Pyridazines as sarm1 inhibitors

Abstract

The present invention relates to novel pyridazine compounds as SARM1 inhibitors, to pharmaceutical compositions comprising the compounds and to methods of using the compounds and compositions to treat and prevent pathological conditions involving axonal degeneration.

Description

PYRIDAZINES AS SARM1 INHIBITORSThe present invention relates to novel SARM1 inhibitors, to pharmaceutical compositions comprising the compounds and to methods of using the compounds and compositions to treat and prevent pathological conditions involving axonal degeneration.Axonal degeneration is a major feature of pathological conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, inherited neuropathy, traumatic brain injury, and glaucoma. These conditions affect millions of patients and present a significant financial burden worldwide.Sterile Alpha and Toll / Interleukin receptor-1 (TIR) motif-containing 1 (SARM1) has been identified as the central executioner in the injury -induced axon death pathway known as Wallerian degeneration (O'Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol., 2007, 7, 353-364; Osterloh, J.M., et al., Science, 2012, 337, 481-484; Gerdts, J., et al., J. Neurosci. 33, 2013, 13569-13580). Mechanistic studies have revealed that activation of SARM1 via axonal injury or forced dimerization of SARM1-TIR domains promotes rapid depletion of nicotinamide adenine dinucleotide (NAD+), resulting in axonal degradation (Gerdts, J., et al., Science, 2015, 348, 453-457). Genetic knockout of SARM1 allows for preservation of axons for fourteen or more days after nerve transection (Osterloh, J.M., et al., Science, 2012, 337, 481-484; Gerdts, J., et al. J. Neurosci., 2013, 33, 13569-13580) and improves functional outcomes in mice after traumatic brain injury (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role of SARM1 in direct axonal injury, SARM1 is also required for axonal degeneration observed in conditions such as chemotherapy-induced peripheral neuropathy. Loss of SARM1 blocks chemotherapy- induced peripheral neuropathy, inhibiting both axonal degeneration and heightened pain sensitivity that develops after chemotherapeutic vincristine treatment (Geisler et al, Brain, 2016, 139, 3092-3108).WO 2021 / 142006 A1 and WO 2022 / 046606 A1 disclose certain compounds and methods useful for inhibiting SARM1 and / or treating and / or preventing axonal degeneration.Currently there are no approved medications for the treatment and / or prevention of axonal degeneration. There is an unmet need for potent SARM1 inhibitors possessingimproved metabolic profiles for the treatment and prevention of pathological conditions involving axonal degeneration. The present invention provides novel SARM1 inhibitors for use in the treatment and prevention of pathological conditions involving axonal degeneration. In addition, the present invention provides novel SARM1 inhibitors that possess improved potency and that are subject to reduced metabolic clearance. Accordingly, the present invention provides a compound of Formula III:wherein X is N and Y is CH, or X is CH and Y is N; R5is selected from hydrogen, halogen, -NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, -OH, or -OCH3wherein: when R5is hydrogen, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,and when R5is selected from halogen, -NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, -OH, or -OCH3, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,R1and R2together with the atoms they are attached to form a 5- to 6-membered saturated heterocyclic ring wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, and wherein one of the carbon atoms is optionally substituted with cyano, -ORd, or C1-3alkyl optionally substituted with -NH2, or -ORd; R3is selected from hydrogen and C1-4alkyl; R4is selected from phenyl optionally substituted with 1 to 3 Rb, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb, and 9- to 10-membered fully or partially aromaticbicyclic heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb; each Rais independently selected from hydrogen, halogen, cyano and C1-4alkyl optionally substituted with halogen, -ORd, -NH2or cyano; each Rbis independently selected from halogen, cyano, C1-4alkyl, -NH2, -OH, monohalomethyl, dihalomethyl, trihalomethyl, and -OC1-4alkyl; and Rcis selected from halogen, cyano, -OC1-3alkyl optionally substituted with Re, and C1-4alkyl optionally substituted with halogen, -ORd, -NH2, or cyano; and Rdis selected from hydrogen, C1-4alkyl and -CH2OP(O)(OH)2; Reis selected fromor a pharmaceutically acceptable salt thereof. In an embodiment of the invention X is N and Y is CH. In a further embodiment R5is hydrogen, and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,In another embodiment R5is selected from halogen, -NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, -OH, or -OCH3and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,In an embodiment R5is selected from -CH3, -CH2OH, -NH2, -CH2F, and -OCH3. In an embodiment the compound is of Formula IIIa:wherein B is selected from O, NH, C-R6, wherein R6is selected from hydrogen, cyano, - OC1-3alkyl, or C1-3alkyl optionally substituted with -NH2, or -ORd, R7and R8are independently selected from hydrogen and -OH, and n is 0 or 1. In another embodiment the compound is of Formula IIIa(i):wherein n is 0 or 1.In a further embodiment the compound is selected from one of Formulas IIIa(ii) to Formula IIIa(xii):In a further embodiment R3is hydrogen. In an embodiment Ring A is selected fromoptionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2, andaeach R is independently selected from hydrogen, cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, - CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, and -Cl. In a further embodiment Ring A isoptionally substituted at one nitrogen atom with -CH2OP(O)(OH)2, and Rcis selected from cyano, -CH3, -CH2OH, - CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, -Cl,In another embodiment R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb. In an embodiment R4is phenyl optionally substituted with 1 to 3 Rb. In another embodiment R4is 5- to 6- membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb. In a further embodiment R4is pyridine optionally substituted with 1 to 3 Rb. In an embodiment R4is selected from:In an4embodiment R is substituted by 1 to 3Rband each Rbis independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl. In a further embodiment R4is selected from:The present invention further provides a compound of Formula IV:whereinX is N and Y is CH, or X is CH and Y is N; R5is selected from hydrogen, and -CH3optionally substituted with -OH, -NH2, or 1-3 halogen atoms, wherein: when R5is C1-3alkyl optionally substituted with -OH, -NH2, or 1-3 halogen atoms, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,when R5is hydrogen, then Ring A is from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2; R1, R2and R3are each independently selected from hydrogen and C1-4alkyl, wherein R2and R3together with the atoms they are attached to may optionally form a 3- to 6- membered saturated carbocyclic ring; R4is selected from phenyl optionally substituted with 1 to 3 Rb, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb, 9- to 10-membered fully or partially aromatic bicyclic heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb; Rais selected from hydrogen, halogen, cyano, and C1-4alkyl; each Rbis independently selected from halogen, cyano, -OH, -NH2, C1-4alkyl, monohalomethyl, dihalomethyl, trihalomethyl and -OC1-4alkyl;Rcis selected from -OC1-3alkyl optionally substituted with -ORdor Re, and -C1-4alkyl substituted with -ORdor 1-3 halogen atoms; and Rdis selected from H, -CH3, -CF3, -CHF2, and -CH2OP(O)(OH)2; and Reis selected fromor a pharmaceutically acceptable salt thereof. In an embodiment of the invention X is N and Y is CH. In a further embodiment R5is C1-3alkyl , optionally substituted with -OH, -NH2, or 1-3 halogen atoms, and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,In an embodiment R5is selected from -CH3, CH2OH, CH2F and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,In another embodiment R5is hydrogen, and Ring A isoptionally substituted at one nitrogen atom with -CH2OP(O)(OH)2. In a further embodiment R1, R2and R3are all hydrogen.In an embodiment Ring A is selected fromoptionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,aand R is selected from hydrogen, cyano and -CH3. In an embodiment Ring A isoptionally substituted at one nitrogen atom with -CH2OP(O)(OH), and Rcis selected from -OCH3, -CH2OCH3, -CH2CH2OCH3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2CH2OCHF2, -CH2CH2OCH2OP(O)(OH)2,In another embodiment R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb. In an embodiment R4is phenyl optionally substituted with 1 to 3 Rb. In another embodiment R4is 5- to 6- membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb. In a further embodiment R4is pyridine optionally substituted with 1 to 3 Rb. In an embodiment R4is selected from:In an embodiment R4is substituted by 1 to 3 Rband each Rbis independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl. In a further embodiment R4is selected from:The present invention also provides a compound of Formula I:wherein X is N and Y is CH, or X is CH and Y is N; Ring A is selected from,R1, R2and R3are each independently selected from hydrogen and C1-4alkyl, wherein R1and R2together with the atoms they are attached to may optionally form a 5- to 6- membered saturated heterocyclic ring wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, or wherein R2and R3together with the atoms they are attached to may optionally form a 3- to 6-membered saturated carbocyclic ring; R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb;Rais selected from hydrogen, halogen, cyano and C1-4alkyl optionally substituted with halogen, -OH, -NH2or cyano; each Rbis independently selected from halogen, cyano, C1-4alkyl, trihalomethyl and - OC1-4alkyl, or a pharmaceutically acceptable salt thereof. In an embodiment of the invention X is N and Y is CH. In a separate embodiment X is CH and Y is N. In an embodiment of the invention R1is hydrogen. In another embodiment R2is hydrogen. In a further embodiment R3is hydrogen. In an embodiment R1, R2and R3are hydrogen. In another embodiment R1, R2and R3are each independently selected from hydrogen and C1-4alkyl, wherein R1and R2together with the atoms they are attached to may optionally form a 5- to 6-membered saturated heterocyclic ring wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, or wherein R2and R3together with the atoms they are attached to may optionally form a 3- to 6-membered saturated carbocyclic ring. In another embodiment the compound is of Formula II:wherein X, Y, Ring A and R4are as defined above and Z is selected from CH2, O, NH or a bond. In an embodiment Z is CH2. In another embodiment Z is O. In an alternative embodiment Z is NH. In another embodiment Z is a bond. In a further embodiment the compound is selected from Formula IIa and Formula IIb:wherein X, Y, Ring A, Z and R4are as defined above. In another embodiment of the invention Rais selected from hydrogen, cyano and C1-4alkyl. In one embodiment Rais hydrogen. In an embodiment Rais methyl. In another embodiment Rais cyano. In an embodiment of the invention Ring A is selected fromIn an embodiment of the invention each Rbis selected from halogen and cyano. In another embodiment each Rbis halogen. In yet another embodiment each Rbis selected from fluorine, chlorine, and bromine. In another embodiment of the invention R4is selected fromIn a further embodiment R4is selected fromIn an embodiment of the invention the compound is selected fromor a pharmaceutically acceptable salt thereof.The present invention provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any of the above embodiments, with one or more pharmaceutically acceptable carriers, diluents, or excipients.The present invention provides a method of treating or preventing a disease associated with axonal degeneration in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, according to any of the above embodiments.The present invention also provides a method of treating or preventing a disease associated with SARM1 activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, according to any of the above embodiments.The present invention also provides a method of treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy-induced peripheral neuropathy in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition according to any of the above embodiments.The present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of the above embodiments for use in therapy.Furthermore, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of the above embodiments for use in the treatment or prevention of a disease associated with axonal degeneration.In addition, the present invention provides a compound or a pharmaceutically acceptable salt thereof according to any one of the above embodiments for use in the treatment or prevention of a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy-induced peripheral neuropathy.The present invention provides the use of a compound or pharmaceutically acceptable salt thereof according to any one of the above embodiments for the manufacture of a medicament for the treatment or prevention of a disease associated with axonal degeneration.In addition, the present invention provides the use of a compound or pharmaceutically acceptable salt thereof, according to any one of the above embodiments for the manufacture of a medicament for the treatment or prevention of