RU2259202C2 - Method for treatment of allergy by using substituted pyrazoles - Google Patents

Abstract

FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 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 allergen to the corresponding allergens in the subject exposed to the allergy leads to cross-linking of the allergen-specific IgE binding to the mast cells, initiating the degranulation and release of pro-inflammatory mediators, such as histamine and eicosanoids, which trigger a well-and-signal response in the skin test. Typically, 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 allergic exposure. 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 weakened ability to represent 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

the dashed line adjacent to CR ⁶ is absent or represents an sp ² bond;

Y represents nitrogen or R ²⁰ C;

Z represents nitrogen or R ²¹ C;

T represents nitrogen or R ² C;

S represents nitrogen or R ³ C;

with the proviso that from 0 to 3 of S, T, Y and Z are nitrogen; and further provided that one of S, T, Y, and Z may be = N ⁺ -O ^- , where the remaining three are not nitrogen;

R ²⁰ selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 halogenated, R ^o R ^p N, R ^o R ^p NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁴ OC = O, R ¹⁴ S, R ¹⁴ SO and R ¹⁴ SO ₂ ;

R ^{21 is} selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 halogenated, R ^c R ^d N, R ^c R ^d NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁵ OC = O, R ¹⁵ S, R ¹⁵ SO and R ¹⁵ SO ₂ ;

R ² selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 halogenated, R ^e R ^f N, R ^e R ^f NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁶ OC = O, R ¹⁶ S, R ¹⁶ SO and R ¹⁶ SO ₂ ;

R ^{3 is} selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 haloalkyl, R ^g R ^h N, C _2-8 acyl, 4-7 membered heterocyclyl , (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁷ OC = O, R ^m R ⁿ NC = O, R ^m R ⁿ NSO ₂ , R ¹⁷ S, R ¹⁷ SO and R ¹⁷ SO ₂ ;

R ⁵ and R ^{6 are} independently selected from hydrogen and C _1-5 alkyl;

R ⁷ and R ⁸ independently represent hydrogen, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkoxy, C _1-5 alkylthio, halogen or 4-7 membered carbocyclyl or heterocyclyl;

alternatively, R ⁷ and R ⁸ may be taken together to form an optionally substituted 5-7 membered carbocyclic or heterocyclic ring, which may be unsaturated or aromatic; said ring is optionally substituted with 1-3 substituents independently selected from halogen, hydroxy, cyano, nitro, amino, R ^t , R ^t O-, R ^t S-, R ^t O (C _1-5 alkylene) -, R ^t O (C = O) -, R ^t (C = O) -, R ^t (C = S), R ^t (C = O) O-, R ^t O (C = O) (C = O) -, R ^t SO ₂ , NHR ^u (C = NH) -, NHR ^u SO ₂ - and NHR ^u (C = O) -;

R ^t represents C _1-6 alkyl, phenyl, benzyl, phenethyl or C _2-5 heterocyclyl, (C _1-5 heterocyclyl) C _1-6 alkylene, NH ₂ , mono- or di (C _1-6 alkyl) N -, or R ⁴⁹ OR ⁵⁰ -, where R ⁴⁹ represents H, C _1-5 alkyl, C _2-5 alkenyl, phenyl, benzyl, phenethyl or C _1-5 heterocyclyl or (C _1-5 heterocyclyl) C _{1- 6} alkylene, and R ⁵⁰ represents C _1-5 alkylene, phenylene or divalent C _1-5 heterocyclyl; and

R ^u may be H in addition to the values for R ^t ;

R ^c represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ¹⁰ OC = O, R ⁱ R ^j NC = O, R ¹⁰ SO-, R ¹⁰ SO ₂ - and R ⁱ R ^j NSO ₂ ;

R ^e represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴⁰ OC = O, R ⁴³ R ⁴⁴ NC = O, R ⁴⁰ SO, R ⁴⁰ SO ₂ and R ⁴³ R ⁴⁴ NSO ₂ ;

R ^m represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴¹ OC = O, R ⁴⁵ R ⁴⁶ NC = O, R ⁴¹ SO, R ⁴¹ SO ₂ and R ⁴⁵ R ⁴⁶ NSO ₂ ;

R ^o represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴² OC = O, R ⁴⁷ R ⁴⁸ NC = O, R ⁴² SO, R ⁴² SO ₂ and R ⁴⁷ R ⁴⁸ NSO ₂ ;

each R ^d , R ^f , R ⁿ and R ^{p are} independently selected from hydrogen, C _1-5 alkyl, phenyl and C _2-5 heterocyclyl; in addition, R ^c and R ^d , R ^e and R ^f , R ^m and R ⁿ or R ^o and R ^p , independently, may be taken together to form an optionally substituted 4-7 membered heterocyclic ring which may be saturated, unsaturated or aromatic;

each R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ⁴⁰ , R ⁴¹ and R ⁴² independently represents C _1-5 alkyl, phenyl or C _2-5 heterocyclyl;

each R ⁱ and R ^j , R ^k and R ^l , R ⁴³ and R ⁴⁴ , R ⁴⁵ and R ⁴⁶ , R ⁴⁷ and R ⁴⁸ independently represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl or C _2-5 heterocyclyl; in addition, R ⁱ and R ^j , and R ^k and R ^l , R ⁴³ and R ⁴⁴ , R ⁴⁵ and R ⁴⁶ , and R ⁴⁷ and R ⁴⁸ , independently, can be taken together to form an optionally substituted 4-7 membered a heterocyclic ring which may be saturated, unsaturated or aromatic;

R ^g represents hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁹ OC = O, R ¹⁸ R ¹⁹ NC = O, R ⁹ SO, R ⁹ SO ₂ or R ¹⁸ R ¹⁹ NSO ₂ ;

R ^h represents hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl;

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

R ¹⁸ and R ¹⁹ independently represent hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl;

alternatively, R ¹⁸ and R ¹⁹ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic; n is 0, 1 or 2;

G is 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 ^k , NR ^k R ^l , (L) -C _1-4 alkylene, R ^k R ^l NCO ₂ , [(L) -C _1-5 alkylene] amino, N ₃ or (L) -C _1-5 alkoxy;

L represents 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;

Ar is a monocyclic or bicyclic aryl or heteroaryl ring optionally substituted with 1-3 substituents independently selected from halogen, C _1-5 alkoxy, C _1-5 alkyl, C _2-5 alkenyl, cyano, azido, nitro, R ²² R ²³ N, R ²² S, R ²² SO, R ²² SO ₂ , R ²² OC = O, R ²² R ²³ NC = O, C _1-5 haloalkyl, C _1-5 haloalkoxy, C _1-5 haloalkylthio and C _{1 -5} alkylthio;

R ²² represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, benzyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ¹¹ OC = O, R ²⁴ R ²⁵ NC = O, R ¹¹ S, R ¹¹ SO, R ¹¹ SO ₂ or R ²⁴ R ²⁵ NSO ₂ ;

R ²² represents hydrogen, C _1-5 alkyl, phenyl, benzyl or C _2-5 heterocyclyl;

alternatively, R ²² and R ²³ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic;

R ²⁴ and R ²⁵ independently represent hydrogen, C _1-5 alkyl, phenyl, benzyl or C _1-5 heteroaryl; alternatively, R ²⁴ and R ²⁵ may be taken together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic;

R ³² represents hydrogen, C _1-5 alkyl, cyano, C _1-5 hydroxyalkyl, C _2-8 acyl, - (C = O) NR ^v R ^x , CHO, or C _1-6 alkoxycarbonyl, where each R ^v and R ^{x are} independently selected from H, C _1-5 alkyl, C _1-5 hydroxyalkyl, C _1-5 heterocyclyl, (C _1-5 heterocyclyl) C _1-5 alkylene, C _1-5 aminoalkylene, C _3-8 acyloxy, CHO, C _1-6 alkoxycarbonyl and cyano;

Q represents NR ³³ , S or O;

R ³³ represents hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl, C _2-5 heterocyclyl, (C _2-5 heterocyclyl) C _1-5 alkylene, C _2-8 acyl, aroyl, R ³⁵ OC = O R ³⁶ R ³⁷ NC = O, R ³⁵ SO, R ³⁵ S, R ³⁵ SO ₂ or R ³⁶ R ³⁷ NSO ₂ ;

R ^{35 is} selected from hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl and C _2-5 heteroaryl;

each R ³⁶ and R ^{37 is} independently selected from hydrogen, C _1-5 alkyl, phenyl or C _2-5 heteroaryl;

alternatively, R ³⁶ and R ³⁷ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic;

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, or a stereoisomeric form thereof.

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.

Additional features and advantages of the invention will be apparent from the following detailed description, including 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.

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, thereby 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, thereby 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 one or more 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 heterocyclyl include thiazolyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, ylindyl, 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-iodicyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2-aminomethyl, 2-aminomethyl, 2-aminomethyl, 2-hydroxymethyl 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 are 4-substituted and 3,4-disubstituted phenyl. The compounds of the invention are further described in the following section.

B. Compounds

An object of the invention is the treatment of an allergic disease using one or more compounds of formula (I), as described above in the Summary of the Invention.

Preferred compounds include those in which:

(a) one of S, T, Y, and Z is nitrogen;

(b) S and T are CR ³ and CR ² , respectively;

(c) S, T, Y, and Z are CR ³ , CR ² , CR ^20, and CR ²¹ , respectively;

(d) (1) Z is N, Y is N, S is CR ³ , and T is CR ² ; or (2) S represents N, T represents N, Y represents CR ²⁰ , and Z represents CR ²¹ ;

(e) R ² represents hydrogen, halogen, C _1-5 alkoxy, cyano, R ^e R ^f N or 5-6 membered heterocyclyl;

(f) R ³ is hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, R ¹⁷ OC = O or R ^g R ^h N, where R ^g and R ^h are H or C _{1- 5} alkyl, or, taken together, form a 5-6 membered heterocyclyl;

(g) each R ² and R ^{3 are} independently selected from hydrogen, halogen, and 5-6 membered heterocyclyl;

(h) R ⁵ and R ^{6 are} independently selected from hydrogen and C _1-3 alkyl;

(i) one of R ⁵ and R ⁶ is H;

(j) each R ⁵ and R ⁶ represents H;

(k) one of R ⁷ and R ⁸ is H and the other is a 5-7 membered carbocyclyl or heterocyclyl; (l) R ⁷ and R ⁸ are taken together to form an optionally substituted 5-7 membered carbocyclic or heterocyclic ring;

(m) R ⁷ and R ⁸ are taken together to form a six membered heterocyclyl;

(n) R ⁷ and R ⁸ taken together form a 5-7 membered heterocyclyl, optionally N-substituted R ^t (C = O) -, R ^t SO ₂ - or NHR ^u (C = O) -, where R ^t represents C _1-6 alkyl, phenyl or C _2-5 heterocyclyl, and R ^u represents H, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl;

(o) each R ^c , R ^e , R ^m and R ^{o are} independently selected from hydrogen, C _1-5 alkyl, C _2-8 acyl, (C _1-5 alkyl) O (C = O) and the corresponding RRNC = O , RSO, RSO ₂ and RRNSO ₂ groups;

(p) each R ^c , R ^d , R ^h , R ^o , R ^f and R ^{p are} independently selected from hydrogen and C _1-5 alkyl; or, independently, R ^e and R ^f , R ^g and R ^h , or R ^o and R ^p taken together form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring;

(q) R ^e and R ^f taken together are morpholinyl, piperidinyl or pyrrolidinyl;

(r) each R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ , R ⁱ , R ^j , R ^k and R ^l independently represents hydrogen or C _1-5 alkyl;

(s) each R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ independently is C _1-5 alkyl;

(t) R ^g represents C _1-5 alkyl, C _2-8 acyl, R ⁹ OC = O, R ¹⁸ R ¹⁹ NC = O, R ⁹ SO, R ⁹ SO ₂ or R ¹⁸ R ¹⁹ NSO ₂ ; and R ^h represents hydrogen or C _1-5 alkyl;

alternatively, R ^g and R ^h may be taken together to form an optionally substituted 5-6 membered heterocyclyl;

(u) each R ^g and R ^h represents C _1-3 alkyl; (v) R ¹⁸ and R ¹⁹ independently represent hydrogen or C _1-5 alkyl;

(w) n is 0 or 1; or n is 1;

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

(y) G is C ₃ alkanediyl optionally substituted with hydroxy;

(z) R ²⁰ and R ^{21 are} independently selected from hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro, 4-7 membered heterocyclyl, and R ^o R ^p N or R ^c R ^d N, respectively;

(aa) R ²⁰ and R ^{21 are} independently selected from hydrogen, halogen, a 5-6 membered heterocyclyl, and R ^o R ^p N or R ^c R ^d N, respectively;

(bb) Ar is a monocyclic ring optionally substituted with 1-2 substituents selected from halogen, C _1-5 alkyl, cyano, nitro, R ²² R ²³ N, C _1-3 haloalkyl and C _1-3 haloalkoxy;

(cc) Ar is a six-membered aromatic ring monosubstituted at the 4-position with halogen, methyl, CF ₃ or OCF ₃ , or disubstituted at the 3- and 4-positions with substituents independently selected from halogen, CF ₃ , methyl and OCF ₃ ;

(dd) each R ²² , R ²³ and R ²⁴ independently represents hydrogen or C _1-5 alkyl;

(her) R ²⁵ and R ²⁶ independently represent hydrogen or C _1-5 alkyl; or, alternatively, R ²⁵ and R ²⁶ are taken together to form an optionally substituted 4-7 membered heterocyclic ring, said ring may be saturated, unsaturated or aromatic;

(ff) R ²⁵ and R ²⁶ independently represent hydrogen or C _1-5 alkyl;

(gg) Q represents NR ³³ or S;

