548.

[0294] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)-4-propoxypiperidine (compound 11c)

[0295] Using NaH as base, this compound was synthesized via general procedure 2 at 50 °C affording compound 11c as a yellow solid, in 10% yield.

[0296] Mp: 38.9-40.6 °C.XH NMR (600 MHz, CDCI3): 6 (ppm) 7.87 (s, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.13-7.10 (m, 1H), 7.05 (d, J = 7.5 Hz, 1H), 7.01-6.95 (m, 3H), 6.93-6.90 (m, 1H), 6.82 (dd, J = 2.2, 8.0 Hz, 1H), 3.84 (s, 3H), 3.51 (s, 2H), 3.18 (t, J = 6.6 Hz, 2H), 2.62-2.56 (m, 4H), 2.23-2.20 (m, 4H), 1.55-1.49 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H);13C NMR (151 MHz, CDCI3) 5 (ppm) 152.43, 151.33, 145.28, 140.43, 137.13, 129.73, 129.23, 128.66, 124.58, 123.31, 121.08, 120.75, 120.44, 119.09, 118.13, 115.91, 112.79, 71.44, 63.60, 62.73, 55.97, 49.27, 34.60, 23.43, 10.84; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C30H34N4O3: 499.2703; found: 499.2694.

[0297] The preparation of 4-fluoro-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidine (compound 12)

[0298] Compound 10a (36.0 mg, 0.08 mmol, 1.00 eq) was dissolved in anhydrous dichloromethane (1.0 mL). The reaction mixture was cooled down at -78 °C for 10 minutes. Then, DAST (0.012 mL) was added and the reaction mixture was stirred at -78 °C for 10 minutes. Afterwards, the reaction mixture was warmed to room temperature. After adding H2O (0.2 mL), the reaction mixture was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (5% of methanol in dichloromethane) to give compound 12 as a yellow solid (29.5 mg, 82% yield).

[0299] Mp: 89.8-91.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (s, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.52 (t, J = 7.7 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.14-7.10(m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.02-6.96 (m, 3H), 6.94-6.90 (m, 1H), 6.83 (dd, J = 2.1, 8.0 Hz, 1H), 3.84 (s, 3H), 3.54 (s, 2H), 2.79-2.76 (m, 2H), 2.52-2.47 (m, 2H), 2.43-2.27 (m, 2H), 2.23-2.17 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.87, 151.61 (d,2JCF = 26.9 Hz), 151.36, 145.21, 140.48, 136.97, 129.76, 129.26, 128.85, 124.65, 123.12, 121.08, 120.80, 120.60, 118.70 (d,3JCF = 4.4 Hz), 117.91, 115.87, 112.79, 90.47 (d,1JCF = 169.0 Hz), 62.59, 55.95, 48.88, 35.61 (d,2JCF = 21.7 Hz); HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C27H27FN4O2: 459.21906; found: 459.2187.

[0300] The preparation of ethyl 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-yl)oxy)acetate (compound 13)

[0301] An oven-dried screw cap test tube was added with a magnetic stir-bar and compound 10a (100.0 mg, 0.22 mmol, 1.00 eq) and rhodium acetate dimer (4.8 mg, 0.01 mmol, 0.05 eq). The tube was then evacuated and back-filled with argon. The evacuation / backfill sequence was repeated with two additional times. The reaction tube was evacuated and backfilled with argon three times. Under counterflow of argon, the solvent anhydrous dichloromethane (4.0 mL) was added, followed by ethyl diazoacetate (100.0 mg, 0.88 mmol, 4.00 eq). The reaction mixture was stirred at room temperature overnight. At last, the reaction mixture was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (3% of methanol in dichloromethane) to give compound 13 as a brown solid (26.3 mg, 22% yield).

[0302] Mp: 45.7-47.2 °C.XH NMR (600 MHz, CDCI3): 6 (ppm) 8.02 (s, 1H), 7.73 (d, J = 7.4 Hz, 2H), 7.52 (t, J = 7.9 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.13-7.10 (m, 1H), 7.05 (d, J = 7.5 Hz, 1H), 7.01-6.96 (m, 3H), 6.93-6.90 (m, 1H), 6.83 (dd, J = 2.0, 8.1 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.98 (s, 2H), 3.84 (s, 3H), 3.59 (s, 2H), 2.71-2.62 (m, 4H), 2.38-2.24 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H);13C NMR (151 MHz, CDCI3) 5 (ppm) 170.55, 157.78, 151.33, 145.29, 140.09, 137.01, 129.76, 129.22, 128.82, 124.60, 123.66, 121.09, 120.74, 120.53, 119.91, 118.47, 116.03, 112.79, 73.40, 61.09, 60.78, 55.98, 49.17, 34.17, 23.79, 14.13; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C31H34N4O5: 543.26017; found: 543.2591.

[0303] The preparation of 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-yl)oxy)ethan-l-ol (compound 14)

[0304] An oven-dried screw cap test tube containing a magnetic stir-bar and compound 13 (25.0 mg, 0.05 mmol, 1.00 eq) was evacuated and backfilled with argon three times. Under a counterflow of argon, anhydrous THF (0.4 mL) was added by a syringe. The reaction mixture was cooled down at 0 °C for 10 minutes. Then, LiAIH4(0.07 mL of a 1.0 M solution in THF) was added and the reaction mixture was stirred at room temperature for 1.5 h. A saturated aqueous ammonium chloride solution (0.1 mL) was added to quench the reaction. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (6% methanol in dichloromethane) to give compound 14 as a white solid (15.1 mg, 66% yield).

[0305] Mp: 39.2-41.0 °C.XH NMR (600 MHz, CDCI3): 6 (ppm) 7.91 (s, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.52 (t, J = 7.9 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.14-7.11 (m, 1H), 7.05 (d, J = 7.5 Hz, 1H), 7.01-6.96 (m, 3H), 6.93-6.90 (m, 1H), 6.82 (dd, J = 1.9, 8.1 Hz, 1H), 3.84 (s, 3H), 3.70 (t, J = 4.5 Hz, 2H), 3.53 (s, 2H), 3.41 (t, J = 4.5Hz, 2H), 2.66-2.54 (m, 4H), 2.22-2.20 (m, 4H);13C NMR (151 MHz, CDCI3) 6 (ppm) 157.85, 151.94, 151.33, 145.22, 140.02, 137.00, 129.76, 129.31, 128.79, 124.64, 123.32, 121.10, 120.77, 120.47, 119.34, 118.15, 115.98, 112.80, 71.93, 63.47, 62.64, 62.16, 55.97, 49.15, 34.73; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C29H32N4O4: 501.24961; found: 501.2493.

[0306] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-nitrophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 17a)

[0307] This compound was synthesized via general procedure 3 affording compound 17a as a white solid, in 59% yield.

[0308] Mp: 58.9-60.1 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.40-8.37 (m, 2H), 8.09 (s, 1H), 7.98-7.95 (m, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.14-7.07 (m, 2H), 7.02-6.89 (m, 4H), 6.81 (dd, J = 2.2, 8.1 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 2H), 2.81-2.78 (m, 2H), 2.67-2.61 (m, 2H), 2.29-2.22 (m, 2H), 2.03-1.99 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.89, 156.27, 151.30, 147.16, 145.03, 141.15, 139.15, 129.42, 125.51, 124.78, 123.45, 121.12, 120.82, 120.46, 118.29, 118.10, 116.08, 112.81, 67.44, 62.45, 55.94, 48.89, 37.36; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C27H27N5O5: 502.20848; found: 502.2087.

[0309] The preparation of 4-(l-(4-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17b)

[0310] This compound was synthesized via general procedure 3 affording compound 17b as a yellow solid, in 37% yield.

[0311] Mp: 123.8-125.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.87 (s, 1H), 7.72-7.67 (m, 2H), 7.27-7.18 (m, 3H), 7.15-7.10 (m, 2H), 7.02-6.90 (m, 4H), 6.84 (dd, J = 1.9, 7.9 Hz, 1H), 3.83 (s, 3H), 3.64 (s, 2H), 2.84-2.81 (m, 2H), 2.71-2.63 (m, 2H), 2.36-2.28 (m, 2H), 2.04-2.01 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 162.45 (d,1JCF = 249.3 Hz), 157.95, 155.24, 151.36, 145.02, 138.67, 133.30 (d,4JCF = 2.6 Hz), 129.49, 124.80, 123.59, 122.59 (d,3JCF = 8.7 Hz), 121.13, 120.91, 118.35, 118.15, 116.73 (d,2JCF = 23.4 Hz), 116.23, 112.82, 67.24, 62.43, 55.96, 48.97, 37.39; HRMS (ESI-Q-TOF): m / z [M + H] + calcd. for C27H27FN4O3: 475.21398; found: 475.2145.

[0312] The preparation of 4-(l-(3-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17c)

[0313] This compound was synthesized via general procedure 3 affording compound 17c as a yellow solid, in 40% yield.

[0314] Mp: 136.4-138.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.91 (s, 1H), 7.54-7.46 (m, 3H), 7.24 (t, J = 7.7 Hz, 1H), 7.16-7.07 (m, 3H), 7.02-6.95 (m, 3H), 6.94-6.90 (m, 1H), 6.83 (dd, J = 2.4, 8.1 Hz, 1H), 3.84 (s, 3H), 3.59 (s, 2H), 2.78-2.76 (m, 2H), 2.65-2.59 (m, 2H), 2.36-2.28 (m, 2H), 2.02-1.99 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 163.07 (d,1JCF = 248.7 Hz), 157.90, 155.56, 151.35, 145.12, 139.43, 138.17 (d,3JCF = 10.2 Hz), 131.20 (d,3JCF = 8.9 Hz), 129.39, 124.72, 123.44, 121.12, 120.86, 118.23, 117.88, 115.96 (d,2JCF = 21.8 Hz), 115.69 (d,2JCF = 20.8 Hz), 112.82, 108.45, 108.19, 67.42, 62.57, 55.96, 48.99, 37.53; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H27FN4O3: 475.21398; found: 475.2137.

[0315] The preparation of 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17d)This compound was synthesized via general procedure 3 affording compound 17d as a yellow solid, in 52% yield.

[0316] Mp: 41.2-43.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.98 (d, J = 2.1 Hz, 1H), 7.94-7.90 (m, 1H), 7.46-7.41 (m, 1H), 7.34-7.24 (m, 3H), 7.16-7.11 (m, 2H), 7.02-6.97 (m, 3H), 6.94-6.90 (m, 1H), 6.84 (dd, J = 1.9, 8.1 Hz, 1H), 3.83 (s, 3H), 3.66 (s, 2H), 2.85-2.83 (m, 2H), 2.74-2.69 (m, 2H), 2.38-2.30 (m, 2H), 2.08-2.04 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.98, 153.38 (d,iJCF= 251.3 Hz), 151.38, 150.96, 144.98, 138.43, 130.27 (d,3JCF = 7.9 Hz), 129.52, 125.25 (d,4JCF = 3.8 Hz), 125.18, 124.96, 124.83, 123.64, 121.14, 121.07, 120.98, 118.34, 117.05 (d,2JCF = 20.0 Hz), 116.27, 112.83, 67.11, 62.36, 55.96, 48.92, 37.25; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H27FN4O3: 475.21398; found: 475.2134.

[0317] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 17e)

[0318] This compound was synthesized via general procedure 3 affording compound 17e as a grey solid, in 61% yield.

[0319] Mp: 106.5-108.1 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.82 (s, 1H), 7.60 (dd, J = 1.4, 8.9 Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.14-7.09 (m, 2H), 7.01-6.96 (m, 5H), 6.93-6.89 (m, 1H), 6.83 (dd, J = 1.9, 8.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.62 (s, 2H), 2.81-2.78 (m, 2H), 2.70-2.64 (m, 2H), 2.32-2.25 (m, 2H), 2.05-2.01 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 159.82, 157.91, 154.99, 151.35, 145.04, 138.98, 130.46, 129.43, 124.76, 123.54, 122.22, 121.11, 120.91, 118.29, 118.16, 116.13, 114.75, 112.81, 67.21, 62.49, 55.95, 55.62, 49.05, 37.45; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C28H30N4O4: 487.23396; found: 487.2339.

[0320] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 17f)

[0321] This compound was synthesized via general procedure 3 affording compound 17f as a yellow solid, in 56% yield.

[0322] Mp: 47.3-49.1 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.91 (s, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.31 (t, J = 2.1 Hz, 1H), 7.24 (t, J = 7.9 Hz, 2H), 7.14-7.09 (m, 2H), 7.01-6.89 (m, 5H), 6.83 (dd, J = 1.6, 8.1 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.62 (s, 2H), 2.81-2.79 (m, 2H), 2.70-2.64 (m, 2H), 2.33-2.26 (m, 2H), 2.05-2.01 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 160.57, 157.92, 155.11, 151.35, 145.04, 138.97, 138.02, 130.51, 129.43, 124.76, 123.54, 121.12, 120.91, 118.29, 118.09, 116.15, 114.68, 112.81, 112.46, 106.37, 67.25, 62.49, 55.95, 55.64, 49.02, 37.43; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C28H30N4O4: 487.23396; found: 487.2342.

[0323] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-methoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 17g)

[0324] This compound was synthesized via general procedure 3 affording compound 17g as a yellow solid, in 42% yield.

