EA047826B1 - PYRAZOLE BASED MAGL INHIBITORS - Google Patents

Abstract

The invention provides a compound having a structure or a pharmaceutically acceptable salt thereof, as well as a pharmaceutical composition containing said compound, a method for treating chronic pain, pain caused by inflammation, migraine, scleroderma or non-alcoholic fatty liver disease (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of said compound, and a method for treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of said compound.

Description

Cross reference

The invention claims the benefit of U.S. Provisional Patent Application No. 62/510,213, filed May 23, 2017, which is incorporated herein by reference in its entirety.

State of the art

Monoacylglycerol lipase (MAGL) is an enzyme responsible for the hydrolysis of endocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate-based lipid, in the nervous system. Fatty acid amide hydrolase (FAAH) is another enzyme responsible for the hydrolysis of endocannabinoids such as anandamide.

Brief description of the present invention

The present invention provides, for example, compounds and compositions that are MAGL modulators and their use as medical agents, methods for their preparation, and pharmaceutical compositions that contain the disclosed compounds as at least one active ingredient. The present invention also provides the use of the disclosed compounds as drugs and/or in the manufacture of drugs for inhibiting MAGL activity in warm-blooded animals such as humans. In one aspect, a compound having the structure

ABOUT

or a pharmaceutically acceptable salt thereof.

In another aspect, a pharmaceutical composition is provided comprising the said compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In some embodiments, a method of treating chronic pain, pain due to inflammation, migraine, scleroderma, or non-alcoholic fatty liver disease (NASH) in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of said compound or a pharmaceutically acceptable salt thereof.

In another embodiment, a method of treating migraine in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of said compound or a pharmaceutically acceptable salt thereof.

Detailed description of the invention

The present invention relates, at least in part, to MAGL modulators or inhibitors. For example, provided herein are compounds capable of inhibiting MAGL.

As used herein and in the appended claims, the singular forms include the plural forms of the designated entities unless the context clearly dictates otherwise. Thus, for example, a reference to an agent includes a plurality of such agents, and a reference to a cell includes a reference to one or more cells (or a plurality of cells) and their equivalents. When ranges are used herein to describe physical properties, such as molecular weight, or chemical properties, such as chemical formulas, it is intended to include all combinations and subcombinations of ranges and specific embodiments thereof. The term "approximately," when referring to a number or a numerical range, means that the number or numerical range to which it refers is an approximation within the variation in results from experiment to experiment (or within the statistical error of the experiment), and thus the number or numerical range varies from 1% to 15% of the stated number or numerical range. It is intended that the term comprising (and related terms such as comprise, or contains, or having, or including) does not exclude an element that in some other embodiments, such as in an embodiment of any composition according to the present invention, composition, method or process, or the like, described herein, may consist of or consist essentially of the described features.

Definitions.

As used in this specification and the appended claims, unless otherwise indicated, the following expressions have the meanings set forth below. Optional or optional implies that the event or circumstance further described may or may not occur, and that the description includes both instances in which the event or circumstance occurs and instances in which it does not. For example, optionally substituted aryl implies that the aryl radical is substituted or unsubstituted, and that the description includes both substituted aryl radicals and aryl radicals that have no substitution. A pharmaceutically acceptable salt includes both acid addition salts and base addition salts.

- 1 047826

A pharmaceutically acceptable salt of any of the pyrazole compounds described herein is intended to encompass any and all forms of pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

A pharmaceutically acceptable acid addition salt means those salts that retain the biological effectiveness and properties of the free bases, which are not undesirable from a biological or other point of view, and which are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphoric acid, etc. Also included are salts formed using organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, illustrative salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, manates, tartrates, methanesulfonates, and the like. Also contemplated are amino acid salts such as arginates, gluconates, and galacturonates (see, e.g., Berge S.m. et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to yield the salt.

A pharmaceutically acceptable base addition salt means those salts that retain the biological effectiveness and properties of the free acids that are not biologically or otherwise undesirable. Such salts are prepared by adding an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine. chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., above.

As used herein, treatment, or treatment, or alleviation, or amelioration are used interchangeably herein. Such terms refer to an approach to obtaining favorable or desired results, including, but not limited to, therapeutic benefit and/or prophylactic benefit. Therapeutic benefit refers to the elimination or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved by eliminating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that the patient experiences improvement despite the fact that the patient is still afflicted with the underlying disorder. In the case of prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease or to a patient exhibiting one or more physiological symptoms of a disease despite the fact that the disease has not been diagnosed.

Connections.

Compounds of formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (li) described herein that are MAGL modulators. In some embodiments, the compounds are MAGL inhibitors. In some embodiments, the compounds of formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) described herein and compositions comprising such compounds are useful for treating pain, migraine, scleroderma, or non-alcoholic fatty liver disease (NASH).

- 2 047826

In some embodiments, a compound of the formula is provided

ABOUT

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In another embodiment, there is provided a method of treating chronic pain, pain caused by inflammation, migraine, scleroderma or non-alcoholic fatty liver disease (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of said compound or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of said compound or a pharmaceutically acceptable salt thereof.

Additional embodiments provided herein include combinations of one or more of the specific embodiments set forth above.

Receiving connections.

The compounds used in the reactions described herein were prepared according to organic synthetic procedures using commercially available chemicals and/or compounds described in the chemical literature. Commercially available chemicals were obtained from standard commercial sources, including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (Westchester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Haupoga, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Haupoga, NY), and Bionet Chemicals (Westchester, PA). (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardina, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, Maryland) and WuXi (Shanghai, China).

Suitable reference books and scientific works that describe in detail the synthesis of reagents useful in the preparation of the compounds described herein, or that cite articles that describe the preparation, include, for example, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York; S. R. Sandier et al., Organic Functional Group Preparations, 2nd Ed., Academic Press, New York, 1983; H. O. House, Modern Synthetic Reactions, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, Heterocyclic Chemistry, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed., Wiley-Interscience, New York, 1992. Additional relevant reference books and scientific works that describe in detail the synthesis of reagents useful in the preparation of the compounds described herein, or that provide references to articles that describe the preparation, include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 4th Edition (1992) John Wiley & Sons, ISBN: 0471-60180-2; Otera, J. (ed.) Modern Carbonyl Chemistry (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. Patai's 1992 Guide to the Chemistry of Functional Groups (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. Organic Chemistry 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., Intermediate Organic Chemistry 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; Organic Reactions (1942-2000) John Wiley & Sons, in over 55 volumes and Chemistry of Functional Groups John Wiley & Sons, in 73 volumes.

Specific and similar reagents can also be identified using the indices of known chemical substances assigned by the Chemical Abstracts Service of the American Chemical Society.

- 3 047826 of the American Chemical Society, which are available in many public and university libraries, as well as through online databases (American Chemical Society, Washington, D.C.). Chemicals that are known but not commercially available in catalogs are not necessarily prepared to order from chemical synthesis facilities, and many of the standard chemical synthesis facilities (such as those listed above) provide custom synthesis services. For reference on the preparation and selection of pharmaceutical salts of the compounds described herein, see P. H. Stahl & C. G. Wermuth Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002. Additional forms of the compounds disclosed herein.

Isomers.

Furthermore, in some embodiments, the compounds described herein are in the form of geometric isomers. In some embodiments, the compounds described herein contain one or more double bonds. The compounds provided herein include all cis-, trans-, syn-, anti-, entgegen- (-E-), and zusammen- (Z-) isomers, as well as corresponding mixtures thereof. In some situations, the compounds are in the form of tautomers. The compounds described herein include all possible tautomers corresponding to the formulas described herein. In some situations, the compounds described herein contain one or more chiral centers, and each center is in the R-configuration or the S-configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers obtained in a single preparation step, by mixing, or by interconversion are useful in the applications described herein. In some embodiments, the compounds described herein are obtained as optically pure enantiomers by chiral chromatographic resolution of a racemic mixture. In some embodiments, the compounds described herein are obtained as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes (e.g., crystalline diastereomeric salts) are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and are separated using such differences. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation/separation techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical method that does not result in racemization.

Labeled compounds.

In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, except that one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that are included in the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. The compounds described herein and pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof that contain the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example those in which radioactive isotopes such as ³ H and ¹⁴ C are included, are useful for drug and/or substrate tissue distribution analysis. The isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavy isotopes such as deuterium, i.e. ² H, provides some therapeutic advantages due to higher metabolic stability, such as an increase in half-life in vivo or a decrease in the required dose. In some embodiments, the isotopically labeled compounds, a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof are prepared by any suitable method.

- 4 047826

In some embodiments, the compounds described herein are labeled using other methods, including, but not limited to, using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts.

In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein contain acidic or basic groups and therefore react with any of a variety of inorganic or organic bases and inorganic and organic acids to form a pharmaceutically acceptable salt. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

Solvates.

In some embodiments, the compounds described herein are in the form of solvates. In some embodiments, methods of treating diseases by administering such solvates are provided. In addition, methods of treating diseases by administering such solvates as pharmaceutical compositions are described herein.

Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed by a crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed if the solvent is water, or alcoholates are formed if the solvent is an alcohol. Solvates of the compounds described herein are conveniently prepared or formed by the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, for purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

Prodrugs.

In some embodiments, the compound described herein is in the form of a prodrug. Also described herein are methods of treating diseases by administering such prodrugs. In addition, described herein are methods of treating diseases by administering such prodrugs as pharmaceutical compositions.

In some embodiments, prodrugs include compounds wherein an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked via an amide or ester bond to a free amino, hydroxy, or carboxylic acid residue group in the compounds described herein. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, prodrugs include compounds wherein a nucleic acid residue or an oligonucleotide of two or more (e.g., two, three, or four) nucleic acid residues is covalently linked to a compound described herein.

Pharmaceutically acceptable prodrugs of a compound described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-substituted Mannich bases, Schiff bases, amino acid conjugates, phosphoric acid esters, metal salts, and sulfonic acid esters. In some embodiments, compounds having free amino, amido, hydroxy, or carboxyl groups are converted into prodrugs. For example, free carboxyl groups are derivatized as amides or alkyl esters. In some cases, all such prodrug moieties include groups including, but are not limited to, ether, amine, and carboxylic acid functional groups.

Prodrugs containing a hydroxy group include esters such as, but not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbo

- 5 047826 nyloxyalkyl esters, alkyl esters, aryl esters, phosphoric acid esters, sulfonic acid esters, sulfuric acid esters and disulfide-containing esters; ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as specified in Advanced Drug Delivery Reviews 1996, 79, 115.

Prodrugs that are amine derivatives include, but are not limited to, the following groups and combinations of groups:

as well as sulfonamides and phosphonamides.

In some cases, sites in any part of the aromatic ring are subject to various metabolic reactions, therefore, the introduction of appropriate substituents at the aromatic ring structures reduces, minimizes or eliminates this metabolic pathway.

Pharmaceutical compositions.

In some embodiments, a compound described herein is administered as a chemically pure substance. In some embodiments, a compound described herein is combined with a pharmaceutically acceptable or acceptable carrier (also referred to herein as a pharmaceutically acceptable (or acceptable) excipient, a physiologically acceptable (or acceptable) excipient, or a physiologically acceptable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

Accordingly, provided herein is a pharmaceutical composition comprising a compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is(are) acceptable or suitable if the carrier is compatible with the other ingredients of the composition and is not deleterious to the recipient (i.e., subject) of the composition.

In some embodiments, the compound described herein is substantially pure, i.e., it contains less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as contaminating intermediates or by-products that are formed, for example, in one or more steps of a synthetic process. Such formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), vaginal, ophthalmic, or aerosol administration, although the most appropriate form of administration in any particular case will depend on the extent and severity of the condition being treated and the nature of the particular compound being employed. For example, the disclosed compositions are formulated as a unit dose and/or formulated for oral or subcutaneous administration.

Illustrative pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semi-solid or liquid form, which contains one or more disclosed compounds as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is formulated, for example, with standard non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active compound of the present invention is included in the pharmaceutical composition in an amount sufficient to provide the desired effect with respect to the disease process or condition.

In some embodiments, to obtain solid compositions such as tablets,

- 6 047826 the main active ingredient is mixed with a pharmaceutical carrier, for example, with conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and with other pharmaceutical diluents, for example, with water, to form a solid preformulated composition containing a homogeneous mixture based on the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to such preformulated compositions as homogeneous, this means that the active ingredient is uniformly distributed throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the composition of the present invention is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or diluents, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, sodium docusate, cetyl alcohol, and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solid compositions of a similar type are also used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols, etc.

In some embodiments, a tablet is prepared by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrating agent (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surface active or dispersing agent. In some embodiments, molded tablets are prepared by molding in a suitable device a mixture of the composition of the present invention moistened with an inert liquid diluent. In some embodiments, tablets and other solid dosage forms such as dragees, capsules, pills and granules are scored or prepared with coatings and shells such as enteric coatings and other coatings. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or in mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and tinctures. In addition to the composition of the present invention, in some embodiments, the liquid dosage forms contain inert diluents such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

In some embodiments, suspensions, in addition to the composition of the present invention, contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitan or sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

In some embodiments, the compositions for rectal or vaginal administration are presented as a suppository, which is prepared by mixing the composition of the present invention with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and will therefore melt in the body cavity and release the active agent.

Dosage forms for transdermal administration of the composition of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In some embodiments, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and with any necessary preservatives, buffers or

- 7 047 826 propellants. In some embodiments, ointments, pastes, creams and gels contain, in addition to the composition of the present invention, auxiliary substances such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

In some embodiments, powders and sprays contain, in addition to the composition of the present invention, auxiliary substances such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powdered polyamide or mixtures of such substances. In some embodiments, sprays additionally contain traditional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

In some embodiments, the compounds described herein are formulated as eye drops for ophthalmic administration. The compositions and compounds disclosed herein are alternatively administered as an aerosol. This is achieved by preparing an aqueous aerosol, a liposomal preparation, or solid particles containing the compound. In some embodiments, a non-aqueous suspension (e.g., with a fluorocarbon propellant) is used. In some embodiments, ultrasonic nebulizers are used because they minimize the effect of shear on the agent, which leads to the degradation of the compounds contained in the compositions of the present invention. Typically, an aqueous aerosol is prepared by formulating an aqueous solution or suspension of the composition of the present invention together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular composition of the present invention, but generally include nonionic surfactants (Tween types, Pluronic types or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are usually prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administration include a composition of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that are resuspended into sterile injectable solutions or dispersions immediately prior to use, which in some embodiments contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended patient, or suspending agents or thickening agents.

Examples of suitable aqueous and non-aqueous carriers that are used in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Also contemplated are pharmaceutical formulations for enteral use containing the disclosed compound, an enteric material, and a pharmaceutically acceptable carrier or excipient corresponding thereto. Enteric-coated materials mean polymers that are essentially insoluble in the acidic environment of the stomach and that are predominantly soluble in intestinal juice at specific pH values. The small intestine is the part of the gastrointestinal tract (intestine) from the stomach to the large intestine and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Accordingly, the enteric materials are insoluble, for example, at a pH of up to about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Illustrative enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, methyl methacrylic acid-methyl methacrylate copolymer, methyl acrylate, methyl methacrylate-methacrylic acid copolymer, methyl vinyl ether-maleic anhydride copolymer (Gantrez ES series), ethyl methyl acrylatemethyl methacrylate-chlorotrimethylammonium ethyl acrylate, natural resins such as zein, shellac and gum, rosin, and some commercially available enteric dispersion systems (e.g.

- 8 047 826 measures, Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric and Aquateric). The solubility of each of the above materials is either known or readily determined in vitro.

The dose of a composition comprising at least one compound described herein varies depending on the condition of the patient (e.g., a human), i.e., the stage of the disease, general health, age, and other factors. The pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and an appropriate duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the route of administration. In general, an appropriate dose and treatment regimen provide the composition(s) in an amount sufficient to provide a therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome such as more frequent complete or partial remissions, or longer disease-free survival and/or overall survival, or a reduction in symptom severity). Optimal doses are typically determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends on the patient's body weight, weight, or blood volume.

Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times daily or more.

Methods.

Disclosed herein are methods for modulating MAGL activity. The contemplated methods, for example, comprise contacting the enzyme with a compound described herein. In some embodiments, the compound used in one or more of the above methods is one of the general group, subgroup, or specific compounds described herein, such as a compound. In some embodiments, provided herein is a compound, wherein the compound is a MAGL inhibitor. In some embodiments, provided herein is a compound, wherein the compound is a selective MAGL inhibitor. The ability of the compounds described herein to modulate or inhibit MAGL is assessed using procedures known in the art and/or described herein. In another aspect, the present invention provides methods for treating a disease associated with MAGL expression or activity in a patient. In some embodiments, provided herein is a compound, wherein the compound is selective for inhibiting MAGL over inhibiting other serine hydrolases. In some embodiments, provided herein is a compound wherein the compound is 10, 100, or 1000 times more selective for inhibition of MAGL compared to inhibition of other serine hydrolases.

In another embodiment, there is provided a method of treating pain in a patient, comprising administering a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to a patient in need thereof, to treat said pain. In another embodiment, there is provided a method of treating neuropathic pain in a patient, comprising administering a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to a patient in need thereof, to treat said neuropathic pain. In another embodiment, there is provided a method of treating pain due to inflammation in a patient, comprising administering a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to a patient in need thereof, to treat said pain due to inflammation. In another embodiment, a method of treating chronic pain in a patient is provided, comprising administering a therapeutically effective amount of a compound described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to a patient in need thereof for treating said chronic pain.

In another embodiment, a method of treating migraine in a patient in need thereof is provided, comprising administering a therapeutically effective amount of a compound described herein or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

In another embodiment, a method of treating scleroderma in a patient in need thereof is provided, comprising administering a therapeutically effective amount of a compound described herein or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

In another embodiment, a method of treating non-alcoholic fatty liver disease (NASH) in a patient in need thereof is provided, comprising administering a therapeutically effective amount of a compound described herein or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

- 9 047826

In certain embodiments, a disclosed compound used in one or more of the above methods is one of the general group, subgroup, or specific compounds described herein, such as a compound.

The disclosed compounds are administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the appropriate dosage for use in any particular application will vary from patient to patient, not only depending on the particular compound or composition selected, but also depending on the route of administration, the nature of the condition being treated, the age and condition of the patient, concomitant medications or a special diet thereafter followed by the patient, and other factors, the appropriate dosage ultimately being determined by the attending physician. For the treatment of the clinical conditions and diseases noted above, the subject compound disclosed herein is administered orally, subcutaneously, topically, parenterally, as a spray by inhalation, or rectally in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration includes subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.

Also contemplated herein are combination therapies, such as co-administration of a disclosed compound and an additional active agent as part of a specific treatment regimen, intended to provide a beneficial effect from the combined action of such therapeutic agents. A beneficial effect of a combination includes, but is not limited to, a pharmacokinetic or pharmacodynamic synergy due to the combination of therapeutic agents. The administration of such therapeutic agents in combination is typically carried out over a period of time (usually weeks, months, or years, depending on the combination selected). Combination therapy is intended to encompass the administration of multiple therapeutic agents sequentially, i.e., with each therapeutic agent administered at different times, as well as the administration of such therapeutic agents, or at least two therapeutic agents, substantially simultaneously. Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition (e.g., a tablet or capsule with a set ratio of each therapeutic agent, or a plurality of single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent depends on any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through the mucosa of tissue. The therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent of a selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all of the therapeutic agents are administered orally or all of the therapeutic agents are administered by intravenous injection.

Combination therapy also encompasses the administration of the therapeutic agents described above in additional combination with other biologically active ingredients and non-drug therapies. If the combination therapy additionally includes non-drug treatment, the non-drug treatment is administered at any appropriate time, provided that a beneficial effect is achieved from the combined action of the combination of therapeutic agents and the non-drug treatment. For example, in appropriate cases, a beneficial effect is achieved if the non-drug treatment is remote in time from the administration of the therapeutic agents, possibly by days or even weeks.

The components of the combination are administered to the patient simultaneously or sequentially. It will be understood that the components are present in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered either simultaneously or sequentially.

In some embodiments, for the contemplated pain relief, the disclosed compound is co-administered with another pain relief therapeutic agent, such as an opioid, cannabinoid receptor (CB-1 or CB-2) modulator, a COX-2 inhibitor, acetaminophen, and/or a non-steroidal anti-inflammatory drug.

Adjunctive therapeutic agents, such as those for pain relief, that are co-administered include morphine, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and levorphanol.

In some embodiments, for the contemplated pain relief, the disclosed compound is co-administered with aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, celecoxib, parecoxib, rimonabant, and/or etoricoxib.

- 10 047826

The following examples are provided solely for illustrative purposes with respect to various embodiments and should not be construed as limiting the present invention in any way.

Examples

List of abbreviations.

As used above and throughout the description of the present invention, the following abbreviations should be understood to have the following meanings unless otherwise indicated.

ACN or MeCN acetonitrile Bn benzyl VOS or Vos mpem-butylcarbamate CDI 1,1'-carbonyldiimidazole Su cyclohexyl DCE dichloroethane (CICH2CH2CI) DCM dichloromethane (CH2CI2) DIPEA or DIEA diisopropylethylamine DMAP 4-(A,A-dimethylamino)pyridine DMF dimethylformamide DMA ΛζΑ-dimethylacetamide DMSO dimetil sulph oxide equiv. equivalent(s) Et ethyl EtOH ethanol EtOAc ethyl acetate HATU 1 - [bis(d and methyl amino)methyl ee] -1 Η-1,2,3-triazolo[4,5 - b]pyridinium-3-oxide hexafluorophosphate HPLC high performance liquid chromatography LAH lithium aluminum hydride Me methyl MeOH methanol MS mass spectrometry NMM /V-methylmorpholine NMR nuclear magnetic resonance PMB //tsra-methoxybenzyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC I. Chemical synthesis. thin layer chromatography

Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. For moisture- and/or oxygen-sensitive synthetic transformations, anhydrous solvents and oven-dried glassware were used. Yields have not been optimized. Reaction times are approximate and have not been optimized. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise stated. Spectra are reported in ppm (δ) and coupling constants (J) are given in hertz. For proton spectra, the solvent peak was used as a reference peak.

Example 1: 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

- 11 047826

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

Vos ₂ O, DMAP ^Vos Et ₃ N, tert-BuOH 65°C, overnight

A flask was charged with 1/3-pyrazole-3-carboxylic acid (5.00 g, 44.6 mmol, 1.00 equiv), tert-butanol (50 mL), di-tert-butyl dicarbonate (39.0 g, 179 mmol, 4.01 equiv), triethylamine (27.0 g, 268 mmol, 6.00 equiv), and DMAP (1.10 g, 9.00 mmol, 0.20 equiv). The resulting solution was stirred overnight at 65 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3x50 mL) and the organic layers were combined, washed with water (3x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 11.2 g of di-tert-butyl-1H-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 169 [M+H-Boc] ⁺ .

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

1,3-Di-tert-butyl N-pyrazole-1,3-dicarboxylate (5.00 g, 18.6 mmol, 1.00 equiv), MeOH (30 mL), NaOH (2.50 g, 62.5 mmol, 3.35 equiv), and water (5 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature and quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3.05 g of tert-butyl N-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, mass/charge): 169 [M+H]+.

Step 3: Preparation of 4-(4-chlorobenzyl)piperazine-1-carbonyl chloride

O triphosgene, DIPEA CI

DCM, 0°C, 2 h.

Triphosgene (210 mg, 1.00 mmol, 1.00 equiv), DCM (10 mL), and 1-[(4-chlorophenyl)methyl]piperazine (206 mg, 0.698 mmol, 0.70 equiv) were placed in a flask. DIPEA (516 mg, 3.99 mmol, 4.00 equiv) was added dropwise at 0°C. The resulting solution was stirred for 2 h at 0°C and quenched with water (20 mL). The mixture was extracted with DCM (3x30 ml) and the organic layers were combined, washed with water (3x10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 250 mg of 4-(4-chlorobenzyl)piperazine-1-carbonyl chloride (crude) as a yellow oil.

Step 4: Preparation of tert-butyl 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylate

60°C, overnight

A flask was charged with 4-(4-chlorobenzyl)piperazine-1-carbonyl chloride (250 mg, 0.920 mmol, 1.00 equiv), THF (10 mL), tert-butyl N-pyrazole-3-carboxylate (155 mg, 0.920 mmol, 1.01 equiv), DIPEA (237 mg, 1.83 mmol, 2.00 equiv), and DMAP (22.0 mg, 0.180 mmol, 0.20 equiv). The resulting solution was stirred overnight at 60 °C and quenched with water (5 mL). The mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 260 mg (70% yield) of tert-butyl 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 405 [M+H]+.

Step 5: Preparation of 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

- 12 047826

A flask was charged with tert-butyl 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (260 mg, 0.861 mmol, 1.00 equiv), DCM (10 mL), and TFA (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford 66.6 mg (30% yield) of 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.34 - 7.39 (m, 4H), 6.75 (s, 1H), 3.68 - 4.14 (m, 4H), 3.52 3.77 (m, 2H), 2.47 - 2.70 (m, 4H). LCMS (ESI, mass/charge): 349 [M+H]+.

Example 2: 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

ABOUT

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

Vos ₂ P, DMAP ^Vos Et ₃ N, tert-BuOH 65°C, overnight

A flask was charged with N-pyrazole-3-carboxylic acid (5.00 g, 44.6 mmol, 1.00 equiv), tert-butanol (50 mL), di-tert-butyl dicarbonate (39.0 g, 179 mmol, 4.01 equiv), triethylamine (27.0 g, 268 mmol, 6.00 equiv), and DMAP (1.10 g, 9.00 mmol, 0.20 equiv). The resulting solution was stirred overnight at 65 °C and quenched with water (20 mL) as described in Example 1, step 1 to give 11.2 g of di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, mass/charge): 169 [M+H-Boc] ⁺ .

Stage 2: preparation of tert-butyl-III-pyrazole-3-carboxylate | ^In °% L__l ° NaOH, MeOH, H ₂ <3 ΗΙ\Γ ^Ν α__Р q Z k.t., overnight q—/—

A flask was charged with 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (5.00 g, 18.6 mmol, 1.00 equiv), MeOH (30 mL), NaOH (2.50 g, 62.5 mmol, 3.35 equiv), and water (5 mL). The resulting solution was stirred overnight at room temperature and quenched with water (10 mL) as described in Example 1, step 2 to give 3.05 g of tert-butyl N-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of tert-butyl 4-(3-phenoxybenzyl)piperazine-1-carboxylate

I^-Воо ^N' ^B ° ^C

NaBH(OAc) ₃ , DCE N

k.t., during the night

A flask was charged with 3-phenoxybenzaldehyde (5.00 g, 25.2 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (4.25 g, 22.8 mmol, 0.90 equiv), and DCE (100 mL). The mixture was stirred for 1 h at room temperature and then sodium triacetoxyborohydride (10.6 g, 50.0 mmol, 1.98 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (50 mL). The mixture was extracted with DCM (3 x 50 mL) and the organic layers were combined, washed with water (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 8.80 g (95% yield) of tert-butyl 4-(3-phenoxybenzyl)piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 369 [M+H]+.

Step 4: Obtaining 1-(3-phenoxybenzyl)piperazine

Tert-butyl 4-(3-phenoxybenzyl)piperazine-1-carboxylate (8.80 g, 23.9 mmol, 1.00 equiv), 1,4-dioxane (50 mL), and concentrated hydrochloric acid (5 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure.

- 13 047826 under pressure to give 6.03 g of 1-(3-phenoxybenzyl)piperazine (crude) as a white solid. LCMS (ESI, m/z): 269 [M+H]+.

Step 5: Preparation of 4-(3-phenoxybenzyl)piperazine-1-carbonyl chloride

DCM, 0°C, 5 h.

triphosgene, DIPEA

Cl

1-(3-Phenoxybenzyl)piperazine (200 mg, 0.751 mmol, 1.00 equiv), DCM (10.0 mL), and triphosgene (135 mg, 0.451 mmol, 0.70 equiv) were placed in a flask. DIPEA (388 mg, 3.00 mmol, 4.00 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 5 h at 0 °C and quenched with water (20 mL). The mixture was extracted with DCM (3x30 ml) and the organic layers were combined, washed with water (3x10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 1, step 3, to give 217 mg of 4-[(3phenoxyphenyl)methyl]piperazine-1-carbonyl chloride (crude) as a yellow oil.

Step 6: Preparation of tert-butyl 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

DIPEA, DMAP, THF 60°C, overnight

A flask was charged with 4-[(3-phenoxyphenyl)methyl]piperazine-1-carbonyl chloride (217 mg, 0.661 mmol, 1.00 equiv), THF (10 mL), tert-butyl 1H-pyrazole-3-carboxylate (110 mg, 0.652 mmol, 1.00 equiv), DMAP (16.2 mg, 0.131 mmol, 0.20 equiv), and DIPEA (169 mg, 1.31 mmol, 2.00 equiv). The resulting solution was stirred overnight at 60 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3x30 mL) and the organic layers were combined, washed with water (3x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 1, step 4. The residue was column chromatographed on silica gel to give 120 mg (40% yield) of tert-butyl 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 463 [M+H] ⁺ .

Step 7: Preparation of 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

Tert-butyl 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (120 mg, 0.261 mmol, 1.00 equiv), DCM (5 mL), and TFA (1 mL) were added to a flask. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure as described in Example 1, step 5. The crude product was purified by preparative HPLC to afford 81.6 mg (77% yield) of 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white powder. 1H NMR: (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.33 - 7.48 (m, 3H), 7.11 - 7.27 (m, 2H), 7.06 - 7.11 (s, 1H), 6.99 - 7.06 (m, 2H), 6.90 - 6.99 (m, 1H), 6.75 - 6.90 (m, 1H), 3.82 - 4.13 (s, 4H), 3.70 - 3.82 (d, J=8.2 Hz, 2H), 2.60 - 2.93 (s, 4H). LCMS (ESI, m/z): 407 [M+H]+.

Example 3: 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

Stage 1: obtaining di-tert-butyl-III-pyrazole-1,3-dicarboxylate Boc ₂ O, DMAP ^Boc %

EtsN, tert-BuOH 80°C, 4 h.

- 14 047826

In a flask were placed 1,3-di-tert-butyl dicarbonate (80.0 g, 366 mmol, 4.00 equiv), 1,3-di-tert-butyl-1,3-pyrazole-1,3-dicarboxylate (crude) (10.0 g, 89.2 mmol, 1.00 equiv). LCMS (ESI, mass/charge): 269 [M+H]+.

Stage 2: obtaining tert-butyl-III-pyrazole-3-carboxylate ^BoC ' _N -N__О NaOH, MeOH, H ₂ O HN' ^N a__л°

O—K.T., 2 hours O—

1,3-Di-tert-butyl-III-pyrazole-1,3-dicarboxylate (25.0 g, 93.2 mmol, 1.00 equiv), NaOH (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 2. The residue was column chromatographed on silica gel to afford 10.0 g (64% yield) of tert-butyl-III-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 2-morpholino-4-(trifluoromethyl)benzaldehyde

A flask was charged with 2-fluoro-4-(trifluoromethyl)benzaldehyde (3.00 g, 15.6 mmol, 1.00 equiv), potassium carbonate (8.62 g, 62.4 mmol, 4.00 equiv), morpholine (2.72 g, 31.2 mmol, 2.00 equiv), and DMSO (40 mL) under nitrogen. The resulting solution was stirred overnight at 100 °C and then quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), and the organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. From the residue 1.86 g (yield 46%) of 2(morpholin-4-yl)-4-(trifluoromethyl)benzaldehyde was obtained as a yellow solid. LCMS (ESI, m/z): 260 [M+H]+.

Step 4: Preparation of tert-butyl 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1carboxylate

To a flask were placed 2-(morpholin-4-yl)-4-(trifluoromethyl)benzaldehyde (0.600 g, 2.31 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.646 g, 3.47 mmol, 1.50 equiv), and DCM (20 mL). The mixture was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (1.96 g, 9.23 mmol, 4.00 equiv) was added as described in Example 2, step 3. The residue was chromatographed to afford 0.920 g (93% yield) tert-butyl 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a yellow oil. LCMS (ESI, mass/charge): 430 [M+H]+.

Step 5: Preparation of 4-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)morpholine

In a 250 mL round bottom flask was placed tert-butyl 4-(2-morpholino-4(trifluoromethyl)benzyl)piperazine-1-carboxylate (920 mg, 2.14 mmol, 1.00 equiv), trifluoroacetic acid (10 mL), and DCM (30 mL) as described in Example 1, step 5 to give 700 mg (99% yield) of 4-(2(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)morpholine as a brown oil. LCMS (ESI, m/z): 330 [M+H]+.

Step 6: Preparation of 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl chloride

- 15 047826

Triphosgene (226 mg, 0.760 mmol, 0.50 equiv), DCM (10 mL) were placed in a flask. 4-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)morpholine (500 mg, 1.52 mmol, 1.00 equiv) and DIPEA (588 mg, 4.56 mmol, 3.00 equiv) were added at 0 °C as described in Example 1, step 3, to give 500 mg (84% yield) of 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl chloride as a yellow oil. LCMS (ESI, m/z): 392 [M+H]+.

Step 7: Preparation of tert-butyl-1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylate

To a flask were placed 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl chloride (400 mg, 1.02 mmol, 1.00 equiv), tert-butyl 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1-(pyrazole-3-carboxylate) (190 mg, 1.13 mmol, 1.10 equiv), DMAP (62.0 mg, 0.510 mmol, 0.50 equiv), DIPEA (396 mg, 3.07 mmol, 3.00 equiv), THF (10 mL) as described in Example 1, step 4. The residue was chromatographed to afford 300 mg (56% yield) of tert-butyl 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1-(pyrazole-3-carboxylate) in as a white solid. LCMS (ESI, m/z): 524 [M+H]+.

Step 8: Preparation of 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-N-pyrazole-3-carboxylate (140 mg, 0.270 mmol, 1.00 equiv), TFA (1 mL), and DCM (10 mL) as described in Example 1, step 5 to give the crude product (250 mg). The residue was purified by preparative HPLC to give 78.2 mg (63% yield) of 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-N-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (400 MHz, Meganol-f) δ 8.14 (d, J=2.6 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.41-7.42 (m, 2H), 6.83 (d, J=2.6 Hz, 1H), 3.81-3.88 (m, 10H), 3.01-3.02 (m, 4H), 2.71 (br, 4H). LCMS (ESI, m/z): 468 [M+H]+.

Example 4: 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-III-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

- 16 047826

A flask was charged with N-pyrazole-3-carboxylic acid (10.0 g, 89.2 mmol, 1.00 equiv), DMAP (2.15 g, 17.6 mmol, 0.20 equiv), triethylamine (27.0 g, 267 mmol, 3.00 equiv), di-tert-butyl dicarbonate (80.0 g, 366 mmol, 4.00 equiv) in tert-butanol (100 mL) as described in Example 1, step 1 to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, m/z): 269 [M+H]+.

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

A flask was charged with 1,3-di-tert-butyl-III-pyrazole-1,3-dicarboxylate (25.0 g, 93.2 mmol, 1.00 equiv), NaOH (5.60 g, 140 mmol, 1.50 equiv) in water (80 mL) and MeOH (240 mL) as described in Example 1, step 2 to give 10.0 g (64% yield) of tert-butyl-III-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate

Tert-butyl 3-(tert-butyl)-1-(4-nitrophenyl)-3-pyrazole-3-carboxylate (2.42 g, 14.4 mmol, 1.00 equiv), DCM (20 mL), 4-nitrophenyl chloroformate (2.90 g, 14.4 mmol, 1.00 equiv), and triethylamine (4.36 g, 43.1 mmol, 3.00 equiv) were added to a flask. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to give 4.80 g of 3-(tert-butyl)-1-(4-nitrophenyl)-3-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 334 [M+H]+.

Step 4: Preparation of 2-morpholino-4-(trifluoromethyl)benzaldehyde

A flask was charged with 2-fluoro-4-(trifluoromethyl)benzaldehyde (5.00 g, 26.0 mmol, 1.00 equiv), potassium carbonate (10.8 g, 78.1 mmol, 3.00 equiv), morpholine (6.79 g, 78.0 mmol, 3.00 equiv), and DMSO (50 mL) under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (50 mL) as described in Example 3, step 3 to give 4.00 g (59% yield) of 2-morpholino-4(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 260 [M+H]+.

Step 5: Preparation of tert-butyl 4-methyl-4-((2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

To a 100 mL round-bottomed flask were placed 2-morpholino-4-(trifluoromethyl)benzaldehyde (2.50 g, 9.64 mmol, 1.00 equiv), MeOH (25 mL), AcOH (1.70 g, 28.3 mmol, 3.00 equiv), and tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (2.46 g, 11.5 mmol, 1.20 equiv). The resulting solution was stirred for 30 min at room temperature. Sodium cyanoborohydride (1.78 g, 28.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with

- 17 047826 water (30 mL). The resulting solution was extracted with DCM (3x30 mL) and the organic layers were combined, washed with brine (2x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 3.51 g (80% yield) of tert-butyl 4-methyl-4-((2-morpholino-4(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 458 [M+H]+.

Step 6: Preparation of tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

In a 100 mL round-bottomed flask were placed tert-butyl 4-methyl-4-((2-morpholino-4(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (3.51 g, 7.67 mmol, 1.00 equiv), paraformaldehyde (2.30 g, 76.7 mmol, 10.0 equiv), triethylamine (2.30 g, 22.7 mmol, 3.00 equiv), and DCE (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (4.80 g, 22.6 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL) as described in Example 2, step 3, to give 3.39 g (94% yield) of tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 472 [M+H]+.

Step 7: Preparation of tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

Tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (3.39 g, 7.19 mmol, 1.00 equiv), DCM (20 mL) and TFA (5 mL) were added to a flask as described in Example 1, step 5 to give 3.50 g of tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (crude) as a white solid. LCMS (ESI, m/z): 372 [M+H]+.

Step 8: Preparation of tert-butyl-1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-III-pyrazole-3-carboxylate

To a flask were placed 3-tert-butyl 1-(4-nitrophenyl)-1-pyrazole-1,3-dicarboxylate (3.50 g, 9.43 mmol, 1.00 equiv), DCM (20 mL), tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (6.28 g, 18.7 mmol, 2.00 equiv), and triethylamine (2.86 g, 28.3 mmol, 3.00 equiv) as described in Example 4, step 3, to give 4.58 g (80% yield) of tert-butyl 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1 -carbonyl)-Spyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 566 [M+H]+.

Step 9: Preparation of 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-III-pyrazole-3-carboxylic acid

- 18 047826

A flask was charged with tert-butyl 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylate (4.58 g, 8.10 mmol, 1.00 equiv), DCM (50 mL), and TFA (10 mL) as described in Example 1, step 5. The crude product (3.50 g) was purified by preparative HPLC to give 694.3 mg (17% yield) of 1-(4-methyl-4-(methyl(2-morpholino-4(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (300 MHz, Methanol^ ₄ ) δ 8.08 (d, J=2.6 Hz, 1H), 7.84 d, J=8.4 Hz, 1H), 7.49 - 7.52 (m, 2H), 6.78 (d, J=2.6 Hz, 1H), 4.12 - 4.25 (m, 4H), 3. 84 - 3.87 (m, 4H), 3.54 - 3.65 (m, 2H), 2.93 3.07 (m, 4H), 2.41 (br, 3H), 2.11-2.16 (m, 2H), 2.03 - 2.10 (m, 2H), 1.41 (br, 3H). LCMS (ESI, mass/charge): 510 [M+H]+.

Example 5: 1-(4-(2-(III-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

A flask was charged with N-pyrazole-3-carboxylic acid (10.0 g, 89.2 mmol, 1.00 equiv), 4-dimethylaminopyridine (2.15 g, 17.6 mmol, 0.20 equiv), triethylamine (27.0 g, 267 mmol, 3.00 equiv), di-tert-butyl dicarbonate (80.0 g, 366 mmol, 4.00 equiv) in tert-butanol (100 mL) as described in Example 1, step 1 to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, m/z): 269 [M+H]+.

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

A flask was charged with 1,3-di-tert-butyl-III-pyrazole-1,3-dicarboxylate (25.0 g, 93.2 mmol, 1.00 equiv), NaOH (5.60 g, 140 mmol, 1.50 equiv) in water (80 mL) and MeOH (240 mL) as described in Example 1, step 2 to give 10.0 g (64% yield) of tert-butyl-III-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

k.t., during the night

2-Bromo-4-(trifluoromethyl)benzaldehyde (500 mg, 1.98 mmol, 1.00 equiv), triethylamine (600 mg, 5.93 mmol, 3.00 equiv), tert-butyl piperazine-1-carboxylate (443 mg, 2.38 mmol, 1.20 equiv) in DCE (10 mL) were placed in a flask. The resulting solution was stirred for 0.5 h at room temperature. Sodium triacetoxyborohydride (1.26 g, 5.94 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (10 mL) as described in Example 2, step 3. The residue was chromatographed to afford 680 mg (81% yield) of tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 423 [M+H]+.

Step 4: Preparation of tert-butyl 4-(2-cyano-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate ___~ R _nr F->CR .Vos

Zn(CN) ₂ , Pd( _PPh3 ) _4fN

L 1 n J ----------- %A/N ₄ J

DMF, 120°C, overnight

BrCN

The flask was charged with tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (680 mg, 1.61 mmol, 1.00 equiv.), zinc cyanide (374 mg, 3.22 mmol, 2.00 equiv.), tetra

- 19 047826 kis(triphenylphosphine)palladium (170 mg, 0.150 mmol, 0.10 equiv) in DMF (10 mL) under nitrogen. The resulting solution was stirred overnight at 120 °C and quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed to afford 230 mg (39% yield) of tert-butyl 4-(2-cyano-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, w/z): 370 [M+H]+.

Step 5: Preparation of tert-butyl 4-(2-(III-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1carboxylate

A flask was charged with tert-butyl 4-(2-cyano-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (230 mg, 0.620 mmol, 1.00 equiv), sodium azide (203 mg, 3.12 mmol, 5.00 equiv), and ammonium chloride (198 mg, 3.70 mmol, 6.00 equiv) in DMF (10 mL). The resulting solution was stirred overnight at 120 °C and quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed to give 140 mg (55% yield) of tert-butyl 4-(2-(1H-tetrazol-5-yl)-4(trifluoromethyl)benzyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 413 [M+H]+.

Step 6: Preparation of 1-(2-(III-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine

Tert-butyl 4-(2-(N-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (140 mg, 0.340 mmol, 1.00 equiv), 1,4-dioxane (10 mL), concentrated hydrochloric acid (3 mL) were added to a flask as described in Example 2, step 4 to give 130 mg of 1-(2-(N-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine (crude) as a white solid. LCMS (ESI, m/z): 313 [M+H]+. Step 7: Preparation of tert-butyl 1-(4-(2-(III-tetrazol-5-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylate

Triphosgene (38.0 mg, 0.130 mmol, 0.40 equiv), tert-butyl-III-pyrazole-3-carboxylate (70.0 mg, 0.420 mmol, 1.30 equiv) in DCM (10 mL) were placed in a flask under nitrogen atmosphere. DIPEA (122 mg, 0.960 mmol, 3.00 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 2 h at 0 °C. 1-(2-(N-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine (100 mg, 0.320 mmol, 1.00 equiv) was added as described in Example 1, step 3 to give 90.0 mg (55% yield) of tert-butyl 1-(4-(2-(N-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-N-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 507 [M+H]+.

Step 8: Preparation of 1-(4-(2-(III-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)III-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 1-(4-(2-(N-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (90.0 mg, 0.180 mmol, 1.00 equiv) and TFA (3 mL) in DCM (10 mL) as described in Example 1, step 5 to give the crude product (100 mg), which was purified by preparative HPLC. Purification afforded 22.3 mg (28% yield) of 1-(4-(2-(N-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-N-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (300 MHz, Methanol^ ₄ ) δ 8.30 (s, 1H), 8.14 (d, J=2.7 Hz, 1H), 7.76 - 7.87 (m, 2H), 6.78 (d, J=2.7 Hz, 1H), 4.44 (s, 2H), 4.18 (br, 4H), 3.24 (br, 4H). LCMS (ESI, m/z): 451 [M+H]+.

Example 6: 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)III-pyrazole-3-carboxylic acid

Step 1: Preparation of 2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzaldehyde

A flask was charged with 2-fluoro-4-(trifluoromethyl)benzaldehyde (400 mg, 2.08 mmol, 1.00 equiv), DMSO (10 mL), potassium carbonate (861 mg, 6.24 mmol, 3.00 equiv), and 1-cyclopropylpiperazine (524 mg, 4.16 mmol, 2.00 equiv) under nitrogen atmosphere as described in Example 3, step 3 to afford the crude product. The residue was chromatographed to afford 460 mg (74% yield) of 2-(4-cyclopropylpiperazin-1-yl)-4(trifluoromethyl)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 299 [M+H]+

Step 2: Obtaining di-tert-butyl-III-pyrazole-1,3-dicarboxylate

N-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equiv), DMAP (2.18 g, 17.9 mmol, 0.20 equiv), triethylamine (27.1 g, 268 mmol, 3.00 equiv), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equiv), and tert-butanol (100 mL) were charged into a flask as described in Example 1, step 1 to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, m/z): 269 [M+H]+.

Step 3: Obtaining tert-butyl-III-pyrazole-3-carboxylate

1,3-Di-tert-butyl N-pyrazole-1,3-dicarboxylate (25.0 g, 93.3 mmol, 1.00 equiv), NaOH (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL) were added to a flask as described in Example 1, step 2 to give the crude product. The residue was chromatographed to give 10.0 g (64% yield) of tert-butyl N-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 4: Preparation of tert-butyl-1-(4-benzylpiperazine-1-carbonyl)-III-pyrazole-3-carboxylate

Triphosgene (1.24 g, 4.18 mmol, 0.70 equiv.) and DCM (20 mL) were placed in a flask. Tert-butyl

- 21 047826

1H-pyrazole-3-carboxylate (1.00 g, 5.95 mmol, 1.00 equiv) at 0 °C. DIPEA (3.07 g, 23.8 mmol, 4.00 equiv) was added at 0 °C. The mixture was stirred at room temperature for 2 h at 0 °C. 1-Benzylpiperazine (1.26 g, 7.15 mmol, 1.20 equiv) was added at 0 °C as described in Example 1, step 3 to give the crude product. The residue was chromatographed to give 1.35 g (61% yield) of tert-butyl 1-(4-benzylpiperazine-1-carbonyl)-1H-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 371 [M+H]+.

Step 5: Preparation of tert-butyl 1-(piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

A flask was charged with tert-butyl 1-(4-benzylpiperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (1.00 g, 2.70 mmol, 1.00 equiv), MeOH (10 mL), EtOAc (10 mL), and palladium on carbon (0.400 g). Hydrogen was introduced. The resulting solution was stirred for 3 h at room temperature and the catalysts were filtered off. The filtrate was concentrated under reduced pressure to give 0.690 g of tert-butyl 1-(piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (crude) as a colorless oil. LCMS (ESI, m/z): 281 [M+H]+.

Step 6: Preparation of tert-butyl 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

To a flask were placed 2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzaldehyde (92.2 mg, 0.309 mmol, 1.00 equiv), tert-butyl 1-[(piperazin-1-yl)carbonyl]-1H-pyrαzole-3-carboxylate (130 mg, 0.464 mmol, 1.50 equiv), DCE (10 mL). The resulting solution was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (262 mg, 1.24 mmol, 4.00 equiv) was added as described in Example 2, step 3 to give the crude product. The residue was chromatographed to give 140 mg (81% yield) of tert-butyl 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1-nitro-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 563 [M+H]+.

Step 7: Preparation of 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1carbonyl)-1H-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (140 mg, 0.250 mmol, 1.00 equiv), DCM (12 mL), and TFA (2 mL) as described in Example 1, step 5. The crude product (127 mg) was purified by preparative HPLC to give 53.2 mg (42% yield) of 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (400 MHz, Methanol^ ₄ ) δ 8.14 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.42 - 7.44 (m, 2H), 6.83 (s, 1H), 3.99 (br, 4H), 3.87 (s, 2H), 3.15 (br, 8H), 2.69 - 2.70 (m, 4H), 2.28 - 2.34 (m, 1H), 0.65 - 0.84 (m, 4H). LCMS (ESI, m/z): 507 [M+H]+.

Example 7: 1-(4-(3-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

- 22 047826

Step 1: Preparation of 3-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde

A flask was charged with 3-bromo-4-(trifluoromethyl)benzaldehyde (380 mg, 1.50 mmol, 1.00 equiv), pyrrolidine (160 mg, 2.25 mmol, 1.50 equiv), tris(dibenzylideneacetone)dipalladium (77.6 mg, 0.0750 mmol, 0.05 equiv), dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (52.5 mg, 0.110 mmol, 0.07 equiv), cesium carbonate (978 mg, 3.00 mmol, 3.00 equiv), and toluene (10 mL) under N2. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with DCM (3x30 mL) and the organic layers were combined, washed with water (3x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed to give 84.0 mg (23% yield) of 3-(pyrrolidin-1-yl)-4(trifluoromethyl)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 244 [M+H]+.

Step 2: Obtaining di-tert-butyl-III-pyrazole-1,3-dicarboxylate

To a flask were placed 1,3-di-tert-butyl 1,3-pyrazole-1,3-dicarboxylate (crude) (20.0 g, 179 mmol, 1.00 equiv), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv), DMAP (4.35 g, 35.7 mmol, 0.20 equiv), triethylamine (54.1 g, 536 mmol, 3.00 equiv), ^and tert-butanol (200 mL).

Step 3: Obtaining tert-butyl-III-pyrazole-3-carboxylate

1,3-Di-tert-butyl N-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), NaOH (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL) were charged into a flask as described in Example 1, step 2 to give 6.70 g of tert-butyl N-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H] ⁺ .

Step 4: Preparation of tert-butyl 1-(4-benzylpiperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

ABOUT

To a flask were placed ret-butyl 1H-pyrazole-3-carboxylate (1.68 g, 10.0 mmol, 1.00 equiv), triphosgene (1.49 g, 5.00 mmol, 0.50 equiv), and DCM (20 mL). Then, DIPEA (3.87 g, 30.0 mmol, 3.00 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature. Then, 1-benzylpiperazine (1.76 g, 10.0 mmol, 1.00 equiv) was added as described in Example 1, step 3 to give the crude product. The residue was chromatographed to afford 2.20 g of tert-butyl 1-[(4-benzylpiperazin-1-yl)carbonyl]-1-pyrazole-3-carboxylate (59% yield) as a yellow oil. LCMS (ESI, m/z): 371 [M+H]+.

Step 5: Preparation of tert-butyl 1-(piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

- 23 047826

A flask was charged with tert-butyl 1-[(4-benzylpiperazin-1-yl)carbonyl]-1H-pyrazole-3-carboxylate (2.20 g, 5.94 mmol, 1.00 equiv), palladium on carbon (200 mg), and THF (20 mL) under hydrogen atmosphere as described in Example 6, step 2, to give 1.37 g of tert-butyl 1-[(piperazin-1-yl)carbonyl]-1H-pyrazole-3-carboxylate (crude) as a white solid. LCMS (ESI, m/z): 281 [M+H]+.

Step 6: Preparation of tert-butyl-1-(4-(3-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1carbonyl)-1-pyrazole-3-carboxylate

3-(Pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde (84.0 mg, 0.350 mmol, 1.00 equiv), tert-butyl 1-[(piperazin-1-yl)carbonyl]-1-pyrazole-3-carboxylate (106 mg, 0.380 mmol, 1.10 equiv), and DCE (10 mL) were placed in a flask. The resulting solution was stirred for 1 h at room temperature and sodium triacetoxyborohydride (148 mg, 0.700 mmol, 2.00 equiv) was added as described in Example 2, step 3 to give the crude product. The residue was chromatographed to afford 83.0 mg (47% yield) of tert-butyl 1-(4-(3-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1-pyrazole-3-carboxylate as a white oil. LCMS (ESI, m/z): 508 [M+H] ⁺ .

Step 7: Preparation of 1-(4-(3-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 1-(4-(3-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (83.0 mg, 0.160 mmol, 1.00 equiv), TFA (1 mL), and DCM (4 mL) as described in Example 1, step 5. The crude product was purified by preparative HPLC to afford 32.0 mg (43% yield) of 1-(4-(3-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1H NMR (300 MHz,

Methanol-^) δ 8.08 - 8.15 (m, 1I), 7.45 - 7.56 (m, 1I), 7.13 (s, 1I), 6.73 - 6.94 (m, 2I), 3.71 - 3.94 (m, 6I), 3.26 - 3.34 (m, 4I), 2.71 - 2.87(m, 4I), 1.74 - 2.01 (m, 4I). LCMS (ESI, m/z): 452 [M+H] ⁺ .

Example 8: 1-(4-(3-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-1H-pyrazole-1,3-dicarboxylate

1H-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equiv), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv), DMAP (4.35 g, 35.7 mmol, 0.20 equiv), triethylamine (54.1 g, 536 mmol, 3.00 equiv), and tert-butanol (200 mL) were charged to a flask as described in Example 1, step 1 to give 20.0 g of 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, wt/z): 169 [M+H-Boc]+.

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

1,3-Di-tert-butyl-III-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), NaOH (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL) were charged into a flask as described in Example 1, step 2 to give 6.70 g of tert-butyl-III-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of tert-butyl 4-(3-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

k.t., during the night

To a flask were placed 3-bromo-4-(trifluoromethyl)benzaldehyde (1.80 g, 7.11 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.20 g, 6.44 mmol, 1.00 equiv), and DCE (50 mL). The resulting solution was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (2.74 g, 12.9 mmol, 2.00 equiv) was then added as described in Example 2, step 3 to give the crude product. The residue was chromatographed to give 1.52 g (56% yield) of tert-butyl 4-(3-bromo-4(trifluoromethyl)benzyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, mass/charge): 423 [M+H]+.

Step 4: Preparation of tert-butyl 4-(3-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

Tert-butyl 4-(3-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (423 mg, 1.00 mmol, 1.00 equiv), 2-(tributylstannyl)-1,3-thiazole (374 mg, 1.00 mmol, 1.20 equiv), tetrakis(triphenylphosphine)palladium (115 mg, 0.100 mmol, 0.10 equiv), and toluene (10 mL) were placed in a flask under nitrogen atmosphere. The resulting solution was stirred overnight at 80 °C and diluted with water (10 mL). The mixture was extracted with ethyl acetate (3x30 ml) and the organic layers were combined, washed with brine (3x10 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed to give 188 mg (44% yield) of tert-butyl 4-(3-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a yellow solid. LCMS (ESI, m/z): 428 [M+H]+.

Step 5: Preparation of 2-(5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)phenyl)thiazole

Tert-butyl 4-(3-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (188 mg, 0.440 mmol, 1.00 equiv), HCl (1 mL), and 1,4-dioxane (4 mL) were added to a flask as described in Example 2, step 4 to give 144 mg of 2-(5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)phenyl)thiazole as a white solid. LCMS (ESI, m/z): 328 [M+H]+.

Step 6: Preparation of tert-butyl-1-(4-(3-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1carbonyl)-1-pyrazole-carboxylate

Tert-butyl 1H-pyrazole-3-carboxylate (74.0 mg, 0.440 mmol, 1.00 equiv), triphosgene (65.0 mg, 0.220 mmol, 0.50 equiv), and DCM (10 mL) were placed in a flask. DIPEA (170 mg, 1.32 mmol, 3.00

- 25,047,826 equiv) at 0°C and the resulting solution was stirred for 2 h at room temperature. Then 2-(5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)phenyl)thiazole (144 mg, 0.440 mmol, 1.00 equiv) was added as described in Example 1, step 3 to give the crude product. The residue was chromatographed to give 119 mg (52% yield) of tert-butyl 1-(4-(3-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate as a colorless oil. LCMS (ESI, m/z): 522 [M+H]+.

Step 7: Preparation of 1-(4-(3-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 1-(4-(3-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-N-pyrazole-3-carboxylate (119 mg, 0.231 mmol, 1.00 equiv), TFA (1 mL), and DCM (4 mL) as described in Example 1, step 5 to give the crude product. The crude product was purified by preparative HPLC to give 31.2 mg (29% yield) of 1-(4-(3-(thiazol-2-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-N-pyrazole-3-carboxylic acid as a white solid. ^1H NMR (300 MHz, Methanol^) δ 8.13 (s, 1H), 7.70 - 7.90 (m, 5H), 6.80 - 6.85 (m, 1H), 3.70 - 3.90 (m, 6H), 2.60 - 2.70 (m, 4H). LCMS (ESI, mass/charge): 466 [M+H]+.

Example 9: 1-(4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-pyrazole-3-carboxylic acid

Step 1: Preparation of tert-butyl 4-(3-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

k.t., during the night

Tert-butyl piperazine-1-carboxylate (0.800 g, 4.30 mmol, 1.00 equiv), 3-bromo-4(trifluoromethyl)benzaldehyde (1.20 g, 4.74 mmol, 1.10 equiv), and DCE (20 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and sodium triacetoxyborohydride (1.83 g, 8.63 mmol, 2.00 equiv) was added as described in Example 2, step 3. The residue was chromatographed to afford 1.56 g (86% yield) of tert-butyl 4-(3-(methoxycarbonyl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, mass/charge): 423 [M+H]+.

Step 2: Preparation of tert-butyl 4-(3-(methoxycarbonyl)-4-(trifluoromethyl)benzyl)piperazine-1carboxylate

The reactor pressure tank was charged with tert-butyl 4-(3-(methoxycarbonyl)-4(trifluoromethyl)benzyl)piperazine-1-carboxylate (600 mg, 1.42 mmol, 1.00 equiv), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (203 mg, 0.280 mmol, 0.20 equiv), triethylamine (421 mg, 4.16 mmol, 3.00 equiv), and MeOH (10 mL). The resulting solution was stirred for 3 days at 100 °C under carbon monoxide (10 atm) and quenched with water (20 mL). The mixture was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed to give 560 mg (98% yield) of tert-butyl 4-(3(methoxycarbonyl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 403 [M+H]+.

Step 3: Preparation of tert-butyl 4-(3-(hydrazinecarbonyl)-4-(trifluoromethyl)benzyl)piperazine-1carboxylate

- 26 047826

A 50 mL round bottom flask was charged with tert-butyl 4-(3-(methoxycarbonyl)-4(trifluoromethyl)benzyl)piperazine-1-carboxylate (560 mg, 1.39 mmol, 1.00 equiv), hydrazine hydrate (209 mg, 4.17 mmol, 3.00 equiv), and EtOH (10 mL). The resulting solution was stirred for 3 h at 100 °C and concentrated under reduced pressure to give 560 mg of tert-butyl 4-(3-(hydrazinecarbonyl)-4(trifluoromethyl)benzyl)piperazine-1-carboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 403 [M+H]+.

Step 4: Preparation of tert-butylide-4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzide)piperazine-1-carboxylate

Tert-butyl 4-(3-(hydrazinecarbonyl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (560 mg, 1.34 mmol, 1.00 equiv) and triethoxymethane (10 mL) were placed in a flask. The resulting solution was stirred for 5 h at 140 °C and concentrated under reduced pressure. The residue was chromatographed to afford 540 mg (94% yield) of tert-butyl 4-(3-(1,3,4-oxadiazol-2-yl)-4(trifluoromethyl)benzyl)piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 413 [M+H]+.

Step 5: Preparation of 2-(5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1,3,4-oxadiazole

F,CL

F ₃ CL ,Vos ³ Nrf % { NH

Il I G HC1, 1,4-dioxane II J. j < Й k.t., 2 h. * D

N' ⁿ

Tert-butyl 4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (540 mg, 1.26 mmol, 1.00 equiv), HCl (3 mL), and 1,4-dioxane (10 mL) were added to a flask as described in Example 2, step 4 to give 409 mg of 2-(5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1,3,4-oxadiazole (crude) as a white solid. LCMS (ESI, m/z): 313 [M+H] ⁺ .

Step 6: Preparation of tert-butyl 1-(4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

2-(5-(piperazin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1,3,4-oxadiazole (264 mg, 1.57 mmol, 1.20 equiv), triphosgene (235 mg, 0.790 mmol, 0.60 equiv) and DCM (10 mL) were placed in a flask. Then DIPEA (676 mg, 5.23 mmol, 4.00 equiv) was added dropwise at 0 °C and the resulting solution was stirred for 2 h at room temperature. Then tert-butyl 1H-niperazole-3-carboxylate (409 mg, 1.31 mmol, 1.00 equiv) was added as described in Example 1, step 3. The residue was chromatographed to afford 302 mg (46% yield) of tert-butyl 1-(4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl)niperazine-1-carbonide)-1Hpyrazole-3-carboxylate as a yellow solid. LCMS (ESI, m/z): 507 [M+H] ⁺ .

Step 7: Preparation of 1-(4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-nirazole-3-carboxylic acid

Tert-butyl 1-(4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (302 mg, 0.600 mmol, 1.00 equiv), TFA (1 mL) and DCM (4 mL) were placed in a flask as

- 27 047826 is described in Example 1, Step 5. The crude product was purified by preparative HPLC to give 60.3 mg (22% yield) of 1-(4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (300 MHz, methanol^) δ 9.14 (s, 1H), 8.08 - 8.15 (m, 1H), 8.06 (s, 1H), 7.88 - 7.99 (m, 1H), 7.76 -7.88 (m, 1H), 6.74 - 6.87 (m, 1H), 3.89 (s, 3H), 3.69 - 3.78 (m, 2H), 2.54 - 2.67 (m, 4H). LCMS (ESI, m/z): 451 [M+H]+.

Example 10: 1-(4-methyl-4-(methyl(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl 1H-pyrazole-1,3-dicarboxylate

1H-pyrazole-3-carboxylic acid (10.0 g, 89.2 mmol, 1.00 equiv), DMAP (2.15 g, 17.6 mmol, 0.20 equiv), triethylamine (27.0 g, 267 mmol, 3.00 equiv), di-tert-butyl dicarbonate (80.0 g, 366 mmol, 4.00 equiv) in tert-butanol (100 mL) were charged to a flask as described in Example 1, step 1 to give 25.0 g of 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, m/z): 269 [M+H]+.

Step 2: Preparation of tert-butyl 1H-pyrazole-3-carboxylate

A flask was charged with 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (25.0 g, 93.2 mmol, 1.00 equiv), NaOH (5.60 g, 140 mmol, 1.50 equiv) in water (80 mL) and MeOH (240 mL) as described in Example 1, step 2 to give 10.0 g (64% yield) of tert-butyl 1H-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate

4-Nitrophenyl chloroformate (448 mg, 2.22 mmol, 1.05 equiv), tert-butyl 1Hpyrazole-3-carboxylate (356 mg, 2.12 mmol, 1.00 equiv), DCM (5 mL), and triethylamine (642 mg, 6.34 mmol, 3.00 equiv) were added to a flask as described in Example 4, step 3 to give 500 mg of 3-tert-butyl 1-(4-nitrophenyl)-1Hpyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 334 [M+H] ⁺ .

Step 4: Preparation of tert-butyl 4-((2-bromo-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1carboxylate

60°C, overnight

2-Bromo-4-(trifluoromethyl)benzaldehyde (970 mg, 3.83 mmol, 1.00 equiv), tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (1.07 g, 4.99 mmol, 1.30 equiv), MeOH (10 mL), and AcOH (696 mg, 11.6 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred for 1 h at 60 °C. Sodium borohydride (441 mg, 11.6 mmol, 3.00 equiv) was added. The residue was chromatographed to give 1.41 g (81% yield) of tert-butyl 4-((2-bromo-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 451 [M+H]+.