a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy -induced peripheral neuropathy.As used herein, the term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, straight, or branched chain hydrocarbon group containing one or more carbon atoms.As used herein, the term “bicyclic heteroaryl” refers to a chemical group wherein two rings, at least one of which is a heterocyclic or heteroaromatic ring, are joined together.As used herein, the term “carbocyclic” refers to a cyclic saturated group containing only carbon atoms.As used herein, the term “heteroaryl” refers to a cyclic aromatic group containing one or more heteroatoms.As used herein, the term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.As used herein, the term “heterocyclic” refers to a cyclic saturated group containing carbon atoms and one or more heteroatoms.As used herein, the term “patient” refers to a human. As used herein, the term “preventing” refers to preventing the occurrence of a disease or averting resulting complications after its onset. As used herein, the term “treating” includes slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. As used herein, the term “effective amount” refers to the amount or dose of compound of the invention, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. The compounds of the present invention are preferably formulated as pharmaceutical compositions administered by any route which makes the compound bioavailable, including oral and transdermal routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing same are well known in the art (See, e.g., Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rd Edition, Elsevier Academic Press, 2020). Several compounds of the present invention contain 5-membered nitrogen heteroaryl rings that can exist in a number of tautomeric forms. For the 1,2,4-triazole ring, there are three possible tautomeric forms:For the pyrazole and imidazole rings, there are two possible tautomeric forms:These tautomeric forms are intended to be encompassed by the present disclosure and claims. When substituted at one nitrogen atom with -CH2OP(O)(OH)2, theaforementioned 5-membered nitrogen heteroaryl rings can take any of the forms listed below:It is to be understood that the present invention contemplates all individual enantiomers and diastereomers, as well as mixtures of enantiomers and / or diastereomers, including racemates of the formulas, substituents, fragments, and compounds described herein.The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be prepared according to the following Preparations and Examples by methods well known and appreciated in the art. Suitable reaction conditions for the steps of these Preparations and Examples are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may be isolated and / or purified by various well-known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. As an illustration, compounds of the preparations and examples can be isolated, for example, by silica gel purification, isolated directly by filtration, or crystallization. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of the present invention is dependent upon the particular compound being synthesized, the starting compound, and the relative liability of the substituted moieties, and is well appreciated by the skilled chemist. Allsubstituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art. Certain abbreviations are defined as follows: “ACN” refers to acetonitrile; “AcOH” refers to acetic acid; “Aib” refers to 2-aminoisobutyric acid; “n-BuLi” refers to n-butyl lithium;“t-BuOH” refers to tert-butanol; “t-BuOK” refers to potassium tert- butoxide; “t-BuONa” refers to sodium tert-butoxide; “Boc2O” refers to di-tert-butyl decarbonate; “DABCO” refers to 1,4-diazabicyclo[2.2.2]octane; “DAST” refers to (diethylamino)sulfur trifluoride; “DBU” refers to 1,8-diazabicyclo[5.4.0]undec-7-ene; “DCM” refers to dichloromethane; “DIPEA” or “DIEA” refers to N, N- diisopropylethylamine; “DMA” refers to dimethylacetamide; “DMAc” refers to dimethylacetamide; “DMF” refers to dimethylformamide; “DMAP” refers to 4- dimethylaminopyridine;“DMSO” refers to dimethyl sulfoxide; “DPPA” refers to diphenylphosphoryl azide; “ee” refers to “enantiomeric excess”; “Et3N” or “TEA” refers to triethylamine; “EtOAc” refers to ethyl acetate; “EtOH” refers for ethyl alcohol; “Et3SiH” refers to triethylsilane; “HATU” refers to (1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; “HFIP” refers to hexafluoroisopropanol; “HPLC” refers to high-performance liquid chromatography; “hr.” or “hrs.” refers to hr or hrs ; “IPA” refers to isopropyl alcohol; “KOAc” refers to potassium acetate;“LDA” refers to lithium diisopropylamide; “LiHMDS” refers to lithium bis(trimethylsilyl)amide; “MeI” refers to methyl iodide; “MeOH” refers to methanol; “NaBH3CN” refers to sodium cyanoborohydride; “NaHMDS” refers to sodium bis(trimethylsilyl)amide solution; “NBS” refers to N-bromosuccinimide; “NCS” refers to N-chlorosuccinimide; “NIS” refers to N-iodosuccinimide; “min” refers to minute or minutes; “Pd(dppf)Cl2” refers to (1,1'bis(diphenylphosphino)ferrocene)dichloropalladium-dichloromethane; “Pd(PPh3)4” refers to tetrakis(triphenylphosphine)palladium(0); “Pd2(dba)3” refers to tris(dibenzylideneacetone)dipalladium(0); “Pd(t-Bu3P)2” refers to bis(tri-tert- butylphosphine)palladium(0); “Pd(OAc)2” refers to palladium(II) acetate; “PMB-Cl” refers to 4-methoxybenzyl chloride; “Prep-HPLC” refers to preparative HPLC; “SEM-Cl” refers to 2-(trimethylsilyl)ethoxymethyl chloride; “SFC” refers to supercritical fluid chromatography; “TBAF” refers to tetra-n-butylammonium fluoride; “TBDPS” refers to tert-butyldiphenylsilyl; “TBHP” refers to tert-butyl hydroperoxide; “TBTU” refers to 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; and “T3P” refers to propanephosphonic acid anhydride; “XPhos” refers to dicyclohexyl[2’,4’,6’-tris(propan- 2-yl)[1,1’-biphenyl]-2-yl]phosphane. Scheme 1 In the schemes below, Rzis an alkyl group such as methyl or hydrogen; Ar is Aryl or a heteroaryl; and X is a N or C.Scheme 1, step A depicts the formation of compound (2) from compound (1) using propiononitrile as a reagent in a solvent such as THF with a base such as LiHMDS. Step B shows a cyclization of compound (2) using EtOH and hydrazine hydrate solution and a base such as Na2CO3in a solvent such as AcOH to give compound (3). Step C shows the addition of (4-methoxybenzyl) hydrazine hydrochloride to compound (3) using an acid such as AcOH in a solvent such as EtOH to give compound (4). Step D depicts amide coupling of compound (4) with an aryl propanoic acid using a coupling reagent such as HATU and a base such as DIPEA in a solvent such as DMA to give compound(5). One skilled in the art will recognize that many other amide coupling reagents, bases, and solvents could be used to perform this coupling. Step E depicts the acidic deprotection of compound (5) with an acid such as TFA in a solvent such as DCM to give compound (6).Scheme 2Scheme 2, step A depicts formation of compound (9) from compound (8) by adding hydrazine hydrate solution in a solvent such as EtOH. Step B shows adding to compound (9) methyl carbamimidothioate sulfate, hydrazine hydrate solution using a base such as NaOH to form compound (10). Step C shows an intramolecular cyclization of compound (10) to compound (11) through use of a base such as NaOH. Step D depicts the coupling of compound (11) with bromopentanoic acid using a coupling reagent such as TBTU and a base such as DIPEA in a solvent such as DMA to give compound (12). One skilled in the art will recognize that many other amide coupling reagents, bases, and solvents could be used to perform this coupling. Step E shows a two-step reaction in which compound (12) undergoes acyl migration followed by an intramolecularcyclization under favorable conditions such as the presence a base such as sodium hydride, and a solvent such as DMF. The product is then reacted with SEM-Cl to give the SEM protected nitrogen of the triazole in compound (13). Step F shows a reaction of compound (13) with an aryl bromo compound such as 1-(bromomethyl)-4-fluorobenzene using a base such as LiHMDS and solvent such as THF to form compound (14). Step G depicts the acidic deprotection of compound (14) with an acid such as TFA in a solvent such as DCM to give compound (15). Scheme 3Scheme 3, step A depicts the transformation of compound (16) through a Curtius rearrangement reaction using DPPA with a base such as Et3N in a solvent such as tert- butanol to form compound (17). Step B shows a Suzuki coupling between compound (17) and methylboronic acid using a catalyst such as Pd(dppf)Cl2and a base such as potassium carbonate in a solvent system such as dioxane and water to give compound (18). One skilled in the art will recognize that there are many catalyst, ligand, base, and solvent combinations which may be utilized to perform this type of coupling. Step C shows the transformation of compound (18) to compound (19) using a catalyst system that includes Ph3P and Pd(OAc)2, Et3SiH as a reducing agent, and Et3N as a base. Step D depictsdeprotection of compound (19) to give compound (20) using an acid such as HCl in a solvent system such as dioxane and DCM. Step E shows bromination of compound (20) using CuBr2and reagent such as tert-butyl nitrite in a solvent such as ACN to form compound (21). Step F shows the coupling of compound (21) with tert-butyl N-(1H- pyrazol-4-yl)carbamate using a catalyst system such as CuI and N,N'-dimethyl-1,2- cyclohexanediamine, and a base such as K3PO4to form compound (22). The acidic deprotection of compound (22) with an acid such as HCl in solvents such as DCM and dioxane to give compound (23) is shown in step G. Step H shows an amide coupling of compound (23) with an aryl propanoic acid using a coupling reagent such as HATU and a base such as DiPEA in a solvent such as DMA to give compound (24). One skilled in the art will recognize that many other amide coupling reagents, bases, and solvents could be used to perform this coupling. Scheme 4Scheme 4, step A depicts the formation of a Weinreb amide from compound (25) using N,O-dimethylhydroxylamine hydrochloride in a solvent such as THF with a base such as LiHMDS to give compound (26). Step B shows the addition of EtOAc to compound (26) using a base such as LDA in a solvent such as THF to give compound (27). Step C shows the addition of trichloroacetonitrile to compound (27) using a base such as sodium acetate trihydrate in a solvent such as EtOH to give compound (28). Step D depicts the cyclization of compound (28) with (4-methoxybenzyl)hydrazine hydrochloride using a base such as Et3N in a solvent such as EtOH to give compound (29). Step E shows a basic hydrolysis of compound (29) using NaOH in a solvent system such as THF, EtOH, and water to give compound (30). Step F shows amide coupling of compound (30) with ammonium chloride using a coupling reagent such as HATU and a base such as DIPEA in a solvent such as DMF to give compound (31). One skilled in the art will recognize that many other amide coupling reagents, bases, and solvents could be used to perform this coupling. Step G shows an amide coupling of compound (31) with an aryl propanoic acid using a coupling reagent such as HATU and a base such as DiPEA in a solvent such as DMA to give compound (32). One skilled in the art will recognize that many other amide coupling reagents, bases, and solvents could be used to perform this coupling. Step H depicts the acidic deprotection of compound (32) with an acid such as TFA in a solvent such as DCM to give compound (33). Step I show dehydration of compound (33) using Burgess reagent (methyl N-(triethylammoniumsulfonyl)carbamate) and a solvent such as DMF to give compound (34).Scheme 5Scheme 5, step A depicts converting compound (35) to compound (36) by adding an aryl bromo compound such as 4-(bromomethyl)-1-chloro-2-fluorobenzene to compound (35) using a strong base such as NaHMDS and a solvent such as THF. Step B shows deprotection of compound (36) using HF.Et3N in a solvent such as THF to give compound (37). Step C depicts oxidation of compound (37) using Dess-Martin reagent in a solvent such as DCM to give compound (38). Step D shows reduction of compound (38) using NaBH3CN and amine coupling with amine such as 3-(5-methylpyridazin-4-yl)- 1H-1,2,4-triazol-5-amine in AcOH and MeOH as a solvent to give compound (39). Step E depicts conversion of compound (39) to compound (40) using H2O2and a base such as LiOH.H2O in a solvent such as THF. Step F shows the intramolecular cyclization of compound (40) to compound (41) through use of a coupling reagents such as T3P a base such as DIPEA in a solvent such as DMA. Alternatively, step G intramolecular cyclization of compound (39) to compound (42) through use of a base such LiOH.H2O in a solvent system such as H2O2, water, and THF.Scheme 6Scheme 6, step A depicts the reaction of compound (42a) with hydrazine hydrate and an acid such as AcOH followed by the reaction of the intermediate with sodiumnitrite to give compound (42b). Step B shows the reaction of compound (42b) with tributyl(prop-1-yn-1-yl)stannane in a solvent such as toluene to form compound (42c). Step C depicts the protection of compound (42d) with SEM-Cl using a base such as NaH in a solvent such as DMF to give compound (43). Step D shows the protection of compound (42e) with Boc2O using a base such as DMAP in a solvent such as DCM to form compound (42f). Step E depicts a reaction of compound (42f) with an aryl bromo compound using a base such as LDA in a solvent such as THF to give compound (42g). Step F shows acidic deprotection of compound (42g) with an