RU2277909C2 - Method for treatment allergy by using substituted pyrazoles - Google Patents

Abstract

FIELD: organic chemistry, medicine, allergology.

SUBSTANCE: invention relates to a method for treatment of allergy by administration to patient the therapeutically effective dose of a pharmaceutical composition comprising compound of the formula (I)

. Invention provides the enhanced effectiveness of treatment.

EFFECT: improved treatment method.

7 cl, 3 dwg, 49 ex

Description

Field of Invention

This invention relates to the use of substituted pyrazoles for the treatment of an allergic disease.

BACKGROUND OF THE INVENTION

Atopic allergy affects at least 20% of the population in developed countries and includes a wide range of IgE-mediated diseases such as hay fever, asthma, atopic dermatitis and food allergies. Exposure of the corresponding allergens to the allergic subject results in cross-linking of the allergen-specific IgE binding to mast cells, initiating degranulation and release of pro-inflammatory mediators, such as histamine and eicosanoids, which trigger a well-and-signal response in the skin test. Usually, such an early response is followed by a prolonged late reaction in which inflammatory cells, in particular eosinophils and activated TH-2 CD4 T cells, are attracted to the site of an allergic effect. Inflammatory cytokines, such as IL-4 and IL-5, both produced by TH-2 cells, are important for the production of IgE by B cells and for eosinophilia, respectively. It has been shown that immunotherapy targeting CD4 T cells is effective in decreasing IgE production, activating pro-inflammatory cells and releasing inflammatory mediators.

Allergy treatments currently targeting CD4 T cells have mixed success. Sensitization using allergen extracts or vaccines is effective for many allergens, such as Hymenoptera insect bites, which can cause life-threatening allergic reactions. The mechanism can be either the induction of T-cell tolerance or the conversion of TH-2 to TH-1. However, such treatment requires a long treatment regimen, frequent visits by the attending physician and preliminary stabilization with the use of other drugs and is associated with some pain and rare deaths. Alternatively, immunosuppressive drugs, such as steroids, that effectively stabilize the onset of allergic responses are often associated with serious side effects.

CD4 T cell activation is a major factor in initiating and maintaining an allergic response. Allergens are absorbed by specialized antigen presenting cells (APCs), such as dendritic cells and B cells. Protein allergens pass through the endosomal and lysosomal systems, where they are destroyed by various proteases. Such peptide fragments are bound by MHC class II molecules, which on the cell surface are heterotrimeric complexes consisting of two transmembrane glycoprotein chains (α and β) that form the binding support for the third component, a peptide of 11-20 amino acids. The MHC class II antigen-molecule complex is recognized by CD4 T cells and leads to T cell activation. Activated T cells, in turn, activate several other components of the immune system, such as B cells and macrophages, which are key to the body's response to pathogens, but also lead to allergy symptoms.

Class II molecules, like other transmembrane proteins, move into the endoplasmic reticulum (ER) after synthesis, where they bind to the third protein, the invariant chain (Ii). An invariant chain molecule is a type II transmembrane protein that serves as a class II-specific companion that promotes the release of class II-Ii complexes from ER and prevents the binding of class II molecules to peptides and unfolded proteins in the ER and secretory pathway. The targeting motif in the cytoplasmic tail Ii directs class II-Ii complexes from the secretory pathway to the endosomal system.

Before MHC class II molecules can be an antigen, Ii must be removed by a series of proteases that cleave Ii. The final Ii peptide fragments, called class II-linked invariant chain peptides (CLIP), take the place of peptide binding of a class II molecule and in most cases do not release spontaneously. CLIP protects the class II binding zone from coagulation both during intracellular transport and after Ii destruction in the endosomal system. The binding of antigenic peptides generated from endocytotic proteins requires a free and already open binding site. Therefore, CLIP must be released at a time when the open binding site is stabilized to allow binding to other peptides. Human leukocyte antigen -DM ("HLA-DM") mediates both of these functions, thus promoting the binding of antigenic peptides. After peptide binding, class II molecules are transported to the cell surface through pathways that are mostly unknown.

Taking into account the above, inhibition of the proteolysis of the invariant chain will prevent the removal of Ii from the class II binding zone, which, in turn, will specifically block the binding of antigen to the MHC class II molecule.

Cathepsin S (CatS) is a cysteine protease expressed in lymphatic tissues. CatS mediates the proteolysis of the invariant chain, which is a prerequisite for peptide loading of class II molecules (Riese et al. (1996) Immunity 4: 357). CatS has 50-60% homology with cathepsins L and K, but differs from them in that it has a broad optimum pH, which is extended to the alkaline pH region. CatS modulates antigenic demonstration in animal models, and inhibitors are effective in an asthma model (Riese et al. (1998) J. Clin. Invest. 101: 2351). Cathepsin S-deficient mice have a reduced ability to present exogenous proteins using professional antigen-presenting cells (Nakagawa et al (1999) Immunity 10: 207; Shi et al. (1999) Immunity 10: 197).

It is believed that compounds that inhibit the proteolytic activity of human cathepsin S can be used to treat chronic autoimmune diseases, including, but not limited to, lupus and rheumatoid arthritis; and have potential utility in modulating the immune response to tissue transplantation. Methods of modulating autoimmunity with an agent that modulates the activity of cathepsin S, for example, proteolysis of the Ii chain, as well as methods of treating a subject having an autoimmune disease, methods for evaluating treatment for its ability to modulate the immune response are described in WO 99/58153.

Compounds somewhat similar to the compounds of the present invention are described in the following references.

Winters et al. ((Winters G., Sala A., Barone D., Baldoli EJMed. Chem., 1985, 28, 934-940; Singh P., Sharma RC, Quant. Struct. -Act. Relat. 1990 , 9, 29-32; Winters G., Sala A., Barone D., US Pat. No. 4,500,525 (1985)) describe the bicyclic pyrazoles of the type shown below: Substituent R never contains a heterocyclic ring and no inhibitory activity is prescribed for these molecules. in relation to protease; they are described as modulators of α1-adrenergic receptors.

Shutske et al. Described the bicyclic pyrazoles below. In their system, the pyridine ring is aromatic (Shutske G.M., Kapples K.J., Tomer J.D. US Patent 5264576 (1993)). Another reference relates to R, which is a linker for a heterocycle, the claims indicate only R = hydrogen. The compounds are mentioned as serotonin reuptake inhibitors.

The compound 2- [4- [4- (3-methyl-5-phenyl-1H-pyrazol-1-yl) butyl] -1-piperazinyl] pyrimidine is known from EP-382637, where pyrimidines having anxiolytic properties are described. This compound and its analogs are further described in EP-502786 as cardiovascular agents and agents for the central nervous system. Pharmaceutical preparations with such compounds are described in EP-655248 for use in the treatment of gastric secretion and as antiulcer agents. WO 9721439 describes medicaments with such compounds for the treatment of obstructive-compulsive disorders, sleep apnea (dyspnea), sexual disorders, vomiting and motion sickness.

Compounds 5-methyl-3-phenyl-1- [4- (4-phenyl-1-piperazinyl) butyl] -1H-indazole and 5-bromo-3- (2-chlorophenyl) -1- [4- (4- phenyl-1-piperazinyl) butyl] -1H-indazole, in particular their hydrochloride salts, are known from WO-9853940 and CA122: 314528, where data and similar compounds are described as kinase inhibitors in the first link and as having affinity for benzodiazepine receptors in the last link.

Summary of the invention

The object of the present invention is the use of cathepsin S inhibitors for the treatment of allergic diseases, including, but not limited to, atopic allergies. Examples of an allergic disease include hay fever, asthma, atopic dermatitis, and food allergies. Allergens include dust, pollen, mold, and pet allergies or pet hair.

In one aspect, the present invention relates to a method for treating a subject suffering from an allergic disease, in particular from an atopic allergic disease, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a cathepsin S inhibitor.

In another aspect, the present invention relates to a method for treating a subject suffering from an IgE-mediated allergic disease, in particular from an atopic allergic disease state, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a cathepsin S inhibitor.

In a third aspect, the invention relates to the use or use of a cathepsin S inhibitor for the manufacture of a medicament for the treatment of an allergic disease, more particularly for the treatment of IgE-mediated allergic diseases, and more particularly for the treatment of hay fever, asthma, atopic dermatitis or food allergies. The invention also relates to anti-allergic pharmaceutical compositions comprising, as an active ingredient, an effective amount of a cathepsin S inhibitor and a pharmaceutically acceptable carrier. The active ingredient may be formulated in any manner suitable for a particular allergic disease, including aerosol, oral and topical preparations, and sustained release preparations.

The present invention relates to the treatment of an allergic disease using one or more compounds, which may be represented by the formula (I):

Where

R ¹ represents hydrogen, azido, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, C _2-5 alkenyl, cyano, nitro, R ⁷ R ⁸ N, C _2-8 acyl, R ⁹ OC = O, R ¹⁰ R ¹¹ NC = O or R ¹⁰ R ¹¹ NSO ₂ , or R ¹ taken together with W, as described below;

R ² represents hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, C _2-5 alkenyl, C _1-5 haloalkyl, cyano or R ⁴⁸ R ⁴⁹ N;

alternatively, R ¹ and R ² may be taken together to form an optionally substituted 5-7 membered carbocyclic or heterocyclic ring, said ring may be unsaturated or aromatic;

each R ³ and R ⁴ independently represents hydrogen or C _1-5 alkyl;

each R ⁵ and R ⁶ independently represents hydrogen, C _1-5 alkyl, C _2-5 alkenyl, C _1-5 alkoxy, C _1-5 alkylthio, halogen or 4-7 membered carbocyclyl or heterocyclyl;

alternatively, R ⁵ and R ⁶ may be taken together to form an optionally substituted 5-7 membered carbocyclic or heterocyclic ring, said ring may be unsaturated or aromatic, and may optionally be substituted with one to three substituents independently selected from halogen, cyano, amino, nitro, R ⁴⁰ , R ⁴⁰ O-, R ⁴⁰ S-, R ⁴⁰ O (C _1-5 alkylene) -, R ⁴⁰ O (C = O) -, R ⁴⁰ (C = O) -, R ⁴⁰ (C = S) -, R ⁴⁰ (C = O) O-, R ⁴⁰ O (C = O) (C = O) -, R ⁴⁰ SO ₂ , NHR ⁶² (C = NH) -, NHR ⁶² SO ₂ - and NHR ⁶² (C = O) -;

R ⁴⁰ represents H, C _1-5 alkyl, C _2-5 alkenyl, phenyl, benzyl, phenethyl, C _1-5 heterocyclyl, (C _1-5 heterocyclyl) C _1-5 alkylene, amino or mono or di ( C _1-5 alkyl) amino, or R ⁵⁸ OR ⁵⁹ -, where R ⁵⁸ represents H, C _1-5 alkyl, C _2-5 alkenyl, phenyl, benzyl, phenethyl, C _1-5 heterocyclyl or (C _{1- 5} heterocyclyl) C _1-6 alkylene, and R ⁵⁹ represents C _1-5 alkylene, phenylene or divalent C _1-5 heterocyclyl; and

R ⁶² may be H in addition to the values for R ⁴⁰ ;

R ⁷ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, naphthyl, C _1-5 heterocyclyl, C _2-8 acyl, aroyl, R ²⁷ OC = O, R ²⁸ R ²⁹ NC = O, R ²⁷ SO, R ²⁷ SO ₂ or R ²⁸ R ²⁹ NSO ₂ ;

R ⁸ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl or C _1-5 heterocyclyl;

alternatively, R ⁷ and R ⁸ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

R ⁹ represents C _1-5 alkyl, phenyl, naphthyl or C _1-5 heterocyclyl;

R ²¹ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, naphthyl, C _1-5 heterocyclyl, C _2-8 acyl, aroyl, R ³⁰ OC = O, R ³¹ R ³² NC = O, R ³⁰ SO, R ³⁰ SO ₂ or R ³¹ R ³² NSO ₂ ;

R ²² represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl or C _1-5 heterocyclyl;

alternatively, R ²¹ and R ²² may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

each R ²³ , R ²⁶ , R ²⁷ , R ³⁰ , R ³³ , R ⁴⁴ , R ⁴⁵ and R ⁵⁰ represents C _1-5 alkyl, phenyl, naphthyl or C _1-5 heterocyclyl;

R ²⁴ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, naphthyl, C _1-5 heterocyclyl, C _2-8 acyl, aroyl, R ³³ OC = O, R ³⁴ R ³⁵ NC = O, R ³³ SO, R ³³ SO ₂ or R ³⁴ R ³⁵ NSO ₂ ;

R ²⁵ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl or C _1-5 heterocyclyl;

alternatively, R ²⁴ and R ²⁵ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

each R ¹⁰ and R ¹¹ independently represents hydrogen, C _1-5 alkyl, C _2-5 alkenyl, phenyl or C _1-5 heterocyclyl;

alternatively, R ¹⁰ and R ¹¹ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

each R ²⁸ , R ²⁹ , R ³¹ , R ³² , R ³⁴ , R ³⁵ , R ⁴⁶ , R ⁵¹ and R ⁵² independently represents hydrogen, C _1-5 alkyl, phenyl or C _1-5 heterocyclyl;

alternatively, R ²⁸ and R ²⁹ , R ³¹ and R ³² , R ³⁴ and R ³⁵ , R ⁴⁶ and R ⁴⁷ , or R ⁵¹ and R ⁵² may independently be taken together to form an optionally substituted 4-7 membered heterocyclic ring, as indicated the ring may be saturated, unsaturated or aromatic;

n is 1 or 2;

G represents C _3-6 alkenediyl or C _3-6 alkanediyl optionally substituted with hydroxy, halogen, C _1-5 alkyl, C _1-5 alkoxy, oxo, hydroxyimino, CO ₂ R ⁶⁰ , R ⁶⁰ R ⁶¹ NCO ₂ , ( L) -C _1-4 alkylene, (L) -C _1-5 alkoxy, N ₃ or [(L) -C _1-5 alkylene] amino;

each R ⁶⁰ and R ⁶¹ independently represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, benzyl, phenethyl or C _1-5 heterocyclyl;

alternatively, R ⁶⁰ and R ⁶¹ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

L is amino, mono- or di-C _1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl or piperazinyl, where available ring nitrogen atoms may optionally be substituted with C _1-5 alkyl, benzyl, C _2-5 acyl, C _1-5 alkylsulfonyl or C _1-5 alkoxycarbonyl;

X represents nitrogen or R ¹² C;

Y represents nitrogen or R ¹³ C;

Z represents nitrogen or R ¹⁴ C;

R ¹² represents hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, C _2-5 alkenyl, cyano, nitro, R ²¹ R ²² N, C _2-8 acyl, C _1-5 haloalkyl, C _{1 -5} heterocyclyl, (C _1-5 heterocyclyl) C _1-5 alkylene, R ²³ OC = O, R ²³ O (C = O) NH-, R ²³ SO, R ²² NHCO- ,, R ²² NH (C = O) NH-, R ²³ (C _1-4 alkylene) NHCO-, R ²³ SO ₂ or R ²³ SO ₂ NH-;

R ¹³ represents hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, C _2-5 alkenyl, cyano, nitro, R ⁴² R ⁴³ N, C _2-8 acyl, C _1-5 haloalkyl, C _{1 -5} heterocyclyl, (C _1-5 heterocyclyl) C _1-5 alkylene R ⁴⁴ OC = O, R ⁴⁴ O (C = O) NH-, R ⁴⁴ SO, R ⁴³ NHCO-, R ⁴³ NH (C = O) NH-, R ⁴⁴ (C _1-4 alkylene) NHCO-, R ⁴⁴ SO ₂ or R ⁴⁴ SO ₂ NH-;

R ¹⁴ represents hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, C _2-5 alkenyl, cyano, nitro, R ²⁴ R ²⁵ N, C _2-8 acyl, C _1-5 haloalkyl, C _{1 -5} heterocyclyl, (C _1-5 heterocyclyl) C _1-5 alkylene R ²⁶ OC = O, R ²⁶ O (C = O) NH-, R ²⁶ SO, R ²⁵ NHCO-, R ²⁵ NH (C = O) NH-, R ²⁶ (C _1-4 alkylene) NHCO-, R ²⁶ SO ₂ or R ²⁶ SO ₂ NH-;

alternatively, R ¹² and R ¹³ or R ¹² and R ² , or R ¹³ and R ¹⁴ may be taken together to form an optionally substituted 5-6 membered carbocyclic or heterocyclic ring, said ring may be unsaturated or aromatic;

Ar is a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted with 1-3 substituents selected from halogen, C _1-5 alkoxy, C _1-5 alkyl, C _2-5 alkenyl, cyano, azido, nitro, R ¹⁵ R ¹⁶ N, R ¹⁷ SO ₂ , R ¹⁷ S, R ¹⁷ SO, R ¹⁷ O (C = O), R ¹⁵ R ¹⁶ NC = O, C _1-5 haloalkyl, C _1-5 haloalkoxy, C _1-5 haloalkylthio and C _1-5 alkylthio;

R ¹⁵ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, benzyl, C _1-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁵³ OC = O, R ⁵⁴ R ⁵⁵ NC = O, R ⁵³ S, R ⁵³ SO, R ⁵³ SO ₂ or R ⁵⁴ R ⁵⁵ NSO ₂ ;

R ¹⁶ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, benzyl or C _1-5 heterocyclyl;

alternatively, R ¹⁵ and R ¹⁶ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

each R ¹⁷ and R ⁵³ represents C _1-5 alkyl, phenyl or C _1-5 heterocyclyl;

each R ⁵⁴ and R ⁵⁵ independently represents hydrogen, C _1-5 alkyl, C _2-5 alkenyl, phenyl, benzyl or C _1-5 heterocyclyl;

alternatively, R ⁵⁴ and R ⁵⁵ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

W represents SO ₂ , C = O, CHR ²⁰ or a covalent bond; or W and R ¹ taken together with a 6-membered ring to which both of them are attached form one of the following two formulas:

where X _a represents O, S or N; and X _b represents O, S or SO ₂ ;

R ²⁰ represents hydrogen, C _1-5 alkyl, phenyl, benzyl, naphthyl or C _1-5 heterocyclyl;

R ⁴² represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, naphthyl, C _1-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴⁵ OC = O, R ⁴⁶ R ⁴⁷ NC = O, R ⁴⁵ SO, R ⁴⁵ SO ₂ or R ⁴⁶ R ⁴⁷ NSO ₂ ;

R ⁴³ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl or C _1-5 heterocyclyl;

alternatively, R ⁴² and R ⁴³ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

R ⁴⁴ represents C _1-5 alkyl, C _2-5 alkenyl, phenyl, naphthyl or C _1-5 heterocyclyl;

R ⁴⁸ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, naphthyl, C _1-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁵⁰ OC = O, R ⁵¹ R ⁵² NC = O, R ⁵⁰ SO, R ⁵⁰ SO ₂ or R ⁵¹ R ⁵² NSO ₂ ;

R ⁴⁹ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl or C _1-5 heterocyclyl;

alternatively, R ⁴⁸ and R ⁴⁹ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic; and

where each of the above hydrocarbon or heterocarbon groups, unless otherwise indicated, and, in addition to any specific substituents, is optionally and independently substituted by 1-3 substituents selected from methyl, halogenmethyl, hydroxymethyl, halogen, hydroxy, amino, nitro, cyano, C _1-5 alkyl, C _1-5 alkoxy, -COOH, C _2-6 acyl, [di (C _1-4 alkyl) amino] C _2-5 alkylene, [di (C _1-4 alkyl) amino] C _2-5 alkyl-NH-CO- and C _1-5 haloalkoxy;

or a pharmaceutically acceptable salt, amide or ester thereof, including their stereoisomeric form.

The compounds described are inhibitors of the proteolytic activity of human cathepsin S with high binding affinity. For use in medicine, it may be desirable to obtain pharmaceutically acceptable salts of the compounds of formula (I).

Some compounds of the present invention may have one stereogenic atom and may exist as two enantiomers. Some compounds of the present invention may have two or more stereogenic atoms and, optionally, may exist as diastereomers. Specialists in this field should understand that all such stereoisomers and mixtures thereof in any ratio are included in the scope of the present invention.

Another aspect of the present invention relates to pharmaceutical antiallergic compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. An additional embodiment of the invention is a method for preparing an anti-allergic pharmaceutical composition, comprising admixing said compound described above with a suitable pharmaceutically acceptable carrier.

The invention also contemplates pharmaceutical compositions comprising more than one compound of formula (I) and compositions comprising a compound of formula (I) and another pharmaceutically active agent.

Another object of the invention is a method of treating an allergic disease or disease condition mediated by the cathepsin S enzyme in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. When more than one active agent is administered, the therapeutically effective amount may be a joint effective amount. The compounds described herein inhibit the protease activity of human cathepsin S, an enzyme involved in the immune response. In preferred embodiments, the inhibition of cathepsin S is selective. As such, the described compounds and compositions can be used to prevent, inhibit or treat allergic diseases, in particular atopic allergic diseases.

Additional features and advantages of the invention will be apparent from the following detailed description and examples and the appended claims.

Brief Description of the Drawings

Figure 1 shows the inhibition of the proliferative responses of human T cells to two types of dust mites, Der p and Der f. Upper diagram, FIG. 1A: Dilution curve for purified PBMC from an allergic donor when cultured with titrated doses of allergenic extracts prepared from Der p and Der f for seven days. T-cell proliferation was scored by measuring ³ H-thymidine incorporation for 18 hours at the end of cultivation. Bottom diagram, FIG. 1B: Effect of titrated doses of LHVS on the proliferative responses of T cells to dust mite extracts.

Figure 2 shows the inhibition of the proliferative responses of human T cells to ragweed, but not ConA, using LHVS. Upper diagram, FIG. 2A: Dilution curve for purified PBMC from an allergic donor when cultured with titrated doses of allergenic extracts prepared from Short Ambrosia and Giant Ambrosia for seven days. T-cell proliferation was scored by measuring ³ H-thymidine incorporation for 18 hours at the end of cultivation. Bottom diagram, FIG. 2B: Effect of titrated doses of LHVS on the proliferative responses of T cells to ragweed extracts.

Figure 3 shows the inhibition of the proliferative responses of human T cells to Der f, but not Con A, two cathepsin S inhibitors, the compounds of Example 11 (Figure 3A) and Example 36 (Figure 3B). Purified PBMC from an allergic donor was cultured with allergen extracts prepared from Der f in the presence of titrated doses of these compounds for seven days. T-cell proliferation was scored by measuring ³ H-thymidine incorporation for 18 hours at the end of cultivation.

DETAILED DESCRIPTION OF THE INVENTION

The purpose of the present invention was to determine whether inhibition of cathepsin S affects the presence of certain antigens in the human system. According to the invention, it has now been found that cathepsin S inhibitors block the presence of several crude allergenic extracts in humans in an ex vivo assay, thus confirming the usefulness of cathepsin S inhibitors for the treatment of such allergic diseases.