- 28 047826

Step 5: Preparation of tert-butyl 4-((2-bromo-4-(trifluoromethyl)benzyl)(methyl)amino)-4methylpiperidine-1-carboxylate F ₃ C

Et ₃ N, DCE k.t., overnight

.Vos

_Vos НСНО, NaBH(OAc) ₃ ^F 3

Tert-butyl 4-((2-bromo-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1-carboxylate (1.41 g, 3.12 mmol, 1.00 equiv), paraformaldehyde (939 mg, 31.2 mmol, 10.0 equiv), triethylamine (948 mg, 9.36 mmol, 3.00 equiv), and DCE (20 mL) were placed in a flask. The resulting solution was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (1.99 g, 9.36 mmol, 3.00 equiv) was added as described in Example 2, step 3. The residue was chromatographed to afford 1.10 g (76% yield) of tert-butyl 4-((2-bromo-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 465 [M+H]+.

Step 6: Preparation of tert-butyl 4-methyl-4-(methyl(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

Sn(n-Bu) _{3 РзС}

F ₃

, Vos In S

Pd( _PPh3 ) ₄ , toluene

Vos

Tert-butyl 4-((2-bromo-4-(trifluoromethyl)benzyl)(methyl)amino)-4 methylpiperidine-1-carboxylate (417 mg, 0.899 mmol, 1.00 equiv), 2-(tributylstannyl)-1,3-thiazole (506 mg, 1.35 mmol, 1.50 equiv), tetrakis(triphenylphosphine)palladium (104 mg, 0.0899 mmol, 0.10 equiv) and toluene (10 mL) were placed in a flask. The resulting solution was stirred overnight at 110°C and quenched with water (10 mL) as described in Example 8, step 4. The residue was chromatographed to afford 400 mg (95% yield) of tert-butyl 4-methyl-4-(methyl(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 470 [M+H]+.

Step 7: Preparation of N,4-dimethyl-N-(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperidin-4-amine

The flask was charged with tert-butyl 4-methyl-4-(methyl(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (495 mg, 1.05 mmol, 1.00 equiv), 1,4-dioxane (5 mL), concentrated HCl (1 mL) as described in Example 2, step 4 to give 500 mg of N,4-dimethyl-N-(2-(thiazol-2-yl)-4(trifluoromethyl)benzyl)piperidin-4-amine (crude) as a yellow oil. LCMS (ESI, m/z): 370 [M+H]+.

Step 8: Preparation of tert-butyl 1-(4-methyl-4-(methyl(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-III-pyrazole-3-carboxylate

The flask was charged with 3-tert-butyl-1-(4-nitrophenyl)-N-pyrazole-1,3-dicarboxylate (708 mg, 2.12 mmol, 2.00 equiv), N,4-dimethyl-N-(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)piperidin-4-amine (391 mg, 1.06 mmol, 1.00 equiv), DCM (10 mL), and triethylamine (321 mg, 3.17 mmol, 3.00 equiv). The resulting solution was stirred for 3 h at room temperature and quenched with water (10 mL) as described in Example 4, step 3. The residue was chromatographed to afford 560 mg (94% yield) of tert-butyl 1-(4-methyl-4-(methyl(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1/3-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 564 [M+H]+.

Step 9: Preparation of 1-(4-methyl-4-(methyl(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-III-pyrazole-3-carboxylic acid

- 29 047826

A flask was charged with tert-butyl 1-(4-methyl-4-(methyl(2-(thiazol-2-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylate (560 mg, 0.990 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL) as described in Example 1, step 5. The crude product (400 mg) was purified by preparative HPLC to give 132.0 mg (26% yield) of 1-(4-methyl-4-(methyl(2-(thiazol-2-yl)-4(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (400 MHz, Methanol-c14) δ 8.00 - 8.10 (m, 4H), 7.84 - 7.88 (m, 2H), 6.80 (d, J=2.7 Hz, 1H), 4.20 - 4.30 (m, 4H), 3.62 (br, 2H), 2.38 (br, 3H), 2.14 (br, 2H), 1.91 (br, 2H), 1.36 (br, 3H). LCMS (ESI, m/z): 508 [M+H]+.

Example 11: 1-(4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-1-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-1H-pyrazole-1,3-dicarboxylate

1H-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equiv), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv), DMAP (4.35 g, 35.7 mmol, 0.20 equiv), triethylamine (54.1 g, 536 mmol, 3.00 equiv), and tert-butanol (200 mL) were charged into a flask as described in Example 1, step 1 to give 20.0 g of 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 169 [M+N-Boc] ⁺ .

Step 2: Preparation of tert-butyl-1H-pyrazole-3-carboxylate

A flask was charged with 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), NaOH (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL). The resulting solution was stirred overnight at room temperature and quenched with water (40 mL) as described in Example 1, step 2 to give 6.70 g of tert-butyl 1H-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H] ⁺ .

Step 3: Preparation of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

_Et3N , DCM

k.t., during the night

Tert-butyl 4-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol, 1.00 equiv), DCM (20 mL), and methanesulfonyl chloride (629 mg, 5.47 mmol, 1.10 equiv) were placed in a flask. Triethylamine (1.51 g, 14.9 mmol, 3.00 equiv) was added dropwise at 0 °C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 1.29 g of tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (crude) as a white solid. LCMS (ESI, w/z): 280 [M+H] ⁺ .

Step 4: Preparation of tert-butyl 4-(2-bromo-4-chlorophenoxy)piperidine-1-carboxylate

- 30 047826

A flask was charged with 2-bromo-4-chlorophenol (367 mg, 1.77 mmol, 1.10 equiv), DMSO (15 mL), tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (450 mg, 1.61 mmol, 1.00 equiv), and potassium carbonate (667 mg, 4.83 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80 °C and quenched with water (30 mL). The mixture was extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed to afford 400 mg (64% yield) of tert-butyl 4-(2-bromo-4-chlorophenoxy)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 390 [M+H]+.

Step 5: Preparation of tert-butyl 4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carboxylate

Tert-butyl 4-(2-bromo-4-chlorophenoxy)piperidine-1-carboxylate (400 mg, 1.02 mmol, 1.00 equiv), toluene (15 mL), pyrrolidine (109 mg, 1.53 mmol, 1.50 equiv), cesium carbonate (665 mg, 2.04 mmol, 2.00 equiv), tris(dibenzylideneacetone)dipalladium-chloroform (52.8 mg, 0.0510 mmol, 0.05 equiv), and dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (35.7 mg, 0.0714 mmol, 0.07 equiv) were added to a flask as described in Example 7, step 1. The residue chromatographed to give 220 mg (56% yield) of tert-butyl 4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 381 [M+H] ⁺ .

Step 6: Preparation of 4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine

Tert-butyl 4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carboxylate (220 mg, 0.582 mmol, 1.00 equiv), 1,4-dioxane (10 mL) and HCl (2 mL) were added to a flask as described in Example 2, step 4 to give 150 mg of 4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine (crude) as a yellow oil. LCMS (ESI, m/z): 281 [M+H] ⁺ .

Step 7: Preparation of 4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl chloride

4-(4-Chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine (150 mg, 0.532 mmol, 1.00 equiv), DCM (10 mL), and triphosgene (79.3 mg, 0.266 mmol, 0.50 equiv) were placed in a flask. DMAP (207 mg, 1.60 mmol, 3.00 equiv) was added dropwise at 0 °C as described in Example 1, step 3 to give 183 mg of 4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl chloride (crude) as a yellow oil.

Step 8: Preparation of tert-butyl 1-(4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)III-pyrazole-3-carboxylate

The flask was charged with 4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl chloride (183 mg, 0.530 mmol, 1.00 equiv.), THF (10 mL), tert-butyl-III-pyrazole-3-carboxylate (89.7 mg, 0.530 mmol, 1.00

- 31 047826 equiv), DIPEA (138 mg, 1.07 mmol, 2.00 equiv) and DMAP (13.1 mg, 0.107 mmol, 0.20 equiv). The resulting solution was stirred overnight at 60 °C and quenched with water (20 mL) as described in Example 1, step 4. The residue was chromatographed to afford 135 mg (53% yield) of tert-butyl 1-(4-(4-chloro-2-pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-3-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 475 [M+H]+.

Step 9: Preparation of 1-(4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-III-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 1-(4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylate (135 mg, 0.282 mmol, 1.00 equiv), DCM (5 mL), and TFA (1 mL) as described in Example 1, step 5. The crude product was purified by preparative HPLC to give 12.6 mg (11% yield) of 1-(4-(4-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a yellow solid. Ή NMR: (300 MHz, Methanol) δ 8.12 (s, 1H), 6.87 -6.95 (m, 1H), 6.82 (m, 1H), 6.66 - 6.75 (m, 2H), 4.60 (m, 1H), 3.92 - 4.11 (m, 2H), 3.60 - 3.80 (m, 2H), 3.32 (m, 2H), 3.29 (m, 2H), 2.00 - 2.20 (m, 2H), 1.80 - 2.00 (m, 6H). LCMS (ESI, m/z): 419 [M+H]+.

Example 12: 1-(4-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)III-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

Botx

Vosgo, DMAP

_Et3N , w^w-BuOH

60°C, overnight

In a flask were charged 1,3-di-tert-butyl 1,3-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equiv), DMAP (2.18 g, 17.9 mmol, 0.20 equiv), triethylamine (27.1 g, 268 mmol, 3.00 equiv), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equiv), tert-butanol (100 mL) as described in Example 1, step 1 to give 25.0 g of 1,3-di-tert-butyl 1,3-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, m/z): 269 [M+H]+.

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

A flask was charged with 1,3-di-tert-butyl-3-pyrazole-1,3-dicarboxylate (25.0 g, 93.3 mmol, 1.00 equiv), NaOH (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL) as described in Example 1, step 2. The residue was column chromatographed on silica gel to afford 10.0 g (64% yield) of tert-butyl-3-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

To a flask were placed 2-bromo-4-(trifluoromethyl)benzaldehyde (2.00 g, 7.90 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (2.94 g, 15.8 mmol, 2.00 equiv), and DCM (30 mL). The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (6.70 g, 31.6 mmol, 4.00 equiv) was added as described in Example 2, step 3. The residue was chromatographed to afford 3.25 g (97% yield) tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a colorless oil. LCMS (ESI, mass/charge): 423 [M+H]+.

Step 4: Preparation of tert-butyl 4-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

Tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (0.500 g, 1.18 mmol, 1.00 equiv), 4-methoxypiperidine (0.271 g, 2.36 mmol, 2.00 equiv), tris(dibenzylideneacetone)dipalladium (0.162 g, 0.177 mmol, 0.15 equiv), 2,2'-bis(diphenylphosphino)-1,1'binaphthyl (0.331 g, 0.531 mmol, 0.45 equiv), cesium carbonate (1.73 g, 5.31 mmol, 4.50 equiv) and toluene (15 mL) were placed in a flask under a nitrogen atmosphere. The resulting solution was stirred overnight at 100 °C and then quenched with water (30 mL). The resulting solution was extracted with DCM (3 x 50 mL) and the organic layers were combined, washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 0.200 g (37% yield) of tert-butyl 4-(2-(4-methoxypiperidin-1-yl)-4(trifluoromethyl)benzyl)piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 458 [M+H] ⁺ .

Step 5: Preparation of 1-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine

°\ °\

Tert-butyl 4-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (200 mg, 0.438 mmol, 1.00 equiv), 1,4-dioxane (5 mL), and concentrated HCl (1 mL) were added to a flask as described in Example 2, step 4 to give 210 mg of (crude) 1-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine as a yellow oil. LCMS (ESI, m/z): 358 [M+H] ⁺ .

Step 6: Preparation of tert-butyl-1-(4-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylate

ABOUT

Triphosgene (90.9 mg, 0.306 mmol, 0.70 equiv) and DCM (10 mL) were placed in a flask. Tert-butyl 1/3-pyrazole-3-carboxylate (147 mg, 0.874 mmol, 2.00 equiv) was added at 0 °C. DIPEA (283 mg, 2.19 mmol, 5.00 equiv) was added at 0 °C. The mixture was stirred for 2 h at room temperature. 1-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine (156 mg, 0.437 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then quenched with water (15 mL) as described in Example 1, step 3 to give 220 mg (92% yield) of tert-butyl 1-(4(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1I-1-yrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 552 [M+H] ⁺ .

Step 7: Preparation of 1-(4-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1carbonyl)-1-pyrazole-3-carboxylic acid

- 33 047826

A flask was charged with tert-butyl 1-(4-(2-(4-methoxypiperidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (220 mg, 0.400 mmol, 1.00 equiv), DCM (5 mL), and TFA (2 mL) as described in Example 1, step 5. The crude product (195 mg) was purified by preparative HPLC to give 68.4 mg (35% yield) of 1-(4-(2-(4-methoxypiperidin-1-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (400 MHz, methanol^) δ 8.14 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.36 - 7.38 (m, 2H), 6.83 (s, 1H), 3.70 - 3.99 (m, 6H), 3.39 - 3.48 (m, 4H), 3.12-3.15 (m, 2H), 2.66 - 2.82 (m, 6H), 2.05 - 2.08 (m, 2H), 1.69 - 1.77 (m, 2H). LCMS (ESI, m/z): 496 [M+H]+.

Example 13: 1-(4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

Vos^

Vosgo, DMAP

ΕίβΝ, w/jem-BuOH 65 °C, overnight

1H-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equiv), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv), DMAP (4.35 g, 35.7 mmol, 0.20 equiv), triethylamine (54.1 g, 536 mmol, 3.00 equiv), and tert-butanol (200 mL) were charged into a flask as described in Example 1, step 1 to give 20.0 g of 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 169 [M+H-Boc]+.

Step 2: Preparation of tert-butyl 1H-pyrazole-3-carboxylate

A flask was charged with 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), NaOH (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL). The resulting solution was stirred overnight at room temperature and quenched with water (40 mL) as described in Example 1, step 2 to give 6.70 g of tert-butyl 1H-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Vos MsCI, Et ₃ N

DCM, candidate of technical sciences, 2 hours. O

Ms

Tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol, 1.00 equiv), triethylamine (3.01 g, 29.8 mmol, 3.00 equiv), and DCM (30 mL) were placed in a flask. Methanesulfonyl chloride (1.71 g, 14.9 mmol, 1.50 equiv) was then added dropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature and quenched with water (30 mL) as described in Example 11, step 3, to give 2.50 g of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (crude) as a white solid.

Step 4: Preparation of tert-butyl 4-(3-chloro-2-nitrophenoxy)piperidine-1-carboxylate

- 34 047826

A flask was charged with 3-chloro-2-nitrophenol (0.500 g, 2.88 mmol, 1.00 equiv), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.804 g, 2.88 mmol, 1.00 equiv), cesium carbonate (1.88 g, 5.77 mmol, 2.00 equiv), and DMF (15 mL). The resulting solution was stirred overnight at 80 °C and quenched with water (10 mL). The mixture was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 0.714 g (69% yield) of tert-butyl 4-(3-chloro-2-nitrophenoxy)piperidine-1-carboxylate as a white solid. LCMS (ESI, m/z): 357 [M+H]+.

Step 5: Preparation of tert-butyl 4-(2-amino-3-chlorophenoxy)piperidine-1-carboxylate

Tert-Butyl 4-(3-chloro-2-nitrophenoxy)piperidine-1-carboxylate (0.400 g, 1.12 mmol, 1.00 equiv), iron (0.628 g, 11.2 mmol, 10.00 equiv), ammonium chloride (1.21 g, 22.6 mmol, 20.00 equiv), and EtOH (15 mL) were placed in a flask. The resulting solution was stirred for 2 h at 80 °C and quenched with water (10 mL). The mixture was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 0.327 g (89% yield) of tert-butyl 4-(2-amino-3-chlorophenoxy)piperidine-1-carboxylate as a white solid. LCMS (ESI, m/z): 327 [M+H]+.

Step 6: Preparation of tert-butyl 4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carboxylate

Tert-butyl 4-(2-amino-3-chlorophenoxy)piperidine-1-carboxylate (327 mg, 1.00 mmol, 1.00 equiv), 1,4-diiodobutane (324 mg, 1.05 mmol, 1.50 equiv) and THF (15 mL) were placed in a flask. Sodium hydride (486 mg, 20.3 mmol, 3.00 equiv) was added dropwise at 0 °C. The resulting solution was stirred overnight at 60 °C and quenched with water (10 mL). The mixture was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 270 mg (71% yield) of tert-butyl 4-(3-chloro-2-(pyrrolidin-1yl)phenoxy)piperidine-1-carboxylate as a white solid. LCMS (ESI, m/z): 381 [M+H] ⁺ .

Step 7: Preparation of 4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine

Tert-Butyl 4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carboxylate (270 mg, 0.710 mmol, 1.00 equiv), TFA (1 mL) and DCM (5 mL) were added to a vessel as described in Example 1, step 5 to give 200 mg of 4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine (crude) as a white solid. LCMS (ESI, m/z): 281 [M+H]+.

Step 8: Preparation of tert-butyl 1-(4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)1 H-i and 1-3 -carboxylate

- 35 047826

0°C, overnight

Tert-butyl 1/3-pyrazole-3-carboxylate (120 mg, 0.710 mmol, 1.00 equiv), triethylamine (287 mg, 2.84 mmol, 4.00 equiv), and DCM (15 mL) were placed in a flask. 4-Nitrophenyl chloroformate (174 mg, 0.860 mmol, 1.20 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature. Then 4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine (200 mg, 0.710 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (10 mL) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 180 mg (53% yield) of tert-butyl 1-(4-(3-chloro-2-(pyrrolidin-1yl)phenoxy)piperidine-1-carbonyl)-1-(pyrazole-3-carboxylate) as a white solid. LCMS (ESI, m/z): 475 [M+H]+.

Step 9: Preparation of 1-(4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-III-pyrazole-3-carboxylic acid

O O

Tert-butyl 1-(4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylate (180 mg, 0.380 mmol, 1.00 equiv), TFA (1 mL) and DCM (5 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure. The crude product was dissolved in saturated NaHCO ₃ solution (10 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 65.1 mg (41% yield) of 1-(4-(3-chloro-2-(pyrrolidin-1-yl)phenoxy)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (400 MHz, Methanol^ ₄ ) δ 7.92 - 8.22 (m, 1H), 6.88 - 7.12 (m, 3H), 6.58 - 6.85 (m, 1H), 4.66 - 4.75 (m, 1H), 3.61 - 4.20 (m, 4H), 3.18 - 3 .29 (m, 4H), 2.04 2.25 (m, 2H), 1.77 - 2.02 (m, 6H). LCMS (ESI, mass/charge): 419 [M+H]+.

Example 14: 1-(4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

ABOUT

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

A flask was charged with N-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equiv), DMAP (2.18 g, 17.9 mmol, 0.20 equiv), triethylamine (27.1 g, 268 mmol, 3.00 equiv), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equiv), tert-butanol (100 mL). The resulting solution was stirred for 4 h at 80 °C and quenched with water (50 mL) as described in Example 1, step 1, to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, mass/charge): 269 [M+H]+.

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

- 36 047826

A flask was charged with 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (25.0 g, 93.3 mmol, 1.00 equiv), sodium hydroxide (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL). The resulting solution was stirred for 2 h at room temperature and quenched with water (30 mL) as described in Example 1, step 2. The residue was chromatographed to afford 10.0 g (64% yield) of tert-butyl pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate

Tert-butyl 1H-pyrazole-3-carboxylate (2.00 g, 11.9 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (2.87 g, 14.2 mmol, 1.20 equiv), triethylamine (3.61 g, 35.7 mmol, 3.00 equiv), and DCM (20 mL) were charged to a flask as described in Example 4, step 3 to give 3-tert-butyl 1-(4-nitrophenyl)-1Hpyrazole-1,3-dicarboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 334 [M+H]+.

Step 4: Production of methyl 4-formyl-2-(trifluoromethyl)benzoate

To a flask were placed 4-bromo-3-(trifluoromethyl)benzaldehyde (1.61 g, 6.36 mmol, 1.00 equiv), 1,1'bis(diphenylphosphino)ferrocenepalladium dichloride (0.466 g, 0.636 mmol, 0.10 equiv), triethylamine (1.93 g, 19.1 mmol, 3.00 equiv), and MeOH (15 mL). Carbon monoxide (10 atm) was introduced. The resulting solution was stirred overnight at 80 °C and then quenched with water (30 mL) as described in Example 9, step 2. The residue was chromatographed to afford 1.00 g (68% yield) of methyl 4-formyl 2-(trifluoromethyl)benzoate as a yellow oil.

Step 5: Preparation of tert-butyl 4-(4-(methoxycarbonyl)-3-(trifluoromethyl)benzyl)piperazine-1carboxylate

Methyl 4-formyl 2-(trifluoromethyl)benzoate (0.800 g, 3.45 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.962 g, 5.17 mmol, 1.50 equiv), and DCM (15 mL) were placed in a flask. The mixture was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (2.93 g, 13.8 mmol, 4.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then quenched with water (30 mL) as described in Example 2, step 3. The residue was chromatographed to afford 1.26 g (91% yield) of tert-butyl 4-(4-(methoxycarbonyl)-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 403 [M+H]+.

Step 6: Preparation of 4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-(trifluoromethyl)benzoic acid

Tert-butyl 4-(4-(methoxycarbonyl)-3-(trifluoromethyl)benzyl)piperazine-1carboxylate (1.21 g, 3.01 mmol, 1.00 equiv), THF (10 mL), water (2 mL), and NaOH (2.41 g, 60.2 mmol, 20.00 equiv) were placed in a flask. The resulting solution was stirred overnight at 60 °C. The pH of the solution was adjusted to 6 with HCl (1 M). The resulting solution was extracted with DCM (3x80 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.40 g of 4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-(trifluoromethyl)benzoic acid (crude) as

- 37 047826 white solid. LCMS (ESI, m/z): 389 [M+H]+.

Step 7: Preparation of tert-butyl 4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate

A flask was charged with 4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2(trifluoromethyl)benzoic acid (1.24 g, 3.19 mmol, 1.00 equiv), N,N,N',N'-tetramethyl-O-(7azabenzotriazol-1-yl)uronium hexafluorophosphate (2.43 g, 6.39 mmol, 2.00 equiv), DIPEA (1.24 g, 12.8 mmol, 4.00 equiv), DMF (10 mL), and ammonia (0.5 M in 1,4-dioxane solution, 63.8 mL, 31.9 mmol, 10.00 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 1.00 g (81% yield) of tert-butyl 4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 388 [M+H] ⁺ .

Step 8: Preparation of 4-(piperazin-1-ylmethyl)-2-(trifluoromethyl)benzamide

Tert-butyl 4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate (520 mg, 1.34 mmol, 1.00 equiv), DCM (10 mL), and TFA (3 mL) were added to a flask as described in Example 1, step 5 to give 550 mg of 4-(piperazin-1-ylmethyl)-2-(trifluoromethyl)benzamide (crude) as a yellow oil. LCMS (ESI, m/z): 288 [M+H] ⁺ .

Step 9: Preparation of tert-butyl-1-(4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

To a flask were placed 4-(piperazin-1-ylmethyl)-2-(trifluoromethyl)benzamide (185 mg, 0.645 mmol, 1.00 equiv), 3-tert-butyl 1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (322 mg, 0.968 mmol, 1.50 equiv), DCM (10 mL), and triethylamine (261 mg, 2.58 mmol, 4.00 equiv) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 200 mg (yield 67%) of tert-butyl 1-(4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate as a yellow solid. oils. LCMS (ESI, mass/charge): 466 [M+H] ⁺ .

Step 10: Preparation of 1-(4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid

A flask was charged with tert-butyl 1-(4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-N-pyrazole-3-carboxylate (200 mg, 0.430 mmol, 1.00 equiv), DCM (15 mL), TFA (4 mL) as described in Example 1, step 5. The crude product (280 mg) was purified by preparative HPLC to give 25.6 mg (14% yield) of 1-(4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-N-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (300 MHz, Methanol^ ₄ ) δ 8.14 (d, J=2.7 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 3.87 (br, 4H), 3.72 (s, 2H), 2.63 - 2.64 (m, 4H). LCMS (ESI, m/z): 424 [M-H] ^- .

Example 15: ^trans^-^-chlorobenzyl^xi^ktahydrocyclopenta^pyrrole^carbonyl^pyrazole-3-carboxylic acid

- 38 047826

Step 1: Preparation of di-tert-butyl 1H-pyrazole-1,3-dicarboxylate

A flask was charged with N-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equiv), DMAP (2.18 g, 17.9 mmol, 0.20 equiv), triethylamine (27.1 g, 268 mmol, 3.00 equiv), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equiv), tert-butanol (100 mL). The resulting solution was stirred for 4 h at 80 °C and quenched with water (50 mL) as described in Example 1, step 1, to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, mass/charge): 269 [M+H]+.

Step 2: Preparation of tert-butyl 1H-pyrazole-3-carboxylate

A flask was charged with 1,3-di-tert-butyl-3-pyrazole-1,3-dicarboxylate (25.0 g, 93.3 mmol, 1.00 equiv), sodium hydroxide (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL). The resulting solution was stirred for 2 h at room temperature and quenched with water (30 mL) as described in Example 1, step 2. The residue was chromatographed to afford 10.0 g (64% yield) of tert-butyl-3-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H] ⁺ .

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate

ABOUT

Tert-butyl 1H-pyrazole-3-carboxylate (225 mg, 1.34 mmol, 1.00 equiv), DCM (10 mL), and triethylamine (406 mg, 4.01 mmol, 3.00 equiv) were placed in a flask. 4-Nitrophenyl chloroformate (296 mg, 1.47 mmol, 1.10 equiv) was added at 0 °C as described in Example 4, step 3 to give 500 mg of 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 334 [M+H] ⁺ .

Step 4: Preparation of tert-butyl trans-5-hydroxyhexahydrocyclopenta[e]pyrrole-2(III)-carboxylate

Tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.00 g, 4.44 mmol, 1.00 equiv) and MeOH (15 mL) were placed in a flask. Sodium borohydride (0.507 g, 13.4 mmol, 3.00 equiv) was added at 0 °C. The resulting solution was stirred for 2 h at room temperature and quenched with water (20 mL). The resulting solution was extracted with DCM (3x30 mL) and the organic layers were combined, washed with brine (1x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.950 g (94% yield) of tert-butyl trans-N-hydroxyhexahydrocyclopentaphenylcarboxylate as a yellow oil. LCMS (ESI, m/z): 228 [M+H] ⁺ .

Step 5: Preparation of tert-butyl trans-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[e]pyrrole2( 1 ^-carboxylate

- 39 047826

A flask was charged with tert-butyl trans-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.500 g, 2.20 mmol, 1.00 equiv), 4-nitrobenzoic acid (0.735 g, 4.40 mmol, 2.00 equiv), triphenylphosphine (1.15 g, 4.40 mmol, 2.00 equiv), and THF (10 mL) under nitrogen atmosphere. Diethyl azodicarboxylate (0.766 g, 4.40 mmol, 2.00 equiv) was added at 0 °C. The resulting solution was stirred overnight at room temperature and quenched with water (20 mL). The resulting solution was extracted with DCM (3x30 mL) and the organic layers were combined, washed with brine (1x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed to afford 0.540 g (65% yield) of tert-butyl trans-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[e]pyrrole-2(III)-carboxylate as a white solid. LCMS (ESI, m/z): 377 [M+H]+.

Step 6: Preparation of tert-butyl trans-(hydroxyhexahydrocyclopentaphenyl)pyrrole(III)carboxylate

A flask was charged with tert-butyl trans-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[e]pyrrole-2(III)-carboxylate (540 mg, 1.43 mmol, 1.00 equiv), potassium carbonate (396 mg, 2.87 mmol, 2.00 equiv), MeOH (15 mL), and water (5 mL). The resulting solution was stirred overnight at room temperature and quenched with water (15 mL). The resulting solution was extracted with DCM (3 x 30 mL), and the organic layers were combined, washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed to afford 270 mg (83% yield) of tert-butyl trans-5-hydroxyhexahydrocyclopenta[e]pyrrole-2(III)-carboxylate as a white solid. LCMS (ESI, m/z): 228 [M+H] ⁺ .

Step 7: Preparation of tert-butyl-trans-5-((2-chlorobenzyl)oxy)hexahydrocyclopenta[e]pyrrole2(1H)-carboxylate

CI

Tert-butyl trans-5-hydroxyhexahydrocyclopenta[e]pyrrole-2(1H)-carboxylate (270 mg, 1.19 mmol, 1.00 equiv) and DMF (10 mL) were placed in a flask. Sodium hydride (95.2 mg, 60% in mineral oil, 2.38 mmol, 2.00 equiv) was added at 0 °C. The mixture was stirred for 20 min at room temperature. 1-(Bromomethyl)-2-chlorobenzene (291 mg, 1.42 mmol, 1.20 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (15 mL). The resulting solution was extracted with EtOAc (3x20 mL) and the organic layers were combined, washed with brine (1x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 380 mg (91% yield) of tert-butyl trans-5-((2-chlorobenzyl)oxy)hexahydrocyclopenta[e]pyrrole 2(1H)-carboxylate as a yellow oil. LCMS (ESI, m/z): 352 [M+H]+.

Step 8: Preparation of trans-5-((2-chlorobenzyl)oxy)octahydrocyclopenta[e]pyrrole

Tert-butyl trans-5-((2-chlorobenzyl)oxy)hexahydrocyclopenta[e]pyrrole-2(1H)carboxylate (380 mg, 1.08 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL) were added to a flask as described in Example 1, step 5 to give 450 mg of trans-5-((2-chlorobenzyl)oxy)octahydrocyclopenta[e]pyrrole (crude) as a yellow oil. LCMS (ESI, m/z): 252 [M+H]+.

- 40 047826

Step 9: Preparation of tert-butyl 1-(trans-5-((2-chlorobenzyl)oxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1H-pyrazole-3-carboxylate

To a flask were placed trans-5-((2-chlorobenzyl)oxy)octahydrocyclopenta[c]pyrrole (260 mg, 1.03 mmol, 1.00 equiv), 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (448 mg, 1.34 mmol, 1.30 equiv), triethylamine (314 mg, 3.10 mmol, 3.00 equiv), and DCM (10 mL) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 340 mg (74% yield) of tert-butyl 1-(trans-5-((2-chlorobenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate. as a colourless oil. LCMS (ESI, m/z): 446 [M+H]+.

Step 10: Preparation of 1-(trans-5-((2-chlorobenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)III-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 1-(trans-5-((2-chlorobenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate (210 mg, 0.470 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure as described in Example 1, step 5, to give 66.2 mg (36% yield) of 1-(trans-5((2-chlorobenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1H NMR (300 MHz, Methanol^ ₄ ) δ 8.14 (d, J=2.7 Hz, 1H), 7.47 - 7.50 (m, 1H), 7.32 - 7.38 (m, 1H), 7.23 - 7.30 (m, 2H), 6.74 (d, J=2.7 Hz, 1H), 4.56 (s, 2H), 4.23 - 4.29 (m, 1H), 3.40 - 4.20 (m, 4H), 2.92 (br, 2H), 2.10 - 2.16 (m, 2H), 1.76 - 1.84 (m, 2H). LCMS (ESI, m/z): 412 [M+Na] ⁺ .

Example 16: 1-(4-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

Step 1: Preparation of 3-methyl-[1,1'-biphenyl]-4-carbaldehyde

4-Bromo-2-methylbenzaldehyde (5.00 g, 25.1 mmol, 1.00 equiv), phenylboronic acid (3.98 g, 32.6 mmol, 1.30 equiv), tetrakis(triphenylphosphine)palladium (2.90 g, 2.51 mmol, 0.10 equiv), potassium carbonate (10.4 g, 75.3 mmol, 3.00 equiv), 1,4-dioxane (200 mL), and water (40 mL) were placed in a flask under nitrogen. The resulting solution was stirred overnight at 80 °C and then quenched with water (250 mL). The resulting solution was extracted with DCM (3x250 mL) and the organic layers were combined, washed with brine (2x150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 4.79 g (97% yield) of 3-methyl-[1,1'-biphenyl]-4-carbaldehyde as a colorless oil. LCMS (ESI, m/z): 197 [M+H] ⁺ .

Step 2: Preparation of tert-butyl 4-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate

- 41 047826

3-Methyl-[1,1'-biphenyl]-4-carbaldehyde (0.700 g, 3.57 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.797 g, 4.28 mmol, 1.20 equiv) and DCM (20 mL) were placed in a flask. The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (2.27 g, 10.7 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL) as described in Example 2, step 3. The residue was column chromatographed on silica gel to afford 1.00 g (76% yield) of tert-butyl 4-((3-methyl-[1,1'-biphenyl]-4yl)methyl)piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 367 [M+H]+.

Step 3: Preparation of 1-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine

Tert-butyl 4-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (300 mg, 0.820 mmol, 1.00 equiv), DCM (8 mL) and TFA (3 mL) were added to a flask as described in Example 1, step 5 to give 218 mg of 1-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine (crude) as a yellow oil. LCMS (ESI, m/z): 267 [M+H]+.

Step 4: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

Bog^

Vos ₂ O, DMAP N ----------------------»- h EtaN, y-BuOH θΗ 65°C, overnight

A flask was charged with N-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equiv), DMAP (2.18 g, 17.9 mmol, 0.20 equiv), triethylamine (27.1 g, 268 mmol, 3.00 equiv), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equiv), tert-butanol (100 mL). The resulting solution was stirred for 4 h at 80 °C and quenched with water (50 mL) as described in Example 1, step 1, to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, mass/charge): 269 [M+H] ⁺ .

Step 5: Preparation of tert-butyl 1H-pyrazole-3-carboxylate

1,3-Di-tert-butyl-III-pyrazole-1,3-dicarboxylate (25.0 g, 93.3 mmol, 1.00 equiv), sodium hydroxide (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and quenched with water (30 mL) as described in Example 1, step 2. The residue was chromatographed to afford 10.0 g (64% yield) of tert-butyl-III-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 6: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate

Tert-butyl 3-(tert-butyl)-1-(4-nitrophenyl)-3-pyrazole-3-carboxylate (2.00 g, 11.9 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (2.87 g, 14.2 mmol, 1.20 equiv), triethylamine (3.61 g, 35.7 mmol, 3.00 equiv), and DCM (20 mL) were charged to a flask as described in Example 4, step 3 to give 4.50 g of 3-(tert-butyl)-1-(4-nitrophenyl)-3-pyrazole-1,3-dicarboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 334 [M+H]+.

Step 7: Preparation of tert-butyl 1-(4-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carbonyl)111-ι 1izole-3-carboxylate

- 42 047826

k.t., during the night

A flask was charged with 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (218 mg, 0.820 mmol, 1.00 equiv), 1-((3-methyl-[1,1'-biphenyl]-4-yl)methyl)piperazine (410 mg, 1.23 mmol, 1.50 equiv), DCM (5 mL), and triethylamine (331 mg, 3.27 mmol, 4.00 equiv) as described in Example 4, step 3. The residue was chromatographed on a silica gel column to afford 200 mg (53% yield). tert-butyl 1-(4-((3-methyl[1,1'-biphenyl]-4-yl)methyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 461 [M+H]+.

Step 8: Preparation of 1-(4-((3-methyl-[1,N-biphenyl]-4-yl)methyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

Tert-Butyl 1-(4-((3-methyl-[1,N-biphenyl]-4-yl)methyl)piperazine-1-carbonyl)-pyrazole-3-carboxylate (200 mg, 0.430 mmol, 1.00 equiv), DCM (5 mL) and TFA (2 mL) were added to a flask. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The crude product was dissolved in saturated NaHCO ₃ solution (10 mL) and extracted with DCM (3 x 20 mL) as described in Example 1, step 5, to give 87.1 mg (50% yield) of 1-(4-((3-methyl-[1,N-biphenyl]-4-yl)methyl)piperazine-1-carbonyl)-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (300 MHz, Methanol^ ₄ ) δ 8.12 (d, J=2.4 Hz, 1H), 7.59 (d, J=7.2 Hz, 2H), 7.29 - 7.46 (m, 6H), 6.81 (d, J=2.4 Hz, 1H), 3.97 (br, 4H), 3.74 (s, 2H), 2.76 (br, 4H), 2.48 (s, 3H). LCMS (ESI, m/z): 405 [M+H] ⁺ .

Example 17: (L-O-morpholino-D-trifluoromethyl-(enzyl-1-hydroxy-pyrrolo[D-(pyrrole-carbonyl))-III-pyrazole-3-carboxamide)

_CF3

Step 1: Preparation of 4-morpholino-2-(trifluoromethyl)benzaldehyde

ACN (100 mL), morpholine (4.50 g, 51.7 mmol, 1.00 equiv), 4-fluoro-2(trifluoromethyl)benzaldehyde (10.0 g, 51.7 mmol, 1.00 equiv), and potassium carbonate (14.0 g, 101 mmol, 2.00 equiv) were placed in a flask under nitrogen. The resulting solution was stirred overnight at 80 °C and quenched with water (150 mL). The mixture was extracted with DCM (3 x 50 mL) and the organic layers were combined, washed with water (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 10.0 g (75% yield) of 4-morpholino-2-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 260 [M+H] ⁺ .

Step 2: Preparation of tert-butyl 5-(4-morpholino-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-pyrrole-2-carboxylate

- 43 047826

4-Morpholino-2-(trifluoromethyl)benzaldehyde (5.00 g, 19.3 mmol, 1.00 equiv), tert-butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (4.10 g, 19.3 mmol, 1.00 equiv), and DCE (100 mL) were placed in a flask. The mixture was stirred for 2 h at room temperature, then sodium triacetoxyborohydride (8.20 g, 38.7 mmol, 2.00 equiv) was added as described in Example 2, step 3. The residue was column chromatographed on silica gel to afford 6.00 g (68% yield) of tert-butyl 5-(4-morpholino-2(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(III)-carboxylate as a light yellow oil. LCMS (ESI, m/z): 456 [M+H]+.

Step 3: Preparation of 4-(4-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-3-(trifluoromethyl)phenyl)morpholine

Tert-butyl 5-(4-morpholino-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4c]pyrrole-2(III)-carboxylate (6.00 g, 13.2 mmol, 1.00 equiv), 1,4-dioxane (100 mL), and concentrated HCl (20 mL) were added to a flask as described in Example 2, step 4 to give 4.00 g of 4-(4-((hexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)methyl)-3-(trifluoromethyl)phenyl)morpholine (crude) as a pink solid. LCMS (ESI, m/z): 356 [M+H] ⁺ .

Step 4: Preparation of 5-(4-morpholino-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(III)-carbonyl chloride

4-(4-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-3(trifluoromethyl)phenyl)morpholine (1.00 g, 2.81 mmol, 1.00 equiv), DCM (10 mL), and triphosgene (0.335 g, 1.14 mmol, 0.40 equiv) were placed in a flask. DIPEA (1.09 g, 8.45 mmol, 3.00 equiv) was added dropwise at 0°C. The resulting solution was stirred for 2 h at 0°C and quenched with water (5 mL) as described in Example 1, step 3, to give 1.12 g of 5-(4-morpholino-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(III)-carbonyl chloride (crude) as a yellow oil.

Step 5: Preparation of 1-(5-(4-morpholino-2-(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1H-pyrαzole-3-carboxamide

_CF3

5-(4-morpholino-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonyl chloride (235 mg, 0.560 mmol, 1.00 equiv), 1H-pyrazole-3-carboxamide (62.0 mg, 0.560 mmol, 1.00 equiv), DIPEA (147 mg, 1.14 mmol, 2.00 equiv), DMAP (14.0 mg, 0.110 mmol, 0.20 equiv), and THF (10 mL) were loaded. The resulting solution was stirred overnight at 60°C and quenched with water (10 mL) as described in Example 1, step 4. The crude product was purified by preparative HPLC to give 35.8 mg (13% yield) of 1-(5-(4-morpholino-2-(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1-nitro-pyrazole-3-carboxamide as a yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 8.30 (d, J=2.6 Hz, 1H), 7.50-7.60 (m, 1H), 6.80-7.20 (m, 3H), 6.60-6.80 (brm, 1H), 5.56-5.70 (br, 1H), 4.00-4.30 (m, 2H), 3.60-3.90 (m, 8H), 3.18-2.26 (m, 4H), 2.80-3.00 (m, 2H), 2.50-2.76 (m, 4H). LCMS (ESI, m/z): 493 [M+H]+.

Example 18: 1-(4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

- 44 047826

A flask was charged with N-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equiv), DMAP (2.18 g, 17.9 mmol, 0.20 equiv), triethylamine (27.1 g, 268 mmol, 3.00 equiv), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equiv), tert-butanol (100 mL). The resulting solution was stirred for 4 h at 80 °C and quenched with water (50 mL) as described in Example 1, step 1, to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, mass/charge): 269 [M+H]+.

Step 2: Obtaining tert-butyl-III-pyrazole-carboxylate

1,3-Di-tert-butyl-III-pyrazole-1,3-dicarboxylate (25.0 g, 93.3 mmol, 1.00 equiv), sodium hydroxide (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and quenched with water (30 mL) as described in Example 1, step 2. The residue was chromatographed to afford 10.0 g (64% yield) of tert-butyl-III-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate

Tert-butyl 1-(4-nitrophenyl)-pyrazole-1,3-dicarboxylate (2.00 g, 11.9 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (2.87 g, 14.2 mmol, 1.20 equiv), triethylamine (3.61 g, 35.7 mmol, 3.00 equiv), and DCM (20 mL) were charged to a flask as described in Example 4, step 3 to give 3.90 g of 3-tert-butyl 1-(4-nitrophenyl)-pyrazole-1,3-dicarboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 334 [M+H] ⁺ .

Step 4: Preparation of 3-(pyridin-3-yloxy)benzaldehyde

80°C, overnight

3-Iodobenzaldehyde (0.928 g, 4.00 mmol, 1.00 equiv), copper(II) iodide (0.152 g, 0.800 mmol, 0.20 equiv), L-proline (0.184 g, 1.60 mmol, 0.40 equiv), cesium carbonate (3.91 g, 12.0 mmol, 3.00 equiv), pyridin-3-ol (0.570 g, 6.00 mmol, 1.50 equiv), and DMF (15 mL) were placed in a flask under nitrogen. The resulting solution was stirred overnight at 120 °C and then quenched with water (15 mL). The resulting solution was extracted with EtOAc (3x20 mL) and the organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 0.160 g (20% yield) of 3-(pyridin-3-yloxy)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 200 [M+H] ⁺ .

Step 5: Preparation of tert-butyl 4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carboxylate

k.t. during the night

To a flask were placed 3-(pyridin-3-yloxy)benzaldehyde (160 mg, 0.800 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (179 mg, 0.960 mmol, 1.20 equiv), and DCM (15 mL). The mixture was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (678 mg, 3.20 mmol, 4.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then quenched with water (20 mL) as described in Example 2, step 3. The residue was chromatographed to yield 270 mg

- 45 047826 (yield 91%) tert-butyl 4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carboxylate as a brown oil.

Step 6: Preparation of 1-(3-(pyridin-3-yloxy)benzyl)piperazine

Tert-butyl 4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carboxylate (270 mg, 0.730 mmol, 1.00 equiv), DCM (15 mL), and TFA (3 mL) were added to a flask as described in Example 1, step 5 to give 1-(3-(pyridin-3-yloxy)benzyl)piperazine (quantitative) as a yellow oil. LCMS (ESI, m/z): 270 [M+H]+.

Step 7: Preparation of tert-butyl-1-(4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carbonyl)-Spirazol-3-carboxylate

Et ₃ N. DCM

k.t., during the night

1-(3-(pyridin-3-yloxy)benzyl)piperazine (197 mg, 0.730 mmol, 1.00 equiv), 3-tert-butyl 1-(4-nitrophenyl)-3-pyrazole-1,3-dicarboxylate (340 mg, 1.02 mmol, 1.40 equiv), DCM (15 mL), and triethylamine (222 mg, 2.19 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred overnight at room temperature and then quenched with water (20 mL) as described in Example 4, step 3. The residue was chromatographed to afford 200 mg (59% yield) of tert-butyl 1-(4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carbonyl)-1/3-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 464 [M+H]+.

Step 8: Preparation of 1-(4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3carboxylic acid

A flask was charged with tert-butyl 1-(4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate (200 mg, 0.430 mmol, 1.00 equiv), DCM (15 mL), and TFA (3 mL) as described in Example 1, step 5. The crude product (200 mg) was purified by preparative HPLC to give 17.9 mg (10% yield) of 1-(4-(3-(pyridin-3-yloxy)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (300 MHz, Methanol^ ₄ ) δ 8.28 - 8.30 (m, 2H), 8.06 (d, J=2.7 Hz, 1H), 7.36 - 7.44 (m, 3H), 7.20 - 7.22 (m, 1H), 7.11 - 7.12 (m, 1H), 6.96 - 7.00 (m, 1H), 6.74 (d, J=2.7 Hz, 1H), 3.86 (br, 4H), 3.60 (s, 2H), 2.57 - 2.60 (m, 4H). LCMS (ESI, m/z): 408 [M+H]+.

Example 19: 1-(4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxylic acid

Step 1: Obtaining bis(4-chlorophenyl)iodonium tetrafluoroborate

m-Chloroperoxybenzoic acid (1.60 g, 9.27 mmol, 1.10 equiv), DCM (10 mL), boron trifluoride ether complex (3.58 g, 25.2 mmol, 3.00 equiv), and 1-chloro-4-iodobenzene (2.00 g, 8.39 mmol, 1.00 equiv) were placed in a flask. The resulting solution was stirred for 0.5 h at room temperature. Then, (4-chlorophenyl)boronic acid (1.44 g, 9.22 mmol, 1.10 equiv) was added at 0 °C. The resulting solution was stirred for 20 min at room temperature and concentrated under reduced pressure. The crude product was triturated to give 3.00 g (yield 78%) of bis(4

- 46 047826 chlorophenyl)iodonium tetrafluoroborate as a white solid. LCMS (ESI, m/z): 349 [M-BF4] ⁺ .

Step 2: Obtaining di-tert-butyl-III-pyrazole-1,3-dicarboxylate

A flask was charged with N-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equiv), DMAP (2.18 g, 17.9 mmol, 0.20 equiv), triethylamine (27.1 g, 268 mmol, 3.00 equiv), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equiv), tert-butanol (100 mL). The resulting solution was stirred for 4 h at 80 °C and quenched with water (50 mL) as described in Example 1, step 1, to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, mass/charge): 269 [M+H] ⁺ .

Step 3: Obtaining tert-butyl-III-pyrazole-3-carboxylate

A flask was charged with 1,3-di-tert-butyl-3-pyrazole-1,3-dicarboxylate (25.0 g, 93.3 mmol, 1.00 equiv), sodium hydroxide (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL). The resulting solution was stirred for 2 h at room temperature and quenched with water (30 mL) as described in Example 1, step 2. The residue was chromatographed to afford 10.0 g (64% yield) of tert-butyl-3-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H] ⁺ .

Step 4: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate

Tert-butyl 1-(4-nitrophenyl)pyrazole-3-carboxylate (208 mg, 1.24 mmol, 1.00 equiv), DCM (10 mL), 4-nitrophenyl chloroformate (264 mg, 1.30 mmol, 1.05 equiv), and triethylamine (378 mg, 3.72 mmol, 3.00 equiv) were charged into a flask as described in Example 4, step 3 to give 450 mg of 3-tert-butyl 1-(4-nitrophenyl)-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 334 [M+H] ⁺ .

Step 5: Preparation of tert-butyl 4-(3-chloro-5-hydroxybenzyl)piperazine-1-carboxylate

k.t., during the night

3-Chloro-5-hydroxybenzaldehyde (300 mg, 1.92 mmol, 1.00 equiv), DCE (10 mL), tert-butylpiperazine-1-carboxylate (536 mg, 2.88 mmol, 1.50 equiv), and triethylamine (582 mg, 5.76 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (1.21 g, 5.76 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 mL) as described in Example 2, step 3. The residue was chromatographed to afford 460 mg (73% yield) of tert-butyl 4-(3-chloro-5-hydroxybenzyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 327 [M+H] ⁺ .

Step 6: Preparation of tert-butyl 4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carboxylate

40°C, overnight

A 50 mL round-bottomed flask was charged with tert-butyl 4-(3-chloro-5-hydroxybenzyl)piperazine-1-carboxylate (300 mg, 0.920 mmol, 1.00 equiv), THF (10 mL), and NaOH (40.4 mg, 1.01 mmol, 1.10 equiv). The resulting solution was stirred for 15 min at 0 °C. Bis(4

- 47 047826 chlorophenyl)iodanium tetrafluoroborate (440 mg, 1.01 mmol, 1.10 equiv). The resulting solution was stirred overnight at 40 °C and quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 100 mg (yield 25%) of tert-butyl 4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carboxylate as a colorless oil. LCMS (ESI, m/z): 437 [M+H] ⁺ .

Step 7: Preparation of 1-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine

Tert-butyl 4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carboxylate (100 mg, 0.229 mmol, 1.00 equiv), DCM (5 mL), and TFA (1 mL) were added to a flask as described in Example 1, step 5 to give 80.0 mg of 1-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine (crude) as a yellow oil. LCMS (ESI, m/z): 337 [M+H]+.

Step 8: Preparation of tert-butyl-1-(4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carbonyl)-Spirazole-3-carboxylate

Cl

EI3IN, UVLVI

k.t., during the night

The flask was charged with 1-[[3-chloro-5-(4-chlorophenoxy)phenyl]methyl]piperazine (80.0 mg, 0.238 mmol, 1.00 equiv), DCM (10 mL), 3-tert-butyl 1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (159 mg, 0.476 mmol, 2.00 equiv), and triethylamine (72.1 mg, 0.714 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (10 mL) as described in Example 4, step 3. The residue was chromatographed to afford 100 mg (79% yield) of tert-butyl 1-(4-(3-chloro-5-(4chlorophenoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 531 [M+H]+.

Step 9: Preparation of 1-(4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3carboxylic acid

Tert-butyl 1-(4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylate (70.0 mg, 0.132 mmol, 1.00 equiv), DCM (5 mL), and TFA (1 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The crude product was dissolved in DCM (10 mL). The pH of the solution was adjusted to 8 with saturated _NaHCO3 solution as described in Example 1, step 5. The crude product (200 mg) was purified by preparative HPLC to give 15.4 mg (25% yield) of 1-(4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (300 MHz, Methanol-f) δ 8.14 (d, J=2.7 Hz, 1H), 7.35 - 7.43 (m, 2H), 7.19 (br, 1H), 7.02 - 7.06 (m, 2H), 6.93 - 6.97 (m, 1H), 6.92 (s, 1H), 6.82 (d, J=2.7 Hz, 1H), 3.86 (br, 4H), 3.60 (s, 2H), 2.57-2.67 (m, 4H). LCMS (ESI, m/z): 475 [M+H]+.

Example 20: 4-chloro-1-(5-(4-(imidazo[1,2-a]pyridin-3-yl)-2-(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid

Step 1: Preparation of tert-butyl 4-chloro-1H-pyrazole-3-carboxylate

- 48 047826

ΗΝ ^Ν <κ^° (Boc) ₂ O, Et ₃ N, DMAP, t-BuOH HN' ^N -x

1^/ OH \ 80°C, overnight \

Cl Cl

A flask was charged with 4-chloro-1H-pyrazole-3-carboxylic acid (2.00 g, 13.6 mmol, 1.00 equiv), di-tert-butyl dicarbonate (11.9 g, 54.5 mmol, 4.00 equiv), DMAP (332 mg, 2.72 mmol, 0.20 equiv), triethylamine (4.12 g, 40.8 mmol, 3.00 equiv), tert-BuOH (20 mL). The resulting solution was stirred overnight at 80 °C and quenched with water (50 mL) as described in Example 1, step 1. The residue was chromatographed to afford 260 mg (9% yield) of tert-butyl 4-chloro-1H-pyrazole-3-carboxylate as a yellow solid. LCMS (ESI, mass/charge): 203 [M+H]+.

Step 2: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzaldehyde

80°C, during the night CF ₃

A flask was charged with 4-bromo-2-(trifluoromethyl)benzaldehyde (2.00 g, 7.90 mmol, 1.00 equiv), 1,1'bis(diphenylphosphino)ferrocenepalladium dichloride (578 mg, 0.790 mmol, 0.10 equiv), potassium acetate (2.32 g, 23.7 mmol, 3.00 equiv), DMSO (30 mL), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.40 g, 9.45 mmol, 1.20 equiv) under nitrogen atmosphere. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3x30 mL) and the organic layers were combined, washed with brine (3x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed to afford 2.00 g (84% yield) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)2-(trifluoromethyl)benzaldehyde as a white solid. LCMS (ESI, m/z): 301 [M+H]+.

Step 3: Preparation of 4-(imidazo[1,2-a]pyridin-3-yl)-2-(trifluoromethyl)benzaldehyde

4-(Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzaldehyde (900 mg, 3.00 mmol, 1.00 equiv), 3-bromimidazo[1,2-a]pyridine (886 mg, 4.50 mmol, 1.50 equiv), tetrakis(triphenylphosphine)palladium (173 mg, 0.151 mmol, 0.05 equiv), potassium carbonate (1.24 g, 8.97 mmol, 3.00 equiv), 1,4-dioxane (10 mL), and water (10 mL) were placed in a flask under nitrogen atmosphere. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with DCM (3x30 ml) and the organic layers were combined, washed with brine (3x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

The residue was chromatographed to give 740 mg (85% yield) of 4-(imidazo[1,2-a]pyridin-3-yl)-2(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 291 [M+H]+.

Step 4: Preparation of tert-butyl 5-(4-(imidazo[1,2-a]pyridin-3-yl)-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

4-(imidazo[1,2-a]pyridin-3-yl)-2-(trifluoromethyl)benzaldehyde (290 mg, 1.00 mmol, 1.00 equiv), DCE (5 mL), and tert-butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (233 mg, 1.10 mmol, 1.10 equiv) were placed in a flask. The resulting solution was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (636 mg, 3.00 mmol, 3.00 equiv) was added as described in Example 2, step 3. The residue was chromatographed to afford 430 mg (88% yield) of tert-butyl 5-(4-(imidazo[1,2-a]pyridin3-yl)-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as a light

- 49 047826 yellow oil. LCMS (ESI, m/z): 487 [M+H]+.

Step 5: Preparation of 3-(4-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-3-(m-fluoromethyl)phenyl)imidazo[ 1 D-pyridine

A flask was charged with tert-butyl 5-(4-(imidazo[1,2-a]pyridin-3-yl)-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3-(4-((hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)-3-(trifluoromethyl)phenyl)imidazo[1,2a]pyridine (crude) as a yellow oil. LCMS (ESI, m/z): 387 [M+H] ⁺ .

Step 6: Preparation of m-butyl 4-chloro-1-(5-(4-(imidazo[1,2-a]pyridin-3-yl)-2-(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate

4-Nitrophenyl chloroformate (212 mg, 1.05 mmol, 1.20 equiv), tert-butyl 4-chloro-1H-pyrazole-3-carboxylate (212 mg, 1.05 mmol, 1.20 equiv) and DCM (5 mL) were placed in a flask. DIPEA (340 mg, 2.64 mmol, 3.00 equiv) was added at 0 °C. The resulting solution was stirred for 2 h at room temperature. 3-(4-((hexahydropyrrolo[3,4<]pyrrol-2(1 H)-yl)methyl)-3-(trifluoromethyl)phenyl)imidazo[1,2a]pyridine (340 mg, 0.881 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 mL) as described in Example 1, step 4. The residue was column chromatographed on silica gel to afford 274 mg (51% yield) of tert-butyl 4-chloro-1-(5-(4(imidazo[1,2-a]pyridin-3-yl)-2-(m-fluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 615 [M+H] ⁺ .

Step 7: Preparation of 4-chloro-1-(5-(4-(imidazo[1,2-a]pyridin-3-yl)-2-(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 4-chloro-1-(5-(4-(imidazo[1,2-a]pyridin-3-yl)-2-(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate (274 mg, 0.45 mmol, 1.00 equiv), DCM (5 mL), and TFA (1 mL) as described in Example 1, step 5. The crude product (301 mg) was purified by preparative HPLC to give 101.1 mg (41% yield). 4-chloro-1-(5-(4-(imidazo[1,2a]pyridin-3-yl)-2-(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazole-3carboxylic acid as a white solid. ^1H NMR (400 MHz, chloroform-d) δ 8.23 8.29 (m, 2H), 7.92 - 8.02 (m, 2H), 7.75 - 7.79 (m, 3H), 7.27 - 7.32 (m, 1H), 6.93 - 7.00 (m, 1H), 3.86 - 4.37 (m, 4H), 3.72 (br, 2H), 2.62 - 3.04 (m, 5H), 2.40 (br, 1H). LCMS (ESI, mass/charge): 559 [M+H] ⁺ .

Example 21: 1-(2-(4-chloro-3-ethoxybenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-III-pyrazole-3-carboxylic acid

Step 1: Preparation of di-ret-butyl-1H-pyrazole-1,3-dicarboxylate

- 50 047826

(Voc) ₂ O, DMAP, Et ₃ N, tert-BuOH

80°C, 2 hours.

Vos

Vi

1H-pyrazole-3-carboxylic acid (22.4 g, 200 mmol, 1.00 equiv), tert-butanol (100 mL), triethylamine (60.6 g, 599 mmol, 3.00 equiv), DMAP (4.88 g, 39.9 mmol, 0.20 equiv), and di-tert-butyl dicarbonate (174 g, 797 mmol, 4.00 equiv) were placed in a flask. The resulting solution was stirred for 2 h at 80 °C and quenched with water (100 mL) as described in Example 1, step 1, to give 62.5 g of 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (crude) as a brown oil. LCMS (ESI, mass/charge): 269 [M+H]+.

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

NaOH, MeOH, _H2O

PhD, 2 hours

1,3-Di-tert-butyl-1H-pyrazole-1,3-dicarboxylate (62.5 g, 233 mmol, 1.00 equiv), MeOH (240 mL), water (80 mL), and sodium hydroxide (14.0 g, 350 mmol, 1.50 equiv) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 2. The residue was column chromatographed on silica gel to afford 16.2 g (41% yield) of tert-butyl 1H-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H] ⁺ .

Step 3: Preparation of tert-butyl 8-(3-(tert-butoxycarbonyl)-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

Tert-butyl 1H-pyrazole-3-carboxylate (2.52 g, 15.0 mmol, 1.50 equiv), 4-nitrophenyl chloroformate (3.02 g, 15.0 mmol, 1.50 equiv), DCM (50 mL), and triethylamine (3.03 g, 29.9 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred for 2 h at room temperature. Tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.40 g, 9.99 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 4.16 g (96% yield) of tert-butyl 8-(3-(tert-butoxycarbonyl)-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate as a white solid. LCMS (ESI, m/z): 435 [M+H]+.

Step 4: Preparation of 1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-III-pyrazole-3-carboxylic acid

Tert-butyl 8-(3-(tert-butoxycarbonyl)-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1740 mg, 4.00 mmol, 1.00 equiv), DCM (15 mL), and TFA (5 mL) were placed in a flask. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to give 1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid (quantitative) 1116 mg as a yellow oil. LCMS (ESI, m/z): 279 [M+H]+.

Step 5: Obtaining 4-chloro-3-ethoxybenzaldehyde

To a flask were placed 4-chloro-3-hydroxybenzaldehyde (785 mg, 5.01 mmol, 1.00 equiv), DMF (10 mL), iododecane (1560 mg, 10.0 mmol, 2.00 equiv), and cesium carbonate (4890 mg, 15.0 mmol, 3.00 equiv). The resulting solution was stirred overnight at 40 °C and quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 x 20 mL), and the organic layers were combined, washed with

- 51 047826 brine (2x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 710 mg (77% yield) of 4-chloro-3-ethoxybenzaldehyde as a yellow oil. 1H NMR (300 MHz, Chloroformd) δ 9.94 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J=7.8 Hz, 1H), 4.20 (m, 2H), 1.51 (t, J=6.9 Hz, 3H).

Step 6: Preparation of 1-(2-(4-chloro-3-ethoxybenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-III-pyrazole-3-carboxylic acid

To a flask were placed 4-chloro-3-ethoxybenzaldehyde (92.5 mg, 0.501 mmol, 1.00 equiv) in DCE (10 mL), 1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid (278 mg, 1.00 mmol, 2.00 equiv), and triethylamine (152 mg, 1.50 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (318 mg, 1.50 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with saturated _NaHCO3 solution (10 mL) as described in Example 2, step 3. The crude product (500 mg) was purified by preparative HPLC to give 92.9 mg (41% yield) of 1-(2-(4-chloro-3-ethoxybenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-1-nitropyrazole-3-carboxylic acid as a white solid. 1H NMR (300 MHz, MeOH-d4) δ 8.06 (d, J=2.7 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.08 - 7.05 (m, 1H), 6.76 (d, J=2.7 Hz, 1H), 4 .34 (s, 2H), 4.14 - 4.07 (m, 2H), 3.86 - 3.69 (m, 4H), 3.44 (t, J=6.9 Hz, 2H), 3.28 (s, 2H), 2.07 (t, J=4.2 Hz, 2H), 1.89 - 1.77 (m, 4H), 1.41 (t, J=6.9 Hz, 3H). LCMS (ESI, m/z): 447 [M+H]+.

Example 22: 1-(1-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)methyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-III-pyrazole-3-carboxamide

Step 1: Preparation of 4-nitrophenyl-3-carbamoyl-III-pyrazole-1-carboxylate

A flask was charged with 1H-pyrazole-3-carboxamide (73.4 mg, 0.660 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (159 mg, 0.790 mmol, 1.20 equiv), DCM (10 mL), and triethylamine (200 mg, 1.98 mmol, 3.00 equiv) as described in Example 4, step 3 to give 182 mg of 4-nitrophenyl 3-carbamoyl 1H-pyrazole-1-carboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 277 [M+H]+.

Step 2: Preparation of tert-butyl 1-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

6-(Trifluoromethyl)-1-benzothiophene-2-carboxylic acid (0.492 g, 2.00 mmol, 1.00 equiv), tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate (0.720 g, 3.00 mmol, 1.50 equiv), DMF (10 mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium (1.52 g, 4.00 mmol, 2.00 equiv), and DIPEA (0.774 g, 6.00 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred overnight at room temperature and quenched with water (10 mL) as described in Example 14, step 7. The residue was column chromatographed on silica gel to give 800 mg (85% yield) of tert-butyl-1-(6

- 52 047826 (trifluoromethyl)benzo[b]thiophene-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate as a yellow solid. LCMS (ESI, m/z): 469 [M+H]+.

Step 3: Preparation of tert-butyl 1-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)methyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Tert-butyl 1-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (300 mg, 0.640 mmol, 1.00 equiv), THF (3 mL), and borane (1 M in THF solution, 2.56 mL, 2.56 mmol, 4.00 equiv) were placed in a flask. The resulting solution was stirred overnight at room temperature. MeOH (20 mL) was added and the resulting mixture was stirred at 60 °C for 1 h and quenched with water (20 mL). The resulting solution was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (1 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 200 mg (yield 69%) of tert-butyl 1-((6-trifluoromethyl-6-phenyl-1-yl-ethyl-6-diazaspiro-6-decane-6-carboxylate as a colorless oil. LCMS (ESI, m/z): 455 [M+H] ⁺ .

