WO2009102937A1 - Processes for the preparation of carbon-linked tetrahydro-pyrazolo-pyridine modulators of cathepsin s - Google Patents

Abstract

Method of making carbon-linked tetrahydro-pyrazolo-pyridine compounds of the following Formula (I) and pharmaceutically acceptable salts thereof: comprising reacting a compound of formula (IX) with a compound of formula (X) to form a compound of Formula (I); wherein: R1 and R2 taken together with the nitrogen to which they are attached form a morpholine ring, unsubstituted or substituted with one or two methyl substituents; R3 is H or OH; R4 is -SO2CH3, -CONH2, or -COCONH2; R5 is H or methyl; R6 is a benzyl group, unsubstituted or substituted with one or two substituents independently selected from the group consisting of C1-4alkyl, CF3, halo, OH, -OC1-4alkyl, -OCF3, -OCHF2, NRddRee, -CO2C1-4alkyl, -SC1-4alkyl, and -SO2C1-4alkyl; where Rdd and Ree are each independently H or C1-4alkyl; R7 is H, fluoro, or chloro; and LG1 is iodide, bromide, or trifluoromethanesulfonate. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by cathepsin S activity, such as psoriasis, pain, multiple sclerosis, atherosclerosis, and rheumatoid arthritis.

Description

PROCESSES FOR THE PREPARATION OF CARBON-LINKED TETRAHYDRO- PYRAZOLO-PYRIDINE MODULATORS OF CATHEPSIN S

[0001] This application claims the benefit of US provisional patent application serial number 61/028,619, filed February 14, 2008 which is incorporated herein by reference.

Field

[0002] The present invention concerns the synthesis of certain carbon-linked tetrahydro-pyrazolo-pyridine compounds, which are useful as modulators of cathepsin S and as agents for treating diseases mediated by cathepsin S.

Background

[0003] Cathepsin S is one of the major cysteine proteases expressed in the lysosome of antigen presenting cells, mainly dendritic cells, B cells and macrophages. Cathepsin S is best known for its critical function in the proteolytic digestion of the invariant chain chaperone molecules, thus controlling antigen presentation to CD4⁺ T cells by major histocompatibility complex class Il molecules or to NK1.1⁺ T cells via CD1 molecules. Cathepsin S also appears to participate in direct processing of exogenous antigens for presentation by MHC class Il to CD4⁺ T cells or crosspresentation by MHC class I molecules to CD8⁺ T cells. In addition, cathepsin S in secreted form is implicated in degradation of extracellular matrix, which may contribute to the pathology of a number of diseases, including arthritis, atherosclerosis, and chronic obstructive pulmonary disease. Therefore, inhibition of cathepsin S is a promising target for the development of novel therapeutics for a variety of indications. For a review, see: Thurmond, R.L. et al. Curr. Opin. Invest. Drugs 2005, 6(5), 473-482.

[0004] Pyrazole inhibitors of cathepsin S were disclosed in a series of applications from Ortho-McNeil, and additional publications on this work have also appeared (See: U.S. Pat. Appl. Publ. Nos. 2002/0040020, 2003/0078419, and 2002/0040019; Wei, J. et al. Bioorg. Med. Chem. Lett. 2007, 17, 5525-5528; Grice, CA. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2209-2212; and Gustin, DJ. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1678-1691). See also: Thurmond, R.L. et al. J. Pharm. Exp. Ther. 2004, 308, 268-276; and Thurmond, R.L. et al. J. Med. Chem. 2004, 47, 4799-4801 ). However, there remains a need for potent cathepsin S modulators with desirable pharmaceutical properties and methods of synthesizing such modulators.

Summary

[0005] In one aspect the invention relates to methods of making compounds of the following Formula (I) and pharmaceutically acceptable salts thereof:

comprising reacting a compound of formula (IX):

with a compound of formula (X):

to form a compound of Formula (I); wherein:

R¹ and R² taken together with the nitrogen to which they are attached form a morpholine ring, unsubstituted or substituted with one or two methyl substituents; R³ is H or OH;

R⁴ is -SO₂CH₃, -CONH₂, Or-COCONH₂; R⁵ is H or methyl; R⁶ is a benzyl group, unsubstituted or substituted with one or two substituents independently selected from the group consisting of C^alkyl, CF₃, halo, OH, -OCi_

₄alkyl, -OCF₃, -OCHF₂, NR^ddR^θθ, -CO₂C^alkyl, -SC-^alkyl, and -SO₂Ci^alkyl; where R^dd and R^θθ are each independently H or Ci^.alkyl; R⁷ is H, fluoro, or chloro; and LG¹ is iodide, bromide, or trifluoromethanesulfonate. [0006] The process for the preparation of compounds of Formula (I) may further comprise reacting a compound of formula (VII):

with a compound of formula (VIII):

where LG² is iodo, bromo, chloro, or trifluoromethanesulfonate; or R³ and LG² taken together with the carbons to which they are attached form an epoxide ring; to form a compound of formula (IX).

[0007] The process for the preparation of compounds of Formula (I) may further comprise: (a) deprotecting a compound of formula (Vl):

to form a compound of formula (Via):

and (b) reacting a compound of formula (Via) with methanesulfonyl chloride, trimethylsilylisocyanate, or oxalamic acid, to form a compound of formula (VII).

[0008] The process for the preparation of compounds of Formula (I) may further comprise: reacting a compound of formula (III):

with an acid chloride of formula (IV):

to form a first reaction product and, subsequently, reacting the first reaction product with hydrazine to form a compound of formula (Vl).

[0009] The process for the preparation of compounds of Formula (I) may further comprise reacting N-Boc-piperidone with a cyclic secondary amine HNR^aR^b to form a compound of formula (III), wherein HNR^aR^b is selected from the group consisting of pyrrolidine, morpholine, and piperidine.

[0010] In certain embodiments, the invention contemplates methods of making a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from those species described or exemplified in the detailed description below.

[0011] Compounds of Formula (I) and pharmaceutically acceptable salts thereof are useful as cathepsin S modulators, whereby cathepsin S is modulated by exposure to at least one such chemical entity. Modulation of cathepsin S may be accomplished where the cathepsin S receptor is in a subject. Thus, compounds of Formula (I), and pharmaceutically acceptable salts thereof, which are prepared according to the synthetic methods described herein, are useful in treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by cathepsin S activity. Diseases, disorders and medical conditions that are mediated by cathepsin S activity include those referred to herein.

[0012] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

Detailed Description

[0013] For the sake of brevity, the disclosures of the publications, including patents, cited in this specification are herein incorporated by reference.

[0014] As used herein, the terms "including", "containing" and "comprising" are used herein in their open, non-limiting sense.

[0015] The term "alkyl" refers to a saturated, straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me, which also may be structurally depicted by a bond, T), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

[0016] The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.

[0017] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system that yields a stable chemical structure.

[0018] Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.