Blocking Ii decomposition should reduce the presence of antigen in CD4 T cells and interrupt the normal immune response. The cathepsin S inhibitor should specifically affect the activation of CD4 T cells, thus limiting the degree of concomitant immunosuppression, undesirable side effects of corticosteroid therapy.

When using cathepsin S inhibitors in accordance with the methods of the present invention, the immunological component of the allergic reaction can be blocked to varying degrees, having an advantage compared to modern therapy, which consists in greater selectivity, the presence of minor or reduced side effects, or both. The present invention is based in part on the discovery that cathepsin S inhibitors can block the presence of crude allergen extracts in humans in an ex vivo assay. Such an ex vivo system closely mimics the process that occurs throughout the body when antigens enter the circulatory system and are represented by antigen-presenting cells, which in turn activate CD4 T cells. In the case of treatment of a subject, the inhibitor or its metabolite will also be present in the blood, as in the ex vivo assay.

The object of the invention is the treatment of an allergic disease using the compounds of pyrazole of the formula (I).

A. Terms

The following terms used in the description are defined below.

“Alkyl” includes optionally substituted linear or branched hydrocarbons having at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl and the like. Alkyl includes cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“Alkenyl” includes optionally substituted linear and branched hydrocarbon radicals, as described above, having at least one carbon-carbon double bond (sp ² ). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa- 2,4-dienyl and the like. Hydrocarbon radicals having a combination of double bonds and triple bonds, such as 2-penten-4-ynyl, are included herein in the definition of alkynyls. Alkenyl includes cycloalkenyl. Cis and trans or (E) and (Z) forms are included in this invention.

“Alkynyl” includes optionally substituted linear and branched hydrocarbon radicals, as described above, having at least one carbon-carbon triple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a combination of double bonds and triple bonds, such as 2-penten-4-ynyl, are included herein in the definition of alkynyls. Alkynyl does not include cycloalkynyl.

“Alkoxy” includes an optionally substituted linear or branched alkyl group with a terminal oxygen linking the alkyl group to the remainder of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy and the like. “Aminoalkyl”, “thioalkyl” and sulfonylalkyl are similar to the alkoxy group, with the terminal oxygen atom in the alkoxy being replaced by NH (or NR), S and SO _2, respectively. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl and the like.

“Aryl” includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl and the like, each of which may optionally be substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl and phenylpropyl. Aryl includes a ring system containing an optionally substituted 6-membered carbocyclic aromatic ring, this system may be bicyclic, bridged and / or condensed. The system may include rings that are aromatic or partially or fully saturated. Examples of ring systems include indenyl, pentalenyl, 1,4-dihydronaphthyl, indanyl, benzimidazolyl, benzothiophenyl, indolyl, benzofuranyl, isoquinolinyl and the like.

“Heterocyclyl” includes optionally substituted aromatic and non-aromatic rings having carbon atoms and at least one heteroatom (O, S, N) or a heteroatom fragment (SO ₂ , CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valency linking it to the remainder of the molecule through a carbon atom, for example 3-furyl or 2-imidazolyl, or through a heteroatom, for example, N-piperidyl or 1-pyrazolyl. Preferably, the monocyclic heterocyclyl contains from 4 to 7 ring atoms or from 5 to 6 ring atoms; the ring may contain from 1 to 5 heteroatoms or heteroatom fragments, and preferably from 1 to 3. The heterocyclyl may be saturated, unsaturated, aromatic (eg, heteroaryl), non-aromatic, or fused.

Heterocyclyl also includes fused, for example bicyclic, rings, such as optionally fused with an optionally substituted carbocyclic or heterocyclic five- or six-membered aromatic ring. For example, “heteroaryl” includes an optionally substituted six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms fused to an optionally substituted five- or six-membered carbocyclic or heterocyclic aromatic ring. The specified heterocyclic five- or six-membered aromatic ring fused to the specified five- or six-membered aromatic ring may contain 1, 2 or 3 nitrogen atoms when it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, when it is a five membered ring.

Examples of heterocyclyls include thiazolyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolisinyldinyl, pyridinyl, pyridinyl, pyridinyl, , pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl and morpholinyl. For example, preferred heterocyclyl or heterocyclic radicals include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino and, more preferably, piperidyl.

Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.

“Acyl” refers to a carbonyl moiety bonded either to a hydrogen atom (ie, a formyl group) or to an optionally substituted alkyl or alkenyl chain, or heterocyclyl.

“Halo” or “halogen” includes fluoro, chloro, bromo and iodo, and chloro or bromo are preferred as a substituent.

“Alkanediyl” or “alkylene” is a linear or branched optionally substituted divalent alkane radical such as, for example, methylene, ethylene, propylene, butylene, pentylene or hexylene.

"Alkendiyl" is, as described above, a linear or branched optionally substituted divalent alkene radical, such as, for example, propenylene, butenylene, pentenylene or hexenylene. In such radicals, the nitrogen-bonding carbon atom should preferably not be unsaturated.

“Aroyl” refers to a carbonyl group bonded to an optionally substituted aryl or heteroaryl group, wherein aryl or heteroaryl are as defined above. In particular, benzoyl is phenylcarbonyl.

As defined herein, two radicals together with the atom (s) to which they are attached can form an optionally substituted 4-7-, 5-7- or 5-6-membered carbocyclic or heterocyclic ring, said ring may be saturated, unsaturated or aromatic. These rings may be as defined above in the Summary of the Invention. Specific examples of such rings are as indicated in the next section.

“Pharmaceutically acceptable salts, esters and amides” include carboxylate salts (eg, C _1-8 alkyl, cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclic), amino acid addition salts, esters and amides that have a suitable benefit / risk ratio, are pharmacologically effective and suitable for contact with patient tissues without excessive toxicity, irritation or allergic response. Examples of salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, , glucoheptonate, lactiobionate and lauryl sulfonate. These may include alkali metal and alkaline earth metal cations, such as sodium, potassium, calcium and magnesium, as well as non-toxic cations of ammonium, quaternary ammonium and amine, such as tetramethylammonium, methylamine, trimethylamine and ethylamine. See, for example, SMBerge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, incorporated herein by reference. Examples of pharmaceutically acceptable amides of the invention include amides that are derived from ammonia, primary C _1-6 alkyl amines and secondary di (C _1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring groups containing at least one nitrogen atom and optionally 1 to 2 additional heteroatoms. Preferred amides are derived from ammonia, C _1-3 alkyl primary amines or di (C _1-2 alkyl) amines. Examples of pharmaceutically acceptable esters of the invention include C _1-7 alkyl, C _5-7 cycloalkyl, phenyl and phenyl (C _1-6 ) alkyl esters. Preferred esters include methyl esters.

A “patient” or “subject” includes mammals, such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) that need to be observed, experimented, treated or prevented in connection with a suitable disease or painful condition. Preferably, the patient or subject is a human.

"Composition" includes a product containing certain ingredients in certain quantities, as well as any product that is obtained directly or indirectly by combining certain ingredients in certain quantities.

“Therapeutically effective amount” or “effective amount” means that amount of the active compound or pharmaceutical agent that elicits a biological or medical response in the tissue system, in the animal or human, required by the researcher, veterinarian, doctor or other clinician, which includes relief symptoms of a disease or disorder being treated.

Concerning the various radicals in this specification and claims, three general points should be made. The first remark concerns valency. For all hydrocarbon radicals, whether they are saturated, unsaturated or aromatic, and whether they are cyclic, linear or branched, and likewise with respect to all heterocyclic radicals, each radical includes substituted radicals of this type and monovalent, divalent and polyvalent radicals, as indicated in the claims. The context will indicate that the substituent is an alkylene or hydrocarbon radical in which at least two hydrogen atoms (divalent) are removed or a larger number of hydrogen atoms (polyvalent) are removed. An example of a divalent radical linking two parts of a molecule is G in formula (I), which binds two rings.

Secondly, it should be understood that radicals or structural fragments, as defined herein, include substituted radicals or structural fragments. Hydrocarbons include monovalent radicals containing carbon and hydrogen, such as alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl (either aromatic or unsaturated), as well as the corresponding divalent radicals, such as alkylene, alkenylene, phenylene and the like. Heterocarbons include monovalent and divalent radicals containing carbon, hydrogen and at least one heteroatom. Examples of monovalent heterocarbons include acyl, acyloxy, alkoxy acyl, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl and the like. Using "alkyl" as an example, it should be understood that "alkyl" includes substituted alkyl having one or more substituents, such as, for example, from 1 to 5, from 1 to 3, from 2 to 4 substituents. Substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro) or different (chlorobenzyl or aminomethyl substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, perfluoromethyl and 3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2-aminomethyl, 2-aminomethyl, 2-aminomethyl, 2-hydromethyl 3-aminopropyl and 2-aminopropyl), nitroalkyl, alkylalkyl and the like. The di (C _1-6 alkyl) amino group includes independently selected alkyl groups to form, for example, methylpropylamino and isopropylmethylamino, in addition to dialkylamino groups having two identical alkyl groups, such as dimethylamino or diethylamino.

Third, only stable compounds are meant. For example, when there is an NR'R "group, and R may be an alkenyl group, the double bond is removed at least one carbon from the nitrogen atom to prevent the formation of enamine. Similarly, when the dashed line is an optional sp ² bond, if it is absent, then the corresponding hydrogen atom (s) is included.

Preferred substituents for Ar include methyl, methoxy, fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl), 1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoro, chloro and bromo, and especially methyl, bromo, chloro, perfluoromethyl, perfluoromethoxy, methoxy and fluoro. Preferred examples of substituted Ar or Ar ₁ are 4-substituted and 3,4-disubstituted phenyl. The compounds of the invention are further described in the following section.

B. Compounds

The object of the invention is the use of compounds of formula (I), as described above in the section "Summary of the invention" for the treatment of allergic diseases.

Preferred compounds include those in which:

(a) R ¹ represents hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, R ⁷ R ⁸ N, C _2-8 acyl or R ¹⁰ R ¹¹ NSO ₂ ;

(b) R ¹ represents halogen, cyano, nitro, R ⁷ R ⁸ N or R ¹⁰ R ¹¹ NSO ₂ ;

(c) R ² represents hydrogen;

(d) each R ³ and R ⁴ independently represents hydrogen or C _1-3 alkyl;

(e) one R ³ and R ⁴ represents hydrogen;

(f) each R ³ and R ⁴ represents hydrogen;

(g) one of R ⁵ and R ⁶ is hydrogen and the other is 5-7 membered carbocyclyl or heterocyclyl optionally substituted;

(h) R ⁵ and R ⁶ taken together form a six-membered heterocyclyl;

(i) R ⁵ and R ⁶ taken together form pyridinyl, pyrimidinyl or piperazinyl optionally N-substituted with R ⁴⁰ O (C = O) (C = O) -, R ⁴⁰ SO ₂ , R ⁴⁰ NHCO ₂ , R ⁴⁰ (C = O) - or R ⁴⁰ N (C = O) -;

(j) each R ⁷ , R ⁸ , R ²¹ , R ²² , R ²⁴ , R ²⁵ independently represents hydrogen or C _1-5 alkyl; or, independently, each of R ⁷ and R ⁸ , R ²¹ and R ²² and R ²⁴ and R ²⁵ can be taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

(k) at least one of R ⁷ and R ⁸ , R ²¹ and R ²² and R ²⁴ and R ²⁵ taken together is morpholinyl, piperidinyl or pyrrolidinyl;

(l) each R ⁹ , R ²³ , R ^26, and R ²⁷ each independently represents hydrogen or C _1-5 alkyl;

(m) G is C _3-4 alkanediyl optionally substituted with hydroxy, (L) -C _1-5 alkyloxy or [(L) -C _1-5 alkylene] amino;

(n) G is C ₃ alkanediyl optionally substituted with hydroxy, (L) -C _1-5 alkyloxy or [(L) -C _1-5 alkylene] amino;

(o) X is nitrogen;

(p) Y represents CR ¹³ ;

(q) Z is CR ¹⁴ ;

(r) X represents CH;

(s) R ¹² represents hydrogen, R ²² O (C = O) NH—, R ²² NH (C = O) NH—, R ²² SO ₂ NH—; R ²³ SO or R ²³ SO ₂ , and R ¹³ represents hydrogen, R ⁴³ O (C = O) NH-, R ⁴³ NH (C = O) NH-, R ⁴³ SO ₂ NH-, R ⁴⁴ SO or R ⁴⁴ SO ₂ ;

(t) R ¹⁴ represents hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro, R ²⁵ O (C = O) NH-, R ²⁵ NH (C = O) NH-, R ²⁵ SO ₂ NH— or R ²⁴ R ²⁵ N;

(u) R ¹⁴ is halogen, R ²⁵ O (C = O) NH—, R ²⁵ NH (C = O) NH—, R ²⁵ SO ₂ NH— or R ²⁴ R ²⁵ N; Ar is a monocyclic ring optionally substituted with 1-2 substituents independently selected from halogen, C _1-5 alkyl, cyano, nitro R ¹⁵ R ¹⁶ N, CF ₃ and OCF ₃ ;

(v) Ar is a six-membered ring substituted with 1-2 substituents independently selected from halogen, CF ₃ and OCF ₃ , said substituent or substituents are in the 4-position or in the 3- and 4-positions, respectively;

(w) W represents SO ₂ , C = O or CHR ²⁰ ;

(x) W is a covalent bond;

(y) W and R ¹ taken together have the formula (I) (a);

(z) W and R ¹ taken together have the formula (I) (b);

(aa) one of R ³ and R ⁴ represents hydrogen; Ar is a monocyclic ring optionally substituted with 1-2 substituents independently selected from halogen, C _1-5 alkyl, cyano, nitro R ¹⁵ R ¹⁶ N, CF ₃ and OCF ₃ ; R ¹² represents hydrogen, R ²³ SO or R ²³ SO ₂ ; R ¹³ represents hydrogen, R ⁴⁴ SO or R ⁴⁴ SO ₂ ; R ¹⁴ represents hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro or R ²⁴ R ²⁵ N; and G is C _3-4 alkanediyl optionally substituted with hydroxy, C _1-3 alkyl, (L) -C _1-5 alkyloxy or [(L) -C _1-5 alkylene] amino;

(bb) each R ³ and R ⁴ represents hydrogen; Ar represents a six-membered ring, optionally substituted with 1-2 substituents independently selected from halogen, C _1-5 alkyl, cyano, nitro, R ¹⁵ R ¹⁶ N, CF ₃ and OCF ₃ ; R ¹² represents hydrogen, R ²³ SO or R ²³ SO ₂ ; R ¹³ represents hydrogen, R ⁴⁴ SO or R ⁴⁴ SO ₂ ; R ¹⁴ represents hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro or R ²⁴ R ²⁵ N; and G is C ₃ alkanediyl optionally substituted with hydroxy, (L) -C _1-5 alkyloxy or [(L) -C _1-5 alkylamino;

(cc) Ar is phenyl;

(dd) a combination of the above values.

Particularly preferred compounds include those exemplified herein, such as

1- [4- (2-amino-6-chlorophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3- c] pyridin-1-yl] propan-2-ol; 1- [3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] -3-methylurea; 1- [3-chloro-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine- 1-yl] propyl} piperazin-1-yl) phenyl] -3-methylurea; 3-amino-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 methyl ester -yl] propyl} piperazin-1-yl) benzoic acid; 3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazine -1-yl) phenylamine; 1- [2- (4- {3- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl } piperazin-1-yl) -3-chlorophenyl] -3-methylurea; amide 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c ] pyridine-5-carboxylic acid; [3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] methyl ester] propyl} piperazin-1-yl) phenyl] carbamic acid; amide 1- [3- (4-benzo [d] isothiazol-3-yl-piperazin-1-yl) propyl] -3- (4-bromophenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridine-5-carboxylic acid; 2- (4- {3- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl methyl ester] piperazin-1-yl) -3-nitrobenzoic acid; 1- [4- (2-chloro-6-nitrophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3- c] pyridin-1-yl] propan-2-ol; 2- (4- {2-hydroxy-3- [3- (4-iodophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazine -1-yl) benzonitrile; 3- (4-bromophenyl) -1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl amide} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5 β-carboxylic acid; 2- (4- {3- [5-acetyl-3- (4-iodophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperazin- 1-yl) benzonitrile; 2- (4- {3- [3- (4-chloro-3-methylphenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2- hydroxypropyl} piperazin-1-yl) benzonitrile; 1- (3- (4-chloro-3-methylphenyl) -1- {3- [4- (2,4-dimethylphenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7- tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone; 1- {3- [4- (3,5-dichloropyridin-4-yl) piperazin-1-yl] propyl} -5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro 1H-pyrazolo [4,3-c] pyridine; 2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo- [4,3-c] pyridin-1-yl] propyl} piperazin-1- sludge) benzonitrile; N- [3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] methanesulfonamide; 3- (3,4-dichlorophenyl) -1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl amide} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine amide -5-carboxylic acid; and amide 3- (4-chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo [4 , 3-c] pyridine-5-carboxylic acid.

In addition, preferred compounds include those in which Ar is selected from 4-trifluoromethylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-chloro-3-methylphenyl and 3,4-dichlorophenyl.

More preferred compounds include those described in Examples 19, 27 and 33.

Related Compounds

The invention relates to the described compounds and closely related pharmaceutically acceptable forms of the described compounds, such as their salts, esters, amides, acids, hydrated or solvated forms; latent or protected forms and racemic mixtures or enantiomerically or optically pure forms. Related compounds also include compounds of the invention that have been modified to detect, for example, labeled with the ¹⁸ F isotope for use as a probe in positron emission tomography (PET) or single photon emission computed tomography (SPECT).

The invention also includes the described compounds having one or more functional groups (e.g., hydroxyl, amino or carboxyl) hidden by protecting groups. See, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd ed., (1999), John Wiley & Sons, NY . Some of these latent or protected compounds are pharmaceutically acceptable; others are useful as intermediates. The synthetic intermediates and methods disclosed herein and their minor modifications are also included in the scope of the invention.

Hydroxy protecting groups

Protection of the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, and silyl ethers.

Substituted methyl ethers

Examples of substituted methyl ethers include methyloxymethyl, methylthiomethyl, tert-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guiacolmethyl, tert-butoxymethylene 2-methoxymethyl 2-methoxymethyl 2-methoxymethylene 2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl , 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, S, S-dioxide 4-methoxytetrahydrothiopyranyl, 1 - [(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Esters

Examples of substituted ethyl ethers include 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2.2 , 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.

Substituted benzyl ethers

Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halogenbenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, N 3-methyl-2-picolyl oxide, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyl diphenylmethyl, p-methoxyphenyl diphenylmethyl, di (p-methoxyphenyl) phenylmethyl, 4 (p) methyl - (4'-bromophenacyloxy) phenyl diphenylmethyl, 4.4'4 '' - tris (4,5-dichlorophthal imidophenyl) methyl, 4.4 ', 4' '- tris (levulinoyloxyphenyl) methyl, 4.4'4' '- tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4.4' '- dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-pyrenylmethyl, 9-anthril, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthril, 1,3- benzodithiolan-2-yl and S, S-dioxide-benzisothiazolyl.

Silyl ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimetilizopropilsililovy, dietilizopropilsililovy, dimetilgeksilsililovy, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzilsililovy, tri-n-ksililsililovy, trifenilsililovy, and tert-difenilmetilsililovy butilmetoksifenilsililovy.

Esters

In addition to ethers, the hydroxyl group may be protected as an ester. Examples of esters include formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-levopentanoate ethylene dithio) pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenyl benzoate, 2,4,6-trimethyl benzoate (mesitoate).

Carbonates

Examples of carbonate protecting groups include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p -nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl and methyldithiocarbonate.

Auxiliary cleavage groups

Examples of auxiliary cleavage groups include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxy) butyrate and 2- (methylthiomethoxymeth )benzoate.

Mixed esters

Examples of mixed esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenyl acetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenoate (tigloate), o- (methoxycarbonyl) benzoate, p-P-benzoate, α-naphthoate, nitrate, alkyl N, N, N ', N' Tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl and 2,4-dinitrophenyl sulfenate.

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate (mesylate), benzyl sulfonate and tosylate.

Protecting groups for amino

Protecting groups for an amino group include carbamates, amides, and special —NH protecting groups.

Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, auxiliary cleavage carbamates, protolytic cleavage carbamates, urea derivatives and mixed carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 9- (2,7-dibromo) fluorenylmethyl, 2,7-di-tert-butyl- [9- (10, 10-dioxo-10,10,10,10,10-tetrahydrothioxanthyl)] methyl and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2, 2-dibromethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-di-tert-butylphenyl) -1-methylethyl, 2 - (2'- and 4'-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, tert-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Auxiliary cleavage groups

Examples of auxiliary cleavage groups include 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2 -triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxyboryl) benzyl, 5-benzisoxazolylmethyl and 2- (trifluoromethyl) -6-chromonylmethyl.

Protolytic cleavage groups

Examples of protolytic cleavage groups include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl and phenyl (o-nitrophenyl) methyl.

Urea-type derivatives

Examples of derivatives of the urea type include phenothiazinyl- (10) -carbonyl derivative, N'-p-toluenesulfonylaminocarbonyl and N'-phenylaminothiocarbonyl.

Mixed carbamates

Examples of mixed carbamates include tert-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) -dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1,1-dimethylpropinyl, di (2-pyridyl) methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p- (p'-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-phenylazophenyl) ethyl, 1-methyl- one -phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri-tert-butylphenyl, 4- (trimethylammonium) benzyl and 2,4,6- trimethylbenzyl.

Examples of amides include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanine derivative, N-benzoyl, N p-phenylbenzoyl.

Auxiliary cleavage groups

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl, N-3- (o-nitrophenyl) propionyl, N-2- methyl-2- (o-nitrophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N- acetylmethionine derivative, N-o-nitrobenzoyl, N-o- (benzoyloxymethyl) benzoyl and 4,5-diphenyl-3-oxazolin-2-one.

Cyclic imide derivatives

N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3, 5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one and 1-substituted 3,5-dinitro-4-pyridonyl.

Special NH protecting groups

Examples of specific NH protecting groups include

N-alkyl and N-aryl amines,

N-methyl, N-allyl, N- [2- (trimethylsilyl) ethoxy] methyl, N-3-acetoxypropyl, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di (4-methoxyphenyl) methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro -9-fluorenylmethylene, N-ferrocenylmethyl and N-2-picolylamine N'-oxide.

Imine derivatives

N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N - [(2-pyridyl) mesityl] methylene and N- (N ', N'-dimethylaminomethylene).

Carbonyl protection

Acyclic acetals and ketals

Examples of acyclic acetals and ketals include dimethyl, bis (2,2,2-trichloroethyl), dibenzyl, bis (2-nitrobenzyl) and diacetyl.

Cyclic acetals and ketals

Examples of cyclic acetals and ketals include 1,3-dioxanes, 5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5- (2-pyridyl) -1,3-dioxane, 1, 3-dioxolanes, 4-bromomethyl-1,3-dioxolane, 4- (3-butenyl) -1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4- (2-nitrophenyl) -1,3- dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane, O, O'-phenylenedioxy and 1,5-dihydro-3H-2,4-benzo-dioxepine.