(hh) Q represents NR ³³ , R ³³ represents hydrogen or C _2-5 heterocyclyl, and R ³² represents hydrogen, C _1-5 alkyl, C _1-5 hydroxyalkyl, - (C = O) NR ^v R ^x , CHO, or C _1-6 alkoxycarbonyl, wherein each R ^v and R ^{x are} independently selected from H, C _1-5 hydroxyalkyl, (C _1-5 heterocyclyl) C _1-5 alkylene and C _1-5 aminoalkylene;

(ii) where Q is S and R ³³ is NR ³⁶ R ³⁷ (C = O), where each R ³⁶ and R ^{37 are} independently selected from hydrogen and C _1-5 alkyl;

(jj) R ^{35 is} selected from hydrogen and C _1-5 alkyl; R ³⁶ and R ^{37 are} independently selected from hydrogen, C _1-5 alkyl, or, alternatively, R ³⁶ and R ³⁷ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring;

(kk) Y represents nitrogen or R ²⁰ C; Z represents nitrogen or R ²¹ C; T represents nitrogen or R ² C; S represents nitrogen or R ³ C; with the proviso that from 0 to 2 of S, T, Y and Z are nitrogen; for example, 1 of them is nitrogen;

(ll) R ² represents hydrogen, halogen, hydroxy, C _1-5 alkoxy, C _1-5 alkyl, or 5-6 membered heterocyclyl or R ^e R ^f N;

(mm) R ³ represents hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, 5-6 membered heterocyclyl or R ^g R ^h N;

(nn) R ⁷ and R ⁸ are independently taken together to form an optionally substituted 5-7 membered unsaturated heterocyclic ring;

(oo) each R ^a , R ^e , R ^m and R ^{o are} independently selected from hydrogen, C _1-5 alkyl, C _2-8 acyl, (C _1-5 alkyl) OC = O and the corresponding RRNC = O, RSO, RSO ₂ and RRNSO ₂ groups;

(pp) each R ^b , R ^f , R ⁿ and R ^{p are} independently selected from hydrogen and C _1-5 alkyl; each R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ⁴⁰ , R ⁴¹ and R ⁴² independently represents C _1-5 alkyl; and each R ^c , R ^d , R ⁱ , R ^j , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ^k and R ^l independently represents hydrogen or C _1-5 alkyl;

(qq) R ^g represents hydrogen or C _1-5 alkyl, C _2-8 acyl, R ⁹ OC = O, R ¹⁸ R ¹⁹ NC = O, R ⁹ SO, R ⁹ SO ₂ or R ¹⁸ R ¹⁹ NSO ₂ ; R ^h represents hydrogen or C _1-5 alkyl;

alternatively, R ^g and R ^h may be taken together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic; R ¹⁸ and R ¹⁹ independently represent hydrogen or C _1-5 alkyl; n is 0 or 1;

(rr) G is C _3-4 alkenediyl or C _3-4 alkanediyl optionally substituted with hydroxy, halogen, C _1-5 alkyloxy, oxo, hydroxyimino, CO ₂ R ^k , R ^k R ^l NCO ₂ , or (L) -C _1-5 alkoxy; L is amino, mono- or di-C _1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl or piperazinyl, where the available ring nitrogen atoms are optionally substituted with C _1-5 alkyl, benzyl, C _2-5 acyl or C _{1- 5} alkoxycarbonyl;

(ss) R ²⁰ and R ^{21 are} independently selected from hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro, and R ^o R ^p N;

alternatively, R ³ and R ²⁰ or R ³ and R ²¹ may be taken together to form an optionally substituted 5-6 membered carbocyclic or heterocyclic ring, said ring may be saturated, unsaturated or aromatic; and Ar is a monocyclic or bicyclic aryl or heteroaryl ring optionally substituted with hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro, R ²² R ²³ N, R ²⁴ SO ₂ , R ²⁴ OC = O R ²⁵ R ²⁶ NC = O, CF ₃ , OCF ₃ , SCF ₃ or C _1-5 alkylthio; R ²² represents hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl, C _2-5 heteroaryl, C _2-8 acyl, aroyl, R ²⁴ OC = O, R ²⁵ R ²⁶ NC = O, R ²⁴ SO, R ²⁴ SO ₂ or R ²⁵ R ²⁶ NSO ₂ ; R ²³ represents hydrogen or C _1-5 alkyl; alternatively, R ²² and R ²³ may be taken together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, said ring may be saturated, unsaturated or aromatic; R ²⁴ represents hydrogen or C _1-5 alkyl; R ²⁵ and R ²⁶ independently represent hydrogen or C _1-5 alkyl; or alternatively, R ²⁵ and R ²⁶ may be taken together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic;

(tt) R ³² represents hydrogen, C _1-5 alkyl, C _1-5 hydroxyalkyl, CHO, C _2-8 acyl, C _1-6 alkoxycarbonyl or - (C = O) NR ^v R ^x , where each R ^v R ^{x are} independently selected from H, C _1-5 alkyl, C _1-5 hydroxyalkyl, C _3-8 acyloxy, (amino) C _1-6 alkylene, (C _1-5 heterocyclyl) C _1-5 alkylene or C _{1 -6} alkoxycarbonyl; and Q represents NR ³³ or S; R ³³ represents hydrogen, C _1-5 alkyl, phenyl, benzyl, (C _2-5 heterocyclyl) C _1-5 alkylene, C _2-8 acyl, aroyl, R ³⁵ OC = O, R ³⁶ R ³⁷ NC = O R ³⁵ SO ₂ or R ³⁶ R ³⁷ NSO ₂ ; R ^{35 is} selected from hydrogen and C _1-5 alkyl; each R ³⁶ and R ^{37 is} independently selected from hydrogen and C _1-5 alkyl;

(uu) one R ⁵ and R ⁶ represents H; R ⁷ and R ⁸ are taken together to form an optionally substituted 6-membered carbocyclic or heterocyclic ring; and Ar is a monocyclic ring optionally substituted with 1-2 substituents selected from halogen, C _1-5 alkyl, cyano, nitro, R ²² R ²³ N, CF ₃ and OCF ₃ .

(vv) both R ⁵ and R ⁶ are H; and

(ww) Ar is a six-membered ring substituted with halogen, CF ₃ , methyl, halogenmethyl or OCF ₃ at the 3- or 4-position or disubstituted at 3- and 4-positions;

(xx) R ⁷ and R ⁸ taken together form pyridinyl, pyrimidinyl or piperazinyl optionally N-substituted with - (C = O) R ^t , SO ₂ —R ^t or - (C = O) NHR ^u ;

(yy) R ^e and R ^f taken together are independently morpholinyl, piperidyl or pyrrolidinyl, optionally substituted;

(zz) the dashed line adjacent to CR ⁶ is absent;

(aaa) or a combination of the above values.

Specific preferred compounds include compounds of the following examples, such as:

1- [1- {2-hydroxy-3- [4- (1H-indol-3-yl) piperidin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone; 1- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol; 1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-chloro-1H- indol-3-yl) piperidin-1-yl] propan-2-ol; 1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5- [chloro-2 -methyl-1H-indol-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-methyl-1H- indol-3-yl) piperidin-1-yl] propan-2-ol; 3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidine -4-yl) -1H-5-carbonitrile; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-methoxy-1H- indol-3-yl) piperidin-1-yl] propan-2-ol; 3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl ethyl ester } piperidin-4-yl) -1H-indole-5-carboxylic acid; 1- [4- (6-chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol; 1- [1- (3- {4- [6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} -2-hydroxypropyl) - 3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [3, 2-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [2, 3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-hydroxy-1H- pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [4- (5-dimethylamino-1H-pyrrolo [3,2-b] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 1- [4- (5-dimethylamino-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidine -4-yl) -1H-pyrrolo [2,3-b] pyridin-6-carbonitrile; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- {4- [1- (2-morpholine -4-yl-ethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] piperidin-1-yl} propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (7-morpholin-4- yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [4- (6-fluoro-2-hydroxymethylbenzo [b] thiophen-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6, 7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 6-fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl ] propyl} piperidin-4-yl) benzo [b] thiophene-2-carbaldehyde; 6-fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 methyl ester -yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid; amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid; and 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl ethylamide } piperidin-4-yl) benzo [b] thiophene-2-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 shown in Examples 4, 9, 13, and 26.

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 PROTECTIVE 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-methoxymethylene 2-methoxymethylene 2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl , 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, S, S-dioxo-4-methoxytetrahydrothiopyranyl, 1 - [(2-chloro-4-methyl) phenyl] -4-methoxypiperidin-4-yl, 1,4-dioxan-2- sludge, 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 idophenyl) 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.

AMINO PROTECTIVE GROUPS

Protecting groups for amino 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-type 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- 1 -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).

PROTECTION FOR THE CARBONILLA GROUP

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-benzodioxepine.

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-methylphenoxide) methylaluminum (MAD).

PROTECTION FOR THE CARBOXYL GROUP

Esters

Substituted methyl esters

Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethylmethyl 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 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 1-12 and examples 1-13. A person of ordinary skill in the art will be able to modify and adapt the procedures described herein to obtain the described compounds.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Scheme 7

Scheme 8

Scheme 9

Pattern 10

Scheme 11

Pattern 12

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, suitable, preferably, 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 main 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 individual 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. Typically, it is 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. These sub-doses can be obtained in the form of unit dosage forms, 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- [4- (5-Chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol.

A. 1-Methanesulfonyl-piperidin-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 mmol), 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 minutes. 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 1 N aqueous HCl (250 ml) and the layer containing CH ₂ Cl ₂ was separated, dried (Na ₂ SO ₄ ) and concentrated. The resulting oil was placed in ethanol (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 using ethanol 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. 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).

D. 4- (5-Chloro-1H-indol-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester.

5-Chloro-1H-indole (3.2 g, 20 mmol), 4-oxopiperidin-1-carboxylic acid tert-butyl ester (7.97 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) added to MeOH (40 ml) and refluxed for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (200 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 100 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated to form a solid. The solid was washed with MeOH (100 ml), filtered and dried, yielding a light yellow solid 6.3 g (94%). TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.8. Mass spectrum (electrospray): exact mass calculated for C ₁₈ H ₂₁ ClN ₂ O ₂ 332.12; m / z found, 355.0 [M ⁺ + Na]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.26 (br s, 1H), 7.83 (d, J = 1.76 Hz, 1H), 7.28 (d, J = 8.80 Hz , 1H), 7.19-7.14 (m, 2H), 6.09 (br s, 1H), 4.15-4.10 (m, 2H), 3.66 (t, J = 5 , 67 Hz, 2H), 2.56-2.49 (m, 2H), 1.50 (s, 9H).

E. 4- (5-Chloro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester.

4- (5-Chloro-1H-indol-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (6.3 g, 18.9 mmol) in EtOH (125 ml ) containing PtO ₂ (1 g) was placed Parr apparatus for hydrogenation at a pressure of 60 psi H ₂ . After 18 hours, the mixture was filtered through celite and evaporated, yielding a white solid of 6.0 g (94%). TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.8. Mass spectrum (electrospray): exact mass calculated for C ₁₈ H ₂₃ ClN ₂ O ₂ , 334.14; m / z found, 335.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.46 (br s, 1H), 7.51 (d, J = 8.41 Hz, 1H), 7.32 (d, J = 1.57 Hz , 1H), 7.06 (dd, J = 6.46 Hz, 2.15 Hz, 1H), 6.92 (d, J = 2.35 Hz, 1H), 4.24 (d, J = 13 , 11 Hz, 2H), 2.98-2.84 (m, 3H), 2.00 (d, J = 12.72 Hz, 2H), 1.69-1.55 (m, 2H), 1 50 (s, 9H).

F. 5-Chloro-3-piperidin-4-yl-1H-indole.

4- (5-Chloro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 10.2 mmol) was allowed to mix in a 1: 1 mixture of TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated and the golden oil was placed in Et ₂ O. A solid formed, it was filtered off, washed with Et ₂ O and dried in air to give 3.5 g (97%) of a white solid as TFA salt. Mass spectrum (electrospray): exact mass calculated for C ₁₂ H ₁₅ ClN ₂ , 234.09; m / z found, 235.1 [M ⁺ + H].

G. 1- [4- (5-Chloro-1H-indol-3-yl) piperidin-1-yl | -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7- tetrahydro-pyrazolo [4,3-c] pyridin-1-yl] propan-2-ol

5-Chloro-3-piperidin-4-yl-1H-indole (350 mg, 1.00 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro -1H-pyrazolo [4,3-c] pyridine (401 mg, 1.00 mmol) was allowed to mix in EtOH (20 ml) containing Et ₃ N (215 μl, 1.54 mmol) at 80 ° C. After 16 hours, the mixture was cooled, evaporated, placed in CH ₂ Cl ₂ and washed with water. The organic portion was dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-10% MeOH / CH ₂ Cl ₂ ) gave 551 mg (88%) of a white solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.8. Mass spectrum (electrospray): exact mass calculated for C ₃₀ H ₃₃ ClF ₃ N ₅ O ₃ S, 635.19; m / z found, 636.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.82 (br s. 1H), 7.68 (d, J = 8.41 Hz, 2H), 7.61 (d, J = 8.6 Hz , 2H), 7.54 (br s, 1H), 7.16 (d, J = 8.41 Hz, 1H), 7.03 (dd, J = 7.0 Hz, 1.6 Hz, 1H ), 6.85 (br s, 1H), 4.43 (dd, J = 25.2 Hz, 14.6 Hz, 2H), 4.30-4.05 (m, 3H), 4.00 -3.88 (m, 1H), 3.62-3.50 (m, 1H), 3.47-3.35 (m, 1H), 3.02-2.89 (m, 2H), 2 88-2.81 (m, 2H), 2.79 (s, 3H), 2.72-2.60 (m, 1H), 2.47-2.28 (m, 3H), 2.12 -2.00 (m, 1H), 1.96-1.85 (m, 2H), 1.74-1.50 (m, 2H).