[0019] To provide a more concise description, some of the quantitative „ expressions given herein are not qualified with the term "about". It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently. [0020] Reference to a chemical entity herein stands for a reference to any one of: (a) the actually recited form of such chemical entity, and (b) any of the forms of such chemical entity in the medium in which the compound is being considered when named. For example, reference herein to a compound such as R-COOH, encompasses reference to any one of, for example, R-COOH(_S), R-COOH(_SOi), and R-COO^"(_SOi). In this example, R-COOH(_S) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation; R-COOH(_SOi) refers to the undissociated form of the compound in a solvent; and R-COO^'(_SOi) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R- COOH, from a salt thereof, or from any other entity that yields R-COO^' upon dissociation in the medium being considered. In another example, an expression such as "exposing an entity to compound of formula R-COOH" refers to the exposure of such entity to the form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such exposure takes place. In this regard, if such entity is for example in an aqueous environment, it is understood that the compound R-COOH is in such same medium, and therefore the entity is being exposed to species such as R-COOH(_aq) and/or R-C00^" _(aq), where the subscript "(aq)" stands for "aqueous" according to its conventional meaning in chemistry and biochemistry. A carboxylic acid functional group has been chosen in these nomenclature examples; this choice is not intended, however, as a limitation but it is merely an illustration. It is understood that analogous examples can be provided in terms of other functional groups, including but not limited to hydroxyl, basic nitrogen members, such as those in amines, and any other group that interacts or transforms according to known manners in the medium that contains the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis, including hydrolysis, solvation, including hydration, protonation, and deprotonation. No further examples in this regard are provided herein because these interactions and transformations in a given medium are known by any one of ordinary skill in the art.

[0021] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶CI, and ¹²⁵I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 1⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0022] When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same choice of the species for the variable appearing elsewhere. In other words, where a variable appears more than once, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula, unless stated otherwise.

[0023] By way of a first example on substituent terminology, if substituent S¹exampie is one of Si and S2, and substituent S² _exampie is one of S3 and S₄, then these assignments refer to embodiments of this invention given according to the choices

S example IS Si and S example IS S3; S example IS Si and S example IS S₄; S example is S2 and

Sample ^is S3; S¹ example is S2 and S² _θχampie is S₄; and equivalents of each one of such choices. The shorter terminology "S¹ _θχam_Pie is one of Si and S₂, and S² _θxampie is one of S₃ and S₄" is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing first example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to any generic substituent symbol used herein. [0024] Furthermore, when more than one assignment is given for any member or substituent, embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof. By way of a second example on substituent terminology, if it is herein described that substituent Sample is one of Si, S2, and S3, this listing refers to embodiments of this invention for which S_βχampiθ is S-i; S_θχampiθ is S2; S_θχampiθ is S3; S_θχampiθ is one of Si and S2; S_θxampiβ is one of Si and S3; S_θχampiθ is one of S2 and S3; S_θxampiθ is one of Si, S2 and S3; and S_amp_le is any equivalent of each one of these choices. The shorter terminology "Sβx_ampie is one of Si, S2, and S3" is accordingly used herein for the sake of brevity, but not by way of limitation. The foregoing second example on substituent terminology, which is stated in generic terms, is meant to illustrate the various substituent assignments described herein. The foregoing convention given herein for substituents extends, when applicable, to any generic substituent symbol used herein.

[0025] The nomenclature "Cj./' with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized. By way of example, the term C₁-₃ refers independently to embodiments that have one carbon member (Ci)₁ embodiments that have two carbon members (C₂), and embodiments that have three carbon members (C₃).

[0026] The term C_n-malkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n ≤ N ≤ m, with m > n.

[0027] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A ≠ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.

[0028] According to the foregoing interpretive considerations on assignments and nomenclature, it is understood that explicit reference herein to a set implies, where chemically meaningful and unless indicated otherwise, independent reference to embodiments of such set, and reference to each and every one of the possible embodiments of subsets of the set referred to explicitly. [0029] In some embodiments of Formula (I), R¹ and R² taken together with the nitrogen to which they are attached form morpholine, 3-methylmorpholine, 2,6- dimethylmorpholine, 3,5-dimethylmorpholine, (3S)-methylmorpholine, or (3R)- methylmorpholine.

[0030] In some embodiments, R³ is H. In other embodiments, R³ is OH.

In some embodiments, R⁴ is -SO2CH₃ or-COCONhfe. In other embodiments, R⁴ is -SO₂CH₃.

[0031] In some embodiments, R⁵ is H.

[0032] In some embodiments, R⁶ is a benzyl group, unsubstituted or substituted with one or two substituents independently selected from the group consisting of chloro or methyl. In other embodiments, R⁶ is 4-chloro-benzyl.

[0033] In some embodiments, R⁷ is H.

[0034] In some embodiments, the compound of Formula (I) is 2-[3-(4-chloro-3- {[4-({[(4.chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-{3-[(3S)-3- methylmoφholin^-yOpropylJ-i^.β^-tetrahydro-δH-pyrazolo^.S-cjpyridin-δ-yl]^- oxoacetamide or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the compound of formula (IX) is 2-{3-(4-chloro-3- iodo-phenyl)-1-[3-((3S)-methyl-morpholin-4-yl)-propyl]-1 ,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-5-yl}-2-oxo-acetamide.

[0036] In some embodiments, the compound of formula (X) is (4-chloro- benzyl)-(4-ethynyl-benzyl)-amine.

[0037] In some embodiments, the compound of formula (VII) is 2-[3-(4-chloro- S-iodo-phenylJ-i^.βJ-tetrahydro-pyrazolo^.S-clpyridin-S-yll^-oxo-acetamide.

[0038] In some embodiments, the compound of formula (VIII) is 4-(3-chloro- propyl)-(3S)-methyl-morpholine.

[0039] In some embodiments, the compound of formula (Vl) is 3-(4-chloro-3- iodo-phenyO-i^.βJ-tetrahydro-pyrazolo^.S-cJpyridine-δ-carboxylic acid tert-butyl ester.

[0040] In some embodiments, the compound of formula (Via) is 3-(4-chloro-3- iodo-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.

[0041] In some embodiments, the compound of formula (III) is 4-morpholin-4- yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester.

[0042] In some embodiments, the compound of formula (IV) is 4-chloro-3-iodo- benzoyl chloride. [0043] The invention includes methods of making pharmaceutically acceptable salts of the compounds represented by Formula (I), preferably of those described above and of the specific compounds exemplified herein, and methods of treatment using such salts.

[0044] A "pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. ScL, 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, and mandelates.

[0045] If the compound of Formula (I) contains a basic nitrogen, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p- toluenesulfoπic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0046] If the compound of Formula (I) is an acid, such as a carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0047] The compounds of Formula (I) and their pharmaceutically acceptable salts, whether alone or in combination, are useful as cathepsin S modulators. Such modulation of cathepsin S activity comprises exposing cathepsin S to an effective amount of at least one chemical entity selected from compounds of Formula (I) and pharmaceutically acceptable salts thereof. Embodiments of this invention inhibit cathepsin S activity.

[0048] In some embodiments, the cathepsin S receptor is in a subject with a disease, disorder, or medical condition mediated by modulation of cathepsin S, such as those described herein. Symptoms or disease states are intended to be included within the scope of "medical conditions, disorders, or diseases." [0049] Accordingly, the compounds prepared by the methods of the invention are useful in treating subjects diagnosed with or suffering from a disease, disorder, or condition mediated through cathepsin S activity, such as an autoimmune disease, an allergic condition, inflammation, a bowel disorder, tissue transplant rejection, pain, or cancer. Compounds of Formula (I) and pharmaceutically acceptable salts thereof may therefore be used as immunomodulating agents, immunosuppressants, anti-allergy agents, anti-inflammatory agents, analgesics, or anti-cancer agents.