Acyclic dithioacetals and ketals

Examples of acyclic dithioacetals and ketals include S, S'-dimethyl, S, S'-diethyl, S, S'-dipropyl, S, S'-dibutyl, S, S'-dipentyl, S, S'-diphenyl, S, S'-dibenzyl; and S, S'-diacetyl.

Cyclic dithioacetals and ketals

Examples of cyclic dithioacetals and ketals include 1,3-dithian, 1,3-dithiolan and 1,5-dihydro-3H-2,4-benzodithiepin

Acyclic monothioacetals and ketals

Examples of acyclic monothioacetals and ketals include O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl and O-methyl-S-2- (methylthio) ethyl.

Cyclic monothioacetals and ketals

Examples of cyclic monothioacetals and ketals include 1,3-oxathiolanes.

Mixed derivatives

O-substituted cyanohydrins

Examples of O-substituted cyanohydrins include O-acetyl, O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

Substituted Hydrazones

Examples of substituted hydrazones include N, N-dimethyl and 2,4-dinitrophenyl.

Oxime derivatives

Examples of oxime derivatives include O-methyl, O-benzyl and O-phenylthiomethyl.

Imines

Substituted methylene derivatives, cyclic derivatives.

Examples of substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2- (1'-hydroxyalkyl) imidazoles, N, N'-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles, diethylamine adducts and a bis complex (2, 6-di-tert-butyl-4-methoxyphenoxide) methylaluminum (MAD).

Protection for carboxyl group

Esters

Substituted methyl esters

Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethylmethylmethyl phenylmethyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl phenyl methyl ether.

2-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2- (trimethylsilyl) ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2- (p- nitrophenylsulphenyl) ethyl, 2- (p-toluenesulfonyl) ethyl, 2- (2'-pyridyl) ethyl, 2- (diphenylphosphino) ethyl, 1-methyl-1-phenylethyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, 3- butene-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl, p- (methyl mercapto) phenyl and benzyl.

Substituted benzyl esters

Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2- (9,10-dioxo) anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2- (trifluoromethyl) -6-chromylmethyl , 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4- (methylsulfinyl) benzyl, 4-sulfobenzyl, piperonyl, 4-picolyl and R-benzyl.

Silyl esters

Examples of silyl esters include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, iso-propyldimethylsilyl, phenyldimethylsilyl and di-tert-butylmethylsilyl.

Activated esters

Examples of activated esters include thiols.

Mixed derivatives

Examples of mixed derivatives include oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl pentaminocobalt (III) group and complex.

Stannyl esters

Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.

Amides and hydrazides

Amides

Examples of amides include N, N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydropentanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-nitro-1,2,3,4-tetrahydroquinolyl and p-P-benzenesulfonamides .

Hydrazides

Examples of hydrazides include N-phenyl and N, N'-diisopropyl hydrazides.

C. Synthesis

Compounds of the present invention can be obtained using conventional synthetic organic chemistry and using matrix or combinatorial methods in accordance with the following schemes 1-11 and the illustrations described in detail in examples 1-24. A person of ordinary skill in the art will be able to modify and adapt the procedures described herein to obtain the described compounds.

D. Formulation and administration

The present compounds inhibit the proteolytic activity of human cathepsin S and are therefore useful as a medicine, especially in methods for treating patients suffering from allergic diseases or conditions that are modulated or regulated by inhibition of cathepsin S activity.

An object of the invention is a method of treating a subject with an allergic disease mediated by cathepsin S, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The invention also relates to a method for inhibiting cathepsin S activity in a subject, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.

Considering the inhibitory effect on the proteolytic activity of human cathepsin S, the compounds of the present invention can be formulated in various pharmaceutical forms for administration purposes. To obtain such pharmaceutical compositions, an effective amount of a particular compound in the form of a base or an acid addition salt as an active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier.

The carrier may have a wide range of forms depending on the form of the preparation desired for administration. Such pharmaceutical compositions are preferred in unit dosage form, preferably suitable for oral administration or parenteral injection. For example, in preparing the compositions in the form of an oral dosage form, any of the usual pharmaceutical media may be used. These include water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Given the ease of administration, tablets and capsules are the preferred oral dosage unit form, in which case solid pharmaceutical carriers are usually employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients, for example, solubility promoting ones, may be included. For example, injectable solutions can be prepared in which the carrier comprises saline solution, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for subcutaneous administration, the carrier optionally comprises a permeation enhancing agent and / or a suitable wetting agent, optionally in combination with suitable additives of any nature in small amounts, and these additives do not cause a significant harmful effect on the skin. Such additives may facilitate administration to the skin and / or may be useful in preparing the desired compositions. Such compositions can be administered in various ways, for example, in the form of a transdermal patch, by applying a stain, in the form of an ointment. Acid addition salts of the compounds of formula I, due to their increased solubility in water compared to the corresponding base form, are more suitable for the preparation of aqueous compositions.

It is particularly preferable to formulate the above pharmaceutical compositions in the form of a unit dosage form for ease of administration and uniformity of dosage. A unit dosage form, as used herein, refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active ingredient calculated to provide the desired therapeutic effect, together with the desired pharmaceutical carrier. Examples of such unit dosage forms are tablets (including notched or coated tablets), capsules, pills, sachets, cachets, injectable solutions or suspensions, teaspoons, tablespoons and the like and their separate components.

Pharmaceutically acceptable acid addition salts include therapeutically active non-toxic acid addition salt forms that the described compounds are capable of forming. The latter can usually be obtained by treating the base form with a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric, nitric, phosphoric and the like; or organic acids, e.g. aminosalicylic, palm and the like. The term “addition salt” also includes solvates that the described compounds, as well as their salts, are capable of forming. Such solvates, for example, are hydrates, alcoholates, and the like. Conversely, the salt form can be converted by treatment with alkali in the form of a free base.

The stereoisomeric forms include all possible isomeric forms that the compounds of formula (I) may have. Unless otherwise noted or indicated, the chemical designation of the compounds means a mixture of all possible stereochemically isomeric forms, these mixtures include all diastereomers and enantiomers of the basic molecular structure. More specifically, stereogenic centers may have an (R) or (S) configuration; substituents on divalent cyclic saturated radicals may have either a cis or trans configuration. The invention includes stereochemically isomeric forms of the described compounds, including diastereoisomers, as well as mixtures thereof in any ratio. The compounds described may also exist in the form of tautomeric forms. It is implied that although such forms are not clearly indicated in the above and the following formulas, they are included in the scope of the present invention.

Specialists in the treatment of diseases or conditions mediated by the cathepsin S enzyme will easily determine the effective daily amount from the following test results and other information. It is generally contemplated that a therapeutically effective dose would be from 0.001 mg / kg to 5 mg / kg body weight, more preferably from 0.01 mg / kg to 0.5 mg / kg body weight. It may be appropriate to administer a therapeutically effective dose in two, three, four or more sub-doses at suitable intervals throughout the day. Said sub-doses can be prepared in unit dosage form, for example, containing from 0.05 mg to 250 mg, and in particular from 0.5 to 50 mg of active ingredient per unit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg and 35 mg dosage forms. The compounds of the invention can also be prepared as sustained release formulations or subcutaneous formulations or transdermal patches. The compounds described can also be formulated as a spray or other formulations for inhalation or topical administration.

The exact dose and frequency of administration depends on the particular compound of formula (I) used, the particular disease being treated, the severity of the disease being treated, the age, weight and general physical condition of the particular patient, as well as other drugs that the patient can take, such as well known to specialists in this field. In addition, it is obvious that the indicated effective daily amount can be reduced or increased depending on the response of the patient being treated, and / or depending on the assessment of the attending physician prescribing the compounds of the present invention. The ranges of effective daily amount noted in this description are, therefore, given only as an indication.

The following section includes detailed information related to the preparation, characterization and use of the described compounds.

E. Examples

EXAMPLE 1

1- (3- (4-Chlorophenyl) -1- {3- [4- (2-fluorophenyl) piperazin-1-yl] propyl} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine -5-yl) ethanone

A. 1- [3- (4-Chlorophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

To a stirred solution of 50 g (0.35 mol) of N-acetyl-4-piperidone and 31 g (0.35 mol) of morpholine in benzene (350 ml) was added a catalytic amount (~ 0.25 g) of p-toluenesulfonic acid. The mixture was refluxed for 10 hours with a Dean-Stark trap. The solvent was removed under reduced pressure to obtain a brown oil. The crude product was diluted with CH ₂ Cl ₂ (175 ml) and 50.0 ml (0.35 mol) Et ₃ N was added. The mixture was cooled to 0 ° C and a solution of 45.0 ml (0) was slowly added over 1 hour through a dropping funnel. , 35 mol) 4-chlorobenzoyl chloride in CH ₂ Cl ₂ (50 ml). The mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then diluted with 1N. HCl (150 ml) and stirred vigorously for 3 hours. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 250 ml) and the combined extracts were dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude oil was diluted with EtOH (350 ml) and cooled to 0 ° C. To this stirred solution, 33.0 ml (1.06 mol) of hydrazine was slowly added and the mixture was allowed to warm to room temperature and stirred overnight, during which time a white precipitate formed. The volume of the reaction mixture was reduced to ~ 150 ml and EtOAc (750 ml) was added to the mixture. The suspension was vigorously stirred for 2 hours and filtered, then washed with EtOAc (2 × 200 ml) and dried in vacuo to give 41.4 g (42% in 3 steps) of a pale yellow solid. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.3. Mass spectrum (electrospray), m / z calculated for C ₁₄ H ₁₄ ClN ₃ O [M + H] ⁺ 276.08, found 276.0, ¹ H NMR (400 MHz, CDCl ₃ , mixture of amide rotamers): 7 65 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 9.3 Hz, 2H), 7.58 (d; J = 10.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 4.94 (s, 2H), 4.78 (s, 2H), 4.08 (t, J = 5.9 Hz, 2H), 3.90 (t, J = 5.8 Hz, 2H), 3.02 (t, J = 5.8 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.36 (s , 3H); 2.31 (s, 3H).

B. 1- [3- (4-Chlorophenyl) -1- (3-chloropropyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

Cs ₂ CO ₃ (2.66 g, 8.2 mmol) was added to a solution of 1- [3- (4-chloro-phenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5 -yl] ethanone (1.0 g, 5.4 mmol) in DMF (10 ml) and stirred for 15 minutes. 1-Bromo-3-chloropropane (1.28 g, 8.2 mmol) was added and stirred under N ₂ at room temperature for 36 hours. Water (50 ml) was added to the reaction mixture and stirred for 5 minutes. The product precipitated. The aqueous portion was decanted and water was added to the residue and decanted again. The semi-solid was placed in CH ₂ Cl ₂ and passed through a short layer of SiO ₂ (5% MeOH / EtOAc) to give 1.06 g (83%) of a pale yellow semi-solid. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₁₉ Cl ₂ N ₃ O, 351.09; m / z found, 352.0 [M + H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1: 1 mixture of rotamers): 7.60 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7 40 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 4.77 (s, 1H), 4.61 (s, 1H), 4 , 20 (t, J = 6.2 Hz, 2H), 3.94 (t, J = 5.8 Hz, 1H), 3.76 (t, J = 5.8 Hz, 1H), 3.52 (q, J = 6.1 Hz, 2H), 2.84 (t, J = 5.5 Hz, 1H), 2.77 (t, J = 5.6 Hz, 1H), 2.37 (sextet , J = 6.1 Hz, 2 H), 2.21 (s, 1.5 H), 2.16 (s, 1.5 H).

C. 1- (3- (4-Chlorophenyl) -1- {3- [4- (2-fluorophenyl) piperazin-1-yl] propyl} -1,4,6,7-tetrahydropyrazolo [4,3-c ] pyridin-5-yl) ethanone

1- [3- (4-Chlorophenyl) -1- (3-chloropropyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (0.053 g, 0.15 mmol ) was dissolved in CH ₃ CN (0.5 ml) and a solution of 1- (2-fluorophenyl) piperazine (0.053 g, 0.30 mmol) in CH ₃ CN (0.5 ml) was added, followed by K ₂ CO ₃ ( 0.031 g, 0.22 mmol) and Bu ₄ NI (0.018 g, 0.05 mmol). The mixture was stirred at room temperature for 7 days. Preparative TLC (silica, 5% MeOH / EtOAc) gave 30 mg (41%) of the title compound. Mass spectrum (electrospray): Exact mass calculated for C ₂₇ H ₃₁ ClFN ₅ O 495.22; m / z found, 496.3 [M + H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1: 1 mixture of rotamers): 7.60 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7 , 39 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.06-6.90 (m, 4H), 4.77 (s, 1H), 4.60 (s, 1H), 4.10 (t, J = 6.8 Hz, 2H), 3.92 (t, J = 5.7 Hz, 1H), 3.74 (t, J = 5.7 Hz, 1H), 3.08 (br s, 4H), 2.83 (t, J = 5.6 Hz, 1H), 2.77 (t, J = 5.7 Hz, 1H), 2.58 (br s, 4H), 2.41-2.38 (m, 2H), 2.19 (s, 1.5H), 2.13 (s, 1.5H), 2 10-2.07 (m, 2H).

EXAMPLE 2

1- {3- (4-Chlorophenyl) -1- [2-hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl} ethanone

A. 1- [3- (4-Chlorophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

To a stirred solution 1.00 g (3.63 mmol) of 1- [3- (4-chlorophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone and 2, 1.30 g (3.99 mmol) of solid Cs ₂ CO _{3 was} added to 85 ml (36.3 mmol) of epichlorohydrin _. The reaction mixture was stirred for 48 hours and the solvent was removed under reduced pressure. The residue was then diluted with H ₂ O (50 ml) and EtOAc (50 ml). The layers were separated and the organic layer was washed with H ₂ O (25 ml) and brine (25 ml), dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-15% acetone / CH ₂ Cl ₂ ) afforded 0.72 g (60%) of a white solid. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.5. Mass spectrum (electrospray): m / z calculated for C ₁₇ H ₁₈ ClN ₃ O ₂ [M + H] ⁺ , 332.11, found 332.0, ¹ H NMR (400 MHz, CDCl ₃ , mixture of amide rotamers) : 7.60 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7 36 (d, J = 8.4 Hz, 2H), 4.80 and 4.73 (A and B quartet AB, J _ab = 15.8 Hz, 2H), 4.60 (s, 2H), 4 47 (dd, J = 15.3, 2.5 Hz, 1H), 4.42 (dd, J = 15.0, 2.7 Hz, 1H), 4.11 (dd, J = 5.3 , 2.5 Hz, 1H), 4.08 (dd, J = 5.1, 3.3 Hz, 1H), 3.99-3.85 (m, 2H), 3.73 (dt, J = 5.9, 1.8 Hz, 2H), 3.37 (m, 2H), 2.87-2.80 (m, 3H), 2.80-2.69 (m, 3H), 2.53 (dd, J = 4.7, 2.5 Hz, 1H), 2.48 (dd, J = 4.6, 2.6, 1H), 2.19 (s, 3H), 2.15 (s , 3H).

B. 1- {3- (4-Chlorophenyl) -1- [2-hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridin-5-yl} ethanone

Solution of 1- [3- (4-chlorophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (0.8 g, 2.42 mmol ) in CH ₂ Cl ₂ (12 ml) was treated with ytterbium (III) triflate (0.15 g, 0.24 mmol) and 1- (0-tolyl) piperazine (0.51 g, 2.90 mmol) at 25 ° C. The reaction mixture was stirred for 24 hours and diluted with EtOAc (100 ml) and H ₂ O (50 ml). The organic layer was separated, washed with H ₂ O (2 × 50 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 1.08 g (88%) of the target compound, white powder. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.38. Mass spectrum (electrospray): m / z 508.3 ([M + H] ⁺ , C ₂₈ H ₃₄ ClN ₅ O _2, calculated 507.2). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.60 and 7.37 (AB system, J _ab = 8.8 Hz, 2H), 7.54 and 7.40 (AB system, J _ab = 8.8 Hz, 2H), 7.18-7.14 (m, 2H), 7.00-6.97 (m, 2H), 4.85 and 4.73 (AV system, J _ab = 15 5 Hz, 1H), 4.62 (s, 1H), 4.20-4.11 (m, 2H), 4.06-4.01 (m, 1H), 3.88-3.70 ( m, 2H), 2.97-2.87 (m, 6H), 2.85-2.75 (m, 2H), 2.65-2.55 (m, 2H), 2.51-2, 48 (m, 2H), 2.29 (s, 3H), 2.21 (s, 1.5H), 2.17 (s, 1.5H).

EXAMPLE 3

1- {3- (4-Chlorophenyl) -1- [2-methoxy-3- (4-o-tolylpiperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl} ethanone

A stirred solution of 1- {3- (4-chlorophenyl) -1- [2-hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridin-5-yl} ethanone (25 mg, 0.05 mmol) in THF (0.2 ml) was treated with NaH (1.42 mg, 0.06 mmol) at 25 ° C. After 20 minutes, methyl iodide (3.7 ml, 0.06 mmol) was added and the reaction mixture was stirred for an additional 2 hours. Preparative TLC (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 14.6 mg (56%) of a colorless film. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.38. Mass spectrum (electrospray): m / z 522.2 ([M + H] ⁺ , C ₂₉ H ₃₆ CIN ₅ O ₂ , 521.3 calculated). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.62 and 7.37 (AV system, J _ab = 8.8 Hz, 2H), 7.55 and 7.40 (AV system, J _ab = 8.8 Hz, 2H), 7.18-7.14 (m, 2H), 7.02-6.95 (m, 2H), 4.82 and 4.75 (AV system, J _ab = 15 5 Hz, 1H), 4.62 (s, 1H), 4.30-4.25 (m, 1H), 4.09-3.73 (m, 4H), 3.29 (s, 1, 5H), 3.27 (s, 1.5H), 2.93-2.55 (m, 12H), 2.30 (s, 3H), 2.21 (s, 1.5H), 2.16 (s, 1.5H).

EXAMPLE 4

1- [1- {2-Hydroxy-3- [4- (2-hydroxyphenyl) piperazin-1-yl] propyl} -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [4.3 -c] pyridin-5-yl] ethanone

A. 1- [3- (4-Iodophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A flask equipped with a Dean-Stark trap was charged with N-acetyl-4-piperidone (27.29 g, 137 mmol), piperidine (16.5 ml, 129 mmol), p-toluenesulfonic acid (0.5 g) and benzene (150 ml). The mixture was heated to 125 ° C. After 8 hours, the mixture was allowed to cool and concentrated in vacuo to give the corresponding enamine (35 g). A solution of p-iodobenzoyl chloride (9.28 g, 34.8 mmol) in CH was added dropwise to a solution of enamine (11.0 g, about 41 mmol) in CH ₂ Cl ₂ (80 ml) at 0 ° C over 2 hours ₂ Cl ₂ (40 ml). The mixture was then allowed to warm to room temperature and was stirred for an additional 17 hours. The solution was treated with 1N. HCl (200 ml) and stirred vigorously for 5 hours. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 150 ml). The combined extracts were dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in EtOH (200 ml) and treated with NH ₂ NH ₂ (16.0 ml, 51 mmol). The mixture was stirred for 17 hours and H ₂ O (300 ml) was added. The resulting precipitate was collected by filtration and dried in air to obtain 8.82 g (59%) of 1- [3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl ] ethanone suitable for use without further purification. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.3. Mass spectrum (electrospray): m / z calculated for C ₁₄ H ₁₅ IN ₃ O [M + H] ⁺ 368.03, found 368.0. ¹ H NMR (CD ₃ OD / CDCl ₃ , 500 MHz, mixture of amide rotamers): 7.72 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H) , 7.24 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 4.69 (s, 2H), 4.56 (s, 2H) 3.83 (t, J = 6.0 Hz, 2H), 3.69 (t, J = 5.8 Hz, 2H), 2.79 (t, J = 5.7 Hz, 2H), 2 72 (t, J = 5.8 Hz, 2H); 2.13 (s, 3H); 2.08 (s, 3H).

B. 1- [3- (4-Iodophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

Cs ₂ CO ₃ (1.30 g, 4.01 mmol) was added to a solution of 1- [3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl ] ethanone (1.34 g, 3.65 mmol) and epichlorohydrin (2.85 ml, 36.4 mmol) in DMF (10.0 ml). The mixture was stirred for 17 hours, then partitioned between EtOAc (400 ml) and saturated NaHCO ₃ solution (150 ml). The NaHCO ₃ -containing layer was extracted with EtOAc (2 × 150 ml). The combined extracts were washed with H ₂ O (2 × 150 ml), brine (150 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica, 10-25% acetone / CH ₂ Cl ₂ ) to give 890 mg (58%) of the title compound. HPLC, t _R = 5.53 min. (Reverse phase conditions: HP 1100 LCMS, Phenomenex luna 2.1 × 150 mm column, 60% MeOH / H ₂ O (0.5% AcOH) to 90% MeOH / H ₂ O (0.5% AcOH), aging under initial conditions for 2 minutes, then brought to final conditions within 5 minutes). Mass spectrum (electrospray), m / z calculated for C ₁₇ H ₁₈ IN ₃ O ₂ Na [M + Na] ⁺ 445.04, found 445.95, ¹ H NMR (CDCl ₃ , 500 MHz, mixture of amide rotamers) : 7.76 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7 35 (d, J = 8.2 Hz, 2H), 4.80 and 4.73 (A and B AB quartets, J _ab = 15.6 Hz, 2H), 4.60 (s, 2H), 4 84 (dd, J = 15.1, 2.1 Hz, 1H), 4.42 (dd, J = 15.0, 2.1 Hz, 1H), 4.11 (t, J = 5.0 , Hz, 1H), 4.08 (t, J = 5.0 Hz, 1H), 3.98-3.87 (m, 2H), 3.74 (m, 2H), 3.34 (m, 2H), 2.87-2.72 (m, 6H), 2.52 (dd, J = 4.6, 2.6 Hz, 1H), 2.48 (dd, J = 4.5, 2, 6, 1H), 2.20 (s, 3H), 2.14 (s, 3H).

C. 1- [1- {2-Hydroxy-3- [4- (2-hydroxyphenyl) piperazin-1-yl] propyl} -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-5-yl] ethanone

1- [3- (4-Iodophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (62 mg, 0.15 mmol) and 4- (2-Hydroxyphenyl) piperazine (34 mg, 0.19 mmol) was combined in CH ₂ Cl ₂ (0.5 ml) and the solution was treated with Yb (OTf) ₃ · H ₂ O (44 mg, 0.071 mmol). The mixture was shaken for 72 hours, then diluted with CH ₂ Cl ₂ (1 ml). Purification by preparative TLC (silica, 10% MeOH / CH ₂ Cl ₂ ) gave 45 mg (51%) of an off-white powder. TLC (silica, 8% MeOH / CH ₂ Cl ₂ ): R _f = 0.2. Mass spectrum (electrospray): m / z calculated for C ₂₇ H ₃₃ IN ₅ O ₃ [M + H] ⁺ 602.15, found 602.2. ¹ H NMR (CDCl ₃ , 500 MHz, mixture of amide rotamers): 7.76 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.14 (m, 1H), 7.80 (t, J = 7.7 Hz , 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 4.83 and 4.72 (A and B AB quartets, J _ab = 15.6 Hz, 1H), 4.61 (s, 1H), 4.22-4.15 (m, 2H), 4.02 (m, 2H), 3.88 (m, 1H) 3.76 (m, 3H); 3.00-2.49 (m, 11H); 2.20 (s, 1.5H); 2.15 (s, 1.5H).