[0325] Mp: 50.2-52.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.00 (s, 1H), 7.75 (dd, J = 1.4, 7.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.15-7.07 (m, 4H), 7.02-6.97 (m, 3H), 6.94-6.90 (m, 1H), 6.84 (dd, J = 1.6, 8.1 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.66 (s, 2H), 2.85-2.83 (m, 2H), 2.75-2.69 (m, 2H), 2.36-2.29 (m, 2H), 2.08-2.05 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.96, 153.62, 151.37, 151.10, 144.99, 138.43, 130.14, 129.51, 126.24, 125.53, 124.81, 123.68, 121.70, 121.20, 121.13, 120.96,118.39, 116.25, 112.82, 112.23, 67.03, 62.43, 55.99, 55.95, 49.02, 37.36; HRMS (ESI-Q-TOF): m / z [M + H] + calcd. for C28H30N4O4: 487.23396; found: 487.2343.

[0326] The preparation of 4-(l-(4-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17h)

[0327] This compound was synthesized via general procedure 3 affording compound 17h as a grey solid, in 40% yield.

[0328] Mp: 103.8-105.2 °C.XH NMR (400 MHz, CD3OD): 6 (ppm) 8.26 (s, 1H), 7.62-7.58 (m, 2H), 7.27 (t, J = 7.9 Hz, 1H), 7.21-7.17 (m, 1H), 7.13-7.10 (m, 1H), 7.05-7.00 (m, 2H), 6.98-6.92 (m, 4H), 6.80 (dd, J = 2.0, 8.2 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 2H), 2.80-2.79 (m, 4H), 2.35-2.25 (m, 2H), 2.04-2.02 (m, 2H);13C NMR (101 MHz, CD3OD) 6 (ppm) 160.11, 159.60, 156.27, 153.26, 145.61, 138.55, 130.79, 130.60, 126.71, 124.75, 123.41, 123.02, 122.37, 120.94, 118.71, 117.16, 116.93, 114.44, 67.55, 63.17, 56.36, 50.02, 37.40; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H28N4O4: 473.21831; found: 473.2187.

[0329] The preparation of 4-(l-(3-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17i)

[0330] This compound was synthesized via general procedure 3 affording compound 17i as a yellow solid, in 79% yield.

[0331] Mp: 162.5-163.9 °C.XH NMR (400 MHz, CD3OD): 6 (ppm) 8.37 (s, 1H), 7.37-7.17 (m, 5H), 7.12-7.01 (m, 3H), 6.98-6.94 (m, 2H), 6.90-6.88 (m, 1H), 6.82 (dd, J = 1.8, 8.1 Hz, 1H), 3.82 (s, 2H), 3.76 (s, 3H), 2.93-2.92 (m, 4H), 2.35-2.28 (m, 2H), 2.07-2.04 (m, 2H);13C NMR (101 MHz, CD3OD) 6 (ppm) 160.19, 160.06, 153.25, 145.47, 139.43, 137.37, 131.81, 130.77, 126.81, 124.94, 123.08, 122.38, 120.89, 118.89, 117.24, 116.96, 114.45, 112.19, 108.62, 67.24, 62.76, 56.36, 49.88, 37.04; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H28N4O4: 473.21831; found: 473.2178.

[0332] The preparation of 4-(l-(2-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17j)

[0333] This compound was synthesized via general procedure 3 affording compound 17j as a brown solid, in 76% yield.

[0334] Mp: 76.8-78.6 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.10 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.25-7.20 (m, 2H), 7.13-7.05 (m, 3H), 6.99-6.88 (m, 5H), 6.84 (dd, J = 1.6, 8.1 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 2H), 2.90-2.87 (m, 2H), 2.81-2.75 (m, 2H), 2.35-2.27 (m, 2H), 2.05-2.02 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 158.10, 153.93, 151.37, 149.50, 144.69, 136.94, 129.89, 129.68, 125.01, 123.87, 123.53, 121.40, 121.16, 121.12, 119.99, 119.69, 118.90, 118.48, 116.55, 112.84, 66.91, 62.05, 55.92, 48.74, 36.65; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H28N4O4: 473.21831; found: 473.2172. The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-(trifluoromethyl)phenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 17k)

[0335] This compound was synthesized via general procedure 3 affording compound 17k as a white solid, in 77% yield.

[0336] Mp: 46.2-48.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.85 (d, J = 7.7 Hz, 1H), 7.74-7.65 (m, 3H), 7.55 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 7.14-7.08 (m, 2H), 7.01-6.96 (m, 3H), 6.93-6.89 (m, 1H), 6.83 (dd, J = 2.1, 8.1 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 2H), 2.78-2.75 (m, 2H), 2.69-2.64 (m, 2H), 2.31-2.24 (m, 2H), 2.06-2.03 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.92, 154.48, 151.37, 145.06, 139.18, 134.79, 133.08,130.46, 129.41, 129.00, 127.30 (q,3JCF = 4.9 Hz), 126.18 (q,2JCF = 31.9 Hz), 124.75, 123.47, 122.60 (q, JCF = 273.9 Hz), 122.50, 121.11, 120.91, 118.22, 116.08, 112.81, 67.22, 62.48, 55.94, 49.00, 37.46; HRMS (ESI-Q-TOF): m / z [M + H] + calcd. for C28H27F3N4O3: 525.21078; found: 525.2103.

[0337] The preparation of 2-(4-(4-hydroxy-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-lH-l,2,3-triazol-l-yl)benzonitrile (compound 171)

[0338] This compound was synthesized via general procedure 3 affording compound 171 as a grey solid, in 80% yield.

[0339] Mp: 53.5-55.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.17 (s, 1H), 7.85-7.77 (m, 3H), 7.61-7.57 (m, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.15-7.10 (m, 2H), 7.01-6.97 (m, 3H), 6.93-6.89 (m, 1H), 6.84 (dd, J = 2.0, 8.0 Hz, 1H), 3.82 (s, 3H), 3.72 (s, 2H), 2.92-2.89 (m, 2H), 2.82-2.76 (m, 2H), 2.43-2.35 (m, 2H), 2.11-2.08 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 158.02, 155.21, 151.38, 144.85, 138.44, 137.69, 134.39, 129.60, 129.57, 125.40, 124.91, 123.80, 121.16, 121.06, 120.69, 118.43, 116.39, 115.72, 112.86, 106.76, 67.07, 62.17, 55.96, 48.86, 36.97; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C28H27N5O3: 482.21865; found: 482.2179.

[0340] The preparation of 4-(l-(2,3-difluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17m)

[0341] This compound was synthesized via general procedure 3 affording compound 17m as a brown solid, in 64% yield.

[0342] Mp: 43.1-44.9 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.01 (d, J = 2.6 Hz, 1H), 7.75-7.70 (m, 1H), 7.32-7.24 (m, 3H), 7.15-7.11 (m, 2H), 7.02-6.97 (m, 3H), 6.94-6.90 (m, 1H), 6.84 (dd, J = 2.0, 8.1 Hz, 1H), 3.83 (s, 3H), 3.68 (s, 2H), 2.88-2.85 (m, 2H), 2.75-2.70 (m, 2H), 2.38-2.31 (m, 2H), 2.08-2.05 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 158.00, 155.00, 151.38, 151.15 (dd,4JCF = 250.7 Hz,2JCF= 11.7 Hz), 144.95, 142.51 (dd,1JCF = 253.9 Hz,2JCF= 15.7 Hz), 138.20, 129.55, 126.73 (d,3JCF = 7.1 Hz), 124.85, 124.80, 124.75, 123.66, 121.06 (d,2JCF = 15.5 Hz), 120.85 (d,3JCF = 8.0 Hz), 119.61 (d,4JCF = 3.6 Hz), 118.37, 117.41 (d,2J = 17.0 Hz), 116.33, 112.83, 67.13, 62.32, 55.96, 48.87, 37.17;19F NMR (377 MHz, CDCI3): 5 (ppm) -147.27 (m, IF), -134.69 (m, 1F);HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H26F2N4O3: 493.20455; found: 493.2044.

[0343] The preparation of 4-(l-(4-chloro-2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17n)

[0344] This compound was synthesized via general procedure 3 affording compound 17n as a brown solid, in 68% yield.

[0345] Mp: 44.8-46.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.95 (d, J = 2.7 Hz, 1H), 7.91 (t, J = 8.5 Hz, 1H), 7.35-7.31 (m, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.14-7.10 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.02-6.95 (m, 3H), 6.93-6.89 (m, 1H), 6.82 (dd, J = 2.1, 8.1 Hz, 1H), 3.84 (s, 3H), 3.57 (s, 2H), 2.76-2.73 (m, 2H), 2.62-2.57 (m, 2H), 2.28-2.21 (m, 2H), 2.02-1.99 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.87, 155.37, 152.94 (d, JCF = 254.3 Hz), 151.35, 145.16, 139.80, 135.31 (d,3JCF = 9.6 Hz), 129.33, 125.75 (d,4JCF = 3.6 Hz), 125.52, 124.67, 124.03 (d,3JCF = 10.5 Hz), 123.35, 120.96 (d,2JCF = 26.5 Hz), 120.78, 118.17, 117.78 (d,2JCF = 23.4 Hz), 115.97, 112.79, 67.45, 62.62, 62.35, 55.95, 48.98, 37.59; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H26CIFN4O3: 509.17500; found: 509.1742.

[0346] The preparation of 4-(l-(2,6-dimethoxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 17o)This compound was synthesized via general procedure 3 affording compound 17o as a grey solid, in 85% yield.

[0347] Mp: 80.3-81.9 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.53 (s, 1H), 7.39 (t, J = 8.5 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.18-7.11 (m, 2H), 7.01-6.97 (m, 3H), 6.94-6.90 (m, 1H), 6.85 (dd, J = 2.2, 8.1 Hz, 1H), 6.65 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H), 3.74 (s, 2H), 3.73 (s, 6H), 2.95-2.92 (m, 2H), 2.87-2.81 (m, 2H), 2.39-2.33 (m, 2H), 2.15-2.11 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 158.03, 155.83, 152.86, 151.38, 144.78, 137.06, 131.46, 129.65, 124.95, 123.98, 123.11, 121.15, 121.10, 118.58, 116.50, 115.15, 112.85, 104.25, 66.60, 62.06, 56.15, 55.94, 48.85, 36.82; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C29H32N4O5: 517.24452; found: 517.2443.

[0348] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3,4,5-trimethoxyphenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 17p)

[0349] This compound was synthesized via general procedure 3 affording compound 17p as a grey solid, in 70% yield.

[0350] Mp: 128.2-129.6 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.89 (s, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.14-7.08 (m, 2H), 7.02-6.96 (m, 3H), 6.93-6.89 (m, 3H), 6.82 (dd, J = 2.0, 8.0 Hz, 1H), 3.91 (s, 6H), 3.88 (s, 3H), 3.83 (s, 3H), 3.62 (s, 2H), 2.81-2.78 (m, 2H), 2.68-2.63 (m, 2H), 2.33-2.26 (m, 2H), 2.04-2.01 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.90, 155.17, 153.87, 151.32, 145.05, 139.11, 138.28, 132.87, 129.42, 124.75, 123.50, 121.11, 120.84, 118.36, 118.30, 116.09, 112.80, 98.53, 67.29, 62.48, 61.03, 56.44, 55.94, 49.01, 37.46; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C30H34N4O6: 547.25509; found: 547.2543.

[0351] The preparation of 4-(l-(furan-3-yl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol (compound 19)

[0352] An oven-dried screw cap test tube was added with a magnetic stir-bar and compound 7 (40.5 mg, 0.12 mmol, 1.00 eq), sodium azide (15.6 mg, 0.24 mmol, 2.00 eq), sodium ascorbate (2.4 mg, 0.012 mmol, 0.10 eq) and copper (I) iodide (2.3 mg, 0.012 mmol, 0.10 eq). The tube was then evacuated and back-filled with argon. The evacuation / backfill sequence was repeated with two additional times. The reaction tube was evacuated and backfilled with argon three times. Under counterflow of argon, the solvent ethanol (0.7 mL) and water (0.3 mL) were added, followed by 1,2-dimethylethylenediamine (2.1 mg, 0.024 mmol, 0.20 eq) and 3-bromofuran (19.4 mg, 0.13 mmol, 1.10 eq). The reaction mixture was stirred at 50 °C overnight. At last, the reaction mixture was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (6% of methanol in dichloromethane) to give compound 19 as a white solid (22.9 mg, 43% yield).

[0353] Mp: 131.8-133.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.91 (s, 1H), 7.72 (s, 1H), 7.50 (t, J = 1.8 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.15-7.08 (m, 2H), 7.02-6.96 (m, 3H), 6.94-6.90 (m, 1H), 6.83 (dd, J = 2.0, 8.1 Hz, 1H), 6.80 (dd, J = 0.6, 1.8 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 2H), 2.79-2.76 (m, 2H), 2.67-2.61 (m, 2H), 2.30-2.23 (m, 2H), 2.01-1.98 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.91, 154.90, 151.35, 145.06, 143.94, 139.05, 133.49, 129.43, 126.23, 124.75, 123.50, 121.12, 120.88, 118.77, 118.28, 116.13, 112.81, 105.29, 67.25, 62.45, 55.95, 48.95, 37.43; HRMS (ESI-Q- TOF): m / z [M + H]+calcd. for C25H26N4O4: 447.20266; found: 447.2025.The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(thiophen-2-yl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 21)

[0354] This compound was synthesized via procedure of compound 19 affording compound 21 as a brown solid, in 49% yield.