[0050] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to treat lupus, asthma, allergic reaction, atopic allergy, hay fever, atopic dermatitis, food allergy, rhinitis (such as allergic rhinitis and the inflammation caused by non-allergic rhinitis), skin immune system disorders (such as psoriasis), uveitis, inflammation, upper airway inflammation, Sjogren's syndrome, arthritis, rheumatoid arthritis, osteoarthritis, type I diabetes, atherosclerosis, multiple sclerosis, coeliac disease, inflammatory bowel disease (IBD), chronic obstructive pulmonary disorder (COPD), tissue transplant rejection, pain, neuropathic pain, chronic pain (such as pain due to conditions such as cancer, neuropathic pain, rheumatoid arthritis, osteoarthritis and inflammatory conditions), or cancer (and cancer-related processes such as angiogenesis, tumor growth, cell proliferation, and metastasis). In certain embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to treat psoriasis, pain, multiple sclerosis, atherosclerosis, or rheumatoid arthritis.

[0051] Thus, a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be used to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated through cathepsin S activity. The term "treat" or "treating" as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of cathepsin S activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of cathepsin S activity. The term "subject" refers to a mammalian patient in need of such treatment, such as a human. "Modulators" include both inhibitors and activators, where "inhibitors" refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate cathepsin S expression or activity, and "activators" are compounds that increase, activate, facilitate, sensitize, or up-regulate cathepsin S expression or activity.

[0052] In the described treatment methods, an effective amount of at least one active agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the active agents of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An exemplary dose is in the range of from about 0.001 to about 200 mg of active agent per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

[0053] Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0054] In addition, compounds of Formula (I) and pharmaceutically acceptable salts thereof may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with a compound of Formula (I) or pharmaceutically acceptable salts thereof, or combined in a pharmaceutical composition. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by cathepsin S activity, such as another cathepsin S modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.

[0055] Compounds of Formula (I) and pharmaceutically acceptable salts thereof are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions. A pharmaceutical composition therefore comprises an effective amount of at least one a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0056] A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0057] Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

[0058] The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.

[0059] For oral administration, the active agents of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the active agents may be formulated to yield a dosage of, e.g., from about 0.05 to about 50 mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. [0060] Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0061] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semisolid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0062] Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p- hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0063] Compounds of Formula (I) and pharmaceutically acceptable salts thereof may also be administered by non-oral routes. For example, compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/miπute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0064] For topical administration, the agents may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery.

[0065] Compounds of Formula (I) and pharmaceutically acceptable salts thereof may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

[0066] Exemplary chemical entities prepared through methods of the invention are described below by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. In addition, artisans will note that the various transformations described in the following Schemes may be performed in a different order than that depicted. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Formulae shown in Schemes A and B are intended to include free base forms and corresponding salt forms. SCHEME A

[0067] In preferred embodiments, compounds of Formula (I) are prepared as shown in Scheme A. N-Boc-Piperidone (II) is reacted with a cyclic secondary amine HNR^aR^b selected from the group consisting of pyrrolidine, morpholine, and piperidine, to form a compound of formula (III). In some embodiments, reactions are performed in the presence of a catalytic amount of an acid catalyst, such as p-toluenesulfonic acid or citric acid, in a nonpolar organic solvent such as benzene or toluene, under dehydrating conditions (involving, for example, addition of molecular sieves or reaction at reflux temperature with a Dean-Stark trap).

[0068] A compound of formula (III) is reacted with an acid chloride of formula (IV), (where LG¹ is iodide, bromide, ortrifluoromethanesulfonate), to provide a compound of formula (V)₁ a corresponding beta-diketone (not shown), or a mixture thereof. Acid chlorides (IV) are prepared using methods known in the art. In some embodiments, reactions are performed in the presence of a tertiary amine base such as triethylamine, diisopropylethylamine, or 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a solvent such as CH₂Cb, dichloroethane (DCE)₁ or toluene. Compounds (V) are not isolated, but are reacted directly with hydrazine, in a solvent such as methanol or ethanol, to form pyrazoles (Vl).

[0069] A compound of formula (VI) is deprotected using methods known in the art. In preferred embodiments, a compound of formula (Vl) is treated with an acid, such as HCI or trifluoroacetic acid (TFA), in a solvent such as CH2CI2 or 1 ,4-dioxane, to give a compound of formula (Via). Installation of R⁴ is accomplished by reaction of a compound of formula (Via) with methanesulfonyl chloride, trimethylsilylisocyanate, or oxalamic acid. In preferred embodiments, reaction with methanesulfonyl chloride in presence of a suitable tertiary amine base, or with oxalamic acid in the presence of a peptide coupling agent such as 1,1'-carbonyldiimidazole (CDI), provides a pyrazole of formula (VII).

[0070] Alkylation of a pyrazole of formula (VII) with a reagent of formula (VIII) (where LG² is iodo, bromo, chloro, ortrifluoromethanesulfonate), in the presence of a suitable base, gives a compound of formula (IX). In preferred embodiments, LG² in formula (VIII) is chloro, and reactions are performed using DMF as the solvent and Cs₂CO₃ as the base.

[0071] A compound of Formula (I) is prepared by reaction of a compound of formula (IX) under palladium-catalyzed conditions with an alkyne (X). In preferred embodiments, palladium-catalyzed couplings are performed in the presence of a palladium(O) catalyst such as PdCI₂(PPh₃)₂, Pd(PPh₃J₄, or Pd₂(dba)₃, or a mixture thereof, a copper(l) salt such as copper(l) iodide, a tertiary amine base such as triethylamine, diisopropylethylamine, or DBU, in a polar aprotic solvent such as tetrahydrofuran (THF) or N,N-dimethylformamide (DMF) or a mixture thereof, at a temperature from about room temperature to the reflux temperature of the solvent.

SCHEME B

(XX) (VMI)

[0072] As shown in Scheme B, compounds of formula (VIII) are prepared by alkylation of a suitably substituted propane (XX). In one embodiment, an amine HNR¹R² is reacted with a compound of formula (XX), where LG² is bromo, chloro, or p- toluenesulfonate, and A is bromo or iodo. In another embodiment, an amine HNR¹R² is reacted with a compound of formula (XX), where A is a nosylate and R³ and LG² taken together with the carbons to which they are attached form an epoxide ring. In another embodiment, an amine HNR¹R² is reacted with a compound of formula (XX), where LG² is chloro and A and R³ taken together with the carbons to which they are attached form an epoxide ring. Reactions are performed in an aprotic organic solvent, such as THF or DMF, in the presence of a suitable base, such as NaH.