EXAMPLE 5

1- [1- [2-Hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A. 1- [3- (4-Trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A solution of N-acetyl-4-piperidone (2.82 g, 20 mmol), morpholine (1.93 ml, 22 mmol) and p-toluenesulfonic acid (5 mg) in benzene (8.5 ml) was refluxed for 8 hours with a Dean-Stark device. The solvent was removed and the residue was dissolved in CH ₂ Cl ₂ (20 ml). Triethylamine (3.1 ml) was added and p-trifluoromethylbenzoyl chloride (3.27 ml, 22 mmol) in CH ₂ Cl ₂ (4 ml) was added dropwise to the solution at 0 ° C. The reaction mixture was stirred at 25 ° C for 24 hours and diluted with aqueous HCl (5%, 25 ml). After stirring for another 30 minutes, the organic layer was separated, washed with H ₂ O (20 ml), dried (Na ₂ SO ₄ ) and concentrated. The residue was dissolved in EtOH (95%, 18 ml) and treated at 0 ° C. with hydrazine (2.9 ml, 60 mmol). The mixture was stirred at 25 ° C for 3 hours and H ₂ O (4 ml) was added. Most volatile components were removed and the residue was extracted with CH ₂ Cl ₂ (50 ml). The organic layer was separated, washed with H ₂ O (20 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) afforded 5.1 g (83%) of white powder. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.30. Mass spectrum (electrospray): m / z 332.0 ([M + Na] ⁺ , C ₁₅ H ₁₄ F ₃ N ₃ O, calculated 309.1). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.73-7.67 (m, 4H), 4.85 (s, 1.2H), 4.68 (s, 0.8H), 3.96 (t, J = 4.5 Hz, 0.8H), 3.78 (t, J = 4.5 Hz, 1.2H), 2.89 (t, J = 4.5 Hz, 1 , 2H), 2.83 (t, J = 4.5 Hz, 0.8H), 2.23 (s, 1.8H), 2.18 (s, 1.2H).

B. 1- [1-Oxiranylmethyl-3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A solution of 1- [3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (2.4 g, 7.77 mmol) in DMF (15 ml) was treated with cesium carbonate (5.05 g, 15.5 mmol) and epichlorohydrin (6.1 ml, 77.7 mmol) at 25 ° C and stirred for 24 hours before dilution with EtOAc (100 ml) and H ₂ O (50 ml). The organic layer was separated, washed with H ₂ O (2 × 50 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 10% acetone / CH ₂ Cl ₂ ) gave 2.30 g (81%) of a white powder. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.35. Mass spectrum (electrospray): m / z 388.0 ([M + Na] ⁺ , C ₁₈ H ₁₈ F ₃ N ₃ O ₂ calculated 365.1. ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers) : 7.77 and 7.63 (AV system, J _ab = 8.2 Hz, 2H), 7.71 and 7.67 (AB system, J _ab = 8.4 Hz, 2H), 4.82 and 4 76 (AV system, J _ab = 15.5 Hz, 1.2H), 4.58 (s, 0.8H), 4.45-4.35 (m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30 (m, 1H), 2.80-2.67 (m , 3H), 2.48-2.42 (m, 1H), 2.13 (s, 1.3H), 2.08 (s, 1.7H).

C. 1- [1- [2-Hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridin-5-yl] ethanone.

Solution of 1- [1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (1.16 g, 3.20 mmol) in CH ₂ Cl ₂ (15 ml) was treated with ytterbium (III) triflate (0.40 g, 0.64 mmol) and 1- (O-tolyl) piperazine (0.84 g, 4.77 mmol) at 25 ° C and stirred for 48 hours before dilution with CH ₂ Cl ₂ (100 ml) and H ₂ O (50 ml). The organic layer was separated, washed with H ₂ O (2 × 50 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 1.54 g (89%) of a white powder. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.35. Mass spectrum (electrospray): m / z 542.3 ([M + H] ⁺ , C ₂₉ H ₃₄ F ₃ N ₅ O ₂ , 541.3 calculated). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.82 and 7.65 (AV system, J _ab = 8.2 Hz, 2H), 7.72 and 7.68 (AV system, J _ab = 8.4 Hz, 2H), 7.18-6.97 (m, 4H), 4.88 and 4.76 (AV system, J _ab = 16 Hz, 0.9H), 4.65 (s, 1.1H), 4.23-4.12 (m, 2H), 4.08-4.00 (m, 2H), 3.88-3.70 (m, 2H), 3.02-2, 85 (m, 6H), 2.85-2.75 (m, 2H), 2.65-2.55 (m, 2H), 2.53-2.45 (m, 2H), 2.29 ( s, 3H), 2.21 (s, 1.8H), 2.17 (s, 1.2H).

EXAMPLE 6

2- (4- {3- [5-Acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperazin- 1-yl) benzonitrile

Solution of 1- [1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (0.84 g, 2.30 mmol) in CH ₂ Cl ₂ (10 ml) was treated with ytterbium (III) triflate (0.29 g, 0.46 mmol) and 1- (2-cyanophenyl) piperazine (0.75 g, 3.5 mmol) at 25 ° C and stirred for 48 hours before dilution with CH ₂ Cl ₂ (100 ml) and H ₂ O (50 ml). The organic layer was separated, washed with H ₂ O (2 × 50 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) afforded 1.15 g (90%) of light yellow crystals. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.30. Mass spectrum (electrospray): m / z 553.3 ([M + H] ⁺ , C ₂₉ H ₃₁ F ₃ N ₆ O ₂ , 552.3 calculated). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.82 and 7.68 (AV system, J _ab = 8.2 Hz, 2H), 7.76 and 7.72 (AV system, J _ab = 8.4 Hz, 2H), 7.60-7.48 (m, 2H), 7.05-7.00 (m, 2H), 4.90 and 4.78 (AV system, J _ab = 16 Hz, 1H), 4.69 (s, 1H), 4.30-3.71 (m, 6H), 3.25 (m, 4H), 3.02-2.75 (m, 4H), 2 70-2.65 (m, 2H), 2.60-2.53 (m, 2H), 2.23 (s, 1.5H), 2.18 (s, 1.5H).

EXAMPLE 7

1- [3- (3,4-Dichlorophenyl) pyrazol-1-yl] -3- (4-o-tolylpiperazin-1-yl) propan-2-ol.

A. 3- (3,4-Dichlorophenyl) -1-oxiranylmethyl-1H-pyrazole

A stirred solution of 3- (3,4-dichlorophenyl) pyrazole (300 mg, 1.4 mmol) in DMF (5 ml) was treated with cesium carbonate (550 mg, 1.69 mmol) and epichlorohydrin (1.1 ml, 14.0 mmol) at room temperature for 18 hours. The crude reaction mixture was then partitioned between EtOAc (50 ml) and water (35 ml). The aqueous phase was further extracted (2 × 50 ml) and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (silica, 25% EtOAc / hexanes) afforded 308 mg (82%) of the title compound. ¹ NMR (400 MHz, CDCl ₃ ): 7.83 (d, J = 2 Hz, 1H), 7.54 (dd, J = 2.8 Hz, 1H), 7.44 (d, J = 2 Hz , 1H), 7.38 (d, J = 8 Hz, 1H), 6.48 (d, J = 2 Hz, 1H), 4.45 (dd, J = 3, 9.7 Hz, 1H), 4.12 (dd, J = 6, 15 Hz, 1H), 3.31 (m, 1H), 2.81 (dd, J = 4.0, 4.6 Hz, 1H), 2.47 (dd , J = 2.6, 4.7 Hz, 1H).

B. 1- [3- (3,4-Dichlorophenyl) pyrazol-1-yl] -3- (4-o-tolylpiperazin-1-yl) propan-2-ol

A solution of 3- (3,4-dichlorophenyl) -1-oxiranylmethyl-1H-pyrazole (30 mg, 0.11 mmol) and 1- (2-methylphenyl) piperazine (22 mg, 0.12 mmol) in EtOH (1 ml ) were heated at 80 ° C overnight. Removal of solvent and purification by column chromatography (silica, 0-5% acetone / CH ₂ Cl ₂ ) afforded 35 mg (70%) of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ): 7.89 (d, J = 2 Hz, 1H), 7.61 (dd, J = 2, 8.7 Hz, 1H), 7.57 (d, J = 2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.16 (m, 2H), 6.99 (m, 2H), 6.54 (d, J = 2 , 3 Hz, 1H), 4.31 (m, 1H), 4.18 (m, 2H), 2.93 (m, 4H), 2.60 (m, 2H), 2.47 (m, 3H ), 2.88 (s, 3H).

EXAMPLE 8

1- [1- [2- (2-piperazin-1-yl-ethylamino) -3- (4-o-tolylpiperazin-1-yl) propyl] -3- (4-trifluoromethylphenyl) -1,4,6, 7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A. 1- [5-Acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- (4-o-tolylpiperazin-1 -yl) propan-2-one

A solution of DMSO (3.55 ml, 50 mmol) in CH ₂ Cl ₂ (7 ml) was treated with oxalyl chloride (2.90 ml, 33 mmol) at -78 ° C and stirred for 30 minutes. Then a solution of 1- [1- [2-hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4, 3-c] pyridin-5-yl] ethanone (1.8 g, 3.3 mmol) in CH ₂ Cl ₂ (7 ml) and the reaction mixture was stirred for an additional 30 minutes before quenching with triethylamine (18.4 ml , 132 mmol). The reaction mixture was slowly heated to 25 ° C and diluted with EtOAc (50 ml) and saturated NaHCO ₃ (30 ml). The organic layer was separated, washed with H ₂ O (2 × 50 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 2-5% MeOH / CH ₂ Cl ₂ ) gave 1.50 g (83%) of a light yellow powder. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.35. Mass spectrum (electrospray): m / z 540.3 ([M + H] ⁺ , C ₂₉ H ₃₂ F ₃ N ₅ O ₂ , 539.3 calculated). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.78 and 7.62 (AV system, J _ab = 8.2 Hz, 2H), 7.70 and 7.64 (AV system, J _ab = 8.4 Hz, 2H), 7.18-6.95 (m, 4H), 5.10 (s, 1H), 5.07 (s, 1H), 4.84 (s, 1H), 4 68 (s, 1H), 3.96 (t, J = 4.4 Hz, 1H), 3.78 (t, J = 4.4 Hz, 1H), 3.47 (s, 4H), 3 34 (s, 2H), 2.74-2.65 (m, 6H), 2.29 (s, 3H), 2.20 (s, 1.5H), 2.17 (s, 1.5H) )

B. 1- [1- [2- (2-Piperazin-1-yl-ethylamino-3- (4-o-tolylpiperazin-1-yl) propyl] -3- (4-trifluoromethylphenyl) -1,4,6,7 Tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone.

Solution 1- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- (4-o-tolylpiperazin-1- il) propan-2-one (54 mg, 0.1 mmol) in 1,2-dichloroethane (0.5 ml) was treated with 1- (2-aminoethyl) piperazine (26 μl, 0.2 mmol) and glacial acetic acid (34 μl, 0.6 mmol) at 25 ° C and stirred for 30 minutes. Sodium triacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the reaction mixture was stirred for an additional 4 hours, after which it was quenched with CH ₂ Cl ₂ (5 ml) and saturated NaHCO ₃ (5 ml). The organic layer was separated, washed with H ₂ O (2 × 5 ml), dried over Na ₂ SO ₄ and concentrated. Preparative TLC (silica, 10% MeOH / CH ₂ Cl ₂ gave 22 mg (35%) of a light yellow film. TLC (10% MeOH / CH ₂ Cl ₂ ): R _f = 0.2. Mass spectrum (electrospray ): m / z 653.3 ([M + H] ⁺ , C ₃₅ H ₄₇ F ₃ N ₈ O calculated 652.4). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.78- 7.60 (m, 4H), 7.18-6.82 (m, 4H), 4.88-4.30 (m, 2H), 4.23-3.90 (m, 2H), 3, 85-3.70 (m, 2H), 3.22-2.85 (m, 10H), 2.85-2.30 (m, 15H), 2.30 (s, 3H), 2.21 ( s, 1.5H); 2.17 (s, 1.5H).

EXAMPLE 9

1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl) -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo tert-butyl ester [4.3 -c] pyridine-5-carboxylic acid

A. 3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

p-Toluenesulfonic acid (0.055 g, 0.29 mmol) and morpholine (4.76 ml, 54 mmol) were added to a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (10.3 g, 52 mmol) in benzene (22 ml). The reaction mixture was heated in a flask equipped with a reflux condenser and a Dean-Stark trap while boiling under reflux for 20 hours. The reaction mixture was cooled and concentrated in vacuo to give enamine, which was used without further purification. Enamine was dissolved in CH ₂ Cl ₂ (60 ml) and cooled to 0 ° C. Triethylamine (8.67 ml, 62 mmol) was added, followed by dropwise addition of 4-iodobenzoyl chloride (13.8 g, 52 mmol) dissolved in CH ₂ Cl ₂ (10 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 72 hours. The reaction mixture was poured into water (200 ml) and the CH ₂ Cl ₂ layer was separated, dried (Na ₂ SO ₄ ) and concentrated. The resulting oil was placed in EtOH (200 ml) and treated with hydrazine (4.88 ml, 155 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred for 17 hours. The mixture was concentrated and the resulting material was triturated with EtOAc to give 9.52 g (43%) of a white solid. TLC (silica, 10% acetone / CH ₂ Cl ₂ ): R _f = 0.18. Mass spectrum (electrospray): m / z 426.0 (426.1 calculated for C ₁₇ H ₂₀ IN ₃ O ₂ [M + H] ⁺ ). ¹ H NMR (400 MHz, CDCl ₃ ): 7.74 (broad s, 2H), 7.31 (broad d, J = 8.0 Hz, 2H), 4.63 (broad s, 2H) 3.73 (br s, 2H); 2.77 (br s, 2H); 1.49 (s, 9H).

B. 3- (4-iodophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

Cesium carbonate (1.84 g, 5.65 mmol) was added to a solution of epichlorohydrin (3.68 ml, 47.05 mmol) and 3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo tert-butyl ether [4,3-c] pyridine-5-carboxylic acid (2.0 g, 4.71 mmol) in DMF (10 ml). The reaction mixture was allowed to stir for 24 hours, then partitioned between aqueous NaHCO ₃ and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by column chromatography (silica, 0-10% acetone / CH ₂ Cl ₂ ) afforded 2.26 g (69%) of a white foam. TLC (silica, 10% acetone / CH ₂ Cl ₂ ): R _f = 0.44. Mass spectrum (electrospray): m / z 482.0 (482.1 calculated for C ₂₀ H ₂₄ IN ₃ O ₃ , [M + H] ⁺ ). ¹ H NMR (400 MHz, CDCl ₃ ): 7.60 (broad s, 2H), 7.28 (broad d, J = 8.2 Hz, 2H), 4.48 (broad s, 2H) 4.32 (broad d, J = 14.8 Hz, 1H), 3.99 (dd, J = 15.0, 5.4 Hz, 1H), 3.61 (broad s, 1H), 3.26-3.20 (m, 1H), 2.72 (t, J = 4.4 Hz, 1H), 2.65-2.58 (m, 2H), 2.40 (br s, 1H), 1.36 (s, 9H).

C. 1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo tert-butyl ester [4 , 3-c] pyridine-5-carboxylic acid.

Ytterbium (III) trifluoromethanesulfonate hydrate (0.193 g, 0.311 mmol) and 1- (2-cyanophenyl) piperazine (0.292 g, 1.56 mmol) were dissolved in CH ₂ Cl ₂ (2 ml) and added to a solution of tert-butyl ether 3 - (4-iodophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid in CH ₂ Cl ₂ (5 ml). The reaction mixture was allowed to stir for 48 hours at 25 ° C. Purification by flash chromatography (silica, 0-15% acetone / CH ₂ Cl ₂ ) afforded 392 mg (56%) of a white foam. TLC (silica, 10% acetone / CH ₂ Cl ₂ ): R _f = 0.41. Mass spectrum (electrospray): m / z 669.2 (669.2 calculated for C ₃₁ H ₃₇ IN ₆ O ₃ [M + H] ⁺ ). ¹ H NMR (400 MHz, CDCl ₃ ): 7.73 (br s, 2H), 7.58-7.56 (m, 1H), 7.52-7.48 (m, 1H), 7, 39 (br.s.d, J = 7.1 Hz, 2H), 7.04-7.00 (m, 2H), 4.60 (br.s, 2H), 4.06-4.04 (m, 2H), 4.06-4.04 (m, 1H), 3.76-3.70 (m, 2H), 3.26 (br s, 4H), 2.84-2.38 (m, 7H), 1.56-1.53 (m, 2H), 1.48 (s, 9H).

EXAMPLE 10

Amide 1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid

A. 2- (4- {2-Hydroxy-3- [3- (4-iodophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1 -yl) benzonitrile.

Trifluoroacetic acid (3 ml) was added to a solution of 1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-iodophenyl) -1,4 tert-butyl ester, 6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid (0.402 g, 0.601 mmol) in CH ₂ Cl ₂ (3 ml) and the reaction mixture was stirred for 2 hours. The mixture was concentrated, then diluted with EtOAc. The organic layer was washed with aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated to give an amine (0.342 g, 100%) as a yellowish foam. TLC (silica, 10% acetone / CH ₂ Cl ₂ ): R _f = 0.14. Mass spectrum (electrospray): m / z 569.2 (569.1, calculated for C ₂₆ H ₂₉ IN ₆ O, [M + H] ⁺ ). ¹ H NMR (400 MHz, CDCl ₃ : CD ₃ OD (6: 1)): 7.73 (d, J = 8.6 Hz, 2H), 7.56 (dd, J = 7.6, 1, 8 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.09 (t, J = 7.6 Hz , 1H), 7.02 (dd, J = 8.4 Hz, 1H), 4.43-4.36 (m, 1H), 4.31 (s, 2H), 4.21 (dd, J = 14.1, 4.5 Hz, 1H), 4.11 (dd, J = 14.5, 6.3 Hz, 1H), 3.54-3.49 (m, 2H), 3.40-3 24 (m, 8H); 3.18-3.06 (m, 3H); 3.03-2.95 (m, 3H).

B. Amide 1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridine-5-carboxylic acid.

Diisopropylethylamine (0.531 ml, 3.05 mmol), DMAP (5 mg) and trimethylsilyl isocyanate (0.413 ml, 3.05 mmol) were added to a solution of 2- (4- {2-hydroxy-3- [3- (4-iodophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) benzonitrile in pyridine (3 ml) and CH ₂ Cl ₂ (6 ml). The reaction mixture was stirred for 20 hours, then partitioned between aqueous NaHCO ₃ and CH ₂ Cl ₂ . The layer containing CH ₂ Cl _{2 was} washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The resulting product was dissolved in CH ₂ Cl ₂ (5 ml) and treated with 21 wt.% Sodium ethoxide in EtOH (0.5 ml) for 3 hours. The reaction mixture was washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Purification by column chromatography (silica, 0-10% MeOH / CH ₂ Cl ₂ ) afforded 290 mg (78%) of the title compound. HPLC (reverse phase conditions), t _R = 4.21 min. Mass spectrum (electrospray): m / z 612.2 (612.5, calculated for C ₂₇ H ₃₀ IN ₇ O ₂ , M ⁺ + H). ¹ H NMR (400 MHz, CDCl ₃ ): 7.73 (d, J = 8.6 Hz, 2H), 7.57 (dd, J = 7.6, 1.6 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 7.00 (d , J = 8.4 Hz, 1H), 4.64 (broad s, 2H), 4.57 (broad s, 2H), 4.30 (broad s, 1H), 4.20 (dd, J = 14.1, 3.3 Hz, 1H), 4.06 (dd, J = 14.1, 6.3 Hz, 1H), 3.82-3.65 (m, 2H), 3.29 -3.20 (m, 4H), 3.04-2.80 (m, 6H), 2.68 (br s, 2H).

EXAMPLE 11

1- [5-Carbamoyl-3- (4-iodophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-ylmethyl] -2- [4- (2-cyanophenyl) piperazine- 1-yl] carbamic acid ethyl ester

The title compound (13 mg, 3%) was obtained together with 1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-iodophenyl) -1,4 , 6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid as described in Example 10. Mass spectrum (electrospray): m / z 655.2 (655.2, calculated for C ₂₈ H ₃₁ IN ₈ O ₃ , [M + H] ⁺ ). HPLC (reverse phase conditions): t _R = 6.29 min. ¹ H NMR (400 MHz, CDCl ₃ ): 7.69 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 7.52, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 6.96 (t, J = 9.0 Hz, 2H), 4.64 (br s, 2H) , 4.08 (d, J = 16.8 Hz, 2H), 3.96 (dd, J = 14.0, 6.6 Hz, 1H), 3.80-3.69 (m, 2H), 3.10-2.80 (m, 4H), 2.66 (br s, 2H), 2.50 (br s, 2H).

EXAMPLE 12

1- {3- (3-amino-4-chlorophenyl) -1- [2-hydroxy-3- (4-o-tolyl-piperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-5-yl} ethanone

A. 1- [3- (4-Chloro-3-nitrophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A flask equipped with a Dean-Stark trap was charged with N-acetyl-4-piperidone (27.29 g, 137 mmol), piperidine (16.5 ml, 129 mmol), p-toluenesulfonic acid (0.5 g) and benzene (150 ml). The mixture was heated to 125 ° C. After 8 hours, the mixture was allowed to cool and concentrated in vacuo to give the corresponding enamine (35 g). A solution of enamine (3.87 g, 20.0 mmol) in dichloromethane (24 ml) was treated with triethylamine (3.07 ml, 22.0 mmol) and 4-chloro-3-nitrobenzoyl chloride (4.84 g, 22.0 mmol). The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 16 hours. Hydrazine (1.88 ml, 60 mmol) was added to the reaction mixture. This solution was stirred at room temperature for an additional 16 hours. Solvents were removed under reduced pressure. Ethyl acetate (100 ml) was added to the residue to form a suspension. This suspension was filtered and dried, yielding 6.4 g (100%) of a yellow solid. Mass spectrum (electrospray): m / z 321.0 (321.0 calculated for C ₁₄ H ₁₃ ClN ₄ O ₃ , [M + H] ⁺ ). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 8.10-8.00 (m, 3H), 4.90 (s, 0.8H), 4.85 (s, 1.2H), 3.96 (m, 2H); 2.95 (m, 2H); 2.20 (s, 3H).

