EP4665330A1 - Plasma kallikrein inhibitors - Google Patents

Abstract

The present invention provides a compound of Formula I and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein.

Description

PLASMA KALLIKREIN INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application claims the benefit of U.S. Provisional Application No. 63/485,692, filed February 17, 2023, hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in plasma. The gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein has 58% homology to factor XI. Proteolytic activation by factor XIIa at an internal I389-R390 bond yields a heavy chain (371 amino acids) and a light chain (248 amino acids). The active site of plasma kallikrein is contained in the light chain. The light chain of plasma kallikrein reacts with protease inhibitors, including alpha 2 macroglobulin and Cl-inhibitor. Interestingly, heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III in the presence of high molecular weight kininogen (HMWK). In blood, the majority of plasma kallikrein circulates in complex with HMWK. Plasma kallikrein cleaves HMWK to liberate bradykinin. Bradykinin release results in increase of vascular permeability and vasodilation (for review, Coleman, R., "Contact Activation Pathway", Hemostasis and Thrombosis, pp.103-122, Lippincott Williams & Wilkins (2001); Schmaier A.H., "Contact Activation", Thrombosis and Hemorrhage, pp.105-128 (1998)). [0003] Patients presenting genetic deficiency on C1-inhibitor suffer from hereditary angioedema (HAE), a lifelong disease that results in intermittent swelling throughout the body, including the hands, feet, face, throat, genitals and gastrointestinal tract. Analysis of blisters arising from acute episodes have been shown to contain high levels of plasma kallikrein, and treatment with a protein-based reversible plasma kallikrein inhibitor, Ecallantide (Kalbitor), has been approved by the FDA for the treatment of acute attacks of HAE (Schneider, L, et al., J.Allergy Clin.Immunol., 120: p.416 (2007)). Recently, an oral plasma kallikrein inhibitor, Berotralstat, gained FDA approval for the prevention of HAE attacks (Zuraw, B., et al., J. Allergy Clin. Immunol.(2020). [0004] Additionally, the plasma kallikrein-kinin system is abnormally abundant in patients diagnosed with advanced diabetic macular edema (DME). Recent publications have shown that plasma kallikrein contributes to observed retinal vascular leakage and dysfunction in diabetic rodent models (A. Clermont, et al., Diabetes, 60:1590 (2011)), and that treatment with a small molecule plasma kallikrein inhibitor ameliorated the observed retinal vascular permeability and other abnormalities related to retinal blood flow. [0005] It would be desirable in the art to develop plasma kallikrein inhibitors having utility to treat a wide range of disorders, including hereditary angioedema, diabetic macular edema and diabetic retinopathy. SUMMARY OF THE INVENTION [0006] The present invention relates to compounds of Formula I: I and pharmaceutically acceptable salts thereof. The compounds of Formula I are inhibitors of plasma kallikrein, and as such may be useful in the treatment, inhibition or amelioration of one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds of this invention could further be used in combination with other therapeutically effective agents, including but not limited to, other drugs useful for the treatment of hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION [0007] The present invention relates to compounds of Formula I: I wherein is phenyl or heteroaryl, which can be monocyclic, bicyclic or tricyclic, wherein said phenyl and heteroaryl groups are optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, R^x, OR^x and SO₂R^x; is a 5-membered heteroaryl ring which is optionally substituted with one or two substituents independently selected from the group consisting of halo, cyano, R^x and OR^x; X is a bond or CR⁵R⁶; each R¹ is independently selected from the group consisting of halo, cyano, R^x and OR^x; R² is hydrogen, halo, cyclopropyl, C_1-3 alkyl, R³ is hydrogen, halo, cyano or methyl; R⁴ is hydrogen, halo, hydroxyl, methyl or CH₂OH; R⁵ is hydrogen or C_1-3 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo and hydroxyl; R⁶ is hydrogen, hydroxyl or C_1-3 alkyl; is a nitrogen-containing heterocyclyl group or a nitrogen-containing heteroaryl group, wherein said nitrogen-containing heterocyclyl and nitrogen-containing heteroaryl groups may be monocyclic or bicyclic and are optionally substituted with one or two substituents independently selected from the group consisting of oxo, R^x, hydroxyl and CONR⁹R¹⁰; is a nitrogen-containing heterocyclyl group, which is optionally substituted with one or two substituents independently selected from the group consisting of R^x and hydroxyl; R⁷ is hydrogen or methyl; R⁹ is hydrogen or C_1-3 alkyl; R¹⁰ is hydrogen or C_1-3 alkyl; R^x is hydrogen or C_1-6 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, methoxy and ethoxy; n is an integer from zero to three; or a pharmaceutically salt thereof. 25208 [0008] In an embodiment of the invention, is pyrimidinyl, phenyl, pyridinyl, cyclopentapyridinyl, tetrahydroisoquinolinyl, tetrahydrothiazolopyridinyl, quinolinyl, dihydroquinazolinyl, imidazopyridinyl, dihydrospirocyclopropaneisoquinolinyl, wherein said pyrimidinyl, phenyl, pyridinyl, cyclopentapyridinyl, tetrahydroisoquinolinyl, tetrahydrothiazolopyridinyl, quinolinyl, dihydroquinazolinyl, imidazopyridinyl, dihydrospirocyclopropaneisoquinolinyl groups are optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, R^x, OR^x and SO₂; or a pharmaceutically acceptable salt thereof. In a class of the embodiment, is pyrimidinyl. In another class of the embodiment, is phenyl. In another class of the embodiment, is pyridinyl. In another class of the embodiment, is cyclopentapyridinyl. In another class of the embodiment, is tetrahydroisoquinolinyl. In another class of the embodiment, is tetrahydrothiazolopyridinyl In another class of the embodiment, is quinolinyl. In another class of the embodiment, is dihydroquinazolinyl. In another class of the embodiment, is imidazopyridinyl. In another class of the embodiment, dihydrospirocyclopropaneisoquinolinyl. [0009] In an embodiment of the invention, is pyrazolyl or triazolyl. In a class of the embodiment, is pyrazolyl. In another class of the embodiment, is triazolyl. [0010] In an embodiment of the invention, is azetidinyl, azabicyclohexanyl, azaspirohexanyl, oxopyridinyl, oxo-azabicyclo[3.1.0]hexanyl, oxopyrimidinyl, pyridinyl, pyrrolidinyl wherein said pyrrolidinyl is optionally substituted with CONR⁹R¹⁰, and azabicyclohexanyl is optionally substituted with oxo. In a class of the embodiment, is azetidinyl. In another class of the embodiment, is azabicyclohexanyl. In a subclass of the embodiment, is oxo-azabicyclo[3.1.0]hexanyl. In another class of the embodiment, is azaspirohexanyl. In another class of the embodiment, is oxopyridinyl. In another class of the embodiment, is oxopyrimidinyl. In another class of the embodiment, is pyridinyl. In another class of the embodiment, is pyrrolidinyl, wherein said pyrrolidinyl is optionally substituted with CONR⁹R¹⁰. [0011] In an embodiment of the invention, is azetidinyl or pyrrolidinyl wherein said azetidinyl and pyrrolidinyl groups are optionally substituted with one or two substituents independenly selected from the group consisting of and R^x and hydroxyl. In a class of the embodiment, is azetidinyl which is optionally substituted with one or two substituents independenly selected from the group consisting of and R^x and hydroxyl. In another class of the embodiment, is pyrrolidinyl, which is optionally substituted with one or two substituents independenly selected from the group consisting of R^x and hydroxyl. [0012] In an embodiment of the invention, R¹ is chloro, fluoro, difluoromethyl, methoxy or cyano. In a class of the embodiment, R¹ is chloro. In another class of the embodiment, R¹ is fluoro. In another class of the embodiment, R¹ is difluoromethyl. In another class of the embodiment, R¹ is methoxy. In another class of the embodiment, R¹ is cyano. [0013] In an embodiment of the invention, R² is hydrogen. In another embodiment invention, R² is halo. In another embodiment invention, R² is cyclopropyl. In another embodiment invention, R² is C_1-3 alkyl. In another embodiment invention, R² is . In another embodiment R⁷ invention, R² is . In another embodiment invention, R² is or . [0014] In an embodiment of the invention, R³ is hydrogen, fluoro or cyano. In a class of the embodiment, R³ is hydrogen. In another class of the embodiment, R³ is fluoro. In another class of the embodiment, R³ is cyano. [0015] In an embodiment of the invention, R⁴ is hydrogen, hydroxyl or CH₂OH. In a class of the embodiment, R⁴ is hydrogen. In another class of the embodiment, R⁴ is hydroxyl. In another class of the embodiment, R⁴ is CH₂OH. [0016] In an embodiment of the invention, R⁵ is hydrogen or methyl. In a class of the embodiment, R⁵ is hydrogen. In another class of the embodiment, R⁵ is methyl. [0017] In an embodiment of the invention, R⁶ is hydrogen. [0018] In an embodiment of the invention, R⁷ is hydrogen or methyl. In a class of the embodiment, R⁷ is hydrogen. In another class of the embodiment, R⁷ is methyl. [0019] In an embodiment of the invention, n is zero. In another embodiment of the invention, n is one. In another embodiment of the invention, n is two. In another embodiment of the invention, n is three. [0020] Reference to the preferred classes and subclasses set forth above is meant to include all combinations of particular and preferred groups unless stated otherwise. [0021] Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 95, or pharmaceutically acceptable salts thereof. [0022] Also included within the scope of the present invention is a pharmaceutical composition which is comprised of a compound of Formula I as described above and a pharmaceutically acceptable carrier. The invention is also contemplated to encompass a pharmaceutical composition which is comprised of a pharmaceutically acceptable carrier and any of the compounds specifically disclosed in the present application. These and other aspects of the invention will be apparent from the teachings contained herein. [0023] The invention includes compositions for treating diseases or condition in which plasma kallikrein activity is implicated. Accordingly the invention includes compositions for treating impaired visual activity, diabetic retinopathy, wet age-related macular degeneration, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, and bleeding from postoperative surgery in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. A class of the invention includes 25208 compositions for treating hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration,diabetic macular edema, diabetic retinopathy and retinal vein occlusion. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions. [0024] The invention also includes compositions for preventing or treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents. [0025] The invention also includes compositions for treating inflammatory conditions of the eye, which includes, but is not limited to, uveitis, posterior uveitis, macular edema, acute macular degeneration, wet age-related macular degeneration, retinal detachments, retinal vein occlusion, ocular tumors, fungal infections, viral infections, multifocal choroiditis, diabetic uveitis, diabetic macular edema, diabetic retinopathy, proliferative vitreoretinopathy, sympathetic opthalmia, Vogt Koyanagi-Harada syndrome, histoplasmosis and uveal diffusion. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents. [0026] The invention also includes compositions treating posterior eye disease, which includes, but is not limited to, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents. [0027] It will be understood that the invention is directed to the compounds of structural Formula I described herein, as well as the pharmaceutically acceptable salts of the compounds of structural Formula I and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations. [0028] The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, 2- naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate and the like. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Also, included are the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. [0029] These salts can be obtained by known methods, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present invention and salts thereof may form solvates with a solvent such as water, ethanol, or glycerol. The compounds of the present invention may form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain. [0030] If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). [0031] The present invention encompasses all stereoisomeric forms of the compounds of Formula I. Unless a specific stereochemistry is indicated, the present invention is meant to comprehend all such isomeric forms of these compounds. Centers of asymmetry that are present in the compounds of Formula I can all independently of one another have (R) configuration or (S) configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both each individual enantiomer and mixtures thereof, are embraced within the Formula. When a particular configuration is depicted, that entantiomer (either (R) or (S), at that center) is intended. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of this invention. [0032] Unless a specific enantionmer or diastereomer is indicated, the invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios. Thus, enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis/trans isomerism the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before 25208 a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I, or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Where compounds of this invention are capable of tautomerization, all individual tautomers as well as mixtures thereof are included in the scope of this invention. The present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof. [0033] In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the specifically and generically described compounds. For example, different isotopic forms of hydrogen (H) include protium (1_H) and deuterium (2_H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the general process schemes and examples herein using appropriate isotopically- enriched reagents and/or intermediates. [0034] When any variable (e.g. R¹, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety. [0035] It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when 25208 comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One of ordinary skill in the art would understand that size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 5:1188-1198; Showell, G.A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558). [0036] It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase “optionally substituted” (with one or more substituents) should be understood as meaning that the group in question is either unsubstituted or may be substituted with one or more substituents. [0037] Furthermore, compounds of the present invention may exist in amorphous form and/or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I are intended to be included within the scope of the present invention. In addition, some of the compounds of the instant invention may form solvates with water (i.e., a hydrate) or common organic solvents. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhydrous forms. [0038] Also, in the case of a carboxylic acid (-COOH) or alcohol group being present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. [0039] Any pharmaceutically acceptable pro-drug modification of a compound of this invention which results in conversion in vivo to a compound within the scope of this invention is also within the scope of this invention. For example, esters can optionally be made by esterification of an available carboxylic acid group or by formation of an ester on an available hydroxy group in a compound. Similarly, labile amides can be made. Pharmaceutically acceptable esters or amides of the compounds of this invention may be prepared to act as pro-drugs which can be hydrolyzed 25208 back to an acid (or -COO- depending on the pH of the fluid or tissue where conversion takes place) or hydroxy form particularly in vivo and as such are encompassed within the scope of this invention. Examples of pharmaceutically acceptable pro-drug modifications include, but are not limited to, -C_1-6alkyl esters and –C_1-6alkyl substituted with phenyl esters. [0040] Accordingly, the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts thereof, pro-drug forms thereof, and salts of pro-drug forms thereof, where such forms are possible unless specified otherwise. [0041] Except where noted herein, the terms "alkyl" and “alkylene” are intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g., methyl, may be represented by conventional abbreviations including “Me” or CH or a symbol that is an extended bond as the termina _{" 3} l group, e.g., , ethyl may be represented by “Et” or CH₂CH₃, propyl may be represented by “Pr” or CH₂CH₂CH₃, butyl may be represented by “Bu” or CH2CH2CH2CH3, etc. “C1-4 alkyl” (or “C1-C4 alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. For example, the structures have equivalent meanings. C_1-4 alkyl includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is specified, 1-4 carbon atoms are intended for linear or branched alkyl groups. [0042] Except where noted, the term “cycloalkyl” means a monocyclic or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, “cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on. [0043] Except where noted, the term “aryl”, as used herein, represents a stable monocyclic or bicyclic ring system of up to 10 carbon atoms in each ring, wherein at least one ring is aromatic. Bicyclic aryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. Aryl groups within the scope of this definition include, but are not limited to: phenyl, indene, isoindene, naphthalene, and tetralin. 25208 [0044] Except where noted, the term “heteroaryl”, as used herein, represents a stable monocyclic or bicyclic ring system of up to 10 atoms in each ring, wherein at least one ring is aromatic, and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic heteroaryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. Heteroaryl groups within the scope of this definition include but are not limited to: azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dihydroindenyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalenyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridopyridinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxinyl, dihydropyrazoloxazinyl, dihydropyrazolyothiazinedioxidyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetra- hydroquinoline, sulfolanyl, 1,3-benzodioxolyl, 3-oxo-3,4dihydro-2N-benzo[b][1,4]thiazine, imidazopyridinyl, 2-oxo-2,3-dihydroimidazolyl, 3,4-dihydrobenzoxazinyl, 2-oxo-2,3- dihydrooxazolyl, dihydroisobenzofuranyl, 1-oxoisoindolinyl, dioxido-2,3- dihydrobenzoisothiazolyl, 2-oxopyridyl, tetrahydroisoquinolyl, tetrahydrothiazolo[5,4-c]pyridyl, 4-oxo-dihydroquinazolinyl, dihydro-1’H-spirocyclopropane-1,4’-isoquinolyl. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. [0045] The term "heterocycle" or “heterocyclyl” as used herein is intended to mean a stable nonaromatic monocyclic or bicyclic ring system of up to 10 atoms in each ring, unless otherwise specified, containing from 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO, or SO₂. Bicyclic heterocyclic ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. “Heterocyclyl” therefore includes, but is not limited to the following: azabicyclohexanyl, azaspirohexanyl, azaspirononanyl, azaspirooctanyl, azetidinyl, dioxanyl, isochromanyl, oxadiazaspirodecenyl, oxaspirooctanyl, oxazolidinonyl, 2-oxo-azabicyclo[3.1.0]hexanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofurnayl, tetrahydropyranyl, 25208 dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition. [0046] Except where noted, the term "halogen" or “halo” means fluorine, chlorine, bromine or iodine. [0047] “Celite®” (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite". [0048] Except where noted herein, structures containing substituent variables such as variable "R" below: which are depicted as not being attached to any one particular bicyclic ring carbon atom, represent structures in which the variable can be optionally attached to any bicyclic ring carbon atom. For example, variable R shown in the above structure can be attached to any one of 6 bicyclic ring carbon atoms i, ii, iii, iv, v or vi. [0049] Except where noted herein, bicyclic ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. [0050] The invention also relates to medicaments containing at least one compound of the Formula I and/or of a pharmaceutically acceptable salt of the compound of the Formula I and/or an optionally stereoisomeric form of the compound of the Formula I or a pharmaceutically acceptable salt of the stereoisomeric form of the compound of Formula I, together with a pharmaceutically suitable and pharmaceutically acceptable vehicle, additive and/or other active substances and auxiliaries. [0051] The term “patient” used herein is taken to mean mammals such as primates, humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice. [0052] The medicaments according to the invention can be administered by oral, inhalative, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents with compounds of the Formulas I and other surfaces which come into contact with blood in the body is possible. [0053] The invention also relates to a process for the production of a medicament, which comprises bringing at least one compound of the Formula I or Ia into a suitable administration form using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries. 25208 [0054] Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations having prolonged release of active substance, in whose preparation customary excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and plant oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol. [0055] The dosage regimen utilizing the plasma kallikrein inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. [0056] Oral dosages of the plasma kallikrein inhibitors, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis). For example, an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/ day. A suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg. Advantageously, the plasma kallikrein inhibitors may be administered in divided doses of two, three, or four times daily. For administration twice a day, a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg. [0057] Intravenously, the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day. Such quantities may be administered in a number of suitable ways, e.g., large volumes of low concentrations of active ingredient during one extended period of time or several 25208 times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g., once a day. Typically, a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/mL, e.g., 0.1 mg/mL, 0.3 mg/mL, and 0.6 mg/mL, and administered in amounts per day of between 0.01 mL/kg patient weight and 10.0 mL/kg patient weight, e.g., 0.1 mL/kg, 0.2 mL/kg, 0.5 mL/kg. In one example, an 80 kg patient, receiving 8 mL twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/mL, receives 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers. The choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art. [0058] Compounds of Formula I can be administered both as a monotherapy and in combination with other therapeutic agents, including but not limited to anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents. [0059] An "anti-inflammatory agent" is any agent which is directly or indirectly effective in the reduction of inflammation when administered at a therapeutically effective level. “Anti- inflammatory agent” includes, but is not limited to steroidal anti-inflammatory agents and glucocorticoids. Suitable anti-inflammatory agents include, but are not limited to, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone. [0060] An “anti-VEGF agent” is any agent which is directly or indirectly effective in inhibiting the activity of VEGF (Vascular Endothelial Growth Factor). Suitable anti-VEGF agents include, but are not limited to, bevacizumab, ranibizumab, brolucizumab and aflibercept. [0061] An “immunosuppressant agent” is any agent which is directly or indirectly effective in suppressing, or reducing, the strength of the body’s immune system. Suitable immunosuppressant agents include, but are not limited to, corticosteroids (for example, prednisone, budesonide, prednisolone), janus kinase inhibitors (for example, tofacitinib), calcineurin inhibitors (for example, cyclosporin, tacrolimus), mTOR inhibitors (for example, sirolimus, everolimus), IMDH inhibitors (for example, azathioprine, leflunomide, mycophenolate), biologics (for example, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, 25208 natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab), and monoclonal antibodies (for example, basiliximab, daclizumab). [0062] Suitable anticoagulants include, but are not limited to, factor XIa inhibitors, thrombin inhibitors, thrombin receptor antagonists, factor VIIa inhibitors, factor Xa inhibitors, factor IXa inhibitors, factor XIIa inhibitors, adenosine diphosphate antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), other anticoagulants such as aspirin, and thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies. Such anticoagulants include, for example, apixaban, dabigatran, cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel, rivaroxaban, and semuloparin. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and thrombin inhibitors. [0063] In certain embodiments the anti-inflammatory agents, anti-VEGF agents, immunosuppressant agents, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are employed in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in editions of the Physicians' Desk Reference, such as the 70th edition (2016) and earlier editions. In other embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressant agents, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are employed in lower than their conventional dosage ranges. [0064] Alternatively or additionally, one or more additional pharmacologically active agents may be administered in combination with a compound of the invention. The additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which is different from the compound of the invention, and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents when such forms are sold commercially or are otherwise chemically possible. Generally, any suitable additional active agent or agents, including but not limited to anti-hypertensive agents, additional diuretics, anti- atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and/or anti- obesity agents may be used in any combination with the compound of the invention in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of 25208 the active agents (co-administration of the separate active agents). Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin II receptor antagonists also known as angiotensin receptor blockers or ARBs, which may be in free-base, free-acid, salt or pro-drug form, such as azilsartan, e.g., azilsartan medoxomil potassium (EDARBI ^), candesartan, e.g., candesartan cilexetil (ATACAND ^), eprosartan, e.g., eprosartan mesylate (TEVETAN ^), irbesartan (AVAPRO ^), losartan, e.g., losartan potassium (COZAAR ^), olmesartan, e.g., olmesartan medoximil (BENICAR ^), telmisartan (MICARDIS ^), valsartan (DIOVAN ^), and any of these drugs used in combination with a thiazide-like diuretic such as hydrochlorothiazide (e.g., HYZAAR ^, DIOVAN HCT ^, ATACAND HCT ^), etc.); potassium sparing diuretics such as amiloride HCl, spironolactone, epleranone, triamterene, each with or without HCTZ; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors; enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5- amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635); endothelin receptor antagonists; vasodilators (e.g. nitroprusside); calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nicardipine); potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam); sympatholitics; beta- adrenergic blocking drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartate, nadolol, propranolol, sotalol, timolol); alpha adrenergic blocking drugs (e.g., doxazosin, prazosin or alpha methyldopa); central alpha adrenergic agonists; peripheral vasodilators (e.g. hydralazine); lipid lowering agents, e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), and fluvastatin (particularly the sodium salt sold in LESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin 25208 (VYTORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled release forms, and particularly niacin in combination with a DP antagonist such as laropiprant and/or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; metabolic altering agents including insulin sensitizing agents and related compounds for the treatment of diabetes such as biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones also referred to as glitazones (e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors, (e.g., sitagliptin (JANUVIA ^), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine), combination medications such as JANUMET ^ (sitagliptin with metformin), and injectable diabetes medications such as exenatide and pramlintide acetate; inhibitors of glucose uptake, such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1, SGLT-2 (e.g., ASP-1941, TS-071, BI-10773, tofogliflozin, LX-4211, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, remogliflozin and sotagliflozin), and SGLT-3; or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases including but not limited to diazoxide; and including the free-acid, free-base, and pharmaceutically acceptable salt forms, pro-drug forms, e.g., esters, and salts of pro-drugs of the above medicinal agents, where chemically possible. Trademark names of pharmaceutical drugs noted above are provided for exemplification of the marketed form of the active agent(s); such pharmaceutical drugs could be used in a separate dosage form for concurrent or sequential administration with a compound of the invention, or the active agent(s) therein could be used in a fixed dose drug combination including a compound of the invention. [0065] Typical doses of the plasma kallikrein inhibitors of the invention in combination with other suitable agents may be the same as those doses of plasma kallikrein inhibitors administered without coadministration of additional agents, or may be substantially less that those doses of plasma kallikrein inhibitors administered without coadministration of additional agents, depending on a patient’s therapeutic needs. [0066] The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat (i.e., prevent, inhibit or ameliorate) the disease condition or treat the progression of the disease in a host. [0067] The compounds of the invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the invention can also be administered in combination with an additional therapeutic agent, as defined below, to a mammal in a therapeutically effective amount. When administered in a combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul.1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of each of the compounds when administered individually as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared with the individual components. [0068] By “administered in combination” or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. The administration of each component does not need to be via the same route of administration; for example, one component can be administered orally, and another can be delivered into the vitreous of the eye. [0069] The present invention is not limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the relevant art and are intended to fall within the scope of the appended claims. GENERAL METHODS [0070] Compounds of the present invention may be prepared using conventional techniques or according to the methodology outlined in the following general synthetic schemes. One skilled in the art can vary the procedures and reagents shown to arrive at similar intermediates and/or final compounds. [0071] NMR spectra were measured on VARIAN or Bruker NMR Systems (400, 500 or 600 MHz). Chemical shifts are reported in ppm downfield and up field from tetramethylsilane (TMS) and referenced to either internal TMS or solvent resonances (¹H NMR: δ 7.27 for CDCl₃, δ 2.50 for (CD₃)(CHD₂)SO, and ¹³C NMR: δ 77.02 for CDCl₃, δ 39.51 for (CD₃)₂SO. Coupling constants (J) are expressed in hertz (Hz), and spin multiplicities are given as s (singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet), and br (broad). Chiral resolutions can be performed on either Waters Thar 80 SFC or Berger MG II preparative SFC systems. LC-MS data can be recorded on SHIMADAZU LC-MS-2020, SHIMADAZU LC-MS-2010, or Agilent 1100 series LC-MS, Agilent Prime-1260, or Waters Acquity LC-MS instruments using C18 columns employing a MeCN gradient in water containing 0.02 to 0.1% TFA. UV detections were at 220 and/or 254 nm and ESI ionization was used for MS detection. [0072] When chiral resolution was achieved by chromatography using chiral columns, the chiral columns used for SFC chiral resolutions are listed in tables. Some of the chiral columns used were CHIRALPAK AD, CHIRALCEL OJ, CHIRALPAK AS, CHIRALPAK AY, CHIRALPAK IA, CHIRALPAK AD-H, and CHIRALPAK AS-H. Henceforth, they will be referred by their two or three letter abbreviations. As a convention, the fast-eluting isomer from a chiral resolution is always listed first in this table followed immediately by the slower-eluting isomer from the same resolution. If more than two isomers were separated, they will be always listed in the tables in order they were eluted, such as Peak 1 followed by Peak 2, Peak 3 and so on. A * symbol near a chiral center in a structure denotes that this chiral center was resolved by chiral resolution without its stereochemical configuration unambiguously determined. [0073] Also, UV is ultraviolet; Å is angstroms; W is watts; wt. % is percentage by weight; x g is times gravity; α_D is the specific rotation of polarized light at 589 nm; % w/v is percentage in weight of the former agent relative to the volume of the latter agent; % v/v is percentage in volume of the former agent relative to the volume of the latter agent; cpm is counts per minute; δ_H is chemical shift; and a mass spectrum obtained by ES-MS may be denoted herein by “LC- MS”; m/z is mass to charge ratio; n is normal; nm is nanometer; nM is nanomolar. [0074] Several catalysts and ligands are used in the following procedures. “XANTPHOS” is also known as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. “XANTPHOS NiG3” is also known as [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate. “BrettPhos” is also known as 2- (dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl and the “BrettPhos Pd G3” is also known as [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1 ′-biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate. These catalysts and ligands are available from Millipore Sigma. 25208 [0075] For purposes of this specification, the following abbreviations have the indicated meanings: Ac acetyl ACN acetonitrile AcOH or HOAc acetic acid APCI atmospheric-pressure chemical ionization aq aqueous Bn benzyl Boc or BOC tert-butoxycarbonyl br broad Brettphos 2-(dicyclohexylphosphino)3,6-dimethoxy- 2′,4′,6′-triisopropyl-1,1′-biphenyl BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy- 2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′- amino-1,1′ -biphenyl)]palladium(II) methanesulfonate Bu butyl Bz benzoyl calc'd calculated cBu cyclobutyl Cbz benyzloxycarbonyl cHep cycloheptyl cHex cyclohexyl cPen cyclopentyl cPr cyclopropyl d doublet DAST (diethylamino)sulfur trifluoride dba dibenzylideneacetone DBAD Di-tert-butyl azodicarboxylate ^DBU _{1,8-diazabicyclo[5.4.0]undec-7-ene} DCE 1,2-dichloroethane 25208 DCM dichloromethane dd doublet of doublets ddd doublet of a doublet of doublets DIAD diisopropyl azodicarboxylate DIBAL or Dibal-H diisobutylaluminum hydride DIEA, DIPEA, or N,N-diisopropylethylamine Hünig’s base DMA 1,2-dimethylacetamide DMAP 4-dimethylaminopyridine DMF dimethylformamide DMP Dess-Martin periodinane (1,1,1-triacetoxy)- 1,1-dihydro-1,2-benziodoxol-3(1H)-one DMS Dimethyl sulfide DMSO dimethyl sulfoxide DPPA Diphenyl phosphoryl azide dppf 1,1'-bis(diphenylphosphino)ferrocene dt doublet of triplets DTT dithiothreitol DPy 2,2′-Dipyridine EDC 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide EDTA ethylenediamine tetraacetic acid ESI electrospray ionization Et ethyl EtOH ethanol EtOAc ethyl acetate g grams GST glutathione S-transferase h hour HATU N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1- yl)uronium hexafluorophosphate 25208 HMDS 1,1,1,3,3,3-hexamethyldisilazane HOBt 1-hydroxybenzotriazole HPLC high-performance liquid chromatography IPA isopropanol iPr isopropyl LC liquid chromatography LCMS liquid chromatography mass spectrometry LDA lithium diisopropylamide mCPBA m-choroperoxybenzoic acid Me methyl MeOH methanol mg milligrams min minute μL microliters mL milliliters mmol millimoles MS mass spectrometry Ms methanesulfonyl (mesyl) MTBE methyl tert-butyl ether NBS N-bromosuccinimide NMO N-methylmorpholine N-oxide NMP n-methyl-2-pyrrolidone NMR nuclear magnetic resonance spectroscopy obsv'd observed p pentet Ph phenyl Pr propyl PS polystyrene q quartet qd quadruplet of doublets quin quintet rac racemic mixture RT or rt room temperature (ambient, about 25 ºC) s singlet satd saturated sxt sextet SFC supercritical fluid chromatography S-phos 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl t triplet TBAF tert-butyl ammonium fluoride TBDPSCl tert-butyldiphenylchlorosilane TBS or TBDMS tert-butyldimethyl silyl TBSCl tert-butyldimethylsilyl chloride ^tBu tert-butyl ^tBu X-phos 2-di-tert-butylphosphino-2′,4′,6′- triisopropylbiphenyl td triplet of doublets TEA triethylamine (Et₃N) Tf triflate TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl Tris tris(hydroxymethyl)aminomethane Ts toluenesulfonyl (tolyl) TSA p-toluenesulfonic acid tt triplet of triplets X-phos 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl Xantphos 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene Starting materials used were obtained from commercial sources, prepared in other examples, or prepared as known in the literature, unless otherwise noted. [0076] The methods used for the preparation of the compounds of this invention are illustrated by the following schemes. Scheme 1. i^midazole BocHN ⁴ [Ni], Zn R n Ar I [0077] Compounds of formula (I) are prepared from an acid such as 1a.1a is converted to 1b by formation of the acid chloride followed by treatment with a reagent such as sodium azide. Formation of the Boc-protected amine followed by reduction with a reagent such as sodium borohydride provides 1c. Generation of the alkyl iodide followed by Ni-mediated reductive coupling with an aryl halide and deprotection provides intermediates such as I. Scheme 2. [0078] Compounds of the general formula (II) are prepared from a cyclic ketone such as 2a. Addition of an arylorganometallic, provides tertiary alcohol 2a. Elimination and subsequent hydrogenation provide intermediates such as II. Scheme 3. 25208 [0079] General synthesis of multiple embodiments of the present invention are summarized in Scheme 3 which depicts the preparation of compounds III from intermediate 3a. Amide coupling of an acid such as 3a with an amine 3b using a reagent such as HATU provides III. Scheme 4. [0080] General synthesis of multiple embodiments of the present invention are summarized in Scheme 4 which depicts the preparation of compounds IV from intermediate 4a and 4b. Mitsunobu reaction of alcohol 4a with a pyrazole such as 4b using a reagent such as diisopropyl azodicarboxylate and triphenylphosphine, followed by ester hydrolysis provides acid 4c. Amide coupling of 4c with an amine such as 4d using a reagent such as N,N,N',N'-tetramethyl-O-(7- azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) followed by oxidation provides 4e. Treatment of sulfone 4e with an amine such as 4f under basic conditions provide IV. Scheme 5. R is any suitable group a^{s defined in Formula I} [0081] General synthesis of multiple embodiments of the present invention are summarized in Scheme 5 which depicts the preparation of compounds V from intermediates 5a and 5b. The Mitsunobu reaction product of alcohol 5a and pyrazole 5b was treated with an amine such as 5c under basic conditions to provide acid 5d. Amide coupling of 5d with an amine such as 5e using 25208 a reagent such as N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) provide II. Scheme 6. [0082] General synthesis of multiple embodiments of the present invention are summarized in Scheme 6 which depicts the preparation of compounds VI from intermediates 6a and 6b. The Mitsunobu reaction product of alcohol 6a and pyrazole 6b was treated with a base such at LiOH to provide the ester hydrolysis product, acid 6c. Amide coupling product of acid 6c and amine 6d was treated with an oxidation reagent such as meta-chloroperoxybenzoic acid (mCPBA) to provide sulfone 6e. Treatment of 6e with an amine such as 6f under basic conditions, followed by oxidation with a reagent such as Dess-Martin periodinane (DMP) provides aldehyde 6g. Reductive amination of 6g with amine 6f using a reagent such as sodium triacetoxyborohydride provide VI. Scheme 7. [0083] General synthesis of multiple embodiments of the present invention are summarized in Scheme 7 which depicts the preparation of compounds VII from intermediate 7a. Generation of an intermediate azide from 7a using a reagent such as diphenyl phosphoryl azide and DBU, followed by treatment with alkyne 7b under Cu-catalyzed conditions provide triazole 7c. Treatment of 7c with an amine such as 7d under basic conditions, provided acid 7e. Amide 25208 coupling of 7e with an amine such as 7f using a reagent such as N,N,N',N'-tetramethyl-O-(7- azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) provide VII. Scheme 8. [0084] General synthesis of multiple embodiments of the present invention are summarized in Scheme 8 which depicts the preparation of compounds VIII from intermediate 8a. Generation of an intermediate azide from 8a using a reagent such as diphenyl phosphoryl azide and DBU, followed by treatment with alkyne 8b under Cu-catalyzed conditions provide triazole 8c. Ester hydrolysis followed by coupling with amine 8d using a reagent such at HATU provides 8e. Oxidation with a reagent, such as mCPBA, followed by treatment with amine 8f under basic conditions provide VIII. Scheme 9. [0085] General synthesis of multiple embodiments of the present invention are summarized in Scheme 9 which depicts the preparation of compounds IX from intermediate 9a. Reduction of a ketone such as 9a, followed by Mitsunobu reaction with a heterocycle such as 9c and treatment with an amine such as 9d provides core 9e. Ester hydrolysis followed by coupling with amine 9f with a regent such as HATU provides IX. Scheme 10. 25208 [0086] General synthesis of multiple embodiments of the present invention are summarized in Scheme 10 which depicts the preparation of compounds X from intermediate 10a. Treatment of 10a with an amine under basic conditions, followed by Suzuki coupling with a reagent such as potassium vinyltrifluoroborate provide intermediate 10c. Dihydroxylation of 10c followed by mono-protection with TBDPSCl provides secondary alcohol 10d. The Mitsunobu reaction product of 10d and pyrazole 10e was treated with basic conditions to provide acid 10f. Amide coupling of 10f with an amine such as 10g provide X. INTERMEDIATES Intermediate A 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid Step 1: 2-(Azetidin-1-yl)-5-(bromomethyl)pyrimidine: [0087] To a solution of [2-(azetidin-1-yl)pyrimidin-5-yl]methanol (80.0 g, 484 mmol, 1.00 equiv) in DCM (1.60 L) cooled to 0 ^oC, was added tribromophosphane (144 g, 533 mmol, 1.10 equiv) dropwise. The resulting solution was stirred for 2 h at 25 ^oC. The solids were collected by filtration to provide the title compound. 25208 Step 2: Ethyl 1-((2-(azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylate: [0088] To a solution of ethyl 1H-pyrazole-4-carboxylate (59.0 g, 421 mmol, 1.20 equiv) in DMF (800 mL), was added potassium carbonate (97.7 g, 701 mmol, 2.00 equiv) and 2-(azetidin- 1-yl)-5-(bromomethyl)pyrimidine (80.0 g, 351 mmol, 1.00 equiv). The resulting solution was stirred for overnight at 50 ^oC. The reaction was quenched by the addition of water/ice. The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was purified by flash silica gel chromatography (30% EtOAc/petroleum ether) to provide the title compound. Step 3: 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid: [0089] To a solution of ethyl 1-[[2-(azetidin-1-yl)pyrimidin-5-yl]methyl]-1H-pyrazole-4- carboxylate (50.0 g, 174 mmol, 1.00 equiv) in THF (600 mL) and H₂O (200 mL) was added LiOH (16.7 g, 696 mmol, 4.00 equiv). The resulting solution was stirred for overnight at 25 ^oC. The resulting mixture was concentrated under vacuum. The reaction mixture was cooled to 0 ^oC with a water/ice bath. The pH value of the solution was adjusted to 3-4 with HCl. The solids were collected by filtration to provide the title compound. MS: 260 (M+1) Intermediate B 1-(4-((2-Oxopyridin-1(2H)-yl)methyl)benzyl)- pyrazole-4-carboxylic acid Step 1: 1-(4-(Bromomethyl)benzyl)pyridin-2 -one [0090] To a solution of pyridin-2(1H)-one g, 21.0 mmol) in acetonitrile (116 mL) was added 1,4-bis(bromomethyl)benzene (16.7 g, 63.1 mmol) and potassium carbonate (2.91 g, 21.0 mmol) The solution was heated to 80 °C for 16 h, then cooled and diluted with water (300 mL). The precipitate was collected by filtration and washed with EtOH. The filtrate was extracted with DCM and the combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and concentrated The residue was purified by flash silica gel chromatography (0-100% EtOAc/Hexane) to give the title compound. MS = 279.8 (M+1). 