[0355] Mp: 116.8-118.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.86 (s, 1H), 7.27-7.25 (m, 1H), 7.23-7.20 (m, 2H), 7.15-7.11 (m, 2H), 7.03-6.97 (m, 4H), 6.94-6.90 (m, 1H), 6.84 (dd, J = 1.9, 8.1 Hz, 1H), 3.83 (s, 3H), 3.68 (s, 2H), 2.87-2.85 (m, 2H), 2.75-2.70 (m, 2H), 2.37-2.29 (m, 2H), 2.05-2.02 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.98, 154.89, 151.36, 144.93, 138.24, 138.06, 129.55, 126.27, 124.86, 123.72, 122.92, 121.14, 120.99, 119.44, 118.41, 118.35, 116.35, 112.83, 67.07, 62.29, 55.96, 48.89, 37.15; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C25H26N4O3S: 463.17982; found: 463.1798.

[0356] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(pyridin-2-yl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 22)

[0357] An oven-dried screw cap test tube was added with a magnetic stir-bar and compound 7 (40.5 mg, 0.12 mmol, 1.00 eq), [l,2,3,4]tetrazolo[l,5-a]pyridine (21.6 mg, 0.18 mmol, 1.50 eq), sodium ascorbate (23.8 mg, 0.12 mmol, 1.00 eq) and copper(II) sulfate (19.2 mg, 0.12 mmol, 1.00 eq). The tube was then evacuated and back-filled with argon. The evacuation / backfill sequence was repeated with two additional times. The reaction tube was evacuated and backfilled with argon three times. Under counterflow of argon, the solvent DMF (0.75 mL) and water (0.25 mL) were added. The reaction mixture was stirred at 85 °C overnight. At last, the reaction mixture was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (6% of methanol in dichloromethane) to give compound 22 as a white solid (17.9 mg, 33% yield).

[0358] Mp: 118.0-119.6 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.50-8.48 (m, 2H), 8.18 (d, J = 8.2 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 6.1 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.15-7.07 (m, 2H), 6.99 (t, J = 9.3 Hz, 3H), 6.92 (t, J = 7.5 Hz, 1H), 6.83 (dd, J = 1.9, 8.0 Hz, 1H), 3.84 (s, 3H), 3.59 (s, 2H), 2.77-2.73 (m, 2H), 2.66-2.61 (m, 2H), 2.31-2.24 (m, 2H), 2.05-2.01 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.90, 154.81, 151.37, 149.17, 148.57, 145.12, 139.14, 129.36, 124.71, 123.60, 123.40, 121.11, 120.90, 118.15, 117.13, 116.02, 113.83, 112.80, 67.34, 62.58, 55.96, 49.05, 37.45; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C26H27N5O3: 458.21865; found: 458.2179.

[0359] The preparation of tert-butyl 5-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (compound 25)

[0360] This compound was synthesized via general procedure 3 affording compound 25 as a yellow crude which was used without further purification.

[0361] The preparation of 5-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-2-(3-(2-methoxyphenoxy)benzyl)-2-azabicyclo[2.2.1]heptan-5-ol (compound 26)

[0362] This compound was synthesized via general procedure 4 affording compound 26 as a yellow solid, in 76% yield.Mp: 76.5-78.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.15 (d, J = 2.6 Hz, 1H), 7.86 (t, J = 7.3 Hz, 1H), 7.45-7.38 (m, 2H), 7.32-7.24(m, 3H), 7.17-7.11 (m, 2H), 7.01-6.98 (m, 2H), 6.95-6.91 (m, 1H), 6.86 (dd, J = 2.0, 8.1 Hz, 1H), 4.15-4.07 (m, 2H), 4.00 (d, J = 10.7 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 1H), 2.97 (d, J = 9.5 Hz, 1H), 2.80 (d, J = 1.4 Hz, 1H), 2.63-2.51 (m, 2H), 2.47 (d, J = 11.8 Hz, 1H), 2.05 (d, J = 11.2 Hz, 1H);13C NMR (101 MHz, CDCI3) 6 (ppm) 158.40, 155.03, 153.48 (d, ^CF = 251.5 Hz), 151.46, 144.27, 134.45, 130.39, 130.30 (d,3JCF = 7.9 Hz), 125.37, 125.27, 125.18 (d,4JCF = 3.7 Hz), 124.94, 123.76, 122.29 (d,3JCF = 7.7 Hz), 121.46, 121.24, 118.37, 117.08 (d,2JCF= 19.8 Hz), 117.05, 112.95, 74.07, 62.96, 58.08, 55.92, 53.12, 49.82, 42.12, 34.95; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C28H27FN4O3: 487.21398; found: 487.2143.

[0363] The preparation of compounds 28a-f

[0364] These compounds were synthesized via general procedure 2 affording compounds 28a-f, in yields ranging from 76% to 98%.

[0365] l-(3-(2-methoxyphenoxy)benzyl)-3-methylpiperidin-4-one (compound 28a)

[0366] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.25 (t, J = 7.8 Hz, 1H), 7.16-7.11 (m, 1H), 7.04-6.97 (m, 4H), 6.94-6.90 (m, 1H), 6.85 (dd, J = 1.9, 8.2 Hz, 1H), 3.84 (s, 3H), 3.57 (s, 2H), 3.10-3.03 (m, 2H), 2.66-2.53 (m, 2H), 2.44-2.31 (m, 2H), 2.09 (t, J = 11.1 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 211.08, 158.03, 151.39, 145.11, 140.15, 129.40, 124.77, 122.91, 121.09, 120.88, 117.69, 116.03, 112.79, 61.48, 60.62, 55.96, 53.73, 44.37, 40.93, 11.99.

[0367] l-(3-(2-methoxyphenoxy)benzyl)-3,3-dimethylpiperidin-4-one (compound 28b)

[0368] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.25 (t, J = 7.8 Hz, 1H), 7.15-7.11 (m, 1H), 7.04-6.97 (m, 4H), 6.94-6.90 (m, 1H), 6.85 (dd, J = 2.4, 8.1 Hz, 1H), 3.84 (s, 3H), 3.52 (s, 1H), 2.70 (t, J = 6.2 Hz, 3H), 2.48 (t, J = 6.3 Hz, 3H), 2.38 (s, 3H), 1.09 (s, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 213.90, 158.16, 151.46, 145.06, 140.56, 129.35, 124.81, 122.66, 121.09, 121.07, 117.23, 116.00, 112.81, 65.43, 61.70, 55.97, 54.07, 45.77, 38.37, 23.63.

[0369] 8-(3-(2-methoxyphenoxy)benzyl)-8-azabicyclo[3.2.1]octan-3-one (compound 28c)XH NMR (400 MHz, CDCI3): 6 (ppm) 7.25 (t, J = 7.9 Hz, 1H), 7.15-7.08 (m, 3H), 7.02-6.97 (m, 2H), 6.94-6.90 (m, 1H), 6.84 (dd, J = 2.2, 7.6 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 2H), 3.47 (t, J = 3.4 Hz, 3H), 2.66-2.61 (m, 2H), 2.19 (d, J = 15.9 Hz, 3H), 2.10-2.06 (m, 2H), 1.61 (d, J = 8.0 Hz, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 210.42, 158.09, 151.42, 145.09, 141.30, 129.39, 124.79, 122.42, 121.10, 120.94, 117.18, 115.86, 112.80, 58.65, 55.96, 54.98, 48.35, 27.82.

[0370] l-(3-(2-methoxyphenoxy)benzyl)-2-methylpiperidin-4-one (compound 28d)

[0371] (S)-l-(3-(2-methoxyphenoxy)benzyl)-2-methylpiperidin-4-one (compound 28e)

[0372] (R)-l-(3-(2-methoxyphenoxy)benzyl)-2-methylpiperidin-4-one (compound 28f)

[0373] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.24 (t, J = 8.0 Hz, 1H), 7.15-7.11 (m, 1H), 7.06-6.96 (m, 4H), 6.94-6.90 (m, 1H), 6.81 (dd, J = 2.1, 7.9 Hz, 1H), 3.92 (d, J = 13.7 Hz, 1H), 3.84 (s, 3H), 3.43 (d, J = 13.7 Hz, 1H), 3.02-2.96 (m, 2H), 2.58-2.50 (m, 2H), 2.38-2.22 (m, 3H), 1.14 (d, J = 6.4 Hz, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 209.71, 158.03, 151.37, 145.12, 140.54, 129.39, 124.74, 122.69, 121.09, 120.83, 117.56, 115.83, 112.77, 56.81, 56.09, 55.95, 48.78, 48.63, 40.94, 17.37.

[0374] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-3-methyl-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 30a)This compound was synthesized via general procedure 3 affording compound 30a as a white solid, in 51% yield.

[0375] Mp: 53.0-54.6 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97-7.95 (m, 1H), 7.75-7.73 (m, 2H), 7.56-7.49 (m, 2H), 7.45-7.40 (m, 1H), 7.29-7.25 (m, 1H), 7.17-7.10 (m, 2H), 7.02-6.97 (m, 3H), 6.94-6.84 (m, 2H), 3.83-3.82 (m, 3H), 3.73-3.68 (m, 2H), 3.05-2.60 (m, 4H), 2.47-2.17 (m, 3H), 0.85-0.76 (m, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 158.08, 157.98, 154.23, 151.39, 151.36, 144.98, 144.92, 138.10, 137.00, 136.98, 129.76, 129.74, 129.56, 128.77, 128.75, 127.27, 124.88, 124.85, 123.73, 123.58, 121.14, 121.09, 120.96, 120.46, 120.43, 118.44, 118.14, 116.36, 112.84, 70.94, 70.06, 65.56, 65.30, 62.29, 61.99, 55.96, 55.63, 49.81, 48.65, 40.53, 39.21, 39.04, 12.47; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C28H30N4O3: 471.23905; found: 471.2395.

[0376] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-3,3-dimethyl-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 30b)

[0377] This compound was synthesized via general procedure 3 affording compound 30b as a white solid, in 52% yield.

[0378] Mp: 47.0-48.8 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.84 (s, 1H), 7.75-7.72 (m, 2H), 7.54-7.49 (m, 2H), 7.45-7.41 (m, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.14-7.09 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.03-6.97 (m, 3H), 6.94-6.89 (m, 1H), 6.84 (dd, J = 1.8, 8.1 Hz, 1H), 3.84 (s, 3H), 3.58 (d, J = 13.6 Hz, 1H), 3.44 (d, J = 13.6 Hz, 1H), 2.82-2.79 (m, 1H), 2.63-2.49 (m, 2H), 2.39 (d, J = 11.3 Hz, 1H), 2.32 (d, J = 11.3 Hz, 1H), 1.74-1.71 (m, 1H), 0.98 (s, 3H), 0.88 (s, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.97, 152.75, 151.39, 145.25, 141.09, 137.03, 129.75, 129.18, 128.71, 124.63, 122.84, 121.08, 120.93, 120.46, 119.10, 117.45, 115.81, 112.80, 72.85, 62.43, 61.46, 55.97, 49.16, 38.68, 34.83, 24.12, 21.62; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C29H32N4O3: 485.25470; found: 485.2546.

[0379] The preparation of (8-(3-(2-methoxyphenoxy)benzyl)-3-(l-phenyl-lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3endo-ol (compound 30c)

[0380] This compound was synthesized via general procedure 3 affording compound 30c as a white solid, in 47% yield.

[0381] Mp: 129.5-131.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.43 (s, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 3H), 7.40 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.15-7.11 (m, 2H), 7.00-6.98 (m, 2H), 6.94-6.90 (m, 1H), 6.87 (dd, J = 2.0, 8.2 Hz, 1H), 3.96 (s, 2H), 3.80 (s, 3H), 3.69 (s, 2H), 2.90-2.87 (m, 2H), 2.68-2.66 (m, 2H), 2.28-2.25 (m, 2H), 2.14-2.12 (m, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 158.26, 155.86, 151.42, 144.40, 136.88, 134.71, 130.25, 129.72, 128.83, 125.26, 124.15, 121.36, 121.22, 120.59, 118.93, 118.40, 117.04, 112.90, 68.14, 60.09, 55.93, 55.19, 43.92, 25.03; HRMS (ESI-Q-TOF): m / z [M+H]+calcd. for C29H30N4O3: 483.23905; found: 483.2390.

[0382] The preparation of l-(3-(2-methoxyphenoxy)benzyl)-2-methyl-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 30d)

[0383] This compound was synthesized via general procedure 3 affording compound 30d as a white solid, in 81% yield.

[0384] Mp: 51.6-53.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.99 (s, 1H), 7.73-7.69 (m, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.16-7.08 (m, 2H), 7.04-6.88 (m, 4H), 6.80 (dd, J = 2.1, 8.1 Hz, 1H), 4.10 (d, J = 13.5 Hz, 1H), 3.81 (s, 3H), 3.22 (d, J = 13.4 Hz, 1H), 2.95-2.73 (m, 2H), 2.50-2.23 (m, 3H), 2.20-1.96 (m, 2H), 1.35-1.23 (m, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.88, 153.52, 151.29, 144.97, 139.31, 136.94, 129.71, 129.44, 128.76, 124.76, 123.41, 121.09, 120.85,120.53, 119.35, 118.20, 116.02, 112.79, 68.63, 57.14, 55.91, 54.61, 48.42, 45.49, 37.41, 19.38; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C28H30N4O3: 471.23905; found: 471.2393.

[0385] The preparation of (2S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)-2-methylpiperidin-4-ol (compound 30e)

[0386] This compound was synthesized via general procedure 3 affording compound 30e as a yellow oil, in 70% yield.