[0073] Compounds of Formula (I) may be converted to their corresponding salts using methods described in the art. For example, a compound of Formula (I) may be treated with trifluoroacetic acid, HCI, citric acid, oxalic acid, tartaric acid, 2-oxo- butanoic acid, 2-oxo-hexanoic acid, 2-keto-glutaric acid, 2-pyrrolidone-5-carboxylic acid, or phosphoric acid in a solvent such as CH₃CN, diethyl ether, CH2CI2, THF, or methanol to provide the corresponding salt form. Alternatively, a compound of Formula (I) may be converted to the corresponding tartrate salt by reaction with tartaric acid in diethyl ether, CH₂CI₂, THF, or methanol; to the corresponding monoethyl oxalate salt by reaction with mono- or diethyl oxalate in CH₃CN; or to the corresponding 2-oxo-pentanoate salt by reaction with 2-oxo-pentanoic acid in CH₃CN.

[0074] Those skilled in the art will recognize that the chemical transformations described above may be performed in a different order than that depicted in the Schemes. Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastero-, or regiospecific synthesis, or by resolution. Compounds prepared according to the schemes above may alternately be obtained as racemic (1:1) or non-racemic (not 1:1) mixtures or as mixtures of diastereomers or regioisomers. Where racemic and non- racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, single isomers may be separated using conventional methods such as chromatography or crystallization.

[0075] The following specific examples are provided to further illustrate the invention and various preferred embodiments. EXAMPLES Chemistry:

[0076] In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0077] Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt). Where solutions are "dried," they are generally dried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were "concentrated", they were typically concentrated on a rotary evaporator under reduced pressure.

[0078] Thin-layer chromatography (TLC) was performed on Merck silica gel 60 plates with the solvent system as noted.

[0079] Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. The MS data presented is the m/z found (typically [M+H]⁺) for the molecular ion.

[0080] Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers (400, 500, or 600 MHz). The format of the ¹H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

[0081] Chemical names were generated using ChemDraw Version 6.0.2 (CambridgeSoft, Cambridge, MA) or ACD/Name Version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

Example 1: 2-[3-(4-Chloro-3-{[4-({[(4- chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-{3-[(3S)-3- methylmorpholin-4-yl]propyl}-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2- oxoacetamide. [0082] A. 4-(3-Chloro-propylH3S)-methyl-morpholine. A solution of (3S)- methyl-morpholine (1 g, 9.9 mmol, 1.0 equiv) and 1-bromo-3-chloro-propane (3.1 g, 19.8 mmol, 2.0 equiv) in THF (5 ml_) was treated with NaH (60%, 2 equiv) in two portions. The resulting slurry was heated at 65 ⁰C for 18 h. Slowly, the reaction was quenched with ice water (20 ml_). During the addition, excess bubbling occurred. The resulting mixture was stirred for 16 h and then was extracted with ethyl acetate (EtOAc; 3 x 15 ml_). The combined organic layers were extracted with 1 N HCI (40 ml_). The aqueous layer was cooled in an ice bath and basified slowly to pH ~9-10 with NaOH pellets. The aqueous layer was extracted with EtOAc (3 x 15 ml_). The combined organic layers were dried and concentrated to give the title compound as a clear oil (1.3 g, 74%). MS found: 178.1. ¹H NMR (500 MHz, CDCI₃): 3.80-3.76 (m, 1 H), 3.68-3.59 (m, 4H), 3.22 (dd, J = 11.2, 9.8 Hz, 1 H), 2.93-2.86 (m, 1 H), 2.72 (dt, J = 11.7, 2.8 Hz, 1H), 2.46-2.39 (m, 1 H), 2.35-2.27 (m, 2H), 1.99-1.83 (m, 2H)₁ 0.98 (d, J = 6.3 Hz, 3H).

[0083] B. (4-Chloro-benzylM4-ethvnyl-benzyl)-amine. 4- Trimethylsilanylethynyl-benzaldehyde (commercially available or available via Sonogashira coupling; 1.0 g, 4.9 mmol, 1.0 equiv) was dissolved in methanol (20 ml_) and 4-chlorobenzylamine (0.74 g, 5.2 mmol, 1.05 equiv) was added. After stirring at rt for 16 h, NaBH₄ (0.19 g, 4.9 mmol, 1.0 equiv) was added slowly. 1 N HCI was slowly added to quench the unreacted NaBH₄. The mixture was concentrated and the residue was partitioned between CH₂Cb and satd. aq. NaHCU₃. The organic layer was dried and concentrated. The crude compound was purified (SiO₂; EtOAc/hexanes) to provide the title compound (1.1 g, 4.3 mmol, 90%). TLC: R_f = 0.54 (50% EtOAc/hexanes). Alternatively, the material was converted to the corresponding HCI salt and purified by recrystallization. MS found: 256.0. ¹H NMR (500 MHz, CDCI₃): 7.52-7.46 (m, 2H), . 7.34-7.26 (m, 6H), 3.81 (s, 2H), 3.78 (s, 2H), 3.07 (s, 1 H).

[0084] C. 4-Morpholin-4-yl-3.6-dihvdro-2H-pyridine-1-carboxylic acid tert-butyl ester. In a 3-L round-bottom flask equipped with a Dean-Stark trap, a reflux condenser and an internal thermocouple, /V-Boc-piperidone (200 g, 1.0 mol, 1.0 equiv), toluene (2 L), morpholine (92 mL, 1.05 mol, 1.05 equiv), and p-toluenesulfonic acid (1.0 g, 0.005 mmol, 0.5% equiv) were added sequentially. The reaction solution was refluxed under N₂ for 16 h (about 18 mL water was collected). The solvent was evaporated and the residue was used directly in the next reaction (colorless oil, -270 g, 100%). MS found: 269.2. [0085] D. 4-Chloro-3-iodo-benzoyl chloride. In a 5-L round-bottom flask equipped with a magnetic stirring bar and a gas scrubber, 4-chloro-3-iodobenzoic acid (275 g, 0.975 mol, 1.0 equiv) was suspended in CH₂Cb (3 L) and DMF (2 mL, 0.026 mol, 2.5% equiv) was added. Under N₂ at 0⁰C, oxalyl chloride (93.5 mL, 1.1 mol, 1.1 equiv) was added dropwise over 1 h. The ice bath was removed and the reaction solution was stirred at rt for 16 h. The solvent was evaporated and the residue was used directly in the next reaction (~290 g, 100%).

[0086] E. 3-(4-Chloro-3-iodo-phenyl)-1 ,4.6,7-tetrahvdro-pyrazolor4,3- clpyridine-5-carboxylic acid tert-butyl ester. 4-Moφholin-4-yl-3,6-dihydro-2H-pyridine-1 - carboxylic acid tert-butyl ester (270 g, 1.0 mol, 1.0 equiv) was dissolved in CH₂CI₂ (1.6 L) and then triethylamine (209 mL, 1.5 mol, 1.5 equiv) was added. At 0 ⁰C under N₂, a solution of 4-chloro-3-iodo-benzoyl chloride (290 g, 1.0 mol, 1.0 equiv) in CH₂CI₂ (400 mL) was added over 30 min. The ice bath was then removed and the reaction solution was stirred at rt for 3 h. All the volatile solvents were removed in vacuo and the residue was re-dissolved in ethanol (1.5 L). At O ⁰C, anhydrous NH₂NH₂ (47 mL, 1.5 mol, 1.5 equiv) was added over 30 min (exothermic reaction). The reaction solution was stirred at rt for 16 h. The precipitated white solid was collected by filtration and washed with cold ethanol to afford the desired pyrazole product (white solid, ~ 333 g, 0.73 mol, >95% purity, 73%). The mother liquor was concentrated and was partitioned between CH₂CI₂ and H₂O. Emulsion was observed due to the low solubility of the desired product in CH₂CI₂. The insoluable solid was collected by filtration to provide an additional portion of the desired product. The organic layer was warmed slightly to assist phase separation. The organic layer was washed with water (3x), dried, and concentrated. The crude product (filtered material plus residue) was recrystallized from hot CH₃CN to give the title compound (74 g, 0.16 mmol, 16%). The total yield was 89% for the three steps. MS found: 460.0. ¹H NMR (500 MHz, CDCI₃): 8.13 (s, 1H), 7.52-7.45 (m, 2H), 4.70^.52 (m, 2H), 3.80-3.64 (m, 2H), 2.86-2.72 (m, 2H), 1.49 (s, 9H).