25208 Step 2: Ethyl 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate [0091] To a suspension of ethyl 1H-pyrazole-4-carboxylate (252 mg, 1.80 mmol) and cesium carbonate (1.47 g, 4.50 mmol) in DMF (7.5 mL) was added 1-(4-(bromomethyl)benzyl)pyridin- 2(1H)-one (417 mg, 1.50 mmol) and the mixture was heated at 50 °C for 18 h. The mixture was cooled, diluted with ethyl acetate, washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash silica gel chromatography (0-30% MeOH/CH₂Cl₂) to give the title compound. MS = 337.9 (M+1). Step 3: 1-(4-((2-Oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid [0092] To a solution of ethyl 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4- carboxylate (450 mg, 1.33 mmol) in tetrahydrofuran (6.0 mL) and water (6.0 mL) was added lithium hydroxide (280 mg, 6.67 mmol) and the reaction was heated to 50 °C for 48 h. The mixture was acidified with 1N HCl to pH 2. The mixture was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and concentrated to provide the title compound. MS = 309.9 (M+1). Intermediate C Ethyl 1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H-pyrazole-4-carboxylate Step 1: 4-(Methoxycarbonyl)-2-methylbenzoic acid [0093] A solution of methyl 4-iodo-3-methylbenzoate (10.0 g, 36.2 mmol) in THF (200 mL) under nitrogen was cooled to -20 °C, a solution of isopropylmagnesium chloride (29.3 mL, 38.0 mmol) (1.3 M in THF) was added dropwise and the suspension was stirred at -20 °C for 1 h. CO₂ (g) was bubbled through the mixture and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and water was added, the pH adjusted to 3 by addition of 3 M HCl. The mixture was extracted with DCM and the combined organic layers dried over Na₂SO₄ and concentrated to give crude product, which was purified by flash silica gel chromatography (0-50% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8.3 Hz, 1H), 7.95 (s, 1H), 7.93 (d, J=8.3 Hz, 1H), 3.95 (s, 3H), 2.23 (s, 3 H). 25208 Step 2: 2-(Difluoromethyl)-4-(methoxycarbonyl)benzoic acid [0094] To a solution of 4-(methoxycarbonyl)-2-methylbenzoic acid (12.0 g, 61.8 mmol) in ACN (200 mL) and water (200 mL) was added potassium persulfate (20.05 g, 74.2 mmol), 1- chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (131 g, 371 mmol) and silver nitrate (2.10 g, 12.4 mmol). The resulting mixture was stirred at 80 °C for 6 h. The pH of the reaction mixture was adjusted to pH 3-4 by addition of 2 M HCl solution and then the mixture was extracted with DCM. The combined organic layers were dried over Na₂SO₄ and concentrated to give crude product, which was purified by flash silica gel chromatography (0- 30% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 8.14-8.17 (m, 1H), 8.06-8.12 (m, 1H), 7.35-7.69 (m, 1H), 3.93 (s, 3H). Step 3: Methyl 3-(difluoromethyl)-4-(hydroxymethyl)benzoate [0095] To a solution of 2-(difluoromethyl)-4-(methoxycarbonyl)benzoic acid (7.00 g, 30.4 mmol) in THF (70 mL) was added BH₃·THF (91 mL, 91 mmol) (1 M in THF) at 0 °C. The resulting mixture was stirred at rt for 3 h. Water was added into the mixture and the pH of the aqueous was adjusted to 3-4 by addition of 2 M HCl solution and extracted with DCM. The combined organic layers were dried (Na₂SO₄) and concentrated to give the title compound which was used in next step directly.¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 8.07 (br d, J=7.8 Hz, 1H), 7.57 (br d, J=7.8 Hz, 1H), 6.66-7.05 (m, 1H), 4.84 (s, 2H), 3.87 (s, 3H). Step 4: Methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)benzoate [0096] To a solution of methyl 3-(difluoromethyl)-4-(hydroxymethyl)benzoate (5.50 g, 25.4 mmol) in THF (70 mL) was added imidazole (5.20 g, 76.0 mmol) and TBSCl (11.5 g, 76.0 mmol) at rt. The resulting mixture was stirred at rt for 3 h. The mixture was diluted by EtOAc, washed by water and brine, dried over Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give crude product, which was purified by flash silica gel chromatography (0-10% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 8.04 (br d, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 6.63-6.97 (m, 1H), 4.82 (s, 2H), 3.85 (s, 3H), 0.85 (s, 9H), 0.02 (s, 6H). Step 5: (4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)phenyl)methanol [0097] To a solution of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-3- (difluoromethyl)benzoate (6.50 g, 19.7 mmol) in THF (60 ml) was added diisobutylaluminum 25208 hydride (59.0 mL, 59.0 mmol) at 0 °C, then the mixture was stirred at 0 °C for 1 h. The mixture was diluted by THF and aq. NaOH (15%) was added at 0 °C till the salts are precipitated off gradually. Na₂SO₄ was added and filtered and the filtrate was concentrated in a vacuum to give crude product, which was purified by flash silica gel chromatography (0-50% EtOAc/petroleum ether) to the title compound.¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.37-7.42 (m, 1H), 7.33-7.36 (m, 1H), 6.62-7.02 (m, 1H), 4.75 (s, 2H), 4.63 (s, 2H), 0.83-0.85 (m, 9H), 0.00 (s, 6H). Step 6: Ethyl 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)benzyl)-1H- pyrazole-4-carboxylate [0098] In a round bottom flask, to a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)-3- (difluoromethyl)phenyl)methanol (4.60 g, 15.2 mmol), ethyl 1H-pyrazole-4-carboxylate (4.26 g, 30.4 mmol) and Ph₃P (7.98 g, 30.4 mmol) in toluene (50 ml) was added DBAD (7.00 g, 30.4 mmol) at rt. The mixture was stirred at 80 °C for 3 h. The mixture was concentrated in a vacuum to give crude product. The residue was purified by flash silica gel chromatography (0-20% EtOAc/petroleum ether) to give ethyl the title compound. MS = 466.2 (M+1+41). Step 7: Ethyl 1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H-pyrazole-4-carboxylate [0099] In a round bottom flask, to a solution of ethyl 1-(4-(((tert- butyldimethylsilyl)oxy)methyl)-3-(difluoromethyl)benzyl)-1H-pyrazole-4-carboxylate (5.50 g, 13.0 mmol) in MeOH (50 mL) was added HCl/MeOH (4N, 10 mL, 40.0 mmol) at rt. The mixture was stirred at rt for 1 h. The mixture was concentrated in a vacuum to give crude product. The residue was purified by flash silica gel chromatography (0-50% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 7.94 (s, 1H), 7.88 (s, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.46 (s, 1H), 7.33 (br d, J=8.3 Hz, 1H), 6.72-7.08 (m, 1H), 5.33 (s, 2H), 4.83 (br d, J=3.1 Hz, 2H), 4.26-4.30 (m, 2H), 1.33 (t, J=7.2 Hz, 3H). Intermediate D tert-Butyl 1-(1-(trifluoro-4-boranyl)ethyl)- pyrazole-4-carboxylate, potassium salt 25208 Step 1: (1-(4-(tert-Butoxycarbonyl)-1H-pyrazol-1-yl)ethyl)boronic acid [0100] To a solution of tert-butyl 1H-pyrazole-4-carboxylate (95.0 g, 565 mmol) at 0 °C in DMF (1L) was added NaH (27.1 g, 678 mmol, 60% dispersion in mineral spirits). The reaction was stirred for 1 h at 0 °C, then 2-(1-iodoethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (239 g, 847 mmol) was added at 0 °C. The reaction was stirred at rt for 15 h. MTBE was added and the mixture was stirred at rt for 30 min. The mixture was filtered and concentrated to afford the title compound. MS = 241.3 (M+1). Step 2: tert-Butyl 1-(1-(trifluoro-l4-boranyl)ethyl)- pyrazole-4-carboxylate, potassium salt [0101] To a solution of (1-(4-(tert- - pyrazol-1-yl)ethyl)boronic acid (180 g, 750 mmol) in MeOH (1.80 L) at rt was added KHF₂ (234 g, 3.00 mmol) in H₂O (900 mL). The solution was stirred at rt for 12 h and concentrated to give a residue. Acetone was added and the mixture at rt for 1 h. The mixture was filtered and concentrated, then purified by recrystallization from MTBE to provide the title compound.¹H NMR (400 MHz, d₆-DMSO) δ 7.86 (s, 1H), 7.56 (s, 1H), 3.21 (br d, J = 3.4 Hz, 1H), 1.45 (s, 9H), 1.12 (d, J =7.2 Hz, 3H) Intermediate E 1-(1-(2'-(tert-butoxycarbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'- yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid Step 1. tert-Butyl 7'-acetyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate [0102] tert-Butyl 7'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (1.10 g, 3.25 mmol) was mixed with tributyl(1-ethoxyvinyl)stannane (1.50 g, 4.23 mmol) and palladium-tetrakis(triphenylphosphine) (188 mg, 0.163 mmol) in a microwave reaction vial. The vial was capped, and air was removed by vacuum, and back-filled with nitrogen (three times). Toluene (8 mL) was introduced with syringe. The resulting mixture was heated at 90 °C for 3 days. The mixture was concentrated and purified by flash silica gel chromatography (0-30% EtOAc/petroleum ether) to give the title compound. MS= 246.2 (M+1) 25208 Step 2. tert-Butyl 7'-(1-hydroxyethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)- carboxylate [0103] tert-Butyl 7'-acetyl-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (900 mg, 3.00 mmol) in MeOH (15 ml) was mixed with NaBH₄ (170 mg, 4.50 mmol). The resulting mixture was stirred at rt overnight. Mixture was quenched by addition of AcOH, diluted with acetone and mixed with silica gel, then concentrated, and purified by flash silica gel chromatography (0-100% EtOAc/hexane) to give the product. MS= 247.2 (M-57+1) Step 3. tert-Butyl 7'-(1-azidoethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)- carboxylate [0104] tert-Butyl 7'-(1-hydroxyethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)- carboxylate (830 mg, 2.74 mmol) was mixed with DBU (0.50 mL, 3.3 mmol) in DCM (0.9 mL). DPPA (903 mg, 3.28 mmol) in DCM (0.9 mL) was added. The resulting mixture was stirred at rt overnight. Mixture was purified by flash silica gel chromatography (0-100% EtOAc/petroleum ether) to give the title compound. MS= 327.2 (M-1) Step 4. tert-Butyl 7'-(1-(4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)ethyl)-1'H-spiro[cyclopropane- 1,4'-isoquinoline]-2'(3'H)-carboxylate [0105] tert-Butyl 7'-(1-azidoethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)- carboxylate (500 mg, 1.52 mmol) was mixed with ethyl propiolate (231 µl, 2.28 mmol) in EtOH (3.8 mL). A solution of copper(II) sulfate pentahydrate (38.0 mg, 0.152 mmol) in water (1.9 mL) was added, followed by a solution of (S)-5-((S)-1,2-dihydroxyethyl)-3-hydroxyfuran-2(5H)-one, sodium salt (27.9 mg, 0.152 mmol) in water (1.9 mL). The mixture was stirred at rt for 15 h, then concentrated. The product was extracted with EtOAc and washed with water and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude mixture was purified by flash silica gel chromatography (0-100% EtOAc/petroleum ether) to give the title compound. MS= 427.2 (M+1) Step 5.1-(1-(2'-(tert-Butoxycarbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'- yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid [0106] tert-Butyl 7'-(1-(4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)ethyl)-1'H- spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (450 mg, 1.05 mmol) was stirred with LiOH (125 mg, 5.24 mmol) in THF (2.6 mL) and water (0.9 mL) at 40 °C for 4 h. The mixture 25208 was concentrated, and co-evaporated with toluene by rotavapor to dryness to give the product. The lithium salt was used in the next step without further purification. MS= 399.3 (M+1) Intermediate F N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide Step 1.5-(tert-Butyl)-2-methyl 6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate [0107] 5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (900 mg, 3.20 mmol) was dissolved in a mixed solvent of DCM (11 mL) and MeOH (5.7 mL). Trimethylsilyldiazomethane solution (1.7 mL, 3.4 mmol, 2 M in hexane) was added dropwise. The resulting mixture was stirred at rt for 1 h. Mixture was concentrated to dryness and was purified by flash silica gel chromatography (0-60% EtOAc/isohexane) to provide the title compound. MS= 299.6 (M+1) Step 2. tert-Butyl 2-(hydroxymethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5 -carboxylate [0108] 5-(tert-Butyl)-2-methyl 6,7-dihydrothiazolo[5,4-c]pyridine-2,5 - (670 mg, 2.20 mmol) in mixed solvent of THF (3.7 mL) and MeOH (3.7 mL) was cooled to 0 °C. NaBH₄ (250 mg, 6.70 mmol) was added in portions, then stirred at rt overnight.1M HCl was added slowly to quench the reaction. Product was extracted with EtOAc. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0-100% EtOAc/Hexanes) to give the title compound. MS= 271.6 (M+1) Step 3. tert-Butyl 2-(azidomethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate [0109] tert-Butyl 2-(hydroxymethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (370 mg, 1.37 mmol) was mixed with DBU (0.25 mL, 1.6 mmol) in toluene (1.4 mL). DPPA (450 mg, 1.64 mmol) in DCM (1.4 mL) was added. The resulting mixture was stirred at rt for 15 h. Mixture was diluted with EtOAc, washed with diluted HCl solution and brine. The organic 25208 layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash silica gel chromatography (0-100% EtOAc/Hexanes) to give the title compound. MS= 296.6 (M+1) Step 4. tert-Butyl 2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6,7-dihydrothiazolo[5,4- c]pyridine-5 -carboxylate [0110] tert- 2-(azidomethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (230 mg, 0.780 mmol) was mixed with ethyl propiolate (0.16 mL, 1.6 mmol) in EtOH (1.9 mL). A solution of copper(II) sulfate pentahydrate (47 mg, 0.19 mmol) in water (1 mL) was added. Then a solution of sodium ascorbate (28.5 mg, 0.156 mmol) in water (1 mL) was added dropwise, and the mixture was stirred at rt overnight. The product was extracted with EtOAc and washed with water and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash silica gel chromatography (0-100% EtOAc/Hexane) to give the title compound. MS= 394.3 (M+1) Step 5.1-((5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)methyl)-1H- 1,2,3-triazole-4-carboxylic acid [0111] tert-Butyl 2-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-6,7- dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.30 g, 0.77 mmol) was mixed with LiOH (55 mg, 2.3 mmol) in THF (2 ml) and water (0.5 ml). Mixture was acidified with diluted HCl solution, and the product was extracted with EtOAc. The organic layer was separated, washed with brine. After being dried over anhydrous sodium sulfate, the solution was filtered and concentrated to give the title compound. MS= 366.3 (M+1) Step 6. tert-Butyl 2-((4-(((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamoyl)-1H-1,2,3- triazol-1-yl)methyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5 -carboxylate [0112] 1-((5-(tert-Butoxycarbonyl)-4,5,6,7- [5,4-c]pyridin-2-yl)methyl)-1H- 1,2,3-triazole-4-carboxylic acid (170 mg, 0.470 mmol) was mixed with 2-((cis)-3- aminocyclobutyl)-4-chlorobenzonitrile, HCl (113 mg, 0.47 mmol), Hunig's base (0.24 mL, 1.4 mmol) in DMF (1.9 mL). HATU (177 mg, 0.470 mmol) was added. The resulting mixture was stirred at for 2 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by 25208 flash silica gel chromatography (0-100% EtOAc/Hexanes) to give the title compound. MS= 554.3 (M+1) Step 7. N- 3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin- -1H-1,2,3-triazole-4-carboxamide [0113] tert-Butyl 2-((4-(((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamoyl)-1H-1,2,3- triazol-1-yl)methyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.25 g, 0.46 mmol) was mixed with 4N HCl in dioxane (5.8 ml, 23 mmol). The resulting mixture was stirred at for 2 h. The mixture was concentrated to dryness and used directly in the next step. MS = 454.3 (M+H). Intermediate G tert-Butyl (3-(3-chlorophenyl)cyclobutyl)carbamate Step 1: tert-Butyl (3-oxocyclobutyl)carbamate: [0114] To a solution of 3-oxocyclobutanecarboxylic acid (331 g, 2.90 mol, 1.0 equiv) in toluene (6 L) was added triethylamine (323 g, 3.19 mol, 1.1 equiv). The solution was cooled below 10 °C and diphenylphosphoryl azide (DPPA) (878 g, 3.19 mol, 1.1 equiv) was added dropwise over 15 minutes under N₂. The solution was warmed to rt and stirred overnight. The reaction mixture was transferred to a separator funnel, washed with aqueous NaHCO₃, water, brine, dried over MgSO₄ and filtered. The filtrate was transferred to a 10 L three neck flask and tert-butanol (516 g, 6.96 mol, 2.4 equiv) was added. The mixture was then heated at reflux overnight. Upon completion, the reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified using flash silica gel chromatography (25-40% EtOAc/hexanes) to provide the title compound. Step 2: tert-Butyl (3-(2-tosylhydrazono)cyclobutyl)carbamate: [0115] To a solution of 4-methylbenzene-1-sulfonohydrazide (254.4 g, 1365 mmol, 1.00 equiv) in MeOH (5.10 L, 125 mol, 91.5 equiv) was added tert-butyl N-(3-oxocyclobutyl)carbamate (253 25208 g, 1.37 mol, 1 equiv). The resulting solution was stirred for 3 h at rt. The solids were collected by filtration to provide the title compound. Step 3: tert-Butyl (3-(3-chlorophenyl)cyclobutyl)carbamate: [0116] To a solution of tert-butyl N-[3-[(4-methylbenzenesulfonamido)imino]- cyclobutyl]carbamate (385 g, 1.0 mol, 1 equiv) in dioxane (5.8 L) was added potassium carbonate (228 g, 1.64 mmol, 1.50 equiv) and (3-chlorophenyl)boronic acid (256 g, 1.634 mmol, 1.50 equiv). The resulting solution was stirred overnight at 100 ^oC. The reaction was then quenched by the addition of water. The resulting solution was extracted with EtOAc. The solids were filtered and the filtrate was dried over anhydrous magnesium sulfate and concentrated. The residue was applied onto a silica gel column with DCM/petroleum ether (1:1). The crude product was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide cis and trans tert-butyl N-[3-(3-chlorophenyl)cyclobutyl]carbamate. MS = 226.1 (M-55). Step 4: 3-(3-Chlorophenyl)cyclobutan-1-amine: [0117] HCl/dioxane (1.5 mL, 6.0 mmol, 4N) was added to the solution of tert-butyl (3-(3- chlorophenyl)cyclobutyl)carbamate (280 mg, 0.994 mmol) in DCM (10 mL), the resultant mixture was stirred at rt for 4 h. The reaction mixture was concentrated in vacuo to give the title compound which was used into next step without further purification. MS = 182.1 (M+1). Intermediate H 2-( -3-Aminocyclobutyl)-4-chlorobenzonitrile with 2,2,2-trifluoroacetic acid (Scheme 1) Step 1: 3-Oxocyclobutane-1-carbonyl chloride: [0118] To a solution of 3-oxocyclobutanecarboxylic acid (122 g, 1.07 mol, 1.0 eq) in dry DCM (1.2 L) at 0 °C was added SOCl₂ (233 mL, 3.21 mol, 3.0 eq) dropwise. The mixture was heated to reflux for 1.5 h and then evaporated in vacuo to provide title compound. 25208 Step 2: 3-Oxocyclobutane-1-carbonyl azide: [0119] To a solution of 3-oxocyclobutanecarbonyl chloride (99.0 g, 749 mmol, 1.0 eq) in acetone (1.0 L) at 0 °C, a solution of NaN₃ (58.4 g, 899 mmol, 1.2 eq) in H₂O (200 mL) at 0 °C was added dropwise. After addition, the mixture was stirred for 1 h and treated with ice (110 g). The resulting mixture was extracted with Et₂O. Combined organic layers were washed with brine, dried over anhydrous Mg₂SO₄ and concentrated to reduced volume. Toluene was added into the residue and the mixture was co-evaporated twice to remove Et₂O (about 30 mL solution left each time to avoid explosion), which provided title compound. Step 3: tert-Butyl (3-oxocyclobutyl)carbamate: [0120] To a solution of 3-oxocyclobutane-1-carbonyl azide in toluene from the previous step, was added toluene (800 mL). The resulting solution was heated to 90 °C until the evolution of N₂ ceased. Next, ^tBuOH (1 L) was added into the reaction mixture and the resulting mixture was stirred overnight at 90 °C. The mixture was cooled and concentrated. The crude residue was purified using flash silica gel chromatography (17% EtOAc/petroleum ether) to provide title compound. Step 4: tert-Butyl (3-hydroxycyclobutyl)carbamate: [0121] To a solution of tert-butyl N-(3-oxocyclobutyl)carbamate (95.0 g, 503 mmol, 1.0 eq) in THF (950 mL) and MeOH (475 mL) cooled to 0 ^oC was added NaBH₄ (38.0 g, 1.01 mol, 1.0 eq), in portions. The mixture was stirred for 1 h at rt. The reaction solution was quenched by addition of 1 L NH₄Cl (aq), THF and MeOH in the solution was evaporated and extracted with DCM. The organic layers were combined and washed with brine. The organic layer was dried by Na₂SO₄ and concentrated under vacuum to provide the title compound Step 5: tert-Butyl (3-iodocyclobutyl)carbamate: [0122] To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (88.9 g, 473 mmol, 1.0 eq) in in DCM (900 mL) was added I₂ (144 g, 567 mmol, 1.2 eq), PPh₃ (148.6 g, 567.4 mmol, 1.2 eq), and imidazole (38.6 g, 567 mmol, 1.2 eq). The reaction mixture was stirred at rt 12 h. The mixture was diluted with H₂O, then filtered, and the liquid was extracted with DCM. The organic layers were combined and washed with brine. The organic layer was dried by Na₂SO₄ and concentrated under vacuum. The residue was purified by flash silica gel chromatography (3% EtOAc/petroleum ether) to afford title compound. 25208 Step 6: tert-Butyl (3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate: [0123] To a solution of NiCl₂(DME) (16.3 g, 74.0 mmol, 0.2 eq) in DMA (1.0 L) was added, DPy (11.6 g, 74.0 mmol, 0.2 eq) and the mixture was degassed with N₂ (three times) and stirred at rt for 30 min. Tert-butyl N-(3-iodocyclobutyl)carbamate (109.9 g, 369.9 mmol, 1.0 eq), 2- bromo-4-chlorobenzonitrile (96.07 g, 443.8 mmol, 1.2 eq), and zinc powder (36.3 g, 555 mmol, 1.5 eq) in DMA (4.0 L)was added. The mixture was degassed with N₂ (three times). The reaction mixture was stirred at rt for 3 h and water was added. The resulting solution was extracted with EtOAc and the organic layers combined. The resulting mixture was washed with brine. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash silica gel chromatography (2-3% EtOAc/petroleum ether) to afford mixture of isomers. The title compounds were resolved by Prep-SFC (EnantioPak-A1-5(02); 5*25 cm; 40% IPA). This resulted in the faster eluting isomer tert-butyl (cis-(5-chloro-2- cyanophenyl)cyclobutyl)carbamate: MS: 305.¹H NMR (300 MHz, CD₃OD): δ 7.66 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 4.10 (p, J = 8.3 Hz, 1H), 3.48 (tt, J = 10.1, 7.6 Hz, 1H), 2.92 – 2.74 (m, 2H), 2.18 – 2.01 (m, 2H), 1.46 (s, 9H). [M-1]-. The slower eluting isomer tert-butyl (trans-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate: MS: 305 [M-1] ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d, J = 8.2 Hz, 2H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 4.17 (dt, J = 14.2, 6.4 Hz, 1H), 3.91 (p, J = 7.6, 7.2 Hz, 1H), 2.54 (t, J = 7.3 Hz, 4H), 1.47 (s, 9H). Step 7: 2-( -3-Aminocyclobutyl)-4-chlorobenzonitrile compound with 2,2,2-trifluoroacetic acid (1:1): [0124] Trifluoroacetic acid (6.0 ml, 78 mmol) was added to a stirred solution of tert-butyl (cis- (5-chloro-2-cyanophenyl)cyclobutyl)carbamate (3.00 g, 9.78 mmol) in DCM at rt. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound. MS = 207.2 (M+1). Table 1. The following compounds were prepared according to procedures similar to those described for Intermediate H using the appropriate starting materials. 25208 Intermediate L 3-(2,5-Dichlorophenyl)cyclobutan-1-amine Step 1: tert-Butyl (3-(2,5-dichlorophenyl)cyclobutyl)carbamate: [0125] 2,5-Dichlorophenyl)boronic acid (58 mg, 0.30 mmol), tert-butyl (trans-3- iodocyclobutyl)carbamate (30 mg, 0.10 mmol), 2-aminocyclohexanol (2.3 mg, 0.020 mmol) and nickel(II) iodide (6.3 mg, 0.020 mmol) were mixed in a microwave reaction vial. The vial was capped. Air was removed by vacuum and back-filled with nitrogen (three times).2-Propanol (0.4 mL) and sodium bis(trimethylsilyl)amide (0.20 mL, 0.20 mmol) were introduced. Air was removed and back-filled with nitrogen (three times). The mixture was heated at 60 °C for 15 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was separated and dried over anhydrous sodium sulfate. After it was filtered and concentrated, the crude was purified by flash silica gel chromatography (0-20% EtOAc/hexane) to provide the title compound. 