[0387] Mp: 51.6-53.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.00 (d, J = 2.7 Hz, 1H), 7.97-7.93 (m, 1H), 7.46-7.41 (m, 1H), 7.34-7.27 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 7.14-7.09 (m, 1H), 7.05-6.88 (m, 5H), 6.79 (dd, J = 1.9, 8.0 Hz, 1H), 4.03 (d, J = 13.5 Hz, 1H), 3.83 (s, 3H), 3.13 (d, J = 13.5 Hz, 1H), 2.91-2.86 (m, 2H), 2.63 (s, 1H), 2.50-2.46 (m, 1H), 2.35-2.32 (m, 1H), 2.21-2.15 (m, 1H), 2.07-1.92 (m, 2H), 1.25 (d, J = 6.2 Hz, 3H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.80, 153.31 (d,1JCF = 250.9 Hz), 153.27, 151.30, 145.20, 140.78, 130.21 (d,3JCF = 7.8 Hz), 129.28, 125.31, 125.26 (d,4JCF = 3.8 Hz), 124.89, 124.62, 123.11, 122.16 (d,3JCF = 8.3 Hz), 121.07, 120.73, 118.01, 117.03 (d,2JCF = 20.0 Hz), 115.78, 112.76, 68.91, 57.24, 55.95, 54.16, 48.42, 45.80, 37.64, 19.70; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C28H29FN4O3: 489.22962; found: 489.2303. The preparation of (2R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)-2-methylpiperidin-4-ol (compound 30f)

[0388] This compound was synthesized via general procedure 3 affording compound 30f as a yellow oil, in 75% yield.

[0389] Mp: 51.6-53.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.00 (d, J = 2.7 Hz, 1H), 7.97-7.93 (m, 1H), 7.46-7.41 (m, 1H), 7.34-7.27 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 7.14-7.09 (m, 1H), 7.05-6.88 (m, 5H), 6.79 (dd, J = 1.8, 8.1 Hz, 1H), 4.02 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 3.11 (d, J = 13.6 Hz, 1H), 2.91-2.86 (m, 2H), 2.59 (s, 1H), 2.50-2.46 (m, 1H), 2.35-2.32 (m, 1H), 2.21-2.15 (m, 1H), 2.07-1.92 (m, 2H), 1.24 (d, J = 6.2 Hz, 3H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.78, 153.29 (d,4JCF = 250.8 Hz), 153.26, 151.29, 145.22, 141.09, 130.19 (d,3JCF = 7.9 Hz), 129.23, 125.31, 125.25 (d,4JCF = 3.8 Hz), 124.88, 124.59, 123.05, 122.14 (d,3JCF = 8.3 Hz), 121.06, 120.70, 117.96, 117.02 (d,2JCF = 19.9 Hz), 115.70, 112.75, 68.94, 57.26, 55.94, 54.06, 48.44, 45.85, 37.68, 19.77; HRMS (ESI-Q-TOF): m / z [M + H]+calcd. for C28H29FN4O3: 489.22962; found: 489.2287. The preparation of (9H-fluoren-9-yl)methyl 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-4-hydroxypiperidine-l-carboxylate (compound 33)

[0390] This compound was synthesized via general procedure 3 affording compound 33 as a yellow oil, in 58% yield.

[0391] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.98-7.94 (m, 2H), 7.76 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H), 7.48-7.29 (m, 7H), 4.47 (d, J = 6.7 Hz, 2H), 4.26 (t, J = 6.7 Hz, 1H), 4.00-3.99 (m, 2H), 3.48-3.46 (m, 2H), 2.76 (s, 1H), 2.06-1.99 (m, 4H);13C NMR (101 MHz, CDCI3) <5 (ppm) 155.23, 153.31 (d,4JCF = 250.7 Hz), 144.06, 141.35, 130.35 (d,3JCF = 7.9 Hz), 127.66, 127.06, 125.33 (d,4JCF = 3.8 Hz), 125.17 (d,3JCF = 10.5 Hz), 124.98, 124.89, 120.91, 120.82, 119.96, 117.07 (d,2JCF = 19.9 Hz), 67.56, 67.19, 47.42, 39.89, 37.38.

[0392] The preparation of l-(4-fluoro-3-phenoxybenzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 35)This compound was synthesized via general procedure 5 affording compound 35 as a yellow oil, in 20% yield.

[0393] Mp: 39.6-41.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.96 (d, J = 2.8 Hz, 1H), 7.94-7.92 (m, 1H), 7.46-7.41 (m, 1H), 7.34-7.27(m, 4H), 7.14-7.04 (m, 4H), 6.99-6.96 (m, 2H), 3.53 (s, 2H), 2.73-2.70 (m, 2H), 2.61-2.56 (m, 2H), 2.27-2.20 (m, 2H), 2.03-2.00 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.49, 155.01, 153.52 (d,1JCF = 248.0 Hz), 153.33 (d,1JCF = 250.9 Hz), 143.26 (d,2JCF = 11.7 Hz), 135.12, 130.22 (d,3JCF = 7.9 Hz), 129.68, 125.33 (d,4JCF = 4.0 Hz), 125.27 (d,4JCF = 3.6 Hz), 125.20, 124.91, 123.00, 122.56, 120.84 (d,3JCF = 8.4 Hz), 117.09, 117.04 (d,2JCF = 19.8 Hz), 116.73 (d,2JCF = 18.4 Hz), 67.41, 61.96, 48.96, 37.61;19F NMR (377 MHz, CDCI3): 6 (ppm) -132.99 (s, IF), -123.61 (m, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C26H24F2N4O2: 463.19399; found: 463.1940.

[0394] The preparation of (3-(2-fluorophenoxy)phenyl)methanol (compound 37a)

[0395] This compound was synthesized via the procedure of compound 2 at 120 °C affording compound 37a as a yellow oil, in 32% yield.

[0396] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.30 (t, J = 7.9 Hz, 1H), 7.20-7.04 (m, 5H), 6.98 (t, J = 2.0 Hz, 1H), 6.89 (dd, J = 2.5, 8.2 Hz, 1H), 4.65 (s, 2H), 1.81 (s, 1H).

[0397] The preparation of (3-(2-chlorophenoxy)phenyl)methanol (compound 37b)

[0398] This compound was synthesized via the procedure of compound 2 at 120 °C affording compound 37b as a yellow oil, in 38% yield.

[0399] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.46 (dd, J = 1.6, 8.0 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.25-7.20 (m, 1H), 7.12-7.08 (m, 2H), 7.00 (dd, J = 1.5, 8.1 Hz, 1H), 6.97 (t, J = 1.7 Hz, 1H), 6.89 (dd, J = 2.2, 8.1 Hz, 1H), 4.66 (s, 2H), 1.81 (s, 1H).

[0400] The preparation of 2-(3-(hydroxymethyl)phenoxy)benzonitrile (compound 39)

[0401] This compound was synthesized via general procedure 2 at 110 °C affording compound 39 as a colorless oil, in 72% yield.

[0402] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.65 (dd, J = 1.6, 7.7 Hz, 1H), 7.50-7.45 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.16-7.12 (m, 1H), 7.10 (t, J = 2.1 Hz, 1H), 6.99 (dd, J = 2.0, 8.1 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.70 (d, J = 5.7 Hz, 2H), 2.07 (t, J = 5.9 Hz, 1H).

[0403] The preparation of compounds 40a-c

[0404] These compounds were synthesized via general procedure 1 affording compounds 40a-c, in yields ranging from 81% to 95%.

[0405] l-(3-(chloromethyl)phenoxy)-2-fluorobenzene (compound 40a)

[0406] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.30 (t, J = 7.9 Hz, 1H), 7.22-7.05 (m, 5H), 7.01 (t, J = 2.0 Hz, 1H), 6.91 (dd, J = 2.1, 8.2 Hz, 1H), 4.54 (s, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.70, 154.43 (d,4JCF = 248.9 Hz), 143.25 (d,2JCF = 11.6 Hz), 139.30, 130.02, 125.20 (d,3JCF = 6.8 Hz), 124.79 (d,4JCF = 3.8 Hz), 123.14, 122.22, 122.21, 117.19 (d,3JCF = 18.3 Hz), 117.07 (d,2JCF = 20.5 Hz), 45.74.

[0407] l-chloro-2-(3-(chloromethyl)phenoxy)benzene (compound 40b)

[0408] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.47 (dd, J = 1.6, 8.0 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.27-7.22 (m, 1H), 7.14-7.10 (m, 2H), 7.02 (dd, J = 1.5, 8.1 Hz, 1H), 6.99 (t, J = 2.0 Hz, 1H), 6.89 (dd, J = 2.2, 8.2 Hz, 1H), 4.54 (s, 2H);13C NMR (101 MHz,CDCI3) 6 (ppm) 157.27, 151.98, 139.38, 130.89, 130.08, 128.05, 126.11, 125.08, 123.30, 121.21, 117.75, 117.54, 45.71.

[0409] 2-(3-(chloromethyl)phenoxy)benzonitrile (compound 40c)

[0410] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.67 (dd, J = 1.5, 7.7 Hz, 1H), 7.52-7.48 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.18-7.14 (m, 1H), 7.13 (t, J = 1.9 Hz, 1H), 7.04 (dd, J = 2.4, 8.1 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.57 (s, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 159.31, 155.39, 139.85, 134.30, 133.97, 130.44, 125.01, 123.20, 119.94, 119.75, 117.32, 115.85, 104.05, 45.43.

[0411] The preparation of l-(3-(2-fluorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 41a)

[0412] This compound was synthesized via general procedure 2 affording compound 41a as a yellow solid, in 33% yield.

[0413] Mp: 38.6-40.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (d, J = 2.8 Hz, 1H), 7.95-7.92 (m, 1H), 7.46-7.41 (m, 1H), 7.34-7.25 (m, 3H), 7.20-7.14 (m, 1H), 7.13-7.04 (m, 5H), 6.86 (dd, J = 2.2, 8.0 Hz, 1H), 3.57 (s, 2H), 2.74-2.72 (m, 2H), 2.62-2.56 (m, 2H), 2.28-2.21 (m, 2H), 2.03-2.00 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.37, 155.11, 154.32 (d, JCF= 248.4 Hz), 153.33 (d,1JCF = 250.8 Hz), 143.85 (d,2JCF = 11.5 Hz), 140.51, 130.19 (d,3JCF = 7.9 Hz), 129.47, 125.34, 125.26 (d,4JCF = 3.9 Hz), 124.91, 124.69 (d,4JCF = 2.7 Hz), 124.63, 123.89, 121.75, 120.85 (d,3JCF = 8.3 Hz), 118.05, 117.06 (d,2JCF = 18.3 Hz), 117.03 (d,2JCF = 20.5 Hz), 115.93, 67.48, 62.61, 49.09, 37.69;19F NMR (377 MHz, CDCI3): 6 (ppm) -131.08 (m, IF), -123.58 (m, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C26H24F2N4O2: 463.19399; found: 463.1943.

[0414] The preparation of l-(3-(2-chlorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 41b)

[0415] This compound was synthesized via general procedure 2 affording compound 41b as a yellow solid, in 33% yield.

[0416] Mp: 41.6-43.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (d, J = 2.8 Hz, 1H), 7.95-7.92 (m, 1H), 7.47-7.41 (m, 2H), 7.34-7.27 (m, 3H), 7.24-7.19 (m, 1H), 7.13-7.06 (m, 2H), 6.99-6.97 (m, 2H), 6.85 (dd, J = 2.3, 8.0 Hz, 1H), 3.58 (s, 2H), 2.75-2.72 (m, 2H), 2.62-2.56 (m, 2H), 2.29-2.21 (m, 2H), 2.03-2.00 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 156.91, 155.09, 153.32 (d,4JCF = 250.9 Hz), 152.60, 140.59, 130.77, 130.19 (d,3JCF = 7.7 Hz), 129.55, 127.90, 125.69, 125.33, 125.26 (d,4JCF = 3.8 Hz), 124.91, 124.53, 124.11, 120.84 (d,3JCF = 8.2 Hz), 120.59, 118.70, 117.03 (d,2JCF = 19.9 Hz), 116.64, 67.48, 62.59, 49.08, 37.69; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C26H24CIFN4O2: 479.16444; found: 479.1638.

[0417] The preparation of 2-(3-((4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-4-hydroxypiperidin-l-yl)methyl)phenoxy)benzonitrile (compound 41c)

[0418] This compound was synthesized via general procedure 2 affording compound 41c as a yellow solid, in 35% yield.

[0419] Mp: 38.0-39.8 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.98 (d, J = 2.8 Hz, 1H), 7.96-7.91 (m, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.49-7.41 (m, 2H), 7.37-7.29 (m, 3H), 7.22 (d, J = 7.6 Hz, 1H), 7.14-7.10 (m, 2H), 6.98 (dd, J = 1.4, 8.0 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 3.60 (s, 2H), 2.75-2.72 (m, 2H), 2.63-2.58 (m, 2H), 2.29-2.22 (m, 2H), 2.04-2.01 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 159.86, 155.09, 153.32 (d,4JCF = 250.9 Hz), 141.19, 134.20, 133.88, 130.21 (d,3JCF = 7.8 Hz), 129.87, 125.70, 125.31, 125.25 (d,4JCF = 4.0 Hz), 125.21, 124.91, 122.72, 120.89 (d,3JCF = 8.1 Hz), 120.52, 118.69, 117.03 (d,2JCF =20.0 Hz), 116.91, 116.07, 103.64, 67.43, 62.46, 49.10, 37.68; HRMS (ESI-Q-TOF): m / z [M+H]+ calcd. for C27H24FN5O2: 470.19866; found: 470.1989.

[0420] The preparation of 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-phenoxybenzyl)piperidin-4-ol (compound 41d)

[0421] This compound was synthesized via general procedure 2 affording compound 41d as a yellow oil, in 34% yield.