[0087] F. 3-(4-Chloro-3-iodo-phenyl)-4,5,67-tetrahvdro-1 H-pyrazolo[4,3- clpyridine. A suspension of 3-(4-chloro-3-iodo-phenyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridine-5-carboxylic acid tert-butyl ester (260 g, 0.57 mol, 1.0 equiv) in CH₂CI₂ (750 mL) was treated with TFA (250 mL) over 20 min. The resulting solution was stirred at rt for 16 h. The mixture was diluted with water (2 L) and then basified with satd. aq. NaOH to a pH > 12. The mixture was stirred for 3 h. The white precipitate was collected by filtration, washed with water and dried in a vacuum oven to provide the title compound (205 g, 0.57 mol, 100%), which was used in the next reaction without further purification. MS found: 360.0. ¹H NMR (400 MHz₁ DMSOd₆): 9.13 (s, 2H), 8.20-8.14 (m, 1 H), 7.80-7.54 (m, 2H), 4.39 (s, 2H), 3.50-3.34 (m, 2H), 3.05-2.92 (m, 2H).

[0088] G. 2-r3-(4-Chloro-3-iodo-phenvn-14.6.7-tetrahvdro-Dyrazolor4.3- clpyridin-5-vπ-2-oxo-acetamide. A suspension of CDI (110.5 g, 0.68 mol, 1.2 equiv) in DMF (1.5 L) was treated with oxalamic acid (60.7 g, 0.68 mol, 1.2 equiv). After 3 h at rt, 3-(4-chloro-3-iodo-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (205 g, 0.57 mol, 1.0 equiv) was added as solid over 10 min. After 20 min, water (2.5 L) was added slowly over 2 h and the mixture was stirred at rt for 16 h. The resulting white precipitate was collected by filtration, washed with water and dried in a vacuum oven to provide the title compound (243 g, 0.56 mol, 100%), which was used in the next reaction without further purification. MS found: 431.0. ¹H NMR (500 MHz, DMSO-d₆): 13.18 (s, 0.3H), 12.95 (s, 0.7H), 8.30-8.00 (m, 2H)₁ 7.84-7.48 (m, 3H), 4.80-4.66 (m, 2H)₁ 3.86-3.66 (m, 2H)₁ 2.90-2.60 (m, 2H).

[0089] H. 2-{3-(4-Chloro-3-iodo-phenyl)-1-r3-f(3S)-methyl-morpholin-4-yl)- propyn-1 ,4,6,7-tetrahvdro-pyrazolor4.3-clpyridin-5-yl}-2-oxo-acetamide. A solution of 2- f3-(4-chloro-3-iodo-phenyl)-1 _l4,6_l7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo- acetamide (190 g, 0.44 mol, 1.0 equiv) in DMF (1.8 L) was treated with Cs₂CO₃ (180 g, 0.55 mol, 1.25 equiv) followed by 4-(3-chloro-propyl)-(3S)-methyl-morpholine (86 g, 0.48 mol, 1.1 equiv). The reaction mixture was stirred via mechanical stirrer at 50 ⁰C under N₂ for 12 h and then cooled to rt. Water (3.5 L) was added slowly over 30 min. The mixture was stirred at rt for 16 h and the resulting white solid was collected by filtration, washed with water and dried in a vacuum oven. The crude compound was triturated from hot ethanol (~1.5 L) to provide the title compound (176 g, 0.31 mol, 70%). MS found: 572.2. ¹H NMR (500 MHz, DMSO-d₆): 8.20-8.12 (m, 1 H), 8.12-8.04 (m, 1 H), 7.78-7.67 (m, 1 H), 7.67-7.63 (m, 1 H)₁ 7.62-7.46 (m, 1 H)₁ 4.74-4.66 (m, 2H)₁ 4.09-4.00 (m, 2H)₁ 3.88-3.72 (m, 2H)₁ 3.70-3.62 (m, 1 H)₁ 3.60-3.44 (m, 2H), 3.14-3.06 (m, 1 H), 2.96-2.64 (m, 4H)₁ 2.38-2.24 (m, 1 H)₁ 2.18-2.08 (m, 2H)₁ 1.97-1.86 (m, 2H), 0.85(s, 1.5H), 0.84(s, 1.5H).

[0090] I. 2-r3-(4-Chloro-3-fr4-((r(4- chlorophenyl)methyllamino)methyl)phenyl1ethvnyl)phenyl)-1-{3-r(3S)-3- methylmorpholin-4-yllpropyl>-1 ,4.6.7-tetrahvdro-5H-pyrazolor4,3-cipyridin-5-yll-2- oxoacetamide. To a 5 L flask equipped with a mechanical stirrer and an internal thermocouple, was added 2-{3-(4-chloro-3-iodo-phenyl)-1-[3-((3S)-methyl-morpholin-4- yO-propyll-IAβJ-tetrahydro-pyrazolo^.S-cføyridin-δ-yl^-oxo-acetamide (120 g, 0.21 mol, 1.0 equiv), (4-chloro-benzyl)-(4-ethynyl-benzyl)-amine (56.3 g, 0.22 mol, 1.0 equiv), DMF (1.5 L) and triethylamine (120 ml_, 0.84 mol, 4.0 equiv) sequentially. A stream of N₂ was bubbled into the solution for 15 min. A mixture of Pd(PPh₃)₂Cl2 (0.37 g, 0.5 mmol, 0.0025 equiv) and CuI (0.2 g, 1.0 mmol, 0.005 equiv) was added under N2. The solution was degassed with N₂ for another 10 min. The reaction solution was stirred at 50 ⁰C for 16 h. The reaction solution was cooled to rt and water (2 L) was added with stirring. The liquid layer was decanted away from an oily precipitate, which was then partitioned between EtOAc (2 L) and 2:1 water/satd. aq. NaHCO₃ (1.5 L). The organic layer was dried and concentrated to provide the crude material as a foamy yellow solid (145 g, ~85% purity by HPLC). The crude material was purified (SiO₂; 2 N NH₃ in methanol/CH₂CI₂) to provide the title compound (87 g, 59%, >98% purity). MS found: 699.2. ¹H NMR: 7.90-7.89 (m, 0.7H), 7.84-7.82 (m, 0.3H), 7.70-7.66 (m, 3H), 7.61-7.55 (m, 3H), 7.53-7.45 (m, 4H), 4.81 (s, 1 H), 4.31 (s, 2H), 4.28 (s, 2H), 4.27-4.22 (m, 2H)₁ 4.05 (d, J = 13, 1 H), 4.02-3.94 (m, 3H), 3.87-3.68 (m, 2H), 3.58-3.39 (m, 4H), 3.35-3.32 (m, 1 H), 3.26-3.13 (m, 3H), 3.02-2.85 (m, 2H), 2.47-2.35 (m, 1H)₁ 2.33-2.20 (m, 1 H), 1.45-1.22 (m, 4H).