EXAMPLE 2

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

A. 4- (7-Chloro-1H-indol-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester.

7-Chloro-1H-indole (3.2 g, 20 mmol), 4-oxopiperidin-1-carboxylic acid tert-butyl ester (7.97 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) were added in MeOH (40 ml) and refluxed for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (200 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 100 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated to obtain a solid. The solid was washed with MeOH (100 ml), filtered and dried, yielding a light yellow solid 6.3 g (94%). TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.8. Mass spectrum (electrospray): exact mass calculated for C ₁₈ H ₂₁ ClN ₂ O ₂ , 332.12; m / z found, 355.0 [M ⁺ + Na]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.26 (br s, 1H), 7.83 (d, J = 1.76 Hz, 1H), 7.28 (d, J = 8.80 Hz , 1H), 7.19-7.14 (m, 2H), 6.09 (br s, 1H), 4.15-4.10 (m, 2H), 3.66 (t, J = 5 , 67 Hz, 2H), 2.56-2.49 (m, 2H), 1.50 (s, 9H).

B. 4- (7-Chloro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester.

4- (7-Chloro-1H-indol-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (6.3 g, 18.9 mmol) in EtOH (125 ml ) containing PtO ₂ (1 g) was placed in a Parr apparatus for hydrogenation at a pressure of 60 psi H ₂ . After 18 hours, the mixture was filtered through celite and evaporated, yielding a white solid of 6.0 g (94%). TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.8. Mass spectrum (electrospray): exact mass calculated for C ₁₈ H ₂₃ ClN ₂ O ₂ , 334.14; m / z found, 335.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.46 (br s, 1H), 7.51 (d, J = 8.41 Hz, 1H), 7.32 (d, J = 1.57 Hz , 1H), 7.06 (dd, J = 6.46 Hz, 2.15 Hz, 1H), 6.92 (d, J = 2.35 Hz, 1H), 4.24 (d, J = 13 , 11 Hz, 2H), 2.98-2.84 (m, 3H), 2.00 (d, J = 12.72 Hz, 2H), 1.69-1.55 (m, 2H), 1 50 (s, 9H).

C. 7-Chloro-3-piperidin-4-yl-1H-indole.

4- (7-Chloro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 10.2 mmol) was allowed to mix in a 1: 1 mixture of TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated and the golden oil was placed in Et ₂ O. A solid formed, which was filtered off, washed with Et ₂ O and dried in air, yielding 3.5 g (97%) of a white solid. Mass spectrum (electrospray): exact mass calculated for C ₁₂ H ₁₅ ClN ₂ , 234.09; m / z found, 235.1 [M ⁺ + H].

D. 1 - [4- (7-Chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7- tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol

7-Chloro-3-piperidin-4-yl-1H-indole (341 mg, 0.97 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro -1H-pyrazolo [4,3-c] pyridine (130 mg, 0.32 mmol) was allowed to mix in EtOH (15 ml) containing Et ₃ N (135 μl, 0.97 mmol) at 80 ° C. After 16 hours, the mixture was cooled, evaporated, placed in CH ₂ Cl ₂ and washed with water. The organic portion was dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-10% MeOH / CH ₂ Cl ₂ ) gave 120 mg (65%) of a white solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.7. Mass spectrum (electrospray): exact mass calculated for C ₃₀ H ₃₃ ClF ₃ N ₅ O ₃ S, 635.19; m / z found, 636.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.55 (broad s, 1H), 7.70 (d, J = 8.22 Hz, 2H), 7.63 (d, J = 8.4 Hz , 2H), 7.49 (d, J = 9.4Hz, 1H), 7.14 (d, J = 7.8Hz, 1H), 7.00 (t, J = 8.02Hz, 1H) 6.94 (br s, 1H); 4.51 (dd, J = 12.5 Hz; 14.5 Hz; 2H); 4.25-4.11 (m, 3H); 4.07- 3.95 (m, 1H), 3.73-3.61 (m, 1H), 3.61-3.50 (m, 1H), 3.11-2.98 (m, 2H), 2, 88-2.85 (m, 2H), 2.83 (s, 3H), 2.82-2.72 (m, 1H), 2.55-2.38 (m, 3H), 2.24- 2.10 (m, 1H); 2.05-1.90 (m, 2H); 1.82-1.61 (m, 2H).

EXAMPLE 3

1- [4- (5-Chloro-2-methyl-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6, 7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

A. 4- (5-Chloro-2-methyl-1H-indol-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester.

5-Chloro-2-methyl-1H-indole (3.3 g, 20 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (7.97 g, 40 mmol) and potassium hydroxide (4, 5 g, 80 mmol) was added in MeOH (40 ml) and refluxed for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (200 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 100 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated to obtain a solid. The solid was washed with MeOH (100 ml), filtered and dried, yielding a light yellow solid of 6.2 g (90%). TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.8. Mass spectrum (electrospray): exact mass calculated for C ₁₉ H ₂₃ ClN ₂ O ₂ , 346.14; m / z found, 347.1 [M ⁺ + H].

B. 4- (5-Chloro-2-methyl-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester

4- (5-Chloro-2-methyl-1H-indol-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (6.2 g, 17.9 mmol) in EtOH (125 ml) containing PtO ₂ (1 g) was placed in a Parr apparatus for hydrogenation at a pressure of 60 psi H ₂ . After 18 hours, the mixture was filtered through celite and evaporated, yielding a white solid of 6.2 g (99%). TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.8. Mass spectrum (electrospray): exact mass calculated for C ₁₉ H ₂₅ ClN ₂ O ₂ , 348.16; m / z found, 349.1 [M ⁺ + H].

C. 5-Chloro-2-methyl-3-piperidin-4-yl-1H-indole.

4- (5-Chloro-2-methyl-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (6.2 g, 107.8 mmol) was allowed to mix in a 1: 1 mixture of TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated and the golden oil was placed in Et ₂ O. The resulting solid was filtered off, washed with Et ₂ O and dried in air to obtain 6.2 g (95%) of a white solid as TFA salt. Mass spectrum (electrospray): exact mass calculated for C ₁₄ H ₁₇ ClN ₂ , 248.11; m / z found, 249.1 [M ⁺ + H].

D. 1- [4- (5-Chloro-2-methyl-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4.5, 6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

5-Chloro-2-methyl-3-piperidin-4-yl-1H-indole (480 mg, 1.32 mmol) and 5-methanesulfonyl-1-oxiranyl-3- (4-trifluoromethylphenyl) -4,5,6 , 7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (177 mg, 0.44 mmol) was allowed to mix in EtOH (20 ml) containing Et ₃ N (215 μl, 1.54 mmol), at 80 ° C. After 16 hours, the mixture was cooled, evaporated, placed in CH ₂ Cl ₂ and washed with water. The organic portion was dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-10% MeOH / CH ₂ Cl ₂ ) gave 169 mg (62%) of a white solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.6. Mass spectrum (electrospray): exact mass calculated for C ₃₁ H ₃₅ ClF ₃ N ₅ O ₃ S, 649.21; m / z found, 650.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.00 (s, 1H), 7.70 (d, J = 8.11 Hz, 2H), 7.64 (d, J = 8.41 Hz, 2H ), 7.57 (d, J = 1.96 Hz, 1H), 7.12 (d, J = 8.61 Hz, 1H), 6.99 (dd, J = 6.85 Hz, 1.96 Hz, 1H), 4.53 (dd, J = 14.28 Hz, 12.91 Hz, 2H), 4.26-4.14 (m, 2H), 4.09-3.99 (m, 1H ), 3.75-3.65 (m, 1H), 3.64-3.54 (m, 1H), 3.14-3.02 (m, 2H), 3.00-2.89 (m , 2H), 2.86 (s, 3H), 2.76-2.63 (m, 1H), 2.54-2.45 (m, 2H), 2.45-2.36 (m, 1H ), 2.34 (s, 3H), 2.25-2.00 (m, 3H), 1.77-1.63 (m, 2H).

EXAMPLE 4

1- {4- [6-Chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} -3- [5-methanesulfonyl-3- (4 trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

A. 6-Chloro-3-piperidin-4-yl-1H-indole

6-Chloro-1H-indole (3.2 g, 20 mmol), piperidin-4-one monohydrate (6.1 g, 40 mmol) and potassium hydroxide (4.5 g, 80 mmol) were added to MeOH (40 ml ) and boiled under reflux for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (200 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 100 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 20-100% MeOH / CH ₂ Cl ₂ with 2% NH ₄ OH) gave 5.89 (100%) of a yellow solid. A solid (5.8 g, 20 mmol) in EtOH (150 ml) containing PtO ₂ (1 g) was placed in a Parr apparatus for hydrogenation at a pressure of 60 psi H ₂ . After 18 hours, the mixture was filtered through celite and evaporated to give an off-white solid, 4.6 g (97%). Mass spectrum (electrospray): exact mass calculated for C ₁₃ H ₁₅ ClN ₂ , 234.09; m / z found, 235.0 [M ⁺ + H].

B. 4- (6-Chloro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of 6-chloro-3-piperidin-4-yl-1H-indole (4.6 g, 19.5 mmol) in DMF (20 ml) was added di-tert-butyl dicarbonate (4.6 g, 21.4 mmol) ) The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was dissolved in EtOAc (400 ml), washed with water (3 × 50 ml), brine (1 × 50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 20-50% EtOAc / hexanes) afforded 4.2 g (64%) of the desired product. TLC (silica, 20% EtOAc / hexanes): R _f = 0.24. Mass spectrum (electrospray): exact mass calculated for C ₁₈ H ₂₃ ClN ₂ O ₂ , 334.14; m / z found, 335.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz) 8.46 (br s, 1H), 7.42 (d, J = 8.61 Hz, 1H), 7.14 (d, J = 1.57 Hz, 1H), 6.96 (dd, J = 6.65 Hz, 1.76 Hz, 1H), 6.74 (s, 1H), 4.14 (br s, 2H), 2.89-2, 70 (m, 3H), 1.90 (d, J = 12.13, 2H), 1.65-1.50 (m, 2H), 1.41 (s, 9H).

C. 4- [6-Chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidine-1-carboxylic acid tert-butyl ester

4- (6-Chloro-1H-indol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.95 mmol) was dissolved in THF (30 ml). Potassium bis (trimethylsilyl) amide (2.37 g, 11.9 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. 4- (2-Chloro-ethyl) morpholine hydrochloride (1.8 g, 11.9 mmol) was added and stirred at room temperature for an additional 1 hour. The mixture was dissolved in EtOAC (250 ml) and washed with water (2 × 30 ml) and brine (30 ml). The organic portion was dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-5% MeOH / CH ₂ Cl ₂ ) afforded 2.6 g (97%) of a white solid. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.67. Mass spectrum (electrospray): exact mass calculated for C ₂₄ H ₃₄ ClN ₃ O, 447.23; m / z found, 448.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 7.45 (d, J = 8.61 Hz, 1H), 7.27 (d, J = 1.57 Hz, 1H), 6.99 (dd, J = 6.65 Hz, 1.76 Hz, 1H), 6.84 (s, 1H), 4.18 (broad s, 2H), 4.06 (t, J = 6.85 Hz, 2H), 3.69-3.60 (m, 4H), 2.92-2.80 (m, 2H), 2.69-2.60 (m, 3H), 2.44 (t, J = 4.89 Hz, 2H), 2.40 (t, J = 4.30 Hz, 2H), 1.94 (d, J = 12.13, 2H), 1.65-1.50 (m, 2H), 1 45 (s, 9H).

D. 6-Chloro-1- (2-morpholin-4-yl-ethyl) -3-piperidin-4-yl-1H-indole

4- [6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-l] piperidine-1-carboxylic acid tert-butyl ester (2.6 g, 5.81 mmol) allowed to mix in a 1: 1 mixture of TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated and the golden oil was placed in Et ₂ O. A solid formed, which was filtered off, washed with Et ₂ O and dried in air to give 2.5 g (95%) of a white solid. Mass spectrum (electrospray): exact mass calculated for C ₁₉ H ₂₆ ClN ₃ O, 347.18; m / z found, 348.2 [M ⁺ + H].

E. 1- {4- [6-Chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

6-Chloro-1- (2-morpholin-4-yl-ethyl) -3-piperidin-4-yl-1H-indole (209 mg, 0.6 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3- ( 4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (120 mg, 0.3 mmol) was allowed to mix in EtOH (20 ml) containing Et ₃ N (84 μl, 0.6 mmol) at 80 ° C. After 16 hours, the mixture was cooled, evaporated, placed in CH ₂ Cl ₂ and washed with water. The organic portion was dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-10% MeOH / CH ₂ Cl ₂ ) gave 180 mg (85%) of a white solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.54. Mass spectrum (electrospray): exact mass calculated for C ₃₆ H ₄₄ ClF ₃ N ₆ O ₄ S, 748.28; m / z found, 749.3 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 7.70 (d, J = 8.61 Hz, 2H). 7.64 (d, J = 8.261 Hz, 2H), 7.47 (d, J = 8.80 Hz, 1H), 7.29 (d, J = 1.96, 1H), 7.02 (dd , J = 6.46 Hz, 1.76 Hz, 1H), 6.81 (br s, 1H), 4.54 (dd, J = 4.09 Hz, 7.43 Hz, 2H), 4, 24-4.14 (m, 2H), 4.14-4.08 (m, 2H), 4.06-3.98 (m, 1H), 3.73-3.57 (m, 5H), 3.12-3.02 (m, 2H), 2.97-2.87 (m, 2H), 2.86 (s, 3H), 2.83-2.74 (m, 1H), 2, 70-2.64 (t, J = 7.24 Hz, 2H), 2.54-2.42 (m, 8H), 2.23-2.14 (m, 1H), 2.05-1, 96 (m, 2H); 1.82-1.60 (m, 2H).