[0422] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (d, J = 2.8 Hz, 1H), 7.95-7.91 (m, 1H), 7.45- 7.40 (m, 1H), 7.35-7.26 (m, 5H), 7.12-7.06 (m, 3H), 7.02-7.00 (m, 2H), 6.88 (dd, J = 2.0, 8.0 Hz, 1H), 3.57 (s, 2H), 2.74-2.72 (m, 2H), 2.63-2.57 (m, 2H), 2.28-2.21 (m, 2H), 2.04-2.00 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.29, 157.19, 155.13, 153.31 (d, JCF= 250.9 Hz), 140.45, 130.18 (d,3JCF = 7.8 Hz), 129.70, 129.50, 125.31, 125.24 (d,4JCF = 3.8 Hz), 124.90, 124.01, 123.12, 120.87 (d,3JCF = 7.7 Hz), 119.61, 118.76, 117.51, 117.02 (d,2JCF = 20.0 Hz), 67.44, 62.63, 49.07, 37.64; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C26H25FN4O2: 445.20341; found: 445.2033.

[0423] The preparation of (R)-4-ethynyl-l-(l-(3-(2-methoxyphenoxy)phenyl)ethyl)piperidin-4-ol or (S)-4-ethynyl-l-(l-(3-(2-methoxyphenoxy)phenyl)ethyl)piperidin-4-ol (compound 43a or 43b)

[0424] These compounds were synthesized via the procedure of compound 2 at 120 °C, and isolated by flash chromatography on silica gel (10% of methanol in dichloromethane) to give crude compounds 43a-b as a dark oil which were to do next step without further purification.

[0425] The preparation of compounds 45c-e

[0426] To an oven-dried screw cap test tube containing a magnetic stirring bar was added Cui (26.7 mg, 0.14 mmol, 0.10 eq), 2-picolinic acid (34.5 mg, 0.28 mmol, 0.20 eq), compound 44c or compound 44e (1.40 mmol, 1.00 eq) and K3PO4 (594.3 mg, 2.80 mmol, 2.00 eq). The reaction tube was evacuated and backfilled with argon three times. Under a counterflow of argon, anhydrous DMSO (2.0 mL) was added, followed by the addition of 2-fluorophenol (235.4 mg, 2.10 mmol, 1.50 eq) using a syringe. Then, the reaction mixture was placed in a heating block at 90 °C for 21 h. Then, the reaction mixture was washed with brine (10.0 mL) and extracted with ethyl acetate (20.0 mL). The organic layer was collected and dried over magnesium sulfate. Then, it was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (10 % of ethyl acetate in petroleum ether) to give compound 45c or compound 45e as a brown oil (30%-33% yield).

[0427] tert-butyl (S)-(l-(3-(2-fluorophenoxy)phenyl)ethyl)carbamate (compound 45c)

[0428] tert-butyl (R)-(l-(3-(2-fluorophenoxy)phenyl)ethyl)carbamate (compound 45d)

[0429] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.27 (t, J = 7.9 Hz, 1H), 7.22-7.15 (m, 1H), 7.13-7.02 (m, 4H), 6.95 (t, J = 2.5 Hz, 1H), 6.82 (dd, J = 2.2, 8.1 Hz, 1H), 4.79-4.73 (m, 2H), 1.43- 1.41 (m, 12H);13C NMR (101 MHz, CDCI3) 5 (ppm) 157.54, 155.01, 154.34 (d, JCF = 248.6 Hz), 146.31, 143.67 (d,2JCF = 11.4 Hz), 129.81, 124.79 (d,3JCF = 7.0 Hz), 124.68(d,4JCF = 4.1 Hz), 121.85, 120.69, 117.08 (d,2JCF = 18.1 Hz), 115.74, 114.90, 79.50, 49.89, 28.36, 22.69.

[0430] tert-butyl (R)-(l-(3-(2,4-difluorophenoxy)phenyl)ethyl)carbamate (compound 45e)XH NMR (400 MHz, CDCI3): 6 (ppm) 7.26 (t, J = 7.9 Hz, 1H), 7.08-7.01 (m, 2H), 6.98-6.91 (m, 2H), 6.87-6.82 (m, 1H), 6.78 (dd, J = 2.4, 8.1 Hz, 1H), 4.79-4.74 (m, 2H), 1.43-1.41 (m, 12H);13C NMR (101 MHz, CDCI3) 5 (ppm) 158.78 (dd,4JCF = 245.4,3JCF= 10.3 Hz), 157.78, 155.02, 154.34 (dd,4JCF = 251.8,3JCF = 12.3 Hz), 146.44, 139.75 (dd,2JCF = 11.8,4JCF = 3.7 Hz), 129.85, 122.81 (dd,3JCF = 9.6,3JCF = 2.0 Hz), 120.61, 115.15, 114.40, 111.38 (dd,2JCF = 22.8,4JCF = 4.1 Hz), 105.47 (dd,2JCF = 26.8,2JCF = 22.2 Hz), 79.54, 49.93, 28.36, 22.68.

[0431] The preparation of (S)-l-(3-(2-fluorophenoxy)phenyl)ethan-l-amine hydrochloride (compounds 46c), (R)-l-(3-(2-fluorophenoxy)phenyl)ethan-l-amine hydrochloride (compounds 46d) and (R)-l-(3-(2,4-difluorophenoxy)phenyl)ethan-l-amine hydrochloride (compounds 46e)

[0432] The compounds 45c-e were dissolved in 1,4-dioxane (2.0 mL) prior to the addition of a hydrogen chloride solution (2.0 mL of a 4.0 M solution in dioxane). This reaction mixture was stirred at room temperature for 6 h. Afterwards, it was concentrated under reduced pressure to give the crude compounds 46c-e which were used for the next step without further purification.

[0433] The preparation of compounds 47a-e

[0434] These compounds were synthesized via general procedure 6 affording compounds 47a-e, in yields ranging from 40% to 52%.

[0435] (S)-l-(l-(3-(2-methoxyphenoxy)phenyl)ethyl)piperidin-4-one (compound 47a)

[0436] (R)-l-(l-(3-(2-methoxyphenoxy)phenyl)ethyl)piperidin-4-one (compound 47b)

[0437] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.24 (t, J = 8.1 Hz, 1H), 7.15-7.11 (m, 1H), 7.04-7.00 (m, 3H), 6.98-6.89 (m, 2H), 6.81 (dd, J = 2.3, 8.3 Hz, 1H), 3.84 (s, 3H), 3.60 (q, J = 6.7 Hz, 1H), 2.79-2.68 (m, 4H), 2.40 (t, J = 6.0 Hz, 4H), 1.39 (d, J = 6.7 Hz, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 209.64, 157.91, 151.31, 145.43, 145.20, 129.33, 124.67, 121.55, 121.08, 120.67, 116.51, 115.88, 112.75, 63.13, 55.94, 49.93, 41.57, 19.17. (S)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)piperidin-4-one (compound 47c)

[0438] (R)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)piperidin-4-one (compound 47d)

[0439] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.27 (t, J = 7.9 Hz, 1H), 7.20-7.14 (m, 1H), 7.13-7.03 (m, 5H), 6.84 (dd, J = 1.9, 8.1 Hz, 1H), 3.61 (q, J = 6.7 Hz, 1H), 2.79-2.68 (m, 4H), 2.40 (t, J = 6.0 Hz, 4H), 1.39 (d, J = 6.7 Hz, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 209.51, 157.45, 154.32 (d,4JCF = 248.5 Hz), 145.87, 143.76 (d,2JCF = 11.2 Hz), 129.52, 124.76 (d,3JCF = 6.8 Hz), 124.67 (d,4JCF = 3.9 Hz), 122.08, 121.72, 117.07 (d,2JCF = 18.2 Hz), 116.28, 115.81, 63.05, 49.91, 41.53, 19.15.

[0440] (R)-l-(l-(3-(2,4-difluorophenoxy)phenyl)ethyl)piperidin-4-one (compound 47e)

[0441] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.26 (t, J = 7.9 Hz, 1H), 7.09-7.03 (m, 2H), 7.01-6.93 (m, 2H), 6.88-6.83 (m, 1H), 6.79 (dd, J = 2.3, 8.1 Hz, 1H), 3.60 (q, J = 6.7 Hz, 1H), 2.79-2.68 (m, 4H), 2.41 (t, J = 6.1 Hz, 4H), 1.39 (d, J = 6.7 Hz, 3H);13C NMR (101 MHz, CDCI3) 5 (ppm) 209.50, 158.78 (dd,4JCF = 245.5,3JCF = 10.1 Hz), 157.72, 154.35 (dd,4JCF = 251.9,3JCF = 12.1 Hz), 146.00, 139.83 (dd,2JCF = 11.8,4JCF = 4.0 Hz), 129.58,122.72 (dd,3JCF = 9.6,3JCF = 2.1 Hz), 122.06, 115.77, 115.18, 111.39 (dd,2JCF = 22.7,4JCF = 3.8 Hz), 105.49 (dd,2JCF = 26.6,2JCF = 22.1 Hz), 63.11, 49.96, 41.55, 19.22. The preparation of (S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2-methoxyphenoxy)phenyl)ethyl)piperidin-4-ol (compound 49a)

[0442] This compound was synthesized via general procedure 3 affording compound 49a as a yellow solid, in 56% yield.

[0443] Mp: 49.6-51.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.98 (d, J = 2.3 Hz, 1H), 7.93-7.90 (m, 1H), 7.46-7.40 (m, 1H), 7.33-7.24 (m, 3H), 7.15-7.10 (m, 2H), 7.02-6.97 (m, 3H), 6.94-6.90 (m, 1H), 6.83 (dd, J = 1.8, 8.0 Hz, 1H), 3.83 (s, 3H), 3.63 (d, J = 6.3 Hz, 1H), 2.96-2.63 (m, 4H), 2.37-2.27 (m, 2H), 2.08-2.00 (m, 2H), 1.48 (d, J = 6.3 Hz, 3H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.91, 154.82, 153.39 (d,4JCF = 251.1 Hz), 151.31, 145.09, 130.25 (d,3JCF = 7.8 Hz), 129.52, 125.30, 125.23 (d,4JCF = 3.8 Hz), 124.97, 124.74, 122.07, 121.12, 120.96, 120.89, 120.78, 117.05, 117.04 (d,2JCF = 19.8 Hz), 116.16, 112.79, 67.14, 64.84, 55.95, 46.31, 37.43, 18.99; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C28H29FN4O3: 489.22962; found: 489.2295.

[0444] The preparation of (R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2-methoxyphenoxy)phenyl)ethyl)piperidin-4-ol (compound 49b)

[0445] This compound was synthesized via general procedure 3 affording compound 49b as a yellow solid, in 55% yield.

[0446] Mp: 49.6-51.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (d, J = 2.3 Hz, 1H), 7.94-7.90 (m, 1H), 7.46-7.40 (m, 1H), 7.33-7.23 (m, 3H), 7.14-7.08 (m, 2H), 7.02-6.96 (m, 3H), 6.93-6.89 (m, 1H), 6.82 (dd, J = 1.9, 8.0 Hz, 1H), 3.84 (s, 3H), 3.57 (d, J = 6.2 Hz, 1H), 2.94-2.63 (m, 4H), 2.35-2.22 (m, 2H), 2.06-1.98 (m, 2H), 1.44 (d, J = 6.5 Hz, 3H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.86, 154.89, 153.37 (d,1JCF = 251.0 Hz), 151.30, 145.19, 130.22 (d,3JCF = 7.9 Hz), 129.43, 125.32, 125.24 (d,4JCF = 3.7 Hz), 124.95, 124.66, 122.00, 121.10, 120.95, 120.86, 120.71, 117.04 (d,2JCF = 19.8 Hz), 117.00, 116.03, 112.77, 67.30, 64.68, 55.95, 46.22, 37.62, 19.10; HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C28H29FN4O3: 489.22962; found: 489.2293.

[0447] The preparation of (S)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 49c)

[0448] This compound was synthesized via general procedure 3 affording compound 49c as a yellow solid, in 60% yield.

[0449] Mp: 83.4-85.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (d, J = 2.7 Hz, 1H), 7.95-7.91 (m, 1H), 7.46-7.40 (m, 1H), 7.34-7.26 (m, 3H), 7.22-7.03 (m, 6H), 6.85 (dd, J = 2.0, 8.0 Hz, 1H), 3.56 (q, J = 6.6 Hz, 1H), 2.93-2.62 (m, 4H), 2.33-2.22 (m, 2H), 2.07-1.98 (m, 2H), 1.44 (d, J = 6.6 Hz, 3H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.35, 154.96, 154.29 (d,1JCF = 248.4 Hz), 153.35 (d,4JCF = 250.9 Hz), 145.54, 143.85 (d,2JCF = 11.5 Hz), 130.21 (d,3JCF = 7.9 Hz), 129.59, 125.32, 125.24 (d,4JCF = 3.7 Hz), 124.94, 124.69, 124.67 (d,4JCF = 4.0 Hz), 122.54, 121.65, 120.89 (d,3JCF = 7.8 Hz), 117.06 (d,2JCF = 18.2 Hz), 117.03 (d,2JCF = 20.0 Hz), 116.85, 115.93, 67.38, 64.58, 46.47, 46.05, 37.72, 19.21;19F NMR (377 MHz, CDCI3): 6 (ppm) -131.08 (s, IF), -123.54 (s, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H26F2N4O2: 477.20964; found: 477.2087.

[0450] The preparation of (R)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 49d)This compound was synthesized via general procedure 3 affording compound 49d as a yellow solid, in 61% yield.