B. 1- [3- (4-Chloro-3-nitrophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone.

Solution of 1- [3- (4-chloro-3-nitrophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (6.4 g, 20.0 mmol) in DMF (60 ml) was treated with cesium carbonate (13.0 g, 40 mmol) and epichlorohydrin (15.6 ml, 200.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for an additional 24 hours before dilution with ethyl acetate (350 ml) and water (50 ml). The organic layer was separated, washed with water (2 × 50 ml), brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10% acetone / CH ₂ Cl ₂ ) to give 7.5 g (83%) of a light yellow powder. Mass spectrum (electrospray): m / z 377.0 (377.0 calculated for C ₁₇ H ₁₇ ClN ₄ O ₄ , [M + H] ⁺ ). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 8.15-8.05 (m, 1H), 7.75-7.65 (m, 1H), 7.55-7.45 (m , 1H), 4.80-4.65 (m, 1.2H), 4.60 (s, 0.8H), 4.45-4.35 (m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.30-3.20 (m, 1H), 2.90-2 67 (m, 3H), 2.55-2.48 (m, 1H), 2.15 (s, 1.7H), 2.10 (s, 1.3H).

C. 1- {3- (4-Chloro-3-nitrophenyl) -1- [2-hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-5-yl} ethanone

Solution of 1- [3- (4-chloro-3-nitrophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (0.754 g, 2.0 mmol) in dichloromethane (10 ml) was treated with ytterbium (III) triflate (0.25 g, 0.40 mmol) and 1- (2-methylphenyl) piperazine (0.705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours and diluted with dichloromethane (100 ml) and water (50 ml). The organic layer was separated, washed with water (2 × 50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) to obtain 0.98 g (90%) of the expected product as a pale yellow solid. Mass spectrum (electrospray): m / z 553.2 (553.2 calculated for C ₂₈ H ₃₃ ClN ₆ O ₄ , [M + H] ⁺ ). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 8.25-8.15 (m, 1H), 7.75-7.70 (m, 1H), 7.63-7.55 (m , 1H), 7.20-7.10 (m, 2H), 7.05-6.95 (m, 2H), 4.90-4.70 (m, 1H), 4.65 (s, 1H ), 4.30-4.15 (m, 2H), 4.10-3.70 (m, 4H), 3.00-2.40 (m, 12H), 2.20 (s, 3H), 2.15 (s, 1.5H); 2.10 (s, 1.5H).

D. 1- {3- [3-amino-4-chlorophenyl) -1- [2-hydroxy-3- (4-o-tolylpiperisin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-5-yl} ethanone.

To a solution of sodium hydrosulfite (1.28 g, 7.3 mmol) in 30 ml of water was added 1- {3- (4-chloro-3-nitrophenyl) -1- [2-hydroxy-3- (4-o-tolylpiperazine -1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl} ethanone (810 mg, 1.5 mmol) in 15 ml THF. The reaction mixture was stirred at room temperature for 5 minutes. The color of the solution changed from light yellow to colorless. A solution of hydrogen chloride (1N., 10 ml) was added to the reaction mixture. This solution was stirred at room temperature for 30 minutes and treated with saturated sodium bicarbonate solution until the solution reached a pH of 7 to 8. The product was extracted with dichloromethane (3 × 80 ml). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give a residue. This residue was purified by column chromatography (silica, 5-20% MeOH / CH ₂ Cl ₂ ) to give 644 mg (84.1%) of the title compound. Mass spectrum (electrospray): m / z 523.3 (523.3, calculated for C ₂₈ H ₃₅ ClN ₆ O ₂ , [M + H] ⁺ ). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.30-6.70 (m, 7H), 4.80-4.60 (m, 1H), 4.55 (s, 1H), 4.20-4.05 (m, 4H), 3.95-3.90 (m, 2H), 3.80-3.60 (m, 2H), 2.90-2.30 (m, 9H ), 2.20 (s, 3H), 2.15 (s, 1.5H), 2.10 (s, 1.5H).

EXAMPLE 13

(R) -1- (3- (4-Bromophenyl) -1- {3- [4- (5-chloro-2-methylphenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6, 7-tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone.

A. (2S) -1-tert-butyldimethylsilylglycidol.

To a solution of R - (+) - glycidol (3.88 g, 52.4 mmol) in CH ₂ Cl ₂ (100 ml) cooled to 0 ° C was added tert-butylchlorodimethylsilane (9.41 g, 62.4 mmol), followed by Et ₃ N (13.5 ml, 96.8 mmol). The solution was allowed to warm to 23 ° C, with stirring, for 17 hours. The resulting pink solution was diluted with Et ₂ O (250 ml) and stirred for an additional 30 minutes. The solution was partitioned between Et ₂ O (800 ml) and saturated aqueous NaHCO ₃ (200 ml). The Et ₂ O-containing layer was washed with saturated aqueous NaHCO ₃ (250 ml), H ₂ O (3 × 200 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated. Purification of the residue by column chromatography (silica, 5-10% Et ₂ O / hexanes) afforded 8.21 g (84%) of the title compound. TLC (silica, 10% Et ₂ O / hexanes): R _f = 0.5. ¹ H NMR (CDCl ₃ , 400 MHz): 3.85 (dd, J = 11.9, 3.2 Hz, 1H), 3.66 (dd, J = 11.9, 4.8 Hz, 1H) , 3.09 (m, 1H), 2.77 (dd, J = 5.0, 4.2 Hz, 1H), 2.64 (dd, J = 5.2, 2.7 Hz, 1H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).

B. 1- [3- (4-Bromophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A flask equipped with a Dean-Stark trap was charged with N-acetyl-4-piperidone (100.1 g, 709 mmol), piperidine (68 ml, 779 mmol), p-TsOH (3.7 g) and benzene (500 ml ) The mixture was heated to 125 ° C. After 17 hours, the mixture was allowed to cool and divided into two portions. To a solution of enamine (about 355 mmol) in CH ₂ Cl ₂ (320 ml) cooled to 0 ° C was added dropwise a solution of p-bromobenzoyl chloride (70.0 g, 319 mmol) in CH ₂ Cl ₂ (400 ml). The mixture was then allowed to warm to 23 ° C and stirred for an additional 5 hours. The solution was treated with 1N. HCl (500 ml) and stirred vigorously for 1.5 hours. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 300 ml). The combined extracts were washed with saturated aqueous NaHCO ₃ (300 ml), H ₂ O (300 ml), brine (300 ml), dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in MeOH (300 ml) and treated with NH ₂ NH ₂ (50.0 ml, 1.59 mol). The mixture was stirred for 17 hours, after which the resulting precipitate was collected by filtration and dried in air to obtain 52 g (50%) of the title compound, which was suitable for use without further purification. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.3. Mass spectrum (electrospray): m / z calculated for C ₁₄ H ₁₆ ⁷⁹ BrN ₃ O [M + H] ⁺ , 320.04, found 320. ¹ H NMR (CD ₃ OD / CDCl ₃ , 400 MHz, amide mixture rotamers): 7.53 and 7.35 (A and B systems AA'BB ', J = 8.5 Hz, 2H), 7.51 and 7.39 (A and B systems AA'BB', J = 8 6 Hz, 2H), 4.72 (s, 2H), 4.58 (s, 2H), 3.85 (t, J = 5.9 Hz, 2H), 3.71 (t, J = 5 , 8 Hz, 2H), 2.81 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 5.8 Hz, 2H), 2.16 (s, 3H), 2, 11 (s, 3H).

C. (S) -1- [3- (4-Bromophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A solution of KHMDS in toluene (0.5 M, 3.7 ml, 1.85 mmol) was added to a 0 ° C solution of 1- [3-bromophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (492 mg, 1.54 mmol) in DMF (4.0 ml). The mixture was stirred for 1 hour, after which (2S) -1-tert-butyldimethylsilylglycidol (870 mg, 4.62 mmol) was added by syringe. The mixture was stirred an additional 48 hours and partitioned between EtOAc (300 ml) and saturated aqueous NaHCO ₃ (100 ml). The aqueous layer was extracted with EtOAc (2 × 100 ml). The combined extracts were washed with H ₂ O (2 × 100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in MeOH (50 ml) and treated with CSA (97 mg). The mixture was stirred for 17 hours and concentrated to dryness. The residue was suspended in MeC (OMe) ₃ (50 ml) and stirred for an additional 17 hours. The mixture was diluted with EtOAc (400 ml) and washed with saturated aqueous NaHCO ₃ (50 ml), H ₂ O (2 × 50 ml), brine (50 ml), dried over Na ₂ SO ₄ and concentrated. The crude orthoester was dissolved in CH ₂ Cl ₂ (5 ml), cooled to 0 ° C and treated with AcBr (0.18 ml, 2.4 mmol). The mixture was allowed to warm with stirring for 4 hours before processing as described above. The crude obtained acetyl bromide was dissolved in MeOH (50 ml), treated with K ₂ CO ₃ (207 mg, 1.50 mmol) and stirred for 4 hours. The reaction mixture was diluted with EtOAc (400 ml) and washed with a saturated aqueous solution of NH ₄ Cl (100 ml). The EtOAc-containing layer was washed with H ₂ O (2 × 100 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silica, 10-40% acetone / CH ₂ Cl ₂ ) to give 158 mg (27%) of the title compound. Chiral HPLC analysis (Daicel OD, 0.5% Et ₂ NH / MeOH) showed> 95% optical purity. HPLC (reverse phase conditions): t _R = 4.90 min. Mass spectrum (electrospray): m / z calculated for C ₁₇ H ₁₉ ⁷⁹ BrN ₃ O ₂ [M ⁺ + H], 376.07, found 376.0. ¹ H NMR (CDCl ₃ , 400 MHz, mixture of amide rotamers): 7.47 (d with slight resolution (partially fuzzy), J = 8.5 Hz, 2H), 7.44 (m, 4H), 7.38 (d with slight splitting, J = 8.5 Hz, 2H), 4.71 and 4.64 (A and B of the AB quartet, J _ab = 15.7 Hz, 2H), 4.51 (s, 2H) , 4.39 (dd, J = 15.1, 2.5 Hz, 1H), 4.34 (dd, J = 15.0, 2.9 Hz, 1H), 4.02 (dd, J = 5 , 2, 3.9 Hz, 1H), 3.98 (dd, J = 5.3, 3.7 Hz, 1H), 3.83 (m, 2H), 3.64 (m, 2H), 3 25 (br.m, 2H), 2.80-2.60 (m, 6H), 2.46 (dd, J = 4.6, 2.6 Hz, 1H), 2.38 (dd, J = 4.6, 2.6 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H).

D. (R) -1- (3- (4-Bromophenyl) -1- {3- [4- (5-chloro-2-methylphenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4, 6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone.

(S) -1- [3- (4-Bromophenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone (37 mg, 0.98 mmol ) and 4- (2-methyl-5-chlorophenyl) piperazine (36 mg, 0.17 mmol) were combined in EtOH (0.4 ml) and heated to 70 ° C. After 18 hours, the mixture was allowed to cool, diluted with CH ₂ Cl ₂ and purified by preparative TLC (silica, 8% MeOH / CH ₂ Cl ₂ ) to give 35 mg (61%) of the title compound. HPLC (reverse phase conditions): t _R = 4.41 min. Mass spectrum (electrospray): m / z calculated for C ₂₈ H ₃₄ ³⁵ Cl ⁷⁹ BrN ₆ O ₂ [M ⁺ + H], 586.16, found 586.2, ¹ H NMR (CDCl ₃ , 400 MHz, mixture amide rotamers): 7.56 (d (partially fuzzy), J = 8.5 Hz, 2H), 7.53 (s, 4H), 7.48 (d, J = 8.5 Hz, 2H), 7 08 (br. D, J = 8.5 Hz, 1H), 6.95 (m, 2H), 4.85 and 4.73 (A and B AB quartets, J _ab = 15.6 Hz, 1H) 4.62 (s, 1H); 4.20 (m, 2H); 4.04 (m, 2H); 3.90-3.71 (m, 2H); 2.92-2.53 (m , 11H); 2.21 (s, 1.5H); 2.16 (s, 1.5H).

EXAMPLE 14

2- (4- {3- [5-Acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-fluoropropyl} piperazin- 1-yl) benzonitrile.

Solution 2- (4- {3- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperazine -1-yl) benzonitrile (150 mg, 0.27 mmol) in CH ₂ Cl ₂ (1 ml) was treated with DAST (Et ₂ NSF ₃ , 7 μl, 0.60 mmol) at -78 ° C. The reaction mixture was slowly heated to 25 ° C for 1 hour and then to 60 ° C for an additional 2 hours. Preparative TLC (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 75 mg (50%) of the title compound as a pale yellow powder. TLC (5% MeOH / CH ₂ Cl ₂ ): R _f = 0.28. Mass spectrum (electrospray): m / z 555.2 ([M + H] ⁺ , C ₂₉ H ₃₀ F ₄ N ₆ O, 554.2 calculated). ¹ H NMR (CDCl ₃ , 400 MHz, mixture of two rotamers): 7.71 and 7.59 (AV system, J _ab = 8.2 Hz, 2H), 7.66 and 7.62 (AV system, J _ab = 8.4 Hz, 2H), 7.50-7.38 (m, 2H), 6.96-6.92 (m, 2H), 5.01 (dp, J = 49.0, 3.0 Hz, 1H), 4.77 and 4.73 (AV system, J _ab = 15.7 Hz, 1.1H), 4.59 (s, 0.9H), 4.41-4.18 (m, 2H), 3.95-3.80 (m, 1H), 3.69 (dd, J = 5.5, 5.5 Hz, 1H), 3.18 (m, 4H), 2.83-2 65 (m, 8H); 2.14 (s, 1.6H); 2.10 (s, 1.4H).

EXAMPLE 15

(3- (4-Chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo methyl ester [ 4,3-c] pyridin-5-yl) oxoacetic acid

A. 4-Chloro-3-methylbenzoyl chloride

To a suspension of 52.55 g (0.31 mol) of 4-chloro-3-methylbenzoic acid in CH ₂ Cl ₂ (1.2 L) with DMF (1 ml) at 0 ° C in an atmosphere of N ₂ with a gas outlet sparged through 2.5n. sodium hydroxide solution, 29.56 ml (0.339 mol) of oxalyl chloride was added. The mixture was allowed to warm to room temperature for 3 hours. The reaction mixture was concentrated and used further in crude form.

B. 3- (4-Chloro-3-methyl-phenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

To a stirred solution of 55.8 g (0.28 mol) of 4-oxopiperidin-1-carboxylic acid tert-butyl ester and 25.7 g (0.29 mol) of morpholine in benzene (125 ml) was added a catalytic amount (~ 0, 25 g) p-toluenesulfonic acid. The mixture was refluxed for 10 hours with a Dean-Stark trap. The solvent was removed under reduced pressure to obtain a brown oil. The crude product was diluted with CH ₂ Cl ₂ (400 ml) and 46.83 ml (0.34 mol) Et ₃ N was added. The mixture was cooled to 0 ° C and a 4-chloro-3- solution was slowly added through a dropping funnel over 2 hours. methylbenzoyl chloride (0.35 mol) in CH ₂ Cl ₂ (200 ml). The reaction mixture was poured into water (400 ml) and the CH ₂ Cl ₂ layer was separated, dried (Na ₂ SO ₄ ) and concentrated. The resulting oil was placed in EtOH (400 ml) and treated with 35 ml of hydrazine at 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred for 17 hours, during which time a white precipitate formed. The volume of the reaction mixture was reduced to ~ 150 ml and Et ₂ O (750 ml) was added. The suspension was vigorously stirred for 2 hours and filtered, then washed with Et ₂ O (2 × 200 ml) and dried in vacuo to give 50.74 g (52% in 3 steps) of 3- (4-chloro-3 tert-butyl ether) methylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid as a pale orange solid. Mass spectrum (electrospray): exact mass calculated for C ₁₈ H ₂₂ ClN ₃ O ₂ , 347.1; m / z found, 348.1 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.26-7.43 (m, 4H), 4.65 (br s, 2H), 3.73 (br s, 2H), 2.77 ( broad s, 2H), 2.34 (s, 3H), 1.49 (s, 9H).

C. 3- (4-Chloro-3-methyl-phenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

To a solution of 3- (4-chloro-3-methylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester (18.26 g, 53 mmol) and epichlorohydrin (41.12 ml, 526 mmol) in DMF (100 ml) was added cesium carbonate (20.56 g, 63 mmol). The reaction mixture was allowed to stir for 72 hours, diluted with EtOAc (200 ml) and washed with saturated NaHCO ₃ solution and brine. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 20% acetone / CH ₂ Cl ₂ ) to give 3- (4-chloro-3-methylphenyl) -1-oxiranylmethyl-1 tert-butyl ether , 4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid (12.0 g, 57%). TLC (silica, 20% acetone / CH ₂ Cl ₂ ): R _f = 0.68. Mass spectrum (electrospray) m / z 491.2 (491.2, calculated for C ₂₇ H ₃₁ ClN ₆ O, [M + H] ⁺ ). ¹ H NMR (400 MHz, CDCl ₃ ): 7.55 (s, 1H), 7.36 (m, 2H), 4.61 (m, 2H), 4.38-4.47 (m, 1H) 4.11 (dd, J = 14.3, 5.7 Hz, 1H), 3.67-3.79 (m, 2H), 3.34 (m, 1H), 2.83 (t, J = 4.5 Hz, 1H), 2.75 (m, 2H), 2.51 (m, 1H), 2.41 (s, 3H), 1.48 (s, 9H).

D. 3- (4-Chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7 tert-butyl ether Tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid

3- (4-Chloro-3-methylphenyl) -1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester (5.33 g, 13, 2 mmol) and 1- (2-cyanophenyl) piperazine (2.97 g, 15.86 mmol) were partially dissolved in EtOH (50 ml) and triethylamine (2 ml). The reaction mixture was heated at 80 ° C for 18 hours. The mixture was concentrated and purified by column chromatography (silica, 20% acetone / CH ₂ Cl ₂ ) to give 3- (4-chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) tert-butyl ester piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid (6.51 g, 83%) as a yellow solid. TLC (silica, 20% acetone / CH ₂ Cl ₂ ): R _f = 0.35. Mass spectrum (electrospray): m / z 591.3 (591.3, calculated for C ₃₂ H ₃₉ ClN ₆ O ₃ , [M + H] ⁺ ).

E. 2- (4- {3- [3- (4-Chloro-3-methylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperazin-1-yl) benzonitrile

3- (4-Chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo tert-butyl ester [4,3-c] pyridine-5-carboxylic acid (1.26 g, 2.13 mmol) was dissolved in trifluoroacetic acid (3 ml) and CH ₂ Cl ₂ (3 ml) and allowed to mix for 2 hours. The reaction mixture was concentrated, placed in EtOAc (50 ml) and washed with an aqueous solution of NaHCO ₃ (2 × 25 ml). The EtOAc-containing layer was dried over Na ₂ SO ₄ and concentrated to give 2- (4- {3- [3- (4-chloro-3-methylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperazin-1-yl) benzonitrile (1.05 g, 99%) as a yellow foam. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.27. Mass spectrum (electrospray): m / z 491.2 (491.2, calculated for C ₂₇ H ₃₁ ClN ₆ O, [M + H] ⁺ ). ¹ H NMR (400 MHz, CDCl ₃ ): 9.8 (br s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 8.2 Hz , 1H), 7.38 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.11 (t , J = 8.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 4.56 (br s, 1H), 4.12-4.32 (m, 4H) 2.98-3.51 (m, 13H); 2.35 (s, 3H).

F. Methyl ester (3- (4-chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl) -1,4,6,7- tetrahydropyrazolo [4,3-c] pyridin-5-yl) oxoacetic acid

2- (4- {3- [3- (4-Chloro-3-methylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl) piperazin- 1-yl) benzonitrile (58 mg, 0.118 mmol) was dissolved in CH ₂ Cl ₂ (0.59 ml) and treated with methyl chloroxoacetate (16 mg, 0.129 mmol). The reaction mixture was allowed to stir for 18 hours at room temperature. Column chromatography (silica, 2-10% MeOH / CH ₂ Cl ₂ ) gave (3- (4-chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1- methyl ester yl] -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl) oxoacetic acid (54 mg, 79%) as a white solid. Mass spectrum (electrospray): m / z 577.3 (577.2, calculated for C ₃₀ H ₃₃ ClN ₆ O ₄ , [M + H] ⁺ ). ¹ H NMR (400 MHz, CDCl ₃ ): 7.32-7.62 (m, 5H), 7.14 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8, 2 Hz, 1H), 4.59-4.80 (m, 3H), 4.12-4.28 (m, 2H), 3.92 (s, 3H), 3.78-3.86 (m , 2H), 3.44-3.60 (m, 5H), 3.15-3.40 (m, 4H), 2.83-3.05 (m, 2H), 2.41 (s, 3H )

EXAMPLE 16

5-Methanesulfonyl-1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine

A. 1-Methanesulfonylpiperidin-4-one

Potassium carbonate (324 g, 2340 mmol) was added to a solution of 4-piperidone hydrochloride monohydrate (90 g, 586 mmol) in chloroform (300 ml) and water (300 ml). The suspension was cooled to 0 ° C and treated with methylsulfonyl chloride (136 ml, 1760 mol), adding dropwise over 1 hour (gas evolution was observed). The reaction was allowed to shake for 72 hours and partitioned between CH ₂ Cl ₂ (500 ml) and saturated aqueous NaHCO ₃ (500 ml). The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 200 ml). The organic layer was washed with 1% KHSO ₄ (250 ml), dried (Na ₂ SO ₄ ) and concentrated to give 90.5 g (87%) of a white solid. Mass spectrum (electrospray): exact mass calculated for C ₆ H ₁₁ NO ₃ S, 177.1; m / z found, 178.1 [M + H] ⁺ . HPLC (reverse phase conditions): t _R = 2.19 min. ¹ H NMR (400 MHz, CDCl ₃ ): 3.60 (t, J = 6.5 Hz, 4H), 2.89 (s, 3H), 2.59 (t, J = 6.3 Hz, 4H )

B. 5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine

p-Toluenesulfonic acid (1.34 g, 7.0 mmol) and morpholine (25.83 ml, 296 mmol) were added to a solution of 1-methanesulfonyl-piperidin-4-one (50.0 g, 282 mmol) in benzene ( 282 ml). The reaction mixture was heated in a flask equipped with a reflux condenser and a Dean-Stark trap, while boiling under reflux for 15 hours. The reaction mixture was cooled and concentrated in vacuo to give enamine, which was used without further purification. Enamine was dissolved in CH ₂ Cl ₂ (200 ml) and cooled to 0 ° C. Triethylamine (47.2 ml, 339 mmol) was added thereto, followed by dropwise addition of 4-trifluoromethylbenzoyl chloride (42.3 ml, 285 mmol) dissolved in CH ₂ Cl ₂ (82 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 20 hours. The reaction mixture was washed with 1N. aqueous HCl (250 ml) and the layer containing CH ₂ Cl ₂ were separated, dried (Na ₂ SO ₄ ) and concentrated. The resulting oil was placed in EtOH (300 ml) and treated with hydrazine (44.3 ml, 1.41 mol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. The mixture was concentrated and the resulting solid was filtered by washing with EtOH and dried in vacuo to obtain 70 g (72%) of 5-methanesulfonyl-3- (4-trifluoromethylphenyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine as a white solid Mass spectrum (electrospray): exact mass calculated for C ₁₄ H ₁₄ F ₃ N ₃ O ₂ S, 345.0; m / z found, 346.0 [M + H] ⁺ . HPLC (reverse phase conditions): t _R = 6.33 min. ¹ H NMR (400 MHz, CDCl ₃ ): 7.72 (s, 4H), 4.58 (s, 2H), 3, 69 (t, J = 5.7 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H), 2.92 (s, 3H).