EXAMPLE 5

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [3, 2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

A. 4- (1H-Pyrrolo [3,2-c] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester.

A solution of 1.9 g (8.47 mmol) of 1H-pyrrolo [3,2-c] pyridine (synthesized according to the procedure described in Synthesis, 1996, 882), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 16.9 mmol) and potassium hydroxide (1.9 g, 33.9 mmol) in MeOH (20 ml) were refluxed for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (100 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 50 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated to form a solid. The solid was washed with MeOH (50 ml), filtered and dried, yielding a light yellow solid of 2.0 g (79%). TLC (silica, 10% MeOH / CH ₂ Cl ₂ : R _f = 0.5. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₂₁ N ₃ O ₂ , 299.16; m / z found 300.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 12.26 (br s, 1H), 9.20 (s, 1H), 8.28 (d, J = 5.67 Hz, 1H), 7.35 (dd, J = 5.09 Hz, 0.78 Hz, 1H), 7.32 (s, 1H), 6.19 (br s, 1H), 4 14 (br s, 2H), 3.68 (t, J = 5.67 Hz, 2H), 2.61-2.55 (m, 2H), 1.48 (s, 9H).

B. 4- (1H-Pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-carboxylic acid tert-butyl ester.

4- (1H-Pyrrolo [3,2-c] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (2 g, 6.6 mmol) in EtOH ( 50 ml) containing PtO ₂ (500 mg) was placed in a Parr apparatus for hydrogenation at a pressure of 60 psi H ₂ . After 18 hours, the mixture was filtered through celite and evaporated to give a white solid (2.0 g, 100%). TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.49. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₂₃ N ₃ O ₂₂ , 301.18; m / z found, 302.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 13.66 (br s, 1H), 8.88 (s, 1H), 8.79 (d, J = 6.46 Hz, 1H), 7.69 (d, J = 6.46 Hz, 1H), 7.30 (s, 1H), 4.14 (br s, 2H), 2.99-2.87 (m, 1H), 2.86- 2.71 (m, 2H), 1.91 (d, J = 11.54 Hz, 2H), 1.64-1.50 (m, 2H), 1.38 (s, 9H).

C. 3-Piperidin-4-yl-1H-pyrrolo [3,2-c] pyridine.

4- (1H-Pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-carboxylic acid tert-butyl ester (2.0 g, 6.6 mmol) was allowed to mix in a 1: 1 mixture of TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated and the golden oil was placed in Et ₂ O. A solid formed, which was filtered off, washed with Et ₂ O and dried in air to obtain 2.1 g (100%) of a white solid as TFA salt. Mass spectrum (electrospray): exact mass calculated for C ₁₂ H ₁₅ N ₃ , 201.13; m / z found, 202.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 9.4 (br s, 1H), 8.96 (s, 1H), 8.26 (d, J = 5.87 Hz, 1H), 7.24 (s, 1H), 6.99 (s, 1H), 3.22-3.16 (m, 2H), 3.05-2.95 (m, 1H), 2.86-2.77 (m , 2H), 2.05 (d, J = 12.72 Hz, 2H), 1.89 (br s, 1H), 1.75-1.63 (m, 2H).

D. 1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [ 3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

3-piperidin-4-yl-1H-pyrrolo [3,2-c] pyridine (159 mg, 0.5 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4,5,6 , 7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (200 mg, 0.5 mmol) was allowed to mix in EtOH (10 ml) containing Et ₃ N (112 μl, 0.77 mmol) at 80 ° C. After 16 hours, the mixture was cooled, evaporated, placed in CH ₂ Cl ₂ and washed with water. The organic portion was dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-10% (2 n NH ₃ in MeOH) / CH ₂ Cl ₂ ) gave 82 mg (27%) of a white solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.8. Mass spectrum (electrospray): exact mass calculated for C ₂₉ H ₃₃ F ₃ N ₆ O ₃ S, 602.23; m / z found, 603.2 [M ++ H]. ¹ H NMR (CDCl ₃ , 400 MHz): 9.62 (s, 1H), 8.90 (s, 1H), 8.21 (d, J = 5.87 Hz, 1H), 7.69 (d , J = 7.83 Hz, 2H), 7.62 (d, J = 8.41 Hz, 2H), 7.23 (d, J = 5.87 Hz, 1H), 6.97 (s, 1H ), 4.51 (dd, J = 14.48 Hz, 8.80 Hz, 2H), 4.23-4.13 (m, 2H), 4.05-3.95 (m, 1H), 3 72-3.54 (m, 3H), 3.11-2.98 (m, 2H), 2.95-2.86 (m, 2H), 2.84 (s, 3H), 2.51 -2.39 (m, 3H), 2.20-2.11 (m, 1H), 2.07-1.97 (m, 2H), 1.85-1.63 (m, 2H).

EXAMPLE 6

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [2, 3-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

A. 4- (1H-Pyrrolo [2,3-b] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester

1H-Pyrrolo [2,3-b] pyridine (3 g, 25 mmol), 4-oxopiperidin-1-carboxylic acid tert-butyl ester (4.2 g, 21 mmol) and potassium hydroxide (3.56 g, 63 mmol) was added in MeOH (60 ml) and refluxed for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (300 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 150 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated to form a solid. The solid was washed with MeOH (150 ml), filtered and dried, yielding a light yellow solid of 5.7 g (91%). TLC (silica, 50% EtOAc / hexanes): R _f = 0.3. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₂₁ N ₃ O ₂ , 299.16; m / o found, 300.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz) 10.97 (br s, 1H), 8.33 (dd, J = 3.33 Hz, 1.37 Hz, 1H), 8.20 (dd, J = 6.65 Hz, 1.37 Hz, 1H), 7.34 (br s, 1H), 7.25 (s, 1H), 7.13 (dd, J = 4.89 Hz, 3.13 Hz , 1H), 4.14 (br s, 2H), 3.68 (t, J = 5.28 Hz, 2H), 2.56 (br s, 2H), 1.49 (s, 9H) .

B. 4- (1H-Pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-carboxylic acid tert-butyl ester

4- (1H-Pyrrolo [2,3-b] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (1 g, 3.3 mmol) in EtOH ( 25 ml) containing PtO ₂ (250 mg) was placed in a Parr apparatus for hydrogenation at a pressure of 60 psi H ₂ . After 18 hours, the mixture was filtered through celite and evaporated, yielding 0.96 g (97%) of a white solid. TLC (silica, 50% EtOAc / hexanes): R _f = 0.5. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₂₃ N ₃ O ₂₂ , 301.18; m / z found, 302.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 10.95 (br s, 1H). 8.26 (dd, J = 3.33 Hz, 1.37 Hz, 1H), 7.96 (dd, J = 6.26 Hz, 1.57 Hz, 1H), 7.11 (s, 1H) 7.05 (dd, J = 4.89 Hz, 3.13 Hz, 1H), 4.22 (br s, 2H), 3.00-2.79 (m, 3H), 1.99 ( d, J = 13.89 Hz, 2H), 1.74-1.60 (m, 2H), 1.47 (s, 9H).

C. 3-piperidin-4-yl-1H-pyrrolo [2,3-b] pyridine.

4- (1H-Pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-carboxylic acid tert-butyl ester (963 mg, 3.2 mmol) was allowed to mix in a 1: 1 mixture of TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated and the golden oil was placed in Et ₂ O. A solid formed, which was filtered off, washed with Et ₂ O and dried in air to give 974 mg (96%) of a white solid as TFA salt. Mass spectrum (electrospray): exact mass calculated for C ₁₂ H ₁₅ N ₃ , 201.13; m / z found, 202.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.09 (dd, J = 3.33 Hz, 1.57 Hz, 1H), 7.89 (dd, J = 6.26 Hz, 1.57 Hz, 1H), 7.01 (s, 1H), 6.99 (dd, J = 4.89 Hz, 3.13 Hz, 1H), 5.04 (br s, 2H), 3.11-3, 04 (m, 2H), 2.88-2.79 (m, 1H), 2.73-2.64 (m, 2H), 1.94 (d, J = 12.52 Hz, 2H), 1 65-1.63 (m, 2H).

D. 1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [ 2,3-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

3-piperidin-4-yl-1H-pyrrolo [2,3-b] pyridine (443 mg, 1.4 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4,5,6 , 7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (289 mg, 0.7 mmol) was allowed to mix in EtOH (10 ml) containing Et ₃ N (146 μl, mmol) at 80 ° C. After 16 hours, the mixture was cooled, evaporated, placed in CH ₂ Cl ₂ and washed with water. The organic portion was dried over Na ₂ SO ₄ and concentrated. Column chromatography (silica, 0-10% (2 n NH ₃ in MeOH / CH ₂ Cl ₂ ) gave 107 mg (25%) of a white solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.45 Mass spectrum (electrospray): exact mass calculated for C ₂₉ H ₃₃ F ₃ N ₆ O ₃ S, 602.23; m / z found, 603.3 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 10.6 (br s, 1H), 8.24 (m, 1H), 7.91 (m, 1H), 7.70 (m, 2H), 7, 63 (m, 2H), 7.05 (br s, 1H), 7.02 (m, 1H), 4.52 (dd, J = 4.28 Hz, 9.78 Hz, 2H), 4, 24-4.16 (m, 2H), 4.06-3.98 (m, 1H), 3.72-3.64 (m, 1H), 3.64-3.55 (m, 1H), 3.11-3.00 (m, 2H), 2.96-2.87 (m, 2H), 2.85 (s, 3H), 2.82-2.74 (m, 1H), 2, 53-2.40 (m, 3H), 2.22-2.12 (m, 1H), 2.05-1.95 (m, 2H), 1.85-1.64 (m, 2H).

EXAMPLE 7

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-morpholin-4- yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

A. [2- (2-Chloro-5-nitropyridin-4-yl) vinyl] dimethylamine.

A solution of 2-chloro-4-methyl-5-nitropyridine (2 g, 11.59 mmol) in DMF (11.6 ml) was treated with 3.08 ml (23.2 mmol, 2 equiv.) Of DMF-dimethyl acetal and the reaction mixture stirred at 100 ° C for 4 hours. All volatile components were removed under reduced pressure. Column chromatography (silica, 20% EtOAc / hexanes) afforded 2.37 g (90%) of [2- (2-chloro-5-nitropyridin-4-yl) vinyl] dimethylamine. TLC (silica, 20% EtOAc / hexanes): R _f = 0.30. Mass spectrum (electrospray): exact mass calculated for C ₉ H ₁₀ ClN ₃ O ₂ , 227.05; m / z found, 228.1 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 8.79 (s, 1H), 8.02 (s, 1H), 7.35 (d, J = 13 Hz, 1H), 5.94 (d, J = 13 Hz, 1H), 2.96 (s, 3H), 2.87 (s, 3H).

B. 5-Morpholin-4-yl-1H-pyrrolo [2,3-c] pyridine.

A solution of 450 mg (2 mmol) of [2- (2-chloro-5-nitropyridin-4-yl) vinyl] dimethylamine in 20 ml of a mixed solvent of MeOH-CH ₂ Cl ₂ (1: 1) was treated with 3 ml of morpholine. The reaction mixture was stirred at 65 ° C for 8 hours. Volatile components were then removed. CH ₂ Cl ₂ (100 ml) and H ₂ O (30 ml) were added. The organic layer was separated and washed with H ₂ O (30 ml), brine (30 ml), dried over Na ₂ SO ₄ and concentrated. The red powder was treated with 4.0 g (63 mmol, 32 equiv.) Of ammonium formate and 10% Pd-C (120 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. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 210 mg (52% for 2 steps) of 5-morpholin-4-yl-1H-pyrrolo [2,3-c] pyridine as a yellow solid. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.40. Mass spectrum (electrospray): exact mass calculated for C ₁₁ H ₁₃ N ₃ O, 203.11; m / z found, 204.2 [M + H] ⁺ .

C. 4- (5-Morpholin-4-yl) -1H-pyrrolo [2,3-c] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester.

A solution of 200 mg (1.0 mmol) of 5-morpholin-4-yl-1H-pyrrolo [2,3-c] pyridine and 398 mg (2.0 mmol, 2 equiv.) Of 4-oxopiperidin-1 tert-butyl ester -carboxylic acid in 5 ml of MeOH was treated with 224 mg (4.0 mmol, 4 equiv.) of potassium hydroxide. The reaction mixture was stirred at 65 ° C for 12 hours and the volatiles were removed. The crude product was partitioned between CH ₂ Cl ₂ (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. The yellow powder was treated with 630 mg (10 mmol, 10 equiv.) Of ammonium formate and 10% Pd-C (50 mg). The reaction mixture was stirred at 65 ° C for 1 hour. The reaction mixture was then filtered through a pad of celite and concentrated to give a yellow solid. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 180 mg (47% for 2 steps) a yellow solid. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.40. Mass spectrum (electrospray): exact mass calculated for C ₂₁ H ₃₀ N ₄ O ₃ , 386.23; m / z found, 387.2 [M + H] ⁺ .

D. 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c) pyridin-1-yl) -3- [4- (5-morpholin- 4-yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

4- (5-Morpholin-4-yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.47 mmol) was dissolved in 3, 0 ml of CH ₂ Cl ₂ and treated with 2.5 ml of trifluoroacetic acid. The reaction mixture was stirred at 25 ° C for 1 hour before removing all volatile components. The solid was dissolved in MeOH (20 ml) and neutralized using a DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure. The residue was dissolved in 2.5 ml of iso-PrOH and treated with 187 mg (0.47 mmol, 1 equiv.) Of 5-methanesulfonyl-1-oxiranylmethyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro 1H-pyrazolo [4,3-c] pyridine. The reaction mixture was stirred at 85 ° C for 3 hours before removing the solvent. Column chromatography (silica, 5-10% MeOH / CH ₂ Cl ₂ , then 5-10% (2N NH ₃ in MeOH) / CH ₂ Cl ₂ ) gave 97 mg (30%) of the title compound. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.25. Mass spectrum (electrospray): exact mass calculated for C ₃₃ H ₄₀ F ₃ N ₇ O ₄ S, 687.28; m / z found, 688.3 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ): 8.47 (br s, 1H), 8.44 (d, J = 1.0 Hz, 1H), 7.70 and 7.65 (AB system, J = 8.4 Hz, 4H), 7.03 (d, J = 2.1 Hz, 1H), 6.76 (s, 1H), 4.58-4.50 (m, 2H), 4.21 -4.00 (m, 3H), 3.90 (t, J = 4.5 Hz, 4H), 3.72-3.58 (m, 2H), 3.40 (t, J = 4.5 Hz, 4H), 3.10-2.85 (m, 4H), 2.88 (s, 3H), 2.80-2.70 (m, 1H), 2.52-2.41 (m, 3H), 2.20-2.00 (m, 3H), 1.80-1.60 (m, 2H).