[0451] Mp: 83.4-85.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (d, J = 2.0 Hz, 1H), 7.94-7.90 (m, 1H), 7.45-7.40 (m, 1H), 7.33-7.25 (m, 3H), 7.20-7.03 (m, 6H), 6.84 (dd, J = 1.7, 8.0 Hz, 1H), 3.56 (q, J = 6.6 Hz, 1H), 2.92-2.60 (m, 4H), 2.32-2.21 (m, 2H), 2.07-1.98 (m, 2H), 1.43 (d, J = 6.6 Hz, 3H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.33, 155.01, 154.27 (d, JCF= 248.7 Hz), 153.35 (d,iJCF= 250.9 Hz), 145.54, 143.84 (d,2JCF = 11.3 Hz), 130.20 (d,3JCF = 7.9 Hz), 129.57, 125.31, 125.23 (d,4JCF = 3.8 Hz), 124.92, 124.69, 124.63 (d,4JCF = 3.4 Hz), 122.54, 121.64, 120.94 (d,3JCF = 7.9 Hz), 117.05 (d,2JCF = 18.3 Hz), 117.02 (d,2JCF = 19.8 Hz), 116.85, 115.92, 67.34, 64.56, 46.46, 46.04, 37.66, 19.21;19F NMR (377 MHz, CDCI3): 5 (ppm) -131.09 (s, IF), -123.54 (s, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H26F2N4O2: 477.20964; found: 477.2103.

[0452] The preparation of (R)-l-(l-(3-(2,4-difluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 49e)

[0453] This compound was synthesized via general procedure 3 affording compound 49e as a yellow solid, in 63% yield.

[0454] Mp: 39.4-41.8 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (d, J = 2.6 Hz, 1H), 7.95-7.91 (m, 1H), 7.46-7.41 (m, 1H), 7.34-7.24 (m, 3H), 7.13-7.02 (m, 3H), 6.98-6.92 (m, 1H), 6.87-6.82 (m, 1H), 6.80 (dd, J = 2.3, 8.1 Hz, 1H), 3.54 (q, J = 6.6 Hz, 1H), 2.91-2.61 (m, 4H), 2.32-2.20 (m, 2H), 2.06-1.97 (m, 2H), 1.42 (d, J = 6.6 Hz, 3H);13C NMR (101 MHz, CDCI3) 6 (ppm) 158.68 (dd,2JCF = 245.3,3JCF = 10.2 Hz), 157.60, 154.99, 154.28 (dd,4JCF = 252.4,3JCF = 12.3 Hz), 153.35 (d,1JCF = 251.0 Hz), 145.81, 139.94 (dd,2JCF = 11.7,4JCF= 4.1 Hz), 130.20 (d,3JCF = 7.7 Hz), 129.59, 125.32, 125.24 (d,4JCF = 3.8 Hz), 124.93, 122.62 (dd,3JCF = 9.6,3JCF = 2.0 Hz), 122.48, 120.89 (d,3JCF = 8.9 Hz), 117.03 (d,2JCF = 20.0 Hz), 116.26, 115.27, 111.35 (dd,2JCF = 23.1,4JCF = 4.3 Hz), 105.45 (dd,2JCF = 26.9,2JCF = 21.9 Hz), 67.40, 64.52, 46.52, 46.00, 37.74, 19.25;19F NMR (377 MHz, CDCI3): <5 (ppm) -125.74 (s, IF), -123.56 (s, IF), -115.19 (s, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H25F3N4O2: 495.20022; found: 495.1997.

[0455] The preparation of (S)-4-(l-(2-chlorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)piperidin-4-ol (compound 49f)

[0456] This compound was synthesized via general procedure 3 affording compound 49f as a yellow solid, in 63% yield.

[0457] Mp: 39.8-41.6°C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.87 (s, 1H), 7.61-7.55 (m, 2H), 7.48-7.41 (m, 2H), 7.27 (t, J = 7.9 Hz, 1H), 7.20-7.03 (m, 6H), 6.84 (dd, J = 2.1, 8.1 Hz, 1H), 3.55 (q, J = 6.6 Hz, 1H), 2.90-2.63 (m, 4H), 2.33-2.20 (m, 2H), 2.08-1.98 (m, 2H), 1.43 (d, J = 6.6 Hz, 3H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.31, 154.29, 154.27 (d,1JCF = 248.6 Hz), 145.59, 143.86 (d,2JCF = 11.1 Hz), 134.89, 130.76, 129.55, 128.61, 127.92, 127.82, 124.67, 124.66 (d,4JCF = 3.6 Hz), 124.60, 122.54, 121.73, 121.62, 117.05 (d,2JCF = 18.3 Hz), 116.87, 115.90, 67.38, 64.52, 46.54, 46.00, 37.76, 19.22;19F NMR (377 MHz, CDCI3): 5 (ppm) -131.10 (s, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H26CIFN4O2: 493.18009; found: 493.1804.

[0458] The preparation of 2-bromo-6-(2-fluorophenoxy)pyridine (compound 51)

[0459] Using NaH as base, this compound was synthesized via general procedure 2 at 100 °C affording compound 51 as a colorless oil, in 84% yield.

[0460] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.53 (t, J = 7.8 Hz, 1H), 7.25-7.14 (m, 5H), 6.87 (dd, J = 0.6, 8.1 Hz, 1H);13C NMR (101 MHz, CDCI3) 5 (ppm) 162.19, 154.59 (d,4JCF = 249.4Hz), 141.20, 140.58 (d,2JCF = 12.0 Hz), 138.98, 126.36 (d,3JCF = 7.2 Hz), 124.63 (d,4JCF = 3.7 Hz), 123.71, 122.60, 116.91 (d,2JCF = 18.4 Hz), 108.96.

[0461] The preparation of 6-(2-fluorophenoxy)picolinaldehyde (compound 52)

[0462] To an oven-dried screw cap test tube containing a magnetic stirring bar was added compound 51 (268.1 mg, 1.00 mmol, 1.00 eq). The reaction tube was evacuated and backfilled with argon three times. Under a counterflow of argon, anhydrous THF (6.0 mL) was added and the reaction mixture was placed at -40 °C for 5 minutes before the addition of n-butyllithium solution (0.48 mL, 2.5 M). Then, the reaction mixture was stirred at -40 °C for 30 minutes before adding DMF (87.7 mg, 1.20 mmol, 1.20 eq). Afterwards, the reaction mixture was stirred at -40 °C for additional 30 minutes and quenched by saturated aqueous ammonium chloride solution (0.4 mL). It was washed with brine (10.0 mL) and extracted with ethyl acetate (20.0 mL). The organic layer was collected and dried over magnesium sulfate. Then, it was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (10 % of ethyl acetate in petroleum ether) to give compound 52 as a yellow oil (140.1 mg, 65% yield).XH NMR (400 MHz, CDCI3): 6 (ppm) 9.76 (s, 1H), 7.90-7.86 (m, 1H), 7.69 (dd, J = 0.8, 7.3 Hz, 1H), 7.30-7.18 (m, 5H);13C NMR (101 MHz, CDCI3) 6 (ppm) 192.73, 163.01, 154.82 (d, JCF = 249.0 Hz), 150.65, 140.51 (d,2JCF = 12.3 Hz), 140.30, 126.44 (d,3JCF = 6.9 Hz), 124.65 (d,4JCF = 3.7 Hz), 123.91, 116.86 (d,2JCF = 18.5 Hz), 116.55, 115.76. The preparation of l-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4-ol (compound 53)

[0463] This compound was synthesized via general procedure 5 affording compound 53 as a yellow solid, in 27% yield.

[0464] Mp: 90.1-92.8 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 7.97 (d, J = 2.8 Hz, 1H), 7.95-7.91 (m, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.47-7.41 (m, 1H), 7.34-7.29 (m, 2H), 7.24-7.12 (m, 5H), 6.80 (d, J = 8.2 Hz, 1H), 3.69 (s, 2H), 2.86-2.74 (m, 4H), 2.34-2.27 (m, 2H), 2.04-2.01 (m, 2H);13C NMR (101 MHz, CDCI3) 6 (ppm) 162.36, 154.82 (d,4JCF = 248.7 Hz), 154.77, 153.36 (d,4JCF = 250.9 Hz), 141.28, 141.16, 140.01, 130.26 (d,3JCF = 7.8 Hz), 125.84 (d,3JCF = 7.2 Hz), 125.26 (d,4JCF = 4.0 Hz), 125.19, 124.94, 124.55 (d,4JCF = 3.7 Hz), 123.83, 120.94 (d,3JCF = 8.1 Hz), 118.25, 117.04 (d,2JCF = 19.9 Hz), 116.72 (d,2JCF = 18.4 Hz), 108.79, 66.98, 62.92, 48.92, 37.24;19F NMR (377 MHz, CDCI3): 6 (ppm) -128.11 (m, IF), -123.54 (m, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C25H23F2N5O2: 464.18924; found: 464.1882.

[0465] The preparation of 5-(2-fluorophenoxy)nicotinonitrile (compound 55)

[0466] Using CS2CO3 as base, this compound was synthesized via general procedure 2 at 130 °C affording compound 55 as a yellow oil, in 38% yield.

[0467] XH NMR (400 MHz, CDCI3): 6 (ppm) 8.60 (t, J = 2.2 Hz, 2H), 7.39-7.38 (m, 1H), 7.30-7.17 (m, 4H);13C NMR (101 MHz, CDCI3) 5 (ppm) 154.21 (d,4JCF = 250.7 Hz), 153.80, 146.23, 143.25, 140.98 (d,2JCF = 12.2 Hz), 127.32 (d,3JCF = 6.9 Hz), 125.50 (d,4JCF = 4.2 Hz), 125.03, 122.87, 117.81 (d,2JCF = 18.1 Hz), 115.95, 110.19.

[0468] The preparation of 5-(2-fluorophenoxy)nicotinaldehyde (compound 56)To an oven-dried screw cap test tube containing a magnetic stirring bar, was added compound 55 (150.0 mg, 0.70 mmol, 1.00 eq). The reaction tube was evacuated and backfilled with argon three times. Under a counterflow of argon, anhydrous toluene (2.0 mL) was added using a syringe. After that, the reaction mixture was cooled to -78°C. Then, DIBAL-H (0.77 mL, 0.77 mmol, 1.1 eq) was added slowly and the reaction mixture was stirred at -78 °C for 2 h. Then, a saturated aqueous ammonium chloride solution (0.7 mL) was added. The reaction mixture was warmed to room temperature and was concentrated under reduced pressure to give the crude product. It was purified by chromatography on silica gel (20% of ethyl acetate in petroleum ether) affording compound 56 as a colorless oil (30.1 mg, 20% yield).

[0469] 1H NMR (400 MHz, CDCI3): 6 (ppm) 10.08 (s, 1H), 8.79 (d, J = 1.3 Hz, 1H), 8.67 (d, J = 2.8 Hz, 1H), 7.57-7.56 (m, 1H), 7.26-7.16 (m, 4H);13C NMR (101 MHz, CDCI3) 5 (ppm) 190.11, 154.86, 154.34 (d,1JCF = 250.1 Hz), 146.58, 145.27, 141.53 (d,2JCF = 11.8 Hz), 132.16, 126.86 (d,3JCF = 6.9 Hz), 125.35 (d,4JCF = 4.1 Hz), 122.82, 120.40, 117.70 (d,2JCF = 18.1 Hz).

[0470] The preparation of methyl 4-(2-fluorophenoxy)picolinate (compound 58)

[0471] Using NaH as base, this compound was synthesized via general procedure 2 at 100 °C affording compound 58 as an orange oil, in 21% yield.

[0472] XH NMR (400 MHz, CDCI3): 6 (ppm) 8.60 (d, J = 5.6 Hz, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.31-7.18 (m, 4H), 7.01 (dd, J = 2.5, 5.6 Hz, 1H), 3.99 (s, 3H);13C NMR (101 MHz, CDCI3) <5 (ppm) 165.37, 165.29, 154.43 (d,4JCF = 250.5 Hz), 151.36, 149.99, 140.49 (d,2JCF = 12.2 Hz), 127.36 (d,3JCF = 6.9 Hz), 125.36 (d,4JCF = 4.0 Hz), 123.45, 117.66 (d,2JCF = 17.9 Hz), 114.17, 112.70, 53.06.

[0473] The preparation of (4-(2-fluorophenoxy)pyridin-2-yl)methanol (compound 59)

[0474] This compound was synthesized via the procedure of compound 14 affording compound 59 as an orange oil, in 67% yield.

[0475] XH NMR (400 MHz, CDCI3): 6 (ppm) 8.42-8.40 (m, 1H), 7.28-7.18 (m, 4H), 6.76 (d, J = 3.5 Hz, 2H), 4.69 (s, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 165.02, 161.50, 154.57 (d,1JCF = 250.4 Hz), 150.13, 140.79 (d,2JCF = 12.0 Hz), 127.01 (d,3JCF = 7.2 Hz), 125.20 (d,4JCF = 3.8 Hz), 123.55, 117.52 (d,2JCF = 18.2 Hz), 110.31, 107.39, 64.19.

[0476] The preparation of compound 60

[0477] This compound was synthesized via the general procedure 1 at 50 °C. When the starting material was finished, it was only concentrated under reduced pressure to afford compound 60 as a crude product which was used for next step without further purification.