C. 3- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-1-ol

Cs ₂ CO ₃ (33.74 g, 103.5 mmol) was added to a solution of 5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (29.8 g, 86.3 mmol) in anhydrous DMF (70 ml) and stirred for 25 minutes. 3-Bromo-1-propanol (8.6 ml, 13.2 g, 94.9 mmol) was added and stirred under N ₂ at room temperature for 18 hours. Water (500 ml) was added to the reaction mixture and stirred for 5 minutes. The precipitated substance was filtered off and washed with water (4 × 100 ml) and freeze-dried. The crude material (31.0 g) was placed in anhydrous DMF (65 ml), Cs ₂ CO ₃ (33.74 g, 103.5 mmol) was added and stirred for 10 minutes. 3-Bromo-1-propanol (8.6 ml, 13.2 g, 94.9 mmol) and MeOH (6.0 ml, 4.75 g, 148 mmol) were added and stirring was continued under N ₂ at room temperature within 15 hours. Water (500 ml) was added to the reaction mixture and stirred for 10 minutes. The precipitated substance was filtered off and washed with water (3 × 100 ml). The filter cake was dissolved in CH ₂ Cl ₂ (200 ml) and washed with brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated. The solid was triturated with Et ₂ O (200 ml), filtered, washed with Et ₂ O and dried, yielding 16.0 g of the target compound. The mother liquor was chromatographed (silica, 0-10% acetone / EtOAc) to give an additional 3.0 g of the title compound. The total yield was 54.6%. Mass spectrum (electrospray): calculated for C ₁₇ H ₂₀ F ₃ N ₃ O ₃ S, 403.12; m / z found, 404.0 [M + H] ⁺ , 426.0 [M + Na] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.71 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 4.55 (s, 2H ), 4.23 (t, J = 6.5 Hz, 2H), 3.70-3.63 (m, 4H), 2.90 (s, 3H), 2.90 (t, J = 5, 1 Hz, 2H), 2.62 (t, J = 5.9 Hz, 1H), 2.06 (q, J = 6.1 Hz, 2H).

D. 3- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propionaldehyde.

Dess-Martin periodinan (3.45 g, 8.2 mmol) was added to a solution of 3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4, 3-c] pyridin-1-yl] propan-1-ol (3.0 g, 7.4 mmol) in CH ₂ Cl ₂ (20 ml) at 0 ° C. under N ₂ . After 15 minutes, the reaction mixture was allowed to warm to room temperature and was stirred for another 1.5 hours. The reaction mixture was diluted with Et ₂ O (60 ml) and 20% aqueous NaHCO ₃ (35 ml) was slowly added. Then, Na ₂ S ₂ O _{3 was} added and stirred at room temperature for 30 minutes. The layers were separated and the aqueous portion was extracted with Et ₂ O (2 × 30 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. Medium pressure liquid chromatography (SDLC) (1-10% MeOH / CH ₂ Cl ₂ ) afforded 2.53 g of the desired aldehyde in 85% yield. Mass spectrum (electrospray): calculated for C ₁₇ H ₁₈ F ₃ N ₃ O ₃ S, 401.11; m / z found, 402.1 [M + H], 434.1 [M + MeOH + H]. ¹ H NMR (400 MHz, CDCl ₃ ): 9.82 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H ), 4.68 (s, 2H), 4.25 (t, J = 6.1 Hz, 2H), 3.63 (t, J = 5.8 Hz, 4H), 3.14 (t, J = 6.1 Hz, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.81 (s, 3H).

E. 5-Methanesulfonyl-1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [ 4,3-c] pyridine

To a stirred solution of 3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propionaldehyde (0.060 g, 0.15 mmol) and 1- (2-nitrophenyl) piperazine (0.032 g, 0.157 mmol) in CH ₂ Cl ₂ (0.5 ml), ice-cold AcOH (8.5 μl, 0.15 mmol) was added and stirred for 15 minutes at room temperature. NaBH (OAc) ₃ (0.041 g, 0.19 mmol) was added and stirred under nitrogen overnight. Then, a saturated solution of NaHCO ₃ (0.5 ml) was added and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (0.5 ml). SDLC purification (silica, 2-15% MeOH / CH ₂ Cl ₂ ) afforded the desired product as a white solid (0.063 g, 71%). TLC (silica, 12% MeOH / CH ₂ Cl ₂ ): R _f = 0.67. Mass spectrum (electrospray): exact mass calculated for C ₂₇ H ₃₁ F ₃ N ₆ O ₄ S, 592.21; m / z found, 593.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.80 (dd, J = 1.6, 8.2 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.52 (ddd, J = 1.6, 7.3, 8.3 Hz, 1H), 7.19 (dd, J = 1.2, 8 , 3 Hz, 1H), 7.09 (m, 1H), 4.59 (s, 2H), 4.17 (t, J = 6.9 Hz, 2H), 3.71 (t, J = 5 , 8 Hz, 2H), 3.13 (br t, J = 4.8 Hz, 4H), 2.96 (t, J = 5.6 Hz, 2H), 2.95 (s, 3H), 2.66 (br t, J = 4.4 Hz, 4H), 2.51 (t, J = 7.0 Hz, 2H), 2.17 (q, J = 6.9 Hz, 2H).

EXAMPLE 17

1- [3-Chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] urea

A. 4- (2-Chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 1,2-dichloro-3-nitrobenzene (0.96 g, 5.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.93 g, 5.0 mmol) in acetonitrile (5 ml ) K ₂ CO ₃ (1.38 g, 10 mmol) was added. The mixture was refluxed for 48 hours. The solvent was removed under reduced pressure. The crude material was partitioned between EtOAc (100 ml) and H ₂ O (20 ml). The organic layer was washed with H ₂ O (2 × 20 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 10-20% EtOAc / hexanes) gave 4- (2-chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 70%). TLC (silica, 20% EtOAc / hexanes): R _f = 0.45. Mass spectrum (electrospray): exact mass calculated for C ₁₅ H ₂₀ ClN ₃ O ₄ , 341.1; m / z found, 364.1 [M + Na] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.56 (dd, J = 8.2, 1.4 Hz, 1H), 7.50 (dd, J = 8.2, 1.4 Hz, 1H) 7.13 (t, J = 8.2 Hz, 1H); 3.38-3.56 (m, 4H); 3.06 (m, 4H); 1.48 (s, 9H).

B. 1- (2-chloro-6-nitrophenyl) piperazine

4- (2-Chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester (1.87 g, 5.47 mmol) was dissolved in trifluoroacetic acid (5.0 ml) and CH ₂ Cl ₂ (5, 0 ml) and allowed to mix for 2 hours. The reaction mixture was concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (silica, 100% CH ₂ Cl ₂ ) to give 1- (2-chloro-6-nitrophenyl) piperazine (1.26 g, 95%). Mass spectrum (electrospray): exact mass calculated for C ₁₀ H ₁₂ ClN ₃ O ₂ , 241.1; m / z found, 242.1 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.54 (dd, J = 8.2, 1.6 Hz, 1H), 7.49 (dd, J = 8.2, 1.6 Hz, 1H) 7.10 (t, J = 8.2 Hz, 1H), 3.08 (br s, 4H), 2.99 (br s, 4H), 2.07-2.12 (m, 1H )

C. 1- {3- [4- (2-Chloro-6-nitrophenyl) piperazin-1-yl] propyl} -5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro 1H-pyrazolo [4,3-c] pyridine

To a stirred solution of 3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propionaldehyde (0.5 g, 1.25 mmol) and 1- (2-chloro-6-nitrophenyl) piperazine (0.301 g, 1.25 mmol) in CH ₂ Cl ₂ (6 ml) were added sodium sulfate (0.354 g, 2.50 mmol) and sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The mixture was allowed to stir at room temperature overnight. The mixture was diluted with CH ₂ Cl ₂ and washed with water. The layer containing CH ₂ Cl _{2 was} dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica, 10% acetone / CH ₂ Cl ₂ ) to give 1- {3- [4- (2-chloro-6-nitrophenyl) piperazin-1-yl] propyl} -5-methanesulfonyl-3 - (4-trifluoromethylphenyl) -1,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (0.380 g, 49%). Mass spectrum (electrospray): exact mass calculated for C ₂₇ H ₃₀ ClF ₃ N ₆ O ₄ S, 626.2; m / z found, 627.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.73 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.54 (dd, J = 8.2, 1.2 Hz, 1H), 7.49 (dd, J = 8.2, 1.2 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H), 4 58 (s, 2H), 4.13 (t, J = 6.5 Hz, 2H), 3.71 (t, J = 5.9 Hz, 2H), 3.01-3.11 (m, 4H), 2.95 (t, J = 5.9 Hz, 2H), 2.92 (s, 3H), 2.42-2.53 (m, 4H), 2.40 (t, J = 6 5 Hz, 2H); 2.12 (q, J = 6.5 Hz, 2H).

D. 3-Chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl } piperazin-1-yl) phenylamine

To a stirred solution of 1- {3- [4- (2-chloro-6-nitrophenyl) piperazin-1-yl] propyl} -5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro -1H-pyrazolo [4,3-c] pyridine (0.153 g, 0.244 mmol) in EtOH (2.44 ml) zinc dust (0.80 mg, 1.22 mmol) was added and acetic acid (0.70) was slowly added. ml). After 15 minutes, the yellow solution became colorless and excess zinc dust was filtered through a celite pad. The filtrate was concentrated and the residue was purified by column chromatography (silica, 0-10% MeOH / CH ₂ Cl ₂ ) to give 3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4 , 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenylamine (0.146 g, 100%). Mass spectrum (electrospray): exact mass calculated for C ₂₇ H ₃₂ ClF ₃ N ₆ O ₂ S 596.2; m / z found, 597.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.73 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 6.88 (t, J = 8.2 Hz, 1H). 6.63 (t, J = 7.6 Hz, 2H), 4.55 (s, 2H), 4.36 (s, 2H), 4.15 (t, J = 6.5 Hz, 2H), 3.60-3.70 (m, 4H), 2.97 (t, J = 5.3 Hz, 2H), 2.90 (s, 3H), 2.83 (d, J = 10.8 Hz , 2H), 2.74 (d, J = 11.5 Hz, 2H), 2.37 (t, J = 6.6 Hz, 2H), 2.11-2.20 (m, 4H).

E. 1- [3-Chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1- sludge] propyl} piperazin-1-yl) phenyl] urea

To a stirred solution of 3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenylamine (0.062 g, 0.104 mmol) in CH ₂ Cl ₂ (0.52 ml) was added trimethylsilyl isocyanate (0.017 ml, 0.125 mmol). The reaction mixture was allowed to stir for 48 hours at room temperature. The reaction did not end, therefore, 0.017 ml (0.125 mmol) of trimethylsilyl isocyanate was additionally added, and the reaction mixture was heated at 45 ° C for 10 hours. Column chromatography (silica, 3-10% MeOH / CH ₂ Cl ₂ ) gave 1- [3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4.5, 6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] urea (0.015 g, 22%). Mass spectrum (electrospray): exact mass calculated for C ₂₈ H ₃₃ ClF ₃ N ₇ O ₃ S, 639.2; m / z found, 640.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 8.26 (br s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz , 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.09 (t, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H ), 4.65 (s, 2H), 4.55 (s, 2H), 4.15 (t, J = 6.7 Hz, 2H), 3.65-3.73 (m, 4H), 2 96 (t, J = 5.6 Hz, 2H), 2.87-2.92 (m, 2H), 2.91 (s, 3H), 2.70 (d, J = 11.4 Hz, 2H), 2.40 (t, J = 6.7 Hz, 2H), 2.09-2.22 (m, 4H).

EXAMPLE 18

Amide 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c ] pyridine-5-sulfonic acid

A. 3- (4-Trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

To a stirred solution of 500 g (2.51 mol) of tert-butoxycarbonyl-4-piperidone and 87.1 g (2.76 mol) of morpholine in benzene (1.25 L) was added a catalytic amount (~ 0.25 g) of p- TsOH. The mixture was refluxed for 36 hours with a Dean-Stark trap. Half of the solvent was removed under reduced pressure, and the resulting solution was cooled and filtered. Then, the filtrate was concentrated to obtain 630 g (94%) of an orange-red oil. Enamine was divided and 320 g (1.19 mol) was diluted with CH ₂ Cl ₂ (1.0 L) and 165.0 ml (1.19 mol) Et ₃ N was added. The mixture was cooled to 0 ° C and slowly added using dropwise funnel for 1 hour, a solution of 225 g (1.08 mol) of 4-trifluoromethylbenzoyl chloride in CH ₂ Cl ₂ (0.5 L). The mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then diluted with 1N. HCl (450 ml) and stirred vigorously for 3 hours. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 500 ml) and the combined extracts were dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude oil was diluted with EtOH (1 L) and cooled to 0 ° C. To this stirred solution was slowly added 115 g (3.57 mol) of hydrazine and the mixture was allowed to warm to room temperature and stirred overnight, during which time a white precipitate formed. The volume of the reaction mixture was reduced to ~ 500 ml and cooled. The precipitate was collected to obtain 285 g (72% of enamine) of a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): 7.63-7.55 (m, 4H), 4.58 (br s, 2H), 3.69-3.62 (br m, 2H), 2.74-2.68 (broad m, 2H); 1.47 (s, 9H).

B. 1- (2-Methoxycarbonylethyl) -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

3- (4-Trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester (1.85 g, 5.04 mmol) and methyl acrylate (0, 50 ml, 5.6 mmol) were combined in toluene (30 ml) and heated to 75 ° C. The resulting mixture was treated with t-BuONa (100 mg) and heating was continued for 48 hours. The mixture was allowed to cool and partitioned between EtOAc (300 ml) and NaHCO ₃ (75 ml). The aqueous layer was extracted with EtOAc (3 × 75 ml). The combined extracts were dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 30-60% EtOAc / hexanes) afforded 343 mg (15%) of the title compound. TLC (silica, 50% EtOAc / hexanes): R _f = 0.4. Mass spectrum (electrospray): m / z calculated for C ₂₂ H ₂₇ F ₃ N ₃ O ₄ [M ⁺ + H] 454.20, found 454.1, ¹ H NMR (CDCl ₃ , 400 MHz): 7, 75 (broad s, J = 8.1 Hz, 2H), 7.64 (broad s, 2H), 4.63 (broad s, 2H), 4.30 (t, J = 6.6 Hz , 2H), 3.75 (broad s, 2H), 3.68 (s, 3H), 2.98 (t, J = 6.6 Hz, 2H), 2.79 (broad t, J = 5.6 Hz, 2H); 1.48 (s, 9H).

C. 1- (3-Hydroxypropyl) -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

A solution of LiBH ₄ (26 mg, 1.2 mmol) in THF (0.5 ml) was added to a solution of 1- (2-methoxycarbonylethyl) -3- (4-trifluoromethylphenyl) -1 tert-butyl ester cooled to 0 ° C. 4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid (317 mg, 0.70 mmol) in THF (4.0 ml). The mixture was stirred for 5 minutes, then LiBH ₄ (15 mg) was further added and stirring was continued for 17 hours. The mixture was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO ₃ (20 ml). The aqueous layer was extracted with EtOAc (2 × 20 ml). The combined extracts were dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-8% MeOH / CH ₂ Cl ₂ ) gave 268 mg (95%) of the title compound. HPLC (reverse phase conditions), t _R = 6.82 min. Mass spectrum (electrospray): m / z calculated for C ₂₁ H ₂₆ F ₃ N ₃ O ₃ [M ⁺ + Na] 448.18, found 448.10, ¹ H NMR (CDCl ₃ , 400 MHz): 7, 73 (broad d, J = 8.2 Hz, 2H), 7.65 (broad s, 2H), 4.64 (broad s, 2H), 4.21 (t, J = 6.4 Hz , 2H), 3.76 (broad s, 2H), 3.66 (t, J = 5.7 Hz, 2H), 2.73 (broad t, J = 5.4 Hz, 2H), 2 04 (q, J = 6.1, 2H); 1.48 (s, 9H).

D. 1- (3-Oxopropyl) -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester

Dess-Martin periodinan (1.43 g, 3.36 mmol) was added portionwise to a stirred solution of 1- (3-hydroxypropyl) -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [ 4,3-c] pyridine-5-carboxylic acid (1.30 g, 3.05 mmol) in CH ₂ Cl ₂ (15 ml) at 0 ° C. under N ₂ . Then the reaction mixture was stirred at 0 ° C for 15 minutes and allowed to warm to room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture was diluted with Et ₂ O (50 ml) and saturated NaHCO ₃ solution (15 ml) was slowly added (Caution! Gas evolution). Then Na ₂ S ₂ O _{3 was} added ^. 5H ₂ O (5.31 g, 21.4 mmol) and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with Et ₂ O (2 × 30 ml). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. SDLC (1-10% MeOH / CH ₂ Cl ₂ ) afforded the aldehyde in 79% yield (1.02 g). TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.67. Mass spectrum (electrospray) calculated for C ₂₁ H ₂₄ F ₃ N ₃ O ₃ , 424.2 ([M + H] ⁺ ), m / z found, 424.2, ¹ H NMR (400 MHz, CDCl ₃ ) : 9.82 (s, 1H), 7.65 (broad s, J = 8.0 Hz, 2H), 7.54 (broad s, 2H), 4.53 (s, 2H), 4, 21 (t, J = 6.2 Hz, 2H), 3.68 (br s, 2H), 3.04 (t, J = 6.2 Hz, 2H), 2.70 (t, J = 5 6 Hz, 2H); 1.39 (s, 9H).

E. 4- (2-Chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 0.96 g (5.0 mmol) of 1,2-dichloro-3-nitrobenzene and 0.93 g (5.0 mmol, 1 equiv.) Of 1-tert-butyloxycarbonylpiperazine in acetonitrile (5 ml) was added 1 , 38 g (10 mmol, 2 equiv.) K ₂ CO ₃ . The mixture was refluxed for 48 hours. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 ml) and 20 ml of H ₂ O. The organic layer was washed with H ₂ O (2 × 20 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 10-20% EtOAc / hexanes) afforded 1.2 g (70%) of 4- (2-chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester. TLC (silica, 20% EtOAc / hexanes): R _f = 0.45. ¹ H NMR (400 MHz, CDCl ₃ ): 7.56 (dd, J = 8.2, 1.4 Hz, 1H), 7.50 (dd, J = 8.2, 1.4 Hz, 1H) 7.13 (t, J = 8.2 Hz, 1H), 3.56-3.38 (m, 4H), 3.10-3.00 (m, 4H), 1.48 (s, 9H )

F. 1- {3- [4- (2-Chloro-6-nitrophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [tert-butyl ether] 4,3-c] pyridine-5-carboxylic acid

4- (2-Chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester (940 mg, 2.75 mmol) in 10 ml of CH ₂ Cl _{2 was} treated with 5 ml of trifluoroacetic acid and stirred at 25 ° C for 1 hour Volatile components were then removed. The residue was placed in CH ₂ Cl ₂ (60 ml) and KOH (4n., 20 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The yellow oil was dissolved in CH ₂ Cl ₂ and added to 996 mg (2.35 mmol) of 1- (3-oxopropyl) -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo tert-butyl ether [4 , 3-c] pyridine-5-carboxylic acid. The yellow solution was treated with glacial acetic acid (0.8 ml, 6 equiv.) And stirred at 25 ° C for 1 hour. NaBH (OAc) ₃ (1.5 g, 7.05 mmol) was added and stirred under a nitrogen atmosphere for 2 hours. Then, a saturated solution of NaHCO ₃ (20 ml) was added, stirred for 30 minutes and the layers were separated. The organic extract was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (silica, 2-5% MeOH / CH ₂ Cl ₂ ) gave 1- {3- [4- (2-chloro-6-nitrophenyl) piperazin-1-yl] propyl} -3- tert-butyl ester (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid as a white solid (1.40 g, 92%). TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.3. Mass spectrum (electrospray): exact mass calculated for C ₃₁ H ₃₆ ClF ₃ N ₆ O ₄ , 648.24; m / z found, 649.3 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.69 (d, J = 8.2 Hz, 1H), 7.60-7.50 (m, 1H), 7.45-7.37 (m, 4H), 7.02 (t, J = 8.2 Hz, 1H), 4.58 (br s, 2H), 4.04 (t, J = 6.7 Hz, 2H), 3.73- 3.65 (m, 2H), 3.05-2.95 (m, 4H), 2.71 (t, J = 5.6 Hz, 2H), 2.50-2.35 (m, 4H) 2.30 (t, J = 6.8 Hz, 2H); 2.05-1.95 (m, 2H); 1.41 (s, 9H).

G. 1- {3- [4- (2-amino-6-chlorophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridine-5-carboxylic acid

A solution of 360 mg (0.56 mmol) of 1- {3- [4- (2-chloro-6-nitrophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4 tert-butyl ester , 6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid in 4 ml of MeOH was treated with 182 mg (5 equiv.) Of zinc dust and glacial acetic acid (1.57 ml, 50 equiv.) At 25 ° C. The reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was then filtered through a pad of celite and concentrated to give a thick oil. The residue was taken up in CH ₂ Cl ₂ (50 ml) and a saturated solution of NaHCO ₃ (20 ml). The organic layer was separated, washed with H ₂ O (2 × 10 ml), dried over Na ₂ SO ₄ and concentrated to give 1- {3- [4- (2-amino-6-chlorophenyl) piperazin-1- tert-butyl ester yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.3. Mass spectrum (electrospray): exact mass calculated for C ₃₁ H ₃₈ ClF ₃ N ₆ O ₂ , 618.27; m / z found, 619.3 [M + H] ⁺ .

H. 1- {3- [4- (2-Chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo tert-butyl ester [4,3-c] pyridine-5-carboxylic acid

1- {3- [4- (2-amino-6-chlorophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4] tert-butyl ester solution , 3-c] pyridine-5-carboxylic acid (257 mg, 0.42 mmol) in 4 ml of CH ₂ Cl _{2 was} treated with 32 L (0.42 mmol, 1.0 equiv.) Of methanesulfonyl chloride and 116 L (0.83 mmol, 2 equiv.) of triethylamine and the reaction mixture was stirred at 25 ° C for 1 hour. EtOAc (40 ml) and saturated NaHCO ₃ solution (20 ml) were added. The organic layer was separated and washed with H ₂ O (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated to obtain the crude tert-butyl ether 1- {3- [4- (2-chloro-6 -methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-carboxylic acid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.3. Mass spectrum (electrospray): exact mass calculated for C ₃₂ H ₄₀ ClF ₃ N ₆ O ₄ S, 696.25; m / z found, 697.2 [M + H] ⁺ .