25208 Step 2: 3-(2,5-Dichlorophenyl)cyclobutanamine, HCl: [0126] tert-Butyl (3-(2,5-dichlorophenyl)cyclobutyl)carbamate (50.0 mg, 0.158 mmol) was treated with 4N HCl in 1,4-dioxane (0.8 mL) at rt for 1 h. The mixture was concentrated to give the product, which was used in the next step without further purification. MS = 216 (M+1). Intermediate M 3-(5-Chloro-2-fluorophenyl)cyclobutan-1-amine (Scheme 2) Step 1: tert-Butyl (3-(5-chloro-2-fluorophenyl)-3-hydroxycyclobutyl)carbamate [0127] n-Butyllithium (2.16 mL, 5.40 mmol) was added to a stirred mixture of 2-bromo-4- chloro-1-fluorobenzene (1.13 g, 5.40 mmol) in THF (3 mL) at -78 °C and stirred (3 mL) for 30 min. Then a solution of tert-butyl (3-oxocyclobutyl)carbamate (500 mg, 2.70 mmol) in THF (3.0 mL) was added slowly and then the reaction mixture stirred at -78 °C for 2 h. Satd. aq. NH₄Cl was added and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure to give a residue. The residue was purified by reverse phase MPLC (1%-20% MeOH\H₂O with 0.5% TFA modifier) provide the title compound. MS =198.0 (M+1-100-18). Step 2: 3-(5-Chloro-2-fluorophenyl)cyclobut-2-enamine [0128] Triethylsilane (51 μL, 0.32 mmol) was added to a stirred mixture of tert-butyl (3-(5- chloro-2-fluorophenyl)-3-hydroxycyclobutyl)carbamate (100 mg, 0.317 mmol) in TFA (2.5 mL) at rt and the mixture was stirred at rt for 1 h. The mixture was concentrated to give a residue, the residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to the title compound. MS =181.0 (M+1-17). Step 3: 3-(5-Chloro-2-fluorophenyl)cyclobutanamine [0129] Pd/C (13.5 mg, 0.126 mmol) was added to a stirred mixture of 3-(5-chloro-2- fluorophenyl)cyclobut-2-enamine (25.0 mg, 0.126 mmol) in MeOH (3 mL) an 5 drops concentrated HCl at rt, and the mixture was stirred at rt for 2 h. The mixture was filtered, washed 25208 with MeOH, the filtrate was concentrated to give the title compounds, which was used directly without further purification. MS =183.0 (M+1-17). Table 2. The following compounds were prepared according to procedures similar to those described for Intermediate M using the appropriate starting materials. Intermediate O 1-Amino-3-(3-chlorophenyl)cyclobutane-1-carbonitrile Step 1: 1-Amino-3-(3-chlorophenyl)cyclobutane-1-carbonitrile: [0130] To a solution of 3-(3-chlorophenyl)cyclobutanone (200 mg, 1.11 mmol) in MeOH (1.7 mL) and water (1.0 mL) was added ammonia (1.6 mL, 11 mmol, 7M in MeOH), NaCN (109 mg, 2.21 mmol), and ammonium chloride (118 mg, 2.21 mmol). The vial was stirred at rt for 3 days and the mixture was diluted with EtOAc and washed with brine. The organic layer was separated, and dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash silica gel chromatography (0-100% EtOAc/Hexanes) to give the title compound as a mixture of cis and trans isomers. MS = 207.1 (M+1) Intermediate P 25208 (1S,2S,4S)-2-Amino-4-(3-chlorophenyl)cyclobutan-1-ol and (1R,2R,4R)-2-Amino-4-(3- chlorophenyl)cyclobutan-1-ol Step 1: tert-Butyl (3-(3-chlorophenyl)-3-hydroxycyclobutyl)carbamate. [0131] To a solution of 1-bromo-3-chlorobenzene (3.10 g, 16.2 mmol) in dry THF (20 mL) was added n-butyllithium (6.5 mL, 16 mmol, 3M in hexanes) dropwise at -78 °C, then the mixture was degassed three times and stirred under nitrogen atmosphere at -78 °C for 20 min. tert-Butyl (3-oxocyclobutyl)carbamate (1.50 g, 8.10 mmol) (dissolved into 1.5 mL of THF) was added dropwise to the reaction mixture and the mixture was stirred at -78 °C for 1 h. The reaction mixture was poured into satd. aq.NH₄Cl and extracted with EtOAc, the organic layer was dried by anhydrous sodium sulfate, filtered and concentrated to give crude product, which was purified by flash silica gel chromatography (0-30% EtOAc/petroleum ether) to give the title compound. MS = 223.9 (M+1-56-18). Step 2: 3-(3-Chlorophenyl)cyclobut-2-enamine. [0132] The mixture of tert-butyl (3-(3-chlorophenyl)-3-hydroxycyclobutyl)carbamate (250 mg, 0.840 mmol) and methanesulfonic acid (0.55 mL, 8.4 mmol) in DCM (6 mL) was stirred at rt for 2 h. The solvent was evaporated and the residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide the title compound as a TFA salt. MS =163.0 (M+1-17). Step 3: (1S,2S,4S)-2-Amino-4-(3-chlorophenyl)cyclobutan-1-ol and -2-Amino-4-(3- chlorophenyl)cyclobutan-1-ol (racemic 2-amino-4-(3-chlorophenyl) [0133] To the 0 °C solution of 3-(3-chlorophenyl)cyclobut-2-enamine, TFA salt (110 mg, 0.375 mmol) in THF (4 mL) was added BH₃ ^.DMS (0.19 mL, 1.9 mmol,10M in DMS) dropwise under N₂, and the mixture was stirred at 0 °C for 5 min and at rt for 4 h. To the reaction was added sodium perborate (153 mg, 1.87 mmol) and water (1 mL) carefully, and the resulting mixture was stirred at rt for another 1 h. The solvent was evaporated and the residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give 2-amino-4-(3- chlorophenyl)cyclobutanol, TFA salt (faster eluting peak, racemic, amide and phenyl ring cis, OH and phenyl ring are trans) MS =198.0 (M+1) and 2-amino-4-(3-chlorophenyl)cyclobutanol, TFA salt (slower eluting peak, racemic, amide and phenyl ring are trans, OH and amide are cis MS =198.0 (M+1). 25208 Intermediate Q ((1S,2S,4R)-2-Amino-4-(3-chlorophenyl)cyclobutyl)methanol and ((1R,2R,4S)-2-Amino- 4-(3-chlorophenyl)cyclobutyl)methanol Step 1: 3-(3-Chlorophenyl)cyclobutanone. [0134] DMA (4.39 mL, 46.9 mmol) was dissolved in DCE (60 mL), and the solution was cooled to 0 °C before Tf₂O (16.6 mL, 98.0 mmol) was added. The solution was stirred for additional 60 min at 0 °C, then 1-chloro-3-vinylbenzene (5.00 g, 36.1 mmol) and 2,4,6- trimethylpyridine (4.59 g, 37.9 mmol) were added. The reaction mixture was heated to reflux (90 °C) for 18 h. The mixture was cooled to rt, water was added and the mixture was extracted with DCM. The combined organic fractions were washed by brine, dried over Na₂SO₄, filtered, the filtrate was evaporated under reduced pressure. The obtained residue was purified by prep-TLC (10% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 7.27- 7.33 (m, 2H), 7.21-7.25 (m, 1H), 7.18 (d, J=7.45 Hz, 1H), 3.61-3.73 (m, 1H), 3.40-3.57 (m, 2H), 3.13-3.35 (m, 2H). Step 2: 3-(3-Chlorophenyl)-2-(hydroxymethyl)cyclobutanone: [0135] To a solution of 3-(3-chlorophenyl)cyclobutanone (100 mg, 0.554 mmol) in water (0.5 mL) and ACN (1 mL) was added potassium carbonate (1.5 mg, 0.011 mmol) and formaldehyde (37 μL, 0.50 mmol) at rt, then the mixture was stirred at 40 °C for 30 min. The mixture was poured into water and extracted with EtOAc, the organic layers were dried by Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give crude product, which was purified by prep- TLC (30% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 7.11-7.47 (m, 4H), 4.04 (br, 1H), 3.85 (br, 1H), 3.67 (q, J=8.5 Hz, 1H), 3.53-3.61 (m, 1H), 3.31- 3.44 (m, 1H), 3.24-3.21 (m, 1H). Step 3: 3-(3-Chlorophenyl)-2-(hydroxymethyl)cyclobutanone oxim: [0136] To a solution of 3-(3-chlorophenyl)-2-(hydroxymethyl)cyclobutanone (400 mg, 1.90 mmol) in EtOH (3 mL) was added hydroxylamine hydrochloride (264 mg, 3.80 mmol) and TEA 25208 (0.53 mL, 3.8 mmol) at rt, then the mixture was stirred at 80 °C for 2 h. The mixture was concentrated in a vacuum to and the residue purified by prep-TLC (EtOAc) to the title compound. MS = 225.9 (M+1). Step 4: ((1S,2S,4R)-2-Amino-4-(3-chlorophenyl)cyclobutyl)methanol and ( -2-Amino- 4-(3-chlorophenyl)cyclobutyl)methanol: [0137] To a solution of 3-(3-chlorophenyl)-2-(hydroxymethyl)cyclobutanone oxime (240 mg, 1.06 mmol) in THF (5 mL) was added LAH (121 mg, 3.19 mmol) at 0 °C, then the mixture was stirred at rt for 1 h. The reaction was quenched by addition of EtOAc, the mixture was concentrated in a vacuum to give a residue, which was purified by flash silica gel chromatography (0-30% MeOH/EtOAc) to the title compounds. MS = 212.1 (M+1). EXAMPLES Example 1 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-( -3-(2,5-dichlorophenyl)cyclobutyl)- 1H-pyrazole-4-carboxamide (Scheme 3) Step 1: 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-( -3-(2,5-dichlorophenyl)cyclobutyl)- 1H-pyrazole-4-carboxamide: [0138] 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid (23 mg, 0.090 mmol) was mixed with 3-(2,5-dichlorophenyl)cyclobutanamine, HCl (23 mg, 0.090 mmol), and Hunig's base (47 µl, 0.27 mmol) in DMF (0.4 mL). HATU (38 mg, 0.099 mmol) was added. The resulting mixture was stirred at rt for 2 h. Mixture was diluted with MeOH and was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound. MS = 457.2, 459.2 (M+H).¹H NMR (600 MHz, d₆-DMSO): δ 2.07-2.13 (m, 2H), 2.28-2.33 (m, 2H), 2.68-2.73 (m, 2H), 3.36-3.43 (m, 1H), 4.05 (t, J = 6.0 Hz, 4H), 4.39-4.46 (m, 1H), 5.19 (s, 2H), 7.33 (dd, J = 8.4, 2.4 Hz, 1H), 7.45 (d, J = 8.4Hz, 1H), 7.47 (d, J = 2.4Hz, 1H), 7.84 (s, 1H), 8.18 (d, J = 8.4Hz, 1H), 8.19 (s, 1H), 8.40 (s, 2H). 25208 Table 3. The following compounds were prepared using procedures similar to those described for Example 1 using the appropriate intermediate or starting materials. Cis/Trans mixtures were separated using chiral columns specified in the table. 25208 25208 Example 10 N-((cis)-3-(2,5-Dichlorophenyl)cyclobutyl)-1-(4-((2-oxopyridin-1 (2H)-yl)methyl)benzyl)-1H- pyrazole-4-carboxamide (Scheme 3) Step 1: N- 3-(2,5-Dichlorophenyl)cyclobutyl)-1-(4-((2-oxopyridin-1 (2H)- yl) -1H-pyrazole-4-carboxamide: [0139] 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (28 mg, 0.090 mmol) was mixed with 3-(2,5-dichlorophenyl)cyclobutanamine, HCl (23 mg, 0.090 mmol), and Hunig's base (47 µl, 0.27 mmol) in DMF (0.4 mL). HATU (38 mg, 0.099 mmol) was added. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with MeOH and was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound. MS = 507.2 (M+1).¹H NMR (600 MHz, d₆-DMSO): δ 2.08-2.14 (m, 2H), 2.67-2.73 (m, 2H), 3.36-3.43 (m, 1H), 4.39-4.46 (m, 1H), 5.07 (s, 2H), 5.32 (s, 2H), 6.23 (dt, J = 6.6, 1.2 Hz, 1H), 6.40 (d, J = 9 Hz, 1H), 7.25 (dd, J = 21.6, 7.8 Hz, 4H), 7.33 (dd, J = 8.4, 2.4 Hz, 1H), 7.40-7.43 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 7.2, 2.4 Hz, 1H), 7.84 (s, 1), 8.19 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H). Table 4. The following compounds were prepared using procedures similar to those described for Example 10 using the appropriate starting materials. Mixtures were separated using chiral columns specified in the table. 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-N-( -3-(3- chlorophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide Step 1.5-(Bromomethyl)-2-(methylthio)pyrimidine. [0140] To a stirred solution of (2-(methylthio)pyrimidin-5-yl)methanol (1.19 g, 7.62 mmol) in DCM (25 mL) at 0 °C was added carbon tetrabromide (3.28 g, 9.90 mmol) and triphenylphosphine (2.60 g, 9.90 mmol). The mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated. The residue was purified by flash silica gel chromatography (0 - 20% EtOAc/hexane) to give the title compound. MS = 221.1 (M+1). Step 2. Methyl 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylate. [0141] Methyl 1H-pyrazole-4-carboxylate (0.760 g, 6.02 mmol) and Cs₂CO₃ (5.35 g, 16.4 mmol) were added to a stirred solution of starting material 5-(bromomethyl)-2- (methylthio)pyrimidine (1.20 g, 5.48 mmol) in DMF (36 mL) at rt. The mixture was stirred at rt for overnight. The mixture was diluted with water, extracted with DCM. The combined organic ^{phases were washed with brine, dried (MgSO} ₄ ^{) and concentrated under reduced pressure. The} residue was purified flash silica gel chromatography (0-60% EtOAc/hexane) to give the title compound. MS = 265.2 (M+1). Step 3.1-((2-(Methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid. [0142] Lithium hydroxide (394 mg, 16.5 mmol) was added to a stirred solution of methyl 1- ((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylate (1.45 g, 5.49 mmol) in THF (50 mL) and water (10 mL) at rt. The mixture was stirred overnight at 60 °C. The mixture was acidified with 1N HCl to pH 2. The mixture was diluted with water, extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄, and concentrated under reduced pressure to afford the title compound. MS = 251.1 (M+1). 25208 Step 4. N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H- pyrazole-4-carboxamide. [0143] Hunig's base (4.6 ml, 25 mmol) and HATU (4.03 g, 10.6 mmol) were added to a stirred solution of 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid, (1.06 g, 4.24 mmol) in DMF (42 mL) at rt. (cis)-3-(3-Chlorophenyl)cyclobutan-1-amine (1.69 g, 9.32 mmol) was added and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with satd. aq. NaHCO₃ and extracted with DCM. The combined organic phases were dried over MgSO₄, filtered and the filtrate was concentrated. The residue was purified flash silica gel chromatography (0-80% ((3:1)EtOAc:EtOH)/heptane) to give the title compound. MS = 414.3 (M+1). Step 5. N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-((2-(methylsulfonyl)pyrimidin-5-yl)methyl)- 1H-pyrazole-4-carboxamide. [0144] mCPBA (1.01 g, 4.52 mmol) was added to a stirred solution of starting material N- ((cis)-3-(3-chlorophenyl)cyclobutyl)-1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4- carboxamide (1.44 g, 3.48 mmol) in DCM (35 mL). The reaction mixture was stirred for 5 h at rt. The reaction mixture was quenched with satd. aq. NaHCO₃ and extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified by flash silica gel chromatography (0 - 60% ((3:1) EtOAc/EtOH)/heptane) to give the title compound. MS = 446.1 (M+1). Step 6.1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(3- chlorophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide. [0145] To a stirred solution of N-((cis)-3-(3-chlorophenyl)cyclobutyl)-1-((2- (methylsulfonyl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (20 mg, 0.045 mmol) in NMP (1 mL) was added 3-azabicyclo[3.1.0]hexane hydrochloride (21.5 mg, 0.179 mmol) and Hunig's base (55 μL, 0.31 mmol). The mixture was heated to 110 °C for 4 h. The reaction mixture was filtered and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide the title compound. MS = 449.4 (M+1).¹H NMR (500 MHz, CDCl₃) δ 8.38 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.31 – 7.17 (m, 4H), 7.11 (d, J = 7.5 Hz, 1H), 5.14 (s, 2H), 4.57 (q, J = 9.1 Hz, 1H), 3.90 (d, J = 11.3 Hz, 2H), 3.61 (s, 2H), 3.25 (t, J = 7.7 Hz, 1H), 2.89 (qd, J = 7.6, 2.8 Hz, 2H), 2.11 – 2.01 (m, 2H), 1.70 (s, 2H), 0.83 (s, 1H), 0.25 (q, J = 4.2 Hz, 1H). 25208 Table 5. The following compounds were prepared using procedures similar to those described for Example 17 using the appropriate starting materials. Racemic products were separated using chiral columns specified in the table. For those pairs of enantiomers, the fast- eluting isomer is listed first. This convention for listing enantiomers from chiral HPLC separations will be used in all the subsequent tables. 25208 25208 Example 25 1-((6-(Azetidin-1-yl)pyridin-3-yl)methyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H- pyrazole-4-carboxamide (Scheme 5) Step 1. Ethyl 1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate: [0146] To a solution of ethyl 1H-pyrazole-4-carboxylate (300 mg, 2.14 mmol) and 5- (chloromethyl)-2-fluoropyridine (343 mg, 2.36 mmol) in ACN (13 mL) was added potassium carbonate (256 mg, 1.85 mmol). The reaction mixture was purged with nitrogen and heated at 100 °C for 24 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography (0 - 30% ((3:1) EtOAc:EtOH)/Hexane gradient) to afford title compound. MS = 250.4 (M+1). Step 2. Ethyl 1-((6-(azetidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate: [0147] To a solution of ethyl 1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate (125 mg, 0.502 mmol) in NMP (2 mL) was added DIEA (0.35 mL, 2.0 mmol) and azetidine (0.20 mL, 3.0 mmol). The reaction mixture was heated at 80 °C for 16 h. Upon reaction completion, the mixture was diluted with water and extracted with DCM. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography (0-20% MeOH/DCM) to afford title compound. MS = 287.07 (M+1). Step 3: 1-((6-(Azetidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxylic acid: [0148] To a solution of ethyl 1-((6-(azetidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-4- carboxylate (166 mg, 0.580 mmol) in THF (2 mL) and water (1 mL) was added LiOH (41.6 mg, 1.74 mmol). The reaction mixture was stirred at rt for 16 h. Additional lithium hydroxide (69 mg, 25208 2.9 mmol) and water (0.5 mL) were added, and the reaction was stirred at rt for 4 h. Upon reaction completion, 1N HCl (5.80 mL, 5.80 mmol) was added and the reaction was concentrated under reduced pressure. The crude was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford title compound. MS = 259.11 (M+1). Step 4: 1-((6-(Azetidin-1-yl)pyridin-3-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide: [0149] To a solution of 1-((6-(azetidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxylic acid, 2,2,2-trifluoroacetate salt (6.3 mg, 0.017 mmol), N-ethyl-N-isopropylpropan-2-amine (11 mg, 0.085 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (6.5 mg, 0.017 mmol) in DMF (1 mL), stirred at rt, was added 2-((cis)- 3-aminocyclobutyl)-4-chlorobenzonitrile hydrochloride (4.1 mg, 0.017 mmol). The reaction was stirred at rt for 3 h, diluted with water and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford title compound as a TFA salt. MS = 447.02 (M+1).¹H NMR (500 MHz, CD₃OD) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.88 (dd, J = 9.3, 2.0 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.44 (dd, J = 8.2, 2.0 Hz, 1H), 6.84 (d, J = 9.3 Hz, 1H), 5.31 (s, 2H), 4.53-4.60 (m, 1H), 4.29 – 4.40 (m, 4H), 3.56-3.65 (m, 1H), 2.90 – 2.99 (m, 2H), 2.60 (p, J = 7.7 Hz, 2H), 2.27 (q, J = 10.6, 9.5 Hz, 2H). Example 26 N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-((2-((S)-2-(((R)-3-hydroxypyrrolidin-1- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (Scheme 6) Step 1: Ethyl 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylate. [0150] To a solution of 5-(bromomethyl)-2-(methylthio)pyrimidine (514 mg, 2.35 mmol) in DMF (8 mL) was added ethyl 1H-pyrazole-4-carboxylate (329 mg, 2.35 mmol) and Cs₂CO₃ (1.53 g, 4.70 mmol). The mixture was heated up to 50 °C for 18 h. The mixture was cooled, diluted with EtOAc, washed with brine, dried over Na₂SO₄, filtered and concentrated. The 25208 residue was purified by flash silica gel chromatography (10-60% EtOAc/Hexane) to give the title compound. MS =279.3 (M+1). Step 2: 1-((2-(Methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid. [0151] A solution of ethyl 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4- carboxylate (640 mg, 2.30 mmol) and lithium hydroxide (482 mg, 11.5 mmol) in THF (10 mL) and water (1 mL) was heated up to 50 °C for 16 h. The mixture was acidified with 1N HCl to pH 2. The mixture was extracted with EtOAc and the combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and concentrated to provide the title compound. Step 3: N-( -3-(3-Chlorophenyl)cyclobutyl)-1-((2-(methylthio)pyrimidin-5-yl)methyl)- pyrazole- [0152] To the solution of 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid (275 mg, 1.10 mmol) and (cis)-3-(3-chlorophenyl)cyclobutan-1-amine hydrochloride (240 mg, 1.10 mmol) in DCM (10 mL) was added DIEA (576 µl, 3.30 mmol) and 1- propanephosphonic anhydride (1.31 mL, 2.20 mmol). The mixture stirred at rt for 2 h, then diluted with 1M Na₂CO₃ and extracted with DCM. The combined organic layer was dried (Na₂SO₄), filtered and concentrated. The residue was purified by flash silica gel chromatography (50-100% EtOAc/hexane) to give the title compound. MS = 414.1 (M+1). Step 4: N-( -3-(3-Chlorophenyl)cyclobutyl)-1-((2-(methylsulfonyl)pyrimidin-5-yl)methyl)- 1H- carboxamide: [0153] To the solution of N-((cis)-3-(3-chlorophenyl)cyclobutyl)-1-((2-(methylthio)pyrimidin- 5-yl)methyl)-1H-pyrazole-4-carboxamide (211 mg, 0.510 mmol) in DCM (5 mL) was added mCPBA (231 mg, 1.02 mmol). The mixture stirred at rt for 2 h and directly purified by flash silica gel chromatography (20-70% ((3:1)EtOAc:EtOH)/hexane) to give the title compound. MS = 446.1 (M+1). Step 5: N-( -3-(3-Chlorophenyl)cyclobutyl)-1-((2-((S)-2-(hydroxymethyl)pyrrolidin-1- yl) yl)methyl)-1H-pyrazole-4-carboxamide: [0154] To a solution of N-((cis)-3-(3-chlorophenyl)cyclobutyl)-1-((2- (methylsulfonyl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (110 mg, 0.247 mmol) and (S)-pyrrolidin-2-ylmethanol (100 mg, 0.987 mmol) in NMP (2 mL) was added DIEA (0.17 mL, 25208 0.99 mmol). The mixture was heated to 125 °C for 3 h, the directly purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound. MS = 467.2 (M+1). Step 6. N- 3-(3-Chlorophenyl)cyclobutyl)-1-((2-((S)-2-formylpyrrolidin-1-yl)pyrimidin-5- yl) - 4-carboxamide: [0155] To the solution of N-((cis)-3-(3-chlorophenyl)cyclobutyl)-1-((2-((S)-2- (hydroxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (111 mg, 0.238 mmol) in DCM (4 mL) was added DMP (121 mg, 0.285 mmol) followed by sodium bicarbonate (30 mg, 0.36 mmol). The mixture was stirred at rt for 3 h, then diluted with satd. aq. NaS₂O₃ and extracted with DCM. The combined organic layer was dried, filtered and concentrated. The residue was purified by flash silica gel chromatography (20-40% ((3:1) EtOAc:EtOH/hexane) to give the title compound. MS = 465.2 (M+1). Step 7. N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-((2-((S)-2-(((R)-3-hydroxypyrrolidin-1- yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide: [0156] To the solution of N-((cis)-3-(3-chlorophenyl)cyclobutyl)-1-((2-((S)-2-formylpyrrolidin- 1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (17 mg, 0.037 mmol) in CH₂Cl₂ (5% AcOH) was added (R)-pyrrolidin-3-ol (6.4 mg, 0.073 mmol) and the mixture was stirred at rt for 0.5 h. Sodium triacetoxyborohydride (16 mg, 0.073 mmol) was added and the reaction was stirred for 3 h. The mixture was diluted with 1M Na₂CO₃ and extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) to give the title compound as a TFA salt: ¹H NMR (300 MHz, d₆-DMSO) δ: 8.46 (s, 1H), 8.24 (s, 2H), 7.86 (s, 1H), 7.36-7.33 (m, 2H), 7.28-7.23 (m, 2H), 5.23 (s, 2H), 4.35-4.47 (m, 3H), 3.91-3.72 (m, 3H), 3.58-3.26 (m, 4H), 3.22-3.15 (m, 2H), 2.65-2.63 (m, 2H), 2.29-2.21 (m, 1H), 2.13-2.07 (m, 3H), 1.99-1.76 (m, 4H). MS = 536.2 (M+1). Table 6. The following compounds were prepared using procedures similar to those described for Examples 26 using the appropriate starting materials. 