EXAMPLE 8

1- [4- (6-Dimethylamino-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

A. Dimethyl- (5-methyl-4-nitro-1-hydroxypyridin-2-yl) amine.

A solution of 2-bromo-5-methyl-4-nitropyridine 1-oxide (674 mg, 278 mmol) in 2M dimethylamine in methanol (20 ml) was heated at 65 ° C for 16 hours. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica, 30-80% EtOAc / hexanes) to give 290 mg (53%) of the expected product. TLC (silica, 50% EtOAc / hexanes): R _f = 0.10. Mass spectrum (electrospray): exact mass calculated for C ₈ H ₁₁ N ₃ O ₃ , 197.08; m / z found, 198.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.04 (s, 1H), 7.50 (s, 1H), 3.00 (s, 6H), 2.44 (s, 3H).

B. Dimethyl- (1H-pyrrolo [3,2-c] pyridin-6-yl) amine.

A solution of dimethyl- (5-methyl-4-nitro-1-hydroxypyridin-2-yl) amine (290 mg, 1.47 mmol) in DMF (3 ml) was treated with DMF-dimethylacetal (390 μl, 2.94 mmol) and the reaction mixture was stirred at 100 ° C for 4 hours. All volatile components were removed under reduced pressure. The red powder was treated with ammonium formate (927 mg, 14.7 mmol) and 10% Pd-C (156 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. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 100 mg (42% in two steps) of the product as a yellow solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.2. Mass spectrum (electrospray): exact mass calculated for C ₉ H ₁₁ N ₃ , 161.10; m / z found, 162.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.55 (s, 1H), 8.28 (br s, 1H), 6.96 (dd, J = 1.96 Hz, 1.37 Hz, 1H ), 6.45-6.43 (m, 1H), 6.39 (s, 1H), 3.08 (s, 6H).

C. 4- (6-Dimethylamino-1H-pyrrolo [3,2-c] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester.

Dimethyl- (1H-pyrrolo [3,2-c] pyridin-6-yl) amine (100 mg, 0.62 mmol), 4-oxopiperidin-1-carboxylic acid tert-butyl ester (248 mg, 1.24 mmol ) and potassium hydroxide (139 mg, 2.48 mmol) were added in MeOH (5 ml) and refluxed for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (20 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 10 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH / CH ₂ Cl ₂ ) to obtain 180 mg (85%) of the title compound. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.58. Mass spectrum (electrospray): exact mass calculated for C ₁₉ H ₂₆ N ₄ O ₂ , 342.21; m / z found, 343.2 (M ⁺ + H). ¹ H NMR (CDCl ₃ , 400 MHz): 9.09 (br s, 1H), 8.76 (s, 1H), 6.90 (d, J = 2.15 Hz, 1H), 6.32 (s, 1H), 6.10 (br s, 1H), 4.10-4.05 (m, 2H), 3.62 (t, J = 5.87 Hz, 2H), 3.03 ( s, 6H), 2.52-2.44 (m, 2H), 1.46 (s, 9H).

D. 4- (6-Dimethylamino-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester.

Solution of 4- (6-Dimethylamino-1H-pyrrolo [3,2-c] pyridin-3-yl) -3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (180 mg, 0.53 mmol) in MeOH (10 ml) was treated with ammonium formate (332 mg, 5.3 mmol) and 10% Pd-C (56 mg). The reaction mixture was stirred at 65 ° C for 1 hour. The reaction mixture was then filtered through a pad of celite and concentrated to give an off-white solid. Column chromatography (silica, 0-5% MeOH / CH ₂ Cl ₂ ) afforded 135 mg (75%) of the product as a white solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.50. Mass spectrum (electrospray): exact mass calculated for C ₁₉ H ₂₈ N ₄ O ₂ , 344.22; m / z found, 345.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.53 (s, 1H), 8.30 (br s, 1H), 6.67 (dd, J = 1.17 Hz, 0.78 Hz, 1H ), 6.34 (d, J = 0.78 Hz, 1H), 4.33-4.16 (m, 2H), 3.05 (s, 6H), 2.97-2.80 (m, 3H), 1.99 (d, J = 12.72 Hz, 2H), 1.69-1.53 (m, 2H), 1.46 (s, 9H).

E. Dimethyl- (3-piperidin-4-yl-1H-pyrrolo [3,2-c] pyridin-6-yl) amine.

4- (6-Dimethylamino-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester (135 mg, 0.39 mmol) was allowed to mix in a 1: 1 mixture of TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated. The residue was dissolved in MeOH (10 ml) and neutralized using a DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure to obtain 96 mg (100%) of a yellow solid. Mass spectrum (electrospray): exact mass calculated for C ₁₄ H ₂₀ N ₄ , 244.17; m / z found, 245.2 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 9.23 (br s, 1H), 8.54 (s, 1H), 6.67 (s, 1H), 6.31 (d, J = 0, 98 Hz, 1H), 3.15 (d, J = 2.13 Hz, 2H), 3.02 (s, 6H), 2.91-2.81 (m, 1H), 2.81-2, 72 (m, 2H), 2.01 (d, J = 12.52 Hz, 2H), 1.69-1.52 (m, 2H).

F. 1- [4- (6-Dimethylamino-1H-pyrrolo [3,2-c] pyridin-3-yl) -piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

Dimethyl- (3-piperidin-4-yl-1H-pyrrolo [3,2-c] pyridin-6-yl) amine (96 mg, 0.53 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3- (4 trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (319 mg, 0.80 mmol) was allowed to mix in iso-PrOH (10 ml) at 80 ° C. After 16 hours, the mixture was cooled and concentrated. The residue was purified by column chromatography (silica, 0-10% (2 n NH ₃ in MeOH) / CH ₂ Cl ₂ to give 61 mg (18%) of a white solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.12 Mass spectrum (electrospray): exact mass calculated for C ₃₁ H ₃₈ F ₇ N ₇ O ₃ S, 645.27; m / z found, 646.3 [M ⁺ + H ]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.53 (s, 1H), 7.93 (br s, 1H), 7.71 (d, J = 8.22 Hz, 2H), 7 64 (d, J = 8.22 Hz, 2H), 6.67 (br s, 1H), 6.33 (d, J = 0.98 Hz, 1H), 4.54 (dd, J = 14.28 Hz, 9.59 Hz, 2H), 4.22-4.10 (m, 2H), 4.04-3.97 (m, 1H), 3.74-3.57 (m, 2H ), 3.13-3.06 (m, 1H), 3.05 (s, 6H), 3.03-2.87 (m. 3H), 2.85 (s, 3H), 2.82- 2.71 (m, 1H), 2.50-2.37 (m, 3H), 2.20-2.11 (m, 1H), 2.06-1.97 (m, 2H), 1, 82-1.61 (m, 2H).

EXAMPLE 9

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl} -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

A. 4- (5-Methyl-4-nitro-1-hydroxypyridin-2-yl) morpholine.

A solution of 2-bromo-5-methyl-4-nitropyridine 1-oxide (500 mg, 2.14 mmol) in morpholine (15 ml) was heated at 70 ° C for 16 hours. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica, 30-80% EtOAc / hexanes) to give 480 mg (94%) of the expected product. TLC (silica, 50% EtOAc / hexanes): R _f = 0.10. Mass spectrum (electrospray): exact mass calculated for C ₁₀ H ₁₃ N ₃ O ₄ , 239.09; m / z found, 240.1 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.09 (s, 1H), 7.55 (s, 1H), 3.90 (t, J = 4.50 Hz, 4H), 3.36 (t , J = 4.70 Hz, 4H); 2.50 (s, 3H).

B. 6-Morpholin-4-yl-1H-pyrrolo [3,2-c] pyridine.

A solution of 4- (5-methyl-4-nitro-1-hydroxypyridin-2-yl) morpholine (480 mg, 2 mmol) in DMF (5 ml) was treated with DMF-dimethylacetal (533 μl, 4 mmol) and the reaction mixture was stirred at 100 ° C for 4 hours. All volatile components were removed under reduced pressure. The red powder was treated with ammonium formate (1.26 g, 20 mmol) and 10% Pd-C (212 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. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 197 mg (49% in two steps) of a yellow solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.55. Mass spectrum (electrospray): exact mass calculated for C ₁₁ H ₁₃ N ₃ O, 203.11; m / z found, 204.1 [M + H] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz) 8.68 (br s, 1H), 8.59 (s, 1H), 7.04 (dd, J = 2.15 Hz, 1.17 Hz, 1H) 6.51 (s, 1H), 6.49-6.47 (m, 1H), 3.86 (t, J = 4.70 Hz, 4H), 3.40 (t, J = 4.70 Hz, 4H).

C. 4- (6-Morpholin-4-yl-1H-pyrrolo [3,2-c] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester

6-Morpholin-4-yl-1H-pyrrolo [3,2-c] pyridine (197 mg, 0.97 mmol), 4-oxopiperidin-1-carboxylic acid tert-butyl ester (387 mg, 1.94 mmol) and potassium hydroxide (218 mg, 3.88 mmol) was added in MeOH (10 ml) and refluxed for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (50 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 20 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH / CH ₂ Cl ₂ ) to give 337 mg (91%) of the desired product. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.50. Mass spectrum (electrospray): exact mass calculated for C ₂₁ H ₂₈ N ₄ O ₃ , 384.22; m / z found, 749.3 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 9.24 (br s, 1H), 8.77 (s, 1H), 6.95 (d, J = 2.15 Hz, 1H), 6.45 (s, 1H), 6.09 (br s, 1H), 4.09-4.04 (m, 2H), 3.66 (t, J = 6.06 Hz, 4H), 3.60 ( t, J = 5.28 Hz, 2H), 3.25 (t, J = 5.09 Hz, 4H), 2.38 (d, J = 6.26 Hz, 2H), 1.44 (s, 9H).

D. 4- (6-Morpholin-4-yl-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester

4- {6-Morpholin-4-yl-1H-pyrrolo [3,2-c] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (337 mg, 0.9 mmol) in MeOH (20 ml) was treated with ammonium formate (568 mg, 9.0 mmol) and 10% Pd-C (95 mg). The reaction mixture was stirred at 65 ° C for 1 hour. The reaction mixture was then filtered through a pad of celite and concentrated to give an off-white solid. Column chromatography (silica, 0-5% MeOH / CH ₂ Cl ₂ ) gave 340 mg (98%) of a white solid. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.40. Mass spectrum (electrospray): exact mass calculated for C ₂₁ H ₃₀ N ₄ O ₃ , 386.23; m / z found, 387.3 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz) 9.14 (br s, 1H), 8.55 (s, 1H), 6.74 (d, J = 1.96 Hz, 1H), 6.45 ( s, 1H), 4.27-4.08 (m, 2H), 3.80 (t, J = 4.50 Hz, 4H), 3.34 (t, J = 4.69 Hz, 4H), 2.96-2.77 (m, 3H), 1.97 (d, J = 12.91 Hz, 2H), 1.67-1.52 (m, 2H), 1.44 (s, 9H) .

E. 6-Morpholin-4-yl-3-piperidin-4-yl-1H-pyrrolo [3,2-c] pyridine

4- (6-Morpholin-4-yl-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester (380 mg, 0.98 mmol) was allowed to mix in a mixture 1: 1 TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated. The residue was dissolved in MeOH (20 ml) and neutralized using a DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered off and MeOH was removed under reduced pressure to obtain 281 mg (100%) of a yellow solid. Mass spectrum (electrospray): exact mass calculated for C ₁₆ H ₂₂ N ₄ O, 286.18; m / z found, 287.1 [M ⁺ + H].

F. 1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin- 4-yl-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl-propan-2-ol.

6-Morpholin-4-yl-3-piperidin-4-yl-1H-pyrrolo [3,2-c] pyridine (281 mg, 0.98 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3- (4- trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (591 mg, 1.47 mmol) was allowed to mix in iso-PrOH (10 ml) at 80 ° C. After 16 hours, the mixture was cooled and concentrated. The residue was purified by column chromatography (silica, 0-10% (2 n NH ₃ in MeOH) / CH ₂ Cl ₂ ) to obtain 468 mg (69%) of a white solid. TLC (silica, 10% (2 n NH ₃ in MeOH / CH ₂ Cl ₂ ): R _f = 0.62. Mass spectrum (electrospray): exact mass calculated for C ₃₃ H ₄₀ F ₃ N ₇ O ₄ S, 687.28; m / z found, 688.3 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.56 (s, 1H), 8.40 (br s, 1H) , 7.69 (d, J = 8.41 Hz, 2H), 7.63 (d, J = 8.41, 2H), 6.73 (br s, 1H), 6.46 (s, 1H ), 4.51 (dd, J = 14.28 Hz, 8.80 Hz, 2H), 4.21-4.10 (m, 2H), 4.03-3.95 (m, 1H), 3 82 (t, J = 4.11 Hz, 4H), 3.71-3.54 (m, 2H), 3.36 (t, J = 4.89 Hz, 4H), 3.10-2, 97 (m, 2H), 2.93-2.86 (m, 2H), 2.84 (s, 3H), 2.82-2.72 (m, 1H), 2.50-2.37 ( m, 3H), 2.20-2.10 (m, 1H), 2.04-1.95 (m, 2H), 1.80-1.60 (m, 2H).