I. Amide 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3 -c] pyridine-5-tert-butoxycarbonylsulfonic acid

Solution 97 mg (0.14 mmol) of 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4 tert-butyl ester , 6,7-tetrahydropyrazolo [4,3-c] pyridine-5-carboxylic acid in 3 ml of CH ₂ Cl _{2 was} treated with 1.5 ml of trifluoroacetic acid. The reaction mixture was stirred at 25 ° C for 1 hour, after which all volatile components were removed. To this crude material in 0.5 ml of CH ₂ Cl _{2 was} added dropwise a pre-mixed solution of chlorosulfonyl isocyanate (18 μl, 0.209 mmol) and 2-methyl-2-propanol (20 μl, 0.209 mmol) in CH ₂ Cl ₂ (0.150 ml ) The reaction mixture was allowed to stir at 25 ° C. overnight. Preparative TLC (silica, 2-10% MeOH / CH ₂ Cl ₂ ) gave the title compound (84 mg, 78%). TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.3. Mass spectrum (electrospray): exact mass calculated for C ₃₂ H ₄₁ ClF ₃ N ₇ O ₆ S ₂ , 775.22; m / z found, 776.2 [M + H] ⁺

J. Amide 1- {3- [4- (2-Chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3 -c] pyridin-5-sulfonic acid

Amide 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c ] pyridine-5-tert-butoxycarbonylsulfonic acid (84 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (0.75 ml) and CH ₂ Cl ₂ (0.75 ml). The reaction mixture was allowed to stir at 25 ° C for 2 hours. Removal of volatile components in a stream of nitrogen gave the amide 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7- tetrahydropyrazolo [4,3-c] pyridin-5-sulfonic acid in quantitative yield as the trifluoroacetic acid salt. Mass spectrum (electrospray): exact mass calculated for C ₂₇ H ₃₃ ClF ₃ N ₄ S ₂ , 675.17; m / z found, 676.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.73 and 7.63 (AV system, J = 8.2 Hz, 4H), 7.37 (d, J = 7.8 Hz, 1H), 7, 13 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 4.32 (s, 2H), 4.20 (t, J = 6.3 Hz, 2H), 3.87-3.80 (m, 2H), 3.80-3.75 (m, 4H), 3.70-3.25 (m, 7H), 3.00-2, 75 (m, 4H); 2.25-2.15 (m, 2H).

EXAMPLE 19

N- [3-Chloro-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine- 1-yl] propyl} piperazin-1-yl) phenyl] methanesulfonamide

A. 5-Methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine

5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (10.0 g, 29.0 mmol) and epichlorohydrin (24 ml, 307 mmol) was allowed to mix in DMF (150 ml) containing Cs ₂ CO ₃ (10.4 g, 31.9 mmol). After stirring at room temperature for 4 days, the mixture was evaporated, placed in EtOAc and washed with water. The organic portion was dried (MgSO ₄ ) and evaporated to give a light yellow solid. Column chromatography (silica, 5% acetone / CH ₂ Cl ₂ ) gave 4.1 g (35%) of a white solid. TLC (silica, 5% acetone / CH ₂ Cl ₂ ): R _f = 0.28. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₁₈ F ₃ N ₃ O ₃ S, 401.10; m / z found, 402.1 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.84 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 4.70-4.62 (m, 3H), 4.25 (d, J = 5.4 Hz, 1H), 3.90-3.70 (m, 2H), 3.47 (m, 1H), 3.10-2, 9 (m, 6H); 2.65-2.60 (m, 1H).

B. 4- (2-Chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 0.96 g (5.0 mmol) of 1,2-dichloro-3-nitrobenzene and 0.93 g (5.0 mmol, 1 equiv.) Of 1-tert-butyloxycarbonylpiperazine in acetonitrile (5 ml) was added 1 38 g (10 mmol, 2 equiv.) K ₂ CO ₃ . The mixture was refluxed for 48 hours. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 ml) and 20 ml of H ₂ O. The organic layer was washed with H ₂ O (2 × 20 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 10-20% EtOAc / hexanes) afforded 1.2 g (70%) of 4- (2-chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester. TLC (silica, 20% EtOAc / hexanes): R _f = 0.45. ¹ H NMR (400 MHz, CDCl ₃ ): 7.56 (dd, J = 8.2, 1.4 Hz, 1H), 7.50 (dd, J = 8.2, 1.4 Hz, 1H) 7.13 (t, J = 8.2 Hz, 1H), 3.56-3.38 (m, 4H), 3.10-3.00 (m, 4H), 1.48 (s, 9H )

C. 4- (2-amino-6-chlorophenyl) piperazine-1-carboxylic acid tert-butyl ester

A solution of 342 mg (1 mmol) of 4- (2-chloro-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester in 5.0 ml of MeOH was treated with 630 mg (10 mmol, 10 equiv.) Of ammonium formate and a catalytic amount 10% Pd-C (34 mg). The reaction mixture was stirred at 65 ° C for 30 minutes. The reaction mixture was then filtered through a pad of celite and concentrated to give a yellow solid. TLC (silica, 5% acetone / CH ₂ Cl ₂ ): R _f = 0.40. Mass spectrum (electrospray): exact mass calculated for C ₁₅ H ₂₂ ClN ₃ O ₂ , 311.14; m / z found, 312.1 [M + H] ⁺ .

D. 4- (2-Chloro-6-methanesulfonylaminophenyl) piperazine-1-carboxylic acid tert-butyl ester

4- (2-amino-6-chlorophenyl) piperazine-1-carboxylic acid tert-butyl ester (163 mg, 0.53 mmol) in CH ₂ Cl _{2 was} treated with 62 L (0.80 mmol, 1.5 equiv.) methanesulfonyl chloride and 148 L (1.06 mmol, 2 equiv.) of triethylamine and the reaction mixture was stirred at 25 ° C for 1 hour. EtOAc (40 ml) and saturated NaHCO ₃ solution (20 ml) were added. The organic layer was separated and washed with H ₂ O (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-5% acetone / CH ₂ Cl ₂ ) afforded 145 mg (70%) of 4- (2-chloro-6-methanesulfonylaminophenyl) piperazine-1-carboxylic acid tert-butyl ester. TLC (silica, 5% acetone / CH ₂ Cl ₂ ): R _f = 0.35. Mass spectrum (electrospray): exact mass calculated for C ₁₆ H ₂₄ ClN ₃ O ₄ S, 389.12; m / z found, 388.1 (negative). ¹ H NMR (400 MHz, CDCl ₃ ): 7.41 (dd, J = 8.2, 1.6 Hz, 1H), 7.11 (t, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.2, 1.6 Hz, 1H), 4.25-3.91 (m, 2H), 3.66-3.52 (m, 2H), 3.01 (s, 3H ), 3.01-2.84 (m, 2H), 2.70-2.56 (m, 2H), 2.55-2.43 (m, 2H), 1.44 (s, 9H).

E. N- [3-Chloro-2- (4- (2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] methanesulfonamide

4- (2-Chloro-6-methanesulfonylaminophenyl) piperazine-1-carboxylic acid tert-butyl ester (145 mg, 0.37 mmol) was dissolved in 3 ml of CH ₂ Cl ₂ and treated with 1.5 ml of trifluoroacetic acid. The reaction mixture was stirred at 25 ° C for 1 hour, after which all volatile components were removed. The solid was treated with CH ₂ Cl ₂ (20 ml) and aqueous KOH (4N, 10 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The crude oil (90 mg) was dissolved in absolute EtOH (1.0 ml) and treated with 96 mg (0.24 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4,5,6,7- tetrahydro-1H-pyrazolo [4,3-c] pyridine. The reaction mixture was refluxed at 85 ° C for 3 hours and then the solvent was removed. Column chromatography (silica, 0-5% MeOH / CH ₂ Cl ₂ ) gave 138 mg (20% in 4 steps) N- [3-chloro-2- (4- {2-hydroxy-3- [5-methanesulfonyl -3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] methanesulfonamide. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.45. Mass spectrum (electrospray): exact mass calculated for C ₂₈ H ₃₄ ClF ₃ N ₆ O ₅ S ₂ , 690.17; m / z found, 691.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 8.28 (s, 1H), 7.65 and 7.59 (AV system, J = 8.4 Hz, 4H), 7.36 (d, J = 8 , 1 Hz, 1H), 7.07 (t, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 4.54-4.44 (m, 2H ), 4.21-3.94 (m, 3H), 3.77-3.52 (m, 4H), 3.41 (m, 2H), 2.96 (s, 3H), 2.81 ( s, 3H), 3.05-2.73 (m, 4H), 2.66-2.20 (m, 4H).

EXAMPLE 20

1- [4- (2,6-Dinitrophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol

A. 4- (2,6-dinitrophenyl) piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 1.01 g (5.0 mmol) of 1-chloro-2,6-dinitrobenzene and 0.93 g (5.0 mmol) of 1-tert-butyloxycarbonylpiperazine in acetonitrile (5 ml) was added 1.38 g ( 10 mmol) K ₂ CO _3. The mixture was refluxed for 48 hours. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 ml) and 20 ml of H ₂ O. The organic layer was washed with H ₂ O (2 × 20 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 10-20% EtOAc / hexanes) afforded 1.31 g of 4- (2,6-dinitrophenyl) piperazine-1-carboxylic acid tert-butyl ester (85%). TLC (silica, 20% EtOAc / hexanes): R _f = 0.35. ¹ H NMR (400 MHz, CDCl ₃ ): 7.75 (d, J = 8.2 Hz, 2H), 7.25 (t, J = 8.2 Hz, 1H), 3.30 (m, 4H ), 2.95 (m, 2H), 1.44 (s, 9H).

B. 1- [4- (2,6-Dinitrophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3- c] pyridin-1-yl] propan-2-ol

4- (2,6-dinitrophenyl) piperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.63 mmol) was dissolved in 5.0 ml of CH ₂ Cl ₂ and treated with 3.0 ml of trifluoroacetic acid. The reaction mixture was stirred at 25 ° C for 1 hour, after which all volatile components were removed. The solid was treated with CH ₂ Cl ₂ (20 ml) and aqueous KOH (4 N, 10 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The crude oil (67 mg) was dissolved in absolute EtOH (1.2 ml) and treated with 141 mg (0.35 mmol, 1.3 eq.) 5-methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine. The reaction mixture was refluxed at 85 ° C for 3 hours and then the solvent was removed. Purification by column chromatography (silica, 10-20% acetone / CH ₂ Cl ₂ ) afforded 150 mg (85%) of 1- [4- (2,6-dinitrophenyl) piperazin-1-yl] -3- [5-methanesulfonyl -3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol. TLC (silica, 10% acetone / CH ₂ Cl ₂ ): R _f = 0.3. Mass spectrum (electrospray): exact mass calculated for C ₂₇ H ₃₀ F ₃ N ₇ O ₇ S, 653.19; m / z found, 654.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.71 (d, J = 8.2 Hz, 2H), 7.64 and 7.58 (AV system, J = 8.4 Hz, 4H), 7, 20 (t, J = 8.2 Hz, 1H), 4.54 (s, 2H), 4.29-4.12 (m, 2H), 3.66 (t, J = 5.3 Hz, 2H ), 3.70-2.95 (m, 9H), 2.91 (s, 3H), 2.67-2.32 (m, 4H).

EXAMPLE 21

2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl methyl ester } piperazin-1-yl) -3-methanesulfonylaminobenzoic acid.

A. 4- (2-Methoxycarbonyl-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 736 mg (2.83 mmol) ethyl 2-bromo-3-nitrobenzoate and 579 mg (3.1 mmol, 1.1 eq.) 1-tert-butyloxycarbonylpiperazine in n-butanol (6 ml) was added 330 mg (3.1 mmol, 1.1 equiv.) Na ₂ CO ₃ . The mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 ml) and 20 ml of H ₂ O. The organic layer was washed with H ₂ O (2 × 20 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 10-20% EtOAc / Hexanes) afforded 744 mg (72%) of 4- (2-methoxycarbonyl-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester. TLC (silica, 20% EtOAc / hexanes): R _f = 0.5. ¹ H NMR (400 MHz, CDCl ₃ ): 7.67 (dd, J = 8.2, 1.4 Hz, 1H), 7.62 (dd, J = 8.2, 1.4 Hz, 1H) 7.16 (t, J = 8.2 Hz, 1H), 3.86 (s, 3H), 3.44-3.36 (m, 4H), 3.03-2.95 (m, 4H ), 1.48 (s, 9H).

B. 2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl methyl ester ] propyl} piperazin-1-yl) -3-methanesulfonylaminobenzoic acid

A solution of 1.0 g (2.73 mmol) of 4- (2-methoxycarbonyl-6-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester in 18 ml of MeOH was treated with 893 mg (13.7 mmol, 5 equiv.) Zinc dust and glacial acetic acid (8 ml). The reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was then filtered through a pad of celite and concentrated to give a thick oil. The residue was taken up in EtOAc (200 ml) and saturated NaHCO ₃ solution (100 ml). The organic layer was separated, washed with H ₂ O (2 × 50 ml), dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 10-30% EtOAc / hexanes) afforded the desired amine (844 mg, 92%). Amine (42 mg, 0.13 mmol) in CH ₂ Cl ₂ (0.5 ml) was treated with 9.7 μl (0.13 mmol, 1.0 equiv.) Of methanesulfonyl chloride and 34.9 μl (0.25 mmol, 2 equiv.) Of triethylamine and the reaction mixture was stirred at 25 ° C for 1 hour. EtOAc (20 ml) and saturated NaHCO ₃ solution (10 ml) were added. The organic layer was separated and washed with H ₂ O (10 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated. The crude oil was dissolved in 2 ml of CH ₂ Cl ₂ and treated with 0.5 ml of trifluoroacetic acid. The reaction mixture was stirred at 25 ° C for 1 hour before removing all volatile components. The crude oil was dissolved in absolute EtOH (1.0 ml) and treated with 40 mg (0.1 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H- pyrazolo [4,3-c] pyridine and 200 μl of triethylamine. The reaction mixture was refluxed at 85 ° C for 4 hours and then the solvent was removed. Preparative TLC (silica, 7% MeOH / CH ₂ Cl ₂ ) gave 35 mg (49% in 3 steps) of the title compound. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.30. Mass spectrum (electrospray): exact mass calculated for C ₃₀ H ₃₇ F ₃ N ₆ O ₇ S ₂ , 714.21; m / z found, 715.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 8.11 (s, 1H), 7.74-7.59 (m, 5H), 7.30 (d, J = 8.1 Hz, 1H), 7 21 (t, J = 8.2 Hz, 1H), 4.62-4.49 (m, 2H), 4.25-3.99 (m, 3H), 3.90 (s, 3H), 3.80-3.57 (m, 3H), 3.53-3.27 (m, 2H), 3.14-2.78 (m, 4H), 3.05 (s, 3H), 2, 86 (s, 3H), 2.76-2.65 (m, 2H), 2.61-2.20 (m, 4H).

EXAMPLE 22

1- {3- [4- (1,1-dioxo-1H-1,6-benzo [d] isothiazol-3-yl) piperazin-1-yl] propyl} -5-methanesulfonyl-3- (4-trifluoromethylphenyl ) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine.

A. 3-piperazin-1-yl-benzo [d] isothiazole 1,1-dioxide

POCl ₃ (10.2 ml, 109.2 mmol) was added to saccharin (5.0 g, 27.3 mmol) and heated at 120 ° C for 20 hours. Excess reagent was removed using a rotary evaporator and water (50 ml) was added to the residue to form a precipitate. The solid was filtered, washed with water (2 × 20 ml) and dried. A portion of the above crude material (2.0 g, 9.95 mmol) and piperazine (4.28 g, 49.75 mmol) were placed in dioxane (10 ml) and heated at 100 ° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and poured into ice water (50 g) and neutralized by the addition of 10% aqueous NaOH. The mixture was extracted with CH ₂ Cl ₂ (3 × 25 ml) and the combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. SDLC (silica, 5-20% MeOH / CH ₂ Cl ₂ ) gave a piperazinyl derivative (0.07 g, 4.2%). Mass spectrum (electrospray): exact mass calculated for C ₁₁ H ₁₃ N ₃ O ₂ S, 251.07; m / z found, 252.1 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.72 (dd, J = 0.8, 7.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.49 (dt, J = 0.8, 7.4 Hz, 1H), 7.43 (dt, J = 1.2, 7.8 Hz, 1H), 3.80 (s, 4H), 2.85 ( broad t, J = 5.0 Hz, 4H), 2.07 (broad s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): 160.8, 145.3, 133.3, 133.0, 128.5, 125.9, 123.2, 49.8, 46.3.

B. 1- {3- [4- (1,1-dioxo-1H-1,6-benzo [d] isothiazol-3-yl-piperazin-1-yl] propyl} -5-methanesulfonyl-3- (4 trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine

To a stirred solution of 3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propionaldehyde (0.040 g, 0.13 mmol) and 1,1-dioxide 3-piperazin-1-yl-benzo [d] isothiazole (0.050 g, 0.21 mmol) in CH ₂ Cl ₂ (0.5 ml) was added ice-cold AcOH (12 μl, 0.21 mmol ) and stirred for 15 minutes at room temperature. NaBH (OAc) ₃ (0.058 g, 0.27 mmol) was added and stirred under nitrogen overnight. Then, a saturated solution of NaHCO ₃ (0.5 ml) was added and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (0.5 ml). SDLC (silica, 2-15% MeOH / CH ₂ Cl ₂ ) gave the desired product as a white solid (0.048 g, 76%). TLC (silica, 12% MeOH / CH ₂ Cl ₂ ): R _f = 0.50. Mass spectrum (electrospray): exact mass calculated for C ₂₈ H ₃₁ F ₃ N ₆ O ₄ S ₂ , 636.18; m / z found, 637.2 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 7.94 (dd, J = 0.8, 7.6 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.73-7.63 (m, 2H), 7.68 (d, J = 8.3 Hz, 2H), 4.57 (s, 2H) , 4.17 (t, J = 6.9 Hz, 2H), 4.04 (br s, 4H), 3.69 (t, J = 5.7 Hz, 2H), 2.94 (s, 3H), 2.92 (t, J = 6.2 Hz, 2H), 2.62 (t, J = 5.0 Hz, 4H), 2.44 (t, J = 6.6 Hz, 2H) 2.13 (q, J = 6.6 Hz, 2H).

EXAMPLE 23

1- [1- {3- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-5-yl] ethanone

A. 6-Chloro-2-piperazin-1-yl-benzothiazole

To a stirred solution of 1.07 g (5.24 mmol) of 2,6-dichlorobenzothiazole in dry DMF (25 ml) was added 2.4 g of potassium carbonate (15.7 mmol) and 0.5 g of piperazine (5.8 mmol) . The mixture was stirred at room temperature for 4 hours. When the reaction was completed, the reaction mixture was partitioned between EtOAc (150 ml) and water (50 ml) and separated. The aqueous layer was extracted with EtOAC (2 × 100 ml). The combined organic layers were then washed with water (2 × 25 ml), brine, dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to obtain 1.33 g (100%) of the desired product as a white solid. Mass spectrum (electrospray): exact mass calculated for C ₁₁ H ₁₂ ClN ₃ S, 253.04; m / z found, 254.0 [M + H] ⁺ .

B. 1- [1- {3- [4- (6-Chlorobenzothiazol-2-yl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-trifluoromethylphenyl) -1,4,6,7- tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

To a stirred solution of 144 mg (0.39 mmol) of 1- [1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone 4 mg EtOH was added 100 mg (0.39 mmol) of 6-chloro-2-piperazin-1-yl-benzothiazole. The solution was heated at 60 ° C. overnight. The solvent was then removed using rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH / EtOAc) to give 220 mg (90%) of a white solid. Mass spectrum (electrospray): exact mass calculated for C ₂₉ H ₃₀ ClF ₃ N ₆ O ₂ S: 618.18; m / z found, 619.2 [M + H] ⁺ . HPLC (reverse phase conditions 40-90%): t _R = 8.27 min. ¹ H NMR (CDCl ₃ , 400 MHz, mixture of amide rotamers): 7.70 (d, J = 8.34 Hz, 1H), 7.62 (m, 2H), 7.57 (d, J = 8, 59 Hz, 1H), 7.48 (d, J = 2.53 Hz, 1H), 7.36 (d, J = 8.59 Hz, 1H), 7.16 (dd, J = 8.59, 2.53 Hz, 1H), 4.80 and 4.68 (A and B AB quartets, J = 15.92 Hz, 1H), 4.58 (s, 1H), 4.18-4.08 (m , 2H), 4.01-3.89 (m, 2H), 3.85-3.60 (m, 2H), 3.59-3.47 (m, 4H), 2.94-2.75 (m, 2H), 2.72-2.62 (m, 2H), 2.55-2.47 (m, 2H), 2.46-2.39 (m, 2H), 2.13 (s 1.5H); 2.08 (s, 1.5H).

EXAMPLE 24

1- [1- [3- (4-Benzo [d] isoxazol-3-yl-piperazin-1-yl) -2-hydroxypropyl] -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A. 4-Benzo [d] isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 100 mg (0.65 mmol) of 3-chloro-1,2-benzisoxazole in pyridine (1 ml) was added 145 mg of piperazin-1-yl-carboxylic acid tert-butyl ester (0.78 mmol) and 0, 18 ml DBU (0.78 mmol). The mixture was stirred at 100 ° C. overnight, then partitioned between EtOAC (50 ml) and water (20 ml) and separated. The aqueous layer was extracted with EtOAC (2 × 30 ml). The combined organic layers were then washed with water (25 ml), brine, dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to give a crude product. Purification by column chromatography (silica, 60-100% CH ₂ Cl ₂ / hexanes) afforded 82 mg (42%) of the expected product as a pale yellow solid. Mass spectrum (electrospray): exact mass calculated for C ₁₆ H ₂₁ N ₃ O ₃ , 303.16; m / z found, 326.1 [M + Na] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz): 7.68 (dt, J = 8.02, 0.98 Hz, 1H), 7.52-7.44 (m, 2H), 7.24 (ddd, J = 8.42, 6.46, 1.57 Hz, 1H), 3.66-3.61 (m, 4H), 3.56-3.49 (m, 4H), 1.49 (s, 9H).