Step 4: Preparation of 1-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)methyl)-1,8-diazaspiro[4.5]decane

Tert-butyl 1-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)methyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.440 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to give 156 mg of 1-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)methyl)-1,8-diazaspiro[4.5]decane (quantitative) as a yellow oil. LCMS (ESI, m/z): 355 [M+H]+.

Step 5: Preparation of 1-(1-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)methyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrαzole-3-carboxamide

1-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)methyl)-1,8-diaαzaspiro[4.5]decane (156 mg, 0.440 mmol, 1.00 equiv), 4-nitrophenyl-3-carbamoyl-1H-pyrαzole-1-carboxylate (182 mg, 0.660 mmol, 1.50 equiv), DCM (10 mL), and triethylamine (133 mg, 1.32 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred overnight at room temperature and then quenched with water (20 mL) as described in Example 4, step 3. The crude product (200 mg) was purified by preparative HPLC to give 80.6 mg (37% yield) of 1-[(1-[[6-(trifluoromethyl)-1-benzothiophen-2-yl]methyl]-1,8-dia-zaspiro[4.5]decan-8-yl)carbonyl]-1H-pyrazole-3-carboxamide as a white solid. ¹ H NMR (300 MHz, Chloroform-d) δ 8.09 (d, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.20 (s, 1H), 6.91 (d, J=2.7 Hz, 1H), 6.64 (br, 1H), 5.47 (br, 1H), 4.60 - 4.47 (m, 2H), 3.96 (s, 2H), 3.15 (t, J=12.9 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H), 2.01 - 1.78 (m, 6H), 1.62 - 1.57 (m, 2H). LCMS (ESI, m/z): 492 [M+H]+.

Example 23: 1-(trans-5-(3-(pyrimidin-5-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)III-pyrazole-3-carboxylic acid

ABOUT

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

- 53 047826

A flask was charged with N-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equiv), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv), DMAP (4.35 g, 35.7 mmol, 0.20 equiv), triethylamine (54.1 g, 536 mmol, 3.00 equiv), and tert-butanol (200 mL). The resulting solution was stirred overnight at 65 °C and quenched with water (200 mL) as described in Example 1, step 1 to give 20.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, mass/charge): 169 [M+H-Boc] ⁺ .

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

1,3-Di-tert-butyl N-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), sodium hydroxide (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature and quenched with water (40 mL) as described in Example 1, step 2 to give 6.70 g of tert-butyl N-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate Ο ₂ Νγ^ ₀ ° ^2Ν Α O

O / Et ₃ N, DCM / —

k.t., 3 h. // θ

Tert-butyl 1-(4-nitrophenyl)-1-pyrazole-3-carboxylate (1.68 g, 9.99 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (3.03 g, 29.9 mmol, 3.00 equiv) were placed in a flask. 4-Nitrophenyl chloroformate (2.42 g, 12.0 mmol, 1.20 equiv) was added at 0 °C as described in Example 4, step 3 to give 3.33 g of 3-tert-butyl 1-(4-nitrophenyl)-1-pyrazole-1,3-dicarboxylate (crude) as a yellow solid.

Step 4: Preparation of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.00 g, 13.3 mmol, 1.00 equiv), MeOH (20 mL), and sodium borohydride (0.760 g, 20.1 mmol, 1.50 equiv) were placed in a flask. The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (40 mL), extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 15, step 4, to give 3.01 g of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopentaenoic acid (crude) as a white solid. LCMS (ESI, m/z): 228 [M+H]+.

Step 5: Preparation of tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopentaphenylpyrrole-3-carboxylate

Tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (1.00 g, 4.40 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (1.34 g, 13.2 mmol, 3.00 equiv) were placed in a flask. Methanesulfonyl chloride (0.608 g, 5.28 mmol, 1.20 equiv) was added dropwise at 0 °C as described in Example 11, step 3, to give 1.34 g of tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclo- 54 047826 penta[c]pyrrole-2(1H)-carboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 306 [M+H]+.

Step 6: Preparation of 3-(pyrimidin-5-yl)phenol

80°C, overnight

5-Bromopyrimidine (1.58 g, 10.0 mmol, 1.00 equiv), (3-hydroxyphenyl)boronic acid (2.07 g, 15.0 mmol, 1.50 equiv), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.731 g, 1.00 mmol, 0.10 equiv), potassium carbonate (4.14 g, 30.0 mmol, 3.00 equiv), ethylene glycol dimethyl ether (16 mL), and water (4 mL) were placed in a flask. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3x20 mL) and the organic layers were combined, washed with water (3x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel (1/1) to give 1.27 g (74% yield) of 3-(pyrimidin-5-yl)phenol as a yellow solid. LCMS (ESI, m/z): 173 [M+H]+.

Step 7: Preparation of tert-butyl (3aR,5s,6aS)-5-(3-(pyrimidin-5-yl)phenoxy)hexahydrocyclopentaMpyrrole-D-carboxylate

3-(pyrimidin-5-yl)phenol (206 mg, 1.20 mmol, 1.00 equiv), tert-butyl (3aR,5r,6aS)-5-(methanesulfonyloxy)-octahydrocyclopenta[c]pyrrole-2-carboxylate (366 mg, 1.20 mmol, 1.00 equiv), cesium carbonate (782 mg, 2.40 mmol, 2.00 equiv), and DMF (15 mL) were placed in a vessel. The resulting solution was stirred overnight at 100°C and quenched with water (10 mL) as described in Example 13, step 4. The residue was column chromatographed on silica gel to afford 320 mg (70% yield) of tert-butyl (3aR,5s,6aS)-5-(3-(pyrimidin-5-yl)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a yellow oil. LCMS (ESI, m/z): 382 [M+H] ⁺ .

Step 8: Preparation of (3aR,5s,6aS)-5-(3-(pyrimidin-5-yl)phenoxy)octahydrocyclopenta[c]pyrrole

Tert-Butyl (3aR,5s,6aS)-5-(3-(pyrimidin-5-yl)phenoxy)hexahydrocyclopentaphenylpyrrole-3-carboxylate (200 mg, 0.520 mmol, 1.00 equiv), TFA (2 mL) and DCM (5 mL) were added to a vessel. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5 to give 147 mg of (3aR,5s,6aS)-5-(3-(pyrimidin-5-yl)phenoxy)hexahydrocyclopentaphenylpyrrole as a yellow oil. LCMS (ESI, m/z): 282 [M+H]+.

Step 9: Preparation of tert-butyl 1-(trans-5-(3-(pyrimidin-5-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrαzole-3-carboxylate

(3aR,5s,6aS)-5-(3-(pyrimidin-5-yl)phenoxy)octahydrocyclopenta[c]pyrrole (147 mg, 0.520 mmol, 1.00 equiv), triethylamine (263 mg, 2.60 mmol, 5.00 equiv), 3-tert-butyl 1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (260 mg, 0.780 mmol, 1.50 equiv), and DCM (15 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 166 mg (67% yield) of tert-butyl 1-(trans-5-(3(pyrimidin-5-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrαzole-3-carboxylate as a white solid. LCMS (ESI, m/z): 476 [M+H]+.

- 55 047826

Step 10: Preparation of 1-(trans-5-(3-(pyrimidin-5-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1H-pyrazole-3-carboxylic acid

Tert-Butyl 1-((3aR,5s,6aS)-5-(3-(pyrimidin-5-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate (166 mg, 0.350 mmol, 1.00 equiv), TFA (2 mL), and DCM (5 mL) were placed in a vessel. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure as described in Example 1, step 5. The crude product was purified by preparative HPLC to afford 82.1 mg (56% yield) of 1-(trans-5-(3-(pyrimidin-5yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR: (300 MHz, MeOH-d ₄ ) δ 9.14 (s, 1H), 9.05 (s, 2H), 8.17 (d, J=9.3 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.08 - 6.98 (m, 1H), 6.80 (d, J=2.7 Hz, 1H), 5.17 - 5.08 (m, 1H), 4.35 - 3.51 (m, 4H), 3.08 - 2.88 (m, 2H), 2.28 - 2.15 (m, 2H), 2.08 - 1.92 (m, 2H). LCMS (ESI, mass/charge): 420 [M+H]+.

Example 24: 1 -((2 S,4 S)-2-methyl-4-(methyl(3 -(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1 ^pyrazole-3-carboxamide

Step 1: Preparation of tert-butyl (^^)-4-hydroxy-2-methylpiperidine-1-carboxylate and tert-butyl (2S,4R)-4-hydroxy-2-methylpiperidine-1-carboxylate

Tert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (10.0 g, 46.9 mmol, 1.00 equiv) and THF (36 mL) were placed in a flask. Sodium borohydride (1.07 g, 28.2 mmol, 0.60 equiv) and MeOH (12 mL) were added dropwise at 0 °C. The resulting solution was stirred for 1 h at 0 °C and quenched with water (50 mL) as described in Example 15, step 4. The crude product (11.0 g) was purified by preparative HPLC to give 4.90 g (49% yield) of tert-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate as a yellow oil (LCMS (ESI, w/z): 216 [M+H]+) and 4.10 g (41% yield) of tert-butyl (2S,4R)-4-hydroxy-2-methylpiperidine-1-carboxylate as a white solid LCMS (ESI, w/z): 216 [M+H] ⁺ .

Step 2: Preparation of tert-butyl (2S,4R)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

Tert-butyl (2S,4R)-4-hydroxy-2-methylpiperidine-1-carboxylate (600 mg, 2.79 mmol, 1.00 equiv), DCM (15 mL), and triethylamine (845 mg, 8.35 mmol, 3.00 equiv) were placed in a flask. Methanesulfonyl chloride (417 mg, 3.63 mmol, 1.30 equiv) was added dropwise at 0 °C as described in Example 11, step 3 to give 817 mg of tert-butyl (2S,4R)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 294 [M+H] ⁺ .

Step 3: Preparation of tert-butyl (2S,4S)-2-methyl-4-(methylamino)piperidine-1-carboxylate

Tert-butyl (2S,4R)-4-(methanesulfonyloxy)-2-methylpiperidine-1-carboxylate (817 mg, 2.78 mmol, 1.00 equiv), ACN (10 mL), and methylamine (2.2 mL, 27.8 mmol, 10.0 equiv, 40% in water) were placed in a flask. The resulting solution was stirred for 3 days at 60 °C and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 420 mg (66% yield) of tert-butyl (2S,4S)-2-methyl-4-(methylamino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 229 [M+H] ⁺ .

- 56 047826

Step 4: Preparation of ret-butyl (2S,4S)-2-methyl-4-(methyl(3-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

k.t., during the night

To a flask were placed 3-(trifluoromethyl)benzaldehyde (264 mg, 1.52 mmol, 1.00 equiv), tert-butyl (2S,4S)-2-methyl-4-(methylamino)piperidine-1-carboxylate (380 mg, 1.66 mmol, 1.10 equiv), DCE (10 mL), and triethylamine (460 mg, 4.55 mmol, 3.00 equiv). The resulting solution was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (967 mg, 4.56 mmol, 3.00 equiv) was added as described in Example 2, step 3 to give the crude product. The residue was column chromatographed on silica gel to afford 400 mg (68% yield) of tert-butyl (2S,4S)-2-methyl-4-(methyl(3(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 387 [M+H]+.

Step 5: Obtaining DO((3-(trifluoromethyl)benzyl)piperidin-4-amine)-X,2-dimethyl-X-(3-(trifluoromethyl)benzyl)piperidin-4-amine

Tert-butyl (2S,4S)-2-methyl-4-(methyl(3-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (400 mg, 1.04 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and concentrated hydrochloric acid (2.5 mL) were placed in a flask. The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to give 296 mg of (2S,4S)-N,2-dimethyl-N(3-(trifluoromethyl)benzyl)piperidin-4-amine (quantitative) as a yellow oil. LCMS (ESI, m/z): 287 [M+H] ⁺ .

Step 6: Preparation of (2S,4S)-2-methyl-4-(methyl(3-(mfluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride

(2S,4S)-N,2-dimethyl-N-(3-(trifluoromethyl)benzyl)piperidin-4-amine (296 mg, 1.03 mmol, 1.00 equiv), DCM (10 mL), and triphosgene (154 mg, 0.520 mmol, 0.50 equiv) were placed in a flask under nitrogen atmosphere. DIPEA (402 mg, 3.12 mmol, 3.00 equiv) was added dropwise at 0°C. The resulting solution was stirred for 3 h at room temperature and quenched with water (10 mL) as described in Example 1, step 3 to give 362 mg of (2S,4S)-2-methyl-4-(methyl(3-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride (crude) as a yellow oil. LCMS (ESI, m/z): 349 [M+H]+.

Step 7: Preparation of 1-((2S,4S)-2-methyl-4-(methyl(3-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-III-pyrazole-3-carboxamide

(2S,4S)-2-methyl-4-(methyl(3-(m-fluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride (181 mg, 0.520 mmol, 1.00 equiv), 1/3-pyrazole-3-carboxamide (86.6 mg, 0.780 mmol, 1.50 equiv), THF (10 mL), DMAP (12.7 mg, 0.104 mmol, 0.20 equiv), and DIPEA (201 mg, 1.56 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred overnight at 60°C and quenched with water (10 mL) as described in Example 1, step 4. The crude product (300 mg) was purified by preparative HPLC to give 54.6 mg (25% yield) of 1-((2S,4S)-2-methyl-4-(methyl(3-(m-fluoromethyl)benzyl)amino)piperidine-1-carbonyl)-III-pyrazole-3-carboxamide as a white semi-solid. ¹ H NMR (300 MHz, Chloroform-d) δ 8.09 (d, J=2.7 Hz, 1H), 7.60 (s, 1H), 7.53 - 7.51 (m, 2H), 7.46 - 7.41 (m, 1H), 6.90 (d, J=2.7 Hz, 1H), 6.68 (br, 1H ), 5.61 (br, 1H), 4.32 - 4.21 (m, 1H), 4.14 - 4.07 (m, 1H), 3.64 (br, 2H), 3.52 - 3.42 (m, 1H), 2.82 (br, 1H), 2.20 (s, 3H), 2.07 - 2.03 (m, 2H), 1.83 - 1.73 (m, 2H), 1.48 (d, J=6.3 Hz, 3H). LCMS (ESI, m/z): 424 [M+H]+.

- 57 047826

Example 25: 1-(trans-5-(3-(oxazol-2-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl 1H-pyrazole-1,3-dicarboxylate

A flask was charged with N-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equiv), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv), DMAP (4.35 g, 35.7 mmol, 0.20 equiv), triethylamine (54.1 g, 536 mmol, 3.00 equiv), and tert-butanol (200 mL). The resulting solution was stirred overnight at 65 °C and quenched with water (200 mL) as described in Example 1, step 1, to give 20.0 g (crude) di-tert-butyl N-pyrazole-1,3-dicarboxylate as a yellow oil. LCMS (ESI, mass/charge): 169 [M+H-Boc] ⁺ .

Step 2: Preparation of tert-butyl 1H-pyrazole-3-carboxylate

Di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), sodium hydroxide (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature and quenched with water (40 mL) as described in Example 1, step 2 to give 6.70 g of tert-butyl 1H-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate

Tert-butyl N-pyrazole-3-carboxylate (1.68 g, 9.99 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (3.03 g, 29.9 mmol, 3.00 equiv) were placed in a flask. 4-Nitrophenyl chloroformate (2.42 g, 12.0 mmol, 1.20 equiv) was added at 0 °C. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure as described in Example 4, step 3, to give 3.33 g of 3-(tert-butyl)-1-(4-nitrophenyl)-N-pyrazole-1,3-dicarboxylate (crude) as a yellow solid.

Step 4: Preparation of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

(3aR,6aS)-tert-butyl 5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.00 g, 13.3 mmol, 1.00 equiv), MeOH (20 mL), and sodium borohydride (0.760 g, 20.1 mmol, 1.50 equiv) were placed in a flask. The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure as described in Example 15, step 4, to give 3.01 g of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (crude) as a white solid. LCMS (ESI, w/z): 228 [M+H]+.

Step 5: Preparation of tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopentaphenylpyrrole-3-carboxylate

- 58 047826

Tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (200 mg, 0.881 mmol, 1.00 equiv), triethylamine (267 mg, 2.64 mmol, 3.00 equiv), and DCM (15 mL) were placed in a flask. Methanesulfonyl chloride (152 mg, 1.32 mmol, 1.50 equiv) was added dropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature. The mixture was quenched with water (10 mL), extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 11, step 3, to give 268 mg of tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (crude) as a yellow oil.

Step 6: Preparation of 3-(oxazol-2-yl)phenol

1,3-Oxazole (1.00 g, 14.5 mmol, 1.00 equiv), 3-bromophenol (1.25 g, 7.25 mmol, 0.50 equiv), potassium carbonate (6.00 g, 43.5 mmol, 3.00 equiv), pivalic acid (0.592 g, 5.80 mmol, 0.40 equiv), and toluene (100 mL) were placed in a flask. Palladium(II) acetate (0.326 g, 1.45 mmol, 0.10 equiv) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (1.35 g, 2.90 mmol, 0.20 equiv) were added under nitrogen atmosphere. The resulting solution was stirred overnight at 110°C. The mixture was quenched with water (20 mL), extracted with EtOAc (3 x 50 mL), and the organic layers were combined, washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 0.220 g (9% yield) of 3-(oxazol-2-yl)phenol as a yellow oil. LCMS (ESI, m/z): 162 [M+H]+.

Step 7: Preparation of tert-butyl (3aR,5s,6aS)-5-(3-(oxazol-2-yl)phenoxy)hexahydrocyclopenta-pyrrole-2(1^-carboxylate

80°C, 2 hours.

3-(Oxazol-2-yl)phenol (142 mg, 0.88 mmol, 1.00 equiv), cesium carbonate (860 mg, 2.63 mmol, 3.00 equiv), tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopenta-pyrrole-III-carboxylate (268 mg, 0.881 mmol, 1.00 equiv), and DMF (15 mL) were placed in a flask. The resulting solution was stirred for 2 h at 80°C. The mixture was quenched with water (10 mL), extracted with EtOAc (3 x 20 mL), and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure as described in Example 13, step 4. The residue was column chromatographed on silica gel to afford 105 mg (32% yield) of tert-butyl (3aR,5s,6aS)-5-(3-(oxazol-2-yl-enoxy-5-oxahydrocyclopenta-pyrrole-III-carboxylate) as a yellow oil. LCMS (ESI, m/z): 371 [M+H]+.

Step 8: Preparation of 2-(3-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)oxazole

Tert-butyl (3aR,5s,6aS)-5-(3-(oxazol-2-yl-phenyl-2-oxahydrocyclopenta-pyrrole-1-yl)-carboxylate (105 mg, 0.284 mmol, 1.00 equiv), TFA (2 mL), and DCM (10 mL) were charged into a vessel as described in Example 1, step 5 to give 76.6 mg of 2-(3-(((3aR,5s,6aS)octahydrocyclopenta-pyrrole-1-yl)-2-phenyl-2-oxazole (quantitative) as a yellow oil. LCMS (ESI, m/z): 271 [M+H]+.

Step 9: Preparation of tert-butyl 1-((3aR,5s,6aS)-5-(3-(oxazol-2- 59 047826 yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate

k.t., during the night

2-(3-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)phenyl)oxazole (76.6 mg, 0.284 mmol, 1.00 equiv), triethylamine (115 mg, 1.14 mmol, 4.00 equiv), 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (142 mg, 0.426 mmol, 1.50 equiv), and DCM (15 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature. The mixture was quenched with water (10 mL), extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 4, step 3. The residue was column chromatographed on silica gel to give 108 mg (82% yield) of tert-butyl 1-((3aR,5s,6aS)-5-(3-(oxazol-2yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 465 [M+H]+.

Step 10: Preparation of 1-(trans-5-(3-(oxazol-2-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1-pyrazole-3-carboxylic acid

Tert-Butyl 1-((3aR,5s,6aS)-5-(3-(oxazol-2-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate (108 mg, 0.232 mmol, 1.00 equiv), TFA (2 mL), and DCM (10 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5. The crude product was purified by preparative HPLC to afford 71.0 mg (75% yield) of 1-(trans-5-(3-(oxazol-2-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1I NMR: (300 MHz, MeOH-d ₄ ) δ 8.17 (d, J=2.7 Hz, 1I), 8.02 - 7.95 (m, 1I), 7.67 - 7.56 (m, 1I), 7.56 - 7.49 (m, 1I), 7.45 - 7.37 (m, 1I), 7.31 - 7.27 (m, 1I), 7.10 - 6.99 (m, 1I), 6.76 (d, J=2.7 Hz, 1I), 5.14 - 5.05 (m, 1I), 4.30 - 3.82 (br, 3I), 3.82 - 3.57 (br, 1I), 3.11 - 2.84 (br, 2I), 2.30 - 2.11 (m, 2I), 2.11 - 1.89 (m, 2I). LCMS (ESI, mass/charge): 409 [M+H]+.

Example 26: 4-chloro-1-(2-(3-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid

ABOUT

Step 1: Obtaining 3-chloro-2-(trifluoromethyl)benzaldehyde

A flask was charged with 1-bromo-3-chloro-2-(trifluoromethyl)benzene (500 mg, 1.94 mmol, 1.00 equiv) and THF (20 mL) under nitrogen atmosphere. n-Butyllithium (0.93 mL, 2.32 mmol, 1.20 equiv, 2.5 M in hexane) was added dropwise at -78 °C. The resulting solution was stirred for 2 h at -78 °C. DMF (10 mL) was added. The resulting solution was stirred for 2 h at -78 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to afford 130 mg (32% yield) of 3-chloro-2-(trifluoromethyl)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 209 [M+I]+.

Step 2: Preparation of tert-butyl 4-chloro-1H-pyrazole-3-carboxylate

- 60 047826

A flask was charged with 4-chloro-1H-pyrazole-3-carboxylic acid (4.00 g, 27.4 mmol, 1.00 equiv), tert-butanol (50 mL), di-tert-butyl dicarbonate (21.5 g, 98.6 mmol, 3.60 equiv), DMAP (468 mg, 3.83 mmol, 0.14 equiv), and triethylamine (8.30 g, 82.2 mmol, 3.00 equiv). The resulting solution was stirred overnight at 65°C and quenched with water (50 mL) as described in Example 1, step 1. The residue was column chromatographed on silica gel to afford 520 mg (9% yield) of tert-butyl 4-chloro-1H-pyrazole-3-carboxylate as a yellow solid. LCMS (ESI, m/z): 203 [M+H]+.

Step 3: Preparation of tert-butyl 8-(3-(tert-butoxycarbonyl)-4-chloro-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

Tert-butyl 4-chloro-1H-pyrazole-3-carboxylate (355 mg, 1.75 mmol, 1.20 equiv) was placed in a flask.

DCM (20 mL), 4-nitrophenyl chloroformate (442 mg, 2.19 mmol, 1.50 equiv) and DIPEA (565 mg, 4.38 mmol, 3.00 equiv) were added. The resulting solution was stirred for 3 h at room temperature. tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (350 mg, 1.46 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 mL). The mixture was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel to afford 650 mg (95% yield) of tert-butyl 8-(3-(tert-butoxycarbonyl)-4-chloro-1N-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate as a yellow oil. LCMS (ESI, m/z): 469 [M+H] ⁺ .

Step 4: Preparation of 4-chloro-1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid

Tert-butyl 8-(3-(tert-butoxycarbonyl)-4-chloro-1-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (650 mg, 1.39 mmol, 1.00 equiv), DCM (10 mL), and TFA (3 mL) were charged to a flask as described in Example 1, step 5 to give 4-chloro-1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-1-pyrazole-3-carboxylic acid (quantitative) as a yellow oil. LCMS (ESI, m/z): 313 [M+H] ⁺ .

Step 5: Preparation of 4-chloro-1-(2-(3-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8carbonyl)-1-pyrazole-3-carboxylic acid

3-Chloro-2-(trifluoromethyl)benzaldehyde (77.8 mg, 0.374 mmol, 1.00 equiv), DCE (20 mL), 4-chloro-1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid (140 mg, 0.449 mmol, 1.20 equiv), and triethylamine (113 mg, 1.12 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (238 mg, 1.12 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with saturated _NaHCO3 solution (20 mL) as described in Example 2, step 3. The crude product (200 mg) was purified by preparative HPLC to give 10.8 mg (6% yield) of 4-chloro-1(2-(3-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1I NMR (300 MHz, MeOH-d ₄ ) δ 8.13 (s, 1I), 7.90 - 7.88 (m, 1I), 7.82 - 7.80 (m, 1I), 7.57 - 7.52 (m, 1I), 4.26 (br, 2I), 3.93 - 3.79 (m, 2I), 3 .69 - 3.57 (m, 2I), 3.14

- 61 047826

3.07 (m, 2H), 2.99 - 2.84 (m, 2H), 1.94 (t, J=7.2 Hz, 2H), 1.84 - 1.72 (m, 4H). LCMS (ESI, m/z): 505 [M+H]+.

Example 27: 1-(4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1-carbonyl)-III-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

The flask was charged with 1/3-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equiv.), DMAP (2.18 g,

17.9 mmol, 0.20 equiv), triethylamine (27.1 g, 268 mmol, 3.00 equiv), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equiv), and tert-butanol (100 mL). The resulting solution was stirred for 4 h at 80 °C and quenched with water (50 mL) as described in Example 1, step 1, to give 25.0 g of 1,3-di-tert-butyl N-pyrazole-1,3-dicarboxylate (crude) as a red oil. LCMS (ESI, m/z): 269 [M+H]+.

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

1,3-Di-tert-butyl-III-pyrazole-1,3-dicarboxylate (25.0 g, 93.3 mmol, 1.00 equiv), sodium hydroxide (5.60 g, 140 mmol, 1.50 equiv), water (80 mL), and MeOH (240 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and quenched with water (30 mL) as described in Example 1, step 2. The residue was column chromatographed on silica gel to afford 10.0 g (64% yield) tert-butyl-III-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate

Tert-butyl 1-(4-nitrophenyl)-1,3-pyrazole-3-carboxylate (2.00 g, 11.9 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (2.87 g, 14.2 mmol, 1.20 equiv), triethylamine (3.61 g, 35.7 mmol, 3.00 equiv), and DCM (20 mL) were placed in a flask. The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to give 3.90 g of 3-tert-butyl 1-(4-nitrophenyl)-1-pyrazole-1,3-dicarboxylate (crude) as a yellow solid. LCMS (ESI, w/z): 334 [M+H] ⁺ .

Step 4: Obtaining bis(4-chlorophenyl)iodonium tetrafluoroborate

To a flask were placed t-CPBA (3.18 g, 18.4 mmol, 1.10 equiv) and DCM (25 mL). Boron trifluoride ether complex (7.16 g, 50.4 mmol, 3.00 equiv) and 1-chloro-4-iodobenzene (4.00 g, 16.8 mmol, 1.00 equiv) were added at 0 °C. The resulting solution was stirred for 0.5 h at room temperature. (4-Chlorophenyl)boronic acid (2.89 g, 18.5 mmol, 1.10 equiv) was added at 0 °C as described in Example 19, step 1. The resulting solution was stirred for 0.5 h at room temperature and concentrated under reduced pressure. The crude product was triturated with ethyl ether to give 5.50 g (75% yield) of bis(4-chlorophenyl)iodonium tetrafluoroborate as a solid.

- 62 047826 white. LCMS (ESI, mass/charge): 349 [M-BF4] ⁺ .

Step 5: Obtaining 3-chloro-5-(4-chlorophenoxy)benzaldehyde np

40°C, overnight

Potassium tert-butoxide (0.840 g, 7.50 mmol, 1.50 equiv) and THF (20 mL) were placed in a flask. 3-Chloro-5-hydroxybenzaldehyde (780 mg, 5.00 mmol, 1.00 equiv) was added at 0 °C and the reaction mixture was stirred for 20 min. Bis(4-chlorophenyl)iodonium tetrafluoroborate (2.62 g, 6.00 mmol, 1.20 equiv) was added at 0 °C. The resulting solution was stirred overnight at 40 °C and quenched with water (20 mL).

The mixture was extracted with DCM (3x40 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 300 mg (19% yield) of 3-chloro-5-(4-chlorophenoxy)benzaldehyde as a colorless oil. LCMS (ESI, m/z): 267 [M+H] ⁺ .

Step 6: Preparation of (3-chloro-5-(4-chlorophenoxy)phenyl)-MeOH

A flask was charged with 3-chloro-5-(4-chlorophenoxy)benzaldehyde (310 mg, 1.16 mmol, 1.00 equiv), MeOH (15 mL), and sodium borohydride (129 mg, 3.41 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at room temperature, then quenched with water (20 mL) as described in Example 15, step 4, to give 303 mg (97% yield) of (3-chloro-5-(4-chlorophenoxy)phenyl)-MeOH as a colorless oil. LCMS (ESI, m/z): 269 [M+H] ⁺ .

Step 7: Preparation of 1-(bromomethyl)-3-chloro-5-(4-chlorophenoxy)benzene

(3-Chloro-5-(4-chlorophenoxy)phenyl)-MeOH (303 mg, 1.13 mmol, 1.00 equiv) and DCM (15 mL) were placed in a flask. Phosphorus tribromide (610 mg, 2.25 mmol, 2.00 equiv) was added at 0 °C. The resulting solution was stirred overnight at room temperature, then quenched with water (20 mL). The resulting solution was extracted with DCM (3 x 40 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 200 mg (54% yield) of 1-(bromomethyl)-3-chloro-5-(4-chlorophenoxy)benzene as a yellow oil. LCMS (ESI, mass/charge): 331 [M+H] ⁺ .

Step 8: Preparation of tert-butyl 4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1-carboxylate

Tert-butyl 4-hydroxypiperidine-1-carboxylate (183 mg, 0.910 mmol, 1.50 equiv) and DMF (5 mL) were placed in a flask. Sodium hydride (72.8 mg, 60% in mineral oil, 1.82 mmol, 3.00 equiv) was added at 0 °C. The mixture was stirred at 0 °C for 5 min. 1-(Bromomethyl)-3-chloro-5-(4chlorophenoxy)benzene (200 mg, 0.606 mmol, 1.00 equiv) was added at 0 °C. The resulting solution was stirred overnight at room temperature and then quenched with water (10 mL) as described in Example 15, step 7. The residue was column chromatographed on silica gel to afford 150 mg (55% yield) of tert-butyl 4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 452 [M+H] ⁺ .

Step 9: Preparation of 4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine

- 63 047826

Tert-butyl 4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1-carboxylate (150 mg, 0.330 mmol, 1.00 equiv), DCM (10 mL), and TFA (3 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure to give 117 mg of 4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine (quantitative) as a yellow oil. LCMS (ESI, m/z): 352 [M+H]+.

Step 10: Preparation of tert-butyl-1-(4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1carbonyl)-1^pyrazole carboxylate

k.t., during the night

4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine (117 mg, 0.330 mmol, 1.00 equiv), 3-tert-butyl 1-(4-nitrophenyl)-3-pyrazole-1,3-dicarboxylate (166 mg, 0.500 mmol, 1.50 equiv), DCM (10 mL), and triethylamine (100 mg, 0.990 mmol, 3.00 equiv) were placed in a flask. The resulting solution was stirred overnight at room temperature and quenched with water (10 mL) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 160 mg (88% yield) of tert-butyl 1-(4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 546 [M+H] ⁺ .

Step 11: Preparation of 1-(4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1-carbonyl)-Spyrazole-3-carboxylic acid

O O

A flask was charged with tert-butyl 1-(4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1-carbonyl)-1-pyrazole-3-carboxylate (160 mg, 0.290 mmol, 1.00 equiv), DCM (10 mL), and TFA (3 mL) as described in Example 1, step 5. The crude product (200 mg) was purified by preparative HPLC to give 60.7 mg (42% yield) of 1-(4-((3-chloro-5-(4-chlorophenoxy)benzyl)oxy)piperidine-1-carbonyl)-pyrazole-3-carboxylic acid as a yellow oil. 1H NMR (300 MHz, MeOH-d ₄ ) δ 8.05 (d, J=2.7 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.15 (s, 1H), 7.04 - 6.99 (m, 2H), 6.92 - 6.89 (m, 2H), 6.76 (d, J=2, 7 Hz, 1H), 4.55 (s, 2H), 4.00 (br, 2H), 3.76 - 3.71 (m, 1H), 3.70 - 3.54 (m, 2H), 2.03 - 1.96 (m, 2H), 1.79 - 1.68 (m, 2H). LCMS (ESI, mass/charge): 490 [M+H] ⁺ .

Example 28: 1-(trans-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-III-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-III-pyrazole-1,3-dicarboxylate

The flask was charged with 1/3-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equiv.), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv.), DMAP (4.35 g, 35.7 mmol, 0.20 equiv.), triethylamine (54.1 g, 536

- 64 047826 mmol, 3.00 equiv) and tert-butanol (200 mL). The resulting solution was stirred overnight at 65 °C and quenched with water (200 mL) as described in Example 1, step 1 to give 20.0 g of 1,3-di-tert-butyl-N-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 169 [M+H-Boc] ⁺ .

Step 2: Obtaining tert-butyl-III-pyrazole-3-carboxylate

1,3-Di-tert-butyl N-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), sodium hydroxide (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature and quenched with water (40 mL) as described in Example 1, step 2 to give 6.70 g of tert-butyl N-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate

Tert-butyl 1H-pyrazole-3-carboxylate (1.68 g, 9.99 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (3.03 g, 29.9 mmol, 3.00 equiv) were placed in a flask. 4-Nitrophenyl chloroformate (2.42 g, 12.0 mmol, 1.20 equiv) was added at 0 °C as described in Example 4, step 3, to give 3.33 g of 3-tert-butyl 1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (crude) as a yellow solid.

Step 4: Preparation of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate

(3aR,6aS)-tert-butyl 5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.00 g, 13.3 mmol, 1.00 equiv), MeOH (20 mL), and sodium borohydride (0.760 g, 20.1 mmol, 1.50 equiv) were placed in a flask. The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure as described in Example 15, step 4, to give 3.01 g of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (crude) as a white solid. LCMS (ESI, w/z): 228 [M+H]+.

Step 5: Preparation of tert-butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopentaphenylcarboxylate

Tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (2.27 g, 9.99 mmol, 1.00 equiv), 4-nitrobenzoic acid (6.68 g, 40.0 mmol, 4.00 equiv), triphenylphosphine (10.5 g, 40.0 mmol, 4.00 equiv), and THF (30 mL) were placed in a flask. Diethyl azodicarboxylate (6.96 g, 40.0 mmol, 4.00 equiv) was added dropwise at 0°C. The resulting solution was stirred overnight at room temperature under nitrogen and quenched with water (50 mL) as described in Example 15, step 5. The residue was column chromatographed on silica gel to afford 2.36 g (62% yield) of tert-butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a white solid. LCMS (ESI, m/z): 377 [M+H]+.

Step 6: Preparation of tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate

- 65 047826

Tert-butyl (3aR,5s,6aS)-5-((4-nigrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.36 g, 6.27 mmol, 1.00 equiv), MeOH (30 mL), potassium carbonate (2.60 g, 18.8 mmol, 3.00 equiv), and water (5 mL) were placed in a flask. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure as described in Example 15, step 6, to give 1.31 g of (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (crude) as a white solid. LCMS (ESI, mass/charge): 228 [M+H]+.

Step 7: Obtaining 1-(bromomethyl)-3-methyl-2-(trifluoromethyl)benzene

The flask was charged with 1-chloro-3-methyl-2-(trifluoromethyl)benzene (800 mg, 4.11 mmol, 1.00 equiv), dibenzoyl peroxide (264 mg, 1.03 mmol, 0.250 equiv), 1-bromo-2,5-pyrrolidinedione (956 mg, 5.37 mmol, 1.30 equiv), and carbon tetrachloride (15 mL). The resulting solution was stirred overnight at 60 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL), and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 400 mg (yield 36%) of 1-(bromomethyl)-3-methyl-2-(trifluoromethyl)benzene as a yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.60 - 7.38 (m, 3H), 4.67 (br, 2H).

Step 8: Preparation of tert-butyl (3aR,5s,6aS)-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)hexahydrocyclopentaenoic acid-carboxylate

Tert-butyl (3aR,5s,6aS)-5-hydroxy-octahydrocyclopenta[c]pyrrole-2-carboxylate (227 mg, 1.00 mmol, 1.00 equiv) and DMF (15 mL) were placed in a flask. Sodium hydride (60% in oil, 80.0 mg, 2.00 mmol, 2.00 equiv) was then added at 0°C.

The resulting solution was stirred for 0.5 h at room temperature. Then 1-(bromomethyl)-3-methyl-2-(trifluoromethyl)benzene (228 mg, 0.830 mmol, 0.800 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 mL) as described in Example 15, step 7. The residue was column chromatographed on silica gel to afford 85.0 mg (24% yield) of tert-butyl (3aR,5s,6aS)-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)hexahydrocyclopentaphenylpyrrole-OH-carboxylate as a yellow oil. LCMS (ESI, m/z): 420 [M+H]+.

Step 9: Preparation of (3aR,5s,6aS)-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta-pyrrole

Tert-butyl (3aR,5s,6aS)-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-OCT-carboxylate (85.0 mg, 0.200 mmol, 1.00 equiv), TFA (2 mL), and DCM (5 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure. This afforded 65.0 mg of (3aR,5s,6aS)-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole (quantitative) as a yellow solid. LCMS (ESI, m/z): 320 [M+H]+.

Step 10: Preparation of tert-butyl 1-((3aR,5s,6aS)-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate

- 66 047826

(3aR,5s,6aS)-5-((3-chloro-2(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole (65.0 mg, 0.200 mmol, 1.00 equiv), triethylamine (124 mg, 1.23 mmol, 6.00 equiv), 3-tert-butyl 1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (99.9 mg, 0.300 mmol, 1.50 equiv), and DCM (15 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature. The mixture was quenched with water (10 mL) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 50.0 mg (48% yield) of tert-butyl 1((3aR,5s,6aS)-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 514 [M+H]+.

Step 11: Preparation of 1-(trans-5-((3-chloro-2-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1-D-pyrazole-3-carboxylic acid

Tert-Butyl 1-((3aR,5s,6aS)-5-(3-chloro-2-(trifluoromethyl)benzyloxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate (50.0 mg, 0.100 mmol, 1.00 equiv), TFA (2 mL), and DCM (5 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5. The crude product was purified by preparative HPLC to afford 30.3 mg (68% yield) of 1-(trans-5-((3-chloro-2(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1I NMR (400 MHz, MeOH-d ₄ ) δ 8.15 (d, J=4.0 Hz, 1I), 7.67-7.61 (m, 1I), 7.55-7.48 (m, 2I), 6.74 (d, J=2.8 Hz, 1I), 4.64 (d, J=2.0 Hz, 2I), 4.25-4.19 (m, 1I), 4.15-3.48 (m, 4I), 2.90 (br, 2I), 2.15-2.05 (m, 2I), 1.85-1.75 (m, 2I). LCMS (ESI, m/z): 458 [M+H] ⁺ .

Example 29: 1-(trans-5-(2-(1H-pyrazol-1-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl-1H-pyrazole-1,3-dicarboxylate

1H-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equiv), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv), DMAP (4.35 g, 35.7 mmol, 0.20 equiv), triethylamine (54.1 g, 536 mmol, 3.00 equiv), and tert-butanol (200 mL) were placed in a flask. The resulting solution was stirred overnight at 65 °C and quenched with water (200 mL) as described in Example 1, step 1 to give 20.0 g of 1,3-di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, mass/charge): 169 [M+I-Vos]+.

Step 2: Preparation of tert-butyl-1H-pyrazole-3-carboxylate

1,3-Di-tert-butyl-1H-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), sodium hydroxide (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL) were placed in a flask. The resulting solution was

- 67 047826 was stirred overnight at room temperature and quenched with water (40 mL) as described in Example 1, step 2 to give 6.70 g of tert-butyl 1H-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate

N-(1H-pyrazol-3-yl)methanesulfonamide (1.68 g, 9.99 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (3.03 g, 29.9 mmol, 3.00 equiv) were placed in a flask. 4-Nitrophenyl chloroformate (2.42 g, 12.0 mmol, 1.20 equiv) was added at 0 °C. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to give 3.33 g of 3-(tert-butyl)-1-(4-nitrophenyl)-1Hpyrazole-1,3-dicarboxylate (crude) as a yellow solid.

Step 4: Obtaining 2-(III-pyrazol-1-yl)phenol

2-Iodophenol (2.00 g, 9.09 mmol, 1.00 equiv), 1/3-pyrazole (0.741 g, 10.9 mmol, 1.20 equiv), potassium carbonate (3.15 g, 22.8 mmol, 2.50 equiv), copper(!) iodide (433 mg, 2.27 mmol, 0.25 equiv), dioxane (8 mL), and water (8 mL) were placed in a flask under N ₂ . The resulting solution was stirred for 5 h at 100 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL), and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 700 mg (48% yield) of 2-(N-pyrazol-1-yl)phenol as a light yellow oil. LCMS (ESI, m/z): 161 [M+H] ⁺ .

Step 5: Preparation of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

(3aR,6aS)-tert-butyl 5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.00 g, 13.3 mmol, 1.00 equiv), MeOH (20 mL), and sodium borohydride (0.760 g, 20.1 mmol, 1.50 equiv) were placed in a flask. The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure as described in Example 15, step 4, to give 3.01 g of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (crude) as a white solid. LCMS (ESI, m/z): 228 [M+H]+.

Step 6: Preparation of tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

ClV /V Et ₃ N, DCM S.

^H0 H k.t., 3h / oh

Tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (1.00 g, 4.40 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (1.34 g, 13.2 mmol, 3.00 equiv) were placed in a flask. Methanesulfonyl chloride (0.608 g, 5.28 mmol, 1.20 equiv) was added dropwise at 0°C. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to give 1.34 g of tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole 2(1H)-carboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 306 [M+H]+.

Step 7: Preparation of tert-butyl (3aR,5s,6aS)-5-(2-(1H-pyrazol-1-yl)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

- 68 047826

2-(1H-pyrazol-1-yl)phenol (160 mg, 1.00 mmol, 1.00 equiv), (3aR,5r,6aS)-methylsulfonyloxy-5-(methylsulfonyloxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (305 mg, 1.00 mmol, 1.00 equiv), potassium carbonate (652 mg, 2.00 mmol, 2.00 equiv), and DMF (15 mL) were placed in a vessel. The resulting solution was stirred overnight at 100°C and quenched with water (20 mL) as described in Example 13, step 4. The residue was column chromatographed on silica gel to afford 313 mg (85% yield) of tert-butyl (3aR,5s,6aS)-5-(2-(1H-pyrazol-1-yl)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a light yellow oil. LCMS (ESI, m/z): 370 [M+H]+.

Step 8: Preparation of (3aR,5s,6aS)-5-(2-(1H-pyrazol-1-yl)phenoxy)octahydrocyclopenta[c]pyrrole

A flask was charged with tert-butyl (3aR,5s,6aS)-5-(2-(1H-pyrazol-1-yl)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (313 mg, 0.850 mmol, 1.00 equiv), TFA (2 mL), and DCM (5 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5, to give 228 mg of (3aR,5s,6aS)-5-(2-(1H-pyrazol-1-yl)phenoxy)octahydrocyclopenta[c]pyrrole (quantitative) as a light yellow oil. LCMS (ESI, m/z): 270 [M+H] ⁺ .

Step 9: Preparation of tert-butyl 1-((3aR,5s,6aS)-5-(2-(1H-pyrazol-1yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate

(3aR,5s,6aS)-5-(2-(1H-pyrazol-1-yl)phenoxy)-octahydrocyclopenta[c]pyrrole (228 mg, 0.850 mmol, 1.00 equiv), triethylamine (429 mg, 4.25 mmol, 5.00 equiv), 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (426 mg, 1.28 mmol, 1.50 equiv), and DCM (15 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature. The mixture was quenched with water (10 mL), extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 4, step 3. The residue was column chromatographed on silica gel to give 295 mg (75% yield) of tert-butyl 1-((3aR,5s,6aS)-5-(2-(1H-pyrazol-1yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate as a colorless oil. LCMS (ESI, m/z): 464 [M+H] ⁺ .

Step 10: Preparation of 1-(trans-5-(2-(1H-pyrazol-1-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1H-pyrazole-3-carboxylic acid

Tert-butyl 1-((3aR,5s,6aS)-5-(2-(1H-pyrazol-1-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate (166 mg, 0.360 mmol, 1.00 equiv), TFA (2 mL) and DCM (5 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure. The crude product was dissolved in saturated NaHCO3 solution (10 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 1, step 5. The crude product

- 69 047826 was purified by preparative HPLC to give 61.2 mg (42% yield) of 1-(trans-5-(2-(1H-pyrazol1-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR: (300 MHz, MeOH-d ₄ ) δ 8.25 (d, J=2.7 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.57 - 7.54 (m, 1H), 7.41 - 7.33 (m, 1H), 7.24 - 7.19 (m, 1H), 7.12 - 7.05 (m, 1H), 6.79 (d, J=2.7 Hz, 1H), 6.50 (t, J=2.1 Hz, 1H), 5.13 - 5.08 (m, 1H), 4.35 - 3.41 (m, 4H), 2.82 (br, 2H), 2.21 - 2.11 (m, 2H), 2.01 - 1.89 (m, 2H). LCMS (ESI, mass/charge): 430 [M+Na]+.

Example 30: 1-(trans-5-(3-(pyrimidin-4-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)III-pyrazole-3-carboxylic acid

Step 1: Preparation of di-tert-butyl 1H-pyrazole-1,3-dicarboxylate

To a flask were placed 1H-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equiv), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equiv), DMAP (4.35 g, 35.7 mmol, 0.20 equiv), triethylamine (54.1 g, 536 mmol, 3.00 equiv), and tert-butanol (200 mL). The resulting solution was stirred overnight at 65 °C and quenched with water (200 mL) as described in Example 1, step 1, to give 20.0 g of di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, mass/charge): 169 [M+H-Boc]+.

Step 2: Preparation of tert-butyl 1H-pyrazole-3-carboxylate

A flask was charged with di-tert-butyl 1H-pyrazole-1,3-dicarboxylate (20.0 g, 74.6 mmol, 1.00 equiv), MeOH (80 mL), sodium hydroxide (10.0 g, 250 mmol, 3.35 equiv), and water (40 mL). The resulting solution was stirred overnight at room temperature and quenched with water (40 mL) as described in Example 1, step 2 to give 6.70 g of tert-butyl 1H-pyrazole-3-carboxylate (crude) as a yellow solid. LCMS (ESI, m/z): 169 [M+H]+.

Step 3: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate

Tert-Butyl 1H-pyrazole-3-carboxylate (1.68 g, 9.99 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (3.03 g, 29.9 mmol, 3.00 equiv) were placed in a flask. 4-Nitrophenyl chloroformate (2.42 g, 12.0 mmol, 1.20 equiv) was added at 0 °C. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure as described in Example 4, step 3, to give 3.33 g of 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (crude) as a yellow solid.

Step 4: Preparation of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.00 g, 13.3 mmol, 1.00 equiv), MeOH (20 mL), and sodium borohydride (0.760 g, 20.1 mmol, 1.50 equiv) were placed in a flask. The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (40 mL), extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 15, step 4, to give 3.01 g of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopentaphenylpyrrole-3-carboxylate (crude) as a white solid. LCMS (ESI, m/z): 228 [M+H]+.

Step 5: Preparation of tert-butyl (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopentaphenylcarboxylate

Tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (1.00 g, 4.40 mmol, 1.00 equiv), DCM (20 mL), and triethylamine (1.34 g, 13.2 mmol, 3.00 equiv) were placed in a flask. Methanesulfonyl chloride (0.608 g, 5.28 mmol, 1.20 equiv) was added dropwise at 0°C. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure as described in Example 4, step 3, to give 1.34 g of (methylsulfonyl sulfonyl hexahydrocyclopentaphenylpyrrole-XEcarboxylate) as a yellow oil. LCMS (ESI, m/z): 306 [M+H]+.

Step 6: Preparation of 4-(3-bromophenyl)pyrimidine

O tert-butyl-(3 aR,5r,6aS)-5(unpurified) in the form

_Br o NH NH

NH

TsOH, DMF 160°C, 2 hours.

^(diformamidomethyl)formamide was placed in the vessel.

Br (1.45 g, 9.99 mmol, 1.00 eq.),

1-(3-Bromophenyl)ethan-1-one (4.00 g, 20.10 mmol, 2.00 equiv), 4-methylbenzenesulfonic acid (172 mg, 1.00 mmol, 0.05 equiv) and DMF (10 mL) were added. The resulting solution was stirred for 2 h at 160 °C and quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 1.05 g (45% yield) of 4-(3-bromophenyl)pyrimidine as a white solid. LCMS (ESI, mass/charge): 235 [M+H]+.

Step 7: Preparation of 3-(pyrimidin-4-yl)phenol

Pd ₂ (dba) ₃ , tBuXPhos

Br KOH, H _? O, dioxane 80°C, overnight

OH mg, 4.00 mmol,

4-(3-bromophenyl)pyrimidine (940) was placed in the vessel.

1.00 equiv), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (339 mg, 0.800 mmol, 0.20 equiv), potassium hydroxide (896 mg, 16.0 mmol, 4.00 equiv), tris(dibenzylideneacetone)dipalladium (414 mg, 0.450 mmol, 0.10 equiv), dioxane (10 mL), and water (10 mL) under N ₂ . The resulting solution was stirred overnight at 80 °C and quenched with water (10 mL). The mixture was extracted with EtOAc (3x30 mL) and the organic layers were combined, washed with water (3x10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 460 mg (67% yield) of 3-(pyrimidin-4-yl)phenol as a yellow solid. LCMS (ESI, m/z): 173 [M+H]+.

Step 8: Preparation of tert-butyl (3aR,5s,6aS)-5-(3-(pyrimidin-4-yl)phenoxy)hexahydrocyclopentaphenylpyrrole-III carboxylate

ABOUT.

"Sunday

СЭрСОз, DMF 100°С, overnight

3-(pyrimidin-4-yl)phenol (172 mg, 1.00 mmol, 1.00 equiv), tert-butyl 71 047826 (3aR,5r,6aS)-5-((methylsulfonyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (305 mg, 1.00 mmol, 1.00 equiv), cesium carbonate (978 mg, 3.00 mmol, 3.00 equiv), and DMF (15 mL) were placed in a flask. The resulting solution was stirred overnight at 100°C and quenched with water (40 mL) as described in Example 13, step 4. The residue was column chromatographed on silica gel to afford 263 mg (69% yield) of tert-butyl (3aR,5s,6aS)-5-(3-(pyrimidin-4-yl)phenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a colorless oil. LCMS (ESI, m/z): 382 [M+H]+.

Step 9: Preparation of (3aR,5s,6aS)-5-(3-(pyrimidin-4-yl)phenoxy)octahydrocyclopenta[c]pyrrole

A flask was charged with tert-butyl (3aR,5s,6aS)-5-(3-(pyrimidin-4-yl)phenoxy)hexahydrocyclopentaphenylpyrrole-N-carboxylate (263 mg, 0.690 mmol, 1.00 equiv), TFA (2 mL), and DCM (10 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5, to give 267 mg (quantitative) of (3aR,5s,6aS)-5-(3-(pyrimidin-4-yl)phenoxy)hexahydrocyclopentaphenylpyrrole as a light yellow oil. LCMS (ESI, m/z): 282 [M+H]+.

Step 10: Preparation of tert-butyl 1-((3aR,5s,6aS)-5-(3-(pyrimidin-4yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate

(3aR,5s,6aS)-5-(3-(pyrimidin-4-yl)phenoxy)octahydrocyclopenta[c]pyrrole (267 mg, 0.950 mmol, 1.00 equiv), triethylamine (576 mg, 5.70 mmol, 6.00 equiv), 3-(tert-butyl)-1-(4-nitrophenyl)-N-pyrazole-1,3-dicarboxylate (476 mg, 1.43 mmol, 1.50 equiv), and DCM (15 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature. The mixture was quenched with water (10 mL), extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 4, step 3. The residue was column chromatographed on silica gel to give 302 mg (67% yield) of tert-butyl 1-((3aR,5s,6aS)-5-(3-(pyrimidin-4yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate as a colorless oil. LCMS (ESI, m/z): 476 [M+H]+.

Step 11: Preparation of 1-(trans-5-(3-(pyrimidin-4-yl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-III-pyrazole-3-carboxylic acid

Tert-Butyl 1-((3aR,5s,6aS)-5-(3-(pyrimidin-4-yl)phenoxy)-octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate (238 mg, 0.500 mmol, 1.00 equiv), TFA (2 mL), and DCM (5 mL) were placed in a vessel. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5. The crude product was purified by preparative HPLC to afford 131.3 mg (63% yield) of 1-(trans-5-(3-(pyrimidin-4yl)phenoxy)-octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ^1H NMR: (400 MHz, MeOH-d ₄ ) δ 9.16 (s, 1H), 8.78 - 8.72 (m, 1H), 8.18 - 8.12 (d, J=2.8 Hz, 1H), 8.01 - 7.91 (m, 1H), 7.72 - 7.65 (m, 2H), 7.44 - 7.37 (m, 1H), 7.12 - 7.08 (m, 1h), 6.78 - 6.72 (d, J=2.4 Hz, 1H), 5.12 - 5.08 (m, 1H), 4.28 - 3.61 (m, 4H), 2.98 (br, 2H), 2.25 - 2.11 (m, 2H), 2.09 - 1.95 (m, 2H). LCMS (ESI, m/z): 420 [M+H]+.

Example 31: 1-(2-(3-(pyrimidin-5-yloxy)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-pyrazole-3-carboxylic acid

- 72 047826

Step 1: Preparation of 3-(pyrimidin-5-yloxy)benzaldehyde

80°C, overnight

5-Bromopyrimidine (500 mg, 3.14 mmol, 1.00 equiv), copper(I) iodide (30.0 mg, 0.160 mmol, 0.05 equiv), picolinic acid (38.9 mg, 0.320 mmol, 0.10 equiv), 3-hydroxybenzaldehyde (463 mg, 3.79 mmol, 1.20 equiv), tribasic potassium phosphate (1.30 g, 6.13 mmol, 2.00 equiv), and DMSO (15 mL) were placed in a flask. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The resulting solution was extracted with EtOAc (3x20 mL) and the organic layers were combined, washed with brine (2x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 130 mg (21% yield) of 3-(pyrimidin-5-yloxy)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 201 [M+H]+.

Step 2: Preparation of tert-butyl 8-(3-(tert-butoxycarbonyl)-III-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5 ]decane-2-carboxylate

k.t., during the night

Tert-butyl 1H-pyrazole-3-carboxylate (3.15 g, 18.8 mmol, 1.50 equiv), DCM (20 mL), 4-nitrophenyl chloroformate (3.80 g, 18.8 mmol, 1.50 equiv), and DIPEA (4.83 g, 37.5 mmol, 3.00 equiv) were added to a flask. The resulting solution was stirred for 3 h at room temperature. Tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (3.00 g, 12.5 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 mL). The mixture was extracted with DCM (3x20 mL) and the organic layers were combined, washed with brine (2x25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 4.00 g (74% yield) of tert-butyl 8-(3-(tert-butoxycarbonyl)-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate as a light yellow solid. LCMS (ESI, m/z): 435 [M+H]+.

Step 3: Preparation of 1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-III-pyrazole-3-carboxylic acid

A flask was charged with tert-butyl 8-(3-(tert-butoxycarbonyl)-N-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (380 mg, 0.870 mmol, 1.00 equiv), DCM (10 mL), and TFA (3 mL) as described in Example 1, step 5. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to give 242 mg of 1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-N-pyrazole-3-carboxylic acid (quantitative) as a yellow oil. LCMS (ESI, m/z): 279 [M+H]+.

Step 4: Preparation of 1-(2-(3-(pyrimidin-5-yloxy)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)III-pyrazole-3-carboxylic acid

- 73 047826

3-(Pyrimidin-5-yloxy)benzaldehyde (130 mg, 0.650 mmol, 1.00 equiv), 1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid (217 mg, 0.780 mmol, 1.20 equiv), triethylamine (196 mg, 1.94 mmol, 3.00 equiv), and DCE (10 mL) were placed in a flask. The mixture was stirred for 0.5 h at room temperature. Sodium triacetoxyborohydride (413 mg, 1.95 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with saturated NaHCO3 solution (20 mL) as described in Example 2, step 3 to give the crude product. The crude product (400 mg) was purified by preparative HPLC to give 30.7 mg (10% yield) of 1-(2-(3-(pyrimidin-5-yloxy)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-III-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.90 (s, 1H), 8.54 (d, J=6.0 Hz, 2H), 8.03 (d, J=2.7 Hz, 1H), 7.50 (m, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.34 (s, 1H), 7 ,21 - 7.18 (m, 1H), 6.72 (d, J=2.7 Hz, 1H), 4.26 (s, 2H), 3.83 - 3.65 (m, 4H), 3.33 - 3.28 (m, 2H), 3.15 (s, 2H), 2.01 (t, J=7.2 Hz, 2H), 1.82 - 1 .72 (m, 4H). LCMS (ESI, m/z): 463 [M+H]+.

Example 32: 1-(1-(3-(III-pyrazol-1-yl)-5-(trifluoromethide)benzyl)-1,8-diazaspiro[4.5]decane-8carbonyl)-III-pyrazole-3-carboxylic acid

Tert-butyl-III-pyrazole-3-carboxylate (70.0 mg, 0.420 mmol, 1.00 equiv), DCM (10 mL), and triethylamine (126 mg, 1.25 mmol, 3.00 equiv) were placed in a flask. 4-Nitrophenyl chloroformate (92.1 mg, 0.460 mmol, 1.10 equiv) was added at 0 °C. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 4, step 3, to give 137 mg of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate as a yellow oil. LCMS (ESI, m/z): 334 [M+H] ⁺ .

Step 2: Preparation of tert-butyl 1-(3-bromo-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

3-Bromo-5-(trifluoromethyl)benzaldehyde (0.504 g, 1.99 mmol, 1.00 equiv), tert-butyl 1,8-diazaspiro[4.5]decane-8-carboxylate (0.576 g, 2.40 mmol, 1.20 equiv), and DCE (20 mL) were placed in a flask. The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (1.27 g, 5.99 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (20 mL) as described in Example 2, step 3. The residue was column chromatographed on silica gel to afford 0.790 g (83% yield) of tert-butyl 1-(3-bromo-5-(trifluoromethyl)benzyl)1,8-diazaspiro[4.5]decane-8-carboxylate as a yellow oil. LCMS (ESI, m/z): 477 [M+H] ⁺ .

Step 3: Preparation of tert-butyl 1-(3-(1H-niαzol-1-yl)-5-(trifluoromethyl)benzyl)-1,8

- 74 047826 diazaspiro[4.5]decane-8-carboxylate

A microwave tube was charged with tert-butyl 1-(3-bromo-5(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (0.600 g, 1.26 mmol, 1.00 equiv), 1Hpyrazole (0.128 g, 1.88 mmol, 1.50 equiv), copper iodide (0.0479 g, 0.250 mmol, 0.20 equiv), cesium carbonate (1.23 g, 3.78 mmol, 3.00 equiv), 1,4,7,10,13,16-hexaoxacyclooctadecane (0.0333 g, 0.130 mmol, 0.10 equiv), and dimethyl sulfoxide (10 mL) in nitrogen atmosphere. The resulting solution was stirred for 6 h at 120 °C under microwave irradiation and quenched with water (20 mL). The resulting solution was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 0.100 g (17% yield) of tert-butyl 1-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carboxylate as a yellow oil. LCMS (ESI, m/z): 465 [M+H]+.

Step 4: Preparation of 1-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane

_{F3CF3C ​}

Tert-butyl 1-[[3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]methyl]-1,8-diazaspiro[4.5]decane-8-carboxylate (100 mg, 0.220 mmol, 1.00 equiv), DCM (15 mL) and TFA (1 mL) were added to a flask. The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to give 78.4 mg of 1-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane (quantitative) as a yellow oil. LCMS (ESI, m/z): 365 [M+H]+.

Step 5: Preparation of tert-butyl-1-(1-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1 I-pyrazole-3-carboxylate

1-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane (78.4 mg, 0.220 mmol, 1.00 equiv), 3-(tert-butyl)-1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (108 mg, 0.320 mmol, 1.50 equiv), triethylamine (65.3 mg, 0.650 mmol, 3.00 equiv), and DCM (10 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and quenched with water (15 mL) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 96.0 mg (80% yield) of tert-butyl 1-(1-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 559 [M+H]+.

Step 6: Preparation of 1-(1-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-III-pyrazole-3-carboxylic acid

Tert-butyl 1-(1-(3-(1H-pyrazol-1-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylate (96.0 mg, 0.170 mmol, 1.00 equiv), DCM (7 mL), and TFA (1 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure. The crude product was dissolved in DCM (15 mL). The pH of the solution was adjusted to 8 with saturated NaHCO3 solution. The mixture was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 1, step 5. The crude product (230 mg) was purified by preparative HPLC to give 46.1 mg (53% yield) of 1-(1-(3-(1H-pyrazol-1-yl)-5(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.41 (d, J=2.4 Hz, 1H), 8.18 (s, 1H), 8.13 8.11 (m, 2H), 7.79 - 7.74 (m, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.60 (s, 1H ), 4.63 (br, 2H), 4.19 (s, 2H), 3.33 - 3.20 (m, 2H), 3.10 - 3.08 (m, 2H), 2.24 - 2.15 (m, 4H), 2.04 - 1.99 (m, 2H), 1.79 - 1.76 (m, 2H). LCMS (ESI, mass/charge): 503 [M+H]+.

Example 33: 4-chloro-1-((2S)-2-methyl-4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

Step 1: Preparation of tert-butyl 4-chloro-1H-pyrazole-3-carboxylate

A flask was charged with 4-chloro-1H-pyrazole-3-carboxylic acid (1.60 g, 10.9 mmol, 1.00 equiv), tert-butanol (100 mL), di-tert-butyl dicarbonate (9.50 g, 43.6 mmol, 4.00 equiv), and triethylamine (3.30 g, 32.7 mmol, 3.00 equiv). The resulting solution was stirred overnight at 90 °C and quenched with water (100 mL) as described in Example 1, step 1. The residue was column chromatographed on silica gel to afford 800 mg (36% yield) of tert-butyl 4-chloro-1H-pyrazole-3-carboxylate as a yellow solid. LCMS (ESI, mass/charge): 405 [2M+H] ⁺ .

Step 2: Preparation of tert-butyl (2S)-2-methyl-4-(methylamino)piperidine-1-carboxylate

Tert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (300 mg, 1.41 mmol, 1.00 equiv), methylamine (5.00 mL, 2.82 mmol, 2.00 equiv, 2 M in THF), DIPEA (545 mg, 4.23 mmol, 3.00 equiv), and titanium tetraisopropoxide (4 mL) were placed in a flask. The mixture was stirred for 1 h at room temperature. Sodium tetrahydroborate (54.0 mg, 1.41 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The mixture was extracted with DCM (3x50 ml) and the organic layers were combined, washed with brine (3x30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 250 mg (78% yield) of tert-butyl (2S)-2-methyl-4-(methylamino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 229 [M+H] ⁺ .