[0478] The preparation of 2-(bromomethyl)-6-(2-fluorobenzyl)pyridine (compound 62)

[0479] To an oven-dried screw cap test tube containing a magnetic stirring bar was added dichlorobis(triphenylphosphine)palladium(II) (70.2 mg, 0.10 mmol, 0.10 eq), (2-fluorophenyl)boronic acid (139.9 mg, 1.00 mmol, 1.00 eq) and K2CO3 (304.1 mg, 2.20 mmol, 2.20 eq). The reaction tube was evacuated and backfilled with argon three times. Under a counterflow of argon, THF (2.0 mL) and water (2.0 mL) were added, followed bythe addition of compound 61 (278.2 mg, 1.05 mmol, 1.05 eq) using a syringe. Then, the reaction mixture was placed in a heating block at 40 °C overnight. Then, the reaction mixture was washed with brine (10.0 mL) and extracted with ethyl acetate (20.0 mL). The organic layer was collected and dried over magnesium sulfate. Then, it was concentrated under reduced pressure affording the crude product. The crude residue was purified by chromatography on silica gel (10 % of ethyl acetate in petroleum ether) to give compound 62 as a brown oil (37.1 mg, 13% yield).

[0480] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.58 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.26-7.20 (m, 2H), 7.10-7.03 (m, 2H), 7.00 (d, J = 7.8 Hz, 1H), 4.54 (s, 2H), 4.19 (s, 2H);13C NMR (101 MHz, CDCI3) 5 (ppm) 160.98 (d,1JCF = 248.9 Hz), 159.77, 156.32, 137.59, 131.45 (d,3JCF = 4.4 Hz), 128.39 (d,3JCF = 8.0 Hz), 126.08 (d,2JCF = 15.6 Hz), 124.22 (d,4JCF = 3.6 Hz), 122.12, 121.15, 115.39 (d,2JCF = 22.0 Hz), 37.38 (d,3JCF = 2.9 Hz), 34.09.

[0481] The preparation of tert-butyl-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-3encfo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 65)

[0482] At -78 °C, stirred solution of (trimethylsilyl)acetylene (259.3 mg, 2.64 mmol, 1.10 eq) in anhydrous THF (3.0 mL) was treated with n-butyllithium solution (1.1 mL, 2.5 M) under argon. The colorless solution was stirred for 30 minutes, followed by the addition of compound 65 (540.7 mg, 2.40 mmol, 1.00 eq) in anhydrous THF (2.0 mL). The reaction was warmed up to room temperature, stirred for 4 h, and quenched with water. After removal of THF, the residue was partitioned between ether and water. The separated organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the crude product. Subsequently, a mixture of the crude and K2CO3 (663.4 mg, 4.80 mmol, 2.40 eq) in methanol was stirred at room temperature for 1 h. The solids was filtered off and washed with ether. The filtrate was concentrated, dissolved in ether, washed with water and brine, and dried over sodium sulfate. At last, it was concentrated under reduced pressure to give the crude product which was used to synthesize compound 65 via general procedure 3 as a brown solid, in 46% yield.

[0483] XH NMR (400 MHz, CDCI3): 6 (ppm) 7.95-7.91 (m, 2H), 7.87 (d, J = 2.8 Hz, 1H), 7.46- 7.40 (m, 1H), 7.34-7.26 (m, 2H), 4.38-4.30 (m, 2H), 2.89 (s, 1H), 2.47-2.32 (m, 4H), 2.08-1.99 (m, 4H), 1.48 (s, 9H);13C NMR (101 MHz, CDCI3) 6 (ppm) 156.83, 153.59, 153.27 (d,4JCF = 250.8 Hz), 130.20 (d,3JCF = 7.9 Hz), 125.27 (d,4JCF = 3.9 Hz), 125.18, 124.84, 120.07 (d,3JCF = 8.5 Hz), 117.04 (d,2JCF = 20.0 Hz), 79.37, 69.42, 53.40, 52.60, 43.92, 28.51, 27.54.

[0484] The preparation of (lR,3r,5S)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (compound 66)

[0485] This compound was synthesized via the procedure of compound 46c affording compound 66 as a crude product which was used for next step without further purification.

[0486] The preparation of 8-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3encfo-ol (compound 67a)The crude compound 66 (48.7 mg, 0.15 mmol, 1.00 eq), compound 52 (65.2 mg, 0.30 mmol, 2.00 eq) and NaHCCh (25.2 mg, 0.30 mmol, 2.00 eq) were dissolved in methanol (2.0 mL), and the reaction mixture was stirred at 0 °C for 5 minutes, followed by the addition of NaBH(OAc)s (63.6 mg, 0.30 mmol, 2.00 eq). The mixture was stirred at room temperature for 10 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (10% of methanol in dichloromethane) to give compound 67a as a white solid (31.2 mg, 43% yield).

[0487] Mp: 57.8-59.6 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.05 (s, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.47-7.38 (m, 2H), 7.33-7.29 (m, 2H), 7.23-7.18 (m, 1H), 7.15-7.12 (m, 3H), 6.89 (d, J = 8.0 Hz, 1H), 3.83 (s, 2H), 3.64 (s, 2H), 2.60-2.48 (m, 4H), 2.14-2.02 (m, 4H);13C NMR (101 MHz, CDCI3) 6 (ppm) 162.32, 155.85, 154.90 (d,1JCF = 248.7 Hz), 153.64 (d,1JCF = 251.8 Hz), 141.08, 140.96, 140.56, 130.43 (d,3JCF = 7.8 Hz), 126.03 (d,3JCF = 7.0 Hz), 125.27, 125.17, 125.14, 124.63 (d,4JCF = 3.7 Hz), 124.02, 120.97 (d,3JCF = 7.0 Hz), 118.89, 117.09 (d,2JCF = 19.8 Hz), 116.60 (d,2JCF = 18.4 Hz), 109.80, 68.11, 60.17, 56.11, 43.64, 25.14;19F NMR (377 MHz, CDCI3): 5 (ppm) -127.87 (s, IF), -123.14 (s, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H25F2N5O2: 490.20489; found: 490.2050.

[0488] The preparation of 8-((6-(2-fluorobenzyl)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3encfo-ol (compound 67b)

[0489] This compound was synthesized via general procedure 2 affording compound 67b as a brown solid, in 66% yield.

[0490] Mp: 49.2-51.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.10 (s, 1H), 7.88 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 7.2 Hz, 2H), 7.45-7.40 (m, 1H), 7.32-7.18 (m, 5H), 7.07-7.01 (m, 3H), 4.17 (s, 2H), 3.90 (s, 2H), 3.48 (s, 2H), 2.70-2.63 (m, 2H), 2.45-2.43 (m, 2H), 2.17-2.08 (m, 4H);13C NMR (101 MHz, CDCI3) 6 (ppm) 161.02 (d,4JCF = 245.4 Hz), 159.07, 156.51, 153.53 (d, JCF = 251.6 Hz), 137.36, 131.45, 131.41, 130.26 (d,3JCF = 7.8 Hz), 128.26 (d,3JCF = 8.0 Hz), 126.51, 126.36, 125.30 (d,3JCF = 10.3 Hz), 125.15 (d,4JCF = 3.7 Hz), 125.07, 124.08 (d,4JCF = 3.5 Hz), 121.57, 120.83, 117.04 (d,2JCF = 20.0 Hz), 115.31 (d,2JCF = 21.9 Hz), 68.62, 59.61, 57.73, 44.25, 37.44 (d,3JCF = 2.7 Hz), 25.61;19F NMR (377 MHz, CDCI3): 5 (ppm) -123.30 (s, IF), -117.49 (m, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C28H27F2N5O: 488.22562; found: 488.2252.

[0491] The preparation of 8-((4-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3encfo-ol (compound 67c)

[0492] This compound was synthesized via general procedure 2 affording compound 67c as a white solid, in 30% yield.

[0493] Mp: 171.2-173.0 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.37 (d, J = 5.7 Hz, 1H), 7.97-7.92 (m, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.48-7.41 (m, 1H), 7.36-7.28 (m, 2H), 7.23-7.17 (m, 5H), 6.69 (dd, J = 2.3, 5.7 Hz, 1H), 3.74 (s, 2H), 3.31 (s, 2H), 2.72 (s, 1H), 2.40-2.30 (m, 4H), 2.07-1.98 (m, 4H);13C NMR (101 MHz, CDCI3) 6 (ppm) 165.01, 163.02, 157.24, 154.64 (d,4JCF = 250.1 Hz), 153.38 (d,4JCF = 250.7 Hz), 150.52, 141.05 (d,2JCF = 11.9 Hz), 130.19 (d,3JCF = 7.7 Hz), 126.67 (d,3JCF = 7.1 Hz), 125.40, 125.28 (d,4JCF = 3.7 Hz), 125.09 (d,4JCF = 3.9 Hz), 125.01, 123.57, 120.14 (d,3JCF = 8.1 Hz), 117.38 (d,2JCF = 18.0 Hz), 117.02 (d,2JCF = 19.9 Hz), 109.54, 109.46, 68.88, 59.06, 58.28, 44.65, 26.09;19F NMR (377 MHz, CDCI3): 5 (ppm) -128.95 (m, IF), -123.59 (s, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H25F2N5O2: 490.20489; found: 490.2041.The preparation of 8-((5-(2-fluorophenoxy)pyridin-3-yl)methyl)-3-(l-(2-fluorophenyl)- lH-l,2,3-triazol-4-yl)-8-azabicyclo[3.2.1]octan-3encfo-ol (compound 67d)

[0494] This compound was synthesized via the procedure of compound 67a affording compound 67d as a yellow solid, in 8% yield.

[0495] Mp: 39.4-41.2 °C.XH NMR (400 MHz, CDCI3): 6 (ppm) 8.34 (s, 1H), 8.25 (s, 1H), 7.92 (t, J = 7.1 Hz, 1H), 7.46-7.41 (m, 2H), 7.34-7.29 (m, 2H), 7.21-7.08 (m, 4H), 3.66 (s, 2H), 3.27 (s, 2H), 2.84 (s, 1H), 2.43-2.32 (m, 4H), 2.03-2.00 (m, 4H);13C NMR (101 MHz, CDCI3) 6 (ppm) 157.26, 154.24 (d,1JCF= 249.3 Hz), 154.07, 153.35 (d,1JCF= 250.9 Hz), 144.32, 142.89, 142.78, 138.32, 130.17 (d,3JCF= 7.8 Hz), 125.61 (d,3JCF= 7.0 Hz), 125.36, 125.24 (d,4JCF= 3.8 Hz), 124.94, 124.92, 124.06, 122.02, 120.34 (d,3JCF= 8.0 Hz), 117.32 (d,2JCF = 18.0 Hz), 117.01 (d,2JCF = 19.9 Hz), 68.99, 58.52, 53.13, 44.24, 26.02;19F NMR (377 MHz, CDCI3): 5 (ppm) -130.15 (s, IF), -123.56 (s, IF); HRMS (ESI-Q-TOF): m / z [M + H]+ calcd. for C27H25F2N5O2: 490.20489; found: 490.2043.

[0496] References

[0497] [1] R. Frlan, S. Gobec, D. Kikelj, Synthesis of ethyl 3-(hydroxyphenoxy)benzyl butylphosphonates as potential antigen 85C inhibitors, Tetrahedron 63 (2007) 10698-10708. https: / / doi.Org / 10.1016 / J.TET.2007.07.078.

[0498] [2] D. Fan, B. Wang, G. Stelitano, K. Savkova, R. Shi, S. Huszar, Q. Han, K. Mikusova, L.R. Chiarelli, Y. Lu, C. Qiao, Structural and Activity Relationships of 6-Sulfonyl-8- Nitrobenzothiazinones as Antitubercular Agents, J. Med. Chem. 64 (2021). https: / / doi.org / 10.1021 / acs.jmedchem.lc01049.

[0499] [3] S. Potratz, A. Mishra, P. Bauerle, Thiophene-based donor-acceptor co-oligomers by copper-catalyzed 1,3-dipolar cycloaddition, Beilstein J. Org. Chem. 8 (2012). https: / / doi.Org / 10.3762 / bjoc.8.76.

[0500] [4] L. Tan, Y. Pan, Q.Y. Zeng, Z.Y. Wang, H. Xu, H.X. Dai, Palladium-Catalyzed Directed Carbon-Carbon Bond Activation of Aryl Nitriles for Cyano Transfer, Org. Lett. (2024). https: / / doi.org / 10.1021 / acs.orglett.4c00429.

[0501] [5] V.H. Vu, F. Louafi, N. Girard, R. Marion, T. Roisnel, V. Dorcet, J.P. Hurvois, Electrochemical access to 8-(l-phenyl-ethyl)-l,4-dioxa-8-aza-spiro[4.5] decane-7- carbonitrile. Application to the asymmetric syntheses of (+)-myrtine and alkaloid (+)-241D, J. Org. Chem. 79 (2014). https: / / doi.org / 10.1021 / jo500104c.

[0502] [6] T. Arai, T. Araya, D. Sasaki, A. Taniguchi, T. Sato, Y. Sohma, M. Kanai, Rational design and identification of a non-peptidic aggregation inhibitor of amyloid-0 based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-], Angew. Chemie - Int. Ed. 53 (2014). https: / / doi.org / 10.1002 / anie.201405109.

[0503] [7] M. Barbasiewicz, M. Bieniek, A. Michrowska, A. Szadkowska, A. Makal, K. Wozniak, K. Grela, Probing of the ligand anatomy: Effects of the chelating alkoxy ligand modifications on the structure and catalytic activity of ruthenium carbene complexes, Adv. Synth. Catal. 349 (2007). https: / / doi.org / 10.1002 / adsc.200600478.

[0504] [8] Q. Li, S. Claes, Y. Verhaegen, S. Anthonissen, T. Van Loy, D. Schols, W. Dehaen, S. De Jonghe, Synthesis and structure-activity relationship study of phenoxybenzylpiperazine analogues as CCR8 agonists, Bioorg. Chem. 139 (2023) 106755. https: / / doi.Org / 10.1016 / J.BIOORG.2023.106755.