B. 1- [1- [3- (4-Benzo [d] isoxazol-3-yl-piperazin-1-yl) -2-hydroxypropyl] -3- (4-trifluoromethylphenyl) -1,4,6,7 Tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone

A solution of 82 mg (0.27 mmol) of 4-benzo [d] isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester in 2 ml of CH ₂ Cl _{2 was} treated with trifluoroacetic acid (0.5 ml) at room temperature during the night. The solvent was then removed and the crude product was dissolved in EtOH and stirred over 100 mg of sodium bicarbonate for 1 hour, the solid was then filtered off and the filtrate was concentrated. The crude piperazine was then dissolved in 4 ml EtOH and treated with 100 mg (0.27 mmol) of 1- [1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine -5-yl] ethanone. The solution was heated at 60 ° C. overnight. The solvent was then removed using a rotary evaporator and the crude product was purified by column chromatography (silica, 0-10% MeOH / EtOAc) to give 105 mg (68%) of a white solid. Mass spectrum (electrospray), exact mass calculated for C ₂₉ H ₃₁ F ₃ N ₆ O ₃ , 568.24; m / z found, 569.2 [M + H] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz, mixture of amide rotamers): 7.77 (d, J = 8.41 Hz, 1H), 7.69 (m, 2H), 7.67-7.62 (m, 2H), 7.50-7.44 (m, 1H), 7.45-7.42 (m, 1H), 7.23-7.18 (m, 1H), 4.93 (broad m, 1H), 4.87 and 4.75 (A and B AB quartets, J = 15.65 Hz, 1H), 4.65 (br s, 1H), 4.27-4.15 (m, 2, 3H), 4.09-3.95 (m, 1.7H), 3.91-3.82 (m, 0.7H), 3.81-3.66 (m, 1.3H), 3, 62-3.49 (m, 4H), 3.01-2.85 (m, 1.5H), 2.85-2.74 (m, 2.5H), 2.71-2.60 (m , 2H), 2.58-2.45 (m, 2H), 2.20 (s, 1.5H), 2.15 (s, 1.5H).

EXAMPLE 25

1- [4- (2-amino-6-chlorophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3- c] pyridin-1-yl] propan-2-ol

EXAMPLE 26

1- [3-Chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] -3-methylurea

EXAMPLE 27

1- [3-Chloro-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine- 1-yl] propyl} piperazin-1-yl) phenyl] -3-methylurea

EXAMPLE 28

3-amino-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 methyl ester -yl] propyl} piperazin-1-yl) benzoic acid

EXAMPLE 29

3-Chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazine -1-yl) phenylamine.

EXAMPLE 30

1- [2- (4- {3- [3- (4-Bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl } piperazin-1-yl) -3-chlorophenyl] -3-methylurea.

EXAMPLE 31

Amide 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c ] pyridine-5-carboxylic acid

EXAMPLE 32

[3-Chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] methyl ester] propyl} piperazin-1-yl) phenyl] carbamic acid

EXAMPLE 33

Amide 1- [3- (4-benzo [d] isothiazol-3-yl-piperazin-1-yl) propyl] -3- (4-bromophenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridine-5-carboxylic acid

EXAMPLE 34

2- (4- {3- [6-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl methyl ester} piperazin-1-yl) -3-nitrobenzoic acid

EXAMPLE 35

1- [4- (2-Chloro-6-nitrophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3- c] pyridin-1-yl] propan-2-ol

EXAMPLE 36

2- (4- {2-Hydroxy-3- [3- (4-iodophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazine -1-yl) benzonitrile.

EXAMPLE 37

Amide 3- (4-bromophenyl) -1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5 carboxylic acid

EXAMPLE 38

2- (4- {3- [5-Acetyl-3- (4-iodophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperazin- 1-yl) benzonitrile

EXAMPLE 39

2- (4- {3- [3- (4-Chloro-3-methylphenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2- hydroxypropyl} piperazin-1-yl) benzonitrile

EXAMPLE 40

1- (3- (4-Chloro-3-methylphenyl) -1- {3- [4- (2,4-dimethylphenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7- tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone

EXAMPLE 41

1- {3- [4- (3,5-Dichloropyridin-4-yl) piperazin-1-yl] propyl} -5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro 1H-pyrazolo [4,3-c] pyridine

EXAMPLE 42

2- (4- {3- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl ) benzonitrile

EXAMPLE 43

N- [3-Chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] methanesulfonamide

EXAMPLE 44

Amide 3- (3,4-dichlorophenyl) -1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine -5-carboxylic acid

EXAMPLE 45

Amide 3- (4-chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1-yl} -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo [4, 3-c] pyridine-5-carboxylic acid

EXAMPLE 46

Cathepsin S Inhibition Assay

Human recombinant cathepsin S (CatS) was expressed into the baculovirus system and purified in a single step using a thiopropylsepharose column. 10 L yielded ~ 700 mg of CatS, and N-terminal sequencing (determination of the primary protein structure) confirmed identity. The analysis was carried out in a 100 mM sodium acetate pH 5.0 solution containing 1 mM DTT and 100 mM NaCl. The substrate for analysis was

(Aedens) EKARVLAEAA (Dabcyl) K-amide

K _m for the substrate is approximately 5 μM, but the presence of substrate inhibition makes kinetic analysis difficult. At 20 μM substrate, the assay rate is linear in the range of 1-8 ng CatS in 100 μl of the reaction mixture. Using 2 ng / well of CatS, the production of the product is linear and gives ~ 7-fold amplified signal after 20 minutes with only 20% substrate loss. Initial analyzes were carried out by stopping the reaction after 20 minutes with 0.1% SDS, and then fluorescence was measured. For other analyzes, measurements are taken every minute for 20 minutes. The speed is calculated from the slope of the increase and based on this, the percentage of inhibition is calculated (see tables 1 and 2 below)

Table 1 EXAMPLE IC ₅₀ (μm) one 0.89 2 1.22 3 0.84 four 0.51 5 0.36 6 0.30 7 6.60 8 0.89 9 1.14 10 0.05 eleven 0,03 12 0.98 13 0.77 fourteen 0.25 fifteen 0.12 16 0.06 17 0.08 eighteen 0.14 19 0.06 twenty 0.17 21 0,07 22 2.15 23 1.10 24 0.47

table 2 EXAMPLE IC ₅₀ (μm) 25 0.04 26 0.04 27 0.04 28 0,07 29th 0,07 thirty 0.08 31 0.10 32 0.10 33 0.10 34 0.11 35 0.12 36 0.12 37 0.12 38 0.12 39 0.13 40 0.13 41 0.13 42 0.13 43 0.13 44 0.13 45 0.13

EXAMPLE 47

Ex vivo Inhibition of Allergic Response by Cathepsin S Inhibitors

The following analysis shows that cathepsin S inhibitors block the response of human T cells to untreated allergen extracts.

Materials and methods

Reagents: Glycerinated crude allergenic extracts of house dust mites (Dermataphagoides pteronyssinus, Dermataphagoides farinae) and ragweed [Ambrosia trifida (giant), Ambrosia artemisiifolia (short)] were obtained from Hollister-Stier Laboratories (Minneapolis. Concanavalin A (ConA) was obtained from Calbiochem (La Jolla, CA).

Donors All allergic donors were pre-screened for their specific types of allergies using RAST tests. Haploid types of HLA class II of these donors were determined using PCR.

Cell culture. Human peripheral blood mononuclear cells (PBMCs) were purified from blood samples of allergic donors using a Ficoll-Hypaque gradient, followed by washing with phosphate buffered saline. PBMCs were cultured in triplicate or duplicate sequences at a rate of 0.5-1.0 × 10 ⁶ cells / well together with titrated doses of allergenic extracts in the presence or absence of the known cathepsin S inhibitor, LHVS (morpholine urea-leucine-homo-phenylalanine-vinylsulfonophenyl) (Palmer et al. (1995), J. Med. Chem. 38: 3193 and Riese et al. (1996), Immunity 4: 357). Initially, serially diluted stock solutions of LHVS in 100% DMSO were prepared and then diluted 1:15 with 40% hydroxypropinylcyclodextrin (HPCD). Three microliters of LHVS in HPCD were added to PBMC cultures (200 μl / well) After 6 days of culture, 1 μCy / well of ³ H-thymidine (TdR) was added. After 18 hours, cells were harvested using a Filtermate Harvester (Packard) and ³ H-TdR administration on a Topcount (Packard) was counted.

Inhibition of proliferative T cell responses to house dust mites

About 10% of the majority of the population is allergic to house dust mites (HDM) of the Dermatophagoides species, with Dermataphagoides pteronyssinus (Der p) and D. Farinae (Der f) being the two main species present in varying proportions in most countries. The main clinical manifestations are asthma and chronic rhinitis (runny nose).

The effect of cathepsin S inhibition on HDM activation of allergen-specific CD4 T cells was tested in an ex vivo analysis of human T cell proliferation. Cultivation of PBMCs with crude extracts of either Der p or Der f led to strong proliferation (Fig. 1A). Such proliferation consisted primarily of allergen-specific CD4 T cells. When cathepsin S activity was blocked by a specific cathepsin S inhibitor, LHVS (see Riese et al. (1996), Immunity 4: 357), proliferation was significantly inhibited (Fig. 1B). Inhibition of LHVS was specific for responses induced by HDM extracts, since the proliferative responses of T cells induced by ConA, a pan-T cell mitogen, were not affected. In addition, such inhibition was observed for all four investigated HDM-allergic donors, regardless of the different haploid types of HLA class II (DR4; DR7, 15; DR11, 15 and Dr4.11).

Such a system is very similar to the in vivo situation. The allergic subject will be exposed to an untreated mixture of allergens, which will lead to proliferation of T cells and an allergic response. Observation of the inhibition of activation of CD4 T cells by a cathepsin S inhibitor shows that such inhibitors can be effective in treating a generalized population of patients prone to allergies to house dust mites.

Inhibition of T-cell proliferative responses to ragweed

About 10% of the US population is prone to ragweed pollen allergy, which makes it one of the most important allergens in terms of clinical illness. Pollen allergens are the main cause of increased runny nose (rhinitis) and asthma in this part of the population.

The effect of cathepsin S inhibition on the activation of ragweed-specific ragweed CD4 T cells was investigated in an ex vivo analysis of human T cell proliferation. The cultivation of PBMCs with crude extracts of both short and giant ragweed resulted in strong proliferation (Fig. 2A). Such proliferation consisted primarily of allergen-specific CD4 T cells. When cathepsin S activity was blocked by a specific cathepsin S inhibitor LHVS (see Riese et al. (1996), Immunity 4: 357), proliferation was significantly inhibited (Figure 2B). Inhibition of LHVS was specific for ambrosia-induced responses, since the proliferative responses of T cells induced by ConA, a pan-T cell mitogen, were not affected. In addition, such inhibition was observed for the two investigated donors allergic to ragweed, regardless of the different haploid types of HLA class II (DR7, 15 and Dr4.11).

A similar experiment was carried out using two additional CatS inhibitors, the compounds of Example 11 and Example 36 above, with the results shown in FIGS. 3A and 3B, respectively.

This system is very similar to the in vivo situation. The allergic subject will be exposed to an untreated mixture of allergens, which will lead to proliferation of T cells and an allergic response. Observation of the inhibition of activation of CD4 T cells by a cathepsin S inhibitor shows that such inhibitors may be effective in treating a generalized population of patients prone to ragweed allergy.

Example 48

Observation of cathepsin S inhibition in human blood

The in vivo effect of the administration of cathepsin S inhibitors in a series of clinical trials can be observed by measuring the accumulation of an intermediate product of decomposition of the invariant chain (Ii), for example, the p10Ii fragment, in the blood of subjects receiving a dose of the substance. After the administration of a cathepsin inhibitor for a certain period of time, for example, from 0.01 to 50 mg / kg / day to create a blood concentration in the range from 1 nM to 10 μM for 16-30 hours, white blood cells are collected and purified by leukocytes (WBC ), for example, by lysing red blood cells or using gradient centrifugation Ficoll-Hypaque. Whole cell leukocyte lysates are then obtained and analyzed using Western blot analysis or ELISA analysis. For Western blot analysis, cell lysates were initially resolved on SDS-PAGE gels. After transfer to the nitrocellulose membrane Ii and its intermediate decomposition products, including p10Ii, can be detected using a mouse anti-Ii mouse mAb, for example, Pin1.1, or rabbit polyclonal antibodies specific for the C-terminal fragment of p10Ii or against the complete fragment of p10Ii. A pair of anti-Ii antibodies can be used for ELISA analysis, including Pin1.1 and a rabbit polyclonal antibody or a murine monoclonal antibody specific for p10Ii. The same assay can also be used to observe the action of cathepsin S inhibitors in vivo in animal studies, such as monkeys, dogs, pigs, rabbits, guinea pigs and rodents.

In the present example, PBMCs from human blood were incubated with a cathepsin S inhibitor, LHVS (morpholine urea-leucine-homo-phenylalanine-vinylsulfonophenyl, also called N - [(1S) -3-methyl-1 - [[[(1S, 2E) -1 - (2-Phenylethyl) -3- (phenylsulfonyl) -2-propenyl] amino] carbonyl] butyl] -4-morpholincarboxamide This compound is described in US Pat. No. 5,976,858 and in Palmer et al. (1995), J. Med. Chem. 38: 3193 and Riese et al. (1996), Immunity 4: 357. After incubation for 24 hours, samples were examined using standard SDS-PAGE protocols, transferred to nitrocellulose membranes and probed with antibody, otorrhea recognizes the invariant chain including r10Ii fragment. In the presence of LHVS observed r10Ii fragment representing a unit formed by the decomposition of Ii due to inhibition of cathepsin S.

EXAMPLE 49

In vivo Observation of Inhibition of Allergic Response by Cathepsin S Inhibitors

To demonstrate the effectiveness of cathepsin S inhibitors in suppressing allergic responses in vivo to allergy-sensitive volunteers, a dose of cathepsin inhibitors was administered at levels at which decomposition of the invariant chain is inhibited. Allergens are administered subcutaneously and the size of the skin reactions is determined after 15 minutes, 6 hours and 24 hours. A skin biopsy is performed after 24 hours. The immediate well-and-signal response is not mediated by the T-cell response, and it was not expected to be affected by cathepsin S inhibitors, while induction (compaction) in the late phase (noticeable after 6 hours, more pronounced after 24 hours) is characterized activation and infiltration of CD4 T cells (as well as eosinophils) and should be inhibited by the administration of cathepsin S inhibitors. A skin biopsy is used to determine the cellular composition in induction and it is suggested that subjects treated with a cathepsin S inhibitor have less its number of activated CD4 T cells is present compared with placebo-treated subjects.

References to these techniques are provided in Eberlein-Konig et al. (1999) Clin. Exp. Allergy 29: 1641-1647 and Gaga et al. (1991) J. Immmunol. 147: 816-822.

Prednisone and cyclosporin A will be used as controls in the experiment. Prednisone will inhibit both the immediate response and the late phase reaction, while cyclosporin A will only inhibit the late phase response.

F. Other Embodiments

The distinguishing features and advantages of the invention are apparent to those of ordinary skill in the art. Based on this description, including the "Summary of the invention", a detailed description, the background of the invention, examples and claims, an ordinary person skilled in the art will be able to make modifications and adaptations to various conditions and applications. Such other embodiments of the invention are also included in the scope of this invention.

Claims (7)

1. A method of treating a subject with an allergic disease, which comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I)

where R ^{1 is} selected from the group consisting of benzoisothiazolyl, 1,1-dioxobenzoisothiazolyl, benzothiazolyl optionally substituted with a chlorine atom, benzoisoxazolyl, and a six-membered aromatic carbocyclic or nitrogen-containing ring, which may be substituted by at least one of the groups including Cl, F, CH ₃ , OH, CN, NO ₂ , NH ₂ , —NH — C (O) —NH ₂ , —SO ₂ , —NH — C (O) —NH — CH ₃ , —C (O) O — CH ₃ , -NH-SO ₂ -CH ₃ , -NH-C (O) O-CH ₃ ; R ^{2 is} selected from the group consisting of OH, —OCH ₃ , piperazinyl ethylamino, —OC (O) —NH ₂ , F; n is 0 or 1; m is 1 or 2; R ³ and R ⁴ independently mean hydrogen, or R ³ and R ⁴ together with the pyrazole ring form a nitrogen-containing unsaturated or saturated six-membered heterocyclic ring which may be substituted on the nitrogen atom with the group —C (O) R ⁵ , —SO ₂ —CH ₃ or -SO ₂ -NH ₂ where R ⁵ means CH ₃ , —O — C (CH ₃ ) ₃ , NH ₂ , —CO (O) —CH ₃ ; Ar means a six-membered aromatic ring which may be substituted by one or more substituents selected from H, C1, NH ₂ , CH ₃ , I, CF ₃ , or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, where Ag is phenyl. 3. The method according to claim 1, where the specified connection is selected from: 1- [4- (2-amino-6-chlorophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3- c] pyridin-1-yl] propan-2-ol; 1- [3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] -3-methylurea; 1- [3-chloro-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine- 1-yl] propyl} piperazin-1-yl) phenyl] -3-methylurea; 3-amino-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 methyl ester -yl] propyl} piperazin-1-yl) benzoic acid; 3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazine -1-yl) phenylamine; 1- [2- (4- {3- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl } piperazin-1-yl) -3-chlorophenyl] -3-methylurea; and amide 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridine-5-carboxylic acid. 4. The method according to claim 1, where the specified connection is selected from: [3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl methyl ester ] propyl} piperazin-1-yl) phenyl] carbamic acid; amide 1- [3- (4-benzo [d] isothiazol-3-yl-piperazin-1-yl) propyl] -3- (4-bromophenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridine-5-carboxylic acid; 2- (4- {3- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl methyl ester ] piperazin-1-yl) -3-nitrobenzoic acid; 1- [4- (2-chloro-6-nitrophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3- c] pyridin-1-yl] propan-2-ol; 2- (4- {2-hydroxy-3- [3- (4-iodophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazine -1-yl) benzonitrile; amide 3- (4-bromophenyl) -1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5 β-carboxylic acid; 2- (4- {3- [5-acetyl-3- (4-iodophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl] piperazin- 1-yl) benzonitrile; 2- (4- {3- [3- (4-chloro-3-methylphenyl) -5-methanesulfonyl-4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2- hydroxypropyl} piperazin-1-yl) benzonitrile; 1- (3- (4-chloro-3-methylphenyl) -1- {3- [4 (2,4-dimethylphenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone; 1- {3- [4- (3,5-dichloropyridin-4-yl) piperazin-1-yl] propyl] -5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro 1H-pyrazolo [4,3-c] pyridine; 2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl ) benzonitrile; N- [3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] methanesulfonamide; amide 3- (3,4-dichlorophenyl) -1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl} -1,4,6,7-tetrahydropyrazolo [4,3-s] pyridine-5-carboxylic acid; and amide 3- (4-chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo [4 , 3-c] pyridine-5-carboxylic acid. 5. The method according to claim 1, where the specified connection is selected from: 1- (3- (4-chlorophenyl) -1- {3- [4- (2-fluorophenyl) piperazin-1-yl] propyl} -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridine -5-yl) ethanone; 1- (3- (4-chlorophenyl) -1- [2-hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [4,3-s] pyridin-5-yl) ethanone; 1- (3- (4-chlorophenyl) -1- [2-methoxy-3- (4-o-tolylpiperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [4,3-s] pyridin-5-yl) ethanone; 1- [1- {2-hydroxy-3- [4- (2-hydroxyphenyl) piperazin-1-yl] propyl} -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [4.3 -c] pyridin-5-yl] ethanone; 1- [1- [2-hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-s] pyridin-5-yl] ethanone; 2- (4- {3- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-hydroxypropyl} piperazin- 1-yl) benzonitrile; 1- [3- (3,4-dichlorophenyl) pyrazol-1-yl] -3- (4-o-tolylpiperazin-1-yl) propan-2-ol; 1- [1- [2- (2-piperazin-1-yl-ethylamino) -3- (4-o-tolylpiperazin-1-yl) propyl] -3- (4-trifluoromethylphenyl) -1,4,6, 7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone; 1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo tert-butyl ester [4.3 -c] pyridine-5-carboxylic acid; amide 1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-iodophenyl) -1,4,6,7-tetrahydropyrazolo [4,3-s] pyridine-5-carboxylic acid; 1- [5-carbamoyl-3- (4-iodophenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-ylmethyl] -2- [4- (2-cyanophenyl) piperazine- 1-yl] carbamic acid ethyl ester; 1- {3- (3-amino-4-chlorophenyl) -1- [2-hydroxy-3- (4-o-tolylpiperazin-1-yl) propyl] -1,4,6,7-tetrahydropyrazolo [4, 3-c] pyridin-5-yl} ethanone; (R) -1- (3- (4-bromophenyl) -1- {3- [4- (5-chloro-2-methylphenyl) piperazin-1-yl] -2-hydroxypropyl) -1,4,6, 7-tetrahydropyrazolo [4,3-c] pyridin-5-yl) ethanone; 2- (4- {3- [5-acetyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -2-fluoropropyl] piperazin- 1-yl) benzonitrile; (3- (4-chloro-3-methylphenyl) -1- {3- [4- (2-cyanophenyl) piperazin-1-yl] -2-hydroxypropyl} -1,4,6,7-tetrahydropyrazolo methyl ester [ 4,3-c] pyridin-5-yl) oxoacetic acid; 5-methanesulfonyl-1- {3- [4- (2-nitrophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H pyrazolo [4,3 -c] pyridine; 1- [3-chloro-2- (4- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperazin-1-yl) phenyl] urea; amide 1- {3- [4- (2-chloro-6-methanesulfonylaminophenyl) piperazin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridin-5-sulfonic acid; N- [3-chloro-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine- 1-yl] propyl} piperazin-1-yl) phenyl] methanesulfonamide; 1- [4- (2,6-dinitrophenyl) piperazin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-s] pyridin-1-yl] propan-2-ol; 2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl methyl ester } piperazin-1-yl) -3-methanesulfonylaminobenzoic acid; 1- {3- [4- (1,1-dioxo-1H-1,6-benzo [d] isothiazol-3-yl) piperazin-1-yl] propyl} -5-methanesulfonyl-3- (4-trifluoromethylphenyl ) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine; 1- [1- {3- [4- (6-chlorobenzothiazol-2-yl) piperazin-1-yl] -2-hydroxypropyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-5-yl] ethanone; and 1- [1- [3- (4-benzo [d] isoxazol-3-yl-piperazin-1-yl) -2-hydroxypropyl] -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone. 6. The method according to claim 1, where the specified connection is selected from: N- [3-chloro-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine -1-yl] propyl} piperazin-1-yl) phenyl] methanesulfonamide; amide 1- [3- (4-benzo [d] isothiazol-3-yl-piperazin-1-yl) propyl] -3- (4-bromophenyl) -1,4,6,7-tetrahydropyrazolo [4,3- c] pyridine-5-carboxylic acid; and 1- [3-chloro-2- (4- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine- 1-yl] propyl} piperazin-1-yl) phenyl] -3-methylurea. 7. The method according to claim 1, wherein said pharmaceutical composition is prepared at a dose amount suitable for treating an allergic disease.

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