Step 3: Preparation of 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde

A flask was charged with 2-fluoro-4-(trifluoromethyl)benzaldehyde (4.00 g, 20.8 mmol, 1.00 equiv), ACN (15 mL), pyrrolidine (2.21 g, 31.0 mmol, 1.50 equiv), and sodium bicarbonate (4.37 g, 52.0 mmol, 2.50 equiv). The resulting solution was stirred overnight at 80 °C and quenched with water (30 mL). The resulting solution was extracted with EtOAc (3 x 50 mL), and the organic layers were combined, washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 2.20 g (yield 43%) of 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde as a yellow oil.

- 76 047826

LCMS (ESI, mass/charge): 244 [M+H]+.

Step 4: Preparation of tert-buty.l-(^)-2-methyl.l-4-('methyl.l('2-('pyrrolidine-1-yl)-4-(trifluoromethyl.l)benzyl)amino)piperidine-1-carboxylate

2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde (200 mg, 0.820 mmol, 1.00 equiv), DCE (10 mL), tert-butyl DO)-2-methyl-4-(methylamino)piperidine-1-carboxylate (225 mg, 0.990 mmol, 1.20 equiv), triethylamine (249 mg, 2.46 mmol, 3.00 equiv) were placed in a flask. The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (523 mg, 2.46 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL) as described in Example 2, step 3. The residue was column chromatographed on silica gel to afford 300 mg (80% yield) of tert-butyl (2S)-2-methyl-4-(methyl(2-(pyrrolin-1-yl)-4(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 456 [M+H] ⁺ .

Step 5: Preparation of (2S)-N,2-dimethyl-N-(2-(pyrrolin-1-yl)-4-(trifluoromethyl)benzyl)piperidin-4-amine

A flask was charged with tert-butyl (DO)-2-methyl-4-(methyl(2-(pyrrolidin-1-yl)-4(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (300 mg, 0.660 mmol, 1.00 equiv), 1,4-dioxane (8 mL) and concentrated hydrochloric acid (2 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure. The crude product was dissolved in 1 M NaOH (30 mL) and extracted with DCM (3x50 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 2, step 4, to give 200 mg (85% yield) of (2S)-N,2-dimethyl-N-(2-(pyrrolin-1-yl)-4(trifluoromethyl)benzyl)piperidin-4-amine as a yellow oil. LCMS (ESI, m/z): 356 [M+H] ⁺ .

Step 6: Preparation of (2S)-2-methyl-4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride

(2S)-N,2-dimethyl-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidin-4-amine (200 mg, 0.560 mmol, 1.00 equiv), DCM (5 mL), and triphosgene (84.0 mg, 0.280 mmol, 0.50 equiv) were placed in a flask. DIPEA (218 mg, 1.68 mmol, 3.00 equiv) was added at 0°C. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 3, to give 234 mg of (D0)-2-methyl-4-(methyl(2-(pyrrolidin-1-yl)-4(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride (crude) as a yellow oil. LCMS (ESI, m/z): 418 [M+H] ⁺ .

Step 7: Preparation of tert-butyl-4-chloro-1-((2S)-2-methyl-4-(methyl(2-(pyrroligin-1-yl)-4(trifluoromethyl)benzyl)amino)piperidin-1- carbonyl)-1H-pyrazole-3-carboxylate

- 77 047826

The flask was charged with (2S)-2-methyl-4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride (150 mg, 0.360 mmol, 1.00 equiv.), THF (5 mL), tert-butyl L-chloro-pyrazole-3-carboxylate (87.0 mg, 0.430 mmol, 1.20 equiv.), DMAP (9.00 mg, 0.0700 mmol, 0.20 equiv.), DIPEA (201 mg, 1.08 mmol, 3.00 equiv.). The resulting solution was stirred overnight at 60°C and quenched with water (10 mL), extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 1, step 4. The residue was column chromatographed on silica gel to give 100 mg (48% yield) of tert-butyl 4-chloro-1((2S)-2-methyl-4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m/z): 584 [M+H]+.

Step 8: Preparation of 4-chloro-1-((2S)-2-methyl-4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1^pyrazole^-carboxylic acid

4-Chloro-1-((2S)-2-methyl-4-(methyl(2-(pyrrolidine-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylate (100 mg, 0.170 mmol, 1.00 equiv), DCM (3 mL), and TFA (1 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure. The crude product was dissolved in DCM (20 mL). The pH of the solution was adjusted to 8 with saturated NaHCO ₃ solution. The mixture was extracted with DCM (3 x 50 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 1, step 5. The crude product (150 mg) was purified by preparative HPLC to give 8.70 mg (10% yield) of 4-chloro-1-((2S)-2-methyl-4-(methyl(2-(pyrrolidin-1yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-nitrazoles-3-carboxylic acid as a white solid. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.21 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J=7.6 Hz, 1H), 5.11 (br, 1H), 4.58 - 4.43 (m, 3H), 4.2 7 - 3.41 (m, 2H), 3.36 - 3.19 (m, 4H), 2.73 - 2.71 (m, 3H), 2.20 - 1.89 (m, 8H), 1.45 - 1.35 (m, 3H). LCMS (ESI, mass/charge): 528 [M+H]+.

Example 34: 1-(trans-5-((3-cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)III-pyrazole-3-carboxylic acid

2-(Cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (747 mg, 3.85 mmol, 1.50 equiv), (3-iodophenyl)MeOH (600 mg, 2.56 mmol, 1.00 equiv), 1,1'bis(diphenylphosphino)ferrocenepalladium dichloride (365 mg, 0.500 mmol, 0.20 equiv), potassium carbonate (704 mg, 5.09 mmol, 2.00 equiv), ethylene glycol dimethyl ether (16 mL), and water (4 mL) were placed in a flask. The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3x20 mL) and the organic layers were combined, washed with water (3x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 23, step 6. The residue was column chromatographed on silica gel to give 350 mg (78% yield) of (3-(cyclopenem-1-en-1-yl)phenyl)MeOH as a yellow oil. LCMS (ESI, m/z): 175 [M+H] ⁺ .

Step 2: Production of (3-cyclopentylphenyl)methanol

- 78 047826

(3-(Cyclopent-1-en-1-yl)phenyl)methanol (0.525 g, 3.01 mmol, 1.00 equiv), 4-methylbenzenesulfonohydrazide (1.12 g, 6.02 mmol, 2.00 equiv), anhydrous sodium acetate (0.738 g, 9.00 mmol, 3.00 equiv), dioxane (8 mL), and water (2 mL) were placed in a flask under N2. The resulting solution was stirred overnight at 90 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL), and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to give 0.130 g (yield 24%) of (3-cyclopentylphenyl)methanol as a yellow oil.

Step 3: Obtaining 1-(bromomethyl)-3-cyclopentylbenzene

(3-Cyclopentylphenyl)-methanol (0.130 g, 0.740 mmol, 1.00 equiv) and DCM (15 mL) were placed in a flask. Tribromophosphine (1.00 g, 3.69 mmol, 5.00 equiv) was then added dropwise at 0 °C. The resulting solution was stirred for 2 h at room temperature and quenched with water (20 mL) as described in Example 27, step 7. The residue was column chromatographed on silica gel to afford 0.095 g (54% yield) of 1-(bromomethyl)-3-cyclopentylbenzene as a yellow oil.

Step 4: Carboxylate formation of tert-butyl-(3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-

(3aR,6aS)-tert-butyl 5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.00 g, 13.3 mmol, 1.00 equiv), MeOH (20 mL), and sodium borohydride (0.760 g, 20.1 mmol, 1.50 equiv) were placed in a flask. The resulting solution was stirred for 5 h at room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (40 mL), extracted with

EtOAc (3x50 mL) and the organic layers were combined, washed with water (3x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 15, step 4, to give 3.01 g of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta-pyrrole-III-carboxylate (crude) as a white solid. LCMS (ESI, m/z): 228 [M+H]+.

Step 5: Preparation of tert-butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopentaphenylpyrrole-III-carboxylate

Tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (2.27 g, 9.99 mmol, 1.00 equiv), 4-nitrobenzoic acid (6.68 g, 40.0 mmol, 4.00 equiv), triphenylphosphine (10.5 g, 40.0 mmol, 4.00 equiv), and THF (30 mL) were placed in a flask. Diethyl azodicarboxylate (6.96 g, 40.0 mmol, 4.00 equiv) was added dropwise at 0°C. The resulting solution was stirred overnight at room temperature under nitrogen and quenched with water (50 mL) as described in Example 15, step 5. The residue was column chromatographed on silica gel to afford 2.36 g (62% yield) of tert-butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a white solid. LCMS (ESI, m/z): 377 [M+H]+.

Step 6: Preparation of tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

- 79 047826

Tert-butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.36 g, 6.27 mmol, 1.00 equiv), MeOH (30 mL), potassium carbonate (2.60 g, 18.8 mmol, 3.00 equiv), and water (5 mL) were placed in a flask. The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure. The reaction mixture was then diluted with water (30 mL), extracted with EtOAc (3 x 50 mL) and the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 3, step 3, to give 1.31 g of tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (crude) as a white solid. LCMS (ESI, m/z): 228 [M+H]+.

Step 7: Preparation of tert-butyl (3aR,5s,6aS)-5-((3-cyclopentylbenzyl)oxy)hexahydrocyclopentaphenylpyrrole-OHC carboxylate

k.t., during the night

Tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (135 mg, 0.590 mmol, 1.50 equiv) and DMF (15 mL) were placed in a flask. Sodium hydride (60% in oil, 32.0 mg, 0.800 mmol, 2.00 equiv) was then added at 0 °C. The resulting solution was stirred for 0.5 h at room temperature, followed by the addition of 1-(bromomethyl)-3-cyclopentylbenzene (95 mg, 0.400 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (20 mL) as described in Example 15, step 7. The residue was column chromatographed on silica gel to afford 135 mg (88% yield) of tert-butyl (3aR,5s,6aS)-5-((3-cyclopentylbenzyl-5-oxo-6-hexahydrocyclopenta-pyrrole-3-carboxylate) as a yellow oil. LCMS (ESI, m/z): 386 [M+H] ⁺ .

Step 8: Preparation of (3aR,5s,6aS)-5-((3-cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole

A flask was charged with tert-butyl (3aR,5s,6aS)-5-((3-cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole carboxylate (135 mg, 0.350 mmol, 1.00 equiv), TFA (2 mL), and DCM (5 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5 to give 100 mg of (3aR,5s,6aS)-5-((3-cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole (quantitative) as a yellow oil. LCMS (ESI, m/z): 286 [M+H]+.

Step 9: Preparation of tert-butyl 1-((3aR,5s,6aS)-5-((3-cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate

(3aR,5s,6aS)-5-((3-cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole (100 mg, 0.350 mmol, 1.00 equiv), triethylamine (212 mg, 2.10 mmol, 6.00 equiv), 3-tert-butyl 1-(4-nitrophenyl)-N-pyrazole-1,3-dicarboxylate (175 mg, 0.525 mmol, 1.50 equiv), and DCM (15 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature. The mixture was quenched with water (10 mL), extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 4, step 3. The residue was column chromatographed on silica gel to give 144 mg (86% yield) of tert-butyl 1-((3aR,5s,6aS)-5-((3cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate as

- 80 047826 yellow solid. LCMS (ESI, m/z): 480 [M+H].

Step 10: Preparation of 1-(trans-5-((3-cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-III-pyrazole-N-carboxylic acid

Tert-butyl 1-((3aR,5s,6aS)-5-((3cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate (144 mg, 0.300 mmol, 1.00 equiv), TFA (2 mL) and DCM (5 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure. The crude product was dissolved in saturated NaHCO ₃ solution (10 mL) and extracted with DCM (3x20 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure as described in Example 1, step 5. The crude product was purified by preparative HPLC to give 47.6 mg (37% yield) of 1-(trans-5-((3-cyclopentylbenzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrαzole-3-carboxylic acid as a white solid. ¹ H NMR: (400 MHz, MeOH-d ₄ ) δ 8.16 (s, 1H), 7.23 7.18 (m, 2H), 7.16 - 7.07 (m, 2H), 6.75 (d, J=2.8 Hz, 1H), 4.41 (s, 2H), 4.25 - 4.15 (m, 1H), 4.11 - 3.48 (m, 4H), 3.01 - 2.91 (m, 1H), 2.88 (br, 2H), 2.15 - 1.98 (m, 4H), 1.85 - 1.51 (m, 8H). LCMS (ESI, mass/charge): 424 [M+H]+.

Example 35: 4-(4-((5-(3-carbamoyl-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)yl)methyl)-3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid

ABOUT

Step 1: Preparation of 4-nitrophenyl-3-carbamoyl-1H-pyrazole-1-carboxylate

A flask was charged with 1H-pyrazole-3-carboxamide (64.0 mg, 0.580 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (129 mg, 0.640 mmol, 1.10 equiv), triethylamine (176 mg, 1.74 mmol, 3.00 equiv), and DCM (10 mL). The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to give 160 mg (crude) 4-nitrophenyl 3-carbamoyl 1H-pyrazole-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 277 [M+H] ⁺ .

Stage 2: Obtaining potassium (^-(tert-butoxycarbonyl)hexahydropyrrolo-D-^pyrrole-III-yl-ethyl)trifluoroborate.

K ₂ CO ₃ , THF, acetone K , _ 80°C, overnight F

Tert-butyl octahydropyrrolo-D-pyrrole-carboxylate (1.20 g, 5.65 mmol, 1.00 equiv), potassium (bromomethyl)trifluoroborohydride (1.13 g, 5.63 mmol, 1.00 equiv), and THF (15 mL) were placed in a flask under nitrogen atmosphere. The mixture was stirred overnight at 80 °C and concentrated under reduced pressure. Potassium carbonate (0.781 g, 5.65 mmol, 1.00 equiv) and acetone (10 mL) were added. The resulting solution was stirred for 2 h at room temperature, dissolved in acetone (2 x 200 mL), and filtered. The filtrate was concentrated under reduced pressure to give 1.40 g (yield 75%) of ((5-(tertbutoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)potassium trifluoroborate as a yellow solid. LCMS (ESI, m/z): 293 [MK] ^- .

Step 3: Obtaining tert-butyl 2-(4-chloro-3-(trifluoromethyl)phenyl)acetate

- 81 047826

A flask was charged with 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (1.00 g, 4.19 mmol, 1.00 equiv), tert-butanol (25 mL), triethylamine (1.27 g, 12.6 mmol, 3.00 equiv), and di-tert-butyl dicarbonate (4.58 g, 20.9 mmol, 5.00 equiv). The resulting solution was stirred overnight at 90 °C and then quenched with water (25 mL) as described in Example 1, step 1. The residue was column chromatographed on silica gel to afford 0.810 g (66% yield) tert-butyl 2-(4-chloro-3-(trifluoromethyl)phenyl)acetate as a yellow oil. ¹ H NMR (300 MHz, Chloroform-d) δ 7.60 (s, 1H), 7.48 - 7.40 (m, 2H), 3.56 (s, 2H), 1.45 (s, 9H).

Step 4: Preparation of tert-butyl 4-(4-chloro-3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylate

CF z

Tert-Butyl 2-(4-chloro-3-(trifluoromethyl)phenyl)acetate (500 mg, 1.70 mmol, 1.00 equiv) and DMF (10 mL) were placed in a flask. Sodium hydride (340 mg, 8.50 mmol, 5.00 equiv, 60% in mineral oil) was added at 0 °C. 1-Bromo-2-(2-bromoethoxy)ethane (782 mg, 3.37 mmol, 2.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL) and the organic layers were combined, washed with brine (1 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 190 mg (yield 31%) of tert-butyl 4-(4-chloro-3-(trifluoromethyl)phenyl)tetrahydro-2Hpyran-4-carboxylate as a yellow oil. ¹ H NMR (300 MHz, Chloroform-d ) δ 7.69 (s, 1H), 7.48 (br, 2H), 3.97 - 3.93 (m, 2H), 3.61 - 3.55 (m, 2H), 2.48 - 2.44 (m, 2H), 1.92 - 1.85 (m, 2H), 1.39 (s, 9H).

Step 5: Preparation of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)tetrahydro-2H-pyran-4-yl)-2(trifluoromethyl-5-enzylic acid hydropyrrolo-5-carboxylate)

The flask was charged with tert-butyl 4-(4-chloro-3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylate (364 mg, 1.00 mmol, 1.00 equiv.), (^-(tert-butoxycarbonyl)hexahydropyrrolo-^D-pyrrole-2(III)-yl)methyl)potassium trifluoroborate (398 mg, 1.20 mmol, 1.20 equiv.), palladium acetate (22.4 mg, 0.100 mmol, 0.10 equiv.), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (95.0 mg, 0.200 mmol, 0.20 equiv.), cesium carbonate (978 mg, 3.00 mmol, 3.00 equiv), 1,4-dioxane (10 ml) and water (2 ml) under nitrogen atmosphere. The resulting solution was stirred overnight at 90 °C and then quenched with water (10 ml). The resulting mixture was extracted with DCM (3 x 15 ml) and the organic layers were combined, washed with brine (1 x 20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 250 mg (yield 45%) of tert-butyl 5-(4-(4-(tert-butoxycarbonyl)tetrahydro-2H-pyran4-yl)-2-(trifluoromethyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as a yellow oil. LCMS (ESI, mass/charge): 555 [M+H]+.

Step 6: Preparation of 4-(4-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid

Tert-butyl 5-(4-(4-(tert-butoxycarbonyl)tetrahydro-2H-pyran-4-yl)-2(trifluoromethyl)-2- ...

- 82 047826 equiv), concentrated hydrochloric acid (4 mL) and 1,4-dioxane (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure as described in Example 2, step 4, to give 180 mg of 4-(4-((hexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)methyl)-3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid (quantitative) as a yellow oil. LCMS (ESI, m/z): 399 [M+H]+.

Step 7: Preparation of 4-(4-((5-(3-carbamoyl-III-pyrazole-1-carbonyl)hexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)methyl)-3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid

K.T., 2 hours.

A flask was charged with 4-(4-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-3(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid (180 mg, 0.450 mmol, 1.00 equiv), 4-nitrophenyl 3-carbamoyl-III-pyrazole-1-carboxylate (138 mg, 0.500 mmol, 1.10 equiv), triethylamine (137 mg, 1.35 mmol, 3.00 equiv), and DCM (10 mL). The resulting solution was stirred for 2 h at room temperature and then quenched with water (10 mL) as described in Example 4, step 3. The crude product (300 mg) was purified by preparative HPLC to give 126.1 mg (52% yield) of 4(4-((5-(3-carbamoyl-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-ηλ)μ6τπλ)-3(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-carboxylic acid as a white solid. ¹ H NMR (300 MHz, Methanol^) δ 8.30 (d, J=2.7 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.67 - 7.65 (m, 1H), 6.88 (d, J=2.7 Hz, 1H), 4.23 - 3.83 (m, 8H), 3.65 - 3.56 (m, 2H), 2.98 (br, 2H), 2.74 - 2.67 (m, 4H), 2.55 - 2.51 (m, 2H), 1.94 - 1.87 (m, 2H). LCMS (ESI, m/z): 536 [M+H] ⁺ .

Example 36: 1-(4-((2-hydroxy-2-methylpropyl)(3-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxamide

Step 1: Preparation of tert-butyl 4-((3-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

3-(Trifluoromethyl)benzaldehyde (522 mg, 3.00 mmol, 1.00 equiv), tert-butyl 4-aminopiperidine-1-carboxylate (1.20 g, 6.00 mmol, 2.00 equiv), and MeOH (15 mL) were placed in a flask.

The mixture was stirred for 4 h at 60 °C. Sodium borohydride (456 mg, 12.0 mmol, 4.00 equiv) was added. The resulting solution was stirred overnight at 60 °C and quenched with water (20 mL) as described in Example 15, step 4. The residue was column chromatographed on silica gel to afford 0.800 g (74% yield) of tert-butyl 4-((3-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 359 [M+H]+.

Step 2: Preparation of tert-butyl 4-((2-hydroxy-2-methylpropyl)(3-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

A flask was charged with tert-butyl 4-((3-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (358 mg, 1.00 mmol, 1.00 equiv), 2,2-dimethyloxirane (360 mg, 5.00 mmol, 5.00 equiv), MeOH (10 mL), and lithium bromide (258 mg, 3.00 mmol, 3.00 equiv). The resulting solution was stirred overnight at 60 °C and quenched with water (20 mL). The resulting mixture was extracted with DCM (3 x 30 mL) and organic

- 83 047826 The aqueous layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 230 mg (yield 53%) of tert-butyl 4-((2-hydroxy-2-methylpropyl)(3-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 431 [M+H]+.

Step 3: Preparation of 2-methyl-1-(piperidin-4-yl(3-(trifluoromethyl)benzyl)amino)propan-2-ol

A flask was charged with tert-butyl 4-((2-hydroxy-2-methylpropyl)(3(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (215 mg, 0.500 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5 to give 165 mg of 2-methyl-1(piperidin-4-yl(3-(trifluoromethyl)benzyl)amino)propan-2-ol (quantitative) as a yellow oil. LCMS (ESI, m/z): 331 [M+H]+.

Step 4: Preparation of 4-((2-hydroxy-2-methylpropyl)(3-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride

ABOUT

Triphosgene (104 mg, 0.350 mmol, 0.70 equiv) and DCM (10 mL) were placed in a flask. 2-Methyl-1(piperidin-4-yl(3-(trifluoromethyl)benzyl)amino)propan-2-ol (165 mg, 0.500 mmol, 1.00 equiv) and DIPEA (258 mg, 2.00 mmol, 4.00 equiv) were added at 0 °C. The resulting solution was stirred for 1 h at room temperature and quenched with water (20 mL) as described in Example 1, step 3, to give 196 mg of 4-((2-hydroxy-2-methylpropyl)(3-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride (crude) as a brown oil. LCMS (ESI, mass/charge): 393 [M+H]+.

Step 5: Preparation of 1-(4-((2-hydroxy-2-methylpropyl)(3-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1-^pyrazole-^-carboxamide

4-((2-hydroxy-2-methylpropyl)(3-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl chloride (196 mg, 0.500 mmol, 1.00 equiv), 1/3-pyrazole-3-carboxamide (66.6 mg, 0.600 mmol, 1.20 equiv), THF (10 mL), DIPEA (258 mg, 2.00 mmol, 4.00 equiv), and DMAP (6.1 mg, 0.0500 mmol, 0.10 equiv) were placed in a flask under nitrogen atmosphere. The resulting solution was stirred overnight at 60°C and then quenched with water (20 mL) as described in Example 1, step 4. The crude product (280 mg) was purified by preparative HPLC to give 106.9 mg (46% yield) of 1-(4-((2-hydroxy-2-methylpropyl)(3(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxamide as an off-white solid. ¹ H NMR (400 MHz, Methanol-dQ δ 8.16 (d, J=2.4 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.55 - 7.49 (m, 2H), 6.87 (d, J=2.4 Hz, sh), 4.49 - 4.46 (m, 2H), 3.95 (s, 2H), 3.00 - 2.86 (m, 3H), 2.56 (s, 2H), 1.97 - 1.94 (m, 2H), 1.75 -1.64 (m, 2H), 1.17 (s, 6H). LCMS (ESI, m/z): 468 [M+H]+.

Example 37: 1-(4-(2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)piperazine-1-carbonyl)-III-pyrazole-3-carboxamide

Step 1: Obtaining 2-chloro-3-(2-hydroxy-2-methylpropoxy)benzaldehyde

- 84 047826

2-Chloro-3-hydroxybenzaldehyde (0.624 g, 4.00 mmol,

1.00 equiv), 2,2-dimethyloxirane (0.576 g, 8.00 mol, 2.00 equiv), DMSO (10 mL), and potassium carbonate (1.66 g, 12.0 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80°C and quenched with water (30 mL).

The resulting mixture was extracted with EtOAc (3x40 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed to afford 550 mg (60% yield) of 2-chloro-3-(2-hydroxy-2-methylpropoxy)benzaldehyde as a colorless oil. LCMS (ESI, m/z): 229 [M+H]+.

Step 2: Preparation of 4-nitrophenyl-3-carbamoyl-III-pyrazole-1-carboxylate

A flask was charged with N-pyrazole-3-carboxamide (0.555 g, 5.00 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (1.21 g, 6.00 mmol, 1.20 equiv), DCM (20 mL), and triethylamine (1.51 g, 15.0 mmol, 3.00 equiv). The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to give 1.38 g of 4-nitrophenyl 3-carbamoyl-N-pyrazole-1-carboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 277 [M+H]+.

Step 3: Preparation of tert-butyl 4-(3-carbamoyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate

To a flask were placed 4-nitrophenyl 3-carbamoyl-N-pyrazole-1-carboxylate (1.38 g, 5.00 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.930 g, 5.00 mol, 1.00 equiv), DCM (15 mL), and triethylamine (1.51 g, 15.0 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (30 mL) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 0.500 g (31% yield) tert-butyl 4-(3-carbamoyl-N-pyrazole-1-carbonyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, mass/charge): 324 [M+H]+.

Step 4: Preparation of 1-(piperazine-1-carbonyl)-III-pyrazole-3-carboxamide

Tert-butyl 4-(3-carbamoyl-N-pyrazole-1-carbonyl)piperazine-1-carboxylate (150 mg, 0.460 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL) were placed in a flask. The resulting solution was stirred for 2 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5, to give 110 mg (quantitative) of 1-(piperazine-1-carbonyl)-N-pyrazole-3-carboxamide as a yellow oil. LCMS (ESI, m/z): 224 [M+H]+.

Step 5: Preparation of 1-(4-(2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)piperazine-1-carbonyl)1-pyrazole-3-carboxamide

1-(piperazine-1-carbonyl)-III-pyrazole-3-carboxamide (75.8 mg, 0.340 mmol, 1.20

- 85 047826 equiv.), 2-chloro-3-(2-hydroxy-2-methylpropoxy)benzaldehyde (64.7 mg, 0.280 mmol, 1.00 equiv.) and DCM (15 mL). The mixture was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (241 mg, 1.14 mmol, 4.00 equiv.) was added.

The resulting solution was stirred overnight at room temperature and then quenched with water (20 mL) as described in Example 2, step 3. The crude product (200 mg) was purified by preparative HPLC to give 52.7 mg (36% yield) of 1-(4-(2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)piperazine-1-carbonyl)-1-nitro-pyrazole-3-carboxamide as a white solid. 1H NMR (300 MHz, Chloroform-d) δ 8.09 (d, J=2.7 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.12 (br, 1H), 6.90 (d, J=2.7 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.65 (br, 1H), 5.47 (br, 1H), 3.85 (s, 6H), 3.71 (s, 2H), 2.65 (br, 4H), 2.40 (s, 1H), 1.39 (s, 6H). LCMS (ESI, m/z): 436 [M+H]+.

Example 38: 1-(trans-5-((2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid

Step 1: Preparation of 3-(tert-butyl)-1-(4-nitrophenyl)-III-pyrazole-1,3-dicarboxylate

Tert-butyl 1H-pyrazole-3-carboxylate (138 mg, 0.822 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (198 mg, 0.986 mmol, 1.20 equiv), triethylamine (249 mg, 2.46 mmol, 3.00 equiv), and DCM (10 mL) were charged to a flask as described in Example 4, step 3. The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure to give 274 mg of 3-tert-butyl 1-(4-nitrophenyl)-1H-pyrazole-1,3-dicarboxylate (crude) as a yellow oil. LCMS (ESI, m/z): 334 [M+H] ⁺ .

Step 2: Preparation of Ίret-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate

H,Vos H.Vos

N NaBH ₄ , МеОН^ ΔΖ N

7" ^ct -' 2 hours, L n BUT'' n

A flask was charged with tert-butyl (3aR,6aS)-5-oxo-octahydrocyclopenta[c]pyrrole-2-carboxylate (1.00 g, 4.44 mmol, 1.00 equiv) and MeOH (15 mL). Sodium borohydride (0.507 g, 13.4 mmol, 3.00 equiv) was added at 0 °C. The resulting solution was stirred for 2 h at room temperature and quenched with water (20 mL) as described in Example 15, step 4 to give 0.950 g (94% yield) of (3aR,6aS)-5-hydroxy-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a yellow oil. LCMS (ESI, m/z): 228 [M+H] ⁺ .

Step 3: Preparation of tert-butyl (3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

(3aR,5r,6aS)-tert-butyl 5-hydroxy-hexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (2.00 g, 8.81 mmol, 1.00 equiv), 4-nitrobenzoic acid (1.470 g, 8.80 mmol, 2.00 equiv), triphenylphosphine (2.30 g, 8.80 mmol, 2.00 equiv), and THF (20 mL) were placed in a flask under nitrogen atmosphere. Diethyl azodicarboxylate (1.53 g, 8.80 mmol, 2.00 equiv) was added at 0 °C. The resulting solution was stirred overnight at room temperature and quenched with water (40 mL) as described in Example 15, step 5. The residue was column chromatographed on silica gel to afford 1.8 g (54% yield) of tert-butyl (3aR,5s,6aS)-5-((4-niobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a white solid. LCMS (ESI, m/z): 377 [M+H] ⁺ .

Step 4: Preparation of tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

- 86 047826

TpeT-6ymun-(3aR,5s,6aS)-5-((4nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.8 g, 4.79 mmol, 1.00 equiv.), potassium carbonate (1.32 g, 9.58 mmol, 2.00 equiv.), MeOH (30 mL), and water (10 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL) as described in Example 15, step 6. The residue was column chromatographed on silica gel to afford 900 mg (82% yield) of tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a white solid. LCMS (ESI, m/z): 228 [M+H]+.

Step 5: Preparation of tert-butyl (3aR,5s,6aS)-5-((3-bromo-2-chlorobenzyl)oxy)hexahydrocyclopentaenoic acid carboxylate

CI

Tert-butyl (3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)carboxylate (600 mg, 2.64 mmol, 1.00 equiv), 1-bromo-3-(bromomethyl)-2-chlorobenzene (820 mg, 2.91 mmol, 1.10 equiv), NaH (211 mg, 5.28 mmol, 2.00 equiv) and DMF (10 mL) were placed in a flask. The resulting solution was stirred overnight at room temperature and quenched with water (20 mL) as described in Example 15, step 7. The residue was column chromatographed on silica gel to afford 660 mg (60% yield) of tert-butyl (3aR,5s,6aS)-5-((3-bromo-2-chlorobenzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a yellow solid. LCMS (ESI, m/z): 430 [M+H] ⁺ .

Step 6: Preparation of tert-butyl (3aR,5s,6aS)-5-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)benzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

A flask was charged with tert-butyl (3aR,5s,6aS)-5-((3-bromo-2-chlorobenzyl-xyphexahydrocyclopentaphenylpyrrole-DHA-carboxylate (500 mg, 1.16 mmol, 1.00 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (444 mg, 1.75 mmol, 1.50 equiv.), bis(triphenylphosphine)palladium dichloride (246 mg, 0.35 mmol, 0.30 equiv.), potassium acetate (341 mg, 3.48 mmol, 3.00 equiv.), 1,4-dioxane (10 mL), and nitrogen. The resulting solution was stirred overnight at 80°C and quenched with water (20 mL). The resulting solution was extracted with EtOAc (3 x 30 mL) and the organic layers were combined, washed with brine (1 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to afford 480 mg (86% yield) of tert-butyl (3aR,5s,6aS)-5-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)hexahydrocyclopentaenoic acid (3aR,5s,6aS)-carboxylate as a white solid. LCMS (ESI, m/z): 478 [M+H] ⁺ .

Step 7: Preparation of tert-butyl (3aR,5s,6aS)-5-((2-chloro-3-hydroxybenzyl)oxy)hexahydrocyclopentaylpyrrole-2(1H)-carboxylate

A flask was charged with tert-Butyl (3aR,5s,6aS)-5-((2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl-benzyl-xyphexahydrocyclopentaphenylpyrrole-1Hf carboxylate (430 mg, 0.90 mmol, 1.00 equiv), sodium hydroxide (72 mg, 1.80 mmol, 2.00 equiv), hydrogen peroxide (1.80 mL, 1.80 mmol, 2.00 equiv), and THF (10 mL). The resulting solution was stirred for 4 h at room temperature and quenched with water (5 mL). The mixture was extracted with EtOAc (3 x 40 mL), and the organic layers were combined, washed with with water (1x50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel to give 260 mg of tert-butyl (3aR,5s,6aS)-5-((2-chloro-3-hydroxybenzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a white solid. LCMS (ESI, m/z): 368 [M+H]+.

Step 8: Preparation of tert-butyl (3aR,5s,6aS)-5-((2-chloro-3-(2-hydroxy-2methylpropoxy)benzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Tert-butyl (3aR,5s,6aS)-5-((2-chloro-3hydroxybenzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (260 mg, 0.708 mmol, 1.00 equiv), 2,2-dimethyloxirane (61 mg, 0.850 mmol, 1.20 equiv), potassium carbonate (294 mg, 2.12 mmol, 3.00 equiv), and DMSO (5 mL) were placed in a flask. The resulting solution was stirred overnight at 100°C and quenched with water (5 mL) as described in Example 41, step 1. The residue was column chromatographed on silica gel to afford 200 mg (64% yield) of tert-butyl (3aR,5s,6aS)-5-((2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a white solid. LCMS (ESI, m/z): 440 [M+H]+.

Step 9: Preparation of 1-(2-chloro-3-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)methyl)phenoxy)-2-methylpropan-2-ol

Tert-butyl (3aR,5s,6aS)-5-((2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (200 mg, 0.456 mmol, 1.00 equiv), DCM (8 mL), and TFA (2 mL) were placed in a flask. The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure.

The crude product was processed as described in Example 1, step 5, to give 136 mg of 1-(2-chloro-3-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)methyl)phenoxy)-2-methylpropan-2-ol (quantitative) as a white solid. LCMS (ESI, m/z): 340 [M+H]+.

Step 10: Preparation of tert-butyl 1-(trans-5-((2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate

The flask was charged with 1-(2-chloro-3-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)methyl)phenoxy)-2-methylpropan-2-ol (136 mg, 0.401 mmol, 1.00 equiv), 3-tert-butyl 1-(4-nitrophenyl)-1Hpyrazole-1,3-dicarboxylate (160 mg, 0.481 mmol, 1.20 equiv), triethylamine (121 mg, 1.20 mmol, 3.00 equiv) and DCM (5 mL). The resulting solution was stirred overnight at room temperature and quenched with water (20 mL) as described in Example 4, step 3. The residue was column chromatographed on silica gel to afford 180 mg (82% yield) of tert-butyl 1-((3aR,5s,6aS)-5-((2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m/z): 534 [M+H]+.

Step 11: Preparation of 1-(trans-5-((2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazole-3-carboxylic acid

Tert-butyl 1-((3aR,5s,6aS)-5-((2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)- 88 047826 oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-III-pyrazole-3-carboxylate (180 mg, 0.338 mmol, 1.00 equiv), DCM (8 mL), and TFA (1 mL) were placed in a flask. The resulting solution was stirred for 1 h at room temperature and concentrated under reduced pressure as described in Example 1, step 5. The crude product (200 mg) was purified by preparative HPLC to give 32.8 mg (21% yield) of 1-(trans-5-((2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid as a white solid. ¹ H NMR (400 MHz, Methanol-dJ δ 8.16 (d, J=2.6 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.76 (d, J=2.6 Hz, 1H), 4.59 (s, 2H), 4.28 (t, J=4.1 Hz, 1H), 3.85 (s, 6H), 2.94 (s, 2H), 2.14 (s, 2H), 1.84 (dd, J=13.1, 6.4 Hz, 2H), 1.38 (s, 6H). LCMS (ESI, m/z): 495 [M+NHX

Examples 39-456: Examples 39-456 were prepared using similar procedures as described in Examples 1-38.

Note. Name Structure NMR (¾ NMR, 300 MHz or 400 MHz, methanol-*/) MS [M+H] ⁺ 39 1-(4-((4-chloro-3(pyrrolidin-1yl)benzyl) (methyl) a mino)-4-methylpiperidine1-carbonyl)-1Hpyrazole-3carboxylic acid ~ XX . o λ-on O δ 8.05 - 8.08 (m, 1H), 7.20 - 7.32 (br, 1H), 6.95 - 7.09 (br, 1H), 6.83 - 6.87 (br, 1H), 6.71 - 6.79 (br, 1H), 3.51 - 4.25 (br, 6H), 3.30 3.41 (br, 4H), 2.26 (s, 3H), 2.02 2.15 (br, 2H), 1.90 - 1.99 (m, 4H), 1.71 - 1.85(br, 2H), 1.20 (s, 3H) 460,1 40 1-(4-(3-(3-oxa-8azabicyclo[3.2.1]o kgan-8-yl)-4(trifluoromethyl)benzyl)piperazine-1 carbonyl)-1Hpyrazole-3carboxylic acid O /-on δ 8.05 - 8.17 (m, 1H), 7.52 - 7.64 (w, 1H), 7.05 - 7.21 (w, 2H), 6.74 - 6.87 (w, 1H), 3.54 - 4.01 (w, 12H), 2.63 -2.71 (w, 4H), 1.91 2.04 (w, 4H) 494,5 41 1-(g/is-5-((2-chlorobenzyl)oxy)o-hydroxycyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid O >=° Z-Z o ι δ 8.05 (d, J = 2.4 Hz, 1H), 7.41 7.44 (m, 1H), 7.30 - 7.37 (m, 1H), 7.22 - 7.26 ( m, 2H), 6.72 (d, J = 2.4 Hz, 1H), 4.56 (s, 2H), 4.24 4.45 (m, 1H), 4.15 - 4.20 ( m, 1H), 3.88 - 4.06 (m, 3H), 2.83 (br, 2H), 2.18 - 2.23 (m, 2H), 1.82 - 1.85 (m, 2H) 412.4 [M+Na] ⁺ 42 1-(4-((3-chloro-5-fluorobenzyl)oxy)p-iperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid O nV U L E~on O CI δ 8.05 (d, J = 2.6 Hz, 1H), 7.22 (s, 1H), 7.07 - 7.10 (m, 2H), 6.75 (d, J = 2.6 Hz, 1H), 4.59 (s, 2H), 4.04 (br, 2H), 3.72 - 3.80 (m, 1H), 3.60 - 3.66 (m, 2H), 1 .99 - 2.07 (m, 2H), 1.73 - 1.83 (m, 2H) 399.1 [M+ _NH4 ] ⁺

- 89 047826

43 1-(2-(5-chloro-2- (trifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid /— N ^with Ч>- ₃ 0 nV ^J Y-OH o δ 8.05 (s, 1H), 7.86 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H) , 6.76 (s, 1H), 3.76 3.80 (m, 6H), 2.71 (t, J = 6.9 Hz, 2H), 2.56 (s, 2H), 1.72 - 1.84 (m, 6H) 471.4 44 1-(2-(3-chloro-5(pyrrolidin-1 yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid CI g-\ /=/ ° С nV) xx A nV Voh О δ 8.06 (d, J = 2.7 Hz, 1H), 6.74 6.82 (m, 2H), 6.64 (s, 1H), 6.60 (s, 1H), 4.22 (s, 2H), 3.85 (br, 2H), 3.69 - 3.71 (m, 2H), 3.48 3.52 (m, 2H), 3.23 - 3.32 (m, 6H), 1.91 - 2.08 (m, 6H), 1.76 - 1.88 (m, 4H) 472.2 45 1-(4-(4-(4-chlorophenoxy)benzyl)piperazine-1carbonyl)-1Hpyrazole-3carboxylic acid O U~on O δ 8.06 (d, J = 2.7 Hz, 1H), 7.31 7.38 (m, 4H), 6.94 - 6.99 (m, 4H), 6.74 (d, J= 2.7 Hz, 1H), 3.87 (br, 4H), 3.58 (s, 2H), 2.59 (t, J = 4.8 Hz, 4H) 441.2 46 1-(4-((4-chloro-2(pyrrolidin-1 yl)benzyl)(methyl)amino)-4methylpiperidine1-carbonyl)-1Hpyrazole-3carboxylic acid ψΑ: ό O X nV U~on O δ 8.07-8.11 (m, 1H), 7.45 - 7.56 (m, 1H), 7.19 - 7.25 (m, 1H), 7.07 - 7.17 (m, 1H), 6.75 (s, 1H), 3.76 - 4.75 (m, 4H), 3.37 - 3.64 (m, 2H), 3.14 (s, 4H), 2.52 (s, 3H), 1.90-2.17 (m, 8H), 2.48 (s, 3H) 460,1

- 90 047826

47 1-(4-((3-chloro-2(pyrrolidin-1yl)benzyl)(methyl)amino)-4methylpiperidine- 1-carbonyl)-1Hpyrazole-3carboxylic acid O N==/ U-OH O ⁰ δ 8.07 - 8.15 (m, 1H), 7.47 - 7.55 (m, 2H), 7.25 - 7.31 (m, 1H), 6.75 (s, 1H), 3 .90 - 4.78 (m, 4H), 3.32 - 3.83 (m, 6H), 2.60 (s, 3H), 1.85 -2.27 (m, 8H), 1.49 (s, 3H) 460.3 48 (7?)-1-(4-(2(hex ahydropyrrolo[1,2-a]pyrazin2(1H)-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid О ^F 3 ^C ^X ГП Г У ^7 ΑΑ^ ^Ν А №/ N У~ ^on А δ 8.07 (d, J = 2.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.43 - 7.47 (m, 2H), 6.76 ( d, J = 2.7 Hz, 1H), 3.83 (br, 4H), 3.70 (s, 2H), 3.50 3.57 (m, 5H), 3.01 - 3.26 ( m, 4H), 2.62 (t, J = 4.8 Hz, 4H), 2.09 2.23 (m, 3H), 1.91 (br, 1H) 507,5 49 (5)-1-(4-(2(hex ahydropyrrolo[1,2-a]pyrazin2(1H)-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid O F ₃ C^^ A Ίτ N G ΐ A n==/ N Y~ ^0H Ά δ 8.07 (d, J = 2.7 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.42 - 7.46 (m, 2H), 6.75 ( d, J= 2.7 Hz, 1H), 3.83 (br, 4H), 3.69 (s, 2H), 3.43 3.50 (m, 5H), 3.12 - 3.15 ( m, 2H), 2.93 - 3.00 (m, 2H), 2.61 (t, J = 4.8 Hz, 4H), 2.06 - 2.13 (m, 3H), 1.82 (br, 1H) 507,5 50 1-(4-(4ethynylbenzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid 0 AAA n==/ U-OH o δ 8.08 (d, J = 2.7 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6 .76 (d, J = 2.7 Hz, 1H), 3.87 (br, 4H), 3.65 (s, 2H), 3.47 (s, 1H), 2.63 (t, J = 5.0 Hz, 4H) 339,0

- 91 047826

51 1-(4-(3-(4-fluorophenoxy)benzyl)piperazine-1carbonyl)-1Hpyrazole-3carboxylic acid Won Oh δ 8.11 (d, 7=2.7 Hz, 1H), 7.33(1, 7= 7.8 Hz, 1H), 6.98 - 7.13 (m, 6H), 6.88 - 6.92 (m, 1H), 6.79 (d, J = 2.7 Hz, 1H), 3.88 (br, 4H), 3.68 (br, 2H), 2.70 (br, 4H ) 425,0 52 1-(4-(3-(pyridin-2yloxy)benzyl)pyrazin-1carbonyl)-1Hpyrazole-3carboxylic acid O A-on O δ 8.12 - 8.14 (m, 2H), 7.80 - 7.86 (m, 1H), 7.41 (t, J= 7.8 Hz, 1H), 7.25 (d, J = 7.5 Hz, lH), 7.18(br, 1H), 7.04 - 7.14 (m, 2H), 6.95 (d, 7=8.7 Hz, 1H), 6.80 (d, 7=2.7 Hz, 1H), 3.89 (br, 4H), 3.76 (br, 2H), 2.77 (br, 4H) 408,0 53 \-(trans-5-{(3chloro-5fluorobenzyl)oxy)o kgahydrocyclopent a[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O N A rY N JT ^Ν Λ ^Η V-OH ίζΑ ο CI δ 8.13 (d, 7= 2.8 Hz, 1H), 7.19 (s, 1H), 7.03 - 7.09 (m, 2H), 6.73 (d, J = 2.8 Hz, 1H), 4.47 (s, 2H), 4.20 - 4.24 (m, 1H), 3.87 - 4.10 (m, 3H), 3.68 - 3.75 (m, 1H), 2.91 (br, 2H), 2.03 - 2.11 (m, 2H), 1.77 - 1.83 (m, 2H) 425.2 [M+ _NH4 ] + 54 4-chloro-1-(4-(((5chloro-2- (trifluoromethyl)benzyl)(methyl)amino)methyl)piperidine1-carbonyl)- 1Hpyrazole-3carboxylic acid CI 0 Λ ¹ Ι^Ί^Α-οι CFo bF _{3 Ο} δ 8.13 (s, 1H), 7.88 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.41 - 7.43 (m, 1H), 4, 37 - 4.40 (m, 2H), 3.67 (s, 2H), 3.08 - 3.14 (m, 2H), 2.33 (d, J = 6.8 Hz, 2H), 2 .24 (s, 3H), 1.86 - 1.93 (m, 3H), 1.22 - 1.32 (m, 2H) 493,0

- 92 047826

55 1-(ti/>ais-5-((4-(4-chlorophenoxy)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid o H Λ G-Λ I ¹ 4% / ' Ν=/ Til \ 11° ⁿ Uon L 1 AJ o δ 8.16 (d, J = 2.7 Hz, 1H), 7.327.38 (m, 4H), 6.95 - 7.00 (m, 4H), 6.77 (d, J = 2.7 Hz, 1H), 4.48 (s, 2H), 3.60 - 4.27 (m, 5H), 2.92 (br, 2H), 2.09 - 2.12 (m, 2H), 1 .77 1.86 (m, 2H) 499.2 [M+ _NH4 ] ⁺ 56 1-(1-(6(trifluoromethyl)benzo[b]thiophene-2-carbonyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid о ω J % Ο 58.29 (s, 1H), 8.12 (d, J = 2.7 Hz, 1H), 8.06 (d,.7 = 8.4 Hz, 1H), 7.84 (s, 1H), 7.63 - 7.67 (m, 1H), 6.78 (d, J= 2.7 Hz, 1H), 4.61 (br, 2H), 3.92 (t, J = 6.6 Hz , 2H), 3.12 3.32 (m, 4H), 2.25 (t, J = 6.6 Hz, 2H), 1.98 - 2.00 (m, 2H), 1.60 1, 64 (m, 2H) 507,0 57 1-(4-(3-((4(trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid CF ₃ 0 AHSA One O 5 8.32 (d, J= 5.2 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.35 - 7.45 (m, 2H), 7.23 - 7.30 (m, 3H), 7.09 - 7.12 (m, 1H), 6.78 (d, J = 2.7 Hz, 1H), 3.89 (br, 4H), 3.75 (s, 2H), 2.74 (br, 4H) 476.4 58 1-(2-(6(trifluoromethyl)benzo[b]thiophene-2carbonyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid ω ¹ O Ζ Ζ-Ζ o ι 5 8.32 (s, 1H), 8.04 - 8.12 (m, 2H), 8.00 (s, 1H), 7.67 (d, J= 8.4 Hz, 1H), 6, 75 - 6.79 (m, 1H), 4.02 - 4.06 (m, 1H), 3.76 - 3.84 (m, 6H), 3.63 (br, 1H), 2.02 - 2.07 (m, 2H), 1.78 - 1.83 (m, 4H) 507.2

- 93 047826

59 1-(4-(3-(pyridin-4yloxy)benzyl)pip erazin-1carbonyl)-1Hpyrazole-3carboxylic acid ahshЪ L~on O δ 8.40 - 8.42 (m, 2H), 8.13 (d, J = 2.7 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.34 ( b,7=7.8Hz, 1H),7.22 (br, 1H), 7.08 - 7.12 (m, 1H), 6.97 - 6.99 (m, 2H), 6.82 ( d, J = 2.7 Hz, 1H), 3.87 (br, 4H), 3.73 (br, 2H), 2.72 (br, 4H) 408.2 60 1-(4-(3-(pyrazin-2yloxy)benzyl)pyrazin-1carbonyl)-1Hpyrazole-3carboxylic acid O o δ 8.41 (s, 1H), 8.28 (s, 1H), 8.13 -8.14 (m, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7, 38 - 7.42 (m, 1H), 7.21 - 7.27 (m, 2H), 7.07 - 7.10 (m, 1H), 6.72 (d.7= 2.7 Hz, 1H), 3.87 (br, 4H), 3.61 (s, 2H), 2.57 - 2.60 (t, J =2.7 Hz, 4H) 409.4 61 1-(4-(3-((5- (trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid o g o P z— z z-z o I δ 8.42 (br, 1H), 8.08 - 8.12 (m, 2H), 7.44 (t, J= 8.0 Hz, 1H), 7.24 - 7.32 (m, 2H ), 7.11 - 7.18 (m, 2H), 6.79 (d.7=2.4 Hz, 1H), 3.79 - 3.90 (m, 6H), 2.78 (br, 4H) 476.4 62 1-(4-(3(pyrimidin-2yloxy)benzyl)pyrazin-1carbonyl)-1Hpyrazole-3carboxylic acid O ^-° ⁿ O δ 8.59 (d, J = 4.8 Hz, 2H), 8.12 (d, 7 = 2.8 Hz, 1H), 7.44 (1.7 = 8.0 Hz, 1H), 7 .30 (d, J = 8.0 Hz, 1H), 7.20 - 7.25 (m, 2H), 7.12-7.15 (m, 1H), 6.80 (d, J = 2 .8 Hz, 1H), 3.89 (br, 4H), 3.77 (s, 2H), 2.76 (1.7 =4.8 Hz, 4H) 409.4 63 1-(4-(3(pyrimidin-4yloxy)benzyl)pip erazin-1carbonyl)-1Hpyrazole-3carboxylic acid O,ιΧοΑ O δ 8.70 (s, 1H), 8.60 (d, 7 = 6.0 Hz, 1H), 8.05 (d,7 = 2.7 Hz, 1H), 7.43 (1.7 = 7.8Hz, 1H),7.31 (d,7=7.8Hz, 1H), 7.22 (s, 1H), 7.03 - 7.11 (m, 2H), 6.73 (d , 7= 2.7 Hz, 1H), 3.87 (br, 4H), 3.62 (s, 2H), 2.59 (1.7 = 4.8 Hz, 4H) 409,0

- 94 047826

64 1-(4-(3(pyrimidin-2yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid O n=/ |ί Ν λ~ ^0Η δ 8.85 (d, J = 5.2 Hz, 2H), 8.47 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.50 7.57 (m, 2H), 7.37 (t, J = 4.8 Hz, 1H), 6.79 (d,7 = 2.4 Hz, 1H ),3.88 - 4.04 (m, 6H), 2.83 (t, J= 4.8 Hz, 4H) 393.4 65 1-(4-(3(pyrimidin-5yloxy)benzyl)pip erazin-1carbonyl)-1Hpyrazole-3carboxylic acid 7 °Η ο δ 8.90 (s, 1H), 8.53 (s, 2H), 8.08 (d.7 = 2.4 Hz, 1H), 7.43 (1.7 = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.04 - 7.07 (m, 1H), 6.76 (d, J = 2.4 Hz , 1H), 3.86 (br, 4H), 3.62 (s, 2H), 2.60 (t, J = 4.8 Hz, 4H) 409.1 66 1-(4-(4-methyl-2(1,3,4-oxadiazol-2yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid 0 ___) Ν=/ I U-on Ο^Ν 0 \=Ν δ 9.07 (s, 1H), 8.09 (d, 7 = 2.8 Hz, 1H), 7.76 (s, 1H), 7.49 - 7.51 (m, 1H), 7, 42 - 7.44 (m, 1H), 6.77 (d, 7= 2.8 Hz, 1H), 4.13 (s, 2H), 3.78 (br, 4H), 2.80 (br , 4H), 2.43 (s, 3H) 397,5 67 1-(4-(4-chloro-2(1,3,4-oxadiazol2- yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid τ Ο Ζ-Ζ ζ—h ζ ρ-Ρ ο δ9.09 (s, 1H), 8.12 (d.7 = 2.4Hz, 1H), 7.92 (s, 1H), 7.60 - 7.64 (m, 2H), 6.82 ( d,7= 2.4 Hz, 1H), 4.01 (s, 2H), 3.69 (br, 4H), 2.62 - 2.64 (m, 4H) 417.4

- 95 047826

68 1-(4-(2-(1,3,4-oxadiazol-2-yl)4- (trifluoromethoxy)benzyl)piperazine- 1-carbonyl)- 1Hpyrazole-3-carboxylic acid ^РзС0 уЦ N==/ 1 Λ-on Ν 0 \=Ν 09.10(8.1H), 8.09(d,7 = 2.4Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 8.5Hz, 1H), 7 .51 - 7.54 (m, 1H), 6.79 (d, J = 2.4 Hz, 1H), 4.01 (s, 2H), 3.68 (br, 4H), 2.57 - 2.59 (m, 4H) 467.4 69 1-(4-(2-(1,3,4oxadiazol-2-yl)4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid τ Ο Ζ-Ζ ο Ο LL? 5 9.12 (s, 1H), 8.09 (s, 1H), 8.09 (d, J = 2.8 Hz, 1H), 7.85 - 7.91 (m, 2H), 6, 80 (d, J = 2.8 Hz, 1H), 4.04 (s, 2H), 3.67 (br, 4H), 2.54 2.56 (m, 4H) 451,5 70 1-(2-(3-chloro-5-fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid F /==( ο α--/ \ K V/ Ρν ^λ νΑ ^V -' ^J Χ~ΟΗ ο δ 8.04 (d, J = 2.7 Hz, 1H), 7.40 (s, 1H), 7.22 - 7.28 (m, 2H), 6.76 (d, J = 2.7 Hz, 1H), 4.13 - 4.19 (m, 2H), 3.77 (br, 2H), 3.63 - 3.68 (m, 2H), 3.22 - 3.32 (m, 2H), 3.10 (br, 2H), 1.96 - 2.01 (m, 2H), 1.68 1.83 (m, 4H) 421,1 71 1-(2-(2-methyl-3(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid /=\ ο ^FsC O ^J Χ-ΟΗ 0 δ 8.05 (d, J= 2.4 Hz, 1H), 7.61 7.65 (m, 2H), 7.31 - 7.39 (m, 1H), 6.76 (d, J = 2.4 Hz, 1H), 3.99 (s, 2H), 3.83 (br, 2H), 3.72 (br, 2H), 2.90 (t, J = 6.6 Hz, 2H) , 2.78 (s, 2H), 2.53 (s, 3H), 1.86 (t, J =7.2 Hz, 2H), 1.75 - 1.82 (m, 4H) 451.2

- 96 047826

72 1-(2-(3-chloro-5(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid __CF ₃ ^ci -Q N O A ^J U-on O 5 8.05 (d, J = 2.7 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 6.76 (d, J = 2.7 Hz, 1H), 3.81 3.86 (w, 4H), 3.68 - 3.71 (m, 2H), 2.83 (t, J = 6.9 Hz, 2H) , 2.68 (s, 2H), 1.85 (1.7 = 6.9 Hz, 2H), 1.81 - 1.70 (w, 4H) 471.2 73 1-(2-([1,H-biphenyl]-3-ylmethyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid ΟΌ U~OH O 5 8.05 (d, J = 2.7 Hz, 1H), 7.83 (s, 1H), 7.74 - 7.66 (w, ZN), 7.66 7.49 (w, 2H) , 7.36 - 7.49 (m, ZN), 6.75 (s, 1H), 4.40 (s, 2H) 3.86 (br, 2H), 3.68 (br, 2H), 3 .42 (1, J = 6.9 Hz, 2H), 3.26 (s, 2H), 2.06 (1, 7 = 6.9 Hz, 2H), 1.84 - 1.76 (w, 4H) 445.3 74 1-(2-(2-chloro-6(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid G ^r z ^s? O U-on O 5 8.06 (br, 1H), 7.68 - 7.73 (w, 2H), 7.46 (4.7=7.8Hz, 1H), 6.78 (br, 1H), 3.98 (s, 2H), 3.70 - 3.77 (w, 4H), 2.76 (1, J = 6.9 Hz, 2H), 2.63 (s, 2H), 1.64 - 1, 74 (m, 6H) 471.2 75 1-(2-(4-(4-chlorophenoxy)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid ^ci O-° '—' ⁰ r^N'^N'% O 5 8.06 (d, J = 2.7 Hz, lH), 7.53 (d, J = 8.7 Hz, 2H), 7.49 - 7.37 (w, 2H), 7.00 - 7.08 (w, 4H), 6.76 (d, 7= 2.7 Hz, 1H), 4.31 (s, 2H), 3.82 - 3.88 (w, 2H), 3.65 - 3.78 (w, 2H), 3.40 (1, J = 7.2 Hz, 2H), 3.23 (s, 2H), 2.06 (t, J = 7.2 Hz, 2H) , 1.86-1.76 (w, 4H) 495.2

- 97 047826

76 1-(1-(2-chloro-4(trifluoromethyl)benzyl)-1,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid CI F ₃ C^V ГК O U-on O δ 8.07 (d, J= 2.7 Hz, 1H), 7.72 7.77 (m, 1H), 7.67 (s, 1H), 7.58 7.61 (m, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.54 - 4.58 (m, 2H), 3.89 (s, 2H), 3.09 - 3.19 (m, 2H) , 2.75 2.80 (m, 2H), 2.00 - 2.04 (m, 4H), 1.91 - 1.98 (m, 2H), 1.82 1.89 (m, 2H) 471.3 77 1-(2-(2-chloro-4(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid F ₃ C O N=/ U-on O δ 8.07 (d, J= 2.7 Hz, 1H), 7.75 7.81 (m, 2H), 7.66 (d, 7= 8.1 Hz, 1H), 6.78 (d ,7 = 2.7 Hz, 1H), 4.00 (s, 2H), 3.72 - 3.86 (m, 4H), 2.91 (t, J = 6.9 Hz, 2H), 2 .76 (s, 2H), 1.86 (t, J = 6.9 Hz, 2H), 1.80 1.72 (m, 4H) 471.2 78 1-(2-(3-chloro-4(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid F ₃ C ^Cl ~w '~~N O ^J U-on O δ 8.07 (d, 7= 2.7 Hz, 1H), 7.83 7.81 (m, 2H), 7.62 (d,7= 7.8 Hz, 1H), 6.79 (d ,7= 2.7 Hz, 1H),4.22 - 4.16 (m, 2H), 3.71 - 3.80 (m, 4H), 2.94 - 3.22 (m, 4H), 1.99 (t, J = 6.9 Hz, 2H), 1.85 - 1.73 (m, 4H) 471.2 79 1-(2-(3,5-difluorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid '<d U~OH O δ 8.08 (d.7= 2.7 Hz, 1H), 7.16 7.20 (m, 2H), 7.06 - 6.99 (m, 1H), 6.79 (d.7= 2.7 Hz, 1H), 4.19 (s, 2H), 3.82 - 3.87 (m, 2H), 3.67 3.72 (m, 2H), 3.25 (t, J = 6.9 Hz, 2H), 3.09 (s, 2H), 2.01 (t, J = 6.9 Hz, 2H), 1.75 - 1.87 (m, 4H) 405.2

- 98 047826

80 1-(1 -(2-((27^55)2,5- dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid o o LL? 0 N=/ U-ON 0 5 8.08 (d, 7 = 2.7 Hz, 1H), 7.81 (d, 7 = 7.8 Hz, 1H), 7.66 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 4.62 (br, 2H), 4.16 (s, 2H), 3.10 - 3.32 ( m, 4H), 2.89 (1.7=6.9 Hz, 2H), 2.01 -2.13(m, 6H), 1.86 - 1.96 (m, 2H), 1.61 1.88 (m, 2H), 1.57 - 1.60 (m, 2H), 0.90 (d, 7=6.0 Hz, 6H) 534.3 81 1-(4-((5-chloro-2(trifluoromethyl)benzyl)(methyl)amino)piperidine-1-carbonyl)-1Hpyrazole-3-carboxylic acid O CF ₃ Ατν-ο Ch |l J 1 U~on O CI 5 8.08 (d,7= 2.7 Hz, 1H), 7.9O (s, 1H), 7.64 (d,7= 8.4 Hz, 1H), 7.40 - 7.44 (m , 1H), 6.80 (d, J = 2.7 Hz, 1H), 4.47 - 4.52 (m, 2H), 3.83 (s, 2H), 3.06 - 3.14 ( m, 2H), 2.81 - 2.89 (m, 1H), 2.26 (s, 3H), 1.93 - 1.96 (m, 2H), 1.69 - 1.82 (m, 2H) 445.1 82 1-(1-(2-(3-oxa-8azabicyclo[3.2.1]o kgan-8-yl)-4(trifluoromethyl)benzyl)-1,8diazaspiro[4.5]dec an-8-carbonyl)1H- pyrazole-3carboxylic acid Ы-J/ ^F3C 4X 0- 0 U~on 0 5 8.09 (d,7 = 2.7 Hz, lH),7.75(d, J= 8.1 Hz, 1H), 7.34 (d, 7= 8.1 Hz, 1H), 7 .23 (s, 1H), 6.78 (d,7 = 2.7 Hz, 1H), 4.63 (br, 2H), 4.26 (s, 2H), 3.92 (d, J = 9.3 Hz, 2H), 3.60 - 3.75 (m, 4H), 3.07 - 3.29 (m, 4H), 2.14 - 2.26 (m, 4H), 1.88 - 2.06 (m, 6H), 1.66 - 1.85 (m, 2H) 548.3 83 1-(4-(2(pyrrolidin-1yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid N Y~°N O ° 5 8.10 (d, 7 = 2.6 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.12 - 7.15 (m, 2H), 6.79 ( d,7=2.6Hz, 1H),3.88 (br, 4H), 3.71 (s, 2H), 3.24 - 3.28 (m, 4H), 2.61 (t, J = 4.9 Hz, 4H), 1.96 -2.03 (m, 4H) 452,0