Example 2: Oxalate Salt Formation - Procedure 1.

[0091] A solution of 2-[3-(4-chloro-3-{[4-({[(4- chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-{3-[(3S)-3- methylmoφholin-4-yl]propyl}-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2- oxoacetamide (100 mg) in CH₃CN (4 mL) was heated to 50 ⁰C. Diethyl oxalate (~ 3 mL) was added drop wise until the solution became cloudy. The solution was left at 50 ⁰C without stirring under N₂ for 16 h. The precipitated crystalline solid was collected by filtration and washed with CH₃CN to afford the oxalate salt. MS found: 699.2. ¹H NMR (500 MHz, DMSO-dβ): 8.18-8.10 (m, 1 H), 7.92-7.82 (m, 1 H), 7.82-7.71 (m, 1 H), 7.70- 7.60 (m, 4H), 7.58-7.44 (m, 6H), 4.75 (s, 0.6H), 4.72 (s, 1.4H), 4.13-4.04 (m, 6H), 4.01 (q, J = 7.1 Hz₁ 2H), 3.90-3.46 (m, 7H), 3.24-3.10 (m, 2H), 2.96-2.74 (m, 4H), 2.42-2.20 (m, 2H), 2.10-1.90 (m, 2H)₁ 1.18 (t, J =7.1 Hz₁ 3H), 0.91 (d, 3H). Example 3: Oxalate Salt Formation - Procedure 2.

[0092] Step A. Water (1 equiv.) was added into a solution of commercially available chloro-oxo-acetic acid ethyl ester in EtOAc (0.36 mol/L) at rt. The solution was concentrated to afford monoethyl oxalate as a colorless oil. ¹H NMR (500 MHz, DMSO-d₆): 4.23 (q, J = 7.1 Hz₁ 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0093] Step B. A solution of 2-[3-(4-chloro-3-{[4-({[(4- chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-{3-[(3S)-3- methylmoφholin-^-yOpropylJ-i ^.ey-tetrahydro-δH-pyrazolo^.S-clpyridin-δ-yl]^- oxoacetamide (100 mg, 1.0 equiv.) in CH₃CN (5 ml_) was heated to 50 ⁰C and treated with monoethyl oxalate (17 mg, 1.0 equiv.). The solution was stirred at 50 ⁰C for 16 h and cooled to rt. The precipitated crystalline solid was collected by filtration and washed with CH₃CN to provide the oxalate salt (85 mg, 85%).

Example 4: 2-Oxopentanoic Acid Salt Formation.

[0094] A solution of 2-[3-(4-chloro-3-{[4-({[(4- chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-{3-[(3S)-3- methyImoφholin-4-yl]propyl}-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2- oxoacetamide (100 mg, 1.0 equiv.) in CH₃CN (5 ml_) was heated to 50 ⁰C and treated with 2-oxo-pentanoic acid (17 mg, 1.0 equiv.). The solution was stirred at 50 ⁰C for 16 h and cooled to rt. The precipitated crystalline solid was collected by filtration and washed with CH₃CN to afford the 2-oxopentanoate salt. MS found: 699.2.

Example 5: Monotartrate Salt Formation.

[0095] A solution of 2-[3-(4-chloro-3-{[4-({[(4- chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-{3-[(3S)-3- methylmoφholin-4-yl]propyl}-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2- oxoacetamide (100 g, 0.14 mol, 1.0 equiv, >98% purity) in EtOAc (1.5 L) was treated with a solution of L-tartaric acid (21.5 g, 0.14 mol, 1.0 equiv) in MeOH (150 mL) over 1 h. After stirring at rt for 1 h further, the precipitated solid was collected by filtration and washed with EtOAc under a N2 stream. The resulting amorphous material contained ~8 wt% residue of solvents (EtOAc and MeOH) by ¹H NMR. High vacuum at 50 ⁰C for a few days failed to reduce the residual solvent level. Trituration of the L-tartrate salt from various solvents (such as ethanol, THF, 2-methyl-THF, or isopropyl acetate) resulted in trapping of the solvents. The amorphous material was dissolved in water ( ~ 500 ml_) and the mixture was concentrated at 50 ⁰C under vacuum to yield material with an organic solvent residue of <0.5 wt%. Subsequent lyophilization of the material afforded the the monotartrate salt as an amorphous white powder (97 g, 80%).

[0096] The compounds in Examples 6-37, and pharmaceutically acceptable salts thereof, may be prepared using methods analogous to those described for Example 1. Analytical data for these compounds may be found in the US patent application entitled, "Carbon-Linked Tetrahydro-pyrazolo-pyridine Modulators of Cathepsin S," by Ameriks et al.

1-[4-({2-Chloro-5-[5-(methylsulfonyl)-1-(3-moφholin-4-ylpropyl)-4,5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-[(3,4- dichlorophenyl)methyl]methanamine

(S)-2-[3-(4-Chloro-3-{4-[(4-chloro-beπzylamino)-methyl]-phenylethynyl}-phenyI)- i^-hydroxy-S-morpholin^-yl-propyO-i^.β.y-tetrahydro-pyrazolo^.S-clpyridin-S- yl]-2-oxo-acetamide

(R)-2-[3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyI)- i^-hydroxy-S-morpholin^-yl-propyO-i ^.e.y-tetrahydro-pyrazolo^.S-clpyridin-δ- yl]-2-oxo-acetamide

(2-{3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-nnethyl]-phenylethynyI}-phenyl)-1-

[(2S)-2-hydroxy-3-((3S)-3-methyl-morphoIin-4-yl)-propyl]-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl}-2-oxo-acetamide

2-{3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyI)-1-

[(2R)-2-hydroxy-3-((3S)-3-methyl-moφholin-4-yl)-propyl]-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl}-2-oxo-acetannide

3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-[(2S)-

2-hydroxy-3-((3S)-3-methyl-morpholin-4-yl)-propyl]-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridine-5-carboxylic acid amide

3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyI}-phenyl)-1-[(2S)-

2-hydroxy-3-((3S)-3-methyl-morpholin-4-yl)-propyl]-1 ,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridine-5-carboxylic acid amide

(S)-3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1- (2-hydroxy-3-morpholin-4-yl-propyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5- carboxylic acid amide

(R)-3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1- (2-hydroxy-3-morpholiπ-4-yl-propyl)-1 ,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5- carboxylic acid amide

(S)-1-[3-(4-Chloro-3-{4-[(4-chloro-beπzylamino)-methyl]-phenylethynyl}-phenyl)- 5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-morpholin-4- yl-propan-2-ol