[0505] [9] J.R. Schmink, M.T. Tudge, Facile preparation of highly-functionalized, nitrogenbearing diarylmethanes, Tetrahedron Lett. 54 (2013). https: / / doi.Org / 10.1016 / j.tetlet.2012.09.112.

[0506] CCR8 calcium mobilization assay

[0507] Human glioblastoma U87 cells that stably express human CCR8 (U87.CD4.CCR8) were used to measure CCR8-dependent Ca2+responses. Cells (20,000 cells / well) were seeded in gelatin-coated black-walled polystyrene 96-well plates and incubated overnight at 37°Cand 5% CO2. The next day, conditioned culture medium was removed and replaced with a fluorescent calcium indicator (calcium 6, Molecular Devices; 80pL / well) after which plates were incubated for 2h at 37°C in the dark. Transient intracellular Ca2+responses were recorded based on calcium 6 fluorescence using the FLIPR (Fluorescent and Luminescent Imaging Plate Reader, Molecular Devices). During the protocol calcium-6 loaded cells were challenged with serial dilutions of test compound or a fixed concentration of recombinant CCL1 (50ng / mL) to evaluate their agonist activity. For each well t he fluorescent readout was normalized by dividing over a baseline value obtained immediately before compound or CCL1 addition. Also background responses from cells without compound or CCL1 stimulation (vehicle control) were subtracted from al l other responses. For each assay plate the CCLl-induced response (at 50ng / mL) was set as 100% and all other responses were calculated relative to this. For the most active compounds (i.e., >90% activity at 50pM) EC50 values were calculated based on dose-dependent activation curves using non-linear regression in Graphpad.

[0508] Certain compounds of the accompanying examples were found to generate EC50 values in this assay of 10 pM or better. Most of these compounds generated values of less than 1 pM. The majority of these compounds generated values of even less than 0.1 pM. The results are shown in Table 1

[0509] Table 1

[0510]

[0511] "

[0512] >

[0513]

[0514]

[0515]

[0516] < "

[0517] <

[0518]

[0519]

[0520] ND: not determined

[0521] In vitro assessment of CCR8 agonism on human Treg function

[0522] In vitro treatment of expanded Treg with compound 17d leads to a dose-dependent increase in CD39 and FOXP3 per cell level (Figure 3B). When compared to the endogenous agonist CCL1 (Figure 3A), compound 17d is more potent in increasing Treg's suppressive potential.

[0523] Assessment of therapeutic potential of CCR8 agonists in a humanized disease model

[0524] The human CCR.8 agonists of the invention are evaluated in a humanized model that mimics auto-inflammatory aspects of immune responses, namely xenogeneic graft-vs-host disease (xGvHD). Briefly, human PBMCs are infused into immune-incompetent NSG mice. This elicits a T-cell-driven graft-vs-host reaction with extensive T-cell activation and expansion. Disease progression will be monitored through an established disease activity index (DAI) and can be ameliorated via Treg-mediated suppression.

[0525] The model is suitable for the evaluation of human CCR.8 agonists as, also upon transfer, human Treg preferentially express CCR8 and do so at higher per cell levels (Figures 4A-C). Notably, the pace of disease progression can be tuned through the number of transplanted PBMC or mild irradiation. Further, compound performance can be evaluated in co-treatment with standard-of-care (SOC) GvHD drugs such as Rapamycin which - given its IL-2-dependent effect on Treg - may synergize with the CCR8 agonists of this invention. Treatment with compound 17d at different doses resulted in a significant increase of CCR8+ Treg and increased per cell CCR8 expression by Treg (Figure 4D). Importantly, significant effects are observed at day 9. These data demonstrate in vivo efficacy activity of the CCR8 agonist 17d.

Claims

63CLAIMS1. A compound of formula I:IAri and Ar2are heteroaryl and aryl groups, wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, Cl-7 alkoxy, hydroxyl, nitro, amino and cyano;X is O, NH, S, CH2;RI and R2are each independently selected from H or Cl-7 alkyl;schematically represents a saturated or partly unsaturated heterocyclic ring with at least one nitrogen in said heterocyclic ring;R3aand R3bare each independently selected from the group consisting of hydrogen, Cl-7 alkyl or a carbonyl group, or R3aand R3b together form a bridge consisting of -(CH2)m-, wherein m is 1 or 2;R4is selected from the group consisting of H, hydroxyl, halogen, Cl-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo Cl-7 alkyl or Cl-7 alkoxy, which is optionally containing one or more functions selected from the group consisting of halogen, carbonyl, hydroxyl, cyano, carboxylic acid, carboxylic acid ester or carboxamide;Rs is selected from the group consisting of H, Cl-7 alkyl or (CH2)n-Ar3,wherein n is 0-2 andwherein Ar3is a heteroaryl and aryl group, and wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-7 alkyl, halo Cl-7 alkyl, nitro, hydroxyl, amino and Cl-7 alkoxy; and / or a pharmaceutical acceptable addition salt thereof and / or a stereoisomer thereof and / or a solvate thereof.

2. The compound according to claim 1, wherein Ari, Ar2and Ar3are each independently selected from the group consisting of an unsubstituted heteroaryl and an aryl group, wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-3 alkyl, halo Cl-3 alkyl, Cl-3 alkoxy, hydroxyl and cyano.

3. The compound according to claim 1 or 2, wherein X is O or CH2, preferentially X is O.

644. The compound according to any one of claims 1 to 3, wherein Ri and R2are each selected from H or Cl-3 alkyl, preferentially Ri and R2are H or methyl.

5. The compound according to any one of claims 1 to 4, whereinschematically represents a saturated heterocyclic ring with one nitrogen in said heterocyclic ring, preferentially said heterocyclic ring is a six-membered ring with one nitrogen in said heterocyclic ring.

6. The compound according to any one of claims 1 to 5, wherein R3aand R3bare each independently selected from the group consisting of a methyl and a carbonyl group, or R3aand R3b together form a bridge consisting of -(CH2)2-.

7. The compound according to any one of claims 1 to 6, wherein R4is selected from the group consisting of hydroxyl and Cl-7 alkoxy which is optionally substituted with one or more functions selected from the group consisting of hydroxyl, carboxylic acid, or carboxylic acid ester.

8. The compound according to any one of claims 1 to 7, wherein R5is Ar3wherein said Ar3is an unsubstituted heteroaryl or an aryl group, and wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, Cl-3 alkyl, Cl-3 alkoxy, halo C-l-3 alkyl, nitro, hydroxyl and cyano.

9. The compound according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of:- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidine- 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidine- l-(3-(2-methoxyphenoxy)benzyl)-4-(lH-l,2,3-triazol-4-yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-methyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol - 4-(l-ethyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol - l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol - 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol - 4-methoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine- 4-ethoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)-4- propoxypiperidine- 4-fluoro-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine65- ethyl 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-yl)oxy)acetate- 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4- yl)oxy)ethan-l-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-nitrophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol- 4-(l-(4-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(3-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-methoxyphenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3-methoxyphenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-methoxyphenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- 4-(l-(4-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(3-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(2-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-(trifluoromethyl)phenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- 2-(4-(4-hydroxy-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-lH-l,2,3-triazol-l- yl)benzonitrile- 4-(l-(2,3-difluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(4-chloro-2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(2,6-dimethoxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3,4,5-trimethoxyphenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- 4-(l-(furan-3-yl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4- ol66- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(thiophen-2-yl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(pyridin-2-yl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol- 5-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-2-(3-(2-methoxyphenoxy)benzyl)-2- azabicyclo[2.2.1]heptan-5-ol- l-(3-(2-methoxyphenoxy)benzyl)-3-methyl-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-3,3-dimethyl-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-ol- (8-(3-(2-methoxyphenoxy)benzyl)-3-(l-phenyl-lH-l,2,3-triazol-4-yl)-8- azabicyclo[3.2.1]octan-3endo-ol- l-(3-(2-methoxyphenoxy)benzyl)-2-methyl-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-ol- (2S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)-2- methylpiperidin-4-ol- (2R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)-2- methylpiperidin-4-ol- l-(4-fluoro-3-phenoxybenzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin-4- ol- l-(3-(2-fluorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol- l-(3-(2-chlorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol- 2-(3-((4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-4-hydroxypiperidin-l- yl)methyl)phenoxy)benzonitrile4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-phenoxybenzyl)piperidin-4-ol -(S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- methoxyphenoxy)phenyl)ethyl)piperidin-4-ol-(R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- methoxyphenoxy)phenyl)ethyl)piperidin-4-ol- (S)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- (R)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- (R)-l-(l-(3-(2,4-difluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3- triazol-4-yl)piperidin-4-ol67- (S)-4-(l-(2-chlorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- fluorophenoxy)phenyl)ethyl)piperidin-4-ol- l-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- 8-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol- 4-yl)-8-azabicyclo[3.2.1]octan-3encfo-ol- 8-((6-(2-fluorobenzyl)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol- 8-((4-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol- 4-yl)-8-azabicyclo[3.2.1]octan-3encfo-ol- 8-((5-(2-fluorophenoxy)pyridin-3-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol- 4-yl)-8-azabicyclo[3.2.1]octan-3encfo-ol.

10. A compound according to any one of the claims 1 to 9, for use as a medicament.

11. A compound according to any one of the claims 1 to 10, for use in the treatment or prevention of a CCR8 mediated disease.

12. The compound for use in the treatment or prevention according to claim 11 wherein the CCR.8 mediated disease is an autoimmune disease.

13. The compound for use in the treatment or prevention according to claim 11 wherein the CCR8 mediated disease is selected from the group consisting of graft-versus-host disease (GVHD), multiple sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, psoriasis and diabetes.

14. The compound for use in the treatment or prevention according to any one of claims 11 to 13, wherein the compound is selected from the group consisting of:- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidine - 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidine - l-(3-(2-methoxyphenoxy)benzyl)-4-(lH-l,2,3-triazol-4-yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-methyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol - 4-(l-ethyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol - l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4-ol - 4-(l-benzyl-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-ol - 4-methoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine- 4-ethoxy-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)-4- propoxypiperidine- 4-fluoro-l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidine- ethyl 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-yl)oxy)acetate- 2-((l-(3-(2-methoxyphenoxy)benzyl)-4-(l-phenyl-lH-l,2,3-triazol-4-yl)piperidin-4- yl)oxy)ethan-l-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-nitrophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- 4-(l-(4-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(3-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(4-methoxyphenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3-methoxyphenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-methoxyphenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- 4-(l-(4-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(3-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(2-hydroxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(2-(trifluoromethyl)phenyl)-lH-l,2,3-triazol- 4-yl)piperidin-4-ol- 2-(4-(4-hydroxy-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-lH-l,2,3-triazol-l- yl)benzonitrile- 4-(l-(2,3-difluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(4-chloro-2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- 4-(l-(2,6-dimethoxyphenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2- methoxyphenoxy)benzyl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(3,4,5-trimethoxyphenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- 4-(l-(furan-3-yl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)piperidin-4- ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(thiophen-2-yl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-4-(l-(pyridin-2-yl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol- 5-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-2-(3-(2-methoxyphenoxy)benzyl)-2- azabicyclo[2.2.1]heptan-5-ol- l-(3-(2-methoxyphenoxy)benzyl)-3-methyl-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-ol- l-(3-(2-methoxyphenoxy)benzyl)-3,3-dimethyl-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-ol- (8-(3-(2-methoxyphenoxy)benzyl)-3-(l-phenyl-lH-l,2,3-triazol-4-yl)-8- azabicyclo[3.2.1]octan-3endo-ol- l-(3-(2-methoxyphenoxy)benzyl)-2-methyl-4-(l-phenyl-lH-l,2,3-triazol-4- yl)piperidin-4-ol- (2S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)- 2-methylpiperidin-4-ol- (2R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-(2-methoxyphenoxy)benzyl)- 2-methylpiperidin-4-ol- l-(4-fluoro-3-phenoxybenzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol- l-(3-(2-fluorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol- l-(3-(2-chlorophenoxy)benzyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)piperidin- 4-ol- 2-(3-((4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-4-hydroxypiperidin-l- yl)methyl)phenoxy)benzonitrile- 4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(3-phenoxybenzyl)piperidin-4-ol -(S)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- methoxyphenoxy)phenyl)ethyl)piperidin-4-ol-(R)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- methoxyphenoxy)phenyl)ethyl)piperidin-4-ol- (S)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- (R)-l-(l-(3-(2-fluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- (R)-l-(l-(3-(2,4-difluorophenoxy)phenyl)ethyl)-4-(l-(2-fluorophenyl)-lH-l,2,3- triazol-4-yl)piperidin-4-ol- (S)-4-(l-(2-chlorophenyl)-lH-l,2,3-triazol-4-yl)-l-(l-(3-(2- fluorophenoxy)phenyl)ethyl)piperidin-4-ol- l-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-4-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)piperidin-4-ol- 8-((6-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol8-((6-(2-fluorobenzyl)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol- 8-((4-(2-fluorophenoxy)pyridin-2-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol- 8-((5-(2-fluorophenoxy)pyridin-3-yl)methyl)-3-(l-(2-fluorophenyl)-lH-l,2,3-triazol-4- yl)-8-azabicyclo[3.2.1]octan-3encfo-ol.

15. A pharmaceutical composition comprising a compound according to any one of the claims 1 to 9, and a pharmaceutically acceptable carrier.

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