- 99 047826

84 1-(4-(3-(3- chlorophenoxy)benzyl)piperazine-1carbonyl)-1Hpyrazole-3carboxylic acid CI O ЬцХСХ U-он O δ 8.10 (d, J= 2.7 Hz, 1H), 7.35 7.47 (m, 1H), 7.28 - 7.34 (m, 1H), 7.21 - 7.27 ( m, 1H), 7.08 - 7.18 (m, 2H), 6.92 - 6.99 (m, 2H), 6.89 - 6.92 (m, 1H), 6.80 (d, J = 2.7 Hz, 1H), 3.89 (br, 4H), 3.73 (s, 2H), 2.72 - 2.76 (m, 4H) 441.2 85 1-(4-(3-(2-chlorophenoxy)benzyl)piperazine-1carbonyl)-1Hpyrazole-3carboxylic acid O aaoch U-on O δ 8.10 (d, J= 2.7 Hz, 1H), 7.47 7.50 (m, 1H), 7.26 - 7.36 (m, 2H), 7.12 - 7.18 ( m, 2H), 7.01 - 7.08 (m, 2H), 6.85 - 6.88 (m, 1H), 6.78 (d, J= 2.7 Hz, 1H), 3.89 (br, 4H), 3.76 (s, 2H), 2.76 - 2.88 (m, 4H) 441.2 86 1-(1-(3-chloro-5(trifluoromethyl)benzyl)-1,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid F ₃ C ^s nJ 1 ¹ / / X___J No.=/ U-ON o δ 8.10 (d, 7= 2.7 Hz, 1H), 7.627.75 (m, 3H), 6.81 (d, J = 2.7 Hz, 1H), 4.55 - 4.59 ( m, 2H), 3.99 (s, 2H), 3.09 - 3.32 (m, 2H), 2.89 2.94 (m, 2H), 2.05 - 2.15 (m, 4H ), 1.91 - 1.99 (m, 2H), 1.71 - 1.89 (m, 2H). 471,0 87 1-(4-(3(pyrrolidin-1yl)-5- (trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid CF ₃ O 1 A уХ nA \__1 U-on O δ 8.11 (d,7 = 2.7 Hz, 1H), 6.91 (s, 1H), 6.83 (s, 1H), 6.80 (d, J = 2.7 Hz, 1H), 6.70 (s, 1H), 3.93 (br, 4H), 3.73 (s, 2H), 3.34 - 3.35 (m, 2H), 3.31 - 3.32 (m, 2H), 2.74 2.78 (m, 4H), 2.04 - 2.10 (m, 4H) 452,0

- 100 047826

88 1-(1-(3(pyrrolidin-1yl)-5- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid F ₃ C gy ⁰ / nJ iiz <1 < fx/ n==/ U-on 0 δ 8.11 (d,J = 2.7Fii, 1H),7.O1 (s, 1H), 6.90 (s, 1H), 6.79 - 6.80 (m, 2H), 4.76 (br, 2H), 4.32 (s, 2H), 3.34 - 3.56 (m, 4H), 3.09 - 3.32 (m, 4H), 2.26 - 2.46 (m , 4H), 1.96 - 2.12 (m, 6H), 1.81 - 1.85 (m, 2H) 506.1 89 1-(2-methyl-4-((3methyl-[1,Hbiphenyl]-4yl)methyl)piperazi and-1-carbonyl)-1Hpyrazole-3carboxylic acid _n ° N=/ 1 U-OH 0 5 8.11 (d,7 = 2.7 Hz, lH),7.59(d, J = 7.2 Hz, 2H), 7.28 - 7.43 (m, 6H), 6.82 ( d,7= 2.7 Hz, 1H), 4.63 (br, 1H), 4.20 - 4.25 (m, 1H), 3.56 (s, 2H), 3.40 - 3.48 (m, 1H), 2.87 - 2.91 (m, 1H), 2.77 - 2.81 (m, 1H), 2.48 (s, 3H), 2.38 - 2.43 (m , 1H), 2.22-2.31 (m, 1H), 1.41 (d, 7=6.6 Hz, 3H) 419.2 90 1-(4-(2(pyrrolidin-1yl)-3- (trifluoromethyl)benzyl)piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid 0 ^N =( NA~OH O ° δ 8.11 (d,7= 2.7 Hz, 1H), 7.92 7.94 (m, 1H), 7.56 - 7.60 (m, 1H), 7.33 - 7.38 ( m, 1H), 6.79 (s, 7 = 2.7 Hz, 1H), 3.89 (br, 4H), 3.67 (s, 2H), 3.21 - 3.32 (m, 4H ), 2.60 - 2.63 (m, 4H), 1.99 - 2.05 (m, 4H) 452,0 91 1-(4-(2-chloro-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid 0 ^f ' ^c yj γΛλ N=/ I /he δ 8.12 (d,7= 2.7 Hz, 1H), 7.72 7.81 (m, 1H), 7.65 (s, 1H), 7.60 7.65 (m, 1H), 6.80 (d, J = 2.7 Hz, 1H), 3.89 (br, 4H), 3.78(s, 2H), 2.67 (t, 7 =5.0 Hz, 4H) 416.9

- 101 047826

92 (5)-1-(4-(2-(3-fluoropyrrolidin-1-yl)-4- (trifluoromethyl/benzyl/piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid N=y N )~ ^0H h ° F δ 8.13 (d, J = 2.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.19 - 7.21 (m, 2H), 6.82 ( d,7=2.6Hz, 1H),5.27 - 5.41 (m, 1H), 3.87 (br, 4H), 3.76 (br, 2H), 3.46 - 3.69 ( m, 3H), 3.21 - 3.26 (m, 1H), 2.65 - 2.67 (m, 4H), 2.22 - 2.34 (m, 2H) 470,5 93 1-(1-(2(pyrrolidin-1yl)-4- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid ω ¹ A o ΞΕ δ 8.13 (d, J = 2.6 Hz, 1H), 7.67 (d, 7 = 7.8 Hz, 1H), 7.49 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 4.70 (br, 2H), 4.39 (br, 2H), 3.19 - 3.24 ( m, 8H), 2.56 (br, 4H), 2.02 - 2.08 (m, 6H), 1.80 - 1.84 (m, 2H) 506.1 94 1-(4-(2-((2Я,55)- 2,5- dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl/piperazine-1-carbonyl)- 1Нpyrazole-3-carboxylic acid ^FsC YDi gal Ν==/ SU ^0N δ 8.13 (d, J = 2.7 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.49 (d, 7= 8.1 Hz, 1H), 6.81 (d, 7 = 2.7 Hz, 1H), 3.89 - 4.02 (m, 6H), 3.06 - 3.20 (m, 2H), 2.55 - 2.67 (m, 4H), 2.05 - 2.12 (m, 2H), 1.53 - 1.58 (m, 2H), 0.90 (d, 7 = 6.0 Hz, 6H) 480.3 95 (A)-1-(4-(2-(2-methylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl/piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid O F ₃ C. A V|] \ NN Ν=/ •^2} c) ^he δ 8.13 (d, 7 = 2.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.81 (d, 7 = 2.8 Hz, 1H), 3.60 - 3.90 (m, 7H), 3.56 - 3.58 (m, 1H), 2.81 - 2.87 (m, 1H), 2.70 (br, 4H), 2.21 - 2.23 (m, 1H), 1.90 - 2.00 (m, 1H), 1, 82 - 1.88 (m, 1H), 1.52 - 1.70 (m, 1H), 0.98 - 1.02 (m, 3H) 466,5

- 102 047826

96 1-(5-(4(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxylic acid ks...... --Х' ^γ Ύ ^{>γ he} δ 8.14 - 8.30 (d, 7=2.7 Hz, 1H), 7.66 - 7.73 (d, J = 0.8 Hz, 2H), 7.59 - 7.66 (d , J = 0.8 Hz, 2H), 6.78 (d, J = 2.7 Hz, 1H), 3.80 4.27 (m, 6H), 2.97 - 3.14 (m, 4H ), 2.63 - 2.92 (d, J = 6.4 Hz, 2H) 409.1 97 1-(4-(4-chloro-2-(4-cyclopropylpiperazin-1 yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid O Ap ν λ~ ^0Η O ⁰ Ν λ δ 8.14 (d, J= 2.5 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.14 - 7.16 (m, 2H), 6.82 ( d,7= 2.5 Hz, 1H), 3.87 (br, 4H), 3.74 (s, 2H), 3.12 - 3.17 (m, 8H), 2.72 - 2.74 (m, 4H), 2.29 (br, 1H), 0.74 (br, 4H) 473,0 98 1-(4-(3-(4-chlorophenoxy)benzyl)piperazine-1carbonyl)-1Hpyrazole-3carboxylic acid ^α ΌΑΧθΑ And ^he 0 δ 8.14 (d,7= 2.6 Hz, 1H), 7.35 7.40 (m, 3H), 7.19 (d, 7 = 7.6 Hz, 1H), 7.09 (s , 1H), 6.92 - 7.01 (m, 3H), 6.82 (d,7=2.6Hz, 1H), 3.92 (br, 4H), 3.76 (br, 2H), 2.79 (br, 4H) 441.4 99 1-(2-(5-chloro-2(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxamide Cl 0 gL Anh ₂ o (Chloroform-T) δ 8.08 (d, 7= 2.7 Hz, 1H), 7.78 (s, 1H), 7.57 (d, 7 = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.91 (d,7 = 2.7 Hz, 1H), 6.68 (br, 1H), 5.49 (br, 1H), 3.54 - 3.90 (m, 6H), 2.60 - 2.76 (m, 2H), 2.52 (s, 2H), 1.75 - 1.77 (m, 6H) 470.2 100 1-(4-(2(piperidin-1-yl)4- (trifluoromethyl)benzyl/piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid T o °=< Z—h z ^-O O LL? δ 8.14 (d, 7 = 2.6 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.36 - 7.39 (m, 2H), 6.82 ( d,7=2.6Hz, 1H),3.88 - 3.90 (m, 6H), 2.92 (br, 4H), 2.77 (br, 4H), 1.76 - 1.77 ( m, 4H), 1.63 (br, 2H) 466,5

- 103 047826

101 (A)-1-(4-(2-(3 fluoropyrrolidin1-yl)-4(trifluoromethyl)benzyl/piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid ^RzS GE gal N U~OH O ⁰ f δ 8.14 (d,7 = 2.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.20 - 7.23 (m, 2H), 6.83 ( d, J= 2.7 Hz, 1H), 5.27 - 5.41 (m, 1H), 3.71 - 4.04 (m, 6H), 3.45-3.71 (m, 3H) , 3.21 3.26 (m, 1H), 2.55 - 2.89 (m, 4H), 2.24 - 2.36 (m, 2H) 470,5 102 1-(4-(2-(4-fluoropiperidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid O A G 11 g ^Ν A AxAx ^N -A ν==7 Ν U-OH Q ⁰ F δ 8.14 (d, 7 = 2.7 Hz, 1H), 7.71 (d, 7 = 7.7 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 2.7 Hz, 1H), 4.69 - 4.88 (m, 1H), 3.87 (br, 4H), 3.79 ( br, 2H), 3.11 - 3.17 (m, 2H), 2.88 - 2.95 (m, 2H), 2.70 (br, 4H), 2.08 - 2.18 (m, 1H), 1.89 -2.05 (m, 3H) 484.5 103 (A)-1-(4-(2-(2-methylpiperidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid O N G N xx n=/ V0 s/ ^0N δ 8.14 (d, 7 = 2.7 Hz, 1H), 7.74 (d, 7 = 8.0 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 2.7 Hz, 1H), 3.80 - 3.89 (m, 6H), 3.02 - 3.11 (m, 2H), 2.69 (br, 4H), 2.57 - 2.64 (m, 1H), 1.83 - 1.88 (m, 2H), 1.70 - 1.75 (m, 2H), 1, 44 - 1.56 (m, 2H), 0.83 (d, 7 = 6.4 Hz, 3H) 480,5 104 (5)-1-(4-(2-(2-methylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid ^FsC Y0i gal Ν 'Ο ° δ 8.14 (d, 7 = 2.8 Hz, 1H), 7.72 (d, 7 = 8.0 Hz, 1H), 7.32 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 2.8 Hz, 1H), 3.63 - 3.90 (m, 7H), 3.57 - 3.61 (m, 1H), 2.82 - 2.87 (m, 1H), 2.70 (br, 4H), 2.12 - 2.26 (m, 1H), 1.98 - 1.99 (m, 1H), 1, 84 - 1.91 (m, 1H), 1.61 - 1.68 (m, 1H), 1.02 (d, 7 = 6.0 Hz, 3H) 466,5

- 104 047826

105 1-(4-(2-(3-oxa-8azabicyclo[3.2.1]o ctan-8-yl)-4chlorobenzyl)piper zin-1-carbonyl)1H-pyrazole-3carboxylic acid t o Ζ-Ζ ζ—ch Ζ o 58.15 (d,7 = 2.5 Hz, 1H), 7.45 (d, 7 = 8.0 Hz, 1H), 6.99 - 7.01 (t, 1H), 6.95 (s , 1H), 6.84 (d, J = 2.5 Hz, 1H), 3.80-3.95 (t, JN), 3.66 - 3.68 (t, 2H), 2.77 ( br, 4H), 1.96 -2.05 (t, 4H) 460.4 106 1-(4-(2(tetrahydro-1Hfuro[3,4-c]pyrrol5(3H)-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid бЛ О cQ^^z— О Ζ-Ζ О I 58.15 (d,7 = 2.6 Hz, 1H), 7.68 (d, 7 = 7.8 Hz, 1H), 7.39 - 7.41 (t, 2H), 6.82 (d, 7= 2.6 Hz, 1H), 3.96 (br, 8H), 3.74 - 3.79 (t, 2H), 3.02 - 3.20 (t, 4H), 3.02 (br , 2H), 2.82 (br, 4H) 494,5 107 1-(4-(4-chloro-2(pyrrolidin-1yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid O ^CI YY ΔΑ NJ~ ^0H O ⁰ 58.15 (d,7 = 2.7 Hz, lH), 7.37 (d, 7 = 8.2 Hz, 1H), 7.00 (s, 1H), 6.89 - 6.92 (t , 1H), 6.83 (d, 7 = 2.7 Hz, 1H), 3.86 -3.91 (t, 6H), 3.30 - 3.19 (t, 4H), 2.80 ( br, 4H), 2.06 - 1.92 (t, 4H) 418,5 108 1-(4-(2-(4,4-difluoropiperidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid o nV Ν λ~ ^ΟΗ U ⁰ FF 58.15 (d,7 = 2.7 Hz, 1H), 7.72 (d, 7 = 7.8 Hz, 1H), 7.40 - 7.43 (t, 2H), 6.85 (d ,7= 2.7 Hz, 1H), 3.87 (br, 4H), 3.80 (s, 2H), 3.10 - 3.13 (t, 4H), 2.69 - 2.72 ( t, 4H), 2.12 - 2.24 (t, 4H) 502,5

- 105 047826

109 1-(4-(2-(4-(2hydroxypropan-2yl)piperidin-1 yl)-4- (trifluoromethyl)benzyl/piperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid О ^FsC V^i Γ'ν ^Λ νΛ ULO nJ NJ~ ^0H ό ° OH δ 8.15 (d,7 = 2.7 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.38 - 7.42 (m, 2H), 6.85 ( d, J = 2.7 Hz, 1H), 3.89 (br, 6H), 3.24 - 3.27 (m, 2H), 2.70 - 2.77 (m, 6H), 1.89 - 1.92 (m, 2H), 1.55 - 1.65 (m, 2H), 1.44 1.50 (m, 1H), 1.25 (s, 6H) 524,5 110 (5)-1.(4-(2-(2methylpiperidin1-yl)-4-(trifluoromethyl)bepzyl)piperazine-1 carbonyl)-1Hpyrazole-3carboxylic acid 0 ^F 3C^^ g il । o^~ ^OH δ 8.15 (d, 7 = 2.7 Hz, 1H), 7.72 (d, 7 = 8.0 Hz, 1H), 7.51 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H), 3.84 - 3.90 (m, 6H), 3.02 - 3.04 (m, 2H), 2.71 (br, 4H), 2.57 - 2.62 (m, 1H), 1.84 - 1.85 (m, 2H), 1.69 - 1.72 (m, 2H), 1, 41 - 1.58 (m, 2H), 0.82 (d, 7 = 6.0 Hz, 3H) 480.2 111 1-(4-(4-chloro-2(tetrahydro-1Hfuro[3,4-c]pyrrole-5(3H)yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid ^α ΥΊι gAl N==/ N λ~ΟΗ 8 ° δ 8.15 (s, 1H), 7.42(d, 7 = 8.0 Hz, 1H), 7.22 (s, 1H), 7.16-7.21 (m, 1H), 7, 15 (s, 1H), 3.93 -4.91 (m, 10H), 3.11 - 3.16 (m, 4H), 2.96 3.01 (m, 6H) 460.4 112 4-chloro-1-(4-((5chloro-2(trifluoromethyl)benzyl)(methyl)amino)piperidine-1-carbonyl)-1Hpyrazole-3-carboxylic acid 0 CF _{3 C} | AJ n==/ ίιψ N \ |l J 1 Aoh 0 Cl δ 8.15 (s, 1H), 7.90 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.41 - 7.47 (m, 1H), 4, 49 - 4.53 (m, 2H), 3.84 (s, 2H), 3.05 - 3.16 (m, 2H), 2.84 - 2.89 (m, 1H), 2.27 ( s, 3H), 1.93 - 2.03 (m, 2H), 1.71 - 1.81 (m, 2H) 479,1

- 106 047826

113 1-(4-(2-(4carbamoylpiperidin-1-yl)-4- (trifluoromethyl)benzyl/piperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid t o Z-Z °=< o LL? δ 8.16 (d, J= 2.7 Hz, 1H), 7.70 7.73 (m, 1H), 7.39 - 7.41 (m, 2H), 6.84 (d, J = 2.7 Hz, 1H), 3.83 3.89 (m, 6H), 3.24 - 3.30 (m, 2H), 2.66 - 2.85 (m, 6H), 2.36 - 2.46 (m, 1H), 1.95 - 1.98 (m, 4H) 509.2 114 1-(4-(2-(2,5- dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid ^FsC YA gal N==/ (U δ 8.17 (d, 7 = 2.3 Hz, 1H), 7.86 (d, J= 8.1 Hz, 1H), 7.66 (s, 1H), 7.51 (d, J= 8.1 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 3.96 (br, 2H), 3.87 (br, 4H), 3.16 - 3.20 ( m, 2H), 2.68 (br, 4H), 2.06 - 2.12 (m, 2H), 1.54 - 1.58 (m, 2H), 0.91 (d, J = 6, 0 Hz, 6H) 480.3 115 1-(5-(3-chloro-5-fluorobenzyl)octa-dropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O .a-a'Ch o δ 8.17 (d, 7 = 2.4 Hz, lH), 7.30 (s, 1H), 7.15 - 7.18 (m, 2H), 6.77 (d, J = 2.4 Hz, 1H), 3.98 (br, 6H), 3.08 (br, 4H), 2.91 - 2.93 (m, 2H) 393,1 116 1-(5-(3-(4-chlorophenoxy)benzyl)octahydropyrrole o [3,4-c]pyrrole-2-carbonyl)- 1Hpyrazole-3-carboxylic acid •όλΑ 0 δ 8.17 (d, 7 =2.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.32 - 7.36 (m, 2H), 7.24 ( d,7=7.6Hz, 1H),7.14 (s, 1H), 7.01 - 7.05 (m, 1H), 6.97 - 7.00 (m, 2H), 6.75 ( d, J = 2.4 Hz, 1H), 3.96 - 4.30 (m, 6H), 3.35 (br, 1H), 3.33 -3.34 (m, 1H), 3.13 (br, 2H), 3.03 - 3.06 (m, 2H) 467.4

- 107 047826

117 1-(5-(3-(trifluoromethoxy)benzyl)octahydropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid W1 O δ 8.17 (d, J= 2.5 Hz, 1H), 7.41 7.52 (m, ZN), 7.24 - 7.30 (m, 1H), 6.76 (d, J = 2.5 Hz, 1H), 3.96 4.12 (m, 6H), 3.27 - 3.32 (m, 2H), 3.00-3.11 (m, 4H) 425.2 118 1-(4-(2-(3-oxa-8azabicyclo[3.2.1]o kgan-8-yl)-4(trifluoromethyl)benzyl)piperazine-1 carbonyl)-1Hpyrazole-3carboxylic acid t O Ζ-Ζ °=< o o LL? δ 8.17 (d, 7 = 2.7 Hz, 1H), 7.7O (d, 7 = 7.9 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7 .17 (s, 1H), 6.85 (d,7 = 2.7 Hz, 1H), 3.96 (d, J = 9.6 Hz, 2H), 3.81 - 3.85 (m, 8H), 3.68 3.70 (m, 2H), 2.70 (br, 4H), 2.03 - 2.08 (m, 2H), 1.95 - 1.99 (m, 2H) 494,5 119 1-(4-(2-(4- acetamidopiperide in-1-yl)-4(trifluoromethyl)benzyl)piperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid O ^F 3 ^C x^X g ii । । Λ CHAHA > Ν==Ζ Ν U-° ^N f ^{0 HN} 'if ^x o δ 8.17 (d, 7 = 2.7 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1H), 3.82 - 3.88 (m, 7H), 3.18 - 3.21 (m, 2H), 2.83 - 2.88 (m, 2H), 2.74 (br, 4H), 1.97 - 2.01 (m, 5H), 1.67 - 1.76 (m, 2H) 523.3 120 1-(4-(2-(4hydroxypiperidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid o UUO nJ Ν ^~ ^0Н ф ° он δ 8.18 (d, 7 = 2.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.38 - 7.42 (m, 2H), 6.86 ( d,7=2.6Hz, 1H), 3.77 - 3.89 (m, 7H), 3.16 - 3.32 (m, 2H), 2.76 - 2.85 (m, 6H), 1.92 2.05 (m, 2H), 1.71-1.79 (m, 2H) 482.5

- 108 047826

121 1-(4-(4-chloro-3(pyrrolidin-1yl)phenoxy)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid t o Z-Z Q o y o , δ 8.19 (d, 7 = 2.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.90 (m, 1H), 6.66 (m, 1H) , 6.58 (m, 1H), 4.68 (m, 1H), 3.87 - 4.05 (m, 2H), 3.69 - 3.85 (m, 2H), 3.36 - 3 .47 (m, 4H), 1.77 - 2.20 (m, 8H) 419.3 122 1-(5-(3(trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxylic acid .Zh-Ach O δ 8.19 (d,7= 2.7 Hz, 1H), 7.58 7.78 (m, 4H), 6.78 (d, J = 2.7 Hz, 1H), 4.16 (s , 2H), 3.96 (br, 4H), 3.23 - 3.32 (m, 2H), 2.99 - 3.11 (m, 4H) 409.4 123 1-(5-(4(pyrrolidin-1yl)-2- (trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxylic acid Oh I.. CF ₃ O δ 8.19 (s, 1H), 7.53 (d, 7 =8.5 Hz, 1H), 6.74 - 6.82 (m, 3H), 3.51 4.61 (m, 6H) , 3.28 - 3.37 (m, 6H), 2.92 - 3.18 (m, 4H), 2.05 (br, 4H) 478,5 124 1-(5-(3-chloro-5(trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxylic acid O ci A , Xьсо Я O δ 8.22 (d,7= 2.7 Hz, 1H), 7.66 7.79 (m, 3H), 6.82 (d, J = 2.7 Hz, 1H), 3.69 - 4 .16 (m, 6H), 3.04 (br, 4H), 2.84 (br, 2H) 443.1

- 109 047826

125 1-(trans-5-([1,Hbiphenyl]-3-yloxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1-Flpyr azole-3-carboxylic acid O Η A Γ №=/ η Y-OH 0 δ 8.23 (m, 1Η), 7.54 - 7.69 (m, 2H), 7.24 - 7.51 (m, 4Η), 7.08 7.23 (m, 2H), 6, 87 - 6.98 (m, 1H), 6.83 (m, 1H), 5.03 - 5.16 (m, 1H), 3.50 - 4.41 (m, 4H), 2.88 - 3.13 (m, 2H), 2.10 - 2.40 (m, 2H), 1.87 -2.10 (m, 2H) 435.2 [M+ _NH4 ] ⁺ 126 1-(1-(2-(1Hhetrazol-5-yl)-4(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid o G/G? Μ 0 Ν==/ U-on 0 δ 8.45 (s, lH), 8.14 (d, J = 2.7 Hz, 1H), 7.80 - 7.88 (m, 2H), 6.82 (d, 7 = 2.7 Hz, 1H), 4.43 - 4.68 (m, 2H), 4.40 (s, 2H), 3.36 - 3.58 (m, 4H), 2.45 - 2.70 (m, 4H), 2.15 2.22 (m, 4H) 505,5 127 1-(2-((4(trifluoromethyl)pyridin-3-yl)methyl)2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Qu F ₃ C 0 . χ Χ-οη Ο δ 8.97 (s, 1H), 8.70 (d, J =5.1 Hz, 1H), 8.07 (d, J= 2.7 Hz, 1H), 7.70 (d, J= 5.1 Hz, 1H), 6.78 (d, 7= 2.7 Hz, 1H), 3.90 (s, 2H), 3.73 - 3.90 (m, 4H), 2.74 ( t, J= 6.9 Hz, 2H), 2.60 (s, 2H), 1.84 - 1.68 (m, 6H) 438.3 128 4-chloro-1-(trais-5((2- chlorobenzyl) (methyl )amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1 FIpyr azole-3-carboxamide H Cl γΛ ue _ΝΗζ Η CI (Chloroform-U) δ 8.25 (s, 1H), 7.44 - 7.46 (m, 1H), 7.33 - 7.35 (m, 1H), 7.16 - 7.22 (m , 2H), 6.62 (s, 1H), 5.75 (s, 1H), 3.96 - 4.15 (m, 2H), 3.60 - 3.77 (m, 4H), 3, 13 - 3.21 (m, 1H), 2.90 (s, 2H), 2.17 (s, 3H), 1.94 -2.02 (m, 2H), 1.61 (s, 2H) 436,0

- 110 047826

129 1-(4-(3-(4chlorophenoxy)benzyl)piperazine-1carbonyl)-4- methyl-1 H-pyrazol3-carboxylic acid 0 ^x. P χγ |] Til 1 Ν Ν __ΰ AA _q AAxz- ^N xA °N δ 7.87 (s, 1H), 7.32 - 7.37 (m, 3H), 7.13 - 7.16 (m, 1H), 7.05 (s, 1H), 6.91 - 6 .99 (m, 3H), 3.85 (s, 4H), 3.62 (s, 2H), 2.60 - 2.63 (m, 4H), 2.26 (s, 3H) 455.2 130 1-(2-(5-chloro-2(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)-4methyl-1 H-pyrazol3-carboxylic acid __ o Ά '^ ⁼ \ '° n δ 8.33 (s, 1H), 7.62 - 7.67 (m, 2H), 7.40 - 7.43 (m, 1H), 3.66 3.86 (m, 6H), 2, 75 - 2.79 (m, 2H), 2.62 (s, 2H), 2.27 - 2.29 (m, 3H), 1.70 - 1.85 (m, 6H) 485.2 131 1-(2-(5-chloro-2(trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]non-7-carbonyl)-4methyl-1 H-pyrazol3-carboxylic acid ? /х А ,Ν Р JL < Ν Ν' Г 11 /тхх* he ΑΑχ^ ^Ν -/ \ CF ₃ δ 7.89 (br, 1H), 7.71 - 7.76 (m, 2H), 7.50 - 7.53 (m, 1H), 4.09 (s, 2H), 3.73 (s , 4H), 3.47 (m, 4H), 2.29 (s, 3H), 1.96 (m, 4H) 471.2 132 4-chloro-1-(4-(3-(4-chlorophenoxy)benzyl)piperazine-1carbonyl)-1Hpyrazole-3carboxylic acid O ΌAΑΑΟ A°n Cl δ 8.20 (s, 1H), 7.35 - 7.38 (m, 3H), 7.18 (d, 7=7.5Hz, 1H), 7.09 (s, 1H), 6.99 - 7.02 (m, 3H), 3.89 (br, 4H), 3.70 - 3.74 (m, 2H), 2.72 (br, 4H) 475,1 133 4-chloro-1-(2-(5chloro-2- (trifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid ^CI 4>C _F 3 o xA '==( OH Cl δ 8.17 (s, 1H), 7.94 (s, 1H), 7.71 - 7.74 (m, 1H), 7.51 - 7.54 (m, 1H), 4.09 (s , 2H), 3.67 - 3.84 (m, 4H), 2.97 - 3.02 (m, 2H), 2.86 (s, 2H), 1.89 - 1.94 (m, 2H ), 1.74 1.86 (m, 4H) 505,0

- 111 047826

134 4-chloro-1-(2-(5chloro-2- (trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]non-7-carbonyl)1H-pyrazole-3-carboxylic acid 9 ¹ /x Α ,Ν p JL < Ν Ν ~ _C1 CF ₃ δ 8.12 (s, 1H), 7.71 - 7.76 (m, 2H), 7.51 - 7.54 (m, 1H), 4.23 4.27 (m, 2H), 3, 65 - 3.82 (m, 8H), 1.93 - 1.97 (m, 4H) 491,0 135 4-methyl-1-(2-(2(pyrrolidin-1yl)-4- (trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]non-7-carbonyl)1H-pyrazole-3-carboxylic acid about ⁰ δ 7.83 (s, 1H), 7.53 - 7.55 (m, 1H), 7.31 (s, 1H), 7.24 - 7.26 (m, 1H), 4.40 (s , 2H), 3.74 - 3.75 (m, 8H), 3.24 - 3.32 (m, 4H), 2.27 (s, 3H), 1.91 -2.06 (m, 8H ) 506.1 136 4-chloro-1-(5-(2,5-dichlorobenzyl)octahydropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O C! II 1 L~on CI O 58.24 (s, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.38 (d,7 = 8.4 Hz, 1H), 7.25 - 7.29 (m, 1H), 3.79 - 4.01 (m, 6H), 2.98 (br, 2H), 2.70 - 2.82 (m, 4H) 443,0 137 4-chloro-1-(5-(3-(4-chlorophenoxy)benzyl)octahydropyrrole o [3,4-c]pyrrole-2-carbonyl)- 1Hpyrazole-3-carboxylic acid ''a.hh.A'CH: about ⁷ 5 8.21 (s, 1H), 7.33 - 7.44 (m, 3H), 7.22 (d,7=7.5Hz, 1H), 7.13 (s, 1H), 6.98 - 7.03 (m, 3H), 3.98 - 4.04 (m, 6H), 3.19 - 3.22 (m, 2H), 3.10 (br, 2H), 2.97 - 3 .00 (m, 2H) 501,1

- 112 047826

138 4-chloro-1-(2-(4(pyrrolidin-1yl)-2- (drifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid O A G N nA _α ^F sC _Ν ^/ 'Ί\Α /=\ U-ON IM δ 8.11 (s, 1H), 7.56 (d, J =8.4 Hz, 1H), 6.79 - 6.86 (m, 2H), 4.22 (br, 2H), 3, 82 (br, 2H), 3.71 (br, 2H), 3.52-3.61 (m, 4H), 3.26 (br, 2H), 3.11 (br, 2H), 2.04 - 2.08 (m, 4H), 1.99 - 2.01 (m, 2H), 1.73 - 1.84 (m, 4H) 540.2 139 4-chloro-1-(1-((6(trifluoromethyl)benzo[b]thiophen-2yl)methyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid RzS-νΓΛ £ ^s Ar chr A- ⁷ Ron O 58.15 (s, 2H), 7.86 (d, 7=8.1 Hz, 1H), 7.55 - 7.58 (m, 1H), 7.38 (s, 1H), 4.49 - 4.53 (m, 2H), 4.11 (br, 2H), 3.13 - 3.22 (m, 2H), 2.93 2.98 (m, 2H), 1.84 - 2, 03 (m, 6H), 1.59 - 1.64 (m, 2H) 527,0 140 4-chloro-1-(5-(4(pyrrolidin-1yl)-2- (trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxylic acid CF ₃ O 5 8.24 (d, J = 2.4 Hz, 1H), 7.51 7.57 (m, 1H), 6.77 - 6.82 (m, 2H), 3.79 - 4.22 ( m, 6H), 3.42 (br, 2H), 3.33 - 3.35 (m, 3H), 3.24 - 3.28 (m, 1H), 3.01 - 3.13 (m, 4H), 1.99 - 2.08 (m, 4H) 512.3 141 1-(5-(4-(1H-hetrazol-5-yl)-2(trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-4chloro-1 H-pyrazole3-carboxylic acid ,Ν-ΝΗ and γ-Ό 'Ύ- ⁰¹ ULnCP ⁿ < T U-on CF ₃ o (DMSO-7 ₆ ) δ 8.61 (s, 1H), 8.23 8.28 (m, 2H), 7.83 - 7.86 (m, 1H), 4.24 (br, 6H), 2.89 (br, 2H), 2.57 - 2.73 (m, 4H) 511,4

- 113 047826

142 1-(4-(4-(1H-hetrazol-5-yl)-2(trifluoromethyl)benzyl)piperazine-1-carbonyl)-4-chloro-1H-pyrazole-3-carboxylic acid N-NH O NJ K ^N 1*11 G ? with N==/ PF CF ₃ J δ 8.38 (s, 1H), 8.25 - 8.28 (m, 2H), 8.00 - 8.03 (m, 1H), 3.81 3.84 (m, 6H), 2, 65 (t, J = 4.6 Hz, 4H) 484.9 143 1-(5-((2-chlorobenzyl)oxy)o-hydroxycyclopent a[c]pyrrole-2-carbonyl)-4(trifluoromethyl)1H-pyrazole-3-carboxylic acid О ^-2 о Г— Z JT'z cr'''*' w 1 0^0 I δ 8.46 (s, 1H), 7.36 - 7.40 (m, 1H), 7.30 - 7.34 (m, 1H), 7.17 7.24 (m, 2H), 4, 53 (s, 2H), 3.82 4.19 (m, 5H), 2.83 (br, 2H), 2.16 (br, 2H), 1.82 - 1.87 (m, 2H) 480.0 [M+Na] ⁺ 144 1-(4-(4- ethynylbenzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxamide 0 No.=/ y~NH ₂ 0 (Chloroform-J) δ 8.09 (d, J = 2.7 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz , 2H), 6.89 (d, J = 2.7 Hz, 1H), 6.66 (br, 1H), 5.63 (br, 1H), 3.84 (br, 4H), 3.56 (s, 2H), 3.08 (s, 1H), 2.54 (t, J = 4.7 Hz, 4H) 338,0 145 4-chloro-1-(4-(4(imidazo[1,2a]pyridin-3-yl)-2(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid О y~N 0 ^N XL X rN N^K-ci N=Z CF3 /~ ^0H (Chloroform-J) δ 8.28 - 8.30 (m, 1H), 8.07 - 8.11 (m, 2H), 7.95 7.98 (m, 1H), 7.80 - 7, 82 (m, 2H), 7.68 - 7.70 (m, 1H), 7.35 - 7.39 (m, 1HG153:G162), 6.95 - 6.99 (m, 1H), 3, 77-4.15 (m, 6H), 2.61 (br, 4H) 533,0

- 114 047826

146 1-(5-(2,5-dichlorobenzyl)octahydropyrrolo[3,4c]pyrrole-2carbonyl)-4(trifluoromethyl)1H-pyrazole-3carboxylic acid O ? AN OLnCP ^he γ cf ₃ Cl (DMSO-t/b) δ 8.62 (s, 1H), 7.46 7.49 (m, 1H), 7.43 (s, 1H), 7.20 7.36 (m, 1H), 3.65 (s, 7H), 2.87 (br, 2H), 2.50 - 2.58 (m, 4H) 476.9 147 1-(5-(3-(4-chlorophenoxy)benzyl)octahydropyrrole o [3,4-c]pyrrole-2-carbonyl)-4(trifluoromethyl)1H-pyrazole-3-carboxylic acid δ 8.45 (s, 1H), 7.37 - 7.43 (m, 1H), 7.29 - 7.34 (m, 2H), 7.19 7.27 (m, 1H), 6, 90 - 7.10 (m, 4H), 4.00 (br, 6H), 3.10 (br, 6H) 535,0 148 1-(2-(5-chloro-2(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)-4(trifluoromethyl)1H-pyrazole-3carboxylic acid o ^N ^A N' ^N y_f A ^0H /=( V- ^J CF ₃ ^CI ~yy~CF ₃ δ 8.61 (s, 1H), 7.90 (s, 1H), 7.64 - 7.72 (m, 1H), 7.43 - 7.46 (m, 1H), 3.88 (s , 2H), 3.54 - 3.80 (m, 4H), 2.72 - 2.77 (m, 2H), 2.61 (s, 2H), 1.74 - 1.95 (m, 6H ) 539,5 149 4-(trifluoromethyl)1-(1-((6- (trifluoromethyl)benzo[b]thiophen-2yl)methyl)-1,8-diazaspiro[4.5 ]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid ^f 3C-VAA ϊ O CF ₃ δ 8.63 (s, 1H), 8.17 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.56 - 7.59 (m, 1H), 7, 39 (s, 1H), 4.41 - 4.45 (m, 2H), 4.13 (s, 2H), 3.20 - 3.28 (m, 2H), 2.97 (t, J = 7.2 Hz, 2H), 1.86 - 2.05 (m, 6H), 1.64 - 1.68 (m, 2H) 561.2

- 115 047826

150 1-(2-(4(pyrrolidin-1yl)-2- (trifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-8-carbonyl)-4(trifluoromethyl)1H-pyrazole-3-carboxylic acid |^Ν^Ν' ^Ν ·Χ-^ F ₃ C OH /=\ CF ₃ σ δ 8.41 (s, 1H), 7.55 - 7.58 (m, 1H), 6.77 - 6.82 (m, 2H), 4.20 (s, 2H), 3.63 - 3 .80 (m, 4H), 3.30 3.32 (m, 4H), 3.23 (t, J = 6.9 Hz, 2H), 3.09 (s, 2H), 1.96 - 2 .04 (m, 6H), 1.67 - 1.86 (m, 4H) 574.3 151 4-chloro-1-(5-(3(pyrrolidin-1yl)-5- (trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxylic acid o cf ₃ n Jk N^x_ _C | 1 H ^N =4 ( N >-OH \__I O δ 8.19 (s, 1H), 6.87 - 6.92 (m, 2H), 6.71 (s, 1H), 3.70 - 4.28 (m, 6H), 3.27 - 3 .32 (m, 6H), 3.05 3.11 (m, 4H), 2.00 - 2.03 (m, 4H) 512,5 152 1-(2-(3-fluoro-5(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid ChooOE U-on O δ 8.07 (d, J = 2.7 Hz, 1H), 7.65 (s, 1H), 7.45 - 7.56 (m, 2H), 6.78 (d, J = 2.7 Hz, 1H), 4.08 (s, 2H), 3.83 - 3.87 (m, 2H), 3.68 - 3.73 (m, 2H), 3.09 (t, J = 1, 8 Hz, 2H), 2.90 (s, 2H), 1.96 (t, J = 6.9 Hz, 2H), 1.73 - 1.85 (m, 4H) 455.2 153 1-(2-(3- (trifluoromethoxy)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid /==\ O F ₃ co-Z \ 11 V# pN N^x ^X — U-OH O δ 8.07 (d, J= 2.7 Hz, 1H), 7.53 7.58 (m, 3H), 7.34 - 7.36 (m, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.23 (s, 2H), 3.84 - 3.87 (m, 2H), 3.60 3.71 (m, 2H), 3.28 - 3.20 ( m, 2H), 3.09 (s, 2H), 2.00 (t, J = 6.9 Hz, 2H), 1.86 - 1.75 (m, 4H) 453.2

- 116 047826

154 1-(2-(3-chloro-4methylbenzyl)-2,8diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid '~N O A g ? A 'xA nA ^J A-on O 5 8.06 (d, J = 2.7 Hz, lH), 7.58 (s, 1H), 7.35 - 3.38 (m, 2H), 6.77 (d, 7 = 2.7 Hz, 1H), 4.29 (s, 2H), 3.84 - 3.89 (m, 2H), 3.66 - 3.71 (m, 2H), 3.32 - 3.40 (m, 2H), 3.22 (s, 2H), 2.40 (s, 3H), 2.05 (t, J = 6.9 Hz, 2H), 1.88 - 1.75 (m, 4H) 417.2 155 1-(2-(3-methyl-4(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid F ₃ C g O A χΑ nA Aon O 5 8.06 (d, 7 = 2.7 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.49 - 7.54 (m, 2H), 6.77 ( d,7= 2.7 Hz, 1H), 4.29 (s, 2H), 3.83 - 3.88 (m, 2H), 3.67 - 3.72 (m, 2H), 3.30 - 3.32 (m, 2H), 3.17 (s, 2H), 2.51 (s, 3H), 2.03 (t, J = 6.9 Hz, 2H), 1.88 1.74 (m, 4H) 451.3 156 1-(5-([1 _; Gbiphenyl]-3ylmethyl/octahydropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O A A ryj W P η L-on ⁰ 5 8.12 (m, 1H), 7.72 (m, 1H), 7.50 - 7.64 (m, 3H), 7.33 - 7.49 (m, 4H), 7.11 - 7 .33 (m, 1H), 6.72 (s, 1H), 3.63 - 4.37 (m, 6H), 3.33 - 3.42 (m, 2H), 2.97 - 3.18 (m, 4H) 417.2 157 1-(ti/>ans-5-((3(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[s]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid t o m u o ь o LL? 5 8.17 (m, 1H), 7.61 - 7.72 (m, 1H), 7.40 - 7.61 (m, 3H), 6.77 (m, 1H), 4.55 (s , 2H), 4.20 - 4.30 (m, 1H), 3.50 - 4.20 (m, 4H), 2.92 (s, 2H), 2.00 - 2.23 (m, 2H ), 1.68 1.94 (m, 2H) 441.2 [M+ _NH4 ] ⁺

- 117 047826

158 1-(ti/>a«c-5-((3-(4-chlorophenoxy)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid 0 n X g-X I ¹ CH J) V—' No/ ⁿ Hon J! J ILo δ 8.16 (m, 1H), 7.28 - 7.43 (m, 3N), 7.06 - 7.19 (m, 1H), 6.87 7.03 (m, 4H), 6, 75 (m, 1H), 4.49 (s, 2H), 3.43 - 4.32 (m, 5H), 2.90 (s, 2H), 1.99-2.18 (m, 2H) , 1.70 -1.91 (m, 2H) 504.2 [M+Na] ⁺ 159 1-(trifluoromethyl-5-((2-methyl-3(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid O N A G-Λ I ¹ CH 1 /4--4 N=/ 4ιη ^{ο n} Aoi XX ° δ 8.17 (m, 1H), 7.60 (m, 2H), 7.27 - 7.41 (m, 1H), 6.77 (m, 1H), 4.57 (s, 2H), 4.22 - 4.37 (m, 1H), 3.47-4.19 (m, 4H), 2.94 (s, 2H), 2.45 (d, J = 1.2 Hz, 3H) , 1.99 2.23 (m, 2H), 1.77-1.91 (m, 2H) 460.2 [M+Na] ⁺ 160 1-(4-((2-((27/,55)2,5- dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)(methyl)amino)4- methylpiperidine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid О РзС^х II UJP/'n 1 ^S \ZN==Z У~ОН \ / О δ 8.11 (d, J= 2.7 Hz, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 4.17 (br, 4H), 3.70 (br, 2H), 3.11 - 3.28 ( m, 2H), 2.33 (s, 3H), 2.01 - 2.21 (m, 4H), 1.87 (br, 2H), 1.50 - 1.66 (m, 2H), 1 .32 (s, 3H), 0.93 (d, J = 6.1 Hz, 6H) 522.3 161 1-(4-(3-(4chlorophenoxy)-5fluorobenzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid g o o=< -4 o 0 O δ 8.14 (d, J= 2.7 Hz, 1H), 7.37 7.42 (m, 2H), 6.99 - 7.07 (m, 2H), 6.92 - 6.95 ( m, 1H), 6.86 (s, 1H), 6.84 (d, J = 2.7 Hz, 1H), 6.67 (d, J = 6.0 Hz, 1H), 3.86 ( br, 4H), 3.62 (s, 2H), 2.62 - 2.67 (m, 4H) 459.2

- 118 047826

162 1-(2-(3,5-dichlorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid CI /=/ o V // < N nA nV '— E~OH O δ 8.07 (d, J= 2.7 Hz, 1H), 7.48 7.51 (m, 3H), 6.79 (d, J= 2.7 Hz, 1H), 4.14 (s, 2H), 3.82 - 3.88 (m, 2H), 3.70 - 3.78 (m, 2H), 3.20 (t, J= 7.2 Hz, 2H), 3.05 (s, 2H), 1.99 (1.7=7.2 Hz, 2H), 1.86- 1.74 (m, 4H) 437,1 163 1-(g/is-5-(([1,Gbiphenyl]-3ylmethyl)(methyl)amino)octahydrocycle penta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid —Z / '—z Z-Z О I δ 8.13 (s, 1H), 8.12 (s, 1H), 7.69 - 7.82 (m, 1H), 7.60 - 7.63 (m, 2H), 7.46 - 7 .60 (m, 2H), 7.30 7.42 (m, 3H), 6.69 (d, J = 2.7 Hz, 1H), 4.34 (s, 2H), 4.00 (br , 4H), 3.62 - 3.74 (m, 1H), 2.82 (br, 2H), 2.67 (s, 3H), 2.46 - 2.55 (m, 2H), 1, 89-2.04 (m, 2H) 445.2 164 1-(g/is-5-([1,Gbiphenyl]-3-yloxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid o. L I / ^—ζ Ζ-Ζ o I δ 8.04 - 8.14 (s, 1H), 7.47 - 7.60 (m, 2H), 7.37 - 7.47 (m, 2H), 7.24 - 7.37 (m, 2H), 7.09 - 7.17 (d, 7 = 8.2 Hz, 1H), 6.97-7.07 (1.7 = 4.0 Hz, 1H), 6.77 - 6.87 (m, 1H), 6.64 - 6.74 (d, J = 2.7 Hz, 1H), 4.92 5.02 (m, 1H), 3.70 - 4.44 (m, 4H) , 2.90 (s, 2H), 2.23 - 2.40 (m, 2H), 1.81 - 2.00 (m, 2H) 435.3 [M+ _NH4 ] ⁺ 165 1-(4-(2-chloro-4morpholinobenzyl) piperazine-1 carbonyl)-1Hpyrazole-3carboxamide f—Q) Ζ—' Ζ—V X— Ζ Ζ-Ζ Ζ I yu δ 8.10 (d, 7 = 2.7 Hz, 1H), 7.27 7.33 (m, 1H), 6.89 - 6.96 (m, 2H), 6.78 - 6.82 ( m, 1H), 6.67 (br, 1H), 5.56 (br, 1H), 3.84 - 3.88 (m, 8H), 3.63 (br, 2H), 3.15 - 3 .18 (m, 4H), 2.63 (br, 4H) 433.2

- 119 047826

166 1-(5-(4-chloro-3(tetrahydro-1Hfuro[3,4-c]pyrrole-5(3H)yl)benzyl)octahydropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid o-, μ Ζ—, *~-ζ >=° Z-Z Oulu o δ 8.17 (d, J = 2.7 Hz, 1H), 7.39 (d, J= 8.1 Hz, 1H), 7.17 (s, 1H), 7.02 (d, J= 8.1 Hz, 1H), 6.75 (d, J = 2.7 Hz, 1H), 3.94 - 4.40 (m, 8H), 3.94 - 3.64 (m, 2H), 3.31 3.36 (m, 2H), 3.08 - 3.30 (m, 8H), 2.92 - 2.99 (m, 2H) 486.2 167 1-(4-(4(pyrrolidin-1yl)-2- (trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid /~~1 o ΊγΪΙ ί ΐ PF S ^r ₀ δ 8.11 (d, J= 2.7 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 6.75 - 6.79 (m, 3H), 3.86 ( br, 4H), 3.68 (s, 2H), 3.28 - 3.32 (m, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.02 - 2.06 (m, 4H) 452.2 168 1-(2-(3-chloro-4(pyrrolidin-1yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid )=\ О ^С| -Ч/ А /х n=Z J У~ОН О 5 8.07 (d,7 = 2.7 Hz, 1H), 7.46 (d, 7 = 2.7 Hz, 1H), 7.28 - 7.31 (m, 1H), 6.95 ( d,7= 8.7 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.23 (s, 2H), 3.84 - 3.89 (m, 2H), 3.72 - 3.68 (m, 2H), 3.37 - 3.45(m, 6H), 3.22 (s, 2H), 2.05 (t, 7 = 7.2 Hz, 2H) , 2.01 - 1.95 (m, 4H), 1.83 - 1.75 (m, 4H) 472.2 169 1-(2-(2-chloro-4morpholinobenzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid o N s/Alr nJ ⁴ - U-OH O 5 8.06 (d,7 = 2.7 Hz, 1H), 7.49 (d, 7 = 8.7 Hz, 1H), 7.07 (d,7 = 2.7 Hz, 1H), 6 .95 - 6.99 (m, 1H), 6.76 (d, J = 2.7 Hz, 1H), 4.42 (s, 2H), 3.81 - 3.88 (m, 6H), 3.72 - 3.62 (m, 2H), 3.45 (t, J = 7.2 Hz, 2H), 3.32 - 3.33 (m, 2H), 3.21 - 3.24 ( m, 4H), 2.06 (t, J = 7.2 Hz, 2H), 1.89 - 1.78 (m, 4H) 488.2

- 120 047826

170 1-(2-((3(trifluoromethyl)[1,1'-biphenyl]-4yl)methyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid O o f ₃ cV. _n / O X/ ^N Λ U~on O δ 8.06 (d, J= 2.8 Hz, 1H), 7.93 7.88 (m, ZN), 7.68 - 7.66 (m, 2H), 7.51 - 7.48 ( m, 2H), 7.39 7.43 (m, 1H), 6.77 (d, J = 2.8 Hz, 1H), 3.97 (s, 2H), 3.81 (br, 2H) , 3.74 (br, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.70 (s, 2H), 1.85 (t, J = 7.2 Hz, 2H) , 1.82 - 1.73 (m, 4H) 513.3 171 1-(2-(4-chloro-2(pyrrolidin-1yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Cl X O o ^N =\ U~on O δ 8.06 (d, J = 2.7 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.76 (d, 7= 2.7 Hz, 1H), 4.38 (s, 2H), 3.83 (br, 2H), 3.72 (br, 2H) , 3.34 3.40 (m, 1H), 3.27 - 3.30 (m, 1H), 3.10 - 3.25 (m, 6H), 2.05 - 2.00 (m, 6H ), 1.86-1.74 (m, 4H) 472.3 172 \-(trans-5-{(3methyl-4(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3carboxylic acid ΎΑ ⁰ ' F ₃ C'^ ^/ SHE . N'X CV №=/ n U~OH O δ 8.10-8.23 (d, J = 2.8 Hz, 1H), 7.53 - 7.65 (d, J = 8.0 Hz, 1H), 7.25 - 7.40 (m , 2H), 6.70 - 6.84 (d, J = 2.8 Hz, 1H), 4.53 (s, 2H), 4.22 - 4.30 (m, 1H), 3.38 - 4.21 (m, 4H), 2.82 - 3.03 (s, 2H), 2.43 - 2.56 (d, J = 1.2 Hz, ZN), 2.02 2.22 (m , 2H), 1.73-1.91 (m, 2H) 438.2 173 1-(4-(2(pyrrolidin-1yl)-4-(trifluoromethyl)benzyl)piperazine-1 carbonyl)-1Hpyr azol-3carboxamide ό ABOUT . A Ν chU Ν=/ Α-ΝΗ ₂ O δ 8.09 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.10 - 7.12 (m, 2H), 6.90 ( d, J = 2.7 Hz, 1H), 6.65 (br, 1H), 5.57 (br, 1H), 3.84 (br, 4H), 3.61 (s, 2H), 3, 22 - 3.26 (m, 4H), 2.56 (br, 4H), 1.93 - 2.00 (m, 4H) 451.2

- 121 047826

174 1-(1-(2(pyrrolidin-1yl)-4- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxamide CXJ T Z Z-Z s H \ 1 > z [ m o LL? δ 8.09 (d, ./= 2.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.12 - 7.16 (m, 2H), 6.91 (d, J= 2.8 Hz, 1H), 6.66 (br, 1H), 5.53 (br, 1H), 4.53 - 4.56 (m, 2H), 3.67 (s, 2H), 3.13 - 3.17 (m, 6H), 2.64 - 2.67 (m, 2H), 1.81 - 1.95 (m, 10H), 1.58 (br, 2H) 505.3 175 1-(4-((4-(trifluoromethyl)pyr idin-3yl)methyl)piperazi and-1-carbonyl)-1Hpyrazole-3carboxamide o ι^'Ν^'Ν^χ AAA n==/ rF A-nh ₂ ^CF 3 O δ 9.00 (s, 1H), 8.71 (ph7 = 5.1 Hz, 1H), 8.10 (d,7 = 2.7 Hz, 1H), 7.53 (d, J = 5.4 Hz, 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.65 (br, 1H), 5.50 (br, 1H), 3.86 (br, 4H), 3, 76 (s, 2H), 2.60 - 2.63 (m, 4H) 383.2 176 1-(4-(methyl(3(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxamide O X |l A 1 Λ-νη ₂ o δ 8.08 (d, J = 2.8 Hz, 1H), 7.60 (s, 1H), 7.51 - 7.53 (m, 2H), 7.42 - 7.46 (m, 1H ), 6.91 (d, J = 2.8 Hz, 1H), 6.68 (br, 1H), 5.56 (br, 1H), 4.52 - 4.56 (m, 2H), 3 .67 (s, 2H), 3.04 - 3.10 (m, 2H), 2.74 2.79 (m, 1H), 2.24 (s, 3H), 1.95 1.98 (m , 2H), 1.69 - 1.79 (m, 2H) 410.2 177 1 -(4-(3 -(pyridazin4- yloxy)benzyl)pyperazin-1carbonyl)-1Hpyrazole-3carboxylic acid axuA A ^0H 0 δ 8.80 (d, J = 7.5 Hz, 1H), 8.09 8.10 (m, 2H), 7.75 (s, 1H), 7.62 7.67 (m, 1H), 7.50 - 7.54 (m, 2H), 6.78 (d, J = 2.7 Hz, 1H), 6.69 6.73 (m, 1H), 3.86 (br, 4H), 3.70 (s, 2H), 2.63 (t, 7= 4.8 Hz, 4H) 409.2 178 1-(2-(3-chloro-5-fluorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxamide o /-n ^/ aM A C'-£L _o Anh ₂ F δ 8.06 (d, 7= 2.4 Hz, 1H), 7.11 (s, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 6.90 (d, J = 2.7 Hz, 1H), 6.66 (br, 1H), 5.46 (br, 1H), 3.62 - 3.81 (m, 4H), 3.56 (s, 2H), 2.63 (t, J = 6.9 Hz, 2H), 2.44 (s, 2H), 1.68 - 1.79 (m, 6H) 420.2

- 122 047826

179 1-(4-(3(pyrimidin-5yl)benzyl)piperase in-1-carbonyl)1H-pyrazole-3carboxamide O [1 J A-NH ₂ N O δ 9.22 (s, 1H), 8.97 (s, 2H), 8.10 (d, J = 2.7 Hz, 1H), 7.60 (s, 1H), 7.51 (d, 7=5.l Hz, 2H), 7.46(1, J = 5.1 Hz, 1H), 6.90 (d, 7 = 2.7 Hz, 1H), 6.64 (br, 1H) , 5.44 (br, 1H), 4.00 (br, 4H), 3.67 (br, 2H), 2.62 (br, 4H) 392.2 180 1-(1-(4-chloro-2(pyrrolidin-1yl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid hO \ K, A '— U-OH O 5 8.09 (d,7 = 2.7 Hz, 1H),7.42 (d, J= 8.1 Hz, 1H), 7.25 (s, 1H), 7.10 (d, 7= 8.1 Hz, 1H), 6.77 (d, 7 = 2.7 Hz, 1H), 4.70 (br, 2H), 4.31 (br, 2H), 3.05 - 3.24 ( m, 8H), 2.15 - 2.41 (m, 4H), 1.90-2.10 (m, 6H), 1.77 - 1.82 (m, 2H) 472.3 181 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)ΙΗ-pyrazole-3carboxamide O ^α ΥΊ oAn W ΝΗ ₂ (Chloroform-T) d8.10(d,7=2.7 Hz, 1H), 7.25 - 7.33 (m, 4H), 6.90 (d, 7= 2.7 Hz, 1H), 6.66 (br, 1H), 5.70 (br, 1H), 3.74 - 3.84 (m, 4H), 3.53 (s, 2H), 2.53 - 2.56 (m, 4H) 348,0 182 1-(5-(4- (trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxamide ^fc ·^ γύΑ'Ά° UVA (DMSO-Tj) 5 8.78 (s, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.61 - 7.73 (m, 2H), 7.42 - 7.60 (m, 2H), 7.28 (s, 1H), 3.43 - 4.16 (m, 6H), 2.85 (s, 2H), 2.53 - 2.60 (m, 2H), 2.41 -2.51 (m, 2H) 408.2 183 1-(5-(4-chlorobenzyl)octa-dropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid ULnCV ^0H 5 8.19 (s, 1H), 7.41 - 7.50 (m, 4H), 6.78 (s, 1H), 3.70 - 4.50 (m, 6H), 3.37 (s , 1H), 3.31 (s, 1H), 3.16 (s, 2H), 2.96-3.10 (m, 2H) 375.1

- 123 047826

184 1-(trans-5-((2-chlorobenzyl)(methyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid O A GU ¹ δ 8.10 (d, J = 2.7 Hz, 1H), 7.52 7.65 (m, 1H), 7.43 - 7.52 (m, 1H), 7.28 - 7.43 ( m, 2H), 6.78 (d, J = 2.7 Hz, 1H), 3.76 - 4.30 (m, 5H), 3.42 - 3.75 (m, 2H), 2.75 - 3.08 (m, 2H), 2.42 (s, 3H), 2.00 - 2.25 (m, 4H) 403.2 185 1-(1-((6(trifluoromethyl)benzo[b]thiophen-2yl)methyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid fsC'VaV £ s \ UmUA nJ i ¹ z / X# ^N x U-on 0 5 8.15(s, 1H),8.O7 (d.7 = 2.7 Hz, 1H), 7.84 - 7.87 (m, 1H), 7.54 7.61 (m, 1H) , 7.35 (s, 1H), 6.78 (d, J = 2.7 Hz, 1H), 4.53 - 4.57 (m, 2H), 4.08 (s, 2H), 3, 09 - 3.32 (m, 2H), 2.88 - 2.92 (m, 2H), 1.92 - 2.03 (m, 4H), 1.83 - 1.90 (m, 2H), 1.57 - 1.62 (m, 2H) 493,0 186 1-(8-(2-(4-fluoropiperidin-1- yl)-4- (trifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-2-carbonyl)1H-pyrazole-3-carboxylic acid F ₃ C Λα ^F Y-OH 0 (Chloroform-T) δ 8.20 (s, 1H), 7.79 - 7.82 (m, 1H), 7.40 - 7.43 (m, 2H), 6.83 (s, 1H), 4.78 - 4.94 (m, 1H), 4.36 (br, 1H), 3.77 - 4.22 (m, 4H), 3.39 - 3.53 (m, 2H), 3, 08 - 3.57 (m, 3H), 2.67 - 2.81 (m, 4H), 1.67 -2.08 (m, 10H) 538,1 187 1-(4-((5-chlorobenzo[b]thiophen n-2-yl)methyl)piperazin-1-carbonyl)-1Hpyrazole-3carboxylic acid ^Cl \ 0 /=\ x VH r N ΝΛ NgJk^N___) N==Z X-OH 0 δ 8.09 - 8.15 (m, 1H), 7.64 - 7.85 (m, 2H), 7.18 - 7.33 (m, 2H), 6.80 - 6.89 (m, 1H), 3.78 - 4.02 (m, 6H), 2.61 - 2.78 (m, 4H) 405.4

- 124 047826

188 1-(4-((5-chloro-3methyl-1H-indol-2yl)methyl)piperazine-1-carbonyl)-1Hpyrazole-3carboxylic acid ^C \ o /=\ / U nV ⁿ U~OH O (DMSO-7 _tf ) d 11.02 (s, 1H), 7.46 - 7.51 (m, 1H), 7.23 - 7.32 (m, 1H), 6.98 - 7.06 ( m, 1H), 6.72 (s, 1H), 3.60 - 3.83 (m, 6H), 2.37 2.62 (m, 4H), 2.20 (s, 3H) 424.0 [M+Na] ⁺ 189 1-(4- (benzo[c1]thiazol-2ylmethyl)piperazine-1-carbonyl)-1Hpyrazole-3carboxylic acid O N==/ U-oh O δ 7.90 - 8.10 (m, 2H), 7.40 - 7.55 (m, 2H), 6.70 - 6.79 (m, 1H), 4.05 (s, 2H), 3 .80 - 3.90 (m, 4H), 2.70 - 2.85 (m, 4H) 372.2 190 1-(4-((3-(4-chlorophenoxy)benzyl)amino)piperidin-1-carbonyl)-1Hpyrazole-3carboxylic acid t o LA m Q ZT ь 0 o δ 8.08 (d, J = 2.7 Hz, 1H), 7.37 7.63 (m, 3H), 7.24 - 7.26 (m, 1H), 7.16 (s, 1H) , 6.93 - 7.06 (m, 3H), 6.77 (d, J = 2.7 Hz, 1H), 4.51 4.70 (m, 2H), 4.11 (s, 2H) , 3.01 3.32 (m, 4H), 2.14 - 2.24 (m, 2H), 1.60-1.91 (m, 2H) 455.1 191 1-(2-(4(pyrrolidin-1yl)-2- (trifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid o f ₃ c /-VAX nV /=\ ⁴ - Λ-on y) ⁰ Su δ 8.06 (d, J = 2.7 Hz, 1H), 7.58 7.60 (m, 1H), 6.76 - 6.85 (m, 3H), 4.33 (s, 2H) , 3.73 - 3.84 (m, 2H), 3.57 - 3.71 (m, 2H), 3.328 - 3.46 (m, 6H), 3.14 - 3.22 (m, 2H) , 2.01 - 2.10 (m, 6H), 1.81 - 1.87 (m, 4H) 506.3 192 1-(2-(3(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid О ϊ Λν nA /—.. J nV z-N \ , / A L-on F3C40 ° δ 8.06 (d, J = 2.7 Hz, 1H), 7.88 (s, 1H), 7.73 - 7.82 (m, 2H), 7.62 - 7.67 (m, 1H ), 6.77 (d, J = 2.7 Hz, 1H), 4.42 (s, 2H), 3.82 (br, 2H), 3.56 - 3.70 (m, 2H), 3 .17 3.32 (m, 2H), 3.06 - 3.17 (m, 2H), 2.02 - 2.05 (m, 2H), 1.80 - 1.96 (m, 4H) 437.2

- 125 047826

193 1-(g/is-5-((3-chloro-5-fluorobenzyl)oxy)octahydrocyclopent a[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O N A G V- ¹ N=/ ⁿ Aon ⁰ CI δ 8.03 (d, ./ = 2.8 Hz, 1H), 7.13 (s, 1H), 7.03 - 7.06 (m, 1H), 6.97 - 6.99 (m, 1H), 6.69 (d, J = 2.8 Hz, 1H), 4.45 (s, 2H), 4.15 - 4.35 (m, 1H), 4.07 - 4.12 (m , 2H), 3.07 - 3.96 (m, 2H), 2.80 (br, 2H), 2.12 -2.19 (m, 2H), 1.78 - 1.82 (m, 2H ) 430.1 [M+Na] ⁺ 194 1-(ti/>ans-5-((4-(4-chlorophenoxy)benzyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid t o aA> Ζ-Ζ m z—, / t*D__/ ΖΤ b 0 o δ 8.14 (d, J = 2.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.35 - 7.38 (m, 2H), 6.97 - 7.06 (m, 4H), 6.74 (d, J = 2.7 Hz, 1H), 4.16 (s, 2H), 3.82 - 3.87 (m, 5H), 2.98 (br, 2H), 2.17 - 2.20 (m, 2H), 2.01 - 2.03 (m, 2H) 481.2 195 1-(2-(4(pyrrolidin-1yl)-2- (trifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxamide o . k [ Ν ^F 3C zr/pA \ /A ⁴ — D~MN ₂ \ / ° Cd (Chloroform-T) d 8.05 (d, J= 2.7 Hz, 1H), 7.48 (br, 1H), 6.89 (d, J = 2.7 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.66 (br, 2H), 5.43 (br, 1H), 3.65 - 3.71 (m, 6H), 3.30 (t, J = 6.6 Hz, 4H), 2.64 (br, 2H), 2.44 (br, 2H), 2.03 (t, J = 6.6 Hz, 4H), 1.72 (br, 6H) 505.3 196 1-(2-(3-chloro-5(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxamide /=/ ^F3 O \-naM λ ^x - Α-ΝΗ ₂ o (Chloroform-T) d 8.07 (d, J= 2.7 Hz, 1H), 7.62 - 7.65 (m, 3H), 6.91 (d, J= 2.7 Hz, 1H) , 6.68 (br, 1H), 5.55 (br, 1H), 3.51 - 3.91 (m, 6H), 2.65 - 2.77 (m, 2H), 2.47 (s , 2H), 1.75 - 1.76 (m, 6H) 470.2