EXAMPLE 10

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-5-hydroxy-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

A. 6-Morpholin-4-yl-1H-pyrrolo [3,2-c] pyridine 5-oxide.

A solution of 4- (5-methyl-4-nitro-1-hydroxypyridin-2-yl) morpholine (480 mg, 2 mmol) in DMF (5 ml) was treated with DMF-dimethylacetal (533 μl, 4 mmol) and the reaction mixture was stirred at 100 ° C for 4 hours. All volatile components were removed under reduced pressure. The red powder was treated with ammonium formate (1.26 g, 20 mmol) and 10% Pd-C (212 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. Column chromatography (silica, 5% MeOH / CH ₂ Cl ₂ ) gave 130 mg (30% for two steps) of a yellow solid. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.28. Mass spectrum (electrospray): exact mass calculated for C ₁₁ H ₁₃ N ₃ O ₂ , 219.10; m / z found, 220.1 [M + H] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz): 8.42 (br s, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 6.82 (s, 1H), 6 35 (s, 1H), 3.79 (t, J = 4.70 Hz, 4H), 3.18 (t, J = 4.70 Hz, 4H).

B. 4- (6-Morpholin-4-yl-5-hydroxy-1H-pyrrolo [3,2-c] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1- tert-butyl ester carboxylic acid.

6-Morpholin-4-yl-1H-pyrrolo [3,2-c] pyridine 5-oxide (130 mg, 0.59 mmol), 4-oxopiperidin-1-carboxylic acid tert-butyl ether (237 mg, 1, 19 mmol) and potassium hydroxide (133 mg, 2.37 mmol) were added in MeOH (8 ml) and refluxed for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water (30 ml). The mixture was extracted with 10% MeOH / CH ₂ Cl ₂ (5 × 10 ml). The organic extracts were dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH / CH ₂ Cl ₂ ) to give 140 mg (59%) of the expected product. TLC (silica, 10% MeOH / CH ₂ Cl ₂ ): R _f = 0.55. Mass spectrum (electrospray): exact mass calculated for C ₂₁ H ₂₈ N ₄ O ₄ , 400.21; m / z found, 401.2 (M ⁺ + H).

C. 4- (6-Morpholin-4-yl-5-hydroxy-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester.

4- (6-Morpholin-4-yl-5-hydroxy-1H-pyrrolo [3,2-c] pyridin-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (140 mg, 0.35 mmol) in EtOH (20 ml) containing PtO ₂ (50 mg) was placed in a Parr apparatus for hydrogenation at a pressure of 60 psi H ₂ . After 18 hours, the mixture was filtered through celite and evaporated to give a white solid. Column chromatography (silica, 0-5% (2N NH ₃ in MeOH / CH ₂ Cl ₂ ) gave 56 mg (40%) of a white solid. TLC (silica, 5% MeOH / CH ₂ Cl ₂ ): R _f = 0.13 Mass spectrum (electrospray): exact mass calculated for C ₂₁ H ₃₀ N ₄ O ₄ , 402.23; m / z found, 403.2 (M ⁺ + H). ¹ H NMR (CDCl ₃ , 400 MHz): 11.63 (broad s, 1H), 8.58 (s, 1H), 6.97 (broad s, 1H), 6.69 (s, 1H), 4.26-4 08 (m, 2H), 3.73 (t, J = 4.30 Hz, 4H), 3.17 (t, J = 4.50 Hz, 4H), 2.92-2.74 (m, 3H), 1.91 (d, J = 11.93 Hz, 2H), 1.62-1.50 (m, 2H), 1.43 (s, 9H).

D. 6-Morpholin-4-yl-3-piperidin-4-yl-1H-pyrrolo [3,2-c] pyridin-5-oxide.

4- (6-Morpholin-4-yl-5-hydroxy-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester (56 mg, 0.14 mmol) allowed to mix in a 1: 1 mixture of TFA / CH ₂ Cl ₂ . After 45 minutes, the mixture was evaporated. The residue was dissolved in MeOH (10 ml) and neutralized using a DOWEX 550A OH anion exchange resin to pH 8. The resin was then filtered and MeOH was removed under reduced pressure to obtain 42 mg (100%) of a yellow solid. Mass spectrum (electrospray): exact mass calculated for C ₁₆ H ₂₂ N ₄ O ₂ , 302.17; m / z found, 303.1 [M * + H].

E. 1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin- 4-yl-5-hydroxy-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol

6-Morpholin-4-yl-3-piperidin-4-yl-1H-pyrrolo [3,2-c] pyridin-5-oxide (42 mg, 0.14 mmol) and 5-methanesulfonyl-1-oxiranylmethyl-3 - (4-trifluoromethylphenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine (84 mg, 0.21 mmol) was allowed to mix in iso-PrOH (5 ml) at 80 ° C. After 6 hours, the mixture was cooled and concentrated. The residue was purified by column chromatography (silica, 0-10% (2 n NH ₃ in MeOH) / CH ₂ Cl ₂ ) to obtain 5.1 mg (5%) of a white solid. TLC (silica, 10% (2 n NH ₃ in MeOH) / CH ₂ Cl ₂ ): R _f = 0.54. Mass spectrum (electrospray): exact mass calculated for C ₃₃ H ₄₀ F ₃ N ₇ O ₅ S 703.28; m / z found, 704.3 [M ⁺ + H]. ¹ H NMR (CDCl ₃ , 400 MHz): 8.60 (s, 1H), 7.71 (d, J = 8.41 Hz, 2H), 7.66 (d, J = 8.41, 2H) , 7.27 (s, 1H), 6.95 (s, 1H), 6.70 (s, 1H), 4.55 (dd, J = 14.48 Hz, 3.13 Hz, 2H), 4 , 23-4.11 (m, 2H), 4.05-3.97 (m, 1H), 3.84 (t, J = 4.30 Hz, 4H), 3.72-3.60 (m , 2H), 3.23 (t, J = 4.30 Hz, 4H), 3.12-2.98 (m, 2H), 2.97-2.89 (m, 2H), 2.88 ( s, 3H), 2.73-2.63 (m, 1H), 2.51-2.36 (m, 3H), 2.17-2.08 (m, 1H), 1.99-1, 90 (m, 2H); 1.78-1.58 (m, 2H).

EXAMPLE 11

(2-Hydroxy-ethyl) amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridine -1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid.

A. 1- [4- (2,4-Difluorobenzoyl) piperidin-1-yl] ethanone.

A stirred solution of 10 g (58.5 mmol) of 1-acetylpiperidin-4-carboxylic acid in anhydrous dichloroethane (35 ml) was treated with 5.1 ml (70.2 mmol) of thionyl chloride in 7 ml of dichloroethane and then heated to 60 ° C for 30 minutes. Another flask was prepared containing a suspension of 8.02 ml (81.8 mmol) of 1,3-difluorobenzene and 17.9 g (134 mmol) of aluminum chloride in 55 ml of dichloroethane, and a previously prepared suspension of acid chloride was added in portions to it. The resulting suspension was refluxed for 4 hours, cooled and then poured onto ice and HCl. The acid solution was extracted with CH ₂ Cl ₂ (3 × 300 ml) and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was recrystallized from hexanes to give 9.5 g (61%) of the expected product as a white solid. Mass spectrum (electrospray): exact mass calculated for C ₁₄ H ₁₅ F ₂ NO ₂ , 267.11; m / z found, 268.1 [M + H] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz): 7.87 (dt, J = 8.41, 6.65 Hz, 1H), 6.98 (m, 1H), 6.88 (ddd, J = 10, 96, 8.61, 2.35 Hz, 1H), 4.55 (m, 1H), 3.87 (m, 1H), 3.32 (dtt, J = 10.76, 3.91, 1, 37 Hz, 1H), 3.19 (ddd, J = 13.89, 11.93, 2.93 Hz, 1H), 2.79 (ddd, J = 13.89, 12.24, 2.93 Hz , 1H), 2.10 (s, 3H), 1.95 (broad d, J = 12.91 Hz, 2H), 1.72 (broad m, 1H), 1.56 (broad m, 1H).

B. 3- (1-Acetyl-piperidin-4-yl) -6-fluoro-benzo [b] thiophene-2-carboxylic acid methyl ester.

To a stirred solution of 33.6 g (0.126 mol) of 1- [4- (2,4-difluorobenzoyl) piperidin-1-yl] ethanone and 13 ml (145 mol) of methylthioglycolate in 320 ml of dry THF was added portionwise 5.8 g ( 145 mol) of 60% sodium hydride in mineral oil. The reaction mixture was refluxed overnight, allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was then partitioned between 300 ml of CH ₂ Cl ₂ and 200 ml of water. The aqueous layer was further extracted with CH ₂ Cl ₂ (2 × 500 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give a residue, which was then triturated with hexanes / EtOAc to give 27.5 g (65%) of the desired product as a white solid. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₁₈ FNO ₈ S, 335.1; m / z found, 336.1 [M + H] ⁺ . ¹ H NMR (DMSO-d ₆ , 400 MHz, mixture of amide rotamers): 7.12 (m, 2H), 6.92 (dt, J = 8.41, 1.77 Hz, 1H), 4.43 ( d, J = 3.79 Hz, 1H), 4.43-4.36 (m, 1H), 3.82 (broad t, J = 14.65 Hz, 1H), 3.57 (s, 3H ), 2.92-2.79 (m, 1H), 2.38-2.34 (m, 1H), 1.94 (s, 1.5H), 1.93 (s, 1.5H), 1.86-1.72 (m, 1H), 1.47-1.38 (m, 1H), 1.38-1.27 (m, 0.5H), 1.27-1.16 (m , 1H), 1.15-1.03 (m, 0.5H).

C. 6-Fluoro-3-piperidin-4-yl-benzo [b] thiophen-2-carboxylic acid methyl ester hydrochloride salt.

A solution of 24.4 g (66.8 mmol) of 3- (1-acetylpiperidin-4-yl) -6-fluorobenzo [b] thiophene-2-carboxylic acid methyl ester in 400 ml of MeOH and 50 ml of concentrated HCl was refluxed within 2 days. After the solution was cooled to room temperature, the white precipitate was filtered off, washed with methanol and dried, yielding 17.9 g (74%) of the product as a white powder. Mass spectrum (electrospray): exact mass calculated for C ₁₅ H ₁₆ FNO ₂ S, 293.09; m / z found, 294.1 [M + H] *. ¹ H NMR (DMSO-d ₆ , 400 MHz): 9.38 (broad s, 1H), 9.02 (broad s, 1H), 8.60 (dd, J = 9.19, 5.09 Hz, 1H), 7.98 (dd, J = 9.00, 2.54 Hz, 1H), 7.36 (dt, J = 9.00, 2.54 Hz, 1H), 4.37 (broad .t, J = 12.72 Hz, 1H), 3.87 (s, 3H), 3.40 (broad d, J = 11.93 Hz, 2H), 3.02 (q, J = 11, 35 Hz, 2H), 2.61 (dq, J = 13.30, 3.72 Hz, 2H), 1.77 (broad d, J = 12.91 Hz, 2H).

D. 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 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. Then 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 temperature for 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, then 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 of the title compound. The total yield of 54.6%. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₂₀ F ₃ N ₃ O ₃ S 403.12; m / z found, 404.0 [M + H] ⁺ . 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).

E. 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 an additional 1.5 hours. The reaction mixture was diluted with Et ₂ O (60 ml) and 20% aqueous NaHCO ₃ (35 ml) was slowly added (Caution! Rapid gas evolution). 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) (silica, 1-10% MeOH / CH ₂ Cl ₂ ) afforded 2.53 g of the desired aldehyde in 85% yield. Mass spectrum (electrospray): exact mass calculated for C ₁₇ H ₁₈ F ₃ N ₃ O ₈ S, 401.11; m / z found, 402.1 [M + 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).

F. 6-Fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl methyl ester ] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid

To a stirred solution of 410 mg (1.25 mmol) of 6-fluoro-3-piperidin-4-yl-benzo [b] thiophene-2-carboxylic acid methyl ester hydrochloride salt in 10 ml of dichloromethane and 0.18 ml (1.25 mmol) of triethylamine was added 500 mg of 3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propionaldehyde (1.25 mmol) and 2 g of NaHCO ₃ . The mixture was stirred for 4 hours before adding 792 mg (3.73 mmol) of sodium triacetoxyborohydride in portions. The reaction mixture was stirred at room temperature for 3 hours, after which it was quenched with 20 ml of water. The aqueous phase was extracted with CH ₂ Cl ₂ (3 × 50 ml). The combined organic layers were then washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (silica, 0-5% MeOH / CH ₂ Cl ₂ ) to give 650 mg (77%) of a white solid. Mass spectrum (electrospray): exact mass calculated for C ₃₂ H ₃₄ F ₄ N ₄ O ₄ S ₂ , 678.20; m / z found, 679.2 [M + H] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz): 7.74 and 7.66 (A and B AB quartets, J = 8.22 Hz, 4H), 7.50 (dd, J = 8.41, 2.54 Hz, 1H), 7.14 (t, J = 8.22 Hz, 1H), 4.56 (s, 2H), 4.17 (m, 3H), 3.91 (s, 3H), 3, 70 (t, J = 5.67 Hz, 2H), 3.03 (br.m, 2H), 3.00 (t, J = 5.67 Hz, 2H), 2.90 (s, 3H), 2.40 (broad m, 4H), 2.13 (broad m, 4H), 1.76 (broad d, J = 11.15 Hz, 4H).

G. 6-Fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl } piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid.