25208 25208 25208 25208 Examples 39 and 40 1-((R)-1-(6-(Azetidin-1-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-1,2,3-triazole-4-carboxamide and 1-((S)-1-(6-(Azetidin-1- yl)pyridin-3-yl)ethyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H-1,2,3-triazole-4- carboxamide (Scheme 7) Step 1.5-(1-Azidoethyl)-2-fluoropyridine: [0157] To a solution of 1-(6-fluoropyridin-3-yl)ethan-1-ol (1.00 g, 7.08 mmol) in toluene (30 ml), stirred at 0 °C, was added DPPA (1.83 ml, 8.50 mmol) and DBU (1.28 ml, 8.50 mmol). The reaction mixture was stirred overnight at rt. Upon reaction completion, the mixture was diluted with EtOAc and washed with water and brine. The organic was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography (0-70% EtOAc/hexane) to afford the title compound. MS = 167.0 (M+1). Step 2. Ethyl-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate: [0158] To a solution of 5-(1-azidoethyl)-2-fluoropyridine (1.30 g, 7.82 mmol) in EtOH(10 mL), stirred at rt, was added ethyl propiolate (1.59 mL, 15.7 mmol), followed by a solution of L- sodium ascorbate (287 mg, 1.57 mmol) in water (5 mL) and a solution of copper(II) sulfate pentahydrate (391 mg, 1.57 mmol) in water (5 mL) The reaction mixture was stirred for 45 min at rt. Upon reaction completion, the mixture was concentrated under reduced pressure. The mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (0-100% EtOAc/hexane) to afford the title compound. MS = 265.0 (M+1). Step 3. Ethyl-1-(1-(6-(azetidin-1-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate: 25208 [0159] To a solution of ethyl 1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (60 mg, 0.23 mmol) in dioxane (1.5 mL) was added DIEA (1.19 mL, 6.81 mmol) and azetidine (389 mg, 6.81 mmol). The reaction mixture was heated at 80 °C for 45 min. Upon reaction completion, the mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (0-20% MeOH/DCM) to afford title compound. MS = 302.0 (M+1). Step 4.1-(1-(6-(Azetidin-1-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid: [0160] To a solution of ethyl 1-(1-(6-(azetidin-1-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4- carboxylate (61 mg, 0.202 mmol) in THF (0.8 mL), water (0.8 mL) and MeOH (0.4 mL) was added LiOH (80 mg, 3.4 mmol). The reaction mixture was stirred at rt for 30 min. Upon reaction completion, the mixture was concentrated under reduced pressure.1M HCl was added and the reaction was concentrated under reduced pressure. The crude was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford title compound. MS = 273.98 (M+1). Step 5.1-((R)-1-(6-(Azetidin-1-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-1,2,3-triazole-4-carboxamide and 1-((S)-1-(6-(Azetidin-1- yl)pyridin-3-yl)ethyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)- 1,2,3-triazole-4- carboxamide: [0161] To a solution of 1-(1-(6-(azetidin-1-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4- carboxylic acid, 2,2,2-trifluoroacetate salt (27 mg, 0.070 mmol), DIEA (0.12 mL, 0.70 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (27 mg, 0.070 mmol) in DMF (1.5 mL), stirred at rt, was added 2- ((cis)-3-aminocyclobutyl)-4-chlorobenzonitrile hydrochloride (17 mg, 0.070 mmol). The reaction stirred at rt for 2 h. Upon reaction completion, the mixture was quenched with brine and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford the mixture of diastereomers as a TFA salt. The enantiopure title compounds were resolved by Chiral SFC (OD-H 21 x 250mm, 50% MeOH.) The compounds were purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier). The faster-eluting enantiomer of the title compound was obtained, as a TFA salt (Example 39): ¹H NMR (500 MHz, CD₃OD) δ 8.48 (s, 1H), 7.94-7.99 (m, 2H), 7.67-7.70 (m, 2H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 6.84 (d, J = 10.0 Hz, 1H), 5.96 (q, J = 7.1 Hz, 1H), 4.57-4.64 (m, 1H), 4.32 – 4.37 (m, 4H), 3.58-3.66 (m, 1H), 2.90—2.97 (m, 2H), 2.59 (p, J = 7.6 Hz, 2H), 2.37 (q, J = 11.4, 10.4 Hz, 2H), 2.00 (d, J = 7.1 Hz, 3H). MS = 461.94 25208 (M+1). The slower-eluting enantiomer of the title compound was obtained, as a TFA salt (Example 40): ¹H NMR (500 MHz, CD₃OD) δ 8.48 (s, 1H), 7.94-7.98 (m, 2H), 7.67-7.70 (m, 2H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 6.82 (d, J = 9.1 Hz, 1H), 5.96 (q, 1H), 4.57-4.64 (m, 1H), 4.30 – 4.35 (m, 4H), 3.58-3.66 (m, 1H), 2.89-2.98 (m, 2H), 2.58 (p, J = 7.7 Hz, 2H), 2.34-2.44 (m, 2H), 2.00 (d, J = 7.1 Hz, 3H). MS = 461.93 (M+1). Table 7. The following compounds were prepared using procedures similar to those described for Examples 39 & 40 using the appropriate starting materials. 25208 Example 45 and 46 1-((R)-1-(2-(5-Azaspiro[2.3]hexan-5-yl)pyrimidin-5-yl)ethyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-1,2,3-triazole-4-carboxamide and 1-((S)-1-(2-(5- Azaspiro[2.3]hexan-5-yl)pyrimidin-5-yl)ethyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)- 1H-1,2,3-triazole-4-carboxamide (Scheme 8) Step 1.1-(2-(Methylthio)pyrimidin-5-yl)ethan-1-ol. [0162] To a stirred solution of 2-(methylthio)pyrimidine-5-carbaldehyde (1.00 g, 6.49 mmol) in THF (20 mL) at 0 °C was added methylmagnesium bromide (2.48 mL, 8.43 mmol) and the mixture was stirred at 0 °C for 1 h. The reaction was partitioned between sat. aq. NH₄Cl and EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (050% EtOAc/Hexane) to give the title compound. MS = 171.2 (M+1). Step 2.5-(1-Azidoethyl)-2-(methylthio)pyrimidine. [0163] To a stirred solution of 1-(2-(methylthio)pyrimidin-5-yl)ethan-1-ol (999 mg, 5.87 mmol) in toluene (26 mL) at 0 °C was added DPPA (1.64 mL, 7.63 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (1.14 mL, 7.63 mmol). The mixture was stirred at rt overnight. 25208 The mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated. The residue was purified by flash silica gel chromatography (0-40% EtOAc/Hexane) to give the title compound. MS = 196.3 (M+1). Step 3. Ethyl 1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-IH-1,2,3-triazole-4-carboxylate. [0164] To a stirred solution of 5-(1-azidoethyl)-2-(methylthio)pyrimidine (1.14 g, 5.84 mmol) in EtOH (7.3 mL) at rt was added ethyl propiolate (1.18 mL, 11.7 mmol) and a solution of sodium ascorbate (231 mg, 1.17 mmol) in water (3.5 mL), followed by the addition of a solution of copper(II) sulfate pentahydrate (292 mg, 1.17 mmol) in water (3.5 mL). The reaction mixture was stirred at rt for 45 min. The mixture was diluted with water and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated. The residue was purified by flash silica gel chromatography (080% EtOAc/petroleum ether) to give the title compound. MS = 294.2 (M+1). Step 4.1-(1-(2-(Methylthio)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid. [0165] To a stirred solution of ethyl 1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-1,2,3- triazole-4-carboxylate (1.24 g, 4.23 mmol) in THF (30 mL) and water (10 mL) at rt was added LiOH (1.01 g, 42.3 mmol), and the mixture was stirred at 60 °C for overnight. The mixture was diluted with 1M HCl to pH 3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄, and concentrated. The residue was purified by flash silica gel chromatography (0-100% EtOAc/petroleum ether) to give the title compound. MS = 266.2 (M+1). Step 5. N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2-(methylthio)pyrimidin-5- yl)ethyl)-1H-1,2,3-triazole-4-carboxamide. [0166] To a stirred solution of 1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4- carboxylic acid (302 mg, 1.48 mmol) in DMF (9.5 mL) at rt was added Hunig's base (0.80 mL, 4.6 mmol) and HATU (1.08 mg, 2.85 mmol), and 2-((cis)-3-aminocyclobutyl)-4- chlorobenzonitrile (353 mg, 1.71 mmol) and the mixture was stirred at rt for 30 min. The mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated. The residue was purified by flash silica gel chromatography (0-80% EtOAc/petroleum ether) to give the title compound. MS = 454.2 (M+1). 25208 Step 6. N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2-(methylsulfonyl)pyrimidin-5- yl) triazole-4-carboxamide. [0167] a solution of N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2- (methylthio)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide (454 mg, 1.00 mmol) in DCM (6.7 mL) at rt was added mCPBA (448 mg, 2.00 mmol) and the mixture was stirred at rt for 6 h. The mixture was diluted with satd. aq. NaHCO₃ and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated. The residue was purified by flash silica gel chromatography (0-80% EtOAc/petroleum ether) to give the title compound. MS = 486.2 (M+1). Step 7.1-((R)-1-(2-(5-Azaspiro[2.3]hexan-5-yl)pyrimidin-5-yl)ethyl)-N-( -3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-1,2,3-triazole-4-carboxamide and 1-((S)-1- Azaspiro[2.3]hexan-5-yl)pyrimidin-5-yl)ethyl)-N-( -3-(5-chloro-2-cyanophenyl)cyclobutyl)- 1H-1,2,3-triazole-4-carboxamide. [0168] To a stirred solution of N-(3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2- (methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide (50 mg, 0.10 mmol) in DMSO (1.0 mL) at rt was added 5-azaspiro[2.3]hexane hydrochloride (24.6 mg, 0.206 mmol) and Cs₂CO₃ (134 mg, 0.412 mmol), and the mixture was stirred at 90 °C for 1 h. The mixture was diluted with water and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated. The residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier). The product was diluted with EtOAc, washed with satd. aq. NaHCO₃, and brine and concentrated to afford the diastereomeric mixture of products. The enantiopure title compounds were resolved by Chiral SFC (OD-H column). The faster-eluting enantiomer of the title compound (Example 45): MS = 489.3 (M+1).¹H NMR (500 MHz, CDCl3) δ 8.33 (s, 2H), 8.02 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.35 – 7.28 (m, 1H), 5.74 (q, J = 7.1 Hz, 1H), 4.63 (p, J = 8.4 Hz, 1H), 4.23 (s, 3H), 3.59 (p, J = 9.7, 9.1 Hz, 1H), 3.09 – 3.00 (m, 2H), 2.25 (q, J = 11.1, 10.4 Hz, 2H), 2.00 (d, J = 7.1 Hz, 2H), 1.28 (s, 1H), 0.73 (s, 4H). The slower-eluting enantiomer of the title compound (Example 46): MS = 489.3 (M+1). ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 2H), 8.01 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.44 (s, 1H), 7.35 – 7.29 (m, 1H), 5.74 (q, J = 7.0 Hz, 1H), 4.64 (q, J = 8.3 Hz, 1H), 4.23 (s, 3H), 3.59 (p, J = 9.5, 9.0 Hz, 1H), 3.05 (q, J = 9.2, 8.4 Hz, 2H), 2.25 (q, J = 11.2, 10.4 Hz, 2H), 2.00 (d, J = 7.1 Hz, 3H), 1.28 (s, 1H), 0.74 (s, 4H). 25208 Table 8. The following compounds were prepared using procedures similar to those described for Examples 45 & 46 using the appropriate starting materials. 25208 Example 53 and 54 1-((R)-3-(Azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide and 1-((S)-3-(Azetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[c]pyridin-7-yl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)- pyrazole-4- carboxamide 25208 Step 1.3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol: [0169] To a solution of 3-chloro-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (1.00 g, 5.97 mmol) in MeOH (60 mL) at 0 °C, was slowly added sodium borohydride (237 mg, 6.27 mmol). The reaction mixture was stirred for 3 h, gradually warming up to rt. Upon reaction completion, the mixture was quenched with satd. aq. NH₄Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (0-20% MeOH/DCM) to afford the title compound. MS = 169.95 (M+1). Step 2. Ethyl-1-(3-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1H-pyrazole-4-carboxylate: [0170] To a solution of 3-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (948 mg, 5.59 mmol), ethyl 1H-pyrazole-4-carboxylate (862 mg, 6.15 mmol), and triphenylphosphine (2.20 g, 8.38 mmol), in THF (40 mL), stirred at rt, was slowly added DIAD (1.63 mL, 8.38 mmol). The reaction mixture was stirred overnight at rt. The mixture was quenched with brine and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (0-100% EtOAc/hexane) to afford the title compound. MS = 292.02 (M+1). Step 3. Ethyl-1-(3-(azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1H-pyrazole-4- carboxylate: [0171] To a solution of ethyl 1-(3-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1H- pyrazole-4-carboxylate (150 mg, 0.514 mmol) in NMP (5 mL), was added (in portions) azetidine (2.76 mL, 40.9 mmol). The reaction stirred for 25 h at 110-130 °C. Upon reaction completion, the mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash silica gel chromatography (0-30% MeOH/DCM) to afford the title compound. MS = 313.03 (M+1). Step 4.1-(3-(Azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1H-pyrazole-4- carboxylic acid: [0172] To a solution of ethyl 1-(3-(azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)- 1H-pyrazole-4-carboxylate (137 mg, 0.439 mmol) in THF (2 mL), water (2 mL and methanol (1 mL), stirred at rt, was added LiOH (158 mg, 6.58 mmol). The reaction mixture was stirred for 4 h 25208 at rt. Upon reaction completion, the mixture was concentrated under reduced pressure. The mixture was quenched with 1M HCl and concentrated under reduced pressure and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford the title compound. MS = 285.01 (M+1). Step 5.1-((R)-3-(Azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-((cis)-3-(5-chloro- 2-cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide and 1-((S)-3-(Azetidin-1-yl)-6,7- dihydro-5H-cyclopenta[c]pyridin-7-yl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H- pyrazole-4-carboxamide: [0173] To a solution of 1-(3-(azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)-1H- pyrazole-4-carboxylic acid, 2,2,2-trifluoroacetate salt (40 mg, 0.10 mmol), DIEA (65 mg, 0.50 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (38.3 mg, 0.101 mmol) in DMF (3 mL), stirred at rt, was added 2-((cis)- 3-aminocyclobutyl)-4-chlorobenzonitrile hydrochloride (24.5 mg, 0.101 mmol). The reaction mixture was stirred for 3.5 h at rt, and the mixture was quenched with brine and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford the mixture of diastereomers. The enantiopure title compounds were resolved by Chiral SFC (OD-H, 21 x 250mm, 45% (MeOH + 0.2% DIPA)). The compounds were purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier). The faster-eluting enantiomer of the title compound (Example 53): ¹H NMR (500 MHz, CD₃OD) δ 8.21 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 6.83 (s, 1H), 5.96 (dd, J = 7.4, 4.9 Hz, 1H), 4.56 (t, J = 7.6 Hz, 1H), 4.35 (t, J = 7.7 Hz, 4H), 3.66 – 3.56 (m, 1H), 3.29 (d, J = 8.3 Hz, 1H), 3.16 – 3.07 (m, 1H), 2.94 (dt, J = 10.8, 7.8 Hz, 2H), 2.79 – 2.69 (m, 1H), 2.60 (p, J = 7.6 Hz, 2H), 2.57 – 2.46 (m, 1H), 2.27 (q, J = 9.2 Hz, 2H). MS = 473.00 (M+1). The slower- eluting enantiomer of the title compound (Example 54): ¹H NMR (500 MHz, CD₃OD) δ 8.21 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 6.83 (s, 1H), 5.96 (dd, J = 7.7, 5.3 Hz, 1H), 4.59 – 4.50 (m, 1H), 4.39 – 4.24 (m, 4H), 3.66 – 3.55 (m, 1H), 3.29 (d, J = 8.1 Hz, 1H), 3.15 – 3.08 (m, 1H), 2.94 (qd, J = 7.7, 2.8 Hz, 2H), 2.80 – 2.69 (m, 1H), 2.60 (p, J = 7.7 Hz, 2H), 2.57 – 2.47 (m, 1H), 2.27 (q, J = 9.3 Hz, 2H). MS = 472.97 (M+1). Table 9. The following compounds were prepared using procedures similar to those described for Examples 53 and 54 using the appropriate starting materials. 25208 25208 Example 61 and 62 1-((1S)-1-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-hydroxyethyl)-N-((cis)-3-(5-chloro- 2-cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide and 1-((1R)-1-(6-(3- Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-hydroxyethyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide (Scheme 10) 25208 Step 1: 3-(5-Bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane. [0174] To a stirred solution 5-bromo-2-fluoropyridine (2.00 g, 11.4 mmol) in NMP (15 mL) was added 3-azabicyclo[3.1.0]hexane hydrochloride (2.72 g, 22.7 mmol) and K₂CO₃ (3.93 g, 28.4 mmol) at rt. After the addition was finished, the reaction was stirred at 100 °C for 12 h. The mixture was concentrated and water was added. The solution was extracted with EtOAc, the combined organic layer was washed with brine, dried over Na₂SO_4. The residue was purified by flash silica gel chromatography (06% EtOAc/petroleum ether) to give the title compound. MS = 239.0 (M+1). Step 2: 3-(5-Vinylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane. [0175] To a stirred solution of potassium vinyltrifluoroborate (2.16 g, 16.3 mmol), TEA (4.5 mL, 32 mmol) and 3-(5-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane (2.60 g, 10.9 mmol) in EtOH (20 mL) was added PdCl₂(dppf) (239 mg, 0.326 mmol) and stirred at 90 °C under N₂ protection for 12 h. The mixture was concentrated, water was added, and the solution was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na₂SO_4. The residue was purified by flash silica gel chromatography (030% EtOAc/petroleum ether) to give the title compound. MS = 187.1 (M+1). Step 3: 1-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethane-1,2-diol. [0176] At rt, an aq. solution osmium(VIII) oxide (1.45 mL, 0.285 mmol, 50 mg/mL) and 4- methylmorpholine 4-oxide (333 mg, 2.85 mmol) were added to a mixed solution of 3-(5- vinylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane (530 mg, 2.85 mmol) in water (0.5 mL) and ACN (1.5 mL) and stirred for 12 h at rt. The reaction was cooled to 0 °C and satd. aq. NaS₂O₃ was added to the reaction and stirred for 0.5 h. Then the mixture was filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (0-20% MeOH/DCM) to give the title compound. MS = 221.0 (M+1). Step 4: 1-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-((tert- butyldiphenylsilyl)oxy)ethanol. [0177] To a solution of 1-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethane-1,2-diol (260 mg, 1.180 mmol) in DMF (5 mL) was added 1H-imidazole (177 mg, 2.60 mmol) and tert- butylchlorodiphenylsilane (292 mg, 1.06 mmol) at rt. The reaction mixture was stirred at 50 °C for 6 h, then concentrated and water was added. The mixture was extracted with EtOAc. The 25208 organic layers were washed with brine, concentrated and purified by flash silica gel chromatography (0-30% EtOAc/petroleum ether) to give the title compound. MS = 458.6 (M+1). Step 5: tert-Butyl 1-(1-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-((tert- butyldiphenylsilyl)oxy)ethyl)-1H-pyrazole-4-carboxylate. [0178] To a solution of 1-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-((tert- butyldiphenylsilyl)oxy)ethanol (270 mg, 0.589 mmol), tert-butyl 1H-pyrazole-4-carboxylate (198 mg, 1.18 mmol) and DIAD (238 mg, 1.18 mmol) in THF (8 mL) was added Ph₃P (309 mg, 1.18 mmol) under N₂. The solution was stirred at 50 °C for 4 h. The mixture was concentrated, water was added, and the solution extracted with EtOAc. The organic layers were washed with brine ^{dried over Na} ₂ ^SO ₄ ^{and concentrated. The residue was purified flash silica gel chromatography} (040% EtOAc/petroleum ether) to give the title compound. MS = 609.8 (M+1). Step 6: 1-(1-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-((tert- butyldiphenylsilyl)oxy)ethyl)-1H-pyrazole-4-carboxylic acid. [0179] To a stirred solution tert-butyl 1-(1-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2- ((tert-butyldiphenylsilyl)oxy)ethyl)-1H-pyrazole-4-carboxylate (70 mg, 0.12 mmol) in DCM (1 mL) was added TFA (0.10 mL, 1.3 mmol) at rt, after the reaction was stirred at rt for 6 h. The mixture was concentrated to give the title compounds, which was used in the next step without further purification. MS = 553.5 (M+1). Step 7: 1-(1-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-((tert- butyldiphenylsilyl)oxy)ethyl)-N-( -3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H-pyrazole-4- carboxamide. [0180] To a solution of 1-(1-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-((tert- butyldiphenylsilyl)oxy)ethyl)-1H-pyrazole-4-carboxylic acid (50 mg, 0.090 mmol) in ACN (1 mL) were added 1-methyl-1H-imidazole (30 mg, 0.37 mmol), N- (chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (30 mg, 0.11 mmol) and 2-(3-aminocyclobutyl)-4-chlorobenzonitrile 2,2,2-trifluoroacetate (36 mg, 0.090 mmol) at rt, the mixture was stirred at rt for 2 h. The residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound. MS = 741.4 (M+1). 25208 Step 8: 1-((1S)-1-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-hydroxyethyl)-N-((cis)-3-(5- chloro-2-cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide and 1-((1R)-1-(6-(3- Azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-hydroxyethyl)-N-( -3-(5-chloro-2- cyanophenyl)cyclobutyl)-iH-pyrazole-4-carboxamide. [0181] To a stirred solution of 1-(1-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-2-((tert- butyldiphenylsilyl)oxy)ethyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H-pyrazole-4- carboxamide (60 mg, 0.081 mmol) in THF (2 mL) was added TBAF (0.30 mL, 0.30 mmol) at rt, after the addition was finished, the reaction was stirred at rt for 2 h. The residue was purified by purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) afford the mixture of isomers. The enantiopure title compounds were resolved by chiral SFC (Amylose-1; 250mm*30mm,5um; 55% 0.1%NH₃H₂O EtOH). The faster-eluting isomer was obtained (Example 61).¹H NMR (500 MHz, CD₃OD) δ 8.27 - 8.29 (m, 1H), 7.98 - 8.02 (m, 2H), 7.92 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.42 (dd, J = 8.3, 2.1 Hz, 1H), 7.05 (d, J = 9.4 Hz, 1H), 5.46 - 5.52 (m, 1H), 4.49 - 4.58 (m, 1H), 4.25 (dd, J = 11.5, 7.6 Hz, 1H), 4.13 (dd, J = 11.5, 5.4 Hz, 1H), 3.68 - 3.76 (m, 4H), 3.54 - 3.63 (m, 1H), 2.88 - 2.95 (m, 2H), 2.19 - 2.30 (m, 2H), 1.89 (br d, J = 3.9 Hz, 2H), 0.91 - 0.98 (m, 1H), 0.26 - 0.33 (m, 1H). MS = 503.3 (M+1). The slower-eluting isomer was obtained (Example 62).¹H NMR (500 MHz, CD₃OD) δ 8.19 - 8.23 (m, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.95 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 8.9, 2.5 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.48 (d, J = 8.8 Hz, 1H), 5.35 (dd, J = 8.0, 5.0 Hz, 1H), 4.50 - 4.58 (m, 1H), 4.29 (dd, J = 11.6, 8.2 Hz, 1H), 4.04 (dd, J = 11.6, 5.0 Hz, 1H), 3.65 (d, J=9.9 Hz, 2H) 3.54 - 3.61 (m, 1H), 3.39 (br d, J = 8.7 Hz, 2H), 2.86 - 2.96 (m, 2H), 2.19 - 2.30 (m, 2H), 1.66 - 1.72 (m, 2H), 0.74 - 0.80 (m, 1H), 0.15 - 0.22 (m, 1H). MS = 503.3 (M+1). Table 10. The following compounds were prepared using procedures similar to those described for Examples 61 and 62 using the appropriate intermediate or starting materials. 25208 Examples 65 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide Step 1: (2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methanol: [0182] To a stirred solution of (2-chloropyrimidin-5-yl)methanol (100 mg, 0.692 mmol) in MeOH (4.60 mL) at rt was added TEA (0.58 mL, 4.2 mmol) and 3-azabicyclo[3.1.0]hexane oxalate (359 mg, 2.08 mmol). The mixture was stirred at 50 °C overnight. An additional aliquot of 3-azabicyclo[3.1.0]hexane oxalate (359 mg, 2.08 mmol) and TEA (0.58 mL, 4.2 mmol) were added and the reaction was stirred at 50 °C overnight. The reaction was quenched with satd. aq. NaHCO₃ and extracted with DCM. The combined organic phases were dried over MgSO₄, filtered and the filtrate was concentrated to give the title compound. MS = 192.0 (M+1). Step 2: Methyl 1-((2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4- carboxylate: 25208 [0183] Methyl 1H-pyrazole-4-carboxylate (107 mg, 0.847 mmol) and Ph₃P (222 mg, 0.847 mmol) were added to a stirred solution of (2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5- yl)methanol (81 mg, 0.42 mmol) in toluene (4.2 mL) at rt and the mixture was stirred at rt for 15 min. DIAD (195 mg, 0.847 mmol) was added. The reaction mixture was stirred at 80 °C overnight. The mixture was diluted with water and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0 - 100% EtOAc/hexane) to give the title compound. MS = 300.1 (M+1). Step 3: 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid: [0184] Lithium hydroxide (110 mg, 4.58 mmol) was added to a stirred solution of methyl 1-((2- (3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylate (137 mg, 0.458 mmol) in THF (2 mL) and water (0.5 mL) at rt, and the mixture was stirred at 60 °C overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0 - 80% EtOH/heptane) to give the title compound. MS = 286.2 (M+1). Step 4: 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-4-carboxamide: [0185] Hunig's base (64 µl, 0.37 mmol) and 1-((2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5- yl)methyl)-1H-pyrazole-4-carboxylic acid (18 mg, 0.061 mmol) were added to a stirred solution of 2-((cis)-3-aminocyclobutyl)-4-chlorobenzonitrile (2,2,2-trifluoroacetate) (53 mg, 0.12 mmol) in DMF (0.6 mL) at rt. HATU (46.6 mg, 0.123 mmol) was added and the mixture was stirred at rt for 4 h. The mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC on silica gel (8% MeOH/DCM) to give the title compound.¹H NMR (500 MHz, CDCl₃) δ: 8.29 (s, 2H), 7.81 (s, 1H), 7.76 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 8.2, 1.9 Hz, 1H), 5.95 (d, J = 7.7 Hz, 1H), 5.12 (s, 1H), 3.87 (d, J = 11.1 Hz, 2H), 3.55 (d, J = 8.8 Hz, 3H), 3.03 (m, 2H), 2.23 (m, 2H), 1.66 (m, 2H), 1.59 (s, 2H), 0.79 (m, 1H), 0.24 (m, 1H). MS = 474.3 (M+1). 