- 126 047826

197 1-(2-(2-chloro-4morpholinobenzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxamide O -N Cl nV ⁴ — A-NH ₂ o (Chloroform-T) δ 8.05 (d, J = 2.7 Hz, 1H), 7.27 (br, 1H), 6.87 - 6.91 (m, 2H), 6.79 (d, J= 8.7 Hz, 1H), 6.66 (br, 1H), 5.46 (br, 1H), 3.83 - 3.86 (m, 4H), 3.64 - 3.77 (m , 6H), 3.13 - 3.17 (m, 4H), 2.69 (br, 2H), 2.51 (br, 2H), 1.73 (br, 6H) 487.3 198 1-(4-(3phenoxybenzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxamide (Chloroform-T) δ 8.09 (s, 1H), 7.26 - 7.37 (m, 3H), 6.69 - 7.13 (m, 7H), 6.66 (s, 1H), 5.61 (s, 1H), 3.82 (m, 4H), 3.54 (m, 2H), 2.54 -2.57 (m, 4H) 406.2 199 1 -(4-(2-morpholino3-(trifluoromethyl)benzyl)piperazine-1 carbonyl)-1Hpyrazole-3carboxamide O . . x [<*>1 | ^N F 4 Γ3*-ζ T \ NA~NH ₂ Q ⁰ (Chloroform-T) d 8.10 - 8.12 (m, 1H), 7.79 (d,7 = 7.7 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H) , 7.28 - 7.32 (m, 1H), 6.88 - 6.91 (m, 1H), 6.75 (br, 1H), 6.23 - 6.41 (m, 1H), 3 .76 - 3.86 (m, 8H), 3.68 (s, 2H), 3.36 - 3.42 (m, 2H), 2.78 - 2.86 (m, 2H), 2.60 - 2.61 (m, 4H) 467,0 200 1-(ti/>ais-5-((2-chlorobenzyl)(methyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3carboxamide „ .vA-v? A nh ₂ Qfi ^h (Chloroform-T) δ 8.25 (d, 7=2.7 Hz, 1H), 7.40 - 7.60 (m, 1H), 7.36 - 7.40 (m, 1H), 7, 17 - 7.22 (m, 2H), 6.92 (d,7= 2.7 Hz, 1H), 6.58 - 6.80 (m, 1H), 5.45 - 5.80 (m, 1H), 3.40 - 4.32 (m, 6H), 2.72 3.36 (m, 3H), 1.82 - 2.39 (m, 7H) 402.2 201 1-(5-(3-chloro-5(trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxamide A ³ αΛλ /Р _ci xx.cP (Chloroform-T) δ 8.26 (d, 7 = 2.6 Hz, 1H), 7.36 - 7.56 (m, 3H), 7.90 (d, J = 2.6 Hz, 1H) , 6.70 (s, 1H), 5.80 (s, 1H), 4.00 - 4.30 (br, 2H), 3.70 -4.00 (br, 2H), 3.60 (s , 2H), 2.90 (s, 2H), 2.60 (s, 4H) 442.2

- 127 047826

202 1-(5-(2,5dichlorobenzyl)octa hydropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxamide CI p A ^nh 2 Cl (Chloroform-T) δ 8.26 (s, 1H), 7.50 - 7.56 (m, 1H), 7.28 - 7.30 (m, 1H), 7.10 - 7.20 (m , 1H), 6.90 (s, 1H), 6.60 - 6.80 (m, 1H), 5.60 (s, 1H), 4.00 - 4.20 (br, 2H), 3, 70 - 4.00 (m, 4H), 2.90 - 3.10 (br, 2H), 2.70 (s, 4H) 407.9 203 1-(5-(4-chlorobenzyl)octa-dropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxamide Cl^^x ULm ^NH2 (Chloroform-T) δ 8.25 (d, J= 2.7 Hz, 1H), 7.20 - 7.30 (m, 4H), 6.90 (d, J = 2.7 Hz, 1H), 6.71 (s, 1H), 6.10 (s, 1H), 3.63 - 4.40 (m, 4H), 3.56 (s, 2H), 2.90 (s, 2H), 2.58 (s, 4H) 374,0 204 1-(g/is-5-(methyl(2(trifluoromethyl)benzyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxamide 0 9 ^F 3 AA ^==/ nh ₂ (Д f ^H (Chloroform-T) δ 8.25 (d, J= 2.7 Hz, 1H), 7.55 (m, 2H), 7.42 (m, 2H), 6.90 (d,7= 2, 7 Hz, 1H), 6.73 (br, 1H), 5.88 (br, 1H), 3.91 (br, 4H), 3.57 (s, 2H), 2.87 - 2.98 ( m, 1H), 2.73 (br, 2H), 2.17 - 2.26 (m, 2H), 2.13 (s, 3H), 1.49 - 1.59 (m, 2H) 436,0 205 1-(g/is-5-(methyl(4(trifluoromethyl)benzyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxamide ^==/ nh ₂ 11 J i (Chloroform-T) δ 8.25 (d, 7= 2.7 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.60 (d, 7=7.8 Hz , 1H), 7.52(1, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 6.90 (d,7 = 2.7 Hz, 1H ),6.75 (br, 1H), 6.18 (br, 1H), 3.68-4.11 (m, 6H), 2.94 - 3.02 (m, 1H), 2.73 ( br, 2H), 2.14 - 2.22 (m, 5H), 1.52 (br, 2H) 436.2 206 1-(g/is-5-((2-chlorobenzyl)(methyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxamide 0 νΆ Α 9 ¹ PV nh ₂ ¹ (Chloroform-T) δ 8.25 (s, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.33 7.36 (m, 1H), 7.15 - 7.26 (m, 2H), 6.89 - 6.90 (m, 1H), 6.71 (br, 1H), 5.70 (br, 1H), 3.95 (br, 4H), 3.63 ( s, 2H), 2.97 - 3.02 (m, 1H), 2.73 (br, 2H), 2.18 - 2.27 (m, 5H), 1.60 (br, 2H) 402.1

- 128 047826

207 1 -(4-((2-(3-oxa-8azabicyclo[3.2.1 ]o ctan-8-yl)-4(trifluoromethyl)benzyl)(methyl)amino)- 4-methylpiperidine1-carbonyl)- 1Hpyrazol- 3carboxylic acid t o °=< A —Z 'рГО ¹ о LL? (DMSO-t/g) δ 8.22 (d, J = 2.7 Hz, 1H), 7.86 - 7.89 (m, 1H), 7.32 7.35 (m, 1H), 7 .05 (s, 1H), 6.80 (d, J = 2.7 Hz, 1H), 3.58 - 3.81 (m, 12H), 1.80 - 2.09 (m, 9H), 1.52 - 1.59 (m, 2H), 1.06 (s, 3H) 536.5 208 1-(5-(3- (trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxamide ABOUT (Chloroform-T) δ 8.24 (d, J = 2.7 Hz, 1H), 7.40 - 7.70 (m, 4H), 8.90 (d, J = 2.7 Hz, 1H) , 6.60 - 6.80 (m, 1H), 5.46 - 5.60 (m, 1H), 4.00 - 4.20 (br, 2H), 3.60 - 4.00 (m, 4H), 3.00 (s, 2H), 2.60 (s, 4H) 408,0 209 1-(4-(((5-chloro-2(trifluoromethyl)benzyl)(methyl)amino)methyl)piperidine1-carbonyl)-1Hpyrazole-3carboxylic acid CI O A । gal N=/ pp OH OF _{3 o} / δ 8.06 (d, J = 2.7 Hz, 1H), 7.88 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.40 - 7.43 ( m, 1H), 6.79 (d, J = 2.7 Hz, 1H), 4.39 - 4.42 (m, 2H), 3.66 (s, 2H), 3.09 - 3.15 (m, 2H), 2.33 (d, J = 6.8 Hz, 2H), 2.23 (s, 3H), 1.90 - 1.93 (m, 3H), 1.22 1.32 (m, 2H) 459.1 210 1-(2-(3-(4-chlorophenoxy)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid 0 /=\ ^x — A-OH y CI δ 8.02 (d, J = 2.7 Hz, 1H), 7.40 7.45 (m, 1H), 7.24 - 7.33 (m, 3H), 7.16 - 7.18 ( m, 1H), 7.04 - 7.11 (m, 1H), 6.96 - 7.01 (m, 2H), 6.72 (d, J = 2.7 Hz, 1H), 4.22 (s, 2H), 3.74 - 3.83 (m, 2H), 3.64 - 3.68 (m, 2H), 3.27 - 3.34 (m, 2H), 3.07 - 3 .13 (m, 2H), 1.97 - 2.02 (m, 2H), 1.71 - 1.82 (m,4H) 495.2

- 129 047826

211 1-(4-(3-chloro-2(tetrahydro-1Hfuro[3,4-c]pyrrole-5(3H)yl)benzyl)phenyl)benzyl-1-carbonyl)1H-pyrazole-3-carboxylic acid O A G|1 A'n _c| AJx,N^J №/ N A-OH % ° δ 8.03 - 8.14 (m, 1H), 7.26 - 7.43 (m, 2H), 7.13 - 7.24 (m, 1H), 6.68 - 6.82 (m, 1H), 3.62 - 4.05 (m, 12H), 2.90 - 3.09 (m, 4H), 2.74 2.90 (m, 4H) 460,1 212 1-(4-(2-(3-oxa-8azabicyclo[3.2.1]o kgan-8-yl)-3chlorobenzyl)piper zin-1-carboxylic)1H-pyrazole-3carboxylic acid o c/^z— Z—(. V- z Z-Z o I δ 8.03 - 8.14 (m, 1H), 7.34 - 7.42 (m, 1H), 7.15 - 7.24 (m, 1H), 6.83 - 6.94 (m, 1H), 6.77 - 6.83 (m, 1H), 3.98 - 4.12 (m, 2H), 3.95 (s, 2H), 3.75 - 3.88(m, 6H) , 3.54 3.67 (m, 2H), 2.54 - 3.73 (m, 4H), 2.01 - 2.24 (m, 4H) 460.3 213 1-(4-(2-chloro-3-(2hydroxy-2methyl proton) benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid T o Z-Z °4 o k T δ 8.09 (d, J= 2.7 Hz, 1H), 7.24 (t, 7=7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6 .98 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 3.85 3.82 (m, 6H), 3.73 (s, 2H ), 2.68 2.64 (m, 4H), 1.36 (s, 6H) 437,1 214 (I)-1-(4-(2-chloro-3(2-hydroxy-2methyl propoxy) benzyl)-2- methylpiperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid 0 Π \ AАжА A ^H0 4 λ /—он Cl δ 8.07 (d, J=2.7 Hz, 1H), 7.23 (t, 7=7.8 Hz, 1H), 7.14 (d, J =7.8 Hz, 1H), 6 .97 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.84 (br, 1H), 4.30 - 4.26 (m, 1H), 3.82 (s, 2H), 3.64 (s, 2H), 3.51 - 3.42 (m, 1H), 2.91 - 2.86 (m, 1H), 2.80 2.76 (m, 1H), 2.46 - 2.41 (m, 1H), 2.34 - 2.25 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H), 1.36 (s, 6H) 451,1

- 130 047826

215 (5)-1-(4-(2-chloro-3(2-hydroxy-2methyl propoxy) benzyl)-2- methylpiperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid About r. uLL ^Η °Ί X Caller ID δ 8.04 (d, J=2.7 Hz, 1H), 7.23 (t, 7=7.8 Hz, 1H), 7.14 (d, J =7.8 Hz, 1H), 6 .96 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 4.70 (br, 1H), 4.34 - 4.29 (m, 1H), 3.82 (s, 2H), 3.63 (s, 2H), 3.46 - 3.41 (m, 1H), 2.89 - 2.86 (m, 1H), 2.79 2.75 (m, 1H), 2.45 - 2.40 (m, 1H), 2.33 - 2.24 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H), 1.36 (s, 6H) 451,1 216 (I)-1-(4-(2-chloro-3(2-hydroxy-2methyl propoxy) benzyl)-2- methylpiperazine-1 carbonyl)- 1Hpyrazole-3carboxamide O O sLl \ lk A, nA ^NO Ч i _o /-nh ₂ (Chloroform-iG) δ 8.10 (d, J = 2.7 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.15 - 7.13 (m, 1H), 6, 92 (d, J = 2.7 Hz, 1H), 6.89 - 6.86 (m, 1H), 6.69 (br, 1H), 5.63 (br, 1H), 4.65 (br , 1H), 4.28 - 4.23 (m, 1H), 3.87 (s, 2H), 3.71 - 3.60 (m, 2H), 3.54 3.44 (m, 1H) , 2.93 - 2.89 (m, 1H), 2.80 - 2.76 (m, 1H), 2.48 - 2.43 (m, 2H), 2.37 - 2.28 (m, 1H), 1.52 (d, J = 6.6 Hz, 3H), 1.41 (s , 6H) 450.2 217 1-(9-(5-chloro-2(trifluoromethyl)benzyl)-3,9- diazaspiro[5.5 ]undecane-3-carbonyl)1 H-pyrazole-3-carboxylic acid O ci A I < N 1 I / [Ί ^N A Ac n 1 o CF ₃ δ 8.06 (d, .7 = 2.7 Hz, 1H), 7.91 (s, 1H), 7.67 (d, .7 = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 3.87 - 3.74 (m, 6H), 2.61 - 2.56 (m, 4H ), 1.70 - 1.64 (m, 8H) 485,5 218 1-(?irdms-5-(methyloxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1 H-pyrazole-3-carboxylic acid O 1 n A Olxv Ch Aon o δ 8.16 (d, .7= 2.7 Hz, 1H), 7.12(1, 7 = 7.8 Hz, 1H), 6.79 - 6.65 (m, 4H), 5.02 - 4.98 (m, 1H), 4.35 3.51 (m, 4H), 2.98 (br, 2H), 2.28 (s, 3H), 2.21 -2.11 (m, 2H), 2.01 - 1.91 (m, 2H) 356.1

- 131 047826

219 \-(trans-5-(3-cyclopropylphenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid ch z-z o δ 8.14 (br, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 6.64 - 6.55 ( m, 3H), 4.98 - 4.92 (m, 1H), 4.28 - 3.51 (m, 4H), 2.96 (br, 2H), 2.18 - 2.08 (m, 2H), 2.01 - 1.89 (m, 2H), 1.88 - 1.79 (m, 1H), 0.95 - 0.88 (m, 2H), 0.68 - 0.61 ( m, 2H) 404.1 [M+Na] ⁺ 220 \-(trans-5-(3-isopropylphenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid R / \.T ^x \ / ^x —~z zz AALX About her δ 8.16 (d, J = 2.7 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 6.81 - 6.65 (m, 411), 5.02 - 4.98 (m, III), 4.43 3.48 (m, 4H), 2.98 (br, 2H), 2.88 - 2.81 (m, 1H), 2.21 - 2.11 (m, 2H), 2.01-1.91 (m, 2H), 1.23 (d, 7=6.9 Hz, 6H) 384.2 221 \-(trans-5-(2-isopropylphenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O n Q χν w Η χ ₀ Η δ 8.14 (d, J= 2.8 Hz, lH), 7.14(d, J= 8.0 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.85 ( t, J= 7.6 Hz, 2H), 6.75 (d, J = 2.4 Hz, 1H), 5.05 - 4.97 (m, 1H), 4.29 - 3.52 (m , 4H), 3.28 - 3.22 (m, 1H), 2.97 (br, 2H), 2.24 - 2.15 (m, 2H), 2.01 - 1.91 (m, 2H ), 1.18 (d, J = 7.2 Hz, 6H) 406.2 [M+Na] ⁺ 222 \-(trans-5-(3chloro-5fluorophenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O / Vz and Z-Z o δ 8.18 (d, J= 2.7 Hz, 1H), 6.82 6.58 (m, 4H), 5.08 - 4.98 (m, 1H), 4.51 - 3.38 ( m, 4H), 3.11 - 2.88 (m, 2H), 2.24 - 2.09 (m, 2H), 2.07 - 1.91 (m, 2H) 416.0 [M+Na] ⁺

- 132 047826

223 1-(2-(2,5-dimethylbenzyl)2,8- diazaspiro [4.5] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid /=/ O C / χΑνΛ рОН O 5 8.04 (d, J = 2.7 Hz, 1H), 7.20 (s, 1H), 7.13 - 7.05 (m, 2H), 6.75 (d, 7 = 2.7 Hz, 1H), 3.97 (s, 2H), 3.90 - 3.84 (m, 2H), 3.71 - 3.68 (m, 2H), 3.07 - 3.02 (m, 2H), 2.90 (s, 2H), 2.38 - 2.32 (m, 6H), 1.93 1.88 (m, 2H), 1.84-1.71 (m, 4H) 397.2 224 1-(4-((3,5-dichlorobenzyl)oxy)piperidine-1-carbonyl)-1Hpyrazole-3-carboxylic acid o ΑιΆνΛ Ok /h. xL JN==/ YV o ^ν f O Cl δ 8.04 (d, J= 2.7 Hz, 1H), 7.33 (s, 3H), 6.75 (d, J = 2.7 Hz, 1H), 4.57 (s, 2H) , 4.07 - 4.01 (m, 2H), 3.79 - 3.72 (m, 1H), 3.66 - 3.58 (m, 2H), 2.07 - 1.98 (m, 2H), 1.82 - 1.81 (m, 2H) 396.1 [ΜΗ]' 225 1-(4-((3- (trifluoromethyl)benzyl)oxy)piperidin-1-carbonyl)-1Hpyrazole-3carboxylic acid t o Z-Z °ч q Ь o LL? δ 8.05 (d, J = 2.7 Hz, 1H), 7.67 7.63 (m, 2H), 7.56 - 7.50 (m, 2H), 6.75 (d, J = 2.7 Hz, 1H), 4.67 (s, 2H), 4.06 - 4.04 (m, 2H), 3.82 3.73 (m, 1H), 3.64 - 3.56 ( m, 2H), 2.09 - 2.01 (m, 2H), 1.84 - 1.73 (m, 2H) 396.1 [ΜΗ]' 226 1-(4-((3(pyrrolidin-1yl)benzyl)oxy)pyridin-1carbonyl)- 1Hpyrazole-3carboxylic acid q ь° z-z cpPP о z δ 8.03 (d, J = 2.8 Hz, 1H), 7.13 (t, 7 = 7.8 Hz, 1H), 6.73 (d, 7 = 2.8 Hz, 1H), 6 .62 - 6.58 (m, 2H), 6.50 - 6.48 (m, 1H), 4.53 (s, 2H), 4.05 (br, 2H), 3.76 - 3.71 (m, 1H), 3.59 (br, 2H), 3.31-3.23 (m, 4H), 2.04 - 1.96 (m, 6H), 1.80 - 1.70 (m , 2H) 399.2 227 1-(2-(3-chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Cl /=/ o Af Ch ⁴ — pOH 0 5 8.04 (d, J = 2.4 Hz, lH), 7.58 (s, 1H), 7.47 - 7.39 (m, 3H), 6.74 (d, 7 = 2.4 Hz, 1H), 4.27 (s, 2H), 3.80 (br, 2H), 3.66 (br, 2H), 3.34 - 3.30 (m, 2H), 3.12 (br , 2H), 2.01 (t, J = 6.8 Hz, 2H), 1.84- 1.73 (m, 4H) 403.2

- 133 047826

228 (7?)-1-(4-([1,Γbiphenyl]-4ylmethyl)-2methylpiperazine-1 carbonyl)-1Hpyrazole-3carboxylic acid С1 ϊ ^ЭЧ О о A A. А„ N==/ ' - «· l U-on O δ 8.11 (d, J= 2.7 Hz, 1H), 7.62 7.59 (m, 4H), 7.47 - 7.40 (m, 4H), 7.35 - 7.29 ( m, 1H), 6.82 (d, J = 2.7 Hz, 1H), 4.67 - 4.63 (m, 1H), 4.32 - 4.28 (m, 1H), 3.74 - 3.70 (m, 1H), 3.64 - 3.55 (m, 1H), 3.54 - 3.46 (m, 1H), 3.07 - 2.96 (m, 1H), 2 .88 - 2.84 (m, 1H), 2.48 2.33 (m, 2H), 1.46 (d, J = 6.9 Hz. 3H) 405.2 229 1 -(4-(3 -(pyridazin3- yloxy)benzyl)pyrazin-1carbonyl)-1Hpyrazole-3carboxylic acid y,a..oCh O δ 8.93 - 8.91 (m, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.76 - 7.72 (m, 1H), 7.47 - 7.39 (m, 2H), 7.31 7.26 (m, 2H), 7.16-7.12 (m, 1H), 6.78 (d, J = 2.7 Hz, 1H), 3.88 (br, 4H), 3.72 (s, 2H), 2.70 (t, J = 4.5 Hz, 4H) 409.2 230 1-(trans-5-(3,5-dichlorophenoxy)oxyhydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O 1 ¹ n A XX Xa X Cr ⁴ N U~OH 0 δ 8.16 (d, J = 2.7 Hz, 1H), 6.97 (t, J = 1.8 Hz, 1H), 6.91 (d, J = 1.8 Hz, 2H), 6 .76 (d, J= 2.7 Hz, 1H), 5.08 - 5.01 (m, 1H), 4.62 - 3.42 (m, 4H), 3.18 - 2.88 (m , 2H), 2.24 - 2.11 (m, 2H), 2.10 - 1.89 (m, 2H) 432.0 [M+Na]+ 231 \-(trans-5-(3(trifluoromethyl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3carboxylic acid o , _s .oA?CH O δ 8.19 (d, J= 2.7 Hz, 1H), 7.53 7.42 (m, 1H), 7.28 - 7.11 (m, 3H), 6.77 (d, J = 2.7 Hz, 1H), 5.13 5.04 (m, 1H), 4.38 - 3.51 (m, 4H), 3.08 - 2.96 (m, 2H), 2.29 - 2.11 (m, 2H), 2.11 - 1.94 (m, 2H) 431.8 [M+Na] ⁺

- 134 047826

232 \-(trans-5-(3-cyclopentylphenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O ° ^^0 Η /-° ⁿ 0 δ 8.17 (d, J = 2.7 Hz, 1H), 7.21 7.03 (m, 1H), 6.87 - 6.63 (m, 4H), 5.10 - 4.91 ( m, 1H), 4.43 - 3.40 (m, 4H), 3.06 - 2.83 (m, 3H), 2.24 - 1.38 (m, 12H) 432.1 [M+Na] ⁺ 233 1-(ti/>ais-5-((4(trifluoromethyl)pyridin-3 yl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3carboxylic acid 0 όίΑ A Ζχ A\ V A- ⁷ n J CF ₃ δ 8.57 (s, 1H), 8.33 (d,.7 = 4.9 Hz, 1H), 8.17 (d, J = 2.7 Hz, 1H), 7.6O (d, J = 4.9 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 5.38 - 5.31 (m, 1H), 4.35 - 3.48 (m, 4H), 3.01 (br, 2H), 2.28 - 2.18 (m, 2H), 2.11 - 2.01 (m, 2H) 411,1 234 \-(trans-5-(3(pyrrolidin-1yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid _r .nA ^f 4. \A O δ 8.17 (d, J= 2.7 Hz, 1H), 7.11 6.95 (m, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.23 - 6 .10 (m, 2H), 6.06 (t, J = 4.4 Hz, 1H), 5.00 - 4.95 (m, 1H), 4.30 - 3.47 (m, 4H), 3.28 3.16 (m, 4H), 3.03 - 2.82 (m, 2H), 2.27 - 2.08 (m, 2H), 2.07 - 1.87 (m, 6H) 411,1 235 1-(4-((2-methyl-3(trifluoromethyl)benzyl)oxy)piperidin-1-carbonyl)-1Hpyrazole-3carboxylic acid 0 I αΆνΛ F ₃ C. /LAJN==/ Ύ^Ι V |l J /-on o δ 8.06 (d, J = 2.7 Hz, 1H), 7.64 7.58 (m, 2H), 7.32 (t, J = 7.5 Hz, 1H), 6.77 (d ,.7= 2.7 Hz, 1H), 4.67 (s, 2H), 4.03 (br, 2H), 3.84 - 3.77 (m, 1H), 3.67 - 3.54 (m, 2H), 2.45 (s, 3H), 2.09 - 2.01 (m, 2H), 1.84 - 1.73 (m, 2H) 410.1 [Μ- Η]'

- 135 047826

236 1-(4-((4-methyl-3(trifluoromethyl)benzyl)oxy)piperidin-1-carbonyl)-1Hpyrazole-3carboxylic acid O f ₃ c. AJ nA Υ/ ° Λ II J Hon o δ 8.05 (d, J = 2.7 Hz, 1H), 7.62 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 6.50 (d, J= 7.8 Hz, 1H), 6.75 (d, 7= 2.7 Hz, 1H), 4.61 (s, 2H), 4.04 (br, 2H), 3.79 - 3.72 ( m, 1H), 3.62 (br, 2H), 2.46 (s, 3H), 2.07 - 1.99 (m, 2H), 1.82-1.71 (m, 2H) 412,1 237 1-(4-(3-(4-hydroxytetrahydro-2H-pyran-4yl)benzyl)piperazin-1-carbonyl)1H-pyrazole-3carboxamide o A no./ААХ'А ⁿ A |] Z~NH ₂ IJ o O (Chloroform-T) δ 8.10 (d, 7=2.4 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.44 - 7.39 (m, 1H), 7, 37 - 7.32 (m, 1H), 7.28 - 7.27 (m, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.69 (br, 1H), 5 .60 (br, 1H), 4.03 - 3.85 (m, 8H), 3.60 (s, 2H), 2.58 (br, 4H), 2.25 2.18 (m, 2H) , 1.73 - 1.70 (m, 3H) 414.2 238 1-(2-(5-chloro-2methylbenzyl)-2,8diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid Cl /=/ O \ / UgAnd nA C—J /-on 0 5 8.03 (d, 7 = 2.7 Hz, 1H), 7.39 (s, 1H), 7.22 - 7.16 (m, 2H), 6.75 (d, 7 = 2.4 Hz, 1H), 3.82 (s,4H), 3.71 - 3.69 (m, 2H), 2.87 (t, 7= 6.6 Hz, 2H), 2.75 (s, 2H ), 2.37 (s, 3H), 1.85 (t, J = 6.6 Hz, 2H), 1.77 1.70 (m, 4H) 417.2 239 1-(trans-5-([1,Hbiphenyl]-2-yloxy/octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3carboxylic acid A z-z aA-A* о ξε 5 8.18 (s, 1H), 7.55 - 7.45 (m, 2H), 7.45 - 7.33 (m, 2H), 7.33 7.21 (m, 3H), 7, 11 - 6.97 (m, 2H), 6.79 (d, J = 2.7 Hz, 1H), 5.04 4.93 (m, 1H), 4.23 - 3.50 (m, 4H ), 2.77 (br, 2H), 2.24 - 2.03 (m, 2H), 1.95 - 1.73 (m, 2H) 439.8 [M+Na] ⁺ 240 1-(trans-5-([1,Hbiphenyl]-4-yloxy/octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid έ >° z-z cvAA о I 5 8.18 (s, 1H), 7.64 - 7.47 (m, 4H), 7.47 - 7.35 (m, 2H), 7.35 7.20 (m, 1H), 7, 03 - 6.91 (m, 2H), 6.78 (d, J = 2.7 Hz, 1H), 5.13 5.01 (m, 1H), 4.39 - 3.46 (m, 4H ), 3.00 (br, 2H), 2.34 - 2.11 (m, 2H), 2.11 - 1.89 (m, 2H) 439.8 [M+Na]+

- 136 047826

241 \-(trans-5-(3(pyridin-3yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid o ^Z '—Z ь° o (DMSO-0J δ 8.89 (d, J = 2.7 Hz, 1H), 8.62 - 8.50 (m, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.15-8.01 (m, 1H), 7.57 - 7.35 (m, 2H), 7.32 7.26 (m, 2H), 7.06 - 6.90 (m, 1H) , 6.74 (d, J = 2.6 Hz, 1H), 5.20 5.03 (m, 1H), 4.29 - 3.29 (m, 4H), 3.00 - 2.80 ( m, 2H), 2.14 - 1.90 (m, 4H) 419.2 242 \-(trans-5-(3(pyridin-2yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid o / Xi ¹ \ / '—Z b° ZZ o I δ 8.61 - 8.55 (m, 1H), 8.15 (d.0 = 2.7 Hz, 1H), 7.91 - 7.78 (m, 2H), 7.47 - 7.42 (m, 2H), 7.38 - 7.31 (m, 2H), 6.99 - 6.95 (m, 1H), 6.73 (d, J = 2.7 Hz, 1H), 5, 13 - 5.08 (m, 1H), 4.38 - 3.51 (m, 4H), 2.98 (br, 2H), 2.25 - 2.15 (m, 2H), 2.05 - 1.95 (m, 2H) 418.8 243 \-(trans-5-(3(pyridin-4yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid o ch Z-Z o I δ 8.52 (d, J= 4.0 Hz, 2H), 8.16 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 6.2 Hz, 2H), 7 .35 (t, J = 7.9 Hz, 1H), 7.24 (d, 0=8.0 Hz, 1H), 7.13 (t, J = 2.0 Hz, 1H), 6.97 - 6.93 (m, 1H), 6.75 (d,0=2.6Hz, 1H), 5.05 - 4.98 (m, 1H), 4.31 - 3.79 (m, 4H) , 2.92 (br, 2H), 2.41 - 2.28 (m, 2H), 1.92 (d,0= 13.6 Hz, 2H) 419,1 244 \-(trans-5-(2- (pyridin-3yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O P Ha 0 ⁿ #~0Η J. O G ” δ 8.64 (d, J = 4.0 Hz, 1H), 8.47 8.41 (m, 1H), 8.16 (d,0 = 2.8 Hz, 1H), 8.00 - 7 .93 (m, 1H), 7.49 7.42 (m, 1H), 7.38 - 7.31 (m, 2H), 7.11-7.01 (m, 2H), 6.76 ( d,0 = 2.8 Hz, 1H), 5.07 - 5.01 (m, 1H), 4.19 - 3.52 (m, 4H), 2.78 (br, 2H), 2.17 - 2.02 (m, 2H), 1.96 - 1.82 (m, 2H) 419,0

- 137 047826

245 (I)-1-(2-methyl-4((3-methyl-[1,1-biphenyl]-4yl)methyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid St a o o AJC/N. A, n==/ 1 /~ ^on O δ 8.13 (d, 7=2.7 Hz, 1H), 7.62 7.59 (br, 2H), 7.45 - 7.38 (m, 4H), 7.34 - 7.29 (br, 2H), 6.83 (d, 7=2.7 Hz, 1H), 4.66 (br, 1H), 4.27 4.23 (br, 1H), 3.57 (s, 2H), 3.51 3.41 (br, 1H), 2.93 - 2.89 (m, 1H), 2.83 - 2.79 (br, 1H), 2.50 (s, 3H), 2.45 - 2.40 (br, 1H), 2.31 - 2.23 (br, 1H), 1.43 (d, 7 = 6.9 Hz, ЗН) 419.3 246 (5)-1-(2-methyl-4((3-methyl-[1,1'biphenyl]-4yl)methyl)piperazine-1-carbonyl)-1Hpyrazole-3carboxylic acid CA o [ 1 A Ci o 1 AoH O δ 8.11 (d,7= 2.7 Hz, 1H), 7.61 7.58 (br, 2H), 7.43 - 7.37 (m, 4H), 7.33 - 7.28 (br, 2H), 6.81 (d, 7 = 2.7 Hz, 1H), 4.64 (br, 1H), 4.26 4.21 (br, 1H), 3.56 (s, 2H), 3.50 3.40 (br, 1H), 2.91 - 2.87 (m, 1H), 2.81 - 2.77 (br, 1H), 2.48 (s, 3H), 2.43 - 2.31 (br, 1H), 2.30 - 2.22 (br, 1H), 1.43 (d, 7 = 6.9 Hz, ЗН) 419.3 247 (I)-1-(2-methyl-4((2-methyl-[1,H-biphenyl]-4yl)methyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid Cl a >|-Λ Λ. Λ. -ΙΑ A №=/ U~° ⁿ O δ 8.10 (d,7= 2.7 Hz, 1H), 7.45 7.42 (br, 2H), 7.40 - 7.25 (m, 5H), 7.18 - 7.16 (br, 1H), 6.80 (d, 7 = 2.7 Hz, 1H), 4.72 (br, 1H), 4.36 4.32 (br, 1H), 3.68 - 3.47 (br, 3H), 2.99 - 2.95 (br, 1H), 2.88 - 2.84 (br, 1H), 2.45 - 2.40 (m, 1H), 2.37 - 2.33 (br, 1H), 2.30 - 2.26 (br, 3H), 1.43 (d, 7 = 6.8 Hz, ЗН) 419,5 248 1-(trans-5-(3- (pyridazin-4yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O P Ha 'a H OH N^ ¹ O δ 9.55 - 9.48 (m, 1H), 9.24 - 9.17 (w, 1H), 8.14 (d, 7= 2.7 Hz, 1H), 8.01 - 7.96 (w, 1H), 7.52 - 7.43 (w, 1H), 7.41 -7.31 (w, 2H), 7.11 - 7.05 (w, 1H), 6.74 (d , 7 = 2.7 Hz, 1H), 5.17-5.08 (w, 1H), 4.41 - 3.53 (w, 4H), 3.01 (br, 2H), 2.28 - 2.12 (w, 2H), 2.09 - 1.96 (w, 2H) 419.9

- 138 047826

249 \-(trans-5-(3(pyrimidin-2yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O P N==/ _n /—on O δ 8.80 (d, J = 4.0 Hz, 2H), 8.16 (d, J = 2.8 Hz, 1H), 7.96 - 7.91 (m, 2H), 7.41 - 7.31 (m, 2H), 7.07 7.01 (m, 1H), 6.74 (d, J = 2.8 Hz, 1H), 5.15 - 5.08 (m, 1H), 4.35 3.53 (m, 4H), 3.01 (br, 2H), 2.25 -2.15 (m, 2H), 2.06 - 1.97 (m, 2H) 419.8 250 (I)-1-(2-methyl-4- (2-methyl-4(pyridin-2yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid o * ь° o t δ 8.59 - 8.57 (m, 1H), 8.07 (d, J= 2.7 Hz, 1H), 7.88 - 7.82 (m, 2H), 7.76 (s, 1H ), 7.71 - 7.68 (m, 1H), 7.40 - 7.32 (m, 2H), 6.76 (d, J = 2.7 Hz, 1H), 4.68 (br, 1H), 4.30 4.25 (m, 1H), 3.55 (s, 2H), 3.45 3.44 (m, 1H), 2.89 - 2.85 (m, 1H), 2 .78 - 2.74 (m, 1H), 2.51 (s, 3H), 2.41 - 2.36 (m, 1H), 2.28 - 2.24 (m, 1H), 1.40 (d, J = 6.6 Hz, 3H) 420,5 251 1-(4-(3-(nitroglycerin)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid xvxoN > ^he o δ 8.12 (d, .7= 2.7 Hz, 1H), 7.31 (t, J= 7.8 Hz, 1H), 7.17 - 7.02 (m, 3H), 7.02 - 7.01 (m, 1H), 6.91 6.86 (m, 3H), 6.80 (d, J = 2.7 Hz, 1H), 3.88 (br, 4H), 3.72 (s, 2H), 2.75 (t, J= 5.1 Hz, 4H), 2.31 (s, 3H) 421.2 252 1-(tyran-5-((3chloro-5fluorobenzyl)oxy)o kgahydrocyclopent a[c]pyrrole-2carbonyl)-4methyl-1 H-pyrazol3-carboxylic acid O N VN Y—J №=/ sk \ II ίΓ ° ⁿ # ^on /d ° F δ 7.95 - 7.86 (m, 1H), 7.23 - 7.17 (br, 1H), 7.13 - 6.98 (m, 2H), 4.48 (s, 2H), 4 .27 - 4.16 (m, 1H), 4.16 - 3.41 (m, 4H), 2.99 - 2.80 (br, 2H), 2.26 (d, J = 0.9 Hz , 3H), 2.19 - 2.01 (m, 2H), 1.87 - 1.71 (m, 2H) 443.8 [M+Na] ⁺

- 139 047826

253 (7?)-1-(4-((3-φτορ[1,G-biphenyl]-4yl)methyl)-2methylpiperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid ⁰ L JL X O O Axk/N. X.„ N==/ 1 /OH O δ 8.11 (d, J= 2.7 Hz, 1H), 7.64 7.61 (m, 2H), 7.56-7.51 (m, 1H), 7.47 - 7.42 ( m, 3H), 7.38 - 7.33 (m, 2H), 6.82 (d, J = 2.4 Hz, 1H), 4.65 (br, 1H), 4.28 - 4.23 (m, 1H), 3.67 (s, 2H), 3.54 - 3.45 (m, 1H), 2.96 - 2.81 (m, 2H), 2.46 - 2.27 (m , 2H), 1.45 (d, J = 6.9 Hz, 3H) 423.2 254 \-(trans-5-(3methyl-4(trifluoromethyl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3carboxylic acid 'laCh. 0 δ 8.16 (d, 7 = 2.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 6.92 - 6.84 (m, 1H), 6.84 - 6.78 (m, 1H), 6.74 (d, J= 2.7 Hz, 1H), 5.11 - 5.01 (m, 1H), 4.39 - 3.50 (m, 4H) , 3.062.85 (m, 2H), 2.48 - 2.33 (m, 3H), 2.27 - 2.09 (m, 2H), 2.09 - 1.92 (m, 2H) 445.8 [M+Na] ⁺ 255 (-(trans-5-((3(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[s]pyrrole-2-carbonyl)1H-pyrazole-3carboxylic acid 0 n xL ϋΛν nA gА ι ι y YJ №=/ γ u o n /-on CHU ⁰ δ 8.18-7.96 (m, 1H), 7.68 - 7.41 (m, 4H), 6.78 - 6.62 (m, 1H), 4.60 - 4.48 (m, 2H), 4.40 - 3.66 (m, 5H), 2.98 - 2.67 (m, 2H), 2.29 2.05 (m, 2H), 1.91-1.68 (m , 2H) 423.8 256 (-(trans-5-(2-methyl-3(trifluoromethyl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxylic acid τ ο ΓΑ Ζ-Ζ °4 ζ—, / τ/ ο LL? δ 8.18 (d, 7 = 2.7 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.21 - 7.14 (m, 2H), 6.76 ( d,7=2.7Hz, 1H),5.13 - 5.08 (m, 1H), 4.38 - 3.56 (m, 4H), 3.02 (br, 2H), 2.96 ( d, J = 1.4 Hz, 3H), 2.28 - 2.15 (m, 2H), 2.08 - 1.96 (m, 2H) 441.2 [M+ _NH4 ] ⁺

- 140 047826

257 1 -((27?,47?)-2-methyl4-(methyl(3(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxamide О F ₃ CL J-.. N=/ |l J 1 z~nh ₂ qT (Chloroform-*/) δ 8.09 (d, J = 2.7 Hz, 1H), 7.60 (s, 1H), 7.53 - 7.51 (m, 2H), 7.46 - 7 .41 (m, 1H), 6.90 (d, J= 2.7 Hz, 1H), 6.68 (br, 1H), 5.67 (br, 1H), 4.30 - 4.21 ( m, 1H), 4.14 - 4.07 (m, 1H), 3.64 (br, 2H), 3.52 - 3.42 (m, 1H), 2.81 (br, 1H), 2 .20 (s, 3H), 2.07 - 2.03 (m, 2H), 1.81-1.67 (m, 2H), 1.49 (d, J = 6.3 Hz, 3H) 424.2 258 1-(4-methyl-4(methyl(3(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxamide 0 1 A, Jk .nJ I iz N=/ У—nh ₂ о δ 8.18 (d, J = 2.4 Hz, 1 Η), 7.69 7.67 (m, 2H), 7.56 - 7.51 (m, 2H), 6.88 (d, J = 2.4 Hz, 1H), 3.94 3.82 (m, 4H), 3.72 (s, 2H), 2.15 2.08 (m, 5H), 1.75 - 1.68 ( m, 2H), 1.15 (s, 3H) 446.1 [M+Na] ⁺ 259 1 -((25,47/)-2-methyl4-(methyl(3(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxamide 0 -V^nX iW γ N \ |l J 1 z~nh ₂ o (Chloroform-*/) δ 8.07 (d, J = 2.7 Hz, 1H), 7.60 - 7.42 (m, 4H), 6.90 (d, J = 2.7 Hz, 1H ), 6.70 (br, 1H), 5.94 (br, 1H), 4.88 - 4.86 (m, 1H), 4.43 - 4.39 (m, 1H), 3.68 ( br, 2H), 3.23 - 3.15 (m, 1H), 3.02 (br, 1H), 2.24 (s, 3H), 2.24 - 1.63 (m, 4H), 1 .37 (d, J =6.9 Hz, ZN) 424.2 260 1 -((27?, 45)-2-methyl4-(methyl(3(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxamide 0 F ₃ C. A J-,.„ N==/ |l J 1 >—nh ₂ o (Chloroform-*/) δ 8.07 (d, J = 2.7 Hz, 1H), 7.60 - 7.41 (m, 4H), 6.90 (d, J = 2.7 Hz, 1H ), 6.70 (br, 1H), 5.91 (br, 1H), 4.88 - 4.84 (m, 1H), 4.43 - 4.38 (m, 1H), 3.66 ( br, 2H), 3.23 - 3.15 (m, 1H), 3.03 - 3.00 (m, 1H), 2.23 (s, 3H), 1.98 - 1.83 (m, 3H), 1.76 - 1.62 (m, 1H), 1.65 (d, J = 5.4 Hz, ZN) 424.2

- 141 047826

261 \-(trans-5-(3(thiazol-2yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid ^He is the one who ... δ 8.24 (d, J= 3.0 Hz, 1H), 7.85 (d, J= 3.3 Hz, 1H), 7.56 (d, J= 3.3 Hz, 1H), 7 .48 - 7.41 (m, 2H), 7.37 - 7.31 (m, 1H), 7.04 - 6.98 (m, 1H), 6.82 (d.7 = 2.7 Hz , 1H),5.17 - 5.06 (m, 1H), 4.31 - 3.58 (m, 4H), 3.11 - 2.88 (m, 2H), 2.28 2.12 ( m, 2H), 2.10-1.97 (m, 2H) 425.1 262 \-(trans-5-(3(thiazol-5yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid o n ₄ η Ha % ^Η /-OH Vs ο δ 8.95 (s, 1H), 8.16 (d, 7=2.7 Hz, 1H), 8.13 (s, 1H), 7.33 - 7.25 (m, 1H), 7, 18-7.12 (m, 1H), 7.11 - 7.08 (m, 1H), 6.87 - 6.83 (m, 1H), 6.75 (d,7= 2.7 Hz, 1H),5.01 - 4.96 (m, 1H), 4.41 - 3.65 (m, 4H), 2.91 (br, 2H), 2.42 - 2.28 (m, 2H) , 1.90 (d, 7= 13.6 Hz, 2H) 425.1 263 1-(4-(4-fluoro-3phenoxybenzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid 0 oSOaUc U-ON O δ 8.13 (d.7= 2.5 Hz, 1H), 7.35 7.26 (m, 2H), 7.23 - 7.15 (m, 3H), 7.11 - 7.06 ( m, 1H), 7.96 - 7.94 (m, 2H), 6.82 (d, J = 2.5 Hz, 1H), 3.87 (br, 4H), 3.73 - 3.62 (m, 2H), 2.88-2.61 (m, 4H) 425,5 264 1-(4-(3-((3-fluoropyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid O ωχ.Υο i ОН о 5 8.11 (d, 7=2.7 Hz, 1H), 7.907.87 (m, 1H), 7.70 - 7.64 (m, 1H), 7.40 (t, 7= 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.17 - 7.12 (m, 1H), 7.11 - 7.06 (m, 1H), 6.79 (d,7= 2.7 Hz, 1H), 3.89 (br, 4H), 3.76 (s, 2H), 2.77 - 2.74 (m, 4H) 426.3

- 142 047826

265 1-(4-(3-((5-fluoropyridine-3-yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid O ,Λ,χχοΝ # HE O δ 8.22 (d, J = 2.4 Hz, 1H), 8.17 (d, ./ = 2.1 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.28 - 7.23 (m, 2H), 7.16 (s, 1H), 7.05 - 7.01 (m, 1H) , 6.73 (d, J = 2.7 Hz, 1H), 3.86 (br, 4H), 3.60 (s, 2H), 2.65 - 2.51 (m, 4H) 426.3 266 1-(4-(3-((5-fluoropyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid хххс/ /-he o δ 8.12 (d, J = 2.4 Hz, 1H), 8.05 8.00 (m, 1H), 7.72 - 7.62 (m, 1H), 7.43 - 7.32 ( m, 1H), 7.26 - 7.18 (m, 1H), 7.15 - 7.14 (m, 1H), 7.07 - 6.98 (m, 2H), 6.88 - 6, 79 (m, 1H), 3.91 (br, 4H), 3.83 - 3.79 (m, 2H), 2.81 (br, 4H) 426.3 267 \-(trans-5-(3(tetrahydro-2Hpyran-4yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid o / A ¹ \ / '—Z ZZ o ΞΕ δ 8.14 (d, J= 2.7 Hz, 1H), 7.31 7.10 (m, 1H), 6.85 - 6.67 (m, 4H), 5.12 - 4.95 ( m, 1H), 4.46 - 3.42 (m, 8H), 3.03 - 2.87 (br, 2H), 2.84 - 2.68 (m, 1H), 2.30 - 2, 08 (m, 2H), 2.07 - 1.90 (m, 2H), 1.90 1.71 (m, 4H) 448.1 [M+Na] ⁺ 268 \-(trans-5-(2(tetrahydro-2Hpyran-4yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid °O—хф А ь° Z-Z о ΞΕ δ 8.21 (d, J= 2.7 Hz, 1H), 7.21 7.11 (m, 2H), 6.93 (d, J = 7.5 Hz, 2H), 6.81 (d , 7= 2.7 Hz, 1H),5,O8 - 5.01 (m, 1H), 4.29 - 3.52 (m, 8H), 3.28 - 3.11 (m, 1H), 3.01 (br, 2H), 2.28 - 2.12 (m, 2H), 2.07 1.93 (m, 2H), 1.88 - 1.66 (m, 4H) 448.2 [M+Na] ⁺

- 143 047826

269 1-(4-(3-chloro-5(pyrimidin-5yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid CI O D γΑ-Λ A N==/ |1 J /-on Ν 0 δ 9.16 (s, 1H), 9.08 (s, 2H), 8.12 (d, J = 2.7 Hz, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 6.80 (d, J = 2.7 Hz, 1H), 3.88 (br, 4H), 3.72 (s, 2H), 2.67 ( t, J= 4.8 Hz, 4H) 427,1 270 4-chloro-1-(4-(3(pyrimidin-5yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid O 00 GAL-s ,l\k A N==/ Ν \ |l J /-on N O 5 8.84 (d, J =4.8 Hz, 2H), 8.41 (s, 1H), 8.33 - 8.29 (m, 1H), 8.12 (s, 1H), 7, 54 - 7.45 (m, 2H), 7.38 7.34 (m, 1H), 3.86 (br, 4H), 3.67 (s, 2H), 2.63 - 2.59 (m , 4H) 427.3 271 (S)-l-(4-(3-chloro-5(trifluoromethyl)benzyl)-2methylpiperazine-1carbonyl)-1Hpyrazole-3carboxamide cf ₃ 0 A rAl A. №=/ cr \ /—nh ₂ 0 (Chloroform-J) 5 8.09 (d, J = 2.7 Hz, 1H), 7.61 - 7.53 (m, 3H), 6.90 (d, J = 2.7 Hz, 1H) , 6.64 (br, 1H), 5.52 (br, 1H), 4.65 (br, 1H), 4.31 - 4.27 (m, 1H), 3.63 - 3.47 (m , 3H), 2.88 - 2.84 (m, 1H), 2.69 2.65 (m, 1H), 2.38 - 2.24 (m, 2H), 1.51 (d, J = 6.9 Hz, 3H) 430,1 272 (I)-1-(4-(3-chloro-5(trifluoromethyl)benzyl)-2methylpiperazine-1-carbonyl)-1Hpyrazole-3-carboxamide сч X Z αά° °А / о с у----\ о (Chloroform-J) 5 8.09 (d, J = 2.7 Hz, 1H), 7.61 - 7.53 (m, 3H), 6.90 (d, J = 2.7 Hz, 1H) , 6.65 (br, 1H), 5.61 (br, 1H), 4.66 - 4.64 (m, 1H), 4.31 - 4.27 (m, 1H), 3.63 - 3 .55 (m, 1H), 3.54 - 3.46 (m, 2H), 2.88 - 2.84 (m, 1H), 2.69 - 2.65 (m, 1H), 2.38 - 2.24 (m, 2H), 1.51 (d, 7=6.9 Hz, 3H) 430,1

- 144 047826

273 1-(trans-5-{{[\, 1 biphenyl]-3ylmethyl)amino)oct ahydrocyclopenta[ c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O P Ha ^an Don ⁿ ° (DMSO-7g) δ 8.25 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.76 - 7.66 (m, 2H), 7.62 - 7, 59 (m, 1H), 7.49 7.40 (m, 5H), 6.75 (d, J = 2.2 Hz, 1H), 3.97 (s, 4H), 3.56 (br, 3H), 2.87 (br, 2H), 1.89 (d, J= 5.1 Hz, 4H) 431.2 274 1-(4-(4-chloro-3(thiazol-2yl)benzyl)piperase in-1-carbonyl)1H-pyrazole-3carboxylic acid с> z-z О ΞΕ δ 8.11 - 8.09 (m, 2H), 7.95 (d, J = 3.3 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.56 - 7.53 (m, 1H), 7.49 7.45 (m, 1H), 6.78 (d, J = 2.7 Hz, 1H), 3.87 (br, 4H), 3.71 ( s, 2H), 2.68 (br, 4H) 432.4 275 1-(4-((3-chloro-5(trifluoromethyl)benzyl)oxy)piperidin-1-carbonyl)-1Hpyrazole-3carboxylic acid O DA^AA, F ₃ C. nV |1 J Aon AD o CI δ 8.06 (d, J = 2.8 Hz, 1H), 7.69 (s, 1H), 7.63 - 7.61 (m, 2H), 6.76 (d, J = 2.8 Hz, 1H), 4.69 (s, 2H), 4.08 (br, 2H), 3.84 - 3.78 (m, 1H), 3.68 - 3.65 (m, 2H), 2 .10 - 2.03 (m, 2H), 1.85 - 1.83 (m, 2H) 449.1 [M+ _NH4 ] ⁺ 276 1-(4-((4-chloro-3(trifluoromethyl)benzyl)oxy)piperidin-1-carbonyl)-1Hpyrazole-3carboxylic acid O aDa A J L~ ^he SG^A o δ 8.24 (d, J = 2.7 Hz, 1H), 7.76 (s, 1H), 7.63 - 7.56 (m, 2H), 6.75 (d, J = 2.7 Hz, 1H), 4.64 (s, 2H), 4.05 (br, 2H), 3.82 - 3.75 (m, 1H), 3.66 - 3.60 (m, 2H), 2 .08 - 2.00 (m, 2H), 1.84- 1.81 (m, 2H) 454.1 [M+Na] ⁺ 277 1-(4-((5-chloro-2(trifluoromethyl)benzyl)oxy)piperidin-1-carbonyl)-1Hpyrazole-3carboxylic acid O CF ₃ DA^AAH D d n==Z IlTΛ |l J /-on ad o Cl δ 8.04 (d, J = 2.1 Hz, 1H), 7.78 (s, 1H), 7.68 - 7.63 (m, 1H), 7.60 - 7.46 (m, 1H ), 6.75 (d, J = 2.1 Hz, 1H), 4.75 - 4.64 (m, 2H), 4.05 (br, 2H), 3.85 - 3.75 (m, 1H), 3.66 - 3.62 (m, 2H), 2.10 - 1.96 (m, 2H), 1.86 - 1.73 (m, 2H) 430.0 [Μ- Η]

- 145 047826

278 1-(trans-5-([1,Hbiphenyl]-3ylmethoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid O N A Q Ha a n D—ON AD ⁰ δ 8.00 (d, J = 2.7 Hz, 1H), 7.64 7.55 (m, 2H), 7.53 - 7.45 (m, 2H), 7.45 - 7.19 ( m, 5H), 6.70 (d, J = 2.7 Hz, 1H), 4.50 (s, 2H), 4.30 4.04 (m, 2H), 4.04 - 3.72 ( m, 3H), 2.88 - 2.64 (m, 2H), 2.22 - 2.01 (m, 2H), 1.90 - 1.67 (m, 2H) 432.2 279 1-(g/is-5-([1 ,Gbiphenyl]-3ylmethoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid O ⁿ A / x Π .ΟΑ a η Αοη ХД ° δ 8.23 (d, J= 2.7 Hz, 1H), 7.70 7.58 (m, 3H), 7.58 - 7.50 (m, 1H), 7.50 - 7.39 ( m, 3H), 7.39 - 7.28 (m, 2H), 6.85 (d, J= 2.7 Hz, 1H), 4.56 (s, 2H), 4.32 - 4.21 (m, 1H), 4.20 - 3.51 (br, 4H), 3.03 - 2.87 (m, 2H), 2.23 - 2.08 (m, 2H), 1.90 -1 .71 (m, 2H) 432.2 280 1-(trans-5-([1,Hbiphenyl]-3-yloxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4methyl-1 H-pyrazole-3-carboxylic acid XX Γν Ν-( ^н Αοη ⁰ δ 8.06 - 7.98 (m, 1H), 7.61 - 7.53 (m, 2H), 7.47 - 7.36 (m, 2H), 7.36 - 7.25 (m, 2H), 7.19-7.11 (m, 1H), 7.11 - 7.02 (m, 1H), 6.90 6.81 (m, 1H), 5.13 - 5.00 (m , 1H), 4.29 - 3.48 (m, 4H), 3.07 - 2.84 (m, 2H), 2.32 (d, J = 0.9 Hz, 3H), 2.25 - 2.09 (m, 2H), 2.08 - 1.88 (m, 2H) 431.9 281 1-(trans-5-([1,Hbiphenyl]-2-yloxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4methyl-1 H-pyrazole3-carboxylic acid °Α ζ—, / Αι δ 7.96 (s, 1H), 7.48 - 7.42 (m, 2H), 7.37 - 7.31 (m, 2H), 7.29 7.22 (m, 3H), 7, 05 - 6.95 (m, 2H), 4.97 - 4.91 (m, 1H), 4.17 - 3.48 (m, 4H), 2.73 (br, 2H), 2.25 ( s, 3H), 2.15 - 2.05 (m, 2H), 1.85 1.75 (m, 2H) 454.2 [M+Na] ⁺

- 146 047826

282 1-(2-(5-chloro-2methoxybenzyl) 2,8- diazaspiro [4.5 ] decane-8-carbonyl) 1H-pyrazole-3-carboxylic acid x o Z-Z °ч Z—Ч 1 5 8.02 (d,J = 2.4 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.40 - 7.37 (m, 1H), 7.07 - 7.05 (m, 1H), 6.74 (d, 7= 2.4 Hz, 1H), 4.21 (s, 2H), 3.88 - 3.82 (m, 5H), 3.68 (br, 2H), 3.31 - 3.28 (m, 2H), 3.15 (s, 2H), 2.00 (t, J =6.8 Hz, 2H), 1.84 - 1, 72 (m, 4H) 433.2 283 (^)-1-(4-((3methoxy-[1,Hbiphenyl]-4yl)methyl)-2methylpiperazine-1carbonyl)-1Hpyrazole-3carboxylic acid X o °4 / o 5 8.10 (d, J= 2.7 Hz, 1H), 7.65 7.62 (m, 2H), 7.48 - 7.41 (m, 3H), 7.36 - 7.31 ( m, 1H), 7.24 - 7.22 (m, 2H), 6.79 (d, J = 2.7 Hz, 1H), 4.77 - 4.76 (m, 1H), 4.45 - 4.41 (m, 1H), 3.94 (s, 3H), 3.87 (s, 2H), 3.57 - 3.47 (m, 1H), 3.14 3.09 (m, 1H), 3.02 - 2.98 (m, 1H), 2.72 - 2.59 (m, 2H), 1.46 (d, J = 6.9 Hz, 3H) 435.2 284 1-(2-(3(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxamide О ) N=/ rN \ , ( VJ /-NH ₂ ^f 3 ^c AI/ ° (Chloroform-yH) δ 8.05 (d, J= 2.7 Hz, 1H), 7.59 (s, 1H), 7.52 - 7.50 (m, 2H), 7.45 - 7, 40 (m, 1H), 6.90 (d, J= 2.7 Hz, 1H), 6.66 (br, 1H), 5.56 (br, 1H), 3.80 - 3.62 (m , 6H), 2.64 (t, J = 6.9 Hz, 2H), 2.44 (s, 2H), 1.76 - 1.68 (m, 6H) 436.2 285 1-(2-(2,5-dichlorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Cl /==/ o X / ^c|/ \-nA\^ W z~oh o 5 8.02 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.38 - 7.36 (m, 1H), 7.28 - 7.25 (m, 1H), 6.74 (d, J = 2.4 Hz, 1H), 3.95 - 3.72 (m, 6H), 2.77 - 2.74 (m, 2H) , 2.62 (s, 2H), 1.81-1.68 (m, 6H) 437.2 286 1-(2-(2,3-dichlorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid /=\ about A ci/v/AJ W Μ-' A ^he about 5 8.02 (d, J= 2.7 Hz, 1H), 7.50 7.44 (m, 2H), 7.31 - 7.26 (m, 1H), 6.73 (d, J = 2.7 Hz, 1H), 3.94 3.53 (m, 6H), 2.83 - 2.78 (m, 2H), 2.66 (s, 2H), 1.82 - 1.70 ( m, 6H) 437.2

- 147 047826

287 1-(8-(3(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-2-carbonyl)1H-pyrazole-3carboxylic acid F ₃ C—/ \ A/ V? fA \--/\__J N==/ /—on O 5 8.22 (d, J = 2.4 Hz, 1H), 7.88 (s, 1H), 7.80 - 7.76 (m, 2H), 7.73 7.65 (m, 1H) , 6.80 (d, J = 2.4 Hz, 1H), 4.32 - 4.15 (m, 2H), 4.07 4.02 (m, 2H), 3.86 - 3.58 ( m, 2H), 3.32 - 3.09 (m, 4H), 2.17 - 1.88 (m, 6H) 437.2 288 1-(4-(3-(2methoxyphenoxy)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid ahdg/c /—he o 5 8.16 (d, J= 2.7 Hz, 1H), 7.33 7.21 (m, 1H), 7.20-7.19 (m, 1H), 7.18 - 7.13 ( m, 1H), 7.08 - 6.95 (m, 4H), 6.85 - 6.81 (m, 2H), 3.93 (br, 4H), 3.82 - 3.78 (m, 5H), 2.85 (br, 4H) 437.2 289 1-(g/is-5-((2-methyl3- (trifluoromethyl)benzyl)oxy)octahydrocyclopenta[s]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid 0 n ZX Ah X/'N 1 γΆ / ' / YJ №=/ ^F 3 ^C vA ^/x n' ⁱ 'AH Y 4 0 Η /—on ⁰ 5 8.18 - 7.90 (m, 1H), 7.63 -7.48 (m, 2H), 7.35 - 7.15 (m, 1H), 6.77 - 6.62 (m, 1H), 4.62 - 4.47 (m, 2H), 4.40 - 3.52 (m, 5H), 2.98 2.69 (br, 2H), 2.48 - 2.30 (m , 3H), 2.28 - 2.07 (m, 2H), 1.91 - 1.72 (m, 2H) 459.8 [M+Na] ⁺ 290 4-methyl-1-(trans5-((3- (trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3carboxylic acid 0 η Α γΚΊ Ό Υ—' №==/ ^11^ ^{0 Η} Α~θ ^{Η 0} 5 7.95 (d, J= 0.8 Hz, 1H), 7.77 7.44 (m, 4H), 4.56 (s, 2H), 4.38 4.20 (m, 1H), 4.20 - 3.42 (m, 4H), 3.03 - 2.75 (br, 2H), 2.30 (d, J = 0.8 Hz, 3H), 2.21 - 2.00 ( m, 2H), 1.90- 1.68 (m, 2H) 437.8

- 148 047826

291 (I)-1-(4-((3-chloro[1,1'-biphenyl]-4yl)methyl)-2methylpiperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid And A ^ΎΊ O o % /N. Х.„ N==/ X · > δ 8.11 (d, J= 2.7 Hz, 1H), 7.54 7.64 (m, 5H), 7.42 - 7.47 (m, 2H), 7.33 - 7.38 ( m, 1H), 6.82 (d, J = 2.7 Hz, 1H), 4.66 (br, 1H), 4.24 4.28 (m, 1H), 3.68 (s, 2H) , 3.45 3.54 (m, 1H), 2.90 - 2.95 (m, 1H), 2.80 - 2.84 (m, 1H), 2.44 - 2.49 (m, 1H ), 2.30 - 2.38 (m, 1H), 1.47 (d, J = 6.9 Hz, 3H) 439.2 292 (^)-1.(4-(3-(4-fluorophenoxy)benzyl)-2- methylpiperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid Won o δ 8.11 (d, J= 2.7 Hz, 1H), 7.33 7.28 (m, 1H), 7.12 - 7.06 (m, 3H), 7.05 - 6.97 ( m, 3H), 6.89 - 6.86 (m, 1H), 6.82 (d, J= 2.7 Hz, 1H), 4.62 (br, 1H), 4.27 - 4.23 (m, 1H), 3.65 - 3.61 (m, 1H), 3.54 - 3.41 (m, 2H), 2.92 - 2.88 (m, 1H), 2.78 - 2 .74 (m, 1H), 2.38 - 2.27 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H) 439.1 293 (5)-1-(4-(3-(4-fluorophenoxy)benzyl)-2- methylpiperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid U-he o δ 8.12 (d, J= 2.7 Hz, 1H), 7.33 7.28 (m, 1H), 7.12 - 7.03 (m, 3H), 7.01 - 6.98 ( m, 3H), 6.90 - 6.87 (m, 1H), 6.83 (d, J= 2.7 Hz, 1H), 4.61 (br, 1H), 4.26 - 4.21 (m, 1H), 3.67 - 3.62 (m, 1H), 3.52 - 3.41 (m, 2H), 2.93 - 2.89 (m, 1H), 2.79 - 2 .75 (m, 1H), 2.39 - 2.28 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H) 439.2 294 (I)-1-(4-(4-fluoro-3phenoxybenzyl)-2methylpiperazine-1 carbonyl)-1Hpyrazole-3carboxylic acid o osaoA U-on o δ 8.12 (s, 1H), 7.36 - 7.22 (m, 2H), 7.22 - 7.07 (m, 4H), 7.10 6.94 (m, 2H), 6, 84 (d, J = 3.0 Hz, 1H), 4.59 (br, 1H), 4.23 - 4.19 (m, 1H), 3.63 - 3.54 (m, 1H), 3 .49 3.32 (m, 2H), 2.91 - 2.87 (m, 1H), 2.75 - 2.72 (m, 1H), 2.37 - 2.27 (m, 2H), 1.40 - 1.35 (m, 3H) 439.2