To a stirred solution of 635 mg (0.94 mmol) of 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo methyl ester [4, 3-c] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid in 10 ml of THF was treated with a solution of 53 mg (0.94 mmol) of KOH in 0.5 ml of water. This mixture was stirred overnight. After hydrolysis was considered complete, 1 ml of 1 N HCl solution was added. This mixture was then extracted with EtOAc (3 × 30 ml). The combined organic layers were then washed with brine, dried over Na ₂ SO ₄ and concentrated to give 622 mg (100%) of a white solid. Mass spectrum (electrospray): exact mass calculated for C ₃₁ H ₃₂ F ₄ N ₄ O ₄ S ₂ , 664.18; m / z found, 665.2 [M + H] ⁺ . ¹ H NMR (DMSO-d ₆ , 400 MHz): 8.12 (dd, J = 8.81, 5.28 Hz, 1H), 7.83 and 7.76 (A and B AB quartet, J = 8 , 41 Hz, 4H), 7.17 (br s, J = 8.61 Hz, 1H), 4.47 (s, 2H), 4.29 (br s, 1H), 4.16 (t , J = 7.04 Hz, 2H), 3.53 (t, J = 5.67 Hz, 2H), 3.28 (br.m, 4H), 3.00 (s, 3H), 2.96 (m, 2H), 2.73 (br s, 2H), 2.52 (br m, 2H), 2.13 (br m, 2H), 1.76 (br m, 2H).

H. (2-Hydroxy-ethyl) amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c ] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid.

Stirred solution 20 mg (0.03 mmol) 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c ] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid in 0.3 ml of dry DMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μl (0.045 mmol) of DIEA. The solution was stirred for 5 minutes before adding 0.01 ml (0.15 mmol) of ethanolamine. The reaction mixture was stirred at room temperature for 30 minutes, then partitioned between EtOAc (30 ml) and saturated NaHCO ₃ solution (20 ml). The aqueous layer was further extracted with EtOAc (2 × 20 ml). The combined organic layers were then washed with brine, dried over Na ₂ SO ₄ and concentrated. Purification by column chromatography (silica, 5-10% 2n NH ₃ in MeOH / CH ₂ Cl ₂ ) afforded 16 mg (76%) of a white solid. Mass spectrum (electrospray): exact mass calculated for C ₃₃ H ₃₇ F ₄ N ₅ O ₄ S ₂ , 707.22; m / z found, 708.2 [M + H] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz): 7.97 (br s, 1H), 7.73 and 7.66 (A and B AB quartet, J = 8.41 Hz, 4H), 7.49 ( dd, J = 8.41, 2.35 Hz, 1H), 7.15 (dt, J = 8.61, 2.54 Hz, 1H), 6.41 (t, J = 5.67 Hz, 1H ), 4.56 (s, 2H), 4.16 (t, J = 7.04 Hz, 2H), 3.84 (dd, J = 5.28, 4.70 Hz, 2H), 3.70 (t, J = 5.67 Hz, 2H), 3.62 (m, 2H), 3.58 (br s, 1H), 3.05 (br. m, 2H), 2.97 (t, J = 5.67 Hz, 2H), 2.91 (s, 3H), 2.40 (broad m, 4H), 2.1 3 (broad m, 4H), 1.84 (broad d, J = 12.32 Hz, 2H).

EXAMPLE 12

(2-aminoethyl) amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 -yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid

Stirred solution 300 mg (0.43 mmol) 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c ] piperidin-1-yl) propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid in 5 ml of dry DMF was treated with 812 mg (2.14 mmol) of HBTU and 0.75 ml (4.28 mmol) ) DIEA. The solution was stirred for 5 minutes before adding 0.28 ml (4.28 mmol) of ethylenediamine. The reaction mixture was stirred at room temperature for 30 minutes, then partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (20 ml). The aqueous layer was further extracted with EtOAc (2 × 20 ml). The combined organic layers were then washed with brine, dried over Na ₂ SO ₄ and concentrated. Purification by column chromatography (silica, 5-10% (2 n NH ₃ in MeOH) / CH ₂ Cl ₂ ) gave 200 mg (66%) of a clear oil. Mass spectrum (electrospray): exact mass calculated for C ₃₃ H ₃₈ F ₄ N ₆ O ₃ S ₂ , 706.24; m / z found, 707.2 [M + H] ⁺ . ¹ H NMR (CD ₃ OD, 400 MHz): 8.14 (m, 1H), 7.84 and 7.72 (A and B AB quartet, J = 8.41 Hz, 4H), 7.68 (m , 1H), 7.21 (dt, J = 8.81, 2.74 Hz, 1H), 4.54 (s, 2H), 4.27 (t, J = 6.26 Hz, 2H), 4 , 00-3.90 (m, 2H), 3.76-3.61 (m, 8H), 3.28-3.23 (br.m, 1H), 3.19-3.09 (br. m, 3H), 2.98 (s, 3H), 2.97-2.93 (m, 2H), 2.67 (broad m, 2H), 2.52-2.37 (m, 3H) 2.02 (broad d, J = 13.89 Hz, 2H).

EXAMPLE 13

(2-Morpholin-4-yl-ethyl) amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3 -c] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid

Stirred solution 20 mg (0.03 mmol) 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c ] pyridin-1-yl] propyl) piperidin-4-yl} benzo [b] thiophene-2-carboxylic acid in 0.3 ml of dry DMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μl (0.045 mmol) of DIEA. The solution was stirred for 5 minutes before adding 20 μl (0.15 mmol) of 4- (2-aminoethyl) morpholine. The reaction mixture was stirred at room temperature for 30 minutes, then partitioned between EtOAc (30 ml) and saturated NaHCO ₃ solution (20 ml). The aqueous layer was further extracted with EtOAc (2 × 20 ml). The combined organic layers were then washed with brine, dried over Na ₂ SO ₄ and concentrated. Purification by column chromatography (silica, 5-10% (2N NH ₃ in MeOH) / CH ₂ Cl ₂ ) gave 15 mg (65%) of a white solid. Mass spectrum (electrospray), exact mass calculated for C ₃₇ H ₄₄ F ₄ N ₆ O ₄ S ₂ , 776.28; m / z found, 777.3 [M + H] ⁺ . ¹ H NMR (CDCl ₃ , 400 MHz): 8.07 (br s, 1H), 7.73 and 7.66 (A and B AB quartet, J = 8.41 Hz, 4H), 7.50 ( dd, J = 8.41, 2.35 Hz, 1H), 7.14 (dt, J = 8.61, 2.54 Hz, 1H), 6.64 (t, J = 4.70 Hz, 1H ), 4.56 (s, 2H), 4.16 (t, J = 6.85 Hz, 2H), 3.80-3.67 (m, 7H), 3.53 (q, J = 5, 48 Hz, 2H), 3.03 (br.m, 2H), 2.98 (t, J = 5.67 Hz, 2H), 2.90 (s, 3H), 2.60 (t, J = 5.87 Hz, 2H), 2.38 (broad m, 4H), 2.12 (broad m. 4H), 1.86-1.73 (broad m, 3H).

EXAMPLE 14

1- [1- {2-Hydroxy-3- [4- (1H-indol-3-yl) piperidin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone.

EXAMPLE 15

1- [4- (5-Fluoro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol.

EXAMPLE 16

1- [3- (4-Bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-chloro-1H- indol-3-yl) piperidin-1-yl) propan-2-ol.

EXAMPLE 17

1- [3- (4-Bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-chloro-2- methyl-1H-indol-3-yl) piperidin-1-yl] propan-2-ol.

EXAMPLE 18

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-methyl-1H- indol-3-yl) piperidin-1-yl] propan-2-ol.

EXAMPLE 19

3- (1- {2-Hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidine -4-yl) -1H-indol-5-carbonitrile.

EXAMPLE 20

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-methoxy-1H- indol-3-yl) piperidin-1-yl] propan-2-ol.

EXAMPLE 21

3- (1- {2-Hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl ethyl ester } piperidin-4-yl) -1H-indole-5-carboxylic acid.

EXAMPLE 22

1- [4- (6-Chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol.

EXAMPLE 23

1- [1- (3- {4- [6-Chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-hydroxypropyl) -3- (4- trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone.

EXAMPLE 24

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [3, 2-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

EXAMPLE 25

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [2, 3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

EXAMPLE 26

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-hydroxy-1H- pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

EXAMPLE 27

1- [4- (5-Dimethylamino-1H-pyrrolo [3,2-b] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

EXAMPLE 28

1- [4- (5-Dimethylamino-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- {4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

EXAMPLE 31

1- [5-Methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (7-morpholin-4- yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol.

EXAMPLE 32

1- [4- (6-Fluoro-2-hydroxymethylbenzo [b] thiophen-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6, 7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol.

EXAMPLE 33

6-Fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl ] propyl} piperidin-4-yl) benzo [b] thiophene-2-carbaldehyde.

EXAMPLE 34

6-Fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 methyl ester -yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid.

EXAMPLE 35

Amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid.

EXAMPLE 36

Ethylamide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid.

EXAMPLE 37

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 a ~ 7-fold amplified signal after 20 minutes with only 20% substrate loss. Initial analyzes were performed 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 percent inhibition is calculated (see tables 1 and 2 below).

Table 1 EXAMPLE IC ₅₀ (μm) 1 0,07 2 0,03 3 0.05 4 0.09 5 0,03 6 0,03 7 0.05 8 0,03 nine 0.02 10 0.02 eleven 0.02 12 0.05 thirteen 0.05

table 2 EXAMPLE IC ₅₀ (μm) 14 0.07 fifteen 0.04 16 0.06 17 0,03 eighteen 0.06 19 0.02 twenty 0.02 21 0.04 22 0,03 23 0.08 24 0.13 25 0.05 26 0.09 27 0.10 28 0,07 29th 0.08 thirty 0.02 31 0,07 32 0.14 33 0.08 34 0.13 35 0,03 36 0.04

EXAMPLE 38

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. Mononuclear cells of human peripheral blood (PBMC) 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 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).

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 39

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, the blood is collected and the leukocytes are purified (WBC), for example, by erythrocyte lysis or by Ficoll-Hypaque gradient centrifugation. 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 mAb, for example, Pin1.1, or rabbit polyclonal antibodies or a mouse monoclonal antibody specific for the p10Ii fragment or against the complete fragment p10Ii. A pair of anti-Ii antibodies can be used for ELISA analysis, including Pin1.1 and a rabbit polyclonal antibody against the C-terminal fragment of p10Ii. The same assay can also be used to observe the effects 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 40

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 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 by activation and infiltration of CD4 T cells (as well as eosinophils) and should have been inhibited by the administration of cathepsin S inhibitors. A skin biopsy is used to determine the cellular composition in induction and it is assumed that subjects treated with a cathepsin S inhibitor have t fewer activated CD4 T cells 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.

As a control in the experiment, prednisone and cyclosporin A will be used. Prednisone will inhibit both the immediate response and the late phase reaction, while cyclosporin A will inhibit only 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 (9)