25208 Example 66 N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-5-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-4H-1,2,4- triazole-3-carboxamide Step 1: Methyl 2-(4-((2-oxopyridin-1(2H)-yl)methyl)phenyl)acetate. [0186] Sodium hydride (296 mg, 7.40 mmol, 60% dispersion in mineral spirits) was added to a stirred mixture of pyridin-2(1H)-one (704 mg, 7.40 mmol) in DMF (15 mL) at 0 °C and the mixture was stirred at 0 °C for 10 min. To the mixture methyl 2-(4-(bromomethyl)phenyl)acetate (1.50 g, 6.17 mmol) was added and it was stirred at rt for 2 h. Water was added and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (2-5% EtOAc/petroleum ether) to afford the title compound. MS = 258.1 (M+1). Step 2: 2-(4-((2-Oxopyridin-1(2H)-yl)methyl)phenyl)acetohydrazide. [0187] Hydrazine hydrate (2.29 g, 38.9 mmol) was added to a stirred mixture of methyl 2-(4- ((2-oxopyridin-1(2H)-yl)methyl)phenyl)acetate (1.00 g, 3.89 mmol) in EtOH (20 mL) and the mixture was stirred at 80 °C for 2 h, then cooled to 0 °C. The residue was filtered and concentrated to give the title compounds, which was used directly without further purification. MS = 258.1 (M+1). Step 3: Ethyl 2-amino-2-(2-(2-(4-((2-oxopyridin-1 - yl)methyl)phenyl)acetyl)hydrazono)acetate. [0188] Ethyl 2-ethoxy-2-iminoacetate (575 mg, 3.96 mmol) was added to a stirred mixture of 2-(4-((2-oxopyridin-1(2H)-yl)methyl)phenyl)acetohydrazide (510 mg, 1.98 mmol) in EtOH (50 mL) and the mixture was stirred at rt for 12 h. The mixture was concentrated to give ethyl 2- amino-2-(2-(2-(4-((2-oxopyridin-1(2H)-yl)methyl)phenyl)acetyl)hydrazono). Crude material was used directly in the next step without further purification. MS = 357.1 (M+1). 25208 Step 4: Ethyl 5-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-4H-1,2,4-triazole-3-carboxylate. [0189] 4Å molecular sieves were added to a stirred mixture of ethyl 2-amino-2-(2-(2-(4-((2- oxopyridin-1(2H)-yl)methyl)phenyl)acetyl)hydrazono)acetate (700 mg, 1.96 mmol) in xylene (10 mL) and the mixture was stirred at 170 °C for 48 h. The mixture was concentrated to give a residue, and the residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford the title compound. MS = 339.2 (M+1). Step 5: N-(3-(3-Chlorophenyl)cyclobutyl)-5-(4-((2-oxopyridin-1 -yl)methyl)benzyl)-4H- 1,2,4-triazole-3-carboxamide. [0190] Trimethyl aluminum (0.47 mL, 0.95 mmol) was added to a stirred mixture of 3-(3- chlorophenyl)cyclobutanamine (86 mg, 0.47 mmol) in toluene (1 mL) at rt, and the mixture was stirred at rt for 10 min. Then a solution of ethyl 5-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)- 4H-1,2,4-triazole-3-carboxylate (80 mg, 0.24 mmol) in DCE (0.5 mL) was added and the mixture was stirred at 80 °C for 12 h. The mixture was concentrated to give a residue, the residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier). The residue was further purified by chiral SFC (Phenomenex-Amylose-1, 30 x 250mm, 50% (0.1% NH₃H₂O EtOH)).¹H NMR (400 MHz, d₆-DMSO) δ 8.94 (br s, 1H), 7.75 (dd, J = 6.8, 1.5 Hz, 1H), 7.52 (s, 1H), 7.40 (ddd, J = 9.1, 6.7, 2.2 Hz, 1H), 7.27-7.34 (m, 2H), 7.20-7.25 (m, 5H), 6.39 (d, J = 9.2 Hz, 1H), 6.22 (td, J = 6.8, 1.3 Hz, 1H), 5.05 (s, 2H), 4.36-4.52 (m, 1H), 4.06 (s, 2H), 3.03-3.21 (m, 1H), 2.55 (br dd, J = 8.1, 2.9 Hz, 2H), 2.21-2.38 (m, 2H). MS = 474.1 (M+1). Example 67 N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-((2-oxopyridin-1(2H)- yl)methyl)benzyl)-1H-pyrazole-4-carboxamide Step 1: Ethyl 1-(3-(difluoromethyl)-4-(((methylsulfonyl)oxy)methyl)benzyl)-1H-pyrazole-4- carboxylate. [0191] To a solution of ethyl 1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H-pyrazole-4- carboxylate (1.00 g, 3.22 mmol) in DCM (15 mL) was added TEA (4.49 mL, 32.2 mmol) and 25208 MsCl (2.51 mL, 32.2 mmol) at rt. The resulting mixture was stirred at rt for 1 h. The mixture was diluted by DCM, washed by water, dried over Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give crude title compound which was used directly. MS = 389.0 (M+1). Step 2: Ethyl 1-(3-(difluoromethyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4- carboxylate. [0192] To a solution of ethyl 1-(3-(difluoromethyl)-4-(((methylsulfonyl)oxy)methyl)benzyl)- 1H-pyrazole-4-carboxylate (200 g, 0.515 mmol) in DMF (4 mL) was added pyridin-2(1H)-one (98 mg, 1.0 mmol) and potassium carbonate (142 mg, 1.03 mmol) at rt. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with satd. aq. NH₄Cl and extracted with EtOAc, the organic layers were washed by water, dried over Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give the crude title compound, which was used directly. MS = 388.0 (M+1). Step 3: 1-(3-(Difluoromethyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4- carboxylic acid. [0193] To a solution of ethyl 1-(3-(difluoromethyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)- 1H-pyrazole-4-carboxylate (270 g, 0.697 mmol) in EtOH (2 mL) and water (2.0 mL) was added sodium hydroxide (139 mg, 3.48 mmol) at rt. The resulting mixture was stirred at rt for 3 h. The mixture was adjusted to pH 2~3 by addition of 2M HCl, the mixture was extracted with DCM, the organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give the crude title compound, which was used in the next step directly. MS = 360.0 (M+1). Step 4: N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-((2-oxopyridin-1(2H)- yl)methyl)benzyl)-1H-pyrazole-4-carboxamide. [0194] To a stirred solution of 1-(3-(difluoromethyl)-4-((2-oxopyridin-1(2H)- yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.278 mmol), DIEA (0.15 mL, 0.84 mmol), EDC (64.0 mg, 0.334 mmol) and HOBT (51.1 mg, 0.334 mmol) in DMF (3 mL) was added 3-(3-chlorophenyl)cyclobutanamine (50.6 mg, 0.278 mmol) at rt, and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated in a vacuum to give a residue, which was purified by prep-TLC (EtOAc). The product was further purified by chiral SFC (Amylose-C, 250 mm * 30 mm, 0.1% NH₃H₂O EtOH) to give the title compound. MS = 523.1 (M+H).¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.77 (s, 1H), 7.41 (s, 1H), 7.35 (ddd, J = 9.0, 6.8, 2.0 25208 Hz, 1H), 7.28 (br d, J = 1.5 Hz, 2H), 7.12-7.24 (m, 4H), 7.07 (br d, J = 3.4 Hz, 1H), 6.77-7.05 (m, 1H), 6.60 (d, J = 9.0 Hz, 1H), 6.20 (t, J = 6.6 Hz, 1H), 6.07 (br d, J = 7.8 Hz, 1H), 5.26 (d, J = 17.9 Hz, 4H), 4.52 (sxt, J = 8.2 Hz, 1H), 3.11-3.26 (m, 1H), 2.78-2.88 (m, 2H), 1.97-2.08 (m, 2H). MS = 523.1 (M+1). Example 68 N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-((2-oxopyrimidin-1 - yl)methyl)benzyl)-1H-pyrazole-4-carboxamide Step 1: 1-(3-(Difluoromethyl)-4-(hydroxymethyl)benzyl)-1H-pyrazole-4-carboxylic acid. [0195] To a solution of ethyl 1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H-pyrazole-4- carboxylate (200 mg, 0.645 mmol) in EtOH (1 mL) and water (1 mL) was added sodium hydroxide (129 mg, 3.22 mmol) at rt. The resulting mixture was stirred at rt for 2 h. The mixture was adjusted to pH 2~3 by addition of 2M HCl, the mixture was extracted with DCM, the organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give the crude title compound, which was used in next step directly. MS = 283.1 (M+1). Step 2: N-(3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H- pyrazole-4-carboxamide. [0196] To a stirred solution of 1-(3-(difluoromethyl)-4-(hydroxymethyl)benzyl)-1H-pyrazole- 4-carboxylic acid (150 mg, 0.531 mmol), DIPEA (0.28 mL, 1.6 mmol), EDC (122 mg, 0.638 mmol) and HOBT (98 mg, 0.64 mmol) in DMF (3 mL) was added 3-(3- chlorophenyl)cyclobutanamine (97 mg, 0.53 mmol) and the mixture was stirred at rt for 2 h. The mixture was concentrated in a vacuum to give a residue, which was purified by prep-TLC (EtOAc) to give the title compound. MS = 446.1 (M+1). Step 3: N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-((2-oxopyrimidin-1 - yl)methyl)benzyl)-1H-pyrazole-4-carboxamide. 25208 [0197] To a solution of N-(3-(3-chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4- (hydroxymethyl)benzyl)-1H-pyrazole-4-carboxamide (120 mg, 0.269 mmol) in DCM (5 mL) was added TEA (0.11 mL, 0.81 mmol) and MsCl (42 μL, 0.54 mmol) at rt. The resulting mixture was stirred at rt for 1 h. The mixture was concentrated in a vacuum to give a residue, which was dissolved in DMF (5 mL). To the mixture was added pyrimidin-2(1H)-one (51.7 mg, 0.538 mmol) and potassium carbonate (74.4 mg, 0.538 mmol), the mixture was stirred at rt for 16 h. The mixture was diluted by DCM, washed with water, dried over Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give a residue, which was purified by prep-TLC (10% MeOH/EtOAc). The resulting residue was further purified by chiral SFC (Amylose-C, 250 mm * 30 mm, 40% 0.1%NH₃H₂O ETOH) to give a crude product. The crude product was purified by was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to the title compound.¹H NMR (400 MHz, CD₃OD) δ 8.58-8.64 (m, 1H), 8.13-8.20 (m, 2H), 7.94 (s, 1H), 7.54 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.23-7.31 (m, 3H), 7.13-7.21 (m, 3H), 6.57 (dd, J = 6.5, 4.3 Hz, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 4.39-4.50 (m, 1H), 3.14-3.26 (m, 1H), 2.70-2.79 (m, 2H), 2.09-2.20 (m, 2H). MS = 524.2 (M+1). Example 69 and 70 N-(cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-(((1R,5S)-2-oxo-3- azabicyclo[3.1.0]hexan-3-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide and N-((cis)-3-(3- Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-(((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3- yl)methyl)benzyl)-1H-pyrazole-4-carboxamide Step 1: 1-(3-(Difluoromethyl)-4-((2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)benzyl)-1H- pyrazole-4-carboxylic acid. [0198] To a solution of 3-azabicyclo[3.1.0]hexan-2-one (150 mg, 1.55 mmol) and ethyl 1-(3- (difluoromethyl)-4-(((methylsulfonyl)oxy)methyl)benzyl)-1H-pyrazole-4-carboxylate (300 mg, 0.772 mmol) in DMF (4 mL) was added sodium hydride (62 mg, 1.55 mmol) at 0 °C. The resulting mixture was stirred at rt for 16 h. To this mixture was added water, and the reaction 25208 mixture was stirred at rt for 2 h. The mixture was adjusted to pH 2~3 by addition of 2M HCl, diluted with EtOAc, washed with water and brine. The organic layer was dried over Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give the crude title compound, which was used in the next step directly. MS = 362.1 (M+1). Step 2: N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-(((1R,5S)-2-oxo-3- azabicyclo[3.1.0]hexan-3-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide and N-( -3-(3- Chlorophenyl)cyclobutyl)-1-(3-(difluoromethyl)-4-(((1S,5R)-2-oxo-3-azabicyclo hexan-3- yl)methyl)benzyl)-1H-pyrazole-4-carboxamide. [0199] To a stirred solution of 1-(3-(difluoromethyl)-4-((2-oxo-3-azabicyclo[3.1.0]hexan-3- yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (160 mg, 0.443 mmol), DIEA (0.23 mL, 1.3 mmol), EDC (102 mg, 0.531 mmol) and HOBT (81 mg, 0.53 mmol) in DMF (3 mL) was added 3-(3-chlorophenyl)cyclobutanamine (80 mg, 0.44 mmol) at rt. The mixture was stirred at rt for 1 h. The reaction mixture was concentrated in a vacuum to give a residue, which was purified by prep-TLC (EtOAc) afford the mixture of diastereomers. The enantiopure title compounds were resolved by chiral SFC (AD; 250 mm * 30 mm; 45% 0.1% NH₃H₂O MEOH) to give a mixture of faster eluting Peak 1 and slower eluting peak 2. Peak 1 and peak 2 were separated again by chiral SFC (AS-H; 250 mm * 30 mm; 50% 0.1% NH₃H₂O ETOH). The faster eluting peak was further purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) (Example 69).¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.84 (s, 1H), 7.41 (s, 1H), 7.18-7.33 (m, 5H), 7.06 (d, J = 7.5 Hz, 1H), 6.58-6.93 (m, 1H), 6.33 (br d, J = 7.9 Hz, 1H), 5.32 (s, 2H), 4.47-4.57 (m, 3H), 3.40 (dd, J = 10.5, 6.1 Hz, 1H), 3.15-3.27 (m, 2H), 2.81-2.89 (m, 2H), 2.01-2.10 (m, 3H), 1.84-1.91 (m, 1H), 1.14 (td, J = 8.1, 4.8 Hz, 1H), 0.60-0.64 (m, 1H). >99.9% ee. MS = 525.1 (M+1). The slower-eluting peak was obtained after further purification by reverse phase HPLC (ACN/water with 0.05% TFA modifier) (Example 70).¹H NMR (400 MHz, CDCl₃) δ 7.95 (s, 1H), 7.86 (s, 1H), 7.40 (s, 1H), 7.16-7.30 (m, 5H), 7.06 (d, J = 7.5 Hz, 1H), 6.59-6.90 (m, 1H), 6.55 (br d, J = 7.5 Hz, 1H), 5.32 (s, 2H), 4.46-4.56 (m, 3H), 3.40 (dd, J = 10.5, 6.1 Hz, 1H), 3.15-3.26 (m, 2H), 2.78-2.88 (m, 2H), 2.00-2.12 (m, 3H), 1.88 (quin, J = 5.9 Hz, 1H), 1.14 (td, J = 8.0, 5.0 Hz, 1H), 0.59-0.64 (m, 1H).99.5% ee. MS = 525.1 (M+1). 25208 Example 71 N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(methylsulfonyl)-4-((2-oxopyridin-1 - yl)methyl)benzyl)-1H-pyrazole-4-carboxamide Step 1: Methyl 4-(bromomethyl)-3-(methylsulfonyl)benzoate. [0200] To a solution of methyl 4-methyl-3-(methylsulfonyl)benzoate (500 mg, 2.19 mmol) in CCl₄ (10 mL) was added NBS (390 mg, 2.19 mmol) and benzoyl peroxide (53.1 mg, 0.219 mmol). The mixture was heated to reflux for 8 h. The mixture was filtered and concentrated to afford the title compound.¹H NMR (400 MHz, CD₃OD) δ 8.61 (d, J = 1.7 Hz, 1H), 8.28 (dd, J = 2.0, 8.1 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 5.14 (s, 2H), 3.95 (s, 3H), 3.29 (s, 3H). Step 2: Methyl 3-(methylsulfonyl)-4-((2-oxopyridin-1 -yl)methyl)benzoate. [0201] The mixture of pyridin-2(1H)-one (208 mg, , methyl 4-(bromomethyl)-3- (methylsulfonyl)benzoate (560 mg, 1.82 mmol) and potassium carbonate (328 mg, 2.37 mmol) in ACN (6 mL) was stirred at 80 °C overnight. The reaction was cooled to rt and water was added. The mixture was extracted with DCM, the extracts were washed with water, brine and dried over anhydrous Na₂SO₄, filtered and concentrated to afford the crude product. The residue was purified by flash silica gel chromatography (50% EtOAc/petroleum ether) to afford the title compound. MS = 322.1 (M+1). Step 3: 1-(4-(Hydroxymethyl)-2-(methylsulfonyl)benzyl)pyridin-2 -one. [0202] LiBH₄ (15.8 mg, 0.728 mmol) was added to a stirred methyl 3- (methylsulfonyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzoate (117 mg, 0.364 mmol) in MeOH (1 mL) at 0 °C, and the mixture was stirred at rt for 18 h. Water was added and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The residue was used directly. MS = 294.1 (M+1). 25208 Step 4: Ethyl 1-(3-(methylsulfonyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4- carboxylate. [0203] DIAD (132 mg, 0.573 mmol) was added to a stirred mixture of 1-(4-(hydroxymethyl)-2- (methylsulfonyl)benzyl)pyridin-2(1H)-one (84 mg, 0.29 mmol), ethyl 1H-pyrazole-4-carboxylate (80 mg, 0.57 mmol) and Ph₃P (150 mg, 0.573 mmol) in toluene (1 mL) at rt, and the mixture was stirred at rt for 2 h. Water was added, and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na₂SO₄), filtered and the solvent was evaporated under reduced pressure. The residue was purified by prep-TLC ((2:1) EtOAc/petroleum ether) to give the title compound. MS = 416.1 (M+1). Step 5: 1-(3-(Methylsulfonyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4- carboxylic acid. [0204] Lithium hydroxide (17.8 mg, 0.424 mmol) was added to a stirred mixture of ethyl 1-(3- (methylsulfonyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (88 mg, 0.21 mmol) in THF (1 mL) and water (0.2 mL) at rt, and the mixture was heated with stirring at 50 °C for 18 h. The mixture was cooled and 1M HCl solution was added to adjust pH 5-6. The mixture was extracted with EtOAc, the organic extracts were concentrated. The residue was used directly in the next step. MS = 388.2 (M+1). Step 6: N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(3-(methylsulfonyl)-4-((2-oxopyridin-1 - yl)methyl)benzyl)-1H-pyrazole-4-carboxamide. [0205] 1-Methyl-1H-imidazole (21.2 mg, 0.258 mmol) was added to a stirred mixture of 1-(3- (methylsulfonyl)-4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (20 mg, 0.052 mmol), (cis)-3-(3-chlorophenyl)cyclobutanamine (9.4 mg, 0.052 mmol) and chloro- N,N,N',N'-tetramethylformamidinium hexafluorophosphate (16 mg, 0.057 mmol) in ACN (1 mL) at rt, and the mixture was stirred at rt for 30 min. The residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound.¹H NMR (500 MHz, CD₃OD) δ 8.21 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.98 (s, 1H), 7.83 (dd, J = 1.8, 6.7 Hz, 1H), 7.65 (ddd, J = 2.1, 6.8, 9.1 Hz, 1H), 7.53 (dd, J = 1.8, 8.2 Hz, 1H), 7.27-7.35 (m, 2H), 7.18-7.23 (m, 2H), 7.05 (d, J = 7.9 Hz, 1H), 6.61 (d, J = 8.9 Hz, 1H), 6.51 (dt, J = 1.2, 6.7 Hz, 1H), 5.61 (s, 2H), 5.48 (s, 2H), 4.43-4.54 (m, 1H), 3.20-3.31 (m, 1H), 2.73-2.85 (m, 2H), 2.12-2.24 (m, 2H). MS = 551.2 (M+1). 25208 Example 72 and 73 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-2-hydroxy-1-(4-(pyridin-2- ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxamide and N-((cis)-3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((R)-2-hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole- 4-carboxamide Step 1: 2-(4-Bromobenzyl)pyridine. [0206] 1-Bromo-4-(bromomethyl)benzene (275 mg, 1.10 mmol) was added dropwise to a suspension of activated zinc (379 mg, 5.80 mmol) in THF (2.5 mL). The reaction was warmed to rt, and the solution was filtered under an inert atmosphere into a mixture of 2-bromopyridine (1.73 g, 11.0 mmol)) and Pd(Ph₃P)₄ (9.9 mg, 0.0086 mmol) in THF (5 mL). The mixture was stirred at rt overnight and diluted with DCM, filtered, and dried over Na₂SO₄ and concentrated. The crude product was purified by flash silica gel chromatography (20% EtOAc/petroleum ether) to give the title compound. MS = 248.0, 250.0 (M+1). Step 2: 2-(4-Vinylbenzyl)pyridine. [0207] A solution of 2-(4-bromobenzyl)pyridine (1.12 g, 4.51 mmol), potassium vinyltrifluoroborate (726 mg, 5.42 mmol), PdCl₂(dppf) (991 mg, 1.354 mmol) and TEA (0.94 mL, 6.8 mmol) in EtOH (12 mL) was stirred at 90 °C for 4 h. The reaction mixture was concentrated, water was added, and the mixture was extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtrated, and concentrated to give the crude product. The crude product was purified by flash silica gel chromatography (0-10% EtOAc/petroleum ether) to give the title compound. MS = 196.2 (M+1). Step 3: 2-(4-(Oxiran-2-yl)benzyl)pyridine. [0208] A solution of 2-(4-vinylbenzyl)pyridine (580 mg, 2.97 mmol) in a 2:1 ratio of water:^tBuOH (10 mL) was treated with NBS (634 mg, 3.56 mmol) in portions and stirred at rt for 18 h. After cooling to 5 °C, a solution of NaOH (356 mg, 8.91 mmol) in water was added and the reaction was stirred for 1 h. The mixture was extracted with EtOAc. The combined organic 25208 fractions were washed with brine, dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (50% EtOAc/petroleum ether) to give the title compound. MS = 212.1 (M+1). Step 4: Ethyl 1-(2-hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxylate. [0209] To a solution of 2-(4-(oxiran-2-yl)benzyl)pyridine (300 mg, 1.42 mmol) and ethyl 1H- pyrazole-4-carboxylate (199 mg, 1.42 mmol) in ACN (1.0 mL) at rt was added yttrium(III) nitrate hexahydrate (54.4 mg, 0.142 mmol) and the mixture was stirred at rt for 15 h. The crude reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (50% EtOAc/petroleum ether) to give the title compound. MS = 352.2 (M+1). Step 5: 1-(2-Hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxylic acid. [0210] Lithium hydroxide monohydrate (14.3 mg, 0.341 mmol) was added to a stirred mixture of ethyl 1-(2-hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxylate (60 mg, 0.17 mmol) in THF (0.5 mL) and water (0.2 mL) at rt and the mixture was stirred at rt for 18 h. The residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound. MS = 324.2 (M+1). Step 6: N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-2-hydroxy-1-(4-(pyridin-2- ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxamide and N-((cis)-3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((R)-2-hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole- 4-carboxamide. [0211] 1-methyl-1H-imidazole (29.7 mg, 0.361 mmol)) was added to a stirred mixture of 1-(2- hydroxy-1-(4-(pyridin-2-ylmethyl)phenyl)ethyl)-1H-pyrazole-4-carboxylic acid, HCl (26 mg, 0.072 mmol), 2-((cis)-3-aminocyclobutyl)-4-chlorobenzonitrile (15 mg, 0.072 mmol)) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (22 mg, 0.079 mmol) in ACN (0.5 mL) at rt, and the mixture was stirred at rt for 30 min. The residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford the mixture of isomers. The enantiopure title compounds were resolved by chiral SFC (AD (250mm*30mm,10um); 55% 0.1% NH₃H₂O MEOH) to provide the faster-eluting isomer of the title compound (Example 72): ¹H NMR (400 MHz, CD₃OD) δ 8.44 - 8.37 (m, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.71 (dt, J = 1.7, 7.7 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.39 (dd, J = 2.0, 8.3 Hz, 1H), 7.29 - 7.20 (m, 6H), 5.44 (dd, J = 4.6, 8.6 Hz, 1H), 4.58 - 4.45 (m, 1H), 4.35 - 4.27 (m, 1H), 4.10 25208 (s, 2H), 4.08 - 4.02 (m, 1H), 3.64 - 3.51 (m, 1H), 2.96 - 2.82 (m, 2H), 2.29 - 2.15 (m, 2H). MS = 512.1 (M+1). The slower-eluting isomer (Example 73):¹H NMR (400 MHz, CD₃OD) δ 8.32 (td, J = 0.8, 5.0 Hz, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 7.62 (dt, J = 1.8, 7.6 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 2.0, 8.3 Hz, 1H), 7.19 - 7.09 (m, 6H), 5.36 (dd, J = 4.6, 8.6 Hz, 1H), 4.49 - 4.36 (m, 1H), 4.27 - 4.16 (m, 1H), 4.01 (s, 2H), 3.95 (d, J = 4.9 Hz, 1H), 3.55 - 3.39 (m, 1H), 2.88 - 2.73 (m, 2H), 2.20 - 2.04 (m, 2H). MS = 512.1 (M+1). Example 74 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-N-( -3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-3- Step 1: Ethyl 1-((2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-3- carboxylate. [0212] To a solution of (2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methanol (219 mg, 1.15 mmol), ethyl 1H-pyrazole-3-carboxylate (321 mg, 2.29 mmol) and DIAD (463 mg, 2.29 mmol) in THF (5 mL) was added triphenylphosphine (601 mg, 2.29 mmol) at 50 °C. The mixture was stirred at 50 °C for 12 h. The mixture was concentrated and purified by flash silica gel chromatography (0-100% EtOAc/petroleum ether) to give faster eluting ethyl 1-((2-(3- azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-5-carboxylate and slower eluting ethyl 1-((2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-3- carboxylate. The slower eluting peak was re-purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier): MS = 314.1 (M+1). Step 2: 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-3- carboxylate, lithium salt. [0213] The mixture of ethyl 1-((2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H- pyrazole-3-carboxylate (58.6 mg, 0.187 mmol) and lithium hydroxide monohydrate (23.5 mg, 0.561 mmol) in MeOH (1 mL), THF (1 mL) and water (0.5 mL) was stirred at 10 °C for 3 h. The 25208 solvent was evaporated to give the crude title compound, which was used in the next step without further purification. MS = 286.0 (M+1). Step 3: 1-((2-(3-Azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-1H-pyrazole-3-carboxamide. [0214] To a solution of 2-((cis)-3-aminocyclobutyl)-4-chlorobenzonitrile (29.0 mg, 0.140 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (51.1 mg, 0.182 mmol) and 1-((2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H- pyrazole-3-carboxylic acid (40 mg, 0.36 mmol) in ACN (2 mL) was added 1-methyl-1H- imidazole (34.5 mg, 0.421 mmol) and the mixture was stirred at rt for 12 h. The mixture was concentrated and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide the title compound, as a TFA salt.¹H NMR (400 MHz, CD₃OD) δ: 8.28 (s, 2H), 7.60 (br s, 1H), 7.46-7.52 (m, 2H), 7.23 (dd, J = 8.3, 1.7 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 5.10 (s, 2H), 4.33-4.44 (m, 1H), 3.65 (d, J = 11.2 Hz, 2H), 3.36-3.47 (m, 3H), 2.72 (qd, J = 7.9, 2.8 Hz, 2H), 2.08-2.21 (m, 2H), 1.47-1.65 (m, 2H), 0.61-0.70 (m, 1H), 0.02 (q, J = 4.3 Hz, 1H). MS = 474.2 (M+1). Example 75 2-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-2H- 1,2,3-triazole-4-carboxamide Step 1: (2-(Azetidin-1-yl)pyrimidin-5-yl)methanol. [0215] To a solution of (2-chloropyrimidin-5-yl)methanol (1.00 g, 6.92 mmol) and azetidine hydrochloride (971 mg, 10.4 mmol) in dioxane (20 mL) was added TEA (4.8 mL, 35 mmol). The mixture was stirred at rt for 16 h. Water was added and it was extracted with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in a vacuum. The reaction mixture was purified by flash silica gel chromatography (0-100% EtOAc/ petroleum ether) to give the title compound. MS = 166.1 (M+1). 