(R)-1-[3-(4-Chloro-3-{4-[(4-chloro-beπzylamino)-methyl]-phenylethynyl}-phenyl)- 5-methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-morphoIin-4- yl-propan-2-ol

1-[2-Chloro-4-({2-chloro-5-[5-(methylsuIfonyl)-1-(3-moφholin-4-ylpropyl)-4,5,6,7-

35 tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-[(4- chlorophenyl)methyl]methanamine

2-(3-{4-Chloro-3-[(4-{[(4-chlorobenzyl)amino]methyl}phenyl)ethynyl]phenyl}-1-{3-

36 [(3R)-3-methylmorpholin-4-yl]propyl}-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridin-5-yl)-2-oxoacetamide

2-(3-{4-Chloro-3-[(4-{[(4-chlorobenzyl)amino]methyl}phenyl)ethynyl]phenyl}-1-[3-

37 (S-methylmorpholin^-ylJpropylJ-i^.e^-tetrahydro-SH-pyrazolo^.S-^pyridin-δ- yl)-2-oxoacetamide

Biological Testing:

[0097] Recombinant human cathepsin S (CatS) was expressed in the baculovirus system and purified in one step with a thiopropyl-sepharose column. 10-L yielded ~700 mg of Cats and N-terminal sequencing confirmed identity. The assay is run in 150 mM sodium acetate pH 5.0 containing 1.5 mM DTT and 150 mM NaCI. The substrate for the assay is: Z-Valine-Valine-Arginine-AMC (catalog # 1-1540, Bachem). The K_m for the substrate is around 5 μM but the presence of substrate inhibition makes kinetic analysis difficult. With 10 μM substrate the assay rate is linear over the range of 1-8 ng CatS in 100 μl_ reaction. Using 2 ng/well of CatS, the production of product is linear and yields ~7-fold signal after 20 min with only 20% loss of substrate. Measurements are taken every min for 20 min. The rate is calculated from the slope of the increase in fluorescence and the percent inhibition is calculated from this.

[0098] Results for the compounds tested in this assay are presented in Table 2 as an average of results obtained. Compounds were tested in free base or hydrochloride salt forms. Table 2.

[0099] While the invention has been illustrated by reference to examples, it is understood that the invention is intended not to be limited to the foregoing detailed description.

Claims

What is claimed is:

1. A method of making a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

comprising reacting a compound of formula (IX):

with a compound of formula (X):

to form a compound of Formula (I); wherein:

R¹ and R² taken together with the nitrogen to which they are attached form a morpholine ring, unsubstituted or substituted with one or two methyl substituents; R³ is H or OH;

R⁴ is -SO₂CH₃, -CONH₂, Or -COCONH₂; R⁵ is H or methyl; R⁶ is a benzyl group, unsubstituted or substituted with one or two substituents independently selected from the group consisting of C^alkyl, CF₃, halo, OH, -OCi- ₄alkyl, -OCF₃, -OCHF₂, NR^ddR^ee, -CO₂C₁ ^aI ky I, -SC_1-4alkyl, and -SO₂C_1-4alkyl; where R^dd and R^ee are each independently H or Ci-4alkyl; R⁷ is H, fluoro, or chloro; and LG¹ is iodide, bromide, or trifluoromethanesulfonate.

2. A method as in claim 1 , further comprising reacting a compound of formula (VII):

with a compound of formula (VIII):

where LG² is iodo, bromo, chloro, or trifluoromethanesulfonate; or R³ and LG² taken together with the carbons to which they are attached form an epoxide ring; to form a compound of formula (IX).

3. A method as in claim 2, further comprising: (a) deprotecting a compound of formula (Vl):

to form a compound of formula (Via):

(b) reacting a compound of formula (Via) with methanesulfonyl chloride, trimethylsilylisocyanate, or oxalamic acid, to form a compound of formula (VII).

4. A method as in claim 3, further comprising reacting a compound of formula (III):

with an acid chloride of formula (IV):

to form a first reaction product and, subsequently, reacting the first reaction product with hydrazine to form a compound of formula (Vl).

5. A method as in claim 4, further comprising reacting N-Boc-piperidone with a cyclic secondary amine HNR^aR^b to form a compound of formula (III); wherein HNR^aR^b is selected from the group consisting of pyrrolidine, morpholine, and piperidine.

6. A method as in claim 1 , wherein R¹ and R² taken together with the nitrogen to which they are attached form morpholine, 3-methylmorpholine, 2,6-dimethylmorpholine, 3,5-dimethylmorpholine, (3S)-methylmorpholine, or (3R)-methylmorpholine.

7. A method as in claim 1 , wherein R³ is H.

8. A method as in claim 1 , wherein R³ is OH.

9. A method as in claim 1 , wherein R⁴ is -SO₂CH₃ or -COCONH₂.

10. A method as in claim 1 , wherein R⁴ is -SO₂CH₃.

11. A method as in claim 1 , wherein R⁵ is H.

12. A method as in claim 1 , wherein R⁶ is a benzyl group, unsubstituted or substituted with one or two substituents independently selected from the group consisting of chloro or methyl.

13. A method as in claim 1 , wherein R⁶ is 4-chloro-benzyl.

14. A method as in claim 1 , wherein R⁷ is H.

15. A method as in claim 1 , wherein the compound of formula (IX) is 2-{3-(4-chloro-3- iodo-phenyl)-1-[3-((3S)-methyl-morpholin-4-yl)-propyl]-1 ,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-5-yl}-2-oxo-acetamide.

16. A method as in claim 1 , wherein the compound of formula (X) is (4-chloro- benzyl)-(4-ethynyl-benzyl)-amine.

17. A method as in claim 2, wherein the compound of formula (VII) is 2-[3-(4-chloro- 3-iodo-phenyl)-1 Aβ^-tetrahydro-pyrazolol^.S-clpyridin-δ-yl^-oxo-acetamide.

18. A method as in claim 2, wherein the compound of formula (VIII) is 4-(3-chloro- propyl)-(3S)-methyl-morpholine.

19. A method as in claim 3, wherein the compound of formula (Vl) is 3-(4-chloro-3- iodo-phenyl)-1 AβJ-tetrahydro-pyrazolol^.S-clpyridine-δ-carboxylic acid tert-butyl ester and the compound of formula (Via) is 3-(4-chloro-3-iodo-phenyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridine.

20. A method as in claim 4, wherein the compound of formula (III) is 4-morpholin-4- yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester.