- 149 047826

295 (4-1-(4-(3-((5-fluoropyridin-2yl)oxy)benzyl)-2methylpiperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid xvcxA /—OH o δ 8.10 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 3.0 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.39 - 7.34 (m, 1H), 7.22 - 7.20 (m, 1H), 7.14 (s, 1H), 7.02 - 6.97 (m, 2H), 6.81 - 6, 80 (m, 1H), 4.64 (br, 1H), 4.29 - 4.24 (m, 1H), 3.69 - 3.65 (m, 1H), 3.56 3.43 (m , 2H), 2.96 - 2.92 (m, 1H), 2.82 - 2.78 (m, 1H), 2.41 - 2.29 (m, 2H), 1.40 (d, J = 6.9 Hz, 3H) 440.3 296 4-chloro-1-(trans-5((3-chloro-5fluorobenzyl)oxy)o-kgahydrocyclopent a[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid o n A _S | Г \—J №=/ II ίΓ ^{0 n} Aon o F δ 8.22 (s, 1H), 7.21 (s, 1H), 7.12 - 7.01 (m, 2H), 4.48 (s, 2H), 4.26 - 4.18 (m , 1H), 4.15 - 3.47 (m, 4H), 2.92 (br, 2H), 2.18 - 2.05 (m, 2H), 1.87 - 1.73 (m, 2H ) 459.1 [M+ _NH4 ] ⁺ 297 \-(trans-5-(5-chloro-2(trifluoromethyl)phenoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1Hpyrazole-3carboxylic acid o—/ V-o ω \---/ h Ζ-Ζ aAX o I δ 8.16 (d, J= 2.7 Hz, lH), 7.58 (d, J= 8.4 Hz, 1H), 7.28 - 7.17 (m, 1H), 7.11 - 6.99 (m, 1H), 6.78 (d, J= 2.7 Hz, 1H), 5.25 - 5.11 (m, 1H), 4.38 - 3.50 (m, 4H) , 3.09 2.84 (m, 2H), 2.30 - 2.10 (m, 2H), 2.10 - 1.88 (m, 2H) 466.8 [M+Na] ⁺ 298 1-(trans-5-(([(, 1 'biphenyl]-3ylmethyl)(methyl)amino)octahydrocycle openta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O Q Ha X ⁿ #~on ⁰ δ 8.18 (s, 1H), 7.70 (s, 1H), 7.62 - 7.53 (m, 3H), 7.44 - 7.30 (m, 5H), 6.80 (s , 1H), 4.35 - 3.80 (m, 5H), 3.65 - 3.56 (m, 2H), 2.91 (s, 2H), 2.50 (s, 3H), 2, 44 - 2.34 (m, 2H), 2.07 - 2.00 (m, 2H) 445.2

- 150 047826

299 (I)-1-(4-(4-chloro-3(thiazol-2yl)benzyl)-2- methylpiperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid O ΥΊ O O U θλ-ΟΗ δ 8.12 - 8.10 (m, 2H), 7.97 (d, J = 3.3 Hz, 1H), 7.79 - 7.76 (m, 1H), 7.57 - 7.55 (m, 1H), 7.51 7.48 (m, 1H), 6.82 (d, J = 2.7 Hz, 1H), 4.66 (br, 1H), 4.30 - 4.27 (m, 1H), 3.70 - 3.65 (m, 1H), 3.59 3.48 (m, 2H), 2.95 - 2.91 (m, 1H), 2.82 - 2, 78 (m, 1H), 2.43 - 2.35 (m, 1H), 2.32 - 2.27 (m, 1H), 1.43 (d, J = 6.0 Hz, 3H) 446.4 300 1-(2-(2-carbamoyl5-chlorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Cl /=/ o \ / /X^lX °=<Α-ν^Μ Μ νη ₂ V- ^J рОН О δ 8.06 (d, J= 2.7 Hz, 1H), 7.81 7.78 (m, 1H), 7.66 (s, 1H), 7.59 7.57 (m, 1H), 6.67 (d, J = 2.7 Hz, 1H), 4.29 (s, 2H), 3.89 (br, 2H), 3.70 (br, 2H), 3.31-3.27 (m, 2H), 3.14 (s, 2H), 2.06 - 2.01 (m, 2H), 1.87 - 1.70 (m, 4H) 446.2 301 1-(2-(3-(pyridin-2yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid fl/r V_Z C-N rf №=/ P° ^h 0 δ 8.62 - 8.60 (m, 1H), 8.13 (s, 1H), 8.03 - 8.00 (m, 2H), 7.88 7.86 (m, 2H), 7, 62 - 7.53 (m, 2H), 7.39 - 7.35 (m, 1H), 6.73 (d, J = 2.7 Hz, 1H), 4.41 (s, 2H), 3 .84 3.79 (m, 2H), 3.68 - 3.63 (m, 2H), 3.40 - 3.30 (m, 2H), 3.32 - 3.27 (m, 2H), 2.06 - 1.97 (m, 2H), 1.84 - 1.73 (m, 4H) 446.2 302 1-(2-(3(pyrimidin-5yl)benzyl)-2,8diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid N-—л .____. N=/ / 0 ύΑχ 1 । /N==/ron 0 δ 9.13 (s, 1H), 9.08 - 9.06 (m, 2H), 8.10 (d,7= 2.7 Hz, 1H), 7.9O (s, 1H), 7, 78 (d, J = 6.3 Hz, 1H), 7.62 (t, J = 6.3 Hz, 2H), 6.72 (d, J = 2.7 Hz, 1H), 4.37 ( s, 2H), 3.84 - 3.79 (m, 2H), 3.67 - 3.65 (m, 2H), 3.38 - 3.36 (m, 2H), 3.24 (br, 2H), 2.03 (t, J= 7.2 Hz, 2H), 1.85 - 1.75 (m, 4H) 447.2

- 151 047826

303 1-(1-(3-methyl-5(trifluoromethyl)benzyl)-1,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid F ₃ C lХ рХ / ΑχΑ ν==/ '— D-ON 0 δ 8.09 (d, J = 2.4 Hz, 1H), 7.55 7.52 (m, 2H), 7.46 (s, 1H), 6.79 (d, J = 2.4 Hz , 1H), 4.63 (br, 2H), 3.99 (br, 2H), 3.24 - 3.15 (m, 2H), 2.99 - 2.93 (m, 2H), 2, 45 (s, 3H), 2.29 - 2.06 (m, 4H), 1.98 - 1.93 (m, 2H), 1.71 - 1.68 (m, 2H) 451.2 304 1-(trans-5-([1,H-biphenyl]-3-yloxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4chloro-1 H-pyrazole-3-carboxylic acid o / ¹ \ / '—Z x° ZZ o o I — δ 8.26 (s, 1H), 7.63 - 7.52 (m, 2H), 7.47 - 7.36 (m, 2H), 7.35 7.23 (m, 2H), 7, 18 - 7.12 (m, 1H), 7.11 - 7.08 (m, 1H), 6.91 - 6.85 (m, 1H), 5.15 - 5.06 (m, 1H), 4.33 - 3.53 (m, 4H), 2.88 (br, 2H), 2.28 -2.12 (m, 2H), 2.09 - 1.91 (m, 2H) 450.1 [Μ- Η]' 305 1-(2-(3-(thiazol-2yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid \ / ΑιίνΛ Χ-ΖΧΑ W ^s —Hon o δ 8.18 (s, 1H), 8.01 - 8.00 (m, 2H), 7.88 (s, 1H), 7.64 - 7.62 (m, 2H), 7.61 - 7 .53 (m, 1H), 6.73 (d, J= 2.7Hz, 1H), 4.38 (s, 2H), 3.85 - 3.81 (m, 2H), 3.69 - 3 .64 (m, 2H), 3.39-3.31 (m, 2H), 3.29 3.23 (m, 2H), 2.06 - 1.98 (m, 2H), 1.86- 1.70 (m, 4H) 452.2 306 4-methyl-1-(trans5-((2-methyl-3(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3carboxylic acid 0 n A ! /О Ά- YJ №=/ F3C4 \ ^14 ° ⁿ Hon xd ° δ 7.95 (s, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 4.52 (s, 2H) , 4.27 - 4.18 (m, 1H), 4.15 - 3.47 (m, 4H), 2.87 (br, 2H), 2.40 (d, J= 1.3 Hz, 3H ), 2.24 (d, J = 0.84 Hz, 3H), 2.19 - 2.02 (m, 2H), 1.85 - 1.17 (m, 2H) 452.2

- 152 047826

307 1-(4-(2(pyrrolidin-1yl)-4- (trifluoromethyl)phenoxi) piperidine-1-carbonyl)-1Hpyrazole-3-carboxylic acid t o °h X o LL? δ 8.10 (d, J = 2.7 Hz, 1 Η), 7.09 7.01 (m, 2H), 6.93 (s, 1H), 6.79 (d, J = 2.7 Hz, 1H), 4.81 - 4.72 (m, 1H), 4.04 (br, 2H), 3.77 (br, 2H), 3.38 - 3.31 (m, 4H), 2 .18 2.11 (m, 2H), 2.03 - 1.91 (m, 6H) 453.2 308 1-(4-(3(pyrrolidin-1yl)-5- (trifluoromethyl)phenoxi) piperidine-1-carbonyl)-1Hpyrazole-3-carboxylic acid t o Ch/ ° Z-Z °h Q O с /-----b δ 8.12 (d, J = 2.7 Hz, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.48 (s, 1H), 6.39 (s, 1H) , 6.34 (s, 1H), 4.76 4.70 (m, 1H), 3.98 (br, 2H), 3.85 (br, 2H), 3.30 - 3.28 (m, 4H), 2.16 - 2.00 (m, 6H), 1.96 - 1.92 (m, 2H) 453.2 309 N-(l-(3-carbamoyl-1H-pyrazole-1carbonyl)piperidin-4-yl)-N-(3(trifluoromethyl)benzyl)glycine About HE δ 8.16 (d, J = 2.7 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.62 - 7.52 ( m, 2H), 6.85 (d, J = 2.7 Hz, 1H), 4.52 - 4.48 (m, 2H), 4.13 (s, 2H), 3.40 (s, 2H ), 3.26 3.22 (m, 1H), 3.14 - 3.05 (m, 2H), 2.18 - 2.08 (m, 2H), 1.84 - 1.74 (m, 2H) 454.1 310 (^)-1.(4-(3-(4chlorophenoxy)benzyl)-2-methylpiperazine-1 carbonyl)-1Hpyrazole-3carboxamide °'α,α.ο% Ζ~νη ₂ 0 δ 8.10 (d, J = 2.7 Hz, 1H), 8.09 7.28 (m, 3H), 7.12 (d, J = 8.1 Hz, 1H), 7.07 (s , 1H), 6.99 - 6.91 (m, 4H), 6.66 (br, 1H), 5.53 (br, 1H), 4.65 - 4.63 (m, 1H), 4, 31 - 4.26 (m, 1H), 3.65 - 3.42 (m, 3H), 2.92 - 2.96 (m, 1H), 2.72 - 2.76 (m, 1H), 2.36 - 2.24 (m, 2H), 1.48 (d, 7=6.6 Hz, 3H) 454.2

- 153 047826

311 (5)-1-(4-(3-(4-chlorophenoxy)benzyl)-2- methylpiperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid O ‘oda Hon o δ 8.12 (d, J= 2.7 Hz, 1H), 7.36 7.31 (m, ZN), 7.14-7.12 (m, 1H), 7.00 (s, 1H) , 6.98 - 6.90 (m, 3H), 6.83 (d, J = 2.7 Hz, 1H), 4.61 (br, 1H), 4.26 - 4.22 (m, 1H ), 3.66 3.62 (m, 1H), 3.54 - 3.42 (m, 2H), 2.92 - 2.89 (m, 1H), 2.78 - 2.74 (m, 1H), 2.39 - 2.26 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H) 455.2 312 2-methyl-2-(2(piperazin-1ylmethyl)-5(trifluoromethyl)phenoxy)propanoic acid t o o Ъ δ 8.14 (d, J= 2.8 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.21 - 7.11 (m, 1H), 7.10 7.06 (m, 2H), 6.97 (s, 1H), 6.90 6.85 (m, 2H), 4.63 (br, 1H) , 4.28 - 4.24 (m, 1H), 3.68 - 3.65 (m, 1H), 3.52 - 3.43 (m, 2H), 2.94 2.91 (m, 1H ), 2.78 - 2.76 (m, 1H), 2.39 - 2.30 (m, 2H), 1.39 - 1.33 (m, 3H) 455.2 313 1-(2-(5-chloro-2(trifluoromethyl)benzyl)-2,7- diazaspiro[3.5]non-7-carbonyl)1H-pyrazole-3-carboxylic acid o X ^.CF ₃ A| GT ^ν α A, A .NJ \ /-on o δ 8.03 (d, J= 2.7 Hz, 1H), 7.70 7.67 (m, 1H), 7.64 (s, 1H), 7.49 7.43 (m, 1H), 6.74 (d, J = 2.7 Hz, 1H), 3.89 (s, 2H), 3.75 (br, 4H), 3.31 (s, 4H), 1.94-1.86 (m, 4H) 457.2 314 4-chloro-1-(tris-5((3- (trifluoromethyl)benzyl)oxy)octahydrocyclopenta[s]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid o UU νΑ,-ci ^RzS ^G° ⁿ A-° ^{n 0} δ 8.19 (s, 1H), 7.69 - 7.49 (m, 4H), 4.5 (s, 2H), 4.26 - 4.21 (m, 1H), 4.19 - 3 .37 (m, 4H), 2.93 (br, 2H), 2.18 - 2.05 (m, 2H), 1.86 1.75 (m, 2H) 475.1 [M+ _NH4 ] ⁺

- 154 047826

315 1-((ZaL,6a5)-5-(4-chloro-3-(thiazol-2yl)benzyl)octahydropyrrolo[3,4c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O N A SK^x 3/ ^NN X T II k/ / _n \ _on Vs o 5 8.20 (d, 7 = 2.4 Hz, lH), 8.16 (d, 7 = 2.8 Hz, 1H), 7.94 (d, 7 = 3.6 Hz, 1H), 7.76 (d, 7 = 3.2 Hz, 1H), 7.60 (d, 7 = 8.4 Hz, 1H), 7.53 7.48 (m, 1H), 6.76 (d, 7 = 2.8 Hz, 1H), 4.13 (s, 3H), 3.95 (br, 3H), 3.31 - 3.21 (m, 2H), 3.13 - 3.01 (m, 4H) 458,1 316 1-(2-(3,5dichlorobenzyl)-2,8diazaspiro[4.5]dec an-8-carbonyl)-4methyl-1H-pyr azo l3-carboxylic acid CI /=( O ν/ - Al/AA n==( ' ^h -J~ ^he 5 7.84 (s. 1H), 7.50 - 7.48 (w, ZN), 4.17 (s, 2H), 3.81 - 3.77 (w, 2H), 3.67 - 3 .60 (m, 2H), 3.24 (br, 2H), 3.10 (br, 2H), 2.27 (s, ZN), 1.99 (1, 7 = 9.0 Hz, 2H) , 1.83 1.71 (m, 4H) 451,1 317 1-(2-(2-(azetidin1-yl)-5chlorobenzyl)-2,8diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid Cl /=/ о 7 nA 7~ΌΗ о 5 8.07 (d, 7 = 2.4 Hz, lH), 7.38(s, 1H), 7.32 - 7.29 (m, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.73 - 6.70 (w, 1H), 4.27 (s, 2H), 4.03 - 3.98 (w, 4H), 3.93 - 3.86 (m, 2H), 3.73 3.71 (m, 2H), 3.42 - 3.32 (m, 2H), 3.25 - 3.21 (m, 2H), 2.43 - 2.33 (m , 2H), 2.05 (1, 7 = 6.9 Hz, 2H), 1.90 - 1.77 (m, 4H) 458.2 318 1-(trans-5-(4-chloro-3-(thiazol-2yl)phenoxy)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid O A o I 5 8.16 (d, 7 = 4.0 Hz, 1H), 7.94 (d, 7 = 3.3 Hz, 1H), 7.74 (d, 7 = 3.3 Hz, 1H), 7 .60 (d, 7 = 3.0 Hz, 1H), 7.42 (d, 7 = 8.9 Hz, 1H), 7.03 6.97 (m, 1H), 6.77 (d, 7 = 2.7 Hz, 1H), 5.07 - 5.01 (m, 1H), 4.48 3.51 (m, 4H), 2.98 (br, 2H), 2.21 -2.11 (m, 2H), 2.05 - 1.91 (w, 2H) 459.1

- 155 047826

319 1-(4-(3-(2-chlorophenoxy)-5-fluorobenzyl)piperazine-1-carbonyl)1H-pyrazole-3-carboxylic acid F O Xi -X A GT A o o GA Ax A\ -N. J №=/ \ /-on o δ 8.05 (d, J= 2.7 Hz, 1H), 7.54 7.51 (m, 1H), 7.39 - 7.33 (m, 1H), 7.25 - 7.20 ( m, 1H), 7.15-7.12 (m, 1H), 6.89 - 6.86 (m, 1H), 6.73 (d, J = 2.7 Hz, 2H), 6.56 - 6.51 (m, 1H), 3.84 (br, 4H), 3.53 (s, 2H), 2.56 - 2.53 (m, 4H) 459.2 320 4-chloro-1-(4-(3-(4-fluorophenoxy)benzyl)piperazine-1carbonyl)-1Hpyrazole-3carboxylic acid shau /-on 0 δ 8.15 (s, 1H), 7.38 - 7.29 (m, 1H), 7.12 - 7.03 (m, 3H), 7.01 6.98 (m, 3H), 6, 90 - 6.88 (m, 1H), 3.85 (br, 4H), 3.65 (s, 2H), 2.68 2.64 (m, 4H) 459.2 321 1-(4-(3-(3-chlorophenoxy)-5-fluorobenzyl)piperazine-1-carbonyl)1H-pyrazole-3-carboxylic acid f/o o z-z scl/ o δ 8.16 (d, J= 2.8 Hz, 1H), 7.41 7.37 (m, 1H), 7.21 - 7.19 (m, 1H), 7.08 (s, 1H) , 7.00 - 6.97 (m, 2H), 6.90 (s, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.74 - 6.71 (m, 1H ), 3.87 (br, 4H), 3.65 (s, 2H), 2.66 (br, 4H) 459.2 322 1-(2-((2-methyl[1,1'-biphenyl]-3 yl)methyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Ah I k—J /~OH O δ 8.05 (d, J= 2.7 Hz, 1H), 7.53 7.33 (m, 5H), 7.30 - 7.25 (m, 3H), 6.76 (d, J = 2.7 Hz, 1H), 4.42 (s, 2H), 3.90 - 3.85 (m, 2H), 3.72 3.68 (m, 2H), 3.46 - 3.42 ( m, 2H), 3.34 - 3.30 (m, 2H), 2.32 (s, 3H), 2.06 (t, J = 7.2 Hz, 2H), 1.87 1.78 ( m, 4H) 459.3 323 4-chloro-1-(4-(3chloro-5(pyrimidin-5yl)benzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid Cl o nA [1 J /—он N 0 δ 9.15 (d, 0 = 4.8 Hz, 1H), 9.09 (s, 2H), 9.18 (s, 1H), 7.71 (t,0 = 1.8 Hz, 1H) , 7.67 (s, 1H), 7.55 (s, 1H), 3.86 (br, 4H), 3.71 (s, 2H), 2.66 (br, 4H) 461.4

- 156 047826

324 1-(2-(3-(pyridin-2yloxy)benzyl)2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Q/-X ° °~l ) A < NN \ —\ A 1 । / ACAA nA ^x - /-OH o δ 8.12 - 8.10 (m, 1H), 8.03 (d, J = 2.7 Hz, 1H), 7.82 - 7.80 (m, 1H), 7.50 - 7.45 (m, 1H), 7.36 - 7.30 (m, 1H), 7.28 (s, 1H), 7.20 - 7.10 (m, 2H), 6.99 (d, J= 8 ,1 Hz, 1H), 6.72 (d, J = 2.7 Hz, 1H), 4.25 (s, 2H), 3.82 - 3.79 (m, 2H), 3.70 3, 63 (m, 2H), 3.42 - 3.31 (m, 2H), 3.15 (br, 2H), 2.00 (t, J = 7.2 Hz, 2H), 1.82 - 1.71 (m, 4H) 462.3 325 (I)-1-(2-methyl-4(2-(pyrrolidin-1 yl)-4(trifluoromethyl)benzyl)piperazine-1 carbonyl)-1Hpyrazole-3carboxamide OJ t Z Ζ-Ζ °Ч / о о IL? δ 8.10 (d, 7 = 2.7 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.12 - 7.10 (m, 2H), 6.92 ( d,7= 2.7 Hz, 1H),6.66 (br, 1H), 5.52 (br, 1H), 4.65 (br, 1H), 4.29 - 4.25 (m, 1H ), 3.56 3.45 (m, 3H), 3.34 - 3.23 (m, 4H), 2.90 - 2.87 (m, 1H), 2.72 - 2.68 (m, 1H), 2.38 - 2.20 (m, 2H), 2.03 - 1.92 (m, 4H), 1.51 (d, 7 = 6.6 Hz, 3H) 465.3 326 (5)-1-(2-methyl-4(2-(pyrrolidin-1 yl)-4- (trifluoromethyl)benzyl)piperazine-1 carbonyl)- 1Hpyrazole-3carboxamide 0 Y1 ί t o γΑ ^Ν \Α ν=/ N / ΝΗ ₂ О ° (Chloroform-7) δ 8.08 (d, 7= 2.7 Hz, 1H), 9.53 (d, J = 6.9 Hz, 1H), 7.26 - 7.10 (m, 2H) , 6.70 (d, J = 2.7 Hz, 1H), 6.64 (br, 1H), 5.48 (br, 1H), 4.63 (br, 1H), 4.27 - 4, 23 (m, 1H), 3.55 - 3.32 (m, 3H), 3.38 - 3.18 (m, 4H), 2.88 - 2.81 (m, 1H), 2.70 - 2.61 (m, 1H), 2.35 2.32 (m, 1H), 2.32-2.19 (m, 1H), 2.01 - 1.92 (m, 4H), 1.26 (d, 7 = 5.4 Hz, 3H) 465.2

- 157 047826

327 (I)-1-(2-methyl-4(2-(pyrrolidin-1 yl)-4(trifluoromethyl)benzyl/piperazine-1 carbonyl)-1Hpyrazole-3carboxylic acid О F ₃ C, А ΤΊ О О к Λ χΝχ Ν=/ у ---''---' Ί, Λ Ν Λ ⁰⁴ О ⁰ δ 8.11 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.82 ( d, J = 2.7 Hz, 1H), 4.66 - 4.61 (m, 1H), 4.28 - 4.23 (m, 1H), 3.63 (s, 2H), 3.56 - 3.45 (m, 1H), 3.32 - 3.22 (m, 4H), 2.92 - 2.82 (m, 1H), 2.74 - 2.67 (m, 1H), 2 .42 - 2.30 (m, 1H), 2.30 2.22 (m, 1H), 2.09 - 1.97 (m, 4H), 1.46 (d, 7=6.6 Hz, 3H) 466.3 328 (5)-1-(2-methyl-4(2-(pyrrolidin-1 yl)-4- (trifluoromethyl)benzyl)piperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid o F ₃ C. XX A x^ ΤΊ O O Ν A ^on O ⁰ δ 8.11 (d, 7 = 2.7 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.12 - 7.09 (m, 2H), 6.83 ( d, J= 2.7 Hz, 1H), 4.63 (br, 1H), 4.28 - 4.24 (m, 1H), 3.63 (s, 2H), 3.56 - 3.41 (m, 1H), 3.34 - 3.26 (m, 4H), 2.91 - 2.86 (m,lH), 2.75 - 2.68 (m, 1H), 2.39 - 2 .30 (m, 1H), 2.29 - 2.21 (m, 1H), 2.04 - 1.98 (m, 4H), 1.46 (d, 7=6.6 Hz, 3H) 466.2 329 (5)-1-(2-methyl-4(4-(pyrrolidin-1 yl)-2- (trifluoromethyl)benzyl)piperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid /A ⁰ \A A x ΊΟ O O 4Α\χ ^ν χ^A o pp /z~~OH C ^p z ¢/ δ 8.12 (d, 7 = 2.7 Hz, 1H), 7.5O (d, J = 8.1 Hz, 1H), 6.83 (d, 7 = 2.7 Hz, 1H), 6 .76 - 6.74 (m, 2H), 4.60 (br, 1H), 4.23 - 4.18 (m, 1H), 3.56 - 3.51 (m, 2H), 3.51 - 3.31 (m, 1H), 3.30 - 3.28 (m, 4H), 2.89 2.80 (m, 1H), 2.76 - 2.72 (m, 1H), 2, 39 -2.29 (m, 1H), 2.34 - 2.12 (m, 1H), 2.12 - 2.02 (m, 4H), 1.43 (d, J = 6.6 Hz, 3H) 466.2

- 158 047826

330 (I)-1-(2-methyl-4(4-(pyrrolidin-1 yl)-2(trifluoromethyl)benzyl)piperazine-1 carbonyl)-1 FIpyr azole-3 carboxylic acid /—। O 1 I । / Part A No.=/ ''sp Hl, ξ pp E OH CF ₃ pf δ 8.11 (d, J = 2.7 Hz, 1H), 7.51 (d, 7 = 8.1 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 6 .76 - 6.74 (m, 2H), 4.62 (br, 1H), 4.24 - 4.17 (m, 1H), 2.55 - 2.50 (m, 2H), 3.49 - 3.32 (m, 1H), 3.30 - 3.28 (m, 4H), 2.88 2.84 (m, 1H), 2.75-2.71 (m, 1H), 2, 37 - 2.32 (m, 1H), 2.32 - 2.14 (m, 1H), 2.06 - 2.02 (m, 4H), 1.42 (d, J = 6.9 Hz, 3H) 466.2 331 1-(4-((3(pyrrolidin-1yl)-5- (trifluoromethyl)benzyl)oxy)piperidin-1-carbonyl)-1Hpyrazole-3carboxylic acid O AnAnA Η |l J Aon o 0 δ 8.05 (d, J = 2.8 Hz, 1H), 6.85 (s, 1H), 6.77 - 6.76 (m, 2H), 6.65 (s, 1H), 4, 58 (s, 2H), 4.03 (br, 2H), 3.78 - 3.72 (m, 1H), 3.62 3.58 (m, 2H), 3.32 - 3.28 (m , 4H), 2.07 - 1.99 (m, 6H), 1.85 - 1.75 (m, 2H) 467,1 332 (5)-1-(4-(2-(3-hydroxypyrrolide in-1-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1-FIpyrazole-3-carboxylic acid o zl / o b° z-z aAxA o ΞΕ δ 8.12 (d, J= 2.7 Hz, 1H), 7.60 7.57 (m, 1H), 7.30 - 7.25 (m, 1H), 7.25 - 7.23 ( m, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.53 - 4.49 (m, 1H), 4.09 - 3.94 (m, 6H), 3.57 - 3.49 (m, 1H), 3.46 - 3.41 (m, 1H), 3.28 - 3.12 (m, 2H), 2.88 (br, 4H), 2.30 - 2 .18 (m, 1H), 1.99 - 1.95 (m, 1H) 468.2 333 (7?)-1-(4-(2-(3-hydroxypyrrolide in-1-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1-FIpyrazole-3-carboxylic acid 0 F ₃ C, A ΥΊ A O N==/ NA ^0H Q ⁰ Ън δ 8.13 (d, J= 2.4 Hz, 1H), 7.60 7.57 (m, 1H), 7.28 (s, 1H), 7.24 7.21 (m, 1H), 6.81 (d, J = 2.4 Hz, 1H), 4.52 - 4.49 (m, 1H), 4.18 3.71 (m, 6H), 3.67 - 3.31 (m , 2H), 3.30 - 3.17 (m, 2H), 2.85 (br, 4H), 2.29 - 2.18 (m, 1H), 1.99 - 1.94 (m, 1H ) 468.2

- 159 047826

334 1-((27?,45)-4-((3-(4chlorophenoxy)benzyl)oxy)-2methylpiperidine-1-carbonyl)-1Hpyrazole-3carboxylic acid o ΙιΥ Ud Λ II J |l J /—on O δ 8.24 - 8.00 (br, 1H), 7.43 - 7.26 (m, 3H), 7.16 (d, J =7.7 Hz, 1H), 7.05 - 6.90 (m, 4H), 6.90 - 6.78 (br, 1H), 4.87 - 4.72 (m, 1H), 4.60 (s, 2H), 4.42 - 4.26 (m , 1H), 4.00 - 3.80 (m, 1H), 3.31 - 3.19 (m, 1H), 2.23 - 1.97 (m, 2H), 1.80 1.50 ( m, 2H), 1.38 (d, J = 7.0 Hz, 3H) 487.2 [M+ _NH4 ] ⁺ 335 1-((25.47?)-4-((3-(4chlorophenoxy)benzyl)oxy)-2methylpiperidine1-carbonyl)-1Hpyrazole-3carboxylic acid o A Jl JL -J /—° ^h δ 8.02 (d, J = 2.7 Hz, 1H), 7.36 7.30 (m, 3H), 7.14 - 7.11 (m, 1H), 6.98 (s, 1H) , 6.97 - 6.93 (m, 2H), 6.91 - 6.88 (m, 1H), 6.73 (d, J = 2.7 Hz, 1H), 4.91 (br, 1H ), 4.57 (br, 2H), 4.44 - 4.38 (m, 1H), 3.88 - 3.82 (m, 1H), 3.25 - 3.21 (m, 1H), 2.14 - 2.09 (m, 1H), 2.04 1.98 (m, 1H), 1.74 - 1.68 (m, 1H), 1.59 - 1.54 (m, 1H), 1.33 (d, J = 7.2 Hz, 3H) 492.0 [M+Na] ⁺ 336 1-((25.45)-4-((3-(4chlorophenoxy)benzyl)oxy)-2methylpiperidine1-carbonyl)-1Hpyrazole-3carboxylic acid 0 jT A A 'j A~oh δ 8.02 (d, J = 2.4 Hz, 1H), 7.36 7.30 (m, 3H), 7.14-7.12 (m, 1H), 7.01 (s, 1H) , 6.98 - 6.94 (m, 2H), 6.92 - 6.89 (m, 1H), 6.75 (d, J = 2.4 Hz, 1H), 4.62 - 4.59 (m, 1H), 4.55 (s, 2H), 4.14 - 4.10 (m, 1H), 3.86 - 3.84 (m, 1H), 3.56 - 3.46 (m , 1H), 1.95 - 1.86 (m, 4H), 1.46 (d, J = 6.6 Hz, 3H) 492.2 [M+Na] ⁺ 337 1-(2-(2,3,5-chlorobenzyl)2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Cl /=/ 0 ^s| -/> Λ y Z < N οι/ν/ΑΑ W ^x У-ОН 0 δ 8.02 (d, J = 2.7 Hz, 1H), 7.52 (s, 2H), 6.74 (d,.7 = 2.7 Hz, 1H), 3.79 - 3.54 (m, 6H), 2.77 - 2.72 (m, 2H), 2.61 (s, 2H), 1.82-1.71 (m, 6H) 471.2

- 160 047826

338 4-chloro-1-(2-(3,5-dichlorobenzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid ,С1 /=/ о ^С| -/} Λ V/ < V νΛ _С| У-N^M ^N 4 ^х /-ОН О δ 8.12 (s, 1H), 7.61 - 7.51 (m, 3H), 4.21 (s, 2H), 3.80 (br, 2H), 3.68 (br, 2H), 3.32 - 3.25 (m, 2H), 3.13 (s, 2H), 2.00 (t, J= 7.2 Hz, 2H), 1.85 - 1.73 (m, 4H) 471,0 339 1-(2-(2-chloro-3(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid /=\ ⁰ F3C-/ > A /h H / <Ν νΛ nV ⁴ - U~on o δ 8.07 (d, J= 2.7 Hz, 1H), 7.97 7.87 (m, 1H), 7.82 - 7.79 (m, 1H), 7.57 - 7.52 ( m, 1H), 6.78 (d, J = 2.7 Hz, 1H), 4.25 - 4.23 (m, 2H), 3.81 - 3.70 (m, 2H), 3.70 - 3.54 (m, 2H), 3.14 - 3.12 (m, 2H), 3.07 - 2.97 (m, 2H), 1.96-1.91 (m, 2H), 1 .84 - 1.73 (m, 4H) 471.2 340 1-(2-(3-chloro-2(trifluoromethyl)benzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid М ) /А Λ /х V/ < ν nA ^F 3C h/U nV - U-on 0 δ 8.01 (d, J= 3.0 Hz, 1H), 7.65 7.59 (m, 1H), 7.53 - 7.48 (m, 2H), 6.73 (d, J = 3.0 Hz, 1H), 3.81 3.57 (m, 6H), 2.65 - 2.61 (m, 2H), 2.47 (s, 2H), 1.80 - 1.64 ( m, 6H) 471,5 341 4-chloro-1-(tris-5((2-methyl-3(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[s]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid o ch Z-Z O o ee — δ 8.21 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.8 Hz, 1H), 4.55 (s, 2H) , 4.28 - 4.21 (m, 1H), 4.23 - 3.43 (m, 4H), 2.88 (br, 2H), 2.40 (d, J = 1.2 Hz, ZN ), 2.21 - 2.08 (m, 2H), 1.85-1.71 (m, 2H) 472.2

- 161 047826

342 1-(2-(5-chloro-2(pyrrolidin-1yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid 01 /=/ O \ /A Si/D/ N=/ x/ /-on O δ 8.06 (d, J= 2.7 Hz, 1H), 7.49 7.48 (m, 1H), 7.38 - 7.34 (m, 1H), 7.24 - 7.21 ( m, 1H), 6.76 (d, J = 2.7 Hz, 1H), 4.40 (s, 2H), 3.87 (br, 2H), 3.61 (br, 2H), 3, 38 - 3.32 (m, 2H), 3.19 - 3.10 (m, 6H), 2.07 - 1.99 (m, 6H), 1.86 - 1.74 (m, 4H) 472.2 343 1-(2-(4-chloro-3(pyrrolidin-1yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid CI ,—\ /=\ ⁰ ί/-ч ) A < Ν N \ —\ , 1 1 7 A k—J Y~OH o δ 8.05 (d,7 = 2.7 Hz, lH), 7.32 (d, 7 = 8.1 Hz, 1H), 7.14 (d, 7 = 2.7 Hz, 1H), 6 .93 - 6.89 (m, 1H), 6.76 (d, J = 2.7 Hz, 1H), 4.31 (s, 2H), 3.84 - 3.80 (m, 2H), 3.72 - 3.66 (m, 2H), 3.43 - 3.32 (m, 6H), 3.32 - 3.30 (m, 2H), 2.06 (t, 7= 7.2 Hz, 2H), 1.96 - 1.90 (m, 4H), 1.83 1.76 (m, 4H) 472.3 344 1-(1-(3-chloro-5(pyrrolidin-1yl)benzyl)-1,8diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid a o V/ '—Z >° Z-Z o I (DMSO-7 ₆ ) δ 8.27 (d, 7 = 2.4 Hz, 1H), 6.86 (d, 7 = 2.4 Hz, 1H), 6.56 (s, 1H), 6.43 - 6.37 (m, 2H), 4.28 - 4.25 (m, 2H), 3.57 (br, 2H), 3.22 -3.16(m, 6H), 2.68 (br , 2H), 1.95 - 1.92 (m, 4H), 1.86 - 1.74 (m, 6H), 1.48 (br, 2H) 472.2 345 1-(thi/>ans-5-((4-chloro-3-(thiazol-2-yl)benzyl)oxy)oct ahydrocyclopenta[ c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid A° sc/D/ O I δ 8.21 (d,7 = 2.4 Hz, 1H), 8, O6 (d, 7 = 2.0 Hz, 1H), 7.94 (d, 7 = 3.2 Hz, 1H), 7 .78 (d, 7 = 3.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.49 7.39 (m, 1H), 6.78 (d, J = 2.8 Hz, 1H), 4.52 (s, 2H), 4.38 - 4.21 (m, 1H), 4.20 - 3.50 (m, 4H), 3.02 2.80 (m, 2H), 2.26 - 2.02 (m, 2H), 1.86 - 1.65 (m, 2H) 473,0

- 162 047826

346 1-(4-(3-(4-chlorophenoxy)-5-fluorobenzyl)piperazine-1-carbonyl)-4methyl-1 H-pyrazol3-carboxylic acid O & g A I δ 7.93 (s, 1H), 7.42 - 7.39 (m, 2H), 7.07 - 7.03 (m, 2H), 6.95 6.92 (m, 1H), 6, 86 (s, 1H), 6.69 6.65 (m, 1H), 3.84 (br, 4H), 3.60 (s, 2H), 2.60 (br, 4H), 2.28 ( s, 3H) 473,1 347 (5)-1-(4-(3-(4chlorophenoxy)-5fluorobenzyl)-2methylpiperazine-1carbonyl)-1Hpyrazole-3carboxylic acid o A Z-Z O I 5 8.09 (d,7 = 2.4 Hz, lH),7.39(d, J = 2.4 Hz, 2H), 7.03 (d, J = 2.0 Hz, 2H), 6 .89 (d, J = 8.8 Hz, 1H), 6.83 - 6.79 (m, 2H), 6.66 (d, J = 2.4 Hz, 1H), 4.64 (s, 1H), 4.27 (d, 7= 12.4 Hz, 1H), 3.57 (d, J = 16.0 Hz, 1H), 3.49 - 3.40 (m, 2H), 2, 85 (d, J = 10.8 Hz, 1H), 2.70 (d, J = 11.2 Hz, III), 2.34 - 2.22 (m, 211), 1.38 (d, J =6.8 Hz, 3H) 473.2 348 (^)-1.(4-(3-(4chlorophenoxy)-5fluorobenzyl)-2methylpiperazine-1carbonyl)-1Hpyrazole-3carboxylic acid F O ^α Ύ> Λ ΙΑΑΑΑα h/-on 0 5 8.11 (d, J = 2.4 Hz, 1H), 7.40 7.36 (m, 2H), 7.05 - 7.01 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.83 6.79 (m, 2H), 6.67 - 6.63 (m, 1H), 4.60 (s, 1H), 4.23 (d, J= 13.2 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H), 3.49-3.41 (m, 2H), 2.86 (d, J = 11.6 Hz, 1H), 2.71 (d, J = 11.6 Hz, 1H), 2.34 - 2.23 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H) 473.2 349 (5)-1-(4-(3-(2chlorophenoxy)-5fluorobenzyl)-2methylpiperazine-1carbonyl)-1Hpyrazole-3carboxylic acid F О rf A ο ^Λ 'ύ> Il A Ax Jx -N- /XN=Z /-0 H о 5 8.10 (d, J = 2.4 Hz, 1H), 7.53 7.51 (m, 1H), 7.38 - 7.33 (m, 1H), 7.25 - 7.21 ( m, 1H), 7.16 - 7.13 (m, 1H), 6.85 - 6.81 (m, 2H), 6.72 (s, 1H), 6.58 - 6.55 (m, 1H), 4.60 (br, 1H), 4.22 (d, J = 13.6 Hz, 1H), 3.57 (d, J = 13.6 Hz, 1H), 3.47 - 3, 39 (m, 2H), 2.86 - 2.83 (m, 1H), 2.70 - 2.67 (m, 1H), 2.32 - 2.24 (m, 2H), 1.35 (d, J = 6.8 Hz, 3H) 473.2

- 163 047826

350 (^)-1-(4-(3-(2chlorophenoxy)-5fluorobenzyl)-2methylpiperazine-1carbonyl)-1Hpyrazole-3carboxylic acid F О rA'fi οΆ) LA Ах Ах Ж /-..,,, Ν==Ζ /—on ο δ 8.12 (d, J= 2.8 Hz, 1H), 7.54 7.51 (m, 1H), 7.38 - 7.34 (m, 1H), 7.25 - 7.21 ( m, 1H), 7.16 - 7.14 (m, 1H), 6.85 - 6.83 (m, 2H), 6.72 (s, 1H), 6.59 - 6.56 (m, 1H), 4.58 (br, 1H), 4.20 (d, J = 13.6 Hz, 1H), 3.57 (d, J = 13.6 Hz, 1H), 3.47 - 3, 39 (m, 2H), 2.86 - 2.83 (m, 1H), 2.70 - 2.67 (m, 1H), 2.33 - 2.22 (m, 2H), 1.35 (d, J = 6.8 Hz, 3H) 473,1 351 (I)-1-(2-methyl-4- ((3- (trifluoromethyl)[1,G-biphenyl]-4yl)methyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid Q 1 /-ух X/ '---''---''Ί, Λ CF Z~ ^{0H CF} 3 y/ δ 8.08 (d, J= 2.7 Hz, 1H), 7.95 7.85 (m, 3H), 7.67 - 7.64 (m, 2H), 7.50 - 7.36 ( m, 3H), 6.78 (d, J = 2.7 Hz, 1H), 4.70 (br, 1H), 4.33 4.29 (m, 1H), 3.72 (s, 2H) , 3.56 3.47 (m, 1H), 2.91 - 2.75 (m, 2H), 2.46 - 2.26 (m, 2H), 1.48 (d, J = 6.9 Hz, 3H) 473.2 352 1-(4-(3-((4(trifluoromethyl)pyridin-3yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid 0 Αα,οΑ A /-one CF ₃ δ 8.53 (d, J = 4.8 Hz, 1H), 8.32 (s, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.77 (d, J = 4.8 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.20 (br, 1H), 7.05 ( d, J= 8.1 Hz, 1H), 6.80 (d,.7= 2.7 Hz, 1H), 3.89 (br, 4H), 3.72 (br, 2H), 2.70 (br, 4H) 476,5 353 1-(4-(3-((6(trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid 0 .XIXWA /—OH 0 δ 8.14 (d, J= 2.7 Hz, 1H), 8.04 7.98 (m, 1H), 7.50 - 7.42 (m, 2H), 7.31 - 7.28 ( m, 1H), 7.25 - 7.23 (m, 1H), 7.23 - 7.20 (m, 1H), 7.16 - 7.13 (m, 1H), 6.82 (d, J = 2.7 Hz, 1H), 4.02 - 3.84 (m, 6H), 2.83 (br, 4H) 476.2

- 164 047826

354 1-(4-(3-((6(trifluoromethyl)pyridin-3 yl)oxy)benzyl)pyperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid /-it δ 8.43 (d, J= 3.3 Hz, 1H), 8.09 (d, J = 2.7 Hz, 1H), 7.80 - 7.77 (m, 1H), 7.52 - 7.47 (m, 1H), 7.45 - 7.42 (m, 1H), 7.30 - 7.28 (m, 1H), 7.20 (s, 1H), 7.09 - 7, 07 (m, 1H), 6.78 (d,7= 2.7 Hz, 1H), 3.85 (br, 4H), 3.64 (s, 2H), 2.62 (t, J = 4 ,8 Hz, 4H) 476.3 355 1-(4-(3-((2(trifluoromethyl)pyridin-4yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid CF ₃ O bzhX U~ si o δ 8.69 (d, J = 5.7 Hz, 1H), 8.11 (d,7 = 2.7 Hz, 1H), 7.50 (1.7 = 7.8 Hz, 1H), 7 .38 - 7.35 (m, 1H), 7.33 - 7.32 (m, 1H), 7.25 (s, 1H), 7.14 - 7.09 (m, 2H), 6.79 (d, J = 2.7 Hz, 1H), 3.86 (br, 4H), 3.69 (s, 2H), 2.65 (br, 4H) 476.3 356 1-(4-(3-((3(trifluoromethyl)pyridin-4yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid O ohiUd CF // OH ^CF 3 (f δ 8.77 (s, 1H), 8.58 - 8.56 (m, 1H), 8.12 (d.7= 2.7 Hz, 1H), 7.54 - 7.40 (m, 1H ), 7.40 - 7.38 (m, 1H), 7.25 (s, 1H), 7.18-7.11 (m, 1H), 6.93 - 6.86 (m, 1H), 6.81 (d, J = 2.7 Hz, 1H), 3.86 (br, 4H), 3.72 (s, 2H), 2.68 (br, 4H) 476.3 357 4-chloro-1-(5-(3chloro-5(trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxylic acid O C ¹ X Jk L-C1 G \—1 No==/ F ₃ C /—OH O δ 8.28 (s, 1H), 7.78 (s, 1H), 7.72 (s, 2H), 4.08 - 3.82 (m, 6H), 3.14 (br, 4H), 3.00 (br, 2H) 477,1

- 165 047826

358 1-(2-((2-chloro-[1,H-biphenyl]-3yl)methyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid pm Ϊ 4=/ H / ΑΑνΛ ⁴ — /—OH O δ 8.06 (d, J= 2.7 Hz, 1H), 7.65 7.62 (d, J = 8.1 Hz, 1H), 7.48 7.35 (m, 7H), 6, 77 (d, J = 2.7 Hz, 1H), 4.28 (s, 2H), 3.88 - 3.83 (m, 2H), 3.74 - 3.72 (m, 2H), 3 .20 (t, 7= 7.2 Hz, 2H), 3.09 (s, 2H), 1.97 (t, 7= 7.2 Hz, 2H), 1.88- 1.80 (m, 4H) 479.3 359 1-(4-(2-((27?,57?)2,5- dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid * O ' o Z-Z o ι δ 8.14 (d, 7 = 2.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.32 - 7.25 (m, 2H), 6.83 ( d,7= 2.7 Hz, 1H), 3.87 (br, 6H), 3.72 - 3.54 (m, 2H), 2.71 - 2.59 (m, 4H), 2.38 - 2.08 (m, 2H), 1.63 - 1.57 (m, 2H), 0.91 (d, 7= 6.3 Hz, ZN), 0.71 (d, 7= 5.7 Hz, ZN) 480.3 360 1-(4-(2-((25,55)-2,5-dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid SLR 4-0 A Ζ-Ζ o I δ 8.14 (d, 7 = 2.7 Hz, 1H), 7.72 (d, 7 = 8.1 Hz, 1H), 7.29 - 7.27 (br, 2H), 6.83 (d, 7 = 2.7 Hz, 1H), 3.87 (br, 6H), 3.71 - 3.60 (br, 2H), 2.74 - 2.65 (br, 4H), 2.29 - 2.16 (br, 2H), 1.63 - 1.57 (br, 2H), 1.03 (d, 7 = 6.0 Hz, 3H), 0.70 (d, 7 = 6.0 Hz, 3H) 480.3 361 1-(4-methyl-4-((2(pyrrolidin-1yl)-4(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid ^F 3 ^C \^\ ? T 11 n ΑΑιΑ kA. f 1 ' / \A №=/ /-on o ° δ 8.07 (d, 7 = 2.7 Hz, 1H), 7.61 (d, 7 = 8.1 Hz, 1H), 7.44 (s, 1H), 7.35 (d, 7 = 8.1 Hz, 1H), 6.75 (d, 7 = 2.7 Hz, 1H), 4.57 - 4.46 (m, 2H), 4.33 (s, 2H), 3.50 - 3.38 (m, 2H), 3.25 - 3.21 (br, 4H), 2.11 - 1.84 (br, 8H), 1.59 (s, 3H) 480.3

- 166 047826

362 1-(4-((2-(azetidin1-yl)-4- (trifluoromethyl)benzyl)(methyl)amino)4- methylpiperidine1-carbonyl)- 1Hpyrazole-3carboxylic acid T || 1 HA A 1 1 7 -Ά Ά Ζ ^Ν \ Ζ~ ^0Η \ζ ° δ 8.11 (d, J = 2.7 Hz, 1H), 7.64 (d, 7 = 7.8 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 6 .87 (s, 1H), 6.80 (d, J= 2.7 Hz, 1H), 4.24 (br, 2H), 4.03 3.98 (m, 6H), 3.58 - 3.53 (m, 2H), 2.47 (s, 3H), 2.42 - 2.32 (m, 2H), 2.14 - 2, 09 (m, 2H), 1.98 (br, 2H), 1.42 (s, 3H) 480.3 363 1-(g/is-5-((4-(4-chlorophenoxy)benzyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxylic acid ο ο ιζ _ζ ° ό δ 8.14 (d, J = 2.7 Hz, 1H), 7.47 7.44 (m, 2H), 7.37 - 7.34 (m, 2H), 7.04 - 6.97 ( m, 4H), 6.74 (d, J = 2.7 Hz, 1H), 4.07 - 3.93 (m, 6H), 3.60 - 3.45 (m, 1H), 2.85 - 2.72 (m, 2H), 2.48 - 2.35 (m, 2H), 1.69 - 1.53 (m, 2H ) 481.3 364 1-((7?)-4-(2-((5)-3fluoropyrrolidin1-yl)-4- (trifluoromethyl)benzyl)-2- methylpiperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid ωΙ Ο ο ⁴ Α° ζ-ζ άΑΑ ο ζτ 5 8.11 (d,.7 = 2.7 Hz, lH), 7.59 (d, 7 = 8.1 Hz, 1H), 7.17 - 7.16 (m, 2H), 6.82 (d,.7= 2.7 Hz, 1H), 5.44 - 5.26 (m, 1H), 4.67 (br, 1H), 4.30 - 4.25 (m, 1H), 3.74 - 3.44 (m, 6H), 3.31 - 3.22 (m, 1H), 2.89 2.85 (m, 1H) , 2.77 - 2.74 (m, 1H), 2.37 - 2.29 (m, 3H), 2.28 - 2.17 (m, 1H), 1.45 (d, J = 6.9 Hz, 3H) 484.2 365 1-((5)-4-(2-((5)-3fluoropyrrolidin1-yl)-4- (trifluoromethyl)benzyl)-2- methylpiperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid 0 F ₃ <A Α ΥΊ Ο Ο ΧΧ/Ν-Χχ ^ν ==/ Ν λ~ ^0Η Q ⁰ 5 8.13 (d, J = 2.7 Hz, 1H), 7.58 7.55 (m, 1H), 7.15-7.14 (m, 2H), 6.85 (d, J = 2.7 Hz, 1H), 5.45 5.27 (m, 1H), 4.64 (br, 1H), 4.26 - 4.22 (m, 1H), 3.74 - 3.46 (m, 6H), 3.30 - 3.22 (m, 1H), 2.93 2.89 (m, 1H), 2.74 - 2.70 (m, 1H), 2.43 - 2.20 (m, 4H), 1.45 (d, J = 6.9 Hz, 3H) 484.2

- 167 047826

366 1-(2-(5-chloro-2(trifluoromethyl)benzoyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid CI /=/ O RzSu-ANhD W o A- ¹ /OH O δ 8.14 - 8.11 (m, 1H), 7.84 - 7.80 (m, 1H), 7.71 - 7.68 (m, 1H), 7.65 - 7.61 (m, 1H), 6.86 - 6.83 (m, 1H), 3.88 - 3.68 (m, 5H), 3.58 (s, 1H), 3.28 (s, lH),3.18(s, 1H), 2.05 - 1.93 (m, 2H), 1.80 - 1.70 (m, 4H) 485.2 367 1-(2-(4-chloro-3(thiazol-2yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid CI 1G-CH >=\ ⁰ A YJ U~OH o δ 8.26 (s, 1H), 8.02 (d,J = 2.7 Hz, 1H), 7.96 - 7.94 (m, 1H), 7.78 7.76 (m, 1H) , 7.61 - 7.55 (m, 2H), 6.74 (d, J = 2.7 Hz, 1H), 4.27 (s, 2H), 3.80 - 3.76 (m, 2H), 3.67 3.57 (m, 2H), 3.32 - 3.27 (m, 2H), 3.13 (s, 2H), 2.00 (t, J= 7.2 Hz, 2H), 1.82 - 1.69 (m, 4H) 486.2 368 4-chloro-1-(4-(4(pyrrolidin-1yl)-2- (trifluoromethyl)benzyl/piperazine-1carbonyl)-1Hpyrazole-3carboxylic acid ω \--/ 0 Ζ-Ζ aadd o O zr — δ 8.19 (s, 1H), 7.53 - 7.50 (m, 1H), 6.78 - 6.75 (m, 2H), 3.88 (br, 4H), 3.77 (s , 2H), 3.41 - 3.32 (m, 3H), 3.29 - 3.24 (m, 1H), 2.77 2.73 (m, 4H), 2.14 - 2.02 (m, 4H) 486,0 369 1-(trans-5-([1,H-biphenyl]-3-yloxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-4(trifluoromethyl)1H-pyrazole-3-carboxylic acid CO LL T O o ZZ °ч Z—. / χι ^х / δ 8.72 - 8.60 (m, 1H), 7.64 - 7.53 (m, 2H), 7.49 - 7.37 (m, 2H), 7.37 - 7.27 (m, 2H), 7.21-7.12 (m, 1H), 7.12 - 7.02 (m, 1H), 6.93 6.78 (m, 1H), 5.14 - 4.98 (m, 1H), 4.27 - 4.01 (br, 1H), 4.01 - 3.74 (br, 2H), 3, 74 - 3.56 (br, 1H), 3.08 - 2.91 (br, 2H), 2.33 - 2.12 (m, 2H), 2.08 - 1.87 (m, 2H) 484.1 [Μ- Η]'

- 168 047826

370 1-(1-(4-chloro-2(piperidin-1 yl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid O ABOUT \ / / '—ζ Ζ—Ζ ABOUT ΞΕ δ 8.13 (d, J = 2.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.25 - 7.23 ( m, 1H), 6.79 (d, J = 2.8 Hz, 1H), 4.76 (br, 2H), 4.28 (br, 2H), 3.32 (s, 2H), 3.27 - 3.21 (m, 2H), 2.90 (br, 4H), 2.36 - 2.20 (m, 4H), 2.09 (br, 2H), 1.87 - 1.84 (m, 2H), 1.78 - 1.75 (m, 4H), 1.63 (br, 2H) 486.2 371 1-(2-(5-chloro-2(trifluoromethoxy)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid CI /=/ O C / ⁴ - Ζ~ΟΗ O 5 8.05 (d,J = 2.7 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 7.43 - 7.42 (m, 1H), 7.40 - 7.39 (m, 1H), 6.76 (d, J= 2.7 Hz, 1H), 3.88 - 3.59 (m, 6H), 2.78 (d, J = 6.6 Hz, 2H), 2.63 (s, 2H), 1.84 - 1.76 (m, 2H), 1.75 - 1.69 (m , 4H) 487.2 372 1-(2-(4-chloro-3morpholinobenzyl)-2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3carboxylic acid Cl /—\ )=\ ⁰ QN—/ \ . 11 \-/ _/ < NNA XXJ iW ⁴ —Aoh 0 5 8.06 (d, J= 2.7 Hz, 1H), 7.46 7.43 (m, 1H), 7.35 (s, 1H), 7.197.16 (m, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.30 (s, 2H), 3.82 - 3.79 (m, 6H), 3.70 - 3.68 (m, 2H), 3.40 3.36 (m, 2H), 3.24 (br, 2H), 3.05 - 3.02 (m, 4H), 2.06 (t, J= 7.2 Hz, 2H), 1.87 - 1.78 (m, 4H) 488.2 373 (5)-1-(2-methyl-4(3-((4- (trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid CF ₃ 0 axuAq Aoh 0 5 8.35 (d, J= 5.4 Hz, lH), 8.12(d, J = 2.7 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.30 - 7.23 (m, 3H), 7.10 7.07 (m, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.67 (br, 1H), 4.32 - 4.27 (m, 1H), 3.72 - 3.68 (m, 1H), 3.59 3.46 (m, 2H), 2.98 - 2.94 (m, 1H), 2.84 - 2.81 (m, 1H), 2.43 - 2.30 (m, 2H), 1.43 (d, J = 6.9 Hz, 3H) 490,1

- 169 047826

374 (I)-1-(2-methyl-4(3-((4- (trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid CF ₃ O AOxCcq Hon o δ 8.35 (d,7 = 5.4 Hz, lH), 8.14 (d, J = 2.7 Hz, 1H), 7.46 - 7.43 (m, 1H), 7.41 - 7.37 (m, 1H), 7.30 7.23 (m, 3H), 7.14 - 7.08 (m, 1H), 6.84 (d, J = 2.7 Hz, 1H), 4.65 (br, 1H), 4.30 - 4.26 (m, 1H), 3.73 3.68 (m, 1H), 3.59 - 3.46 (m, 2H), 2.98 - 2.95 (m, 1H), 2.85 2.81 (m, 1H), 2.44 - 2.30 (m, 2H), 1.43 (d, J =6.9 Hz, 3H) 490,1 375 (5)-1-(2-methyl-4(3-((5- (trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid Hon Oh δ 8.42 (s, 1H), 8.12 - 8.08 (m, 2H), 7.43 - 7.39 (m, 1H), 7.28 7.26 (m, 1H), 7, 21 (s, 1H), 7.13 7.11 (m, 1H), 7.08 - 7.06 (m, 1H), 6.82 (d, J = 2.8 Hz, 1H), 4.62 4.58 (m, 1H), 4.26 - 4.23 (m, 1H), 3.68 - 3.67 (m , 1H), 3.55 - 3.45 (m, 2H), 2.95 - 2.91 (m, 1H), 2.81 - 2.78 (m, 1H), 2.39 - 2.28 (m, 2H), 1.41 (d, J = 7.8 Hz, 3H) 490,1 376 (I)-1-(2-methyl-4(3-((5- (trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)- 1Hpyrazole-3-carboxylic acid ^f,c wac6q Hong Oh δ 8.42 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.13 - 8.10 (m, 1H), 7.44 7.40 (m, 1H) , 7.29 - 7.27 (m, 1H), 7.21 (s, 1H), 7.14-7.09 (m, 1H), 7.07 - 7.06 (m, 1H), 6.84 (d, J = 2.4 Hz, 1H), 4.62 (br, 1H), 4.26 4.23 (m, 1H), 3.71 - 3.67 (m, 1H), 3.57 - 3.46 (m, 2H), 2.96 - 2.94 (m, 1H), 2.83 - 2.80 (m, 1H), 2.41 - 2.31 (m, 2H), 1.42 (d, J = 7.8 Hz, 3H) 490.2 377 1-(2-((6(trifluoromethyl)benzo[b]thiophen-2yl)methyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxamide cm T Z °ч Z--к 0У О ! СО δ 8.19 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.60 - 7.58 ( m, 1H), 7.36 (s, 1H), 6.86 (d, J = 2.4 Hz, 1H), 3.98 (s, 2H), 3.58 - 3.50 (m, 4H), 2.79 (t, 7= 7.0 Hz, 2H), 2.61 (s, 2H), 1.79 (t, J =7 .0 Hz, 2H), 1.74- 1.66 (m, 4H) 492.2

- 170 047826

378 4-chloro-1-(4-(3-(4chlorophenoxy)-5fluorobenzyl)piperazine-1-carbonyl)1H-pyrazole-3carboxylic acid F O E|| III |A 'ιΧ—01 No.=/ /-on ABOUT δ 8.20 (s, 1H), 7.42 - 7.39 (m, 2H), 7.08 - 7.04 (m, 2H), 6.92 (d, J= 9.0 Hz, 1H ), 6.87 (s, 1H), 6.70 - 6.67 (m, 1H), 3.86 (br, 4H), 3.70 (s, 2H), 2.66 (br, 4H) 493,1 379 1-(4-(4(tetrahydro-1Hfuro[3,4-c]pyrrol5(3H)-yl)-2(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid t o Z-Z °h O /-----( with I-Z O-' δ 8.13 (br, 1H), 7.56 (d, J = 8.1 Hz, 1H), 6.87 - 6.81 (m, 3H), 3.99 - 3.94 (m, 2H ), 3.85 (br, 4H), 3.69 - 3.65 (m, 4H), 3.48 - 3.43 (m, 2H), 3.32 - 3.24 (m, 2H), 3.11 3.08 (m, 2H), 2.65 (br, 4H) 494.3 380 1-(4-(2-(8-oxa-3azabicyclo[3.2.1]o kgan-3-yl)-4(trifluoromethyl)benzyl)piperazine-1 carbonyl)-1Hpyrazole-3carboxylic acid o Z-Z °ch o o LL? δ 8.20 (d, J= 2.0 Hz, 1H), 7.79 7.77 (m, 1H), 7.51 (s, 1H), 7.487.45 (m, 1H), 6.88 (d, J = 2.0 Hz, 1H), 4.41 (br, 2H), 4.05 (br, 2H), 3.93 (br, 4H), 3.09 - 3.05 (m, 2H), 2.91 - 2.84 (m, 6H), 2.23 - 2.09 (m, 2H), 2, 09 - 1.94 (m, 2H) 494.3 381 1-(4-methyl-4(methyl(3(pyrrolidin-1yl)-5- (trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid CF ₃ Y ³ o [Ί 1 Uch. -N. I 1 7 '--J /-on O δ 8.09 (d, J = 2.7 Hz, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.78 (s, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.58 4.39 (m, 2H), 4.10-3.98 (m, 2H), 3.58 - 3.36 (m, 2H), 3.34 - 3.31 (m, 4H), 2.52 (s, 3H), 2.14-1.84 (m, 8H), 1, 46 (s, 3H) 494.3

- 171 047826

382 1-(4-methyl-4(methyl(2(pyrrolidin-1yl)-3- (trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid O jOatVA F ₃ C y ^N =A /A /-°H O ⁰ δ 8.07 (d, ./= 2.7 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.37 (t, J= 7.8 Hz, 1H), 6.77 (d,7= 2.7 Hz, 1H), 3.91 (br, 4H), 3.69 (br, 2H), 3.21 - 3.17 (m, 4H), 2.17 (s, 3H), 2.09 - 1.99 (m, 6H), 1.82 - 1.63 (m, 2H), 1.17 (s, 3H) 494.3 383 1-(4-methyl-4(methyl(4(pyrrolidin-1yl)-3(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid o Vn^ , _ y | Ί 1 Αν ^Λ νΛ F ₃ CT Ά nA /-OH 0 δ 8.09 (d, 7= 2.7 Hz, 1H), 7.69 (s, 1H), 7.51 (d, 7= 5.7 Hz, 1H), 7.10 (d, 7= 5.7 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.53 (br, 2H), 4.18 (br, 2H), 3.38 - 3.34 (m, 6H), 2.58 (s, 3H), 2.10 (br, 4H), 2.00 1.96 (m, 4H ), 1.52 (s, 3H) 494.3 384 1-(4-methyl-4(methyl(2(pyrrolidin-1yl)-5- (trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid CF ₃ Y ³ o [Ί i nJ /A /-° ^H VJ ⁰ δ 8.07 (d, 7= 2.7 Hz, 1H), 7.90 (s, 1H), 7.44 (d, 7= 4.2 Hz, 1H), 7.11 (d, 7= 6.3 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 4.02 - 3.78 (m, 6H), 3.32 - 3.22 (m, 4H), 2.23 (s, 3H), 2.06 - 1.98 (m, 6H), 1.96 1.81 (m, 2H), 1.27 (s, 3H) 494.3