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 the dashed line adjacent to CR ⁶ is absent or represents an sp ² bond; Y represents nitrogen or R ²⁰ C; Z represents nitrogen or R ²¹ C; T represents nitrogen or R ² C; S represents nitrogen or R ³ C; with the proviso that from 0 to 1 of S, T, Y and Z are nitrogen; and further provided that one of S, T, Y, and Z may be = N ⁺ -O ^- , where the remaining three are not nitrogen; R ^{20 is} selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 halogenated, R ^o R ^p N, R ^o R ^p NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) - C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁴ OS = O, R ¹⁴ S, R ¹⁴ SO and R ¹⁴ SO ₂ ; R ^{21 is} selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 halogenated, R ^c R ^d N, R ^c R ^d NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁵ OC = O, R ¹⁵ S, R ¹⁵ SO and R ¹⁵ SO ₂ ; R ² selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 halogenated, R ^e R ^f N, R ^e R ^f NC = O, C _2-8 acyl, 4-7 membered heterocyclyl, (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁶ OC = O, R ¹⁶ S, R ¹⁶ SO and R ¹⁶ SO ₂ ; R ^{3 is} selected from hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, cyano, nitro, C _1-5 haloalkyl, R ^g R ^h N, C _2-8 acyl, 4-7 membered heterocyclyl , (4-7 membered heterocyclyl) -C _1-5 alkylene, phenyl, (phenyl) C _1-5 alkylene, R ¹⁷ OC = O, R ^m R ⁿ NC = O, R ^m R ⁿ NSO ₂ , R ¹⁷ S, R ¹⁷ SO and R ¹⁷ SO ₂ ; R ⁵ and R ^{6 are} independently selected from hydrogen and C _1-5 alkyl; R ⁷ and R ⁸ independently represent hydrogen, C _1-5 alkyl, C _1-5 alkenyl, C _1-5 alkoxy, C _1-5 alkylthio, halogen or 4-7 membered carbocyclyl or heterocyclyl; alternatively, R ⁷ and R ⁸ may be taken together to form an optionally substituted 5-7 membered carbocyclic or heterocyclic ring which may be unsaturated or aromatic, said ring optionally substituted with 1-3 substituents independently selected from halogen, hydroxy, cyano, nitro, amino, R ^t , R ^t O-, R ^t S-, R ^t O (C _1-5 alkylene) -, R ^t O (C = O) -, R ^t (C = O) -, R ^t (C = S) -, R ^t (C = O) O-, R ^t O (C = O) (C = O) -, R ^t SO ₂ , NHR ^u (C = NH) -, NHR ^u SO ₂ - and NHR ^u (C = O) -; R ^t represents C _1-6 alkyl, phenyl, benzyl, phenethyl or C _2-5 heterocyclyl, (C _1-5 heterocyclyl) C _1-6 alkylene, NH ₂ , mono- or di (C _1-6 alkyl) N -, or R ⁴⁹ OR ⁵⁰ -, where R ⁴⁹ 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 ⁵⁰ represents C _1-5 alkylene, phenylene or divalent C _1-5 heterocyclyl; and R ^u may be H in addition to the values for R ^t ; R ^c represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ¹⁰ OC = O, R ⁱ R ^j NC = O, R ¹⁰ SO-, R ¹⁰ SO ₂ - and R ⁱ R ^j NSO ₂ ; R ^e represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴⁰ OC = O, R ⁴³ R ⁴⁴ NC = O, R ⁴⁰ SO, R ⁴⁰ SO ₂ and R ⁴³ R ⁴⁴ NSO ₂ ; R ^m represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴¹ OC = O, R ⁴⁵ R ⁴⁶ NC = O, R ⁴¹ SO, R ⁴¹ SO ₂ and R ⁴⁵ R ⁴⁶ NSO ₂ ; R ^o represents hydrogen, C _1-5 alkyl, phenyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁴² OC = O, R ⁴⁷ R ⁴⁸ NC = O, R ⁴² SO, R ⁴² SO ₂ and R ⁴⁷ R ⁴⁸ NSO ₂ ; each R ^d , R ^f , R ⁿ and R ^{p are} independently selected from hydrogen, C _1-5 alkyl, phenyl and C _2-5 heterocyclyl, in addition, R ^c and R ^d , R ^e and R ^f , R ^m and R ⁿ or R ^o and R ^p , independently, can be taken together to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic; each R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ⁴⁰ , R ⁴¹ and R ⁴² independently represents C _1-5 alkyl, phenyl or C _2-5 heterocyclyl; each R ⁱ and R ^j , R ^k and R ^l , R ⁴³ and R ⁴⁴ , R ⁴⁵ and R ⁴⁶ , R ⁴⁷ and R ⁴⁸ independently represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl or C _2-5 heterocyclyl, in addition, R ⁱ and R ^j , and R ^k and R ^l , R ⁴³ and R ⁴⁴ , R ⁴⁵ and R ⁴⁶ , and R ⁴⁷ and R ⁴⁸ , independently, can be taken together to form an optionally substituted A 4-7 membered heterocyclic ring which may be saturated, unsaturated or aromatic; R ^g represents hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ⁹ OC = O, R ¹⁸ R ¹⁹ NC = O, R ⁹ SO, R ⁹ SO ₂ or R ¹⁸ R ¹⁹ NSO ₂ ; R ^h represents hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl; alternatively, R ⁹ and R ¹¹ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic; R ¹⁸ and R ¹⁹ independently represent hydrogen, C _1-5 alkyl, phenyl or C _2-5 heterocyclyl; alternatively, R ¹⁸ and R ¹⁹ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic; n is 1; G is 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 ^k , NR ^k R ^l , (L) -C _1-4 alkylene, R ^k R ^l NCO ₂ , [(L) -C _1-5 alkylene] amino, N ₃ or (L) -C _1-5 alkoxy; L represents 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; Ar is a monocyclic or bicyclic aryl or heteroaryl ring optionally substituted with 1-3 substituents independently selected from halogen, C _1-5 alkoxy, C _1-5 alkyl, C _2-5 alkenyl, cyano, azido, nitro, R ²² R ²³ N, R ²² S, R ²² SO, R ²² SO ₂ , R ²² OC = O, R ²² R ²³ NC = O, C _1-5 haloalkyl, C _1-5 haloalkoxy, C _1-5 haloalkylthio and C _{1 -5} alkylthio; R ²² represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, phenyl, benzyl, C _2-5 heterocyclyl, C _2-8 acyl, aroyl, R ¹¹ OC = O, R ²⁴ R ²⁵ NC = O, R ¹¹ S, R ¹¹ SO, R ¹¹ SO ₂ or R ²⁴ R ²⁵ NSO ₂ ; R ²³ represents hydrogen, C _1-5 alkyl, phenyl, benzyl or C _2-5 heterocyclyl; alternatively, R ²² and R ²³ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic; R ²⁴ and R ²⁵ , independently, are hydrogen, C _1-5 alkyl, phenyl, benzyl or C _1-5 heteroaryl; alternatively, R ²⁴ and R ²⁵ may be taken together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic; R ³² represents hydrogen, C _1-5 alkyl, cyano, C _1-5 hydroxyalkyl, C _2-8 acyl, - (C = O) NR ^v R ^x , CHO, or C _1-6 alkoxycarbonyl, where each R ^v and R ^{x are} independently selected from H, C _1-5 alkyl, C _1-5 hydroxyalkyl, C _1-5 heterocyclyl, (C _1-5 heterocyclyl) C _1-5 alkylene, C _1-5 aminoalkylene, C _3-8 acyloxy, CHO, C _1-6 alkoxycarbonyl and cyano; Q represents NR ³³ , S or O; R ³³ represents hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl, C _2-5 heterocyclyl, (C _2-5 heterocyclyl) C _1-5 alkylene, C _2-8 acyl, aroyl, R ³⁵ OC = O R ³⁶ R ³⁷ NC = O, R ³⁵ SO, R ³⁵ S, R ³⁵ SO ₂ or R ³⁶ R ³⁷ NSO ₂ ; R ^{35 is} selected from hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl and C _2-5 heteroaryl; each R ³⁶ and R ^{37 is} independently selected from hydrogen, C _1-5 alkyl, phenyl or C _2-5 heteroaryl; alternatively, R ³⁶ and R ³⁷ may be taken together to form an optionally substituted 4-7 membered heterocyclic ring, which may be saturated, unsaturated or aromatic; 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, or a stereoisomeric form thereof. 2. The method according to claim 1, where R ²⁰ and R ²¹ are independently selected from hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro, 4-7 membered heterocyclyl, and R ^o R ^p N or R ^c R ^d N, respectively. 3. The method according to claim 1, where Y represents nitrogen or R ²⁰ C; Z represents nitrogen or R ²¹ C; T represents nitrogen or R ² C; S represents nitrogen or R ³ C; with the proviso that 0 or 1 of S, T, Y and Z are nitrogen; R ² represents hydrogen, halogen, hydroxy, C _1-5 alkoxy, C _1-5 alkyl, 5-6 membered heterocyclyl or R ^e R ^f N; R ³ represents hydrogen, halogen, C _1-5 alkoxy, hydroxy, C _1-5 alkyl, 5-6 membered heterocyclyl or R ^g R ^h N; each R ⁵ and R ⁶ represents H; R ⁷ and R ^{8 are} independently taken together to form an optionally substituted 5-7 membered unsaturated heterocyclic ring; each R ^a , R ^e , R ^m and R ^{o are} independently selected from hydrogen, C _1-5 alkyl, C _2-8 acyl, (C _1-5 alkyl) OC = O and the corresponding RRNC = O, RSO, RSO ₂ and RRNSO ₂ groups; each R ^b , R ^f , R ⁿ and R ^{p are} independently selected from hydrogen and C _1-5 alkyl; each R ⁹ , R ¹¹ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ⁴⁰ , R ⁴¹ and R ⁴² independently represents C _1-5 alkyl; each R ^c , R ^d , R ⁱ , R ^j , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ^k and R ^l independently represents hydrogen or C _1-5 alkyl; R ^g represents hydrogen or C _1-5 alkyl, C _2-8 acyl, R ⁹ OC = O, R ¹⁸ R ¹⁹ NC = O, R ⁹ SO, R ⁹ SO ₂ or R ¹⁸ R ¹⁹ NSO ₂ ; R ^h represents hydrogen or C _1-5 alkyl; alternatively, R ^g and R ^h may be taken together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic; R ¹⁸ and R ¹⁹ independently represent hydrogen or Ci-s alkyl; n is 1; G is C _3-4 alkenediyl or C _3-4 alkanediyl optionally substituted with hydroxy, halogen, C _1-5 alkyloxy, oxo, hydroxyimino, CO ₂ R ^k , R ^k R ^l NCO ₂ , or (L) -C _{1 -5} alkoxy; L is amino, mono- or di-C _1-5 alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl or piperazinyl, where the available ring nitrogen atoms are optionally substituted with C _1-5 alkyl, benzyl, C _2-5 acyl or C _{1- 5} alkoxycarbonyl; R ²⁰ and R ^{21 are} independently selected from hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkyl, cyano, nitro and R ^o R ^p N; alternatively, R ³ and R ²⁰ or R ³ and R ²¹ may be taken together to form an optionally substituted 5-6 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic; Ar is a monocyclic or bicyclic aryl or heteroaryl ring optionally substituted with hydrogen, C _1-5 alkoxy halogen, C _1-5 alkyl, cyano, nitro, R ²² R ²³ N, R ²⁴ SO ₂ , R ²⁴ OC = O, R ²⁵ R ²⁶ NC = O, CF ₃ , OCF ₃ , SCF ₃ or C _1-5 alkylthio; R ²² represents hydrogen, C _1-5 alkyl, phenyl, benzyl, phenethyl, C _2-5 heteroaryl, C _2-8 acyl, aroyl, R ²⁴ O (C = O), R ²⁵ R ²⁶ NC = O, R ²⁴ SO, R ²⁴ SO ₂ or R ²⁵ R ²⁶ NSO ₂ ; R ²³ represents hydrogen or C _1-5 alkyl; alternatively, R ²² and R ²³ may be taken together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic; R ²⁴ represents hydrogen or C _1-5 alkyl; R ²⁵ and R ²⁶ independently represent hydrogen or C _1-5 alkyl; or alternatively, R ²⁵ and R ²⁶ may be taken together to form an optionally substituted 4-7 membered carbocyclic or heterocyclic ring, which may be saturated, unsaturated or aromatic; R ³² represents hydrogen, C _1-5 alkyl, C _1-5 hydroxyalkyl, CHO, C _2-8 acyl, C _1-6 alkoxycarbonyl or - (C = O) NR ^v R ^x , where each R ^v R ^x independently selected from H, C _1-5 alkyl, C _1-5 hydroxyalkyl, C _3-8 acyloxy, (amino) C _1-6 alkylene, (C _1-5 heterocyclyl) C _1-5 alkylene or C _1-6 alkoxycarbonyl ; and Q represents NR ³³ or S; R ³³ represents hydrogen, C _1-5 alkyl, phenyl, benzyl, (C _2-5 heterocyclyl) C _1-5 alkylene, C _2-8 acyl, aroyl, R ³⁵ OC = O, R ³⁶ R ³⁷ NC = O R ³⁵ SO ₂ or R ³⁶ R ³⁷ NSO ₂ ; R ^{35 is} selected from hydrogen and C _1-5 alkyl; each R ³⁶ and R ^{37 are} independently selected from hydrogen and C _1-5 alkyl. 4. The method according to claim 1, where one of R ⁵ and R ⁶ represents H; R ⁷ and R ⁸ are taken together to form an optionally substituted 6-membered carbocyclic or heterocyclic ring; and Ar is a monocyclic ring optionally substituted with 1-2 substituents selected from halogen, C _1-5 alkyl, cyano, nitro, R ²² R ²³ N, CF ₃ and OCF ₃ . 5. The method of claim 4, wherein R ²² and R ²³ , taken together, are independently morpholinyl, piperidyl or pyrrolidinyl, optionally substituted. 6. The method according to claim 1, where the specified connection is selected from 1- [4- (5-chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol; 1- [4- (7-chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4, 3-c] pyridin-1-yl] propan-2-ol; 1- [4- (5-chloro-2-methyl-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6, 7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 1- {4- [6-chloro-1 (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [3, 2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [2, 3-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-morpholin-4- yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [4- (6-dimethylamino-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-5-hydroxy-1H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 (2-hydroxyethyl) amide -yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid; 6-Fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 (2-aminoethyl) amide -yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid; and 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] (2-morpholin-4-yl-ethyl) amide ] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid. 7. The method according to claim 1, where the specified connection is selected from 1- [1- {2-hydroxy-3- [4- (1H-indol-3-yl) piperidin-1-yl] propyl} -3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone; 1- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol; 1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-chloro-1H- indol-3-yl) piperidin-1-yl] propan-2-ol; 1- [3- (4-bromophenyl) -5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-chloro-2- methyl-1H-indol-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-methyl-1H- indol-3-yl) piperidin-1-yl] propan-2-ol; 3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidine -4-yl) -1H-indol-5-carbonitrile; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-methoxy-1H- indol-3-yl) piperidin-1-yl] propan-2-ol; 3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl ethyl ester } piperidin-4-yl) -1H-indole-5-carboxylic acid; 1- [4- (6-chloro-1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [ 4,3-c] pyridin-1-yl] propan-2-ol; 1- [1- (3- {4- (6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] piperidin-1-yl} -2-hydroxypropyl) - 3- (4-trifluoromethylphenyl) -1,4,6,7-tetrahydropyrazolo [4,3-c] pyridin-5-yl] ethanone; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [3, 2- b] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (1H-pyrrolo [2, 3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-hydroxy-1H- pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [4- (5-dimethylamino-1H-pyrrolo [3,2-b] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 1- [4- (5-dimethylamino-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4, 5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidine -4-yl) -1H-pyrrolo [2,3-b] pyridin-6-carbonitrile; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- {4- [1- (2-morpholine -4-yl-ethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (7-morpholin-4- yl-1H-pyrrolo [2,3-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; 1- [4- (6-fluoro-2-hydroxymethyl-benzo [b] thiophen-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4.5, 6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 6-fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl ] propyl} piperidin-4-yl) benzo [b] thiophene-2-carbaldehyde; 6-fluoro-3- (1- {2-hydroxy-3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1 methyl ester -yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid; amide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid; and ethylamide 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propyl } piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid. 8. The method according to claim 1, where the specified connection is selected from 1- {4- [6-chloro-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl) piperidin-1-yl] -3- [5-methanesulfonyl-3- (4 trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] propan-2-ol; 6-fluoro-3- (1- {3- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-morpholin-4-yl-ethyl) amide -c] pyridin-1-yl] propyl} piperidin-4-yl) benzo [b] thiophene-2-carboxylic acid; 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (5-hydroxy-1H- pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol; and 1- [5-methanesulfonyl-3- (4-trifluoromethylphenyl) -4,5,6,7-tetrahydropyrazolo [4,3-c] pyridin-1-yl] -3- [4- (6-morpholin-4- yl-3-H-pyrrolo [3,2-c] pyridin-3-yl) piperidin-1-yl] propan-2-ol. 9. The method according to p. 1, where the specified pharmaceutical composition is prepared with a dose of the active substance suitable for the treatment of allergic diseases.

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