21. A method as in claim 4, wherein the compound of formula (IV) is 4-chloro-3-iodo- benzoyl chloride.

22. A method as in claim 1 , wherein the compound of Formula (I) is: 2-[3-(4-Chloro-3-{[4-({[(4-chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1- {S-^SSJ-S-methylmorpholin^-ylJpropylJ-I Λ.βJ-tetrahydro-δH-pyrazolo^.S-cJpyridin-δ- yl]-2-oxoacetamide;

Benzyl-(4-{2-chloro-5-[5-methanesulfonyl-1-(3-morpholin-4-yl-propyl)-4, 5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]-phenylethynyl}-benzyl)-amine; (4-{2-Chloro-5-[5-methanesulfonyl-1-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridin-3-yl]-phenylethynyl}-benzyl)-(4-methyl-benzyl)-amine; (4-Chloro-benzyl)-(4-{2-chloro-5-[5-methanesulfonyl-1-(3-morpholin-4-yl-propyl)- 4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]-phenylethynyl}-benzyl)-amine; 243-(4-Chloro-3-{[4-({[(4-chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-

(3-morpholin-4-ylpropyl)-1 ,4.6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2- oxoacetamide;

S^-Chloro-S-^-^^-chlorophenylJmethylJaminoJmethylJphenylJethynylJphenylJ-I^S- morpholin^-ylpropyO-I Λ.βJ-tetrahydro-δH-pyrazolo^.a-cJpyridine-δ-carboxamide;

2-(3-{4-Chloro-3-[(4-{[(4-chlorobenzyl)amino]methyl}phenyl)ethynyl]phenyl}-1-{3-

[(3S,5S)-3,5-dimethylmorpholin-4-yl]propyl}-1 ,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridin-5-yl)-2-oxoacetamide; i^-^-Chloro-δ-ti-IS^SSJ-S-methylmorpholin^-ylJpropylJ-δ^methylsulfonylH.δ.e.Z- tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-[(4- chlorophenyl)methyl]methanamine;

N-l^-^-Chloro-δ-tδ^methylsulfonyO-I^S-morpholin^-ylpropylH.δ.e.Z-tetrahydro-I H- pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]methyl}-1-phenylethanamine;

1 -[4-({2-Chloro-δ-[δ-(methylsulfonyl)-1 -(3-morpholin-4-ylpropyl)-4,δ,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-[(3,4- dichlorophenyl)methyl]methanamine;

(S)-2-[3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-(2- hydroxy-S-morpholin^-yl-propyO-I Λ.βJ-tetrahydro-pyrazolo^.S-cJpyridin-δ-ylJ^-oxo- acetamide;

(R)-2-[3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-(2- hydroxy-3-morpholin-4-yl-propyl)-1 ,4.6,7-tetrahydro-pyrazolo[4,3-c]pyridin-δ-yl]-2-oxo- acetamide;

(2-{3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-[(2S)-2- hydroxy-3-((3S)-3-methyl-morpholin-4-yl)-propyl]-1 ,4.6.7-tetrahydro-pyrazolo[4,3- c]pyridin-δ-yl}-2-oxo-acetamide;

2-{3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-[(2R)-2- hydroxy-3-((3S)-3-methyl-morpholin-4-yl)-propyl]-1 ,4.6,7-tetrahydro-pyrazolo[4,3- c]pyridin-δ-yl}-2-oxo-acetamide;

3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-[(2S)-2- hydroxy-3-((3S)-3-methyl-morpholin-4-yl)-propyl]-1 ,4.6.7-tetrahydro-pyrazolo[4,3- c]pyridine-δ-carboxylic acid amide;

3δ 3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-[(2S)-2- hydroxy-3-((3S)-3-methyl-morpholin-4-yl)-propyl]-1 ,4.6.7-tetrahydro-pyrazolo[4,3- c]pyridine-5-carboxylic acid amide;

(S)-3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-(2- hydroxy-3-morpholin-4-yl-propyl)-1 ,4.6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5- carboxylic acid amide;

(R)-3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-1-(2- hydroxy-3-morpholin-4-yl-propyl)-1 ,4.6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5- carboxylic acid amide;

(S)-1-[3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-5- methanesulfonyl^.δ.e.Z-tetrahydro-pyrazolo^.S-cJpyridin-i-ylJ-S-morpholin^-yl- propan-2-ol;

(R)-1-[3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-5- methanesulfonyl^.δ.β.Z-tetrahydro-pyrazolo^.S-cJpyridin-i-ylJ-S-morpholin^-yl- propan-2-ol;

(2S)-1-[3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-5- methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-((3S)-3-methyl- morpholin-4-yl)-propan-2-ol;

(2S)-1-[3-(4-Chloro-3-{4-[(4-chloro-benzylamino)-methyl]-phenylethynyl}-phenyl)-5- methanesulfonyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-((3S)-3-methyl- morpholin-4-yl)-propan-2-ol;

1-[3-(4-Chloro-3-{[4-({[(4-chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-5-

(methylsulfonyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-1-yl]-3-morpholin-4- ylpropan-2-ol;

1 -[4-({2-Chloro-5-[5-(methylsulfonyl)-1 -(3-morpholin-4-ylpropyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-{[4-

(methyloxy)phenyl]methyl}methanamine;

1-[4-({2-Chloro-5-[1-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propyl}-5-(methylsulfonyl)-

4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-[(4- chlorophenyl)methyl]methanamine;

3-(4-Chloro-3-{[4-({[(4-chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-{3-

[(SSJ-S-methylmorpholin^-ylJpropylJ-I Λ.βJ-tetrahydro-δH-pyrazolo^.S-cJpyridine-δ- carboxamide; 1 -[4-({2-Chloro-5-[5-(methylsulfonyl)-1 -(3-morpholin-4-ylpropyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)-2-fluorophenyl]-N-[(4- chlorophenyl)methyl]methanamine;

(2R)-1-[3-(4-Chloro-3-{[4-({[(4- chlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-5-(methylsulfonyl)-4,5,6,7- tetrahydro-I H-pyrazolo^.S-cJpyridin-i-ylJ-S-^SSJ-S-methylmorpholin^-ylJpropan^-ol;

1-[4-({2-Chloro-5-[1-{3-[(3R)-3-methylmorpholin-4-yl]propyl}-5-(methylsulfonyl)-4,5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-[(4- chlorophenyl)methyl]methanamine; i-^-Chloro^-^-chloro-δ-tδ^methylsulfonyO-I^S-morpholin^-ylpropylH.δ.e,?- tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-

(phenylmethyl)methanamine; i-^-Chloro^-^-chloro-δ-tδ^methylsulfonyO-I^S-morpholin^-ylpropylH.δ.e,?- tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl]phenyl}ethynyl)phenyl]-N-[(4- chlorophenyl)methyl]methanamine;

2-(3-{4-Chloro-3-[(4-{[(4-chlorobenzyl)amino]methyl}phenyl)ethynyl]phenyl}-1-{3-[(3R)-

3-methylmorpholin-4-yl]propyl}-1 ,4.6,7-tetrahydro-δH-pyrazolo[4,3-c]pyridin-δ-yl)-2- oxoacetamide;

2-(3-{4-Chloro-3-[(4-{[(4-chlorobenzyl)amino]methyl}phenyl)ethynyl]phenyl}-1-[3-(3- methylmorpholin-4-yl)propyl]-1 ,4.6,7-tetrahydro-δH-pyrazolo[4,3-c]pyridin-δ-yl)-2- oxoacetamide; or a pharmaceutically acceptable salt thereof.

23. A method as in claim 1 , wherein the compound of Formula (I) is 2-[3-(4-chloro-3- {[4-({[(4^hlorophenyl)methyl]amino}methyl)phenyl]ethynyl}phenyl)-1-{3-[(3S)-3- methylmorpholin-4-yl]propyl}-1 ,4.6,7-tetrahydro-δH-pyrazolo[4,3-c]pyridin-δ-yl]-2- oxoacetamide or a pharmaceutically acceptable salt thereof.