- 172 047826

385 1-(4-methyl-4(methyl(3(pyrrolidin-1yl)-4- (trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid O F ₃ C^^ U 1 Ί 1 aLD .Ν- 1 1 7 Ν==/ HU /~on O δ 8.08 (d, J = 2.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.41 - 4.09 (m, 2H), 3.97 (br, 2H), 3.60 - 3.54 (m, 2H), 3.48-3.31 (m, 4H), 2.44 (s, 3H), 2.14-2, 11 (m, 2H), 2.03 1.91 (m, 6H), 1.27 (s, 3H) 494.3 386 (I)-1-(2-methyl-4((3-methyl-3 (methylsulfonyl)[1,G-biphenyl]-4yl)methyl)piperazine-1-carbonyl)-1Hpyrazole-3carboxylic acid t o z-z °Ч / Q лг>' о \ 5 8.17(1.7 = 1.5 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.99 - 7.93 (m, 1H), 7.93 - 7.90 (m, 1H), 7.73 7.68 (m, 1H), 7.52 (s, 1H), 7.49 7.41 (m, 1H), 7.41 -7.38(m, 1H), 6.81 (d, J =2.4 Hz, 1H), 4.65 (br, 1H), 4.27 - 4.23 (m, 1H), 3.56 3.53 (m, 2H), 3.50 - 3.40 (m, 1H), 3.18 (s, 3H), 2.91 - 2.87 (m, 1H), 2.80 - 2.76 (m, 1H), 2.51 (s, 3H), 2.43 - 2.38 (m, 1H), 2.31 - 2 .22 (m, 1H), 1.42 (d, J = 6.6 Hz, 3H) 497,5 387 1-(1-(4-chloro-2-(4-fluoropiperidin-1 yl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid o Λ I» ' Ζ-Ζ ATA about her δ 8.13 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.26 - 7.24 ( m, 1H), 6.79 (d, J = 2.4 Hz, 1H), 4.92 - 4.42 (m, 3H), 4.27 (br, 2H), 3.30 - 3.20 (m, 4H), 3.11 - 3.06 (m, 2H), 2.89 - 2.86 (m, 2H), 2, 35 - 2.26 (m, 4H), 2.15 - 1.99 (m, 6H), 1.85 - 1.83 (m, 2H) 504.2

- 173 047826

388 4-chloro-1-(2-(3chloro-5- (trifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid 01 /=/ O F ₃ CZ > ZX A x V/ G tf nA _Cl AZAA ⁿ A VJ /—OH o δ 8.19 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 4.36 (s, 2H), 3.82 - 3.77 (m, 2H), 3.69 - 3.64 (m, 2H), 3.42 - 3.37 (m, 2H), 3.22 (br, 2H), 2.03 (t, J= 7.2 Hz, 2H), 1.75 - 1.70 (m, 4H) 505,1 389 1-(1-(6(trifluoromethyl)benzo[b]thiophene-2carbonyl)-1,8diazaspiro[4.5]dec an-8-carbonyl)1H-pyrazole-3carboxamide CN Z Z-Z. °A ω cSO (Chloroform-T) δ 8.15 (s, 1H), 8.10 (d, 7=2.7 Hz, 1H), 7.91 (d, 7= 8.4 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 2.7 Hz, 1H), 6.75 (br, 1H), 5.52 (br, 1H), 4.55 - 4.51 (m, 2H), 3.92 (t, 7= 6.6 Hz, 2H), 3.35 - 3.14 (m, 4H), 2, 19 - 2.14 (m, 2H), 2.05 1.96 (m, 2H), 1.64 - 1.47 (m, 2H) 523.2 [M+ _NH4 ] ⁺ 390 1-(2-(6(trifluoromethyl)benzo[b]thiophene-2carbonyl)-2,8diazaspiro[4.5]dec an-8-carbonyl)1H-pyrazole-3carboxamide CN T z Z-Z °A 0 00° cd LL? δ 8.34 (s, 1H), 8.14 - 8.10 (m, 1H), 8.01 (s, 1H), 7.75 - 7.69 (m, 2H), 6.91 - 6 .86 (m, 1H), 4.06 (t, 7 = 7.0 Hz, 1H), 3.85 - 3.80 (m, 2H), 3.78 - 3.58 (m, 5H), 2.09 2.01 (m, 2H), 1.82 - 1.68 (m, 4H) 506.1 391 1-(2-(5(pyrrolidin-1yl)-2- (trifluoromethyl)benzyl)-2,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid 0 /=/ 0 \ / ΟιΆνΛ F3c\- _n A^ nV A ^oh 0 δ 8.06 (d, 7= 2.7 Hz, 1H), 7.53 7.50 (m, 1H), 7.04 (s, 1H), 6.78 (d, J = 2.7 Hz , 1H), 6.61 (d, J = 7.8 Hz, 1H), 4.35 (s, 2H), 3.83 3.79 (m, 2H), 3.72 - 3.67 (m , 2H), 3.32 (br, 4H), 3.21 - 3.14 (m, 4H), 2.06 - 1.99 (m, 6H), 1.82 - 1.69 (m, 4H ) 506.3

- 174 047826

392 1 -((27?)-2-methyl-4(2-(tetrahydro-1Hfuro[3,4-c]pyrrol5(3H)-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid t o Ζ-Ζ °Ч / o ^OC° o LL? δ 8.14 (d, 7 = 2.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.33 - 7.30 (m, 2H), 6.84 ( d,7= 2.7 Hz, 1H), 4.65 (br, 1H), 4.30 - 4.25 (m, 1H), 4.02 - 3.97 (m, 2H), 3.71 - 3.67 (m, 4H), 3.67 - 3.47 (m, 1H), 3.24 3.12 (m, 2H), 3.12 - 3.06 (m, 2H), 3, 06 - 2.91 (m, 3H), 2.79 - 2.75 (m, 1H), 2.44 - 2.36 (m, 1H), 2.36 - 2.28 (m, 1H), 1.47 (d, 7 = 6.9 Hz, 3H) 508.2 393 1-((27?)-4-(2-(3oxa-8- azabicyclo [3.2.1 ] o kgan-8-yl)-4(trifluoromethyl)benzyl)-2methylpiperazine-1 carbonyl)- 1Hpyrazole-3carboxylic acid «K O * r ° Ζ-Ζ srff o I δ 8.13 (d, 7 = 2.7 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.15 ( s, 1H), 6.84 (d,7=2.7 Hz, 1H), 4.67 (br, 1H), 4.33 - 4.25 (m, 1H), 4.03 - 3.89 (m, 4H), 3.74 - 3.63 (m, 4H), 3.56 - 3.42 (m, 1H), 2.96 - 2.81 (m, 1H), 2.81 2, 78 (m, 1H), 2.47 - 2.42 (m, 1H), 2.37 - 2.28 (m, 1H), 2.06 - 1.94 (m, 4H), 1.43 (d, J = 6.6 Hz, 3H) 508.3 394 1-((25)-2-methyl-4(2-(tetrahydro-1Hfuro[3,4-c]pyrrol5(3H)-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid o F ₃ Ck A ΥΊ O O ⁿ⁼⁼ \ Ν Λ~ ^0Η δ 8.13 (d,7= 2.7 Hz, 1H), 7.72 7.69 (m, 1H), 7.33 - 7.30 (m, 2H), 6.84 (d, J = 2.7 Hz, 1H), 4.67 (br, 1H), 4.31 - 4.26 (m, 1H), 4.01 3.96 (m, 2H), 3.71 - 3.62 ( m, 4H), 3.57 - 3.48 (m, 1H), 3.23 - 3.19 (m, 2H), 3.13 - 3.07 (m, 2H), 3.10 - 2, 92 (m, 3H), 2.79 - 2.75 (m, 1H), 2.44 - 2.29 (m, 2H), 1.47 (d, 7=6.9 Hz, 3H) 508.2

- 175 047826

395 1-((25)-4-(2-(3oxa-8-azabicyclo[3.2.1]o ctan-8-yl)-4(trifluoromethyl)benzyl)-2methylpiperazin-1 carbonyl)-1Hpyrazole-3carboxylic acid t o A Hna o [A? δ 8.14 (d, J= 2.7 Hz, 1H), 7.69 7.66 (m, 1H), 7.27 - 7.25 (m, 1H), 7.16 (s, 1H) , 6.84 (d, J = 2.7 Hz, 1H), 4.67 (br, 1H), 4.30 - 4.25 (m, 1H), 4.00 - 3.89 (m, 4H ), 3.75 3.63 (m, 4H), 3.56 - 3.43 (m, 1H), 3.00 - 2.92 (m, 1H), 2.82 - 2.78 (m, 1H), 2.47 - 2.42 (m, 1H), 2.37 - 2.28 (m, 1H), 2.09 - 1.92 (m, 4H), 1.44 (d, J = 6.6 Hz, 3H) 508.2 396 1-(5-(4-(4-hydroxytetrahydro-2H-pyran-4-yl)2- (trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1Hpyrazole-3-carboxamide o ? |/ ^he X to AC xx v'n nA Гу—' N==/ | /-nh ₂ CF ₃ o δ 8.31 (d, J = 2.7 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 6.89 (d, J= 2.7 Hz, 1H), 4.35 - 3.78 (m, 10H), 2.97 (br, 2H), 2.78 - 2.70 (m, 2H), 2.62 - 2.57 (m, 2H), 2.20 -2.10 (m, 2H), 1.67 - 1.63 (m, 2H) 508.3 397 1-(4-methyl-4(methyl(2(piperidin-1-yl)4- (trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid ^F - ^C x, ϊ UUijAAn ___N===A Ax /~OH 0 ⁰ δ 8.08 (d, 0 = 2.7 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 4.58 - 4.34 (m, 2H), 4.19 - 4.09 (m, 2H), 3.61 - 3.54 (m, 2H), 2.90 (t, 0 = 5.1 Hz, 4H), 2.48 (s, 3H), 2.24 - 2.10 (m, 2H) , 2.03 - 1.89 (m, 2H), 1.80 - 1.75 (m, 4H), 1.64 - 1.62 (m, 2H), 1.46 (s, 3H) 508.3

- 176 047826

398 1,1,1,3,3,3hexafluoropropan2-yl-4-(7cyclobutyl-Nmethyl-5,6,7,8hetrahydroimidazo[1,2-a]pyrazine-2carboxamido)-4methylpiperidine-1-carboxylate ^F 3 ^C V% ? шл оγ \___> Ν==Ζ 0 <г ^он 57.86 (s, 1H), 7.78 (d, J =8.0 Hz, 1H), 7.36 - 7.31 (m, 2H), 4.16 4.02 (m, 4H), 3.63 (br, 2H), 3.19 - 3.13 (m, 4H), 2.35 (br, 3H), 2.26 (s, 3H), 2.10 - 2.04 (m, 2H), 2.02 -1.96 (m, 4H), 1.89 (br, 2H), 1.34 (s, 3H) 508.3 399 4-chloro-1-(4-(3-((4(trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid CF ₃ 0 /PA/ U-on 0 δ 8.32 (d, J =5.4 Hz, 1H), 8.19 (s, 1H), 7.47 - 7.42 (m, 1H), 7.37 7.29 (m, 2H) , 7.26 (s, 2H), 7.15 7.12 (m, 1H), 3.91 (br, 4H), 3.85 (s, 2H), 2.91 - 2.82 (m, 4H) 510.2 400 1-(2-(2-chloro-4(tetrahydro-1Hfuro[3,4-c]pyrrole5(3H)-yl)benzyl)2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid 0-, CN X=\ o C / c/ xxACH k— ³ Y~OH O δ 8.06 (d, J = 2.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 6.76 - 6.74 (m, 2H), 6.67 - 6.65 (m, 1H), 4.39 (s, 2H), 3.99 - 3.95 (m, 2H), 3.88 (br, 2H), 3.71 - 3.68 (m, 4H), 3.50 3.48 (m, 2H), 3.43 (br, 2H), 3.34 -3.28 (m, 4H), 3.12 (t, J = 3.2 Hz, 2H), 2.06 (1.7=7.2 Hz, 2H), 1.88 - 1.80 (m, 4H) 514.3 401 1-(2-(4-chloro-3(tetrahydro-1Hfuro[3,4-c]pyrrole5(3H)-yl)benzyl)2,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid CI λ 2==\ ⁰ A /x X / Лы Л N—J /—OH 0 δ 8.06 (d,J = 2.7 Hz, 1H), 7.49 (d, J= 8.1 Hz, 1H), 7.26 (s, 1H), 7.09 (d, J= 8.1 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 4.27 (s, 2H), 3.99 3.94 (m, 2H), 3.82 (br , 2H), 3.70 (br, 2H), 3.61 - 3.56 (m, 2H), 3.39 - 3.34 (m, 2H), 3.22 (s, 6H), 2, 92 (br, 2H), 2.05 (t, J= 7.2 Hz, 2H), 1.84-1.76 (m, 4H) 514.3

- 177 047826

402 1-(1-(3(pyrimidin-5-yl)5- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid F ₃ C fX ϊ /хА ⁷ \ An nA n \ nA । 7 O ( ρΆ n==/ N \_J \ /—on O δ 9.23-9.17 (br, 3H), 8.13-8.08 (br, 3H), 7.95 (s, 1H), 6.82 (s, 1H), 4.64 (br, 2H), 4.26 (br, 2H), 3.27 - 3.20 (br, 2H), 3.15 (br, 2H), 2.27 - 2.20 (br, 4H), 2.05 - 2.01 (br, 2H), 1.82- 1.70 (br, 2H) 515.2 403 1-(1-(2(pyrrolidin-1yl)-4- (trifluoromethyl)benzoyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid оХ О Ж Ζ-Ζ о ι δ 8.17 (d, J = 2.7 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.96 - 6.93 (m, 2H), 6.84 ( d,.7= 2.7 Hz, 1H),4.57 (br, 2H), 3.50 - 3.38 (m, 4H), 3.32 - 3.09 (m, 6H), 2, 31-2.13 (m, 2H), 2.03 - 1.97 (m, 4H), 1.93 1.84 (m, 2H), 1.64 (br, 2H) 520.3 404 1-(1-(2(piperidin-1 -yl)4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]dec an-8-carbonyl)1H-pyrazole-3carboxylic acid w ¹ O O G \ / / ΰ ° Ζ-Ζ ΆρΧΑ o δ 8.08 (d,J = 2.7 Hz, 1H), 7.69 (d, 7 = 7.8 Hz, 1H), 7.47 (s, 1H), 7.43 - 7.41 ( m, 1H), 6.76 (d, J = 2.7 Hz, 1H), 4.83 - 4.60 (m, 2H), 4.25 - 4.06 (m, 2H), 3.30 - 3.21 (m, 2H), 3.17 - 3.01 (m, 2H), 2.99 - 2.88 (m, 4H), 2.30 - 2.14 (m, 4H), 2 .03 - 1.95 (m, 2H), 1.75 (br, 6H), 1.63 (br, 2H) 520.3 405 1 -(1 -(2-morpholino4- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid о А>° Ζ-Ζ о I 6 8.11 (d,.7 = 2.7 Hz, 1H), 7.74 (d, 7 = 8.1 Hz, 1H), 7.60 (s, 1H), 7.56 - 7.50 (m, 1H), 6.79 (d, J = 2.7 Hz, 1H), 4.80 - 4.67 (m, 2H), 4.27 - 4.19 (m, 2H), 3, 87 - 3.84 (m, 4H), 3.32 - 3.18 (m, 4H), 3.07 2.89 (m, 4H), 2.40 - 2.21 (m, 4H), 2 .11 - 2.00 (m, 2H), 1.82 - 1.78 (m, 2H) 522.3

- 178 047826

406 1-(4-((2-((2^,5A)- 2,5- dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)(methyl)amino)4- methylpiperidine-1-carbonyl)- 1Hpyrazole-3carboxylic acid od O nV U-OH O 5 8.07 (d,7 = 2.7 Hz, 1H), 7.88 (d, 7 = 8.4 Hz, 1H), 7.33 (d, 7 = 8.0 Hz, 1H), 7 .28 (s, 1H), 6.77 (d, J= 2.7 Hz, 1H), 4.17 - 3.83 (m, 6H), 3.77 - 3.50 (m, 2H), 2.35 - 2.26 (m, 1H), 2.19-2.11 (w, 4H), 2.08 - 2.00 (m, 2H), 1.85 - 1.62 (w, 2H ), 1.60 - 1.58 (m, 2H), 1.19 (s, ZN), 1.04 (d, J =5.6 Hz, ZN), 0.70 (d, J = 6.4 Hz, ZN) 522.3 407 1-(4-((2-((25)55)2,5- dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)(methyl)amino)4- methylpiperidine-1-carbonyl)- 1Hpyrazole-3carboxylic acid Zx o LL? O 1 1 / n=V U~on O 5 8.11 (d, 7 = 2.4 Hz, 1H), 7.81 (d, 7 = 8.0 Hz, 1H), 7.42 - 7.37 (w, 2H), 6.80 ( D,7 = 2.4 Hz, 1H), 4.65 - 3.80 (m, 6H), 3.86 - 3.50 (w, 2H), 2.63 - 2.12 (m, 5H), 2.14 1.80 (m, 4H), 1.66 - 1.54 (m, 2H), 1.37 - 1.20 (w, ZN), 1.08 (d, 7 = 6.0 Hz , ZN), 0.73 (d, 7 = 6.0 Hz, ZN) 522.3 408 1-(4-(3-(4-chlorophenoxy)-5-fluorobenzyl)piperazine-1-carbonyl)-4(trifluoromethyl)1H-pyrazole-3-carboxylic acid F -k Tu £ j O nV U-on o δ 8.54 (s, 1H), 7.42 - 7.39 (m, 2H), 7.08 - 7.04 (m, 2H), 6.92 (d, 7= 9.0 Hz, 1H ), 6.87 (s, 1H), 6.70 - 6.67 (m, 1H), 3.86 (br, 4H), 3.70 (s, 2H), 2.66 (br, 4H) 527,1

- 179 047826

409 4-chloro-1-(4-methyl4-(methyl(2(pyrrolidin-lyl)-4- (trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid ^F 3 ^C \Z\ ш О 0 N==/ /-ОН 0 δ 8.12 (s, 1H), 7.91 (0.7=8.1Hz, 1H), 7.25 - 7.20 (m, 2H), 3.96 (br, 2H), 3.81 (br, 2H), 3.68 (s, 2H), 3.20 - 3.09 (m, 4H), 2.11 - 1.90 (m, 9H), 1.72 - 1.65 (m , 2H), 1.15 (s, ZN) 528.2 410 1-(1-(2-((25,55)-2,5-dimethylpyrrolidin-1-yl)-4(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid / \ \ / A \—z G O o LL? \A ^N =/ /~ ^he o δ 8.13 (d, J= 2.8 Hz, 1H), 7.71 7.70 (m, 1H), 7.49 - 7.47 (m, 2H), 6.81 (d, J = 2.8 Hz, 1H), 4.89 4.32 (m, 3H), 4.24 - 4.21 (m, 1H), 4.01 - 3.94 (m, 2H), 3.33 - 3.06 (m, 4H), 2.36 - 2.25 (m, 6H), 2.09 - 2.05 (m, 2H), 1.95 - 1.86 (m, 2H), 1, 67 - 1.57 (m, 2H), 1.11 (d, J = 6.0 Hz, 3H), 0.75 (d, J = 6.4 Hz, 3H) 534.3 411 1-(1-(2-((2^,57?)2,5- dimethylpyrrolidin-1-yl)-4- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid o o * G ^ζ —( A/ -Лх 1 1 / \А ν==/ /-° ^no δ 8.13 (d, J= 2.8 Hz, 1H), 7.71 7.69 (m, 1H), 7.49 - 7.42 (m, 2H), 6.81 (d, J = 2.8 Hz, 1H), 4.89 4.41 (m, 3H), 4.30 - 4.20 (m, 1H), 4.01 - 3.94 (m, 2H), 3.33 - 3.10 (m, 4H), 2.49 - 2.25 (m, 6H), 2.08 - 2.00 (m, 2H), 2.00 - 1.77 (m, 2H), 1, 67 - 1.57 (m, 2H), 1.11 (d, 7=6.0 Hz, 3H), 0.75 (d, .7 = 6.4 Hz, 3H) 534.3

- 180 047826

412 1-(1-(3-(4methylpiperazin-1 yl)-5- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5 ] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid (A O /—-\ \---V ' agaa \ n-- ⁷ 6 >° ZZ o δ 8.09 (d, 7 = 2.8 Hz, 1H), 7.33 (s, 1H), 7.24 (s, 1H), 7.21 (s, 1H), 6.79 (d, J = 2.8 Hz, 1H), 4.60 (br, 2H), 4.04 (br, 2H), 3.42 (br, 4H), 3.22 - 3.15 (m, 2H), 3.06 (br, 2H), 2.98 (br, 4H), 2.64 (s, 3H), 2.32 2.13 (m, 4H), 1.98 - 1.95 (m, 2H ), 1.78 - 1.69 (m, 2H) 535.3 413 1-(1-(2-(4-fluoropiperidin-1-yl)-4- (trifluoromethyl)benzyl)-1,8- diazaspiro [4.5] decane-8-carbonyl)1H-pyrazole-3-carboxylic acid Г _z nA FsCAAf О I\l I 1 z < pA ⁿ A '— /—OH 0 δ 8.11 (d, ./= 2.7 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 6.78 (d, J = 2.7 Hz, 1H), 4.87 (s, 1H), 4.77 - 4.46 (m, 2H), 4.27 (br, 2H), 3.31-3, 08 (m, 6H), 2.91 - 2.88 (m, 2H), 2.31 - 2.15 (m, 4H), 2.13-1.90 (m, 6H), 1.89 - 1.68 (m, 2H) 538.3 414 4-(trifluoromethyl)1-(4-(3-((4(trifluoromethyl)pyridin-2yl)oxy)benzyl)pyperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid CF ₃ 0 0l ₀ ZAO ^a A ^f ' /—oh 0 5 8.65 (s, 1H), 8.37 (d.7= 5.1 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.30 7.23 (m, 3H) , 7.13 - 7.10 (m, 1H), 3.83 (br, 4H), 3.70 (s, 2H), 2.69 (br, 4H) 544.2

- 181 047826

415 1-(1-(2(tetrahydro-Shfuro[3,4-c]pyrrol5(3H)-yl)-4(trifluoromethyl)benzyl)-1,8- diazaspiro[4.5]decane-8-carbonyl)1H-pyrazole-3-carboxylic acid o Z-Z °ч ай o o LL? 5 8.07 (d,7 = 2.7 Hz, 1H), 7.71 (d, 7 = 8.1 Hz, 1H), 7.51 - 7.47 (w, 1H), 7.44- 7.41 (w, 1H), 6.76 (d, 7 = 2.7 Hz, 1H), 4.86 - 4.41 (w, 2H), 4.41 - 4.24 (m, 2H) , 3.94 3.79 (w, 4H), 3.29 - 3.01 (m, 6H), 3.07 - 2.96 (w, 4H), 2.33 - 2.19 (w, 4H ), 2.09 - 1.92 (m, 2H), 1.87 - 1.69 (w, 2H) 548.3 416 1-(1-(2-(8-oxa-3azabicyclo[3.2.1]o kgan-3-yl)-4(trifluoromethyl)benzyl)-1,8diazaspiro[4.5]dec an-8-carbonyl)1H- pyrazole-3carboxylic acid ёР o o o ° z-z О I 5 8.11 (d,7 = 2.7 Hz, lH), 7.79(d, 7 = 7.8 Hz, 1H), 7.46 - 7.42 (w, 2H), 6.81 ( d,7= 2.7 Hz, 1H), 4.73 - 4.52 (w, 2H), 4.43 (br, 2H), 4.10 (s, 2H), 3.34 - 3.10 (w, 2H), 3.09 - 3.05 (w, 2H), 2.94 - 2.89 (w, 2H), 2.83 - 2.78 (m, 2H), 2.18 2, 01 (w, 6H), 2.00 - 1.92 (m, 4H), 1.73 - 1.65 (w, 2H) 548.2 417 (^)-1-(1-(2(hexahydropyrrol o[1,2-a]pyrazin2(1H)-yl)-4(trifluoromethyl)benzyl)-1,8diazaspiro [4.5] dec an-8 -carbonyl)1H-pyrazole-3carboxylic acid t o Z-Z °Ч o o LL? δ 8.07 (d, 7= 2.7 Hz, 1H), 7.63 (d, 7= 8.1 Hz, 1H), 7.56 (s, 1H), 7.46 (d, 7= 8.1 Hz, 1H), 6.78 (d, 7 = 2.7 Hz, 1H), 4.58 (br, 2H), 4.35 - 3.70 (br, 3H), 3.55 - 3.31 (br, 5H), 3.20 - 2.85 (m, 8H), 2.14 (br, 3H), 2.10-1.70 (br, 6H), 1.59 - 1.54 (br, 2H) 561.3

- 182 047826

418 (5)-1-(1-(2-(hexahydropyrrol o[1,2-a]pyrazin2(1H)-yl)-4(trifluoromethyl)benzyl)-1,8diazaspiro [4.5]dec an- 8-carbonyl)1H-pyrazole-3carboxylic acid o /A Z-Z o δ 8.07 (d, J = 2.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 4.58 (br, 2H), 4.35 - 3.70 (m, 3H), 3.55 - 3.46 (m, 4H), 3.30 - 3.07 (m, 6H), 2.97 (br, 3H), 2.13 (br, 4H), 2.03 -1.78 (m, 5H), 1.58 - 1.54 (m, 2H) 561.3 419 1-(1-(3-(8-oxa-2azaspiro[4.5]decane-2-yl)-5-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decan-8-carbonyl)1H- pyrazole-3carboxylic acid \—Z \===\ w O' ^z >° z-z o ξε δ 8.12 (d, J = 2.4 Hz, 1H), 7.04 (s, 1H), 6.94 (s, 1H), 6.82 - 6.80 (m, 2H), 4, 69 (br, 2H), 4.26 (br, 2H), 3.80 - 3.70 (m, 4H), 3.51 3.43 (m, 2H), 3.32 - 3.15 (m , 6H), 2.37 - 2.17 (m, 4H), 2.11 - 2.07 (m, 2H), 2.03 - 2.00 (m, 2H), 1.93 - 1.84 (m, 2H), 1.66 (br, 4H) 576.3 420 1-(4-(4chlorobenzyl)piper zin-1-carboxyl)N-methyl-Spirazol-3carboxamide O Hcho (Chloroform-iG) δ 8.07 (s, 1H), 7.32 - 7.25 (m, 4H), 6.88 (s, 1H), 6.73 (s, 1H), 3.82 - 3.74 (m, 4H), 3.52 (m, 2H), 3.00 - 2.98 (m, 3H), 2.55 - 2.52 (m, 4H) 362.2 421 1-(7-(4-chlorobenzyl)-2,7-diazaspiro[4.4]non-2-carbonyl)1H-pyrazole-3-carboxamide o Tug n tr \_ιι \A/ ^N V\J Ч=/ 'nh ₂ (Chloroform-iH) δ 8.26 (m, 1H), 7.32 - 7.27 (m, 3H), 7.26 - 7.20 (m, 1H), 6.90 (s, 1H), 6.65 (s, 1H), 5.66 - 5.41 (m, 1H), 5.11 4.82 (m, 2H), 3.80 - 3.49 (m, 4H), 2.79 - 2.28 (m, 4H), 2.07 - 1.80 (m, 4H) 388.2

- 183 047826

422 1-(7-(4- chlorobenzyl)-2,7 diazaspiro[4.4]non-2-carbonyl)-Nmethyl-1 H-pyrazol3-carboxamide O T 1 G V Ν Ν \ Ts A A Ν, /\ 1 1 / X \—1 A/ νη / (Chloroform-7) δ 8.22 (s, 1H), 7.33 - 7.27 (m, 3H), 7.26 - 7.20 (m, 1H), 6.88 (s, 1H), 6.73 (s, 1H), 4.11 - 3.80 (m, 2H), 3.78 3.50 (m, 4H), 3.09 - 2.93 (m, 3H), 2.84 - 2.31 (m, 4H), 2.07 - 1.80 (m, 4H) 402.2 423 N-methyl-!-(4-(3phenoxybenzyl)pyrazine-1-carbonyl)-1Hpyrazole-3-carboxamide OHAHAHAH (Chloroform-T) δ 8.07 (s, 1H), 7.38 - 7.30 (m, 2H), 7.28 (s, 1H), 7.13 - 7.05 (m, 2H), 7.05 - 6.98 (m, 3H), 6.96 - 6.89 (m, 1H), 6.89 - 6.87 (m, 1H), 6.72 (br, 1H), 3, 84 (m, 4H), 3.67 (m, 2H), 2.99 (m, 3H), 2.57 (m, 4H) 420.3 424 1-(5-(4-chlorobenzyl)octa-dropyrrolo[3,4c]pyrrole-2carbonyl)-N-methyl-1 H-pyrazol3-carboxamide y—( VACA / ^nh (Chloroform-T) δ 8.21 (s, 1H), 7.30 - 7.26 (m, 4H), 6.89 (s, 1H), 6.76 (s, 1H), 4.10 ( m, 2H), 3.77 (m, 2H), 3.60 (m, 2H), 3.02 (s, 3H), 2.95 (m, 2H), 2.62 (m, 4H) 388,1 425 N-methyl-!-(5-(4(trifluoromethyl)benzyl)octahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxamide O ^F - ^c -x·. rA'r 'CS-C UVCA/ ^NH (Chloroform-T) δ 8.22 (s, 1H), 7.58 - 7.56 (m, 2H), 7.45 - 7.43 (m, 2H), 6.89 - 6.74 (s , 2H), 4.11 (m, 2H), 3.78 (m, 2H), 3.68 (m, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2 .63 (m, 4H) 422.2 426 1-(7-(2,5-dichlorobenzyl)-2,7-diazaspiro[4.4]non-2-carbonyl)1H-pyrazole-3-carboxamide about ULO ^MNg CI (Chloroform-T) δ 8.26 (s, 1H), 7.52 - 7.48 (m, 1H), 7.28 - 7.26 (m, 1H), 7.17 - 7.15 (m , 1H), 6.90 (s, 1H), 6.69 (br, 1H), 5.61 (br, 1H), 4.10 - 3.85 (m, 2H), 3.81 3.61 (m, 4H), 2.83 - 2.45 (m, 4H), 2.08 - 1.93 (m, 4H) 422,1

- 184 047826

427 1-(g/is-5-((2-chlorobenzyl)(methyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)-Nmethyl-1 H-pyrazole3-carboxamide O χ^Α-γ/ 1 C/X A/ NH C ΐ' ^{n 7} (Chloroform-/) δ 8.22 (d, J = 2.7 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.37 - 7.34 (m, 1H) , 7.26 - 7.17 (m, 2H), 6.88 (d, J = 2.7 Hz, 1H), 6.77 (br, 1H), 4.01 - 3.80 (m, 4H ), 3.62 (s, 2H), 3.02 - 2.96 (m, 4H), 2.74 (br, 2H), 2.28 - 2.18 (m, 5H), 1.59 ( br, 2H) 416,1 428 1-(7-(2,5- dichlorobenzyl)-2,7-diazaspiro[4.4]non-2-carbonyl)-Nmethyl-1 H-pyrazol3-carboxamide o u AA A/ NH UAO ' CI (Chloroform-/) δ 8.23 (s, 1H), 7.52 - 7.43 (m, 1H), 7.28 - 7.26 (m, 1H), 7.18 - 7.15 (m , 1H), 6.88 (s, 1H), 6.75 (br, 1H), 4.05 - 3.87 (m, 2H), 3.75 - 3.60 (m, 4H), 3, 01 (br, 3H), 2.75 - 2.51 (m, 4H), 2.07 - 1.87 (m, 4H) 436.1 429 1-(7-(3(trifluoromethyl)benzyl)-2,7- diazaspiro[4.4]non-2-carbonyl)1H-pyrazole-3-carboxamide o Α ldA ιΊι rV ^NH2 АААА (Chloroform-/) δ 8.25 (s, 1H), 7.60 - 7.41 (m, 4H), 6.90 (s, 1H), 6.70 - 6.65 (m, 1H), 5.58 (br, 1H), 4.06 - 3.85 (m, 2H), 3.80 - 3.46 (m, 4H), 2.72 - 2.42 (m, 4H), 2, 02 - 1.76 (m, 4H) 422.2 430 1-(5-(2,5-dichlorobenzyl)octahydropyrrolo[3,4c]pyrrole-2carbonyl)-N-methyl-1 H-pyrazol3-carboxamide ^C| ? _γ -Αν^νΑ__^ ⁾ Cl (Chloroform-/) δ 8.26 (d, J = 2.6 Hz, 1H), 7.48 (s, 1H), 7.25 (m, 1H), 7.16 (m, 1H), 6 .90 (s, 1H), 6.86 - 6.70 (br, 1H), 4.26 - 4.00 (br, 2H), 3.90 - 3.76 (br, 2H), 3.70 (s, 2H), 3.05 (d, J = 5.0 Hz, 3H), 2.95 (m, 2H), 2.66 (s, 4H) 422 431 \-(trans-5-((2-chlorobenzyl)(methyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)-Nmethyl-1 H-pyrazole3-carboxamide O H A R An n Cl gA I | T 1 V-J ^==/ NH (DE n ’ (Chloroform-/) δ 8.24 (d, J = 2.7 Hz, 1H), 7.60 - 7.42 (m, 1H), 7.42 - 7.30 (m, 1H), 7, 24 - 7.15 (m, 2H), 7.90 (d, J= 2.7Hz, 1H), 6.80 - 6.62 (m, 1H), 4.30 - 3.90 (m, 2H ), 3.85 - 3.32 (m, 4H), 3.32 3.12 (m, 1H), 3.12 -2.98 (m, 3H), 2.98 - 2.70 (m, 2H), 2.18 (s, 3H), 2.12-1.82 (m, 4H) 416.2

- 185 047826

432 I-methyl-1-(5-(3(trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxamide t V n Z—. '—Z A (Chloroform-7) δ 8.26 (d, J= 2.8 Hz, 1H), 7.68 - 7.55 (m, 3H), 7.52 - 7.40 (m, 1H), 6.90 (d, J = 2.8 Hz, 1H), 6.75 (br, 1H), 4.20 - 4.00 (br, 2H), 4.00 - 3.54 (br, 2H), 3.70 (s, 2H), 3.10 - 2.90 (m, 5H), 2.70 (s, 4H) 422 433 1-(7-(3-chloro-5(trifluoromethyl)benzyl)-2,7- diazaspiro[4.4]non-2-carbonyl)1H-pyrazole-3-carboxamide count ύ A ζ— '—Ζ with /~ / ^th_ ) o (Chloroform-T) δ 8.26 (s, 1H), 7.67 - 7.48 (m, 3H), 6.90 (s, 1H), 6.87 - 6.66 (m, 1H), 5.59 (br, 1H), 4.05 - 3.89 (m, 2H), 3.75 - 3.53 (m, 4H), 2.87 - 2.34 (m, 4H), 2, 01 - 1.77 (m, 4H) 456.2 434 I-methyl-1-(g/is-5(methyl(2(trifluoromethyl)benzyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxamide O V'-nAhO' 9 ^F 3 A=/ NH (y G ⁿ ' (Chloroform-T) δ 8.22 (d, J= 2.7 Hz, 1H), 7.55 (d, J= 8.1 Hz, 2H), 7.42 (d, J = 2 Hz, 2H ), 6.88 - 6.82 (m, 2H), 4.01 - 3.96 (m, 4H), 3.56 (s, 2H), 3.01 (d, J = 5.0 Hz, 3H), 2.97 - 2.86 (m, 1H), 2.73 (br, 2H), 2.26 - 2.12 (m, 2H), 2.09 (s, 3H), 1.58 - 1.48 (m, 2H) 450,1 435 1-(7-(3-chloro-5(trifluoromethyl)benzyl)-2,7- diazaspiro[4.4]non-2-carbonyl)-1Hmethyl-1 H-pyrazol3-carboxamide t SK/A V Z— —Z with /==\ ^th V/ o (Chloroform-T) δ 8.23 (s, 1H), 7.61 - 7.48 (m, 3H), 6.89 (s, 1H), 6.88 - 6.76 (m, 1H), 4.04 - 3.85 (m, 2H), 3.71-3.43 (m, 4H), 3.03 - 3.00 (m, 3H), 3.00 - 2.43 (m, 4H ), 2.00 - 1.75 (m, 4H) 470.2 436 1-(7-(4-morpholino2- (trifluoromethyl)benzyl)-2,7- diazaspiro[4.4]non-2-carbonyl)1H-pyrazole-3-carboxamide 0 A ω \=---· Ζ— g>I m (Chloroform-T) δ 8.25 (s, 1H), 7.63 - 7.43 (m, 1H), 7.13-7.11 (m, 1H), 7.04 - 7.01 (m , 1H), 6.97 (s, 1H), 6.89 - 6.65 (m, 1H), 5.55 (br, 1H), 4.01 - 3.96 (m, 2H), 3, 88 - 3.85 (m, 4H), 3.72 - 3.57 (m, 4H), 3.20 - 3.17 (t, J = 4.6 Hz, 4H), 2.86 - 2, 77 (m, 1H), 2.66 2.47 (m, 2H), 2.47 - 2.44 (m, 1H), 1.97 - 1.73 (m, 4H) 507,1

- 186 047826

437 1-(5-(3-chloro-5(trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-Nmethyl-1 H-pyrazol3-carboxamide o Z—. -Z I (Chloroform-7) δ 8.26 (d, J = 2.6 Hz, 1H), 7.70 - 7.40 (m, 3H), 6.90 (d, J = 2.6 Hz, 1H) , 6.80 - 6.60 (br, 1H), 4.30 - 4.00 (br, 2H), 3.98 - 3.70 (br, 2H), 3.60 (s, 2H), 3 ,10 - 2.90 (m, 5H), 2.80 - 2.50 (m, 4H) 456.2 438 N-methyl-!-(7-(4morpholino-2(trifluoromethyl)benzyl)-2,7diazaspiro[4.4]non-2-carbonyl)1H-pyrazole-3carboxamide T Ογ ^ζ χ I A / / co o (Chloroform-T) δ 8.20 (s, 1H), 7.60 - 7.54 (m, 1H), 7.10 (s, 1H), 7.09 - 6.92 (m, 1H), 6.88 - 6.85 (m, 1H), 6.71 (br, 1H), 4.06 - 3.71 (m, 6H), 3.82 - 3.54 (m, 4H), 3, 17 - 3.14 (t, J = 4.8 Hz, 4H), 2.99 2.85 (m, 3H), 2.75 - 2.61 (m, 1H), 2.61 - 2.41 (m, 2H), 2.41 - 2.30 (m, 1H), 1.91 - 1.69 (m, 4H) 521.3 439 X-methyl-1-(g/is-5(methyl(4(trifluoromethyl)benzyl)amino)octahydrocyclopenta[c]pyrrole-2-carbonyl)1H-pyrazole-3-carboxamide 0 VAA-/ CHU νη Λ J ¹ F ₃ C ^/X ^ (Chloroform-T) δ 8.23 (d, J= 2.7 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.61 - 7.52 (m, 2H) , 7.32 (t, J = 7.5 Hz, 1H), 6.88 - 6.84 (m, 2H), 3.93 - 3.68 (m, 6H), 3.03 - 2.94 (m, 4H), 2.73 (br, 2H), 2.22 - 2.15 (m, 5H), 1.57 - 1.52 (m, 2H) 450.2 440 N-methyl-!-(5-(4-morpholino-2(trifluoromethyl)benzyl)ocahydropyrrolo[3,4-c]pyrrole2-carbonyl)-1Hpyrazole-3carboxamide τ =Q ζ—. -z , J co 0 (Chloroform-T) δ 8.30 (d, 7=2.6 Hz, 1H), 7.60 - 7.50 (m, 1H), 7.13 (d, J = 2.3 Hz, 1H) , 7.05 - 6.92 (m, 1H), 6.85 (d, 7= 2.7 Hz, 1H), 6.80 - 6.68 (br, 1H), 4.30 - 4.00 (m, 2H), 3.98 - 3.85 (m, 4H), 3.82 - 3.60 (m, 4H), 3.10 - 3.22 (m, 4H), 3.05 (d ,7= 5.0 Hz, 3H), 2.95 (m, 2H), 2.70 - 2.50 (m, 4H) 507,1

- 187 047826

441 N,N-dimethyl-1-(4(2-morpholino-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxamide O ΎΊ O O 4A/N\/ y κι An _Q 0 . (Chloroform-7) δ 8.10 - 8.09 (m, 1H), 7.63 - 7.62 (m, 1H), 7.36 7.27 (m, 2H), 6.74 - 6, 73 (m, 1H), 4.02 (br, 8H), 3.65 (br, 2H), 3.28 - 3.27 (m, 3H), 3.13 - 3.12 (br, 3H) , 2.97 (br, 4H), 2.59 (br, 4H) 495,1 442 (5)-1-(4-(3-(4chlorophenoxy)benzyl)-2- methylpiperazine-1 carbonyl)-4- methyl-1 H-pyrazol3-carboxylic acid UCu/q- AoH o (Chloroform-T) δ 7.77 (br, 1H), 7.30 - 7.26 (m, 3H), 7.08 - 7.06 (m, 1H), 7.01 (s, 1H), 6.95 - 6.92 (m, 2H), 6.90 - 6.88 (m, 1H), 6.76 (br, 1H), 4.59 (br, 1H), 4.23 - 4.20 (m, 1H), 3.58 - 3.54 (m, 1H), 3.49 - 3.39 (m, 2H) , 2.86 - 2.83 (m, 1H), 2.69 - 2.66 (m, 1H), 2.32 2.09 (m, 5H), 1.39 (d, J = 6.4 Hz, 3H) 469.2 443 4-chloro-1-(4-(2(pyrrolidin-1yl)-4- (trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid о c-y) О А° z-z CxjA* о о ι — (Chloroform-7) δ 8.20 (br, 1H), 8.03 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7 ,15-7.13 (m, 1H), 4.20 - 3.80 (m, 6H), 3.20 (br, 4H), 2.82 (br, 4H), 1.96 (br, 4H) 486.2 444 (5)-1.(4-(3-(4chlorophenoxy)benzyl)-2- methylpiperazine-1-carbonyl)-4(trifluoromethyl)1H-pyrazole-3-carboxylic acid xvxoA Aoi 0 (Chloroform-T) δ 8.65 (br, 1H), 7.70 (br, 1H), 7.32 - 7.30 (m, 3H), 7.17 - 7.08 (m, 1H), 7.03 (s, 1H), 6.96 - 6.91 (m, 3H), 4.59 (br, 1H), 4.26 - 4.24 (m, 1H), 3.63 - 3.60 (m, 1H), 3.48 - 3.45 (m, 2H), 2.94 - 2.91 (m, 1H ), 2.74 - 2.71 (m, 1H), 2.34 - 2.20 (m, 2H), 1.50 1.43 (m, 3H) 523,1

- 188 047826

445 \-(trans-5-(2-chloro-3-methoxyphenoxy)-(2-hydroxy ... ABOUT N A XX 50N nA η xCa A N U-on CI O δ 8.18 (d, J= 2.8 Hz, 1H), 7.22 7.17 (m, 1H), 6.77 (d, J = 2.8 Hz, 1H), 6.71 - 6 .69 (m, 2H), 5.08 5.05 (m, 1H), 4.19 - 3.69 (m, 7H), 3.04 (br, 2H), 2.22 - 2.20 (m, 2H), 2.05 - 1.95 (m, 2H) 423.2 [M+ _NH4 ] ⁺ 446 \-(trans-5-(2-chloro-3-(thiazol-4yl)phenoxy)octahydrocyclopenta[s]pyrrole-2carbonyl)-Spyrazole-3carboxylic acid O AH Aa \ Ζ'ίιΑ' ^{3 n} # ^he V CI ⁰ δ 9.08 (d, J= 1.6 Hz, 1H), 8.23 (d, 7=2.4 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7 .37 - 7.34 (m, 2H), 7.17 - 7.13 (m, 1H), 6.83 (d, J = 2.4 Hz, 1H), 5.15 (br, 1H), 4.35 - 3.57 (m, 4H), 3.15 - 3.07 (m, 2H), 2.35 -2.17 (m, 2H), 2.04 - 2.00 (m, 2H) 459.1 447 \-(trans-5-{(2-chloro-3-(thiazol-4-yl)benzyl)oxy)oxy ahydrocyclopenta[ c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid 0 ^H /X A /x y% nA /==N Cl G-D J 1 / ^S \AAA/\ ^N \ HZ~OH ⁰ 59.10(s, 1H), 8.17 (d.7 = 2.4Hz, 1H), 7.91 (s, 1H), 7.67 (d.7=7.6Hz, 1H), 7 .59 (d, J = 7.6 Hz, 1H), 7.42 (t, 7 = 7.6 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 4.74 (s, 2H), 4.33 (br, 1H), 4.27 - 3.50 (m, 4H), 2.96 (br, 2H), 2.20 - 2.17 (m, 2H), 1.87 - 1.84 (m, 2H) 473.2 448 \-(trans-5-(2chloro-3isobutoxyphenox and)octahydrocyclopenta[c]pyrrole-2carbonyl)-1Hpyrazole-3carboxylic acid 0 ^H /XA XX xx nA. jOl xLa A \ρ _ο ζ^γχ _ο ζχ/ h V-oh 1 Cl 0 δ 8.18 (s, 1H), 7.18 - 7.14 (m, 1H), 6.77 (s, 1H), 6.70 - 6.65 (m, 2H), 5.06 (br , 1H), 4.17 - 3.87 (m, 3H), 3.81 - 3.80 (m, 2H), 3.73 3.50 (m, 1H), 3.16 - 3.04 (m, 2H), 2.20 - 2.13 (m, 2H), 2.12 - 2.04 (m, 1H), 1, 99- 1.96 (m, 2H), 1.11 -1.01 (m, 6H) 465.1 [M+ _NH4 ] ⁺

- 189 047826

449 4-chloro-1-(4-(2morpholino-3(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid 9 o Z-Z °ч o o LL? δ 8.15 (s, 1H), 7.81 (<1.7 = 7.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.34 - 7.29 ( m, 1H), 4.10 - 3.70 (m, 10H), 3.48 - 3.25 (m, 2H), 2.90 2.82 (m, 2H), 2.69 (br, 4H) 502.1 450 (5)-1-(4-(2-chloro-3(2-hydroxy-2methyl pro on ox i) benzyl)-2- methylpiperazine-1 carbonyl)- 1Hpyrazole-3carboxamide O o iodine X y-mn ₂ (Chloroform-T) δ 8.10 (d, J = 2.7 Hz, 1H), 7.25 -7.20 (m,lH), 7.15 - 7.13 (m, 1H), 6, 92 (d, J = 2.7 Hz, 1H), 6.89 - 6.86 (m, 1H), 6.68 (br, 1H), 5.61 (br, 1H), 4.65 (br, 1H), 4.28 - 4.24 (m, 1H), 3.87 (s, 2H), 3.67 - 3.65 (m, 2H), 3.53 3.49 (m, 1H), 2.93 - 2.89 (m, 1H), 2.80 - 2.76 (m, 1H), 2.48 - 2.45 (m, 2H), 2.36 - 2.29 (m, 1H), 1.52 (d, J = 6.6 Hz, ZN), 1.40 (s, 6H) 450.2 451 \-(trans-5-(2- chloro-3-(2hydroxy-2methylpropoxy)phenoxy)octahydrocyclopenta[c]pyrrole -2-carbonyl)- 1Hpyrazole-3carboxylic acid 0 N Λ _Λ ⁿ °x>ADl Uon δ 8.25 (d, J = 2.7 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1H), 6.85 (d, J = 2.7 Hz, 1H), 6 .79 - 6.68 (m, 2H), 5.11 - 5.05 (m, 1H), 4.29 - 3.89 (m, 3H), 3.89 - 3.80 (s, 2H), 3.75 3.55 (m, 1H), 3.12 - 2.99 (m, 2H), 2.30 - 2.18 (m , 2H), 2.05 - 1.90 (m, 2H), 1.41-1.31 (s, 6H) 486.2 [M+Na] ⁺ 452 \-(trans-5-(2- chloro-3-(2hydroxy-2methylpropoxy)phenoxy)octahydrocyclopenta[c]pyrrole -2-carbonyl)- 1Hpyrazole-3carboxamide \ 1 Gas ⁿ c X Ό y O Η AnH ₂ Cl ° δ 8.34 (d, J = 2.7 Hz, 1H), 7.19(1, J = 8.4 Hz, 1H), 6.89 (d, J = 2.7 Hz, 1H), 6 .77 - 6.65 (m, 2H), 5.12 - 5.05 (m, 1H), 4.40 - 3.89 (m, 3H), 3.89 - 3.80 (s, 2H), 3.80 3.50 (m, 1H), 3.19 - 2.99 (m, 2H), 2.32 - 2.18 (m , 2H), 2.06 - 1.91 (m, 2H), 1.45 - 1.34 (s, 6H) 485.2 [M+Na] ⁺

- 190 047826

453 1-(4-(2-morpholino3- (trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid t o Z-Z °=( o o LL? δ 8.04 (d, J = 2.7 Hz, 1H), 7.75 7.77 (m, 1H), 7.49-7.51 (m, 1H), 7.23 - 7.27 ( m, 1H), 6.73 (d, J = 2.7 Hz, 1H), 3.61 - 3.75 (m, 10H), 3.31 - 3.35 (m, 2H), 2.73 - 2.76 (m, 2H), 2.52 - 2.54 (m, 4H) 468,0 454 1-(4-(3(tetrahydro-1Hfuro[3,4-c]pyrrol5(3H)-yl)-4(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1Hpyrazole-3-carboxylic acid ΣΙΧΟΥ IxJ Aon o δ 8.04 - 8.16 (m, 1H), 7.57 - 7.64 (m, 1H), 7.40 (s, 1H), 7.15 - 7.27 (m, 1H), 6 .78 - 6.88 (m, 1H), 3.94 - 4.07 (m, 2H), 3.89 (s, 4H), 3.74 (s, 2H), 3.44 - 3.59 (m, 2H), 3.08 -3.21 (m, 2H), 2.83 - 3.02 (m, 4H), 2, 71 (s,4H) 494.1 455 4-(3-((4-(3carbamoyl-1Hpyrazole-1carbonyl)piperazi n-1- yl)methyl)phenyl)tetrahydro-2Hpyran-4carboxylic acid сч X X <ΓΆ° Z-Z °ч о X \ .о О δ 8.17 (d, J = 2.4 Hz, 1H), 7.50 (s, 1H), 7.46 - 7.40 (m, 1H), 7.37 - 7.28 (m, 1H ), 7.25 - 7.20 (m, 1H), 6.84 (d,.7= 2.4 Hz, 1H), 3.91 - 3.83 (m, 6H), 3.68 - 3.53 (m, 4H), 2.62 - 2.59 (m, 4H), 2.53 2.48 (m, 2H), 1.95 - 1.87 (m, 2H) 442.2 456 1-(4-methyl-4(methyl(2(pyrrolidin-1yl)-4(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)1H-pyrazole-3carboxylic acid t o A/A ⁰ ZZ g, Y X / \ yU o LL? δ 8.04-8.17 (m, 1H), 7.68 - 7.81 (m, 1H), 7.40 - 7.50 (m, 1H), 7.29 - 7.40 (m, 1H), 6.72 - 6.85 (m, 1H), 4.25 - 4.51 (m, 2H), 4.00 4.25 (m, 2H), 3.42 - 3.67 (m, 2H), 3.10 - 3.26 (m, 4H), 2.37 - 2.58 (m, 3H), 1, 88-2.21 (m, 8H), 1.31 - 1.56 (m, 3H) 494.3

II. Biological assessment.

Protein characterization based on in vitro competitive activity.

Proteomes (mouse brain membrane fraction for mouse assays; human prefrontal cortex membrane fractions for human assays) (50 mL, total protein concentration 1.0 mg/mL) were preincubated with various concentrations of inhibitors at 37°C. After 30 min, FP-Rh (1.0 mL, 50 mM in DMSO) was added and the mixture was incubated for an additional 30 min at 37°C. Reactions were quenched with SDS loading buffer (15 µL - 4X) and analyzed on SDS-PAGE. After gel visualization, serine hydrolase activity was determined by measuring

- 191 047826 The fluorescence intensities of the bands on the gel corresponding to MAGL and FAAH were determined using ImageJ 1.43u software. The IC ₅₀ data obtained from this assay are shown in Table 1. All compounds in Table 1 were more potent inhibitors of MAGL than FAAH.

Obtaining a mouse brain proteome taken after treating mice with an inhibitor.

Inhibitors were administered to wild-type C57Bl/6J by gavage in polyethyleneglycol vehicle. Each animal was sacrificed 4 h after administration and brain proteomes were prepared and analyzed according to previously established methods (See Niphakis, M. J., et al. (2011) ACS Chem. Neurosci. and Long, J. Z., et al. Nat. Chem. Biol. 5:37–44).

The compounds demonstrated activity in the assays described in this paper as listed in Table 1.

Table 1

MAGL, FAAH, MAGL, FAAH, MAGL, FAAH, MAGL, FAAH, Note. % ING. % ING. % ING. % ING. 1C ₅₀ IC50 % ING. % ING. 1 μM 1 μM 1 μM 1 μM (μM) (μM) 5 mg/kg 5 mg/kg (Human) (Human) (mouse) (mouse) (Human) (Human) (mouse) (mouse) 1 WITH A(YumkM) IN D 2 A WITH 3 A D *** * D D 4 A D A D D D 5 A D IN D

- 192 047826

6 A D A D D D 7 A D A D D D 8 A D A D D D 9 A D A D 10 A D A D D D 11 A D A D D D 12 A D A D D D 13 A D 14 C D C D 15 A A A C ** ** 16 A D A IN *** * 17 A A *** *** 18 IN D C D 19 A A A A *** ** 20 A A A A ** * 21 C C 22 A A *** 23 A A 24 A A 25 A A ** 26 A A *** D 27 A A *** 28 A A 29 A A ** 30 A A 31 D IN 32 *** 33 IN 34 A A *** 35 A A *** D 36 *** 37 A A *** 38 *** 39 A D A D 40 A D A D D D 41 A A D D

- 193 047826

42 A A A D ** ** 43 A IN A A *** * D D 44 A D A D 45 A A A A *** ** 46 A D A D 47 A D A D 48 A D A D D D 49 A D A D 50 A (10 mkM) A(IOmkM) D D 51 A IN A D *** ** D D 52 A D A D 53 A A A A *** ** 54 A A A A *** ** 55 A A A A *** *** D D 56 A D A IN 57 A IN A IN *** ** D D 58 A D A IN 59 A D A D 60 C D D D 61 A A A A *** ** 62 IN D D D 63 C IN D D 64 A D A D 65 IN D C D 66 A D A D 67 A D A D 68 A D A D 69 A D A D 70 C IN D D 71 A D A D 72 A D A D *** * 73 A D A IN 74 A D A D

- 194 047826

75 A D IN IN 76 A D A D D D 77 A D A D *** * 78 A D A D 79 A (10 mkM) In (YumkM) D D 80 A D A D 81 A IN A D *** ** 82 A D A D 83 A D A D *** * D D 84 A D A IN *** ** 85 A D A IN *** * 86 A D A D D D 87 A D A D 88 A D A D D D 89 A A A A *** ** 90 A D A D D D 91 A D A D D D 92 A D A D *** * D D 93 A D A D *** * D D 94 A D A D 95 A D A D D D 96 A C 97 A D A D 98 A A A A *** ** D D 99 A A A A *** *** 100 A D A D *** * D D 101 A D A D D D 102 A C A D 103 A D A D 104 A D A D D D 105 A D A D D D 106 A D A D D D 107 A D A D D D 108 A D A D 109 A D A D D D

- 195 047826

BY A D A D 111 A D A D D D 112 A A A A *** ** 113 A D A D D D 114 A D A D D D 115 WITH IN D A 116 A A A D ** ** D D 117 IN D IN IN 118 A D A D D D 119 A D A D D D 120 A D A D D D 121 A D A D D D 122 IN D WITH IN 123 A IN A A D D 124 A IN A A *** ** D WITH 125 A A A A *** *** 126 WITH D D D 127 A D A D 128 A A A A *** *** 129 A A A A *** ** 130 A IN A IN *** ** D D 131 A D A D ** * 132 A A A A *** *** D D 133 A A A A *** ** D D 134 A A A IN *** ** 135 A D A D D D 136 A A A A *** ** 137 A A A A ** ** 138 A D A IN *** ** 139 A A A A *** *** D D 140 A IN A IN *** ** D D 141 A (10 μM) A (50 μM) D D 142 A (10 μM) D D D 143 D A D A * ** 144 A A A A *** ***

- 196 047826

145 A IN A A 146 A A IN A 147 A A D A 148 A A A A *** ** D C 149 A C A A ** * 150 C IN C A 151 A c A C 152 A D A IN 153 A D A c 154 A D A D 155 A D A D ** * 156 A D A A 157 A A A A *** ** D D 158 A A A A *** *** D D 159 A A A A *** ** D D 160 A D A D 161 A A A A *** *** 162 A A A C *** ** 163 D C D D 164 A A A C *** 165 A A A IN 166 IN D A D 167 A C A D *** * 168 IN D D D 169 C D D D 170 A A *** ** 171 A D A D ** * 172 A A A IN *** *** 173 A A A IN *** *** 174 A D A WITH 175 A A A A *** ** 176 A A A A *** *** 177 C D 178 A A 179 A IN

- 197 047826

180 A D 181 A A A A 182 A A A A 183 C C 184 D C 185 A D A D D D 186 IN D A D 187 A C A D D D 188 A D A D D D 189 A D A D 190 C C D IN 191 A D A D 192 A D C D 193 C A C A 194 195 A A D A *** *** 196 A A *** *** 197 A A A A *** ** 198 A A 199 A A A A *** ** A D 200 A A *** *** 201 A A *** *** 202 A A *** *** 203 A A A A 204 A A *** *** 205 A A *** *** 206 A A *** *** 207 A D A D D D 208 A A *** *** 209 A A A A *** ** 210 A A A A ** * D D 211 A D A D D D 212 A D A D D D 213 A A *** 214 IN A 215 A A **

- 198 047826

216 A A *** 217 A A *** 218 A A ** 219 A A *** 220 A A *** c 221 A A *** 222 A A *** 223 A D 224 A A 225 A A ** 226 A A 227 A C 228 A A ** 229 C D 230 A A *** D 231 A A *** 232 A A *** 233 A A ** 234 A A *** 235 A A *** 236 A A *** 237 A 238 A A ** 239 A A *** 240 A A *** 241 A A *** D 242 A A *** 243 A A ** 244 A A *** 245 A A *** D 246 A A ** 247 A A ** 248 C D 249 A A ** 250 A A ** 251 A A *** D 252 A A *** D 253 A A ***

- 199 047826

254 A A *** 255 A A ** 256 A IN ** 257 A A *** A 258 A A *** 259 A A *** 260 A A *** A 261 A A *** 262 A IN ** 263 A A 264 A A 265 A A ** 266 A A *** 267 A A ** 268 A A *** 269 A A *** D 270 A A 271 A A *** 272 A A *** 273 A (10 mkM) 274 A A *** 275 A A *** 276 A A *** 277 A A 278 A A *** 279 A A 280 A A *** 281 A A 282 IN D 283 A A *** 284 A A *** 285 A A ** 286 A A *** 287 C D 288 A A ** 289 A A *** 290 A A ***

- 200 047826

291 A A *** c 292 A A ** 293 A A *** 294 A A 295 IN A 296 A A *** 297 A A *** 298 A A 299 A A *** 300 A (10 mkM) D 301 A (10 mkM) D 302 A (10 mkM) D 303 A *** 304 A A *** 305 IN D 306 A A *** 307 A A *** D 308 A A *** D 309 A A ** 310 A A 311 A A *** D 312 A A ** 313 A A *** 314 A A *** 315 A A 316 A A 317 A A 318 A A *** 319 A A *** 320 A A *** 321 A A *** 322 A A 323 A A *** 324 C D 325 A A ***

- 201 047826

326 A A 327 A A *** D 328 A A D 329 A A *** 330 A A ** 331 A A *** 332 A A 333 A A *** 334 IN D 335 A A ** 336 A IN 337 A A *** D 338 A A ** 339 A A *** 340 A A 341 A A *** 342 A A ** 343 C D 344 A 345 A A *** 346 A A *** 347 A A *** D 348 A A *** 349 A A *** 350 A A 351 A A *** 352 A A *** 353 A A *** 354 A A 355 A A *** 356 A A ** 357 A A *** 358 A A *** 359 A A *** D 360 A A *** D 361 A A 362 A A 363 D D

- 202 047826

364 A A ** D 365 A A D 366 A (10 μM) D 367 A A ** 368 A A *** 369 A A 370 A ** 371 A A *** 372 D C 373 A A *** 374 A A *** 375 A A *** 376 A A ** 377 D D 378 A A *** 379 A A 380 A A *** 381 A A *** D 382 A A D 383 A A 384 A A *** D 385 A A *** D 386 IN A 387 A ** 388 A A *** D 389 A A *** 390 A A ** 391 A A *** 392 A A ** D 393 A A D 394 A A D 395 A A D 396 A A *** 397 A A *** D 398 A A *** 399 A A ***

- 203 047826

400 A (10 μM) D 401 WITH D 402 * 403 A A D 404 A A D 405 A A 406 ** 407 ** 408 A A *** 409 A A ** 410 A 411 A ** 412 D * 413 A A D 414 A A *** 415 A A 416 A A *** 417 WITH D 418 WITH D 419 A ** 420 A 421 A 422 A ** 423 A 424 A *** A 425 A 426 A *** A 427 A ** 428 A *** 429 A *** 430 A *** 431 A *** 432 A *** 433 A *** A 434 A *** 435 A *** 436 A ***

- 204 047826

437 A *** 438 A ** 439 A *** 440 A *** 441 A ** 442 A *** 443 A *** 444 IN * 445 A 446 A 447 A (10 μM) 448 A *** 449 A 450 A A *** 451 A A *** D 452 A A 453 A D *** * D D 454 A D A D D D 455 A A 456 A D A D D D

* ** IC50 is less than or equal to 100 nM;

* * IC50 is more than 100 nM and less than 1 μM;

* IC50 is greater than or equal to 1 μM and less than or equal to 10 μM.

A=% inhibition that is greater than or equal to 75%;

B=% inhibition, which is greater than or equal to 50% and less than 75%;

C=% inhibition, which is greater than or equal to 25% and less than 50%;

D=% inhibition, which is greater than or equal to 0% and less than 25%.

- 205 -

Claims (4)

1. A compound having the structure or a pharmaceutically acceptable salt thereof. 2. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 3. A method for treating chronic pain, pain caused by inflammation, migraine, scleroderma or non-alcoholic fatty liver disease (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 4. A method for treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.