25208 Step 2: Methyl 2-((2-(azetidin-1-yl)pyrimidin-5-yl)methyl)-2H-1,2,3-triazole-4-carboxylate. [0216] To a solution of (2-(azetidin-1-yl)pyrimidin-5-yl)methanol (500 mg, 3.03 mmol), methyl 1H-1,2,3-triazole-4-carboxylate (769 mg, 6.05 mmol) and Ph₃P (1.59 g, 6.05 mmol) in THF (30 mL) was added DBAD (1.39 g, 6.05 mmol) at rt. The mixture was stirred at 80 °C for 1.5 h. The mixture was concentrated and purified by flash silica gel chromatography (0-100% EtOAc/ petroleum ether) to give the title compound. MS = 275.1 (M+1). Step 3: 2-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-2H-1,2,3-triazole-4-carboxylic acid. [0217] To a stirred solution of methyl 2-((2-(azetidin-1-yl)pyrimidin-5-yl)methyl)-2H-1,2,3- triazole-4-carboxylate (100 mg, 0.365 mmol) in MeOH (2 mL) was added lithium hydroxide (43.7 mg, 1.82 mmol) in water (0.4 mL), the mixture was stirred at rt for 16 h. The mixture was concentrated and purified by purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide the title compound. MS = 261.1 (M+1). Step 4: 2-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)-2H-1,2,3-triazole-4-carboxamide. [0218] To a solution of 2-((2-(azetidin-1-yl)pyrimidin-5-yl)methyl)-2H-1,2,3-triazole-4- carboxylic acid (16 mg, 0.062 mmol) in ACN (1 mL) was added 1-methyl-1H-imidazole (15.4 mg, 0.187 mmol), 2-(3-aminocyclobutyl)-4-chlorobenzonitrile 2,2,2-trifluoroacetate (25 mg, 0.062 mmol), N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V) (21 mg, 0.075 mmol), the mixture was stirred at rt for 2 h. The mixture was concentrated and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide the title compound, as a TFA salt.¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 2H), 8.05 (s, 1H), 7.52-7.57 (m, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.40-7.44 (m, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.27-7.32 (m, 1H), 7.30 (dd, J = 8.2, 2.0 Hz, 1H), 6.99 (br d, J = 7.8 Hz, 1H), 5.43 (s, 2H), 4.55- 4.65 (m, 1H), 4.31 (t, J = 7.6 Hz, 4H), 3.44-3.62 (m, 1H), 2.90-3.09 (m, 2H), 2.48 (quin, J = 7.6 Hz, 2H), 2.17-2.33 (m, 2H). MS = 449.1 (M+1). Example 76 25208 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-( -3-(5-chloro-2-cyanophenyl)cyclobutyl)- 1,2,4-triazole- Step 1: Methyl 1-((2-(azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-1,2,4-triazole-3-carboxylate. [0219] To a solution of triphenylphosphine (1.27 g, 4.84 mmol), DBAD (1.12 g, 4.84 mmol) and (2-(azetidin-1-yl)pyrimidin-5-yl)methanol (400 mg, 2.42 mmol) in THF (10 mL) was added methyl 1H-1,2,4-triazole-3-carboxylate (616 mg, 4.84 mmol) at 50 °C. The mixture was stirred at 50 °C for 4 h. The mixture was concentrated under vacuum. The crude product was purified by flash silica gel chromatography (0-100% MeOH/EtOAc) to give methyl 1-((2-(azetidin-1- yl)pyrimidin-5-yl)methyl)-1H-1,2,4-triazole-5-carboxylate (faster-eluting peak) and a mixture of another two isomers (slower eluting peak). The slower eluting peak was purified by prep-TLC (10% MeOH/DCM) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ: 8.30 (s, 2H), 8.14 (s, 1H), 5.21 (s, 2H), 4.13 (t, J = 7.4 Hz, 4H), 3.94 (s, 3H), 2.35 (quin, J = 7.6 Hz, 2H). MS = 274.9 (M+1). Step 2: 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-1,2,4-triazole-3-carboxylic acid. [0220] The mixture of methyl 1-((2-(azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-1,2,4-triazole-3- carboxylate (46.7 mg, 0.170 mmol) and lithium hydroxide, H₂O (21.4 mg, 0.511 mmol) in MeOH (1mL), THF (1mL) and water (0.5 mL) was stirred at 15 °C for 1 h. The mixture was diluted with 1M HCl to pH 6 and concentrated. The crude product was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide the title compound MS = 260.9 (M+1). Step 3: 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-((cis)-3-(5-chloro-2- cyanophenyl)cyclobutyl)- triazole-3-carboxamide. [0221] To a solution of 1- 1-yl)pyrimidin-5-yl)methyl)-1H-1,2,4-triazole-3- carboxylic acid (13 mg, 0.051 mmol), EDC (29.4 mg, 0.153 mmol) and pyridine (17 μL, 0.20 mmol) in DCM (2 mL) was added 2-((cis)-3-aminocyclobutyl)-4-chlorobenzonitrile (16 mg, 0.077 mmol), the mixture was stirred at 15 °C for 1 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layers were collected, dried over Na₂SO₄, concentrated by vacuum. The crude product was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ: 8.32 (s, 2H), 8.15 (br s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.29 (d, J = 2.0 Hz, 1H), 5.20 (s, 2H), 25208 4.56-4.66 (m, 1H), 4.16 (t, J = 7.6 Hz, 4H), 3.54 (br t, J = 9.4 Hz, 1H), 2.99 (br d, J = 7.0 Hz, 2H), 2.39 (br t, J = 7.6 Hz, 2H), 2.21-2.29 (m, 2H). MS = 449.1 (M+1). Example 77 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)-1H-1,2,3-triazole-4-carboxamide Step 1: tert-Butyl 6-(azidomethyl)-3,4-dihydroisoquinoline-2 -carboxylate. [0222] tert-Butyl 6-(hydroxymethyl)-3,4- -carboxylate (400 mg, 1.50 mmol) was mixed with DPPA (500 mg, 1.80 mmol) in toluene (2.0 mL). DBU (0.28 mL, 1.8 mmol) in DCM (1.0 mL) was added. The resulting mixture was stirred at 45 °C for 15 h. The mixture was diluted with EtOAc, and washed with 1M HCl solution and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash silica gel chromatography (0-100% EtOAc/hexane) to give the title compound. MS = 289.2 (M+1). Step 2: tert-Butyl 6-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-3,4-dihydroisoquinoline- 2 -carboxylate. tert-Butyl 6-(azidomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (270 mg, 0.940 mmol) was mixed with ethyl propiolate (0.19 mL, 1.9 mmol) in EtOH (2 mL). A solution of copper(II) sulfate pentahydrate (47 mg, 0.19 mmol) in water (1 mL) was added. Then a solution of (S)-5-((S)-1,2-dihydroxyethyl)-3-hydroxyfuran-2(5H)-one, sodium salt (34 mg, 0.19 mmol) in water (1 mL) was added dropwise. The mixture was stirred at rt overnight. The product was extracted with EtOAc and washed with water and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude was purified by flash silica gel chromatography (0-100% EtOAc/Hexane) to give the title compound. MS = 387.3 (M+1). Step 3. Lithium 1-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-1H- 1,2,3-triazole-4-carboxylate. 25208 [0224] tert-Butyl 6-((4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl)methyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (310 mg, 0.800 mmol) was mixed with LiOH (38 mg, 1.6 mmol) in a mixed solvent of THF (2 mL) and water (0.7 mL). The mixture was stirred at 40 °C for 3 h, then was concentrated, and co-evaporated with toluene in a rotavapor to dryness to give the title compound. MS = 359.3 (M+1). Step 4. tert-Butyl 6-((4-(( -3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamoyl)- 1,2,3- triazol-1-yl)methyl)-3,4- 2 -carboxylate. [0225] Lithium 1-((2-(tert-butoxycarbonyl)- tetrahydroisoquinolin-6-yl)methyl)-1H- 1,2,3-triazole-4-carboxylate (150 mg, 0.410 mmol) was mixed with 2-((cis)-3-aminocyclobutyl)- 4-chlorobenzonitrile, HCl (100 mg, 0.410 mmol), and DIEA (220 µl, 1.23 mmol) in DMF (1.6 mL). HATU (157 mg, 0.410 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (0-100% EtOAc/hexane) to provide the title compound. MS = 547.3 (M+1). Step 5. N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)- triazole-4-carboxamide. [0226] tert-Butyl 6-((4-(((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamoyl)-1H-1,2,3- triazol-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (130 mg, 0.238 mmol) was treated with 4M HCl in dioxane (3 mL, 12 mmol) at rt for 1 h. The mixture was concentrated to dryness to give the title product as an HCl salt. MS = 447.2 (M+1) Step 6. N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((2-ethyl-1,2,3,4- 6-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. [0227] N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)-1H-1,2,3-triazole-4-carboxamide, HCl (30 mg, 0.062 mmol) was mixed with acetaldehyde (0.050 mL, 0.25 mmol, 5M in THF) and MeOH (0.6 mL). Sodium cyanoborohydride (12 mg, 0.19 mmol) was added. The resulting mixture was stirred at rt for 1 h, then quenched with acetic acid (5 drops). The solution was then purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier), to give the title product as a TFA salt. MS = 475.4 (M+1).¹H NMR (500 MHz, CD₃OD): δ 1.46 (t, J = 7.5 Hz,3H), 2.37 (q, J = 10 Hz,2H), 2.93 (m, 25208 2H), 3.36-3.43 (m, 1H), 4.05 (t, J = 6.0 Hz, 4H), 4.39-4.46 (m, 1H), 5.19 (s, 2H), 7.33 (dd, J = 8.4, 2.4 Hz, 1H), 7.45 (d, J = 8.4Hz, 1H), 7.47 (d, J = 2.4Hz, 1H), 7.84 (s, 1H), 8.18 (d, J = 8.4Hz, 1H), 8.19 (s, 1H), 8.40 (s, 2H). Example 78 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide Step 1. N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((5-methyl-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. [0228] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, HCl (30 mg, 0.061 mmol) was mixed with formaldehyde (12 mg, 0.15 mmol) and sodium cyanoborohydride (12 mg, 0.18 mmol) in MeOH (0.3 mL), and stirred at rt for 1 h. The mixture was diluted with DMF, then acidified with TFA (3 drops). The solution was then purified by purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide the title compound. MS = 468.3 (M+H).¹H NMR (500 MHz, CD₃OD): δ 2.33-2.43 (m, 2H), 2.88-2.99 (m, 2H), 3.11 (s, 3H), 3.21 (m, 2H), 3.55-3.85 (m, 3H), 4.45-4.75 (m, 3H), 6.04 (s, 2H), 7.43 (d, J = 8.5 Hz, 1H), 7.68 (m, 2H), 8.54 (s, 1H). Example 79 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((5-ethyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide 25208 Step 1. N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((5-ethyl- [5,4-c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4- [0229] N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (30 mg, 0.053 mmol) was mixed with acetaldehyde (42 μL, 0.21 mmol, 5M in THF) in MeOH (0.35 mL). Sodium cyanoborohydride (10 mg, 0.16 mmol) was added, and the resulting mixture was stirred at rt for 15 h. The mixture was acidified with TFA (4 drops) and was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier), to give the title compound. MS = 482.3 (M+H).¹H NMR (500 MHz, CD₃OD): δ 1.45 (t, J = 7.5 Hz, 3H), 2.33-2.44 (m, 2H), 2.90-2.99 (m, 2H), 3.20 (m, 2H), 3.39- 3.47 (m, 2H), 3.57-3.70 (m, 2H), 3.75 (br, 1H), 4.55 (br, 1H), 4.62 (m, 2H), 6.05 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.69 (m, 2H), 8.53 (s, 1H). Example 80 N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-3-((3-chloroquinolin-6-yl)methyl)-1H-1,2,4- triazole-5-carboxamide Step 1. N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-3-((3-chloroquinolin-6-yl)methyl)-1H- 1,2,4- carboxamide. [0230] Lithium 3-((3-chloroquinolin-6-yl)methyl)-1H-1,2,4-triazole-5-carboxylate (25 mg, 0.085 mmol) was mixed with 2-((cis)-3-aminocyclobutyl)-4-chlorobenzonitrile, HCl (28 mg, 0.10 mmol), and DIEA (59 µl, 0.34 mmol) in DMF (420 µl). HATU (36 mg, 0.093 mmol) was added. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with MeOH and was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier), to give the product as a TFA salt. MS (ESI) m/z 477.0 (M+H).¹H NMR (500 MHz, d₆-DMSO): δ 2.36-2.45 (m, 2H), 2.65-2.73 (m, 2H), 3.40-3.52 (m, 1H), 4.34 (s, 2H), 4.50-4.62 (m, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.80 (m, 2H), 7.92 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 8.57 (s, 1H), 8.86 (s, 1H), 9.02 (s, br, 1H). 25208 Example 81 and 82 N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-2-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-2H-1,2,3- triazole-4-carboxamide and N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(4-((2-oxopyridin-1(2H)- yl)methyl)benzyl)-1H-1,2,3-triazole-4-carboxamide Step 1. Methyl 2-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-2H-1,2,3-triazole-4-carboxylate and Methyl 1-(4-((2-oxopyridin-1 -yl)methyl)benzyl)-1H-1,2,3-triazole-4-carboxylate. [0231] To a solution of 1,2,3-triazole-4-carboxylate (466 mg, 3.67 mmol) in DMF (20 mL) was added 1-(4-(bromomethyl)benzyl)pyridin-2(1H)-one (850 mg, 3.06 mmol) and potassium carbonate (16.9 mg, 12.2 mmol)in DMF (20 mL), and the mixture was stirred at 40 °C overnight. The mixture was diluted with water, extracted with DCM, and the combined organic ^{phases were washed with brine, dried over MgSO} ₄ ^{and concentrated. The residue was purified} by flash silica gel chromatography (0-80% EtOAc/Hexane) to give the title compounds. MS = 324.9 (M+1). Step 2.2-(4-((2-Oxopyridin-1(2H)-yl)methyl)benzyl)-2H-1,2,3-triazole-4-carboxylic acid and 1- (4-((2-Oxopyridin-1(2H)-yl)methyl)benzyl)-1H-1,2,3-triazole-4-carboxylic acid. [0232] LiOH (207 mg, 8.63 mmol) was added to a stirred solution of methyl 2-(4-((2- oxopyridin-1(2H)-yl)methyl)benzyl)-2H-1,2,3-triazole-4-carboxylate and methyl 1-(4-((2- oxopyridin-1(2H)-yl)methyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (700 mg, 2.16 mmol) in 1,4-dioxane (6 mL) and water (6 mL). The mixture was stirred at 50 °C for 4 h, then diluted with water and extracted with DCE. The combined organic phases were washed with brine, dried over MgSO₄ and concentrated under reduced pressure to give the crude products. MS = 310.8 (M+1). Step 3. N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-2-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)- 2H-1,2,3-triazole-4-carboxamide and N-((cis)-3-(3-Chlorophenyl)cyclobutyl)-1-(4-((2- oxopyridin-1(2H)-yl)methyl)benzyl)-1H-1,2,3-triazole-4-carboxamide. 25208 [0233] DIEA (190 µL, 1.04 mmol) and (cis)-3-(3-chlorophenyl)cyclobutan-1-amine (47.4 mg, 0.261 mmol) were added to a stirred solution of 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)- 1H-1,2,3-triazole-4-carboxylic acid and 2-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-2H-1,2,3- triazole-4-carboxylic acid (54 mg, 0.17 mmol) in DMF (1.7 mL). The mixture was stirred at rt for 5 min, and HATU (165 mg, 0.435 mmol) was added. The reaction mixture was stirred for 3 h, then quenched with satd. aq. NaHCO₃ and extracted with DCM. The combined organic fractions were dried over MgSO₄, filtered and concentrated. The residue was purified by preparative TLC (100% EtOAc) to give the title compounds (two regioisomers). The faster eluting isomer: MS = 474.4 (M+1).¹H NMR (500 MHz, CDCl₃) δ 8.07 (s, 1H), 7.37 – 7.17 (m, 9H), 7.11 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 9.2 Hz, 1H), 6.17 (t, J = 6.2 Hz, 1H), 5.57 (s, 2H), 5.14 (s, 2H), 4.59 (q, J = 8.2 Hz, 1H), 3.26 (p, J = 10.0 Hz, 1H), 2.89 (qd, J = 7.7, 2.8 Hz, 2H), 2.17 – 2.07 (m, 2H). The slower eluting isomer: MS = 474.4 (M+1).¹H NMR (500 MHz, CDCl₃) δ 7.95 (s, 1H), 7.39 – 7.31 (m, 3H), 7.29 – 7.24 (m, 5H), 7.24 – 7.18 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.19 (td, J = 6.7, 1.3 Hz, 1H), 5.55 (s, 2H), 5.16 (s, 2H), 4.59 (q, J = 7.5 Hz, 1H), 3.25 (ddd, J = 17.9, 10.2, 7.8 Hz, 1H), 2.93 – 2.84 (m, 2H), 2.14 (qd, J = 9.3, 2.8 Hz, 2H). Example 83 and 84 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-((cis)-3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((S)-1-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl)-1H-1,2,3- triazole-4-carboxamide Step 1: 6-Bromo-3-methylquinazolin-4 -one. [0234] 2-Amino-5-bromobenzoic g, 55.5 mmol) was reacted with N- methylformamide (50.0 mL, 55.5 mmol) at rt, and the mixture was stirred at 180 °C for 8 h. The 25208 mixture was cooled to rt, water was added, and the solvent was evaporated to give the title compound. MS = 238.9 (M+1). Step 2: 6-Acetyl-3-methylquinazolin-4 -one. [0235] Tetrakis (triphenylphosphine) (0) (1.45 g, 1.26 mmol) was dissolved in toluene (15 mL), then tributyl(1-ethoxyvinyl)stannane (5.05 mL, 15.0 mmol) and 6-bromo-3- methylquinazolin-4(3H)-one (3.00 g, 12.6 mmol) were added at rt. The resulting mixture was stirred for 18 h at 130 °C, cooled to rt, then 6M HCl was added, and the mixture was stirred at rt for 1 h. Water was added, and the mixture was extracted with DCM. The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash silica gel chromatography (50% EtOAc/petroleum ether) to give the title compound. MS = 203.0 (M+1). Step 3: 6-(1-Hydroxyethyl)-3-methylquinazolin-4 -one. [0236] NaBH₄ (140 mg, 3.71 mmol) was added to a mixture of 6-acetyl-3- methylquinazolin-4(3H)-one (1.50 g, 7.42 mmol) in THF (10 mL) at 0 °C, and the mixture was stirred at rt for 1 h. Satd. aq NH₄Cl was added, and the mixture was extracted with DCM. The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (65% EtOAc/petroleum ether) to give the title compound. MS = 205.1 (M+1). Step 4: 6-(1-Azidoethyl)-3-methylquinazolin-4(3H)-one. [0237] To a solution of 6-(1-hydroxyethyl)-3-methylquinazolin-4(3H)-one (700 mg, 3.43 mmol), triphenylphosphine (1.35 mg, 5.14 mmol) and DPPA (3.69 ml, 17.1 mmol) in THF (10 mL) was added DIAD (1.01 mL, 5.14 mmol) at 0 °C. The mixture was warmed to rt, water was added, and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash silica gel chromatography (100% EtOAc/petroleum ether) to give the title compound. MS = 230.0 (M+1). Step 5: Methyl 1-(1-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl)-1H-1,2,3-triazole-4- carboxylate. 25208 [0238] The mixture of 6-(1-azidoethyl)-3-methylquinazolin-4(3H)-one (800 mg, 0.872 mmol), methyl propiolate (95.0 mg, 1.13 mmol), copper(II) sulfate pentahydrate (43.6 mg, 0.174 mmol) and sodium ascorbate (190 mg, 0.960 mmol) in tert-butanol (1 mL) and water (1 mL) was stirred at 45 °C for 14 h. The mixture was diluted with satd. aq. NaHCO₃, and the aq. layer was extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (80% EtOAc/petroleum ether) to give the title compound. MS = 314.1 (M+1). Step 6: 1-(1-(3-Methyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid. [0239] Lithium hydroxide hydrate (33.5 mg, 0.798 mmol) was added to a stirred mixture of methyl 1-(1-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (50 mg, 0.16 mmol) in THF (2 mL) and water (0.4 mL) at rt, and the mixture was stirred at rt for 2 h. The reaction was adjusted to pH 6 with 1M HCl and extracted with DCM. The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to give the title compound. The crude material used directly without further purification. MS = 300.1 (M+1). Step 7: N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-( 3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((S)-1-(3-methyl-4-oxo-3,4- ethyl)-1H-1,2,3- triazole-4-carboxamide. [0240] N-((ethylimino)methylene)- N,N-dimethylpropane-1,3-diamine hydrochloride (28.8 mg, 0.150 mmol) was added to a stirred mixture of 1-(1-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (30 mg, 0.10 mmol), 2-((cis)-3-aminocyclobutyl)-4- chlorobenzonitrile 2,2,2-trifluoroacetate (32 mg, 0.10 mmol) in pyridine (2 mL) at rt, and the mixture was stirred at rt for 12 h. The mixture was evaporated under reduced pressure. The residue was purified by purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) afford the mixture of diastereomers. The enantiopure title compounds were resolved by SFC (AD; 55% 0.1% NH₃H₂O EtOH in CO₂). The faster eluting isomer (Example 83): ¹H NMR (500 MHz, d₆-DMSO) δ 8.95 (d, J = 9.0 Hz, 1H), 8.86 (s, 1H), 8.38 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.79-7.83 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 6.22 (q, J = 7.0 Hz, 1H), 4.50-4.61 (m, 1H), 3.48 (s, 3H), 2.67-2.73 (m, 2H), 2.62-2.65 (m, 25208 1H), 2.36 (br dd, J = 3.7, 1.8 Hz, 2H), 1.98 (d, J = 7.2 Hz, 3H). MS = 488.2 (M+1). The slower eluting isomer (Example 84): ¹H NMR (500 MHz, d₆-DMSO) δ 8.96 (d, J = 8.9 Hz, 1H), 8.86 (s, 1H), 8.38 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.78-7.83 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 6.23 (q, J = 7.1 Hz, 1H), 4.50-4.61 (m, 1H), 3.48 (s, 3H), 2.66-2.74 (m, 2H), 2.63 (br s, 1H), 2.34-2.38 (m, 2H), 1.98 (d, J = 7.0 Hz, 3H) MS = 488.1 (M+1). Example 85 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-((trans)-3-(3-chlorophenyl)-3-fluorocyclobutyl)- 1H-pyrazole-4-carboxamide Step 1: tert-Butyl (3-(3-chlorophenyl)-3-hydroxycyclobutyl)carbamate. [0241] To a solution of 1-bromo-3-chlorobenzene (3.10 g, 16.2 mmol) in THF (20 mL) was added n-butyllithium (6.48 mL, 16.2 mmol, 3M in hexanes) dropwise at -78 °C. The mixture was stirred under a nitrogen atmosphere at -78 °C for 20 min and a solution of tert-butyl (3- oxocyclobutyl)carbamate (1.50 g, 8.10 mmol) in THF (1.5 mL) was added into the reaction mixture dropwise. The mixture was stirred at -78 °C for 1 h, then poured into satd. aq. NH₄Cl and extracted with EtOAc. The organic layer was dried by anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by flash silica gel chromatography (0- 30% EtOAc/petroleum ether) to give the title compound. MS = 223.9 (M+1-56-18). Step 2: 3-Amino-1-(3-chlorophenyl)cyclobutanol. [0242] To a solution of tert-butyl (3-(3-chlorophenyl)-3-hydroxycyclobutyl)carbamate (500 mg, 1.68 mmol) in DCM (2 mL) was added TFA (0.2 mL) dropwise at rt. The mixture was stirred at rt for 0.5 h, and the reaction mixture was concentrated under vacuum to give the title compound as a TFA salt, which was used in next step directly. MS = 198.0 (M+1). 25208 Step 3: 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-(3-(3-chlorophenyl)-3- hydroxycyclobutyl)-1H-pyrazole-4-carboxamide. [0243] To a stirred solution of 1-((2-(azetidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4- carboxylic acid (300 mg, 0.903 mmol), TEA (252 μL, 1.81 mmol) and HATU (412 mg, 1.08 mmol) in DMF (3 mL) was added 3-amino-1-(3-chlorophenyl)cyclobutanol (178 mg, 0.903 mmol) at rt. After the mixture was stirred at rt for 3 h, the mixture was concentrated in a vacuum to give crude product, which was purified by prep-TLC (50% EtOAc/petroleum ether) to give the title compound. MS = 439.2 (M+1). Step 4: 1-((2-(Azetidin-1-yl)pyrimidin-5-yl)methyl)-N-( 3-(3-chlorophenyl)-3- fluorocyclobutyl)-1H-pyrazole-4-carboxamide. [0244] To a stirred solution of 1-((2-(azetidin-1-yl)pyrimidin-5-yl)methyl)-N-(3-(3- chlorophenyl)-3-hydroxycyclobutyl)-1H-pyrazole-4-carboxamide (120 mg, 0.273 mmol) in DCM (2 mL) was added a solution of DAST (0.11 mL, 0.82 mmol) in DCM (0.2 mL) at -78 °C. The mixture was stirred at -30 °C for 1 h, then satd. aq. NaHCO₃ was added, and the mixture was extracted with DCM. The organic layers were dried by Na₂SO₄, filtered and the filtrate was concentrated in a vacuum to give the crude product, which was purified by prep-TLC (EtOAc) to afford a mixture of cis/trans isomer. The isomers were separated by chiral SFC (Amylose-C; 40% 0.1% NH₃H₂O IPA) to provide the faster eluting isomer (trans isomer, Example 85) which was further purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 2H), 7.86 (s, 1H), 7.76 (s, 1H), 7.41 (s, 1H), 7.28 - 7.35 (m, 3H), 6.24 (br d, J = 5.1 Hz, 1H), 5.12 (s, 2H), 4.69 - 4.90 (m, 1H), 4.25 (br t, J = 7.5 Hz, 4H), 2.93 - 3.12 (m, 2H), 2.57 - 2.74 (m, 2H), 2.44 - 2.49 (m, 2H). MS = 441.2 (M+1). Example 86 and 87 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2-cyclopropylimidazo[1,2- a]pyridin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-((cis)-3-(5-Chloro-2- 25208 cyanophenyl)cyclobutyl)-1-((R)-1-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)ethyl)-1H-1,2,3- triazole-4-carboxamide Step 1: 6-Bromo-2-cyclopropylimidazo[1,2-a]pyridine. [0245] 5-Bromopyridin-2-amine (5.00 g, 28.9 mmol) was added to a stirred mixture of 2- bromo-1-cyclopropylethanone (7.07 g, 43.3 mmol) in EtOH (160 mL) at rt, and the mixture was stirred at 90 °C for 12 h. The mixture was concentrated, water was added, and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by flash silica gel chromatography (0-100% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 8.09-8.25 (m, 1H), 7.39 (d, J = 9.5 Hz, 1H), 7.33 (s, 1H), 7.16 (dd, J = 9.5, 2.0 Hz, 1H), 1.93-2.09 (m, 1H), 0.77-1.16 (m, 4H). MS = 237.0 (M+1). Step 2: 1-(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)ethanone. [0246] 6-Bromo-2-cyclopropylimidazo[1,2-a]pyridine (2.60 g, 11.0 mmol) was dissolved in toluene (40 mL), then tributyl(1-ethoxyvinyl)stannane (5.55 mL, 16.5 mmol) and (PPh₃)₂PdCl₂ (770 mg, 1.10 mmol) were added at rt. The mixture was stirred at 90 °C for 16 h, then cooled to rt, and 6M HCl was added. The mixture was stirred at rt for 1 h. The mixture was extracted with EtOAc, the combined organic fractions were washed with satd. aq. KF and brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by flash silica gel chromatography (0-100% EtOAc/petroleum ether) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 8.61-8.78 (m, 1H), 7.62 (dd, J = 9.3, 1.7 Hz, 1H), 7.33-7.52 (m, 2H), 2.57 (s, 3H), 2.02 (tt, J = 8.0, 5.3 Hz, 1H), 0.88-1.05 (m, 4H). Step 3: 1-(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)ethanol [0247] To a solution of 1-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)ethanone (1.00 g, 4.99 mmol) in THF (10 mL) and MeOH (2 mL) was added NaBH₄ (227 mg, 5.99 mmol) at 0 °C. The reaction was stirred at rt for 1 h, satd. aq. NH₄Cl was added, then the aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 7.83-8.09 (m, 1H), 7.34 (d, J = 9.3 Hz, 1H), 7.24 (s, 1H), 7.03 (dd, J = 9.3, 1.5 Hz, 1H), 4.74-5.00 (m, 1H), 1.91-2.08 (m, 2H), 1.49 (d, J = 6.4 Hz, 3H), 0.61-1.17 (m, 4H). MS = 203.1(M+1). Step 4: 6-(1-Chloroethyl)-2-cyclopropylimidazo[1,2-a]pyridine 25208 [0248] 1-(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)ethanol (310 mg, 1.53 mmol) was added to a stirred mixture of sulfurous dichloride (0.56 mL, 7.7 mmol) in DCM (4 mL) at 0 °C, and the mixture was stirred at rt for 2 h. The reaction was concentrated to give the title compound, which was used directly without further purification. MS = 221.1(M+1). Step 5: 6-(1-Azidoethyl)-2-cyclopropylimidazo[1,2-a]pyridine. [0249] To a solution of 6-(1-chloroethyl)-2-cyclopropylimidazo[1,2-a]pyridine (338 mg, 1.53 mmol) in DMF (10 mL) was added sodium azide (1.06 g, 16.3 mmol) at 0 °C, and the mixture was stirred at 50 °C for 12 h. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to give the title compound, which was used directly in the next step without further purification. MS = 228.2 (M+1). Step 6: tert-Butyl 1-(1-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)ethyl)-1H-1,2,3-triazole-4- carboxylate. [0250] To a stirred solution of tert-butyl propiolate (251 mg, 1.99 mmol) and 6-(1-azidoethyl)- 2-cyclopropylimidazo[1,2-a]pyridine (348 mg, 1.53 mmol) in tert-butanol (7 mL) and water (7 mL) were added sodium ascorbate (607 mg, 3.06 mmol) and Cu₂SO₄·5H₂O (38.2 mg, 0.153 mmol) at rt, then the reaction mixture was stirred at rt for 4 h. The mixture was concentrated, diluted with water, extracted with EtOAc, the combined organic layers were washed with brine, ^{dried over Na} ₂ ^SO ₄ ^{and concentrated. The obtained crude product was purified by flash silica gel} chromatography (0-100% EtOAc/petroleum ether) to give the title compound. MS = 354.2(M+1). Step 7: 1-(1-(2-Cyclopropylimidazo[1,2-a]pyridin-6-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid. [0251] To a stirred solution of tert-butyl 1-(1-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)ethyl)- 1H-1,2,3-triazole-4-carboxylate (140 mg, 0.396 mmol) in DCM (2.5 mL) was added TFA (0.7 mL) at rt. After the addition was finished, the reaction was stirred at rt for 12 h. The mixture was concentrated to give the title compound, which was used in the next step without further purification. MS = 298.0 (M+1). 25208 Step 8: N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2-cyclopropylimidazo[1,2- a]pyridin- -1H-1,2,3-triazole-4-carboxamide and N-( -3-(5-Chloro-2- cyanophenyl)cyclobutyl)-1-((R)-1-(2-cyclopropylimidazo[1,2- 6-yl)ethyl)-1H-1,2,3- triazole-4-carboxamide. [0252] Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (306 mg, 1.09 mmol) was added to a stirred mixture of 1-(1-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)ethyl)-1H-1,2,3- triazole-4-carboxylic acid (108 mg, 0.363 mmol), 1-methyl-1H-imidazole (149 mg, 1.82 mmol) and 2-((cis)-3-aminocyclobutyl)-4-chlorobenzonitrile (188 mg, 0.363 mmol) in ACN (6 mL) at rt. The mixture was stirred at rt for 4 h, then concentrated, and the residue was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford the mixture of diastereomers. The enantiopure title compounds were resolved by chiral SFC (REGIS (s,s) WHELK-O1 (250mm*30mm,5um), 50% EtOH (0.1% NH₃H₂O)). The faster eluting isomer was obtained (Example 86).¹H NMR (400 MHz, CD₃OD) δ 8.35-8.49 (m, 2H), 7.61-7.66 (m, 2H), 7.59 (s, 1H), 7.35-7.41 (m, 2H), 7.22 (dd, J = 9.3, 1.7 Hz, 1H), 5.98 (q, J = 7.1 Hz, 1H), 4.56 (br t, J = 7.6 Hz, 1H), 3.47-3.71 (m, 1H), 2.80-2.94 (m, 2H), 2.24-2.38 (m, 2H), 1.92-2.05 (m, 4H), 1.27 br(s, 1H), 0.90-1.03 (m, 2H), 0.78-0.87(m, 2H).100% ee. MS = 486.2 (M+1). The slower eluting isomer was obtained (Example 87).¹H NMR (400 MHz, CD₃OD) δ 8.39-8.49 (m, 2H), 7.52-7.67 (m, 3H), 7.36-7.44 (m, 2H), 7.24 (dd, J = 9.4, 1.6 Hz, 1H), 5.89-6.10 (m, 1H), 4.56 (br t, J = 7.6 Hz, 1H), 3.57 (br t, J = 7.7 Hz, 1H), 2.88 (qd, J = 8.0, 2.7 Hz, 2H), 2.25-2.37 (m, 2H), 1.93-2.06 (m, 4H), 1.27 (br s, 1H), 0.91-1.00 (m, 2H), 0.81-0.89 (m, 2H).100% ee. MS = 486.2 (M+1). Example 88 N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((2'-methyl-2',3'-dihydro-1'H- spiro 1,4'-isoquinolin]-7'-yl)methyl)-1H-pyrazole-4-carboxamide Step 1. tert-Butyl 7'-((4-(tert-butoxycarbonyl)-1H-pyrazol-1-yl)methyl)-1'H-spiro[cyclopropane- 1,4'-isoquinoline]-2'(3'H)-carboxylate. 25208 [0253] tert-Butyl 7'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (200 mg, 0.590 mmol) was mixed with potassium ((4-(tert-butoxycarbonyl)-1H-pyrazol-1- yl)methyl)trifluoroborate (187 mg, 0.650 mmol), cesium carbonate (771 mg, 2.40 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43 mg, 0.059 mmol) in a microwave reaction vial. The vial was capped, air was removed and the vial was back-filled with nitrogen (three times).1,4-Dioxane (2.6 mL) and water (1.3 mL) were introduced with syringe. The mixture was heated by microwave reactor at 140 °C for 10 min, cooled to rt, diluted with EtOAc, and washed with brine. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by flash silica gel chromatography (0-30% EtOAc/petroleum ether) to give the title compound. MS= 440.2 (M+1) Step 2.1-((2',3'-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)methyl)-1H-pyr azole-4-carboxylic acid, TFA. [0254] tert-Butyl 7'-((4-(tert-butoxycarbonyl)-1H-pyrazol-1-yl)methyl)-1'H- spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (90 mg, 0.20 mmol) was treated with TFA (2 mL) at rt overnight. The mixture was concentrated and used directly in the next step without further purification. MS= 284.2 (M+1) Step 3.1-((2'-Methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)methyl)- pyrazole-4-carboxylic acid, TFA. [0255] 1-((2',3'-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)methyl)-1H-pyrazole- 4-carboxylic acid (56.7 mg, 0.200 mmol) was mixed with formaldehyde (33 mg, 0.40 mmol, 33% w/v aq. solution) and sodium cyanoborohydride (38 mg, 0.60 mmol) in MeOH (2 mL), and stirred at rt for 1 h. The mixture was diluted with MeOH, then acidified with acetic acid (3 drops). The solution was then purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound. MS= 298.2 (M+1) Step 4. N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((2'-methyl-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)methyl)-1H-pyrazole-4-carboxamide. [0256] 1-((2'-Methyl-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)methyl)-1H- pyrazole-4-carboxylic acid, TFA (22 mg, 0.053 mmol) was mixed with 2-((cis)-3- aminocyclobutyl)-4-chlorobenzonitrile, HCl (13 mg, 0.053 mmol), DIEA (37 µL, 0.21 mmol) in DMF (0.2 mL). HATU (24 mg, 0.064 mmol) was added. The resulting mixture was stirred at rt 25208 for 2 h, then was diluted with MeOH, and was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound.¹H NMR (500 MHz, CD₃OD): δ 0.97-1.53 (m, 5H), 2.26 (q, J = 9.7 Hz,2H), 2.93 (m, 2H), 3.06 (s, 3H), 3.26 (m, 1H), 3.60 (m, 2H), 4.40-4.67 (m, 3H), 5.35 (s, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 7.26 (d, J = 8.4Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 7.62 (s, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.96 (s, 1H), 8.15 (s, 1H). MS (ESI) m/z 486 (M+H). Example 89 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-((cis)- 3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'- isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide Step 1. tert-Butyl 7'-(1-(4-(((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamoyl)-1H-1,2,3- triazol-1-yl)ethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate. [0257] 1-(1-(2'-(tert-Butoxycarbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]- 7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (80 mg, 0.20 mmol) was mixed with DIEA (140 µL, 0.803 mmol) in DMF (0.8 mL). HATU (92 mg, 0.24 mmol) was added. After 5 min, 2-((cis)- 3-aminocyclobutyl)-4-chlorobenzonitrile HCl (48.8 mg, 0.201 mmol) was added, and the resulting mixture was stirred at rt for 2 h, then diluted with MeOH, and purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to give the title compound. MS= 587.3 (M+1) Step 2. N-( -3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-( -1-(2',3'-dihydro-1'H- spiro 1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3- 4-carboxamide and N-((cis)- 3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1- -1-(2',3'-dihydro-1'H-spiro[cyclopropane-1,4'- isoquinolin]-7'-yl)ethyl)-1H-1,2,3- [0258] tert-Butyl 7'-(1-(4-(((1s,3s)-3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamoyl)-1H- 1,2,3-triazol-1-yl)ethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-carboxylate (70 mg, 0.12 mmol) was mixed with HCl (1.5 mL, 6 mmol, 4M in dioxane). The resulting mixture was 25208 stirred at rt for 2 h, then concentrated to dryness. A portion of the crude product was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) to provide the title compounds.¹H NMR (500 MHz, CD₃OD): δ 1.13-1.36 (m, 5H), 2.00 (d, J = 6.4 Hz,3H), 2.37 (q, J = 9.4Hz, 2H), 2.94 (d, J = 7.8Hz, 2H), 3.62 (m, 1H), 4.48 (s, 2H), 4.60 (m, 1H), 5.96 (d, J = 6.6Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.68 (s, 2H), 8.38 (s, 1H). MS (ESI) m/z 487 (M+H). Example 90 and 91 N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(2'-methyl-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-((cis)- 3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2'-methyl-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide Step 1. N- (5-Chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(2'-methyl-2',3'-dihydro-1'H- spiro 1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide and N-((cis)- 3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2'-methyl-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide. [0259] N-((cis)-3-(5-Chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide, HCl (50 mg, 0.096 mmol) was mixed with formaldehyde (38.8 mg, 0.478 mmol, 37% wt/v aq. solution) in MeOH (0.9 mL). Sodium cyanoborohydride (18 mg, 0.29 mmol) was added, and the resulting mixture was stirred at rt for 15 h. The mixture was acidified with acetic acid (4 drops) and diluted with MeOH. The solution was then purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier), to afford the diastereomeric mixture of products. The enantiopure title compounds were resolved by chiral SFC (OJ-H ((21 x 250mm), 35% MeOH + DIPA). The faster eluting isomer was obtained (Example 90).¹H NMR (500 MHz, CD₃OD): δ 7.16 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.91 (d, J = 6.8 Hz, 1H), 4.69 – 4.52 (m, 1H), 25208 3.72 (s, 2H), 3.67 – 3.56 (m, 1H), 2.93 (d, J = 8.0 Hz, 2H), 2.59 (s, 2H), 2.44 (s, 3H), 2.36 (q, J = 9.3 Hz, 2H), 1.98 (d, J = 6.7 Hz, 3H), 1.31 (s, 1H), 1.35-0.96 (m, 3H). MS (ESI) m/z 501 (M+H). The slower eluting isomer was obtained (Example 91).¹H NMR (500 MHz, CD₃OD) δ 8.38 (s, 1H), 7.68 (d, J = 5.5 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.97 (d, J = 6.7 Hz, 1H), 4.72 – 4.54 (m, 2H), 4.48 (s, 1H), 3.71 – 3.52 (m, 2H), 3.26 (s, 1H), 3.06 (s, 3H), 2.93 (d, J = 8.0 Hz, 2H), 2.36 (q, J = 9.4 Hz, 2H), 1.99 (d, J = 6.6 Hz, 3H), 1.47 (s, 1H), 1.35 – 0.96 (m, 3H). MS (ESI) m/z 501 (M+H). N-((1R,2R,3R)-3-(3-Chlorophenyl)-2-hydroxycyclobutyl)-1-((R)-1-(2'-methyl-2',3'- dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H- triazole-4-carboxamide, N-((1R,2R,3R)-3-(3-Chlorophenyl)-2-hydroxycyclobutyl)-1-((S)- 2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl) triazole-4-carboxamide, N- ((1S,2S,3S)-3-(3-Chlorophenyl)-2- - - (2'-methyl-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide, and N- ((1S,2S,3S)-3-(3-Chlorophenyl)-2-hydroxycyclobutyl)-1-((S)-1-(2'-methyl-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide Step 1. tert-Butyl 7'-(1-(4-((3-(3-chlorophenyl)-2-hydroxycyclobutyl)carbamoyl)-1H-1,2,3- triazol-1-yl)ethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2' -carboxylate. [0260] 1-(1-(2'-(tert-Butoxycarbonyl)-2',3'-dihydro-1'H-spiro 1,4'-isoquinolin]- 7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (120 mg, 0.300 mmol) was mixed with DIEA 25208 (210 µL, 1.20 mmol) in DMF (1.2 mL) and HATU (137 mg, 0.360 mmol) was added. After 5 min, (1S,2S,4S)-2-amino-4-(3-chlorophenyl)cyclobutan-1-ol and (1R,2R,4R)-2-amino-4-(3- chlorophenyl)cyclobutan-1-ol (94 mg, 0.30 mmol) was added. The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with MeOH and was purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier), to give the title compound. MS= 578.3 (M+1) Step 2. N-(3-(3-Chlorophenyl)-2-hydroxycyclobutyl)-1-(1-(2',3'-dihydro-1'H-spiro[cyclopropane- 1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide. [0261] tert-Butyl 7'-(1-(4-(((1R,3R and 1S,3S)-3-(3-chlorophenyl)-2-hydroxycyclobutyl) carbamoyl)-1H-1,2,3-triazol-1-yl)ethyl)-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)- carboxylate (80 mg, 0.14 mmol) was mixed with HCl (1.7 mL, 6.8 mmol, 4M in dioxane). The resulting mixture was stirred at rt for 2 h. The mixture was concentrated to dryness and used directly in the next step without further purification. MS= 478.3 (M+1) Step 3. N-(3-(3-Chlorophenyl)-2-hydroxycyclobutyl)-1-(1-(2'-methyl-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide. [0262] N-(3-(3-Chlorophenyl)-2-hydroxycyclobutyl)-1-(1-(2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide HCl (70 mg, 0.14 mmol) was mixed with formaldehyde (33 mg, 0.40 mmol, 37% w/v aq. solution) in MeOH (1.4 mL). Sodium cyanoborohydride (26 mg, 0.40 mmol) was added, and the resulting mixture was stirred at rt for 15 h. The mixture was acidified with acetic acid (4 drops) and diluted with MeOH. The solution was then purified by reverse phase HPLC (ACN/water with 0.05% TFA modifier), to afford the diastereomeric mixture of products. The enantiopure title compounds were resolved by Chiral SFC OJ-H(21 x 250mm, 20% MeOH + 0.2% DIPA). The first eluting isomer was obtained (Example 92): ¹H NMR (500 MHz, CD₃OD) δ 8.34 (s, 1H), 7.37 (s, 1H), 7.35-7.20 (m, 3H), 7.17 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.91 (d, J = 6.6 Hz, 1H), 4.41 – 4.26 (m, 1H), 4.14 (t, J = 7.6 Hz, 1H), 3.76 (s, 2H), 3.00 (q, J = 8.8 Hz, 1H), 2.64 (s, 2H), 2.60 – 2.51 (m, 1H), 2.47 (s, 3H), 1.97 (d, J = 6.6 Hz, 3H), 1.74 (q, J = 10.0 Hz, 1H), 1.02 (d, J = 38.2 Hz, 4H). MS (ESI) m/z 492 (M+H). The second eluting isomer was obtained (Example 93).¹H NMR (500 MHz, CD₃OD) δ 8.35 (s, 1H), 7.38 (s, 1H), 7.34-7.21 (m, 3H), 7.17 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.78 (d, J = 7.9 Hz, 1H), 5.91 (d, J = 6.7 Hz, 1H), 4.33 (q, J = 7.8 Hz, 1H), 4.15 (t, J = 7.4 Hz, 1H), 3.74 (s, 2H), 3.00 (q, J = 8.9 Hz, 1H), 2.61 (s, 2H), 2.54 (q, J = 9.8, 9.3 Hz, 1H), 2.46 (s, 3H), 1.98 (d, J = 6.4 Hz, 3H), 1.75 (q, J = 10.0 Hz, 25208 1H), 1.01 (d, J = 38.8 Hz, 4H). MS (ESI) m/z 492 (M+H). The third eluting isomer was obtained (Example 94) ¹H NMR (500 MHz, CD₃OD) δ 8.34 (s, 1H), 7.37 (s, 1H), 7.34-7.21 (m, 3H), 7.17 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.91 (d, J = 6.5 Hz, 1H), 4.33 (q, J = 8.0 Hz, 1H), 4.15 (t, J = 7.6 Hz, 1H), 3.74 (s, 2H), 3.00 (q, J = 8.9 Hz, 1H), 2.62 (s, 2H), 2.54 (q, J = 9.4, 9.0 Hz, 1H), 2.46 (s, 3H), 1.98 (d, J = 6.5 Hz, 3H), 1.74 (q, J = 10.0 Hz, 1H), 1.01 (d, J = 38.7 Hz, 4H). MS (ESI) m/z 492 (M+H). The fourth eluting isomer was obtained (Example 95). ¹H NMR (500 MHz, CD₃OD) δ 8.36 (s, 1H), 7.37 (s, 1H), 7.34-7.19 (m, 4H), 7.13 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.93 (d, J = 6.6 Hz, 1H), 4.38 – 4.27 (m, 1H), 4.15 (t, J = 7.6 Hz, 1H), 3.99 (s, 2H), 3.00 (q, J = 8.8 Hz, 1H), 2.87 (s, 2H), 2.64 (s, 3H), 2.54 (q, J = 8.8 Hz, 1H), 1.98 (d, J = 6.6 Hz, 3H), 1.74 (q, J = 10.3 Hz, 1H), 1.08 (d, J = 35.8 Hz, 4H). MS (ESI) m/z 492 (M+H). Plasma Kallikrein assay [0263] The effectiveness of a compound of the present invention as an inhibitor of plasma kallikrein can be determined using a relevant purified serine protease, and an appropriate synthetic substrate. The rate of hydrolysis of the chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and presence of compounds of the present invention. Assays were conducted at rt or at 37 °C. Hydrolysis of the substrate resulted in release of amino trifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by measuring the increase in emission at 510 nm with excitation at 405 nm. A decrease in the rate of fluorescence change in the presence of inhibitor is indicative of enzyme inhibition. Such methods are known to one skilled in the art. The results of this assay are expressed as the half- maximal inhibitory concentrations (IC₅₀), or the inhibitory constant, K_i. [0264] Plasma kallikrein determinations were made in 50 mM HEPES buffer at pH 7.4 containing 150 mM NaCl, 5 mM CaCl₂, and 0.1% PEG 8000 (polyethylene glycol; Fisher Scientific). Determinations were made using purified Human plasma kallikrein at a final concentration of 0.5 nM (Enzyme Research Laboratories) and the synthetic substrate, Acetyl-K- P-R-AFC (Sigma # C6608) at a concentration of 100 mM. [0265] Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ≤ 0.2 Km into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. The reactions were performed under linear progress curve conditions and fluorescence increase measured at 405 Ex/510 Em nm. Values were converted to percent inhibition of the control reaction (after subtracting 100% Inhibition value). IC₅₀ was determined 25208 by inflection point from a four parameter logistic curve fit. Ki was calculated using the Cheng Prusoff equation, Ki = IC₅₀/(1+([S]/Km)). [0266] The activities shown by this assay indicate that the compounds of the invention may be therapeutically useful for treating or preventing various ophthalmic, cardiovascular and/or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndrome, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, stroke such as thrombotic stroke or embolic stroke, venous thrombosis, coronary and cerebral arterial thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation, reocclusion or restenosis of recanalized vessels, hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. [0267] Plasma Kallikrein (PKal) IC₅₀ (nM) for selected compounds are as follows: 25208 25208 25208

25208 WHAT IS CLAIMED IS: 1. A compound of the formula: wherein is phenyl or heteroaryl, which can be monocyclic, bicyclic or tricyclic, wherein said phenyl and heteroaryl groups are optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, R^x, OR^x and SO₂R^x; is a 5-membered heteroaryl ring which is optionally substituted with one or two substituents independently selected from the group consisting of halo, cyano, R^x and OR^x; X is a bond or CR⁵R⁶; each R¹ is independently selected from the group consisting of halo, cyano, R^x and OR^x; R³ is hydrogen, halo, cyano or methyl; R⁴ is hydrogen, halo, hydroxyl, methyl or CH₂OH; R⁵ is hydrogen or C1-3 alkyl, which is optionally substituted with one to three substituents selected from the group consisting of halo and hydroxyl; R⁶ is hydrogen, hydroxyl or C_1-3 alkyl; is a nitrogen-containing heterocyclyl group or a nitrogen-containing heteroaryl group, wherein said nitrogen-containing heterocyclyl and nitrogen-containing heteroaryl groups may be monocyclic or bicyclic and are optionally substituted with one or two substituents independently selected from the group consisting of oxo, R^x, hydroxyl and CONR⁹R¹⁰; is a nitrogen-containing heterocyclyl group, which is optionally substituted with one or two substituents independently selected from the group consisting R^x and hydroxyl; R⁷ is hydrogen or methyl;

Claims

25208 R⁹ is hydrogen or C_1-3 alkyl; R¹⁰ is hydrogen or C_1-3 alkyl; R^x is hydrogen or C_1-6 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo, hydroxyl, methoxy and ethoxy; n is an integer from zero to three; or a pharmaceutically acceptable salt thereof. 2. The compound of Claim 1 wherein is pyrazolyl or triazolyl; or a pharmaceutically acceptable salt thereof. 3. The compound of Claim 1 or 2 wherein is pyrimidinyl, phenyl, pyridinyl, cyclopentapyridinyl, tetrahydroisoquinolinyl, tetrahydrothiazolopyridinyl, quinolinyl, dihydroquinazolinyl, imidazopyridinyl, dihydrospirocyclopropaneisoquinolinyl, wherein said pyrimidinyl, phenyl, pyridinyl, cyclopentapyridinyl, tetrahydroisoquinolinyl, tetrahydrothiazolopyridinyl, quinolinyl, dihydroquinazolinyl, imidazopyridinyl, dihydrospirocyclopropaneisoquinolinyl groups are optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, R^x, OR^x and SO₂; or a pharmaceutically acceptable salt thereof. [0268] 4. The compound of any one of Claims 1 to 3 wherein is azetidinyl, azabicyclohexanyl, azaspirohexanyl, oxopyridinyl, oxopyrimidinyl, pyridinyl, pyrrolidinyl wherein said pyrrolidinyl is optionally substituted with CONR⁹R¹⁰, and azabicyclohexanyl is optionally substituted with oxo; or a pharmaceutically acceptable salt thereof. 5. The compound of any one of Claims 1 to 4 wherein is azetidinyl or pyrrolidinyl wherein said azetidinyl and pyrrolidinyl groups are optionally substituted with one or two substituents independenly selected from the group consisting of and R^x and hydroxyl; or a pharmaceutically acceptable salt thereof. 25208 6. The compound of any one of Claims 1 to 5 wherein R¹ is chloro, fluoro, difluoromethyl, methoxy or cyano; n is one, two or three; or a pharmaceutically acceptable salt thereof. 7. The compound of any one of Claims 1 to 5 wherein R³ is hydrogen, fluoro or cyano; or a pharmaceutically acceptable salt thereof. 8. The compound of any one of Claims 1 to 7 wherein R⁴ is hydrogen, hydroxyl or CH₂OH; or a pharmaceutically acceptable salt thereof. 9. The compound of any one of Claims 1 to 8 wherein n is one or two; or a pharmaceutically acceptable salt thereof. 10. The compound of Claim 1 selected from any one of compounds numbered 1-95, or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising a compound of any one of Claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 12. A method for treating impaired visual activity, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, or bleeding from postoperative surgery in a mammal, comprising administering a composition of Claim 11 to a mammal in need of thereof. 13. A method for treating hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion in a mammal comprising administering a composition of Claim 11 to a mammal in need thereof. 14. A method of treating diabetic retinopathy in a mammal comprising administering a composition of Claim 11 to a mammal in need thereof. 25208 15. A method of treating diabetic macular edema in a mammal comprising administering a composition of Claim 11 to a mammal in need thereof. 16. A compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion in a mammal in need thereof. 17. The compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in therapy. 18. The composition of Claim 11 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents. 19. The method of Claim 12 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.