acid such as HCl in a solvent such as dioxane to form compound (42h). Step G depicts a Stille coupling of compound (43) with compound (42c) in a catalyst system such as Pd(PPh3)4and CuI in a solvent such as DMF to give compound (44). Step H shows the coupling of compound (44) with compound (42h) in a catalyst system such as CuI and N,N'-dimethyl-1,2- cyclohexanediamine and a base such as K3PO4to form compound (45). Step I shows acidic deprotection of compound (45) with an acid such as TFA in a solvent such as DCM to give compound (46). Scheme 7Scheme 7, step A depicts conversion of compound (47) to compound (48) by addition of 6-fluoronicotinaldehyde using a strong base such as LDA in a solvent such asTHF. Step B shows reduction of compound (48) to compound (49) using Pd / C in presence of H2gas in a solvent such as EtOH. Step C depicts coupling compound (49) with an amine compound such as 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine using a coupling reagent such as TBTU and a base such as DIPEA in a solvent such as DMAP to give compound (50). One skilled in the art will recognize that many other amide coupling reagents, bases, and solvents could be used to perform this coupling. Step D shows converting compound (50) to compound (51) by using a base such as t-BuOK in a solvent such as DMF through a two-step reaction that involves acyl transfer followed by intramolecular cyclization.Scheme 8 In the scheme below, R6is H, OTBDPS or OH when n = 1; R6is H when n = 0; Ar is Aryl; Z is CH, N or C-Rc.Scheme 8, step A depicts the protection of compound (52) with SEM-Cl using a base such as NaH in a solvent such as ACN to give compound (53). Step B shows amide coupling of compound (53) and an acyl chloride (54) using a base such as TEA or pyridine in a solvent such as ACN of DCM to form compound (55). Step C depicts the conversion of compound (55) to compound (58) by using a base such as t-BuOK or K2CO3in a solvent such as ACN.Alternatively, compound (58) can be prepared by a reaction as shown in step D which shows the protection of compound (56) is with SEM-Cl or PMB-Cl and coupling with a cyclic amine using a base such as DIPEA to give compound (57). Step E depicts the oxidation of compound (57) using reagents such as RuCl3.H2O and NaClO in a solvent such as EtOAc to form compound (58). Step F shows a reaction of compound (58) with an aryl bromo compound using a base such as LiHMDS or LDA in a solvent such as THF to give compound (59). Optionally, the TBDPS group on R6of compound (59) can be deprotected using TBAF in a solvent such as THF to reveal the alcohol group. Step G depicts the Stille coupling of compound (59) with a stannous pyridazine compound in a catalyst system such as Pd(tBu3P)2and CsF or Pd(PPh3)4in a solvent such as dioxane to form compound (60). Alternatively, compound (59) can be coupled with bis(pinacolato)diboron using a catalyst such as Pd(dppf)Cl2and a base such as KOAc in a solvent such as dioxane. The boronate ester intermediate is then coupled with a pyridazine compound in a catalyst system such as Pd(dppf)Cl2and a base such as K2CO3in a solvent such as dioxane to give compound (60). Step H shows acidic deprotection of compound (60) with an acid such as TFA or a mixture of TFA and triflic acid in a solvent such as DCM to give compound (61). Step I depict a reaction of compound (61) with di-tert-butyl (chloromethyl) phosphate using a base such as Cs2CO3or CsF in a solvent such as DMF to form isomeric compounds (62) and (63). Step J shows acidic deprotection of compounds (62) and (63) with an acid such as TFA or AcOH in a solvent such as DCM or H2O to give compounds (64) and (65).Scheme 9Scheme 9, step A depicts the coupling of compounds (66) and (67) using a base such as K2CO3in a solvent such as ACN to give compound (68). Step B shows the dechlorination of compound (68) in a catalyst system such as Pd(OAc)2, PPh3and Et3SiH and a base such as TEA in a solvent such as EtOH to form compound (69). Step C depicts the saponification of compound (69) using a base such as LiOH in a solvent such as THF and H2O to give compound (70). Step D shows the reaction of compound (70) with DPPA using a base such as DiPEA in a solvent such as t-BuOH an dioxane to form compound (71). Step E depicts the acidic deprotection of compound (71) using an acid such as HFIP to give compound (72). Step F shows the amide coupling of compounds (72) and (73) using a coupling reagent such as POCl3in a solvent such as pyridine to form compound (74). Step G depicts the cyclization reaction of compound (74) using a base such as K2CO3in a solvent such as ACN to produce compound (75).Scheme 10 In the scheme below, Rais H or Cl.Scheme 10, step A depicts the chlorination reaction of compound (76) using sulfuryl chloride in a solvent such as DCM to give compound (77). Step B shows the conversion of compound (77) into the ester (78) using a base such as NaOH in a solvent such as MeOH. Step C depicts the bromination of compound (78) using bromine in an acid such as AcOH to form compound (79). Step D shows the coupling of compounds (79) and (80) in a catalyst system such as CuI and N,N'-dimethyl-1,2-cyclohexanediamine using a base such as K3PO4in a solvent such as DMF to give compound (81). Step E depicts the bromination of compound (81) using NBS in a solvent such as DCM to form compound (82). Step F shows the protection reaction of compound (82) with SEM-Cl using a base such as NaH in a solvent such as THF to give compound (83). Step G depictsthe Stille coupling of compound (83) with a stannous pyridazine compound in a catalyst system such as Pd(tBu3P)2and CsF in a solvent such as dioxane to form compound (84). Step H shows the saponification of compound (84) using a base such as LiOH in a solvent such as THF and H2O to give compound (85). Step I depicts the amide coupling of compound (85) and NH4Cl using a coupling reagent such as HATU and a base such as DIPEA in a solvent such as DMF to form compound (86). Step J shows the conversion of the amide of compound (86) into a nitrile using SOCl2in a solvent such as DMF to give compound (87). Step K depicts acidic deprotection of compounds (87) with an acid such as TFA in a solvent such as DCM to produce compound (88).Scheme 11Scheme 11, step A shows the reaction of compound (89) with hydrazine in a solvent such as EtOH to give the compound (90). Step B depicts the intermolecular cyclization of compounds (90) and (91) using a base such as K2CO3in a solvent such as EtOH to form compound (92). Step C shows the dechlorination of the pyrazidine of compound (92) using Pd / C and H2gas in a solvent such as MeOH to give compound (93). Step D depicts a Sandmeyer reaction on compound (93) using tert-butyl nitrite and CuCl2in a solvent such as ACN to form compound (94). Step E shows the saponification of compound (94) using a base such as LiOH in a solvent such as THF and H2O to give compound (95). Step F depicts the bromination of compound (95) using bromine and a base such as NaOH in a solvent such as H2O to form compound (96). Step G shows thecoupling reaction of compounds (96) and (97) in a catalyst system such as CuI and N,N'- dimethyl-1,2-cyclohexanediamine using a base such as K3PO4in a solvent such as DMF to give compound (98). Scheme 12Scheme 12, step A depicts the protection of compound (99) with SEM-Cl using a base such as NaH in a solvent such as THF to give compound (100). Step B shows the hydrogenation reaction of compound (100) using Pd / C and H2gas in a solvent such as MeOH to form compound (101). Step C depicts the coupling of compounds (101) and (102) using a base such as pyridine in a solvent such as DCM, followed by use of a base such as K2CO3in a solvent such as MeOH to give compound (103). Step D shows the cyclization reaction of compound (103) using a base such as K2CO3in a solvent such as ACN to give compound (104). Step E shows a reaction of compound (104) with an aryl bromo compound using a base such as LiHMDS in a solvent such as THF to givecompound (105). Step F depicts acidic deprotection of compound (105) with an acid such as TFA in a solvent such as DCM to form compound (106). Step G shows iodination reaction of compound (106) using NIS in a solvent such as ACN to give compound (107). Step H depicts the reaction of compound (107) using Na2SO3in a solvent mixture such as EtOH, H2O and ACN to form compound (108). Step I shows a Stille coupling of compound (108) with a pyridazine compound (109) in a catalyst system such as Pd2(dba)3and XPhos in a solvent such as DMF to produce compound (110). Scheme 13Scheme 13, step A depicts a reaction of compound (111) with an aryl bromo compound using a base such as LiHMDS in a solvent such as THF to give compound (112). Step B shows acidic deprotection of compound (112) with an acid such as HCl in a solvent such as dioxane to form compound (113). Step C depicts the cyclization of compound (114) with an aryl amine compound in a solvent such as toluene to give compound (115). Step D shows a reaction of compound (115) with an aryl bromo compound using a base such as LDA in a solvent such as THF to give compound (116). Step E depicts the conversion of the carboxylic acid of compound (116) into an amide using Boc2O, NH4HCO3, a base such as pyridine in a solvent such as ACN to form compound (117). Step F shows the conversion of the amide of compound (117) into a nitrile using POCl3in a solvent such as DMF to give compound (118). Step G depicts acidic deprotection of compounds (118) with an acid such as triflic acid in a solvent such as TFA to form compound (113). Step H shows the coupling reaction of compounds (119) and (113) in a catalyst system such as CuI and N,N'-dimethyl-1,2- cyclohexanediamine using a base such as K3PO4in a solvent such as DMF to give compound (120). Step I depict the reduction of the aldehyde of compound (120) using a reducing agent such as NaBH4in a solvent such as MeOH to form compound (121). Step J shows acidic deprotection of compounds (121) with an acid such as TFA in a solvent such as DCM to produce compound (122). Preparation 1 2-Methyl-3-(5-methylpyridazin-4-yl)-3-oxopropanenitrileTo a mixture of propiononitrile (500 mg, 9 mmol) in THF (10 mL) was added LiHMDS (1.6M in THF, 5.6 mL, 9 mmol) slowly at -60 °C. The reaction mixture was stirred for 1 hr., and then a solution of ethyl 5-methylpyridazine-4-carboxylate (747 mg, 4.5 mmol) in THF (5 mL) was added slowly at -60 °C and stirred for 2 hrs. The reaction mixture was concentrated in vacuo to give the title compound (788 mg, crude). ES / MS m / z 176 (M+H).The compound in Table 1 was prepared in a manner essentially analogous to that found in Preparation 1. Table 1Preparation 2a 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazoleTo a solution of 4-chloro-1H-imidazole (5.00 g, 48.8 mmol) in THF (30 mL) was added NaH (2.34 g, 97.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr., and then 2-(chloromethoxyethyl)trimethyl silane (8.94 g, 53.6 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hrs. The reaction was quenched by ice-water and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with water (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo to give crude product as a yellow oil (9.50 g, crude). ES / MS (m / z): 233 (M+H).Preparation 2b 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehydeTo a solution of crude 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazole (9.50 g, 40.8 mmol) in THF (30 mL) was added n-butyllithium (3.92 g, 61.2 mmol) at - 78 °C. The mixture was stirred at -78 °C for 30 min, then DMF (14.9 g, 204 mmol) was added at the same temperature. The reaction mixture was stirred at -78 °C for 2 hrs., then quenched by saturated ammonium chloride (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with water (30 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a yellow oil (6.20 g, 53% over two steps). ES / MS (m / z): 233 (M-28+H). Preparation 2c Ethyl 3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylateTo a solution of ethyl 3-chloro-1H-pyrazole-5-carboxylate (700 mg, 4.02 mmol) in THF (10 ml) was added DIEA (1.04 g, 8.04 mmol) and SEM-Cl (873 mg, 5.23 mmol). The mixture was stirred at ambient temperature for 16 hrs. The solvent was removed to give the crude, which was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-50%) to give the title compound as a colorless oil (1.3 g, 98%). ES / MS (m / z): 305 (M+H).Preparation 2e (3-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)methanolTo a solution of ethyl 3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 5-carboxylate (1.3 g, 4.3 mmol) in THF (15 mL) was added LiAlH4(3.2 mL, 6.4 mmol, 2M in THF). The mixture was stirred at 0 °C for 2 hrs. The reaction was quenched with 10% NaOH. The mixture was filtered, and the filter cake was washed with THF. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a colorless oil (1.05 g, 93%). ES / MS (m / z): 263 (M+H). Preparation 2j tert-Butyl 3-(4-chloro-3-fluorobenzyl)-2-oxopyrrolidine-1-carboxylateTo a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (3 g, 16.2 mmol) in THF (15 mL) was dropped LiHMDS (21.1 mL, 1M in THF, 21.1 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 hr., then a solution of 4-(bromomethyl)-1- chloro-2-fluorobenzene (3.60 g, 16.2 mmol) in THF (15 mL) was added at - 78 °C. The reaction mixture was stirred at -78 °C for additional 2 hrs., and then quenched by saturated NH4Cl (50 mL). The mixture was extracted with EtOAc (80 mL x 3). The combined organic layer was washed with water (50 mL) and saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-10%) to give the title compound as a colorless oil (1.17 g, 22%). ES / MS (m / z): 272.0 (M-tBu+H). The compound in Table 1c was prepared in a manner essentially analogous to that found in Preparation 2j.Table 1cPreparation 2aa 3-(4-Chloro-3-fluorobenzyl)pyrrolidin-2-oneTo a solution of tert-butyl 3-(4-chloro-3-fluorobenzyl)-2-oxopyrrolidine-1- carboxylate (1.17 g, 3.58 mmol) in DCM (10 mL) was added HCl (4M in dioxane, 10 mL). The reaction mixture was stirred at ambient temperature for 2 hrs. The solvents were removed in vacuo to give the title compound as a white solid (750 mg, 92%). ES / MS (m / z): 228 (M+H). The compounds in Table 1d were prepared in a manner essentially analogous to that found in Preparation 2aa.Table 1dPreparation 2aq 1-(3-Bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-5-hydroxy-3-(3,4,5- trifluorobenzyl)piperidin-2-oneTo a mixture of 1-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-5-((tert- butyldiphenylsilyl)oxy)-3-(3,4,5-trifluorobenzyl)piperidin-2-one (2.10 g, 2.12 mmol) in THF (5 mL) was added TBAF (4.34 mL, 70-75% w / w aqueous solution, 10.6 mmol). The reaction mixture was stirred at 25 °C for 4 hrs. The mixture was diluted by water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-50%) to give the title compound as a yellow oil (860 mg, 74%). ES / MS (m / z): 527 (M+H).Preparation 2au 1-Bromo-4-fluoro-2-(fluoromethyl)benzeneTo a solution of (2-bromo-5-fluorophenyl)methanol (CAS registry No.202865-66- 5) (3.00 g, 14.6 mmol) in DCM (30 mL) was added dropwise DAST (2.03 mL, 15.4 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 2 hrs., and then warmed to ambient temperature. The reaction was quenched by 1N NaHCO3(30 mL). The mixture was extracted with DCM (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0- 3%) to give the title compound as a colorless oil (2.86 g, 91.3%).1H NMR (CDCl3) δ 7.55-7.51 (m, 1H), 7.24 (dd, J = 2.8 Hz & 8.8 Hz, 1H), 6.96 (td, J = 2.8 Hz & 8.8 Hz, 1H), 5.45 (d, J = 46.8 Hz, 2H). The compound in Table 1f was prepared in a manner essentially analogous to that found in Preparation 2au. Table 1fPreparation 2aw 4-Fluoro-2-(fluoromethyl)benzaldehyden-BuLi (2.125 mL, 2.5M in hexane, 5.313 mmol) was added to a solution of 1- bromo-4-fluoro-2-(fluoromethyl)benzene (1.00 g, 4.830 mmol) in THF (10 mL) at -78 °C. The reaction mixture was stirred for 30 min and DMF (529.7 mg, 7.246 mmol) was added, stirring was continued for 4 hrs., at -78 °C. The reaction was quenched by saturated NH4Cl (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-3%) to give the title compound as a colorless crystal (240 mg, 29.2%).1H NMR (CDCl3): δ 10.04 (s, 1H), 7.92-7.88 (m, 1H), 7.46 (dd, J = 1.4 Hz & 9.6 Hz, 1H), 7.25-7.20 (m, 1H), 5.91 (d, J = 34.4 Hz, 2H). Preparation 2ax 1-(Bromomethyl)-4-fluoro-2-(fluoromethyl)benzeneTo a solution of 4-fluoro-2-(fluoromethyl)benzaldehyde (400 mg, 2.28 mmol) in MeOH (4 mL) was added NaBH4(173 mg, 4.56 mmol) at ambient temperature. After stirring at 25 °C for 1 hr., the reaction mixture was quenched by water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. To a solution of the crude material (385 mg, 2.43 mmol) in DCM (2 mL) was added PBr3(1.36 g, 5.01 mmol) at 0 °C. After stirring at 0 °C for 1 hr., the reaction mixture was quenched by saturated NaHCO3(5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a brownish oil (290 mg, 52% over two steps).1H NMR (CDCl3): δ 7.41- 7.37 (m, 1H), 7.17 (dd, J = 2.4 Hz & 9.2 Hz, 1H), 7.08-7.04 (m, 1H), 5.56 (d, J = 46.8 Hz, 2 H), 4.54 (s, 2H). The compound in Table 1g was prepared in a manner essentially analogous to that found in Preparation 2ax. Table 1gPreparation 2bg tert-Butyl 3-hydroxy-2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidine-1-carboxylateTo a solution of tert-butyl 2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidine-1- carboxylate (1.50 g, 3.85 mmol) in THF (30 mL) was added drop wise NaHMDS (918 mg, 5.01 mmol) at -78 °C under nitrogen. The reaction mixture was stirred at -78 °C for 1 hr.3-Phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (1.01 g, 3.85 mmol) in THF (10 mL) was added drop wise into the mixture at -78 °C. After stirring at -78 °C for 30 min, the reaction was quenched by addition of water (50 mL) and extracted with EtOAc (200 mL). The combined organic layer was washed with saturated aqueous NaCl (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a white solid (500 mg, 18.9%). ES / MS (m / z): 290 (M+H).Preparation 2bh 2-(Difluoromethyl)-4-fluoro-1-methylbenzeneTo a solution of 5-fluoro-2-methylbenzaldehyde (6.00 g, 43.4 mmol) in DCM (20 mL) was added DAST (35.0 g, 217 mmol) at 0 °C. The mixture was warmed up and stirred at ambient temperature for 16 hrs. The reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography eluting with petroleum ether (100%) to give the title compound (5.00 g, 72%) as a colorless oil. ES / MS (m / z): 161 (M+H). The compounds in Table 1h were prepared in a manner essentially analogous to that found in Preparation 2bh. Table 1hPreparation 2bo Methyl 6-(difluoromethyl)nicotinateTo a mixture of 5-bromo-2-(difluoromethyl)pyridine (2.00 g, 9.7 mmol) in DMF (10 mL) was added Et3N (2.94 g, 29.1 mmol), MeOH (995 µL, 24.6 mmol) and Pd(OAc)2(216 mg, 0.97 mmol). The reaction mixture was stirred at 75 °C for 24 hrs., under CO atmosphere, and then cooled to ambient temperature. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (1%) to give the title compound (1.5 g, 82%) as a colorless oil. ES / MS (m / z): 188 (M+H). The compounds in Table 1i were prepared in a manner essentially analogous to that found in Preparation 2bo. Table 1iPreparation 2bt (6-(Difluoromethyl)pyridin-3-yl)methanolTo a solution of methyl 6-(difluoromethyl)nicotinate (500 mg, 2.7 mmol) in THF (6 mL) was added the solution of 1M LiAlH4in THF (3.24 mL, 3.24 mmol) at ambient temperature, and then stirred at 25 °C for 1 hr. The reaction mixture was poured onto ice water (20 mL) and extracted with EtOAc (40 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (170 mg, 40%) as a yellow oil. ES / MS (m / z): 160 (M+H). The compound in Table 1j was prepared in a manner essentially analogous to that found in Preparation 2bt.Table 1jPreparation 2bv 5-(Bromomethyl)-2-(difluoromethyl)pyridineTo a solution of (6-(difluoromethyl)pyridin-3-yl)methanol (170 mg, 1.1 mmol) in DCM (5 mL) was added PBr3(577 mg, 2.2 mmol) at 0 °C and then stirred at 25 °C for 2 hrs. The reaction mixture was poured onto ice water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether (100%) to give the title compound (70 mg, 30%) as a colorless oil. ES / MS (m / z): 224 (M+H). The compounds in Table 1k were prepared in a manner essentially analogous to that found in Preparation 2bv. Table 1kPreparation 3 4-Methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-amineTo a mixture of 2-methyl-3-(5-methylpyridazin-4-yl)-3-oxopropanenitrile (788 mg, 4.5 mmol) in EtOH (20 mL) was added AcOH (1.1 g, 18 mmol) and hydrazine hydrate solution (80% in water) (563 mg, 9.0 mol). The mixture was stirred at 80 °C for 16 hrs. To the reaction mixture was then added saturated aqueous Na2CO3solution to adjust pH to 8-9, and the organic solvents were then removed in vacuo. Water (20 mL) was added, and the mixture was stirred for 1 hr. The resulting solid was filtered, and the cake was washed with water (10 mL x 2), and dried at 60 °C for 10 hrs. to give the title compound (500 mg, 57%) as a brown solid. ES / MS m / z 176 (M+H). The compound in Table 2 was prepared in a manner essentially analogous to that found in Preparation 3.Table 2Preparation 4a Chloro-2-fluoro-4-iodo-5-methoxybenzeneTo a solution of 2-chloro-1-fluoro-4-methoxybenzene (5.00 g, 31.1 mmol) in trichloromethane (300 mL) was added silver (I) 2,2,2-trifluoroacetate (24.8 g, 112 mmol) and iodine (16.6 g, 65.4 mmol) at 20 °C. After stirring at 20 °C for 2 hrs., the reaction mixture was filtered through a diatomaceous earth pad. The filtrate was diluted with DCM (100 mL), washed with sodium sulfite solution (100 mL x 2) and saturated aqueous NaCl (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-1%) to give the title compound as a colorless oil (8.00 g, 86.7%).1HNMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 6.4 Hz, 1H), 3.84 (s, 3H). Preparation 4b 1-Chloro-2-fluoro-5-methoxy-4-methylbenzeneTo a solution of 1-chloro-2-fluoro-4-iodo-5-methoxybenzene (4.00 g, 13.5 mmol) in 1,4-dioxane (80 mL) and water (20 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane in THF (9.49 g, 75.6 mmol), potassium carbonate (3.73 g, 27.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (988 mg, 1.35 mmol) at ambient temperature. The reaction mixture was stirred at 85 °C for 2 hrs., under nitrogen. After cooling down to ambient temperature, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (80 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-1%) to give the title compound as a colorless oil (880 mg, 36%).1HNMR (DMSO-d6) δ 7.24 (dd, J = 9.8 Hz and 0.6 Hz, 1H), 7.10 (d, J = 6.4 Hz, 1H), 3.79 (s, 3H), 2.13 (s, 3H). Preparation 4c 1-(Bromomethyl)-4-chloro-5-fluoro-2-methoxybenzeneTo a solution of 1-chloro-2-fluoro-5-methoxy-4-methylbenzene (880 mg, 4.85 mmol) in carbon tetrachloride (15 mL) was added NBS (820 mg, 4.60 mmol) and 2,2'- azobis(2-methylpropionitrile) (79.6 mg, 485 μmol) at ambient temperature. The reaction mixture was stirred at 80 °C for 16 hrs., under nitrogen. After cooling to ambient temperature, the reaction mixture was quenched with water (15 mL) and extracted with DCM (30 mL x 3). The combined organic layer was washed with sodium thiosulfate (20 mL x 2), saturated aqueous NaCl (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-1%) to give the title compound as a white solid (900 mg, 71%).1H NMR (DMSO-d6) δ 7.54 (d, J = 12.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.59 (s, 2H), 3.87 (s, 3H). The compounds in Table 2a were prepared in a manner essentially analogous to that found in Preparation 4c.Table 2aPreparation 4i tert-Butyl 5-chloropentanoateTo a solution of tert-butanol (17 g, 0.23 mol) in pyridine (20 mL) was added 4- dimethylaminopyridine (39 mg, 0.32 mmol) and 5-chloropentanoyl chloride (10 g, 65mmol) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 hrs. The mixture was poured into sodium bicarbonate solution (150 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with 1N HCl (200 mL), saturated aqueous NaCl (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title crude compound as a yellow oil (13.0 g, 73%).1H NMR (DMSO-d6) δ 3.63 (t, J = 6.5 Hz, 2H), 2.23 (t, J = 7.3 Hz, 2H), 1.78 – 1.66 (m, 2H), 1.64 – 1.52 (m, 2H), 1.40 (s, 9H). Preparation 4j tert-Butyl 5-chloro-2-(4-chloro-5-fluoro-2-methoxybenzyl)pentanoateTo a solution of LDA (3.87 mL, 2M in THF, 7.74 mmol) in THF (10 mL) was added a solution of tert-butyl 5-chloropentanoate (1.42 g, 5.16 mmol) in THF (4 mL) at 0 °C under nitrogen protection. The reaction mixture was stirred at 0 °C for 1 hr. A solution of 1-(bromomethyl)-4-chloro-5-fluoro-2-methoxybenzene (720 mg, 2.75 mmol) in THF (10 mL) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hrs. The reaction mixture was quenched with ammonium chloride solution (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-5%) to give the title compound as a yellow oil (770 mg, 28.3%).1H NMR (CDCl3) δ 6.92 (d, J = 9.4 Hz, 1H), 6.81 (d, J = 6.1 Hz, 1H), 3.81 (s, 3H), 3.53 (t, J = 6.4 Hz, 2H), 2.76-2.73 (m, 2H), 2.63 – 2.58 (m, 1H), 1.87 – 1.75 (m, 2H), 1.71 – 1.58 (m, 2H), 1.35 (s, 9H). The compound in Table 2b was prepared in a manner essentially analogous to that found in Preparation 4j.Table 2bPreparation 4l 5-Chloro-2-(4-chloro-5-fluoro-2-methoxybenzyl)pentanoic acidTo a solution of tert-butyl 5-chloro-2-(4-chloro-5-fluoro-2- methoxybenzyl)pentanoate (720 mg, 1.37 mmol) in DCM (12 mL) was added TFA (6 mL) at 20 °C. After stirring for 2 hrs., the reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a brown oil which was used for next step (660 mg, crude). ES / MS (m / z): 309 (M-H). The compound in Table 2c was prepared in a manner essentially analogous to that found in Preparation 4l.Table 2cPreparation 4n Methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylateTo a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (3.0 g, 10.74 mmol) in MeOH (40 mL) was added SOCl2(2.56 g, 21.48 mmol) at 0 °C and stirred at 70 °C for 16 hrs. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo to give the title compound as a colorless oil (2.9 g, 80%). ES / MS (m / z): 293 (M+H). Preparation 4o 1-(2,4-Dimethoxybenzyl)-4-(hydroxymethyl)pyrrolidin-2-oneTo a solution of methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (2.50 g, 7.50 mmol) in MeOH (40 mL) was added NaBH4(1.419 g, 37.50 mmol) at ambient temperature. The reaction mixture was stirred at 50 °C for 4 hrs., under nitrogen. After cooling to ambient temperature, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (60 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL x 3), dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-100%) to give the title compound as a yellow oil (2.1 g, 89%). ES / MS (m / z): 265 (M+H). Preparation 4p 2-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazoleTo a solution of 2-nitro-1H-imidazole (10.00 g, 88.43 mmol) in THF (100 mL) was added sodium hydride (4.24 g, 106.1 mmol) at 0 °C under nitrogen. The mixture was stirred for 1 hr., at 0 °C, and then (2-(chloromethoxy)ethyl)trimethylsilane (16.22 g, 97.28 mmol) was added into the mixture at 0 °C. After stirring at 25 °C for 16 hrs., the reaction mixture was quenched by water (50 ml) and extracted with EtOAc (40 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-25%) to give the title compound as a yellow solid (20.0 g, 92%). ES / MS (m / z):186 (M+H). Preparation 4q 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-amineTo a suspension of 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (20.0 g, 82.3 mmol) and palladium (10% on carbon, 2.0 g, 10% w / w) in MeOH (300 mL) was stirred for 16 hrs., at 25 °C under hydrogen balloon. The mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated to give the title compound as a black oil. (16.8 g, 97%,). ES / MS (m / z): 214 (M+H).Preparation 4r 5-Chloro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pentanamideTo a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-amine (16.80 g, 77.95 mmol) and pyridine (18.50 g, 233.9 mmol) in DCM (200 mL) was added 5- chloropentanoyl chloride (36.25 g, 233.9 mmol) at 0 °C. After stirring at 25 °C for 3 hrs., the reaction mixture was washed with saturated aqueous sodium bicarbonate (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (200 mL) and K2CO3(43.09 g, 311.8 mmol) was added. After stirring at 25 °C for 4 hrs., the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (22.0 g, 84%). ES / MS (m / z): 332 (M+H). Preparation 4s 1-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidin-2-oneTo a solution of 5-chloro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2- yl)pentanamide (22.0 g, 63.0 mmol) in ACN (300 mL) was added potassium carbonate (34.8 g, 252 mmol) at ambient temperature. The mixture was stirred at 70 °C for 16 hrs. After cooling to ambient temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with MeOH in DCM (0-5%) to give the title compound as a yellow oil (17.0 g, 96%) ES / MS (m / z): 296 (M+H).Preparation 4t 3-(3,4-Difluorobenzyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2- yl)piperidin-2-oneTo a mixture of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2- yl)piperidin-2-one (5.0 g, 16.75 mmol) in THF (60 mL) was added LiHMDS (67.0 mL, 1M in THF, 67.01 mmol) at -78 °C under nitrogen. The mixture was stirred for 2 hrs., at - 78 °C, and then a solution of 4-(bromomethyl)-1,2-difluorobenzene (2.428 g, 11.73 mmol) in THF (20 mL) was added slowly. After stirring at -78 °C for 1 hr., the reaction mixture was quenched by ammonium chloride (30 ml) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-40%) to give the title compound as a yellow oil (3.80 g, 51%). ES / MS (m / z): 422 (M+H). Preparation 4u 3-(3,4-Difluorobenzyl)-1-(1H-imidazol-2-yl)piperidin-2-oneTo a mixture of 3-(3,4-difluorobenzyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-2-yl)piperidin-2-one (3.80 g, 8.56 mmol) in DCM (10 mL) was added TFA (9.76 g, 85.6 mmol) at 25 °C. After stirring at 25 °C for 16 hrs., the reaction mixture was quenched by saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (50mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a yellow solid (2.60 g, 98%). ES / MS (m / z): 292 (M+H). Preparation 4v 3-(3,4-Difluorobenzyl)-1-(4,5-diiodo-1H-imidazol-2-yl)piperidin-2-oneTo a mixture of 3-(3,4-difluorobenzyl)-1-(1H-imidazol-2-yl)piperidin-2-one (2.20 g, 7.175 mmol) in ACN (30 mL) was added 1-iodopyrrolidine-2,5-dione (2.26 g, 10.04 mmol) in ACN (20 mL) slowly at 25 °C. After stirring at 25 °C for 2 hrs., the reaction was quenched by water (20 ml) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was concentrated in vacuo to give crude product as a brown oil. (3.50 g, 65%). ES / MS (m / z): 544 (M+H). The compound in Table 2d was prepared in a manner essentially analogous to that found in Preparation 4v. Table 2dPreparation 4x 3-(3,4-Difluorobenzyl)-1-(4-iodo-1H-imidazol-2-yl)piperidin-2-oneA mixture of 3-(3,4-difluorobenzyl)-1-(4,5-diiodo-1H-imidazol-2-yl)piperidin-2- one (3.50 g, 4.64 mmol) and sodium sulfite (11.7 g, 92.8 mmol) in EtOH (40 mL), water (40 mL) and ACN (30 mL) was stirred at 100 °C for 16 hrs. After cooling to ambient temperature, the reaction mixture was extracted with EtOAc (30 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-15%) to give the title compound as a yellow oil (1.40 g, 67%). ES / MS (m / z): 418 (M+H). The compound in Table 2e was prepared in a manner essentially analogous to that found in Preparation 4x. Table 2ePreparation 4z 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidineTo a solution of 3,5-dibromo-4H-1,2,4-triazole (150.0 g, 661.2 mmol) in THF (1.5 L) was added dropwise DIPEA (147 mL, 846.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 min, then SEM-Cl (150 mL, 846.3 mmol) was added at 10 °C. The mixture was warmed up and stirred at ambient temperature for 2 hrs. Piperidine (340 mL, 3.438 mol) was added to the above solution at ambient temperature. The resulting mixture was heated to 70 °C and stirred for 16 hrs. The reaction mixture was poured into ice-water (1.5 L) and extracted with EtOAc (1.5 L x 3). The combined organic phase was washed with 1N HCl, saturated aqueous NaCl, dried over anhydrous Sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give title compound as a white solid (230 g, 96.6%). ES / MS (m / z): 363 (M+H). The compounds in Table 2f were prepared in a manner essentially analogous to that found in Preparation 4z. Table 2fPreparation 4ac 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-oneTo a stirred solution of 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- 1,2,4-triazol-5-yl)piperidine (115.0 g, 318.2 mmol) in EtOAc (1.2 L) was added sodium hypochlorite (392.9 mL, 7.5% wt., 477.4 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 min. To the mixture was added a suspension of ruthenium(III) chloride trihydrate (7.921 g, 35.13 mmol) in EtOAc (100 mL) at 10 °C. After warming up and stirring at ambient temperature for 16 hrs., the mixture was filtered to remove solid. The filtrate was extracted EtOAc (1 L x 3). The combined organic phase was washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give title compound as pale-yellow oil (95 g, 75%). ES / MS (m / z): 375 (M+H) The compounds in Table 2g were prepared in a manner essentially analogous to that found in Preparation 4ac. Table 2gPreparation 4af 3,5-Dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazoleTo a suspension of 3,5-dibromo-1H-1,2,4-triazole (1.00 g, 4.41 mmol) in DMF (10 mL) was added cesium carbonate (2.87 g, 8.82 mmol) at ambient temperature. To the mixture was added 1-chloromethyl-4-methoxy-benzene (1.04 g, 6.61 mmol) to the mixture, stirred at ambient temperature for 16 hrs., diluted with water (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give the title compound as a white solid (1.20 g, 59.5%) ES / MS (m / z): 348 (M+H). Preparation 4ag 3,5-Dibromo-4-methyl-1H-pyrazoleTo a solution of 3,4,5-tribromo-1H-pyrazole (5 g, 16.55 mmol) in THF (25 mL) was added dropwise n-BuLi (2.5M in THF, 14.6 mL, 36.45 mmol) at -78 °C. The mixturewas stirred at -78 °C for 30 min, and then a solution of MeI (2.35 g, 16.55 mmol) in THF (25 mL) was added at the same temperature. After stirring at -78 °C for additional 1 hr., the reaction mixture was quenched by saturated aqueous NH4Cl and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel and Prep-HPLC to give the title compound as a white solid (1.52 g, 38.6%). ES / MS (m / z): 239 (M+H). Preparation 4ah 3,5-Dibromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleTo a suspension of 3,5-dibromo-4-methyl-1H-pyrazole (1.52 g, 6.39 mmol) in THF (15 mL) was added NaH (60% in oil, 307 mg, 7.67 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 30 min, and then SEM-Cl (1.06 g, 6.39 mmol) was added 0 °C. After stirring at 0 °C for 2 hrs., the mixture was treated with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-5%) to give the title compound as a brownish solid (2.08 g, 32.5%). ES / MS (m / z): 369 (M+H). Preparation 4ai 1,2,4,5-TetrazineFormamidine acetate (60.0 g, 576.3 mmol) was cooled with ice water bath at 0 °C, and then hydrazine hydrate (94.72 mL, 1.556 mol) was added dropwise. The reactionmixture was stirred at 25 °C for 1 hr., and then re-cooled to 0 °C. Water (20 mL) was added to the reaction mixture and stirred at 0 °C for another 1 hr. The precipitate was collected by filtration, dissolved in acetic acid (200 mL) and cooled to 0 °C. Sodium nitrite (19.88 g, 288.2 mmol) was added to the reaction mixture in small portions at 0 °C. After stirring at 0 °C for 1 hr., the reaction was quenched with water (300 mL) and extracted with DCM (300 mL x 4). The organic layers were washed with saturated aqueous NaHCO3until it was neutralized, dried with MgSO4, filtered, and concentrated in vacuo at 25 °C to give title compound as a red solid (7.41 g, 12.7%).1HNMR (CDCl3) δ 10.41 (s, 2 H). Preparation 4aj 4-Methyl-5-(tributylstannyl)pyridazineTo a stirred solution of tributyl(prop-1-yn-1-yl)stannane (182.9 g, 555.6 mmol) in toluene (1.5 L) was slowly added 1,2,4,5-tetrazine (38.00 g, 463.0 mmol) at 120 °C. After stirring at 120 °C for 30 min, the mixture was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0 to 10%) to give title compound as a yellow oil (151.0 g, 84%). ES / MS (m / z): 385 (M+H). Preparation 4ak (5-(Trimethylstannyl)pyridazin-4-yl)methanolTo a solution of 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5- (trimethylstannyl)pyridazine (1.00 g, 2.532 mmol) in EtOH (10 mL) was added p- toluenesulfonic acid monohydrate (481.6 mg, 2.532 mmol). The reaction mixture wasstirred at 60 °C for 2 hrs. After cooling to ambient temperature, the solvent was removed in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated sodium carbonate solution (30 mL) and saturated aqueous NaCl (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a solid (528 mg, 71.2%): ES / MS (m / z): 275 (M+H). Preparation 4al 4-(Methoxymethyl)-5-(trimethylstannyl)pyridazineTo a suspension of (5-(trimethylstannyl)pyridazin-4-yl)methanol (200 mg, 682 µmol) in THF (5 mL) was added NaH (40.9 mg, 60% in oil, 1.02 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min, then MeI (96.7 mg, 682 µmol) was added at the same temperature. After stirring at 0 °C for 6 hrs., the mixture was quenched by water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a brown oil. (120 mg, 46%): ES / MS (m / z): 289.0 (M+H). Preparation 4am (2-Amino-4-chlorophenyl)methanolTo a solution of 1M BH3in THF (39.6 mL, 39.6 mmol) was added 2-amino-4- chlorobenzoic acid (2.00 g, 11.7 mmol) in portions, and then stirred at 25 °C for 3 days. The mixture was quenched with MeOH (200 mL) then concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (1:1) to give the title compound (1.40 g, 71%) as a white solid. ES / MS (m / z): 158 (M+H). The compound in Table 2h was prepared in a manner essentially analogous to that found in Preparation 4am.Table 2hPreparation 4ao tert-Butyl (5-chloro-2-(hydroxymethyl)phenyl)carbamateTo a solution of (2-amino-4-chlorophenyl)methanol (5.5 g, 35 mmol) in EtOH (100 mL) was added di-tert-butyl dicarbonate (8.4 g, 38 mmol) dropwise at 25 °C, and then stirred at 50 °C for 2 days under N2. The mixture was concentrated in vacuo to give the title compound (10.01 g, 99+%) as a yellow oil. ES / MS (m / z): 184 (M+H-Boc).1H NMR (DMSO-d6) δ 8.70 (s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.09 (dt, J = 17.3, 8.6 Hz, 1H), 5.66 – 5.41 (m, 1H), 4.48 (t, J = 14.0 Hz, 2H), 1.47 (s, 9H). Preparation 4ap tert-Butyl (2-(bromomethyl)-5-chlorophenyl)carbamateTo a solution of tert-butyl (5-chloro-2-(hydroxymethyl)phenyl)carbamate (5.00 g, 19.4 mmol) in THF (50 mL) was added triphenylphosphine (7.63 g, 29.1 mmol) and NBS (5.18 g, 29.1 mmol) in portions. After stirring at 25 °C for 2 hrs., the reaction mixture was added to water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flashchromatography eluting with EtOAc in petroleum ether (9:1) to give the title compound (5.9 g, 76%) as a yellow solid. ES / MS (m / z): 264 (M+H-t-Bu). The compound in Table 2i was prepared in a manner essentially analogous to that found in Preparation 4ap. Table 2iPreparation 5 5-Methylpyridazine-4-carbohydrazideTo a solution of ethyl 5-methylpyridazine-4-carboxylate (6 g, 36.14 mmol) (prepared as described in Heinisch, G, et al., Heterocycles, 1984, 22(6), 1395-1402) in EtOH (20 mL) was added hydrazine hydrate solution (80% in water) (5.4 g, 108.43 mmol). The mixture was stirred for 2 hrs. at 120 °C, then concentrated in vacuo to give the title compound (6 g, crude) as a yellow solid. ES / MS m / z 153 (M+H).Preparation 6 2-(5-Methylpyridazine-4-carbonyl)hydrazine-1-carboximidamideTo a solution of crude 5-methylpyridazine-4-carbohydrazide (6 g, 39.21 mmol) in water (20 mL) was added methyl carbamimidothioate sulfate (8.18 g, 58.82 mmol) and NaOH (1.17 g, 29.39 mmol), and then the mixture was stirred for 16 hrs. at ambient temperature. The resulting precipitate was filtered and dried in vacuo to give the title compound (4 g, 52.6%) as a yellow solid. ES / MS (m / z): 195 (M+H). Preparation 7 3-(5-Methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amineTo a solution of 2-(5-methylpyridazine-4-carbonyl)hydrazine-1-carboximidamide (4 g, 20.51 mmol) in water (20 mL) was added NaOH (8 mg, 0.2 mmol), and the solution was stirred for 16 hrs. at 100 °C. The resulting solid was filtered, and dried in vacuo to give the title compound (3.1 g, 85%) as a white solid. ES / MS m / z 177 (M+H). Preparation 8 1-(4-Methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-amineTo a stirred mixture of crude 3-(5-methylpyridazin-4-yl)-3-oxopropanenitrile (10.3 g, 64 mmol) in EtOH (120 mL) was added AcOH (11.7 g, 192 mmol) slowly, followed by (4-methoxybenzyl) hydrazine hydrochloride (18 g, 96 mmol), and then thereaction mixture stirred at reflux overnight. The mixture was concentrated to dryness. The residue was purified via silica gel flash chromatography eluting with DCM / MeOH (97:3) to give the title compound (11 g, 58.5%) as a brown solid. ES / MS m / z 296 (M+H). Preparation 8a 4-MethoxypyridazineTo a solution of 4-bromopyridazine hydrobromide (4.50 g, 18.8 mmol) in MeOH (100 mL) was added sodium methoxide (16.9 g, 93.8 mmol) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hrs. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with MeOH in DCM (0-3%) to give the title compound as a black oil (1.5 g, 68%) ES / MS (m / z): 111 (M+H). Preparation 8b 4-Bromo-5-methoxypyridazineTo a solution of 4-methoxypyridazine (500 mg, 4.25 mmol) in ACN (20 mL) was added NBS (756 mg, 4.25 mmol). The reaction mixture was stirred at 80 °C for 2 hrs. After cooling to ambient temperature, the reaction mixture was quenched with sodium sulfite solution (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with MeOH in DCM (0-3%) to give the title compound as a brown oil (180 mg, 21.3%). ES / MS (m / z): 189 (M+H).Preparation 8c 4-Methoxy-5-(trimethylstannyl)pyridazineTo a solution of 4-bromo-5-methoxypyridazine (250 mg, 1.26 mmol) in 1,4- dioxane (5 mL) was added bis-(triphenylphosphino)-palladous chloride (88.3 mg, 126 µmol) and 1,1,1,2,2,2-hexamethyldistannane (824 mg, 2.52 mmol) at ambient temperature. The reaction mixture was stirred at 100 °C for 16 hrs., under nitrogen. After cooling to ambient temperature, aqueous potassium fluoride solution (20 mL) was added to the reaction mixture. After stirring at 20 °C for 0.5 hr., the reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a brown oil (250 mg, 20.4%). ES / MS (m / z): 275 (M+H). Preparation 8d 3-Chloro-5-hydrazineylpyridazineTo a solution of 3,5-dichloropyridazine (10.0 g, 67.1 mmol) in EtOH (150 mL) at 80 °C was added hydrazine hydrate (4.30 g, 134 mmol) dropwise. The mixture was stirred at 80 °C for 1 hr. After cooling to ambient temperature, the mixture was concentrated in vacuo to give the crude title compound as a yellow solid (9.0 g, 78%). ES / MS (m / z): 145 (M+H). Preparation 8e Ethyl 5-amino-1-(6-chloropyridazin-4-yl)-1H-pyrazole-4-carboxylateA mixture of 3-chloro-5-hydrazineylpyridazine (9.00 g, 62.3 mmol), ethyl (E)-2- cyano-3-ethoxyacrylate (15.80 g, 93.39 mmol) and potassium carbonate (17.20 g, 124.6 mmol) in EtOH (200 mL) was stirred at 80 °C for 1 hr. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and water (100 mL) was added and separated. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-50%) to give the title compound as a yellow solid (10.00 g, 50.2%). ES / MS (m / z): 268 (M+H). Preparation 8f Ethyl 5-amino-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylateA mixture of ethyl 5-amino-1-(6-chloropyridazin-4-yl)-1H-pyrazole-4-carboxylate (10.0 g, 37.4 mmol) and Pd / C (1.0 g, 10% w / w) in MeOH (500 mL) was stirred at 50 °C for 3 hrs., under a hydrogen balloon. After cooling to ambient temperature, the mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated in vacuo. The residue was triturated with EtOAc (50 mL) to give the title compound as a yellow solid (6.0 g, 55%). ES / MS (m / z): 234 (M+H). The compound in Table 2h was prepared in a manner essentially analogous to that found in Preparation 8f. Table 2hPreparation 8h Ethyl 5-chloro-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylateTo a mixture of tert-butyl nitrite (0.79 g, 7.7 mmol) and CuCl2(1.2 g, 12 mmol) in ACN (20 mL) was stirred at 65 °C for 10 min. Ethyl 5-amino-1-(pyridazin-4-yl)-1H- pyrazole-4-carboxylate (1.5 g, 5.1 mmol) was added to the mixture. After stirring at 65 °C for 2 hrs., the reaction was cooled to ambient temperature, quenched with ammonium hydroxide (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (100 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give the title compound as a yellow solid (1.2 g, 90%). ES / MS (m / z): 253 (M+H). Preparation 8i 5-Chloro-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylic acidTo a solution of ethyl 5-chloro-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylate (1.2 g, 4.6 mmol) in THF (10 mL) and water (10 mL) was added LiOH (0.33 g, 14 mmol) at ambient temperature. After stirring at ambient temperature for 2 hrs., the reaction mixture was adjusted to pH 4 with HCl (2M) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (30 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a yellow solid (1 g, 90%). ES / MS (m / z): 225 (M+H). The compound in Table 2i was prepared in a manner essentially analogous to that found in Preparation 8i.Table 2iPreparation 8k 4-(4-Bromo-5-chloro-1H-pyrazol-1-yl)pyridazineTo a solution of 5-chloro-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylic acid (300 mg, 1.34 mmol) in water (3 mL) was added NaOH (53.4 mg, 1.34 mmol) and Br2(213 mg, 1.34 mmol). After stirring at 20 °C for 1 hr., the reaction mixture was treated with water (10 mL) and extracted with EtOAc (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to get the crude material. The crude material was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give the title compound as a yellow solid (120 mg, 32%). ES / MS (m / z): 259 (M+H). The compound in Table 2j was prepared in a manner essentially analogous to that found in Preparation 8k. Table 2jPreparation 8m Methyl 2-(6-chloropyridazin-4-yl)-2H-1,2,3-triazole-4-carboxylateTo a solution of methyl 2H-1,2,3-triazole-4-carboxylate (2.0 g, 15.7 mmol) in dry ACN (150 mL) was added 3,5-dichloropyridazine (2.34 g, 15.7 mmol) and K2CO3(6.52 g, 47.2 mmol) at ambient temperature. The mixture was stirred at 90 °C for 16 hrs. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-50%) to give the title compound as an off-white solid (1.49 g, 40%). ES / MS (m / z): 240 (M+H). Preparation 8n Methyl 2-(pyridazin-4-yl)-2H-1,2,3-triazole-4-carboxylateTo a solution of methyl 2-(6-chloropyridazin-4-yl)-2H-1,2,3-triazole-4- carboxylate (1.44 g, 6 mmol) in EtOH (150 mL) was added Et3SiH (1.4 g, 12 mmol), TEA (1.22 g, 12 mmol), PPh3(157 mg, 0.6 mmol) and Pd(OAc)2(135 mg, 0.6 mmol) at ambient temperature. After purging with N2and degassing for three times, the mixture was stirred at 60 °C for 2 hrs., under nitrogen. After cooling to ambient temperature, the solution was concentrated in vacuo to give the residue. The residue was purified by flash column chromatography on silica gel eluting with EtOAc in petroleum ether (0-50%) to give the title compound as an off-white solid (1.2 g, 98%). ES / MS (m / z): 206 (M+H). Preparation 8o 2-(Pyridazin-4-yl)-2H-1,2,3-triazole-4-carboxylic acidTo a suspension of methyl 2-(pyridazin-4-yl)-2H-1,2,3-triazole-4-carboxylate (1.1 g, 5.36 mmol) in THF / water (120 mL, 5 / 1) was added LiOH•H2O (901 mg, 21.5 mmol) at ambient temperature. After stirring at ambient temperature for 2 hrs., the reaction mixture was adjusted to pH =3 with 1N HCl. The precipitated solid was filtered and dried under vacuum overnight to give the title compound as an off-white solid (700 mg, 70%). ES / MS (m / z): 192 (M+H). Preparation 8p tert-Butyl (2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-yl)carbamateTo a solution of 2-(pyridazin-4-yl)-2H-1,2,3-triazole-4-carboxylic acid (750 mg, 3.93 mmol) in 1,4-dioxane / t-BuOH(60 mL, 2 / 1) was added DIPEA (1.52 g, 11.8 mmol) and DPPA (2.16 g, 7.85 mmol) at ambient temperature. The mixture was stirred at 110 ºC for 3 hrs. After cooling to ambient temperature, the mixture was concentrated in vacuo to give the residue. The residue was purified by flash column chromatography on silica gel eluting with MeOH in DCM (0-10%) to give the title compound as a brown solid (871 mg, 85%). ES / MS (m / z): 263 (M+H). Preparation 8q 2-(Pyridazin-4-yl)-2H-1,2,3-triazol-4-amineThe solution of tert-butyl (2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-yl)carbamate (5.80 g, 21.0 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (60 mL) was stirred at 100 °C for 16 hrs. The solvent was removed to give the crude material, which was washed with MeOH to give the title compound as a brown solid. ES / MS (m / z): 163 (M+H).Preparation 8r 4-BromopyridazineTo a suspension of cuprous bromide (42.99 g, 299.7 mmol) in ACN (200 mL) was added tert-butyl nitrite (47.39 g, 459.5 mmol) at ambient temperature. The reaction was stirred at 65 °C for 0.5 hrs., and then pyridazin-4-amine (19.00 g, 199.8 mmol) was added into the mixture. After stirring at 65 °C for 3 hrs., the reaction mixture was cooled down to ambient temperature, quenched by addition of ammonium hydroxide (100 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (100 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a yellow solid (15 g, 44%). ES / MS (m / z): 161 (M+H). Preparation 8s 4-(4-Bromo-1H-pyrazol-1-yl)pyridazineTo a solution of 4-bromo-1H-pyrazole (8.60 g, 58.5 mmol) and 4- bromopyridazine (10.00 g, 58.40 mmol) in DMF (50 mL) was added K2CO3(16.14 g, 116.8 mmol) at ambient temperature. After stirring at 100 °C for 3 hrs., the reaction mixture was cooled down to ambient temperature, quenched by addition of water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (100 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give the title compound as a yellow solid (8 g, 50%). ES / MS (m / z): 227 (M+H). The compound in Table 2k was prepared in a manner essentially analogous to that found in Preparation 8s.Table 2kPreparation 8u 4-Bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbaldehydeTo a mixture of 4-(4-bromo-1H-pyrazol-1-yl)pyridazine (1.00 g, 4.01 mmol) in THF (100 mL) was added dropwise LDA (645 mg, 6.02 mmol) at -70 °C under nitrogen. The reaction was stirred at -70 °C for 1 hr., then DMF (2.93 g, 40.1 mmol) was added dropwise into the mixture. After stirring for 3 hrs., the reaction was quenched with water (50 mL) slowly and extracted with EtOAc (200 mL x 2). The combined organic layer was washed with saturated aqueous NaCl (100 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a yellow solid (1.00 g, 37.5%). ES / MS (m / z): 253 (M+H). Preparation 8v (4-Bromo-1-(pyridazin-4-yl)-1H-pyrazol-5-yl)methanolTo a solution of 4-bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbaldehyde (1.00 g, 1.50 mmol) in MeOH (20 mL) was added NaBH4(171 mg, 4.51 mmol) at 20 °C. The reaction was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated in vacuo to get the crude material. The crude material was purified by flash chromatography on silicagel eluting with MeOH in DCM (0-5%) to give the title compound as a yellow solid (300 mg, 75.5%). ES / MS (m / z): 255 (M+H). Preparation 8w 4-(4-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazol-1-yl)pyridazineTo a solution of (4-bromo-1-(pyridazin-4-yl)-1H-pyrazol-5-yl)methanol (300 mg, 1.14 mmol) in THF (20 mL) was added imidazole (309 mg, 4.54 mmol) and tert- butyldimethylsilyl chloride (342 mg, 2.27 mmol) at ambient temperature. The reaction was stirred at 50 °C for 3 hrs. After cooling to ambient temperature, the reaction was quenched by water (20 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with saturated aqueous NaCl (50 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a white solid (320 mg, 73.3%). ES / MS (m / z): 369 (M+H). Preparation 8x (E)-3-Bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbaldehyde oximeTo a mixture of 4-(3-bromo-1H-pyrazol-1-yl)pyridazine (760 mg, 3.32 mmol) in THF (20 mL) was added dropwise LDA (2.0M in THF, 4.97 mmol) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 1 hr., and then DMF (485 mg, 6.63 mmol) was added. After stirring at -78 °C for 4 hrs., the reaction mixture was quenched by saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product.To a suspension of the crude material (900 mg, 35% purity, 1.24 mmol) and sodium carbonate (528 mg, 4.98 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (259 mg, 3.73 mmol) at ambient temperature. The mixture was stirred at 60 °C for 2 hrs., and then was filtered to remove inorganic salts. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and washed with water (20 mL). The organic layer was washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with MeOH in DCM (0-3%) to give the title compound as a brownish solid (290 mg, 80.9%). ES / MS (m / z): 268 (M+H). Preparation 8y 3-Bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbonitrileTo a solution of (E)-3-bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbaldehyde oxime (290 mg, 1.01 mmol) in ACN (5 mL) was added DMSO (0.2 mL) and then TEA (509 mg, 5.03 mmol) at 0 °C. The mixture was stirred for 0.5 hr., and then oxalyl chloride (639 mg, 5.03 mmol) was added at 0 °C. After stirring at ambient temperature for 16 hrs., the mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layer was washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with MeOH in DCM (0-2%) to give the title compound as a brown solid (110 mg, 40.2%) ES / MS (m / z): 268 (M+H). Preparation 8z Ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoateA solution of ethyl 3-oxobutanoate (30.0 g, 230.8 mmol) in DMF-DMA (50 mL) was stirred at 80 °C for 16 hrs. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel eluting with EtOAc in petroleum ether (0-80%) to give title compound as a yellow oil (41.0 g, 96%). ES / MS (m / z): 186 (M+H). Preparation 8aa Ethyl 1-(6-chloropyridazin-4-yl)-5-methyl-1H-pyrazole-4-carboxylateTo a solution of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (9.00 g, 48.6 mmol) in MeOH (30 mL) was added 3-chloro-5-hydrazineylpyridazine (7.00 g, 48.6 mmol) at ambient temperature. The mixture was stirred at 80 °C for 16 hrs. After cooling to ambient temperature, the solvent was removed by evaporation and the residue was purified by flash column chromatography on silica gel eluting with EtOAc in petroleum ether (0-70%) to give title compound as a yellow oil (2.60 g, 20%) ES / MS (m / z): 267 (M+H). Preparation 8ab 3-(4-Chloro-3,5-difluorobenzyl)-1-(4-chloro-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-oneTo a solution of 3-(4-chloro-3,5-difluorobenzyl)-1-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-one (390 mg, 0.75 mmol) in DMF (5 mL) was added NCS (302 mg, 2.25 mmol). The reaction mixture was stirred at70 °C for 2 hrs. To the mixture was added EtOAc (20 mL), then washed with water (20 mL) and saturated aqueous NaCl (20 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-100%) to give the title compound as a yellow oil (350 mg, 84%). ES / MS (m / z): 554 (M+H). The compound in Table 2l was prepared in a manner essentially analogous to that found in Preparation 8ab. Table 2lPreparation 8ad 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-3-(4-fluoro-2- (fluoromethyl)benzyl)piperidin-2-oneTo a solution of 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- triazol-5-yl)piperidin-2-one (736 mg, 1.94 mmol) in THF (10 mL) was added LiHMDS (3.88 mL, 1.0M in THF, 3.88 mmol) dropwise at -78 °C under nitrogen. After stirring at - 78 °C for 1 hr., 1-(bromomethyl)-4-fluoro-2-(fluoromethyl)benzene (412 mg, 1.75 mmol)was added then stirred for 2 hrs., at -78 °C. The reaction mixture was quenched by saturated ammonium chloride (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give the title compound as a colorless oil (460 mg, 46.0%). ES / MS (m / z): 515 (M+H). The compounds in Table 2m were prepared in a manner essentially analogous to that found in Preparation 8ad. Table 2mPreparation 8bd 3-(4-Fluoro-2-(fluoromethyl)benzyl)-1-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-oneA mixture of 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5- yl)-3-(4-fluoro-2-(fluoromethyl)benzyl)piperidin-2-one (20 mg, 38 µmol), 4- (tributylstannyl)pyridazine (14 mg, 38 µmol), CsF (18 mg, 0.12 mmol) and bis[tris(tert- butyl)phosphine]palladium (2.0 mg, 3.8 µmol) in 1,4-dioxane (1 mL) was degassed and purged with nitrogen (x3) at ambient temperature, then heated to 100 °C and stirred for 2 hrs. After cooling to ambient temperature, the reaction mixture was quenched with saturated aqueous potassium fluoride (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (5 mL), dried oversodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with MeOH in DCM (0-3%) to give the title compound as a yellow oil (14 mg, 62%). ES / MS (m / z): 515 (M+H). The compounds in Table 2n were prepared in a manner essentially analogous to that found in Preparation 8bd. Table 2nPreparation 9 N-Methoxy-N,5-dimethyl-pyridazine-4-carboxamideA mixture of ethyl 5-methylpyridazine-4-carboxylate (1.2 g, 7.23 mmol), N,O- dimethylhydroxylamine hydrochloride (1.42 g, 14.46 mmol) in THF (20 mL) was stirred at -70 °C for 5 min. LiHMDS (1M in THF, 50.6 mL, 50.6 mmol) was added slowly, and stirred at -70 °C for 2.0 hrs. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL) solution and was extracted with DCM (50 mL x 3). The combinedorganic layer was dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (3:97) to give the title compound (0.94 g, 71.2%) as a yellow oil. ES / MS m / z 182 (M+H). Preparation 10 Ethyl 3-(5-methylpyridazin-4-yl)-3-oxo-propanoateTo a mixture of EtOAc (1.37 g, 15.6 mmol) in THF (20 mL) was added LDA (1M in THF, 15.6 mL) solution slowly at -70 °C and stirred for 1.5 hrs. N-Methoxy-N,5- dimethyl-pyridazine-4-carboxamide (0.94 g, 5.2 mmol) in THF (8 mL) was added slowly and stirred at -70 °C for 2.0 hrs. The reaction mixture was poured to saturated aqueous NH4Cl (200 mL) solution and extracted with DCM (50 mL x 3). The combined organic layer was dried and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1:1) to give the title compound (0.53 g, 49.1%) as a yellow oil. ES / MS m / z 209 (M+H). Preparation 11 Ethyl (Z)-3-amino-4,4,4-trichloro-2-(5-methylpyridazine-4-carbonyl)but-2-enoateTo a mixture of ethyl 3-(5-methylpyridazin-4-yl)-3-oxo-propanoate (530 mg, 2.55 mmol) in EtOH (10 mL) was added trichloroacetonitrile (404 mg, 2.81 mmol) and sodium acetate trihydrate (251 mg, 3.06 mmol), and the mixture was stirred at ambient temperature for 2.0 hrs. The reaction mixture was concentrated in vacuo to give the title compound (1.08 g, crude) as a yellow oil. ES / MS m / z 352 (M+H).Preparation 12 Ethyl 5-amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4- carboxylateTo a mixture of ethyl (Z)-3-amino-4,4,4-trichloro-2-(5-methylpyridazine-4- carbonyl)but-2-enoate (1.08 g, crude) in EtOH (10 mL) was added Et3N (0.77 g, 7.6 mmol) and (4-methoxybenzyl)hydrazine hydrochloride (0.58 g, 3.05 mmol), and then the mixture was stirred at 65 °C for 2 hrs. The reaction mixture was then concentrated in vacuo. The crude was purified by column chromatography on silica gel eluting with EtOAc in petroleum ether (3:97) to give the title compound (0.54 g, 58.1%) as a yellow brown oil. ES / MS m / z 368 (M+H). Preparation 13 5-Amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylic acidTo a mixture of ethyl 5-amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)- 1H-pyrazole-4-carboxylate (540 mg, 1.47 mmol) in THF (4mL), EtOH (4 mL), and water (2 mL) was added NaOH (118 mg, 2.94 mmol). The mixture was stirred at 75 °C for 4 hrs. then the reaction mixture was concentrated in vacuo.1M aqueous HCl was added to adjust pH to 3~4. The resulting slurry was filtered, and the filter cake washed with 20 mL of ice water then dried in vacuo to give the title compound (350 mg, 70.1%) as a yellow solid. ES / MS m / z 340 (M+H).Preparation 14 5-Amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxamideA mixture of 5-amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H- pyrazole-4-carboxylic acid (350 mg, 1.03 mmol), ammonium chloride (1.09 g, 20.6 mmol), HATU (783 mg, 2.06 mmol), and DIPEA (399 mg, 3.09 mmol) in DMF (5 mL) was stirred at ambient temperature for 4 hrs. The mixture was added to water (30 mL) which was extracted with DCM (30 mL x 5). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound (400 mg, crude) as a brown oil. ES / MS m / z 339 (M+H). Preparation 15 1-(4-Methoxybenzyl)-4-methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-amineTo a mixture of 2-methyl-3-(5-methylpyridazin-4-yl)-3-oxopropanenitrile (788 mg, 4.5 mmol) in EtOH (20 mL) was added AcOH (1.1 g, 18 mmol) and (4- methoxybenzyl)hydrazine hydrochloride (1.0 g, 5.4 mol), and the mixture was stirred at 80 °C for 16 hrs. To the reaction mixture was added saturated aqueous Na2CO3solution slowly to adjust pH to 8-9 and extracted with EtOAc (80 mL x 2). The combined organic layer was dried and concentrated in vacuo to give crude material (1.8 g), which waspurified by reverse phase chromatography (ACN in 10 mM NH4HCO3= 2-30%) to give the title compound (800 mg, 58%) as a brown solid. ES / MS m / z 310 (M+H). Preparation 16 3-(6-Chloro-5-fluoropyridin-3-yl)-N-(1-(4-methoxybenzyl)-4-methyl-3-(5- methylpyridazin-4-yl)-1H-pyrazol-5-yl)propanamideA mixture of 1-(4-methoxybenzyl)-4-methyl-3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-amine (490 mg, 1.6 mmol), 3-(6-chloro-5-fluoropyridin-3-yl)propanoic acid (386 mg, 1.9 mmol), DIPEA (426 mg, 3.3 mmol), and HATU (1.4 g, 2.2 mmol) in DMA (5 mL) was stirred at 65 °C for 3 hrs. The mixture was added to water (10 mL) which was then extracted with EtOAc (80 mL x 2). The combined organic layer was dried and concentrated in vacuo. The crude material was purified by reverse phase chromatography (ACN in 10 mM NH4HCO3= 2-60%) to give the title compound (360 mg, 46%) as a light-yellow solid. ES / MS m / z 495 (M+H). The compound in Table 3 was prepared in a manner essentially analogous to that found in Preparation 16.Table 3Preparation 18 5-(3-(6-Fluoropyridin-3-yl)propanamido)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4- carboxamideA mixture of 5-(3-(6-fluoropyridin-3-yl)propanamido)-1-(4-methoxybenzyl)-3-(5- methylpyridazin-4-yl)-1H-pyrazole-4-carboxamide (110 mg, 0.3 mmol) and TFA (2 mL) in DCM (1 mL) was stirred at ambient temperature for 12 hrs. The reaction mixture was concentrated in vacuo. To the residue was added sodium bicarbonate solution to adjust pH to about 8. The slurry was filtered, and the filter cake was washed with ice water (20 mL), dried in vacuo to give the title compound (70 mg, crude) as a brown solid. ES / MS m / z 370 (M+H).Preparation 18a 2,2,2-Trichloro-1-(4-chloro-1H-pyrrol-2-yl)ethan-1-oneTo a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethan-1-one (20.00 g, 94.14 mmol) in DCM (40 mL) was added sulfuryl dichloride (15.25 g, 113.0 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 20 hrs., under nitrogen atmosphere. The mixture was diluted by DCM (100 mL) and poured into ice-water. The mixture was adjusted to pH > 7 with sodium bicarbonate and extracted with DCM (200 mL x 3). The combined organic layer was washed with water (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a white solid (12.20 g, 48%). ES / MS (m / z): 246 (M+H). Preparation 18b Methyl 4-chloro-1H-pyrrole-2-carboxylateTo a solution of 2,2,2-trichloro-1-(4-chloro-1H-pyrrol-2-yl)ethan-1-one (12.10 g, 44.11 mmol) in MeOH (20 mL) was added sodium hydrate (5.293 g, 132.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hrs. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to get the crude material. The crude material was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a white solid (4.96 g, 63%). ES / MS (m / z): 160 (M+H).Preparation 18c Methyl 5-bromo-4-chloro-1H-pyrrole-2-carboxylateTo a solution methyl 4-chloro-1H-pyrrole-2-carboxylate (1.5 g, 8.1 mmol) in AcOH (10 mL) was added dropwise Br2(1.4 g, 8.9 mmol) at ambient temperature. The reaction mixture was stirred at 60 °C for 15 min. After cooling down to ambient temperature, the reaction mixture was concentrated to get the crude material. The crude material was dissolved in water (10 mL), adjusted to pH >7 with saturated sodium bicarbonate and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a white solid (1.2 g, 60%). ES / MS (m / z): 238 (M+H). Preparation 18d Methyl 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1H-pyrrole-2- carboxylateTo a mixture of 3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (500 mg, 1.80 mmol) and methyl 5-bromo-4-chloro-1H-pyrrole-2-carboxylate (487 mg, 1.80 mmol) in DMF (10 mL) was added CuI (343 mg, 1.80 mmol), potassium phosphate tribasic (1.15 g, 5.41 mmol) and N,N'-dimethyl-1,2-cyclohexanediamine (513 mg, 3.60 mmol) at 20 °C. The reaction was stirred at 60 °C for 14 hrs., in sealed tube under nitrogen. After cooling to ambient temperature, the reaction was quenched by addition of water (20 mL) and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a colorless oil (500 mg, 67.8%). ES / MS (m / z): 387 (M+H). The compound in Table 3a was prepared in a manner essentially analogous to that found in Preparation 18d. Table 3aPreparation 18f Methyl 3-bromo-4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1H-pyrrole- 2-carboxylateTo a solution of methyl 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1- yl)-1H-pyrrole-2-carboxylate (450 mg, 1.10 mmol) in DCM (10 mL) was added dropwise a solution of NBS (215 mg, 1.21 mmol) in DCM (10 mL) at ambient temperature. The reaction mixture was stirred at 20 °C for 4 hrs. The reaction was quenched by addition of water (10 mL) and extracted with DCM (50 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a white solid (300 mg, 58.6%). ES / MS (m / z): 467 (M+H).The compound in Table 3b was prepared in a manner essentially analogous to that found in Preparation 18f. Table 3bPreparation 18i Methyl 3-bromo-4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylateTo a solution of methyl 3-bromo-4-chloro-5-(2-oxo-3-(3,4,5- trifluorobenzyl)pyrrolidin-1-yl)-1H-pyrrole-2-carboxylate (200 mg, 430 µmol) in THF (10 mL) was added NaH (15.5 mg, 644 µmol) under nitrogen at 0 °C. The reaction was stirred at 20 °C for 5 min. SEM-Cl (107 mg, 644 µmol) was added into the mixture. After stirring at 20 °C for 5 hrs., the reaction was quenched by addition of water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a white solid (200 mg, 76.8%) ES / MS (m / z): 617 (M+Na).The compound in Table 3c was prepared in a manner essentially analogous to that found in Preparation 18i. Table 3cPreparation 18k Methyl 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (Compound 1) Methyl 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (Compound 2)To a solution of methyl 3-bromo-4-chloro-5-(2-oxo-3-(3,4,5- trifluorobenzyl)pyrrolidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2- carboxylate (200 mg, 301 µmol) in 1,4-dioxane (10 mL) was added 4- (tributylstannyl)pyridazine (111 mg, 301 µmol), bis[tris(tert-butyl)phosphine]palladium (15.4 mg, 30.1 µmol) and cesium fluoride (137 mg, 903 µmol) at ambient temperature under nitrogen. The reaction mixture was stirred at 100 °C for 2 days. After cooling downto ambient temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with MeOH in DCM (0-3%) to give the title compound 1 as a white solid (100 mg, 26.1%): ES / MS (m / z): 561(M+H) and title compound 2 as a white solid (100 mg, 26.4%): ES / MS (m / z): 595 (M+H).The compounds in Table 3d were prepared in a manner essentially analogous to that found in Preparation 18k.Table 3dPreparation 18m 5-(2-Oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid (Compound 1) 4-Chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid (Compound 2)To a mixture of methyl 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3- (pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (90 mg, 71 µmol) and methyl 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3- (pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (90 mg, 71 µmol) in THF (6 mL) and water (2 mL) was added lithium hydroxide (17 mg, 0.71 mmol) at ambient temperature. The reaction was stirred at 60 °C for 3 hrs. After cooling to ambient temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound 1 as a yellow solid (80 mg, 93%) ES / MS (m / z): 547 (M+H) and title compound 2 as a yellow solid (80 mg, 88%) ES / MS (m / z): 581 (M+H). The compounds in Table 3e were prepared in a manner essentially analogous to that found in Preparation 18m.Table 3ePreparation 18o 5-(2-Oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxamide (Compound 1) 4-Chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxamide (Compound 2)To a solution of 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4- yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid (70 mg, 58 µmol) and 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid (70 mg, 54 µmol) in DMF (5 mL) was added DIEA (21 mg, 0.16 mmol), HATU (31 mg, 81 µmol) and ammonium chloride (5.8 mg, 0.11 mmol) at 20 °C. After stirring at 20 °C for 1 hr., the reaction was quenched by addition of water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-50%) to give the title compound 1 as a yellow solid (70 mg, 96%) ES / MS (m / z): 546 (M+H) and title compound 2 as a yellow solid (70 mg, 98%) ES / MS (m / z): 580 (M+H). The compounds in Table 3f were prepared in a manner essentially analogous to that found in Preparation 18o. Table 3fPreparation 18r 5-(2-Oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbonitrile (Compound 1) 4-Chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbonitrile (Compound 2)To a mixture of 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4- yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxamide (60 mg, 45 µmol) and 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxamide (60 mg, 52 µmol) in DMF (6 mL) was added dropwise SOCl2(27 mg, 0.22 mmol) at 0 °C. After stirring at 0 °C for 1 hr., the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-50%) to give the title compound 1 as a yellow solid (20 mg, 80%); ES / MS (m / z): 528 (M+H) and the title compound 2 as a yellow solid (20 mg, 83%); ES / MS (m / z): 562 (M+H). The compounds in Table 3g were prepared in a manner essentially analogous to that found in Preparation 18r.Table 3gPreparation 18v 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehydeTo a solution of 1H-pyrrole-2-carbaldehyde (1.00 g, 10.5 mmol) in DMF (15 mL) was added NaH in oil (631 mg, 60% wt, 15.8 mmol) at 0 °C. After stirring for 2 hrs., SEM-Cl (2.28 g, 13.7 mmol) was added at 0 °C, and then stirred at 0 °C for 12 hrs. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1:9) to give the title compound (1.80 g, 49%) as a yellow oil. ES / MS (m / z): 226 (M+H).Preparation 18w 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehydeTo a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde (1.50 g, 6.66 mmol) in ACN (20 mL) was added NCS (978 mg, 7.32 mmol). After stirring at 90 °C for 12 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1: 4) to give the mixture of two isomers of the title compound (1.50 g, 23%) as a yellow oil. The crude was used in next step directly. ES / MS (m / z): 260 (M+H). Preparation 18x Ethyl (E)-3-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylateTo a solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2- carbaldehyde (1.40 g, 5.39 mmol) in DCM (20 mL) was added ethyl 2-(triphenyl-l5- phosphaneylidene)acetate (4.69 g, 13.5 mmol). After stirring at 25 °C for 12 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1:10) to give the title compound (0.47 g, 25%) as a yellow oil. ES / MS: (m / z) = 330 (M+H). Preparation 18y N-(2-Bromo-5-fluoropyridin-3-yl)pivalamideTo a mixture of 2-bromo-5-fluoropyridin-3-amine (7.00 g, 36.6 mmol) and N- ethyl-N-isopropylpropan-2-amine (9.47 g, 73.3 mmol) in ACN (70 mL) was added pivaloyl chloride (13.30 g, 110.3 mmol) dropwise. After stirring at 25 °C for 5 hrs., the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (95: 5) to give the title compound (10.0 g, 99%) as a yellow oil. ES / MS (m / z): 275 (M+H). The compound in Table 3h was prepared in a manner essentially analogous to that found in Preparation 18y. Table 3hPreparation 18aa Ethyl (E)-3-(5-fluoro-3-pivalamidopyridin-2-yl)acrylateTo a mixture of N-(2-bromo-5-fluoropyridin-3-yl)pivalamide (4.35 g, 15.8 mmol) in DMF (25 mL) was added 1,4-diazabicyclo[2.2.2]octane (0.35 g, 3.1 mmol), ethyl acrylate (3.16 g, 31.6 mmol), K2CO3(4.36 g, 31.5 mmol) and Pd(OAc)2(0.71 g, 3.2 mmol) under nitrogen. After stirring at 120 °C for 3 hrs., the reaction mixture was cooled to ambient temperature and filtered. The filtrate was added to water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed withsaturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM (100%) to give the title compound (857.0 mg, 15%) as a yellow solid. ES / MS (m / z): 295 (M+H). The compounds in Table 3i were prepared in a manner essentially analogous to that found in Preparation 18aa. Table 3iPreparation 18ad Ethyl 3-(5-fluoro-3-pivalamidopyridin-2-yl)propanoateTo a mixture of ethyl (E)-3-(5-fluoro-3-pivalamidopyridin-2-yl)acrylate (857 mg, 2.91 mmol) and nickel(II) chloride hexahydrate (692 mg, 2.91 mmol) in MeOH (10 mL)was added NaBH4(165 mg, 14.37 mmol) in portions at 0 °C. After stirring at 0 °C for 5 hrs.., the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (830 mg, 85%) as a yellow solid. ES / MS (m / z): 297 (M+H). The compounds in Table 3j were prepared in a manner essentially analogous to that found in Preparation 18ad. Table 3jPreparation 18ag 3-(5-Fluoro-3-pivalamidopyridin-2-yl)propanoic acidTo a solution of ethyl 3-(5-fluoro-3-pivalamidopyridin-2-yl)propanoate (830 mg, 2.8 mmol) in THF (6.4 mL) and H2O (1.6 mL) was added the solution of lithium hydroxide monohydrate (235 mg, 5.6 mmol) in H2O (1.5 mL). After stirring at 25 °C for4 hrs., IM HCl (6 mL) was added, and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM in MeOH (95:5) to give the title compound (608 mg, 76%) as a yellow oil. ES / MS (m / z): 269 (M+H).The compounds in Table 3k were prepared in a manner essentially analogous to that found in Preparation 18ag.Table 3kPreparation 18al Ethyl 3-(5-fluoro-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)propanoateTo a solution of ethyl (E)-3-(5-fluoro-6-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)pyridin-3-yl)acrylate (1.20 g, 3.88 mmol) in MeOH (20 mL) was added Pd / C (480 mg, 0.45 mmol). After stirring for 3 hrs. at ambient temperature under hydrogen atmosphere, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (1.10 g, 95%) as an orange solid. ES / MS (m / z): 228 (M+H-84). The compound in Table 3l was prepared in a manner essentially analogous to that found in Preparation 18al. Table 3lPreparation 18an Ethyl 3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoateTo a solution of ethyl 3-(5-fluoro-6-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)pyridin-3-yl)propanoate (1.10 g, 3.79 mmol) in DCM (10 mL) was added TFA (10 mL). After stirring for 2 hrs., at ambient temperature under nitrogen, the reaction mixture was concentrated in vacuo. To the residue was added to water (20 mL), basified to pH = 8 with saturated NaHCO3solution, and extracted with DCM (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (800 mg, 91%) as an orange oil. ES / MS (m / z): 228 (M+H). Preparation 18ao Ethyl 3-(5-fluoro-6-formylpyridin-3-yl)propanoateTo a solution of 3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoate (700 mg, 3.08 mmol) in DCM (10 mL) was added MnO2(1.93 g, 22.2 mmol). After stirring for 2 hrs at 40 ℃ under nitrogen, the reaction mixture was diluted with DCM (30 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (650 mg, 94%) as an orange liquid. ES / MS (m / z): 254 (M+H). Preparation 18ap Ethyl 3-(6-(difluoromethyl)-5-fluoropyridin-3-yl)propanoateTo a solution of ethyl 3-(5-fluoro-6-formylpyridin-3-yl)propanoate (500 mg, 2.22 mmol) in DCM (10 mL) was added DAST (1.78 g, 11.1 mmol). After stirring for 10 min at -78 ℃ under nitrogen, the reaction mixture was stirred for 2 hrs., at ambient temperature under nitrogen. The reaction was quenched with H2O (20 mL) and extracted with DCM (20 mL x 3). The organic phases were combined, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to give the title compound (500 mg, 92%) as an orange liquid. ES / MS (m / z): 248 (M+H). Preparation 18aq Diethyl 2-((2-chlorothiazol-5-yl)methyl)malonateTo a mixture of 2-chloro-5-(chloromethyl)thiazole (4.00 g, 23.8 mmol) and diethyl malonate (38.13 g, 238 mmol) in t-BuOH (120 mL) was added t-BuONa (7.66 mL, 71.41 mmol) in portions at 0 °C under nitrogen. After stirring at 0 °C for 2 hrs., under nitrogen, the reaction mixture was quenched with H2O (40 mL) and extracted with DCM (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (92:8) to give the title compound (31.0 g, crude) as a yellow oil. ES / MS (m / z): 292 (M+H). Preparation 18ar 2-((2-Chlorothiazol-5-yl)methyl)malonic acidTo a solution of diethyl 2-((2-chlorothiazol-5-yl)methyl)malonate (31.0 g, crude) in THF (100 mL) was added the solution of lithium hydroxide monohydrate (13.0 g, 0.31 mol) and H2O (25 mL). After stirring at 20 °C for 9 hrs., the reaction mixture was concentrated in vacuo to remove organic solvent. To the residue was added to water (40 mL) and washed with petroleum ether (120 mL x 3). The aqueous solution was used in next step directly without further purification. ES / MS (m / z): 236 (M+H).Preparation 18as 3-(2-Chlorothiazol-5-yl)propanoic acidThe solution of 2-((2-chlorothiazol-5-yl)methyl)malonic acid was acidified to pH = 2-3 with sulfuric acid (4M), and then stirred at 100 °C for 16 hrs. The reaction mixture was cooled to ambient temperature and extracted with EtOAc (40 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1:3) to give the title compound (1.3 g, 28.6% over 3 steps) as a white solid. ES / MS (m / z): 192 (M+H). Preparation 18at 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleTo a solution of 3,5-dibromo-1H-pyrazole (1 g, 4.4 mmol) in DMF (10 mL) was added NaH (60%, 0.27 g, 6.7 mmol) at 0 °C. After stirring for 1 hr., at 0 °C, SEM-Cl (0.89 g, 5.4 mmol) was added, and then stirred at 0 °C for 2 hrs. The mixture was quenched with cold water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (1 g, 63%) as a colorless oil. ES / MS (m / z): 299 (M+H- 58).Preparation 18au 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehydeTo a solution of 3,4,5-tribromo-1H-pyrazole (90.0 g, 295 mmol) in THF (2 L) was added the solution of n-BuLi in THF (236 mL, 590 mmol) at -60 °C dropwise. After stirring at -60 °C for 1 hr., the reaction mixture was added DMF (114 mL, 1.48 mol) dropwise. The mixture was stirred at -60 °C for another 1 hr., and at ambient temperature for 3 hrs. To the mixture was added SEM-Cl (78.4 mL, 443 mmol) dropwise at ambient temperature, and the resulting mixture was stirred for 16 hrs. The reaction mixture was poured into NaHCO3solution (1.5 L) and extracted with EtOAc (1.5 L x 3). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ester (0 to 10%) to give the title compound (50 g, 42%) as a yellow oil.1H NMR (DMSO-d6) δ 9.74 (s, 1H), 5.57 (s, 2H), 3.66 (t, 2H), 0.90 (t, 2H), 0.00 (s, 9H). Preparation 18av 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanolTo a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carbaldehyde (10 g, 26 mmol) in MeOH (100 mL) was added NaBH4(2 g, 52 mmol) inportions at -5 ℃, and then stirred at -5 ℃ for 2 hrs. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (7 g, 70%) as a white solid. ES / MS (m / z): 409 (M+Na). Preparation 18aw 3,5-Dibromo-4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleTo a solution of (3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4- yl)methanol (1.3 g, 5.3 mmol) in DMF (30 mL) was added NaH (0.439 g, 10.7 mmol) at 0 ℃, and then MeI (7.37 g, 27.3 mmol) was added. After stirring at 0 °C for 2 hrs., the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1:1) to give the title compound (2.1 g, 95%) as a yellow solid. ES / MS (m / z): 401 (M+H). Preparation 18ax 3,5-Dibromo-4-fluoro-1H-pyrazoleTo a solution of 4-fluoro-1H-pyrazole (25 g, 290 mmol) in EtOH / H2O (1:1.5) (400 mL) was added NaOAc (167 g, 2034 mmol) and Br2(186 g, 1163 mmol) at 0 °C. The mixture was warmed up and stirred at ambient temperature for 12 hrs. The mixturewas combined, extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (15%) to give the title compound (18 g, 26%) as a colorless oil. ES / MS (m / z): 245 (M+H). Preparation 18ay 3,5-Dibromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleTo a solution of 3,5-dibromo-4-fluoro-1H-pyrazole (18 g, 74 mmol) in DMF (200 mL) was added NaH (60%, 4.5 g, 111 mmol) at 0 °C in portions. After stirring for 1 hr., SEM-Cl (15 g, 89 mmol) was added at 0 °C dropwise, and then stirred at ambient temperature for 2 hrs. The mixture was quenched with water (400 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (10%) to give the title compound (19 g, 67%) as a yellow oil.1H NMR (DMSO) δ 5.49 (q, J = 11.4 Hz, 2H), 3.72 – 3.66 (m, 2H), 0.92 (dd, J = 8.7, 7.6 Hz, 2H), 0.02 – -0.02 (m, 9H) Preparation 18az 3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amineTo a solution of 3-bromo-1H-pyrazol-5-amine (10 g, 62.11 mmol) in dry ACN (20 mL) cooled at 0 °C was added NaH (60%, 3.7 g, 93.17 mmol) slowly. The mixture wasstirred at 0 °C for 30 min, and then SEM-Cl (11.3 g, 68.32 mmol) was added slowly. After stirring at ambient temperature for 2 hrs., the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (12%) to give the title compound (7 g, 39%) as a yellow oil. ES / MS (m / z): 292 (M+H). Preparation 18ba 5-Bromo-N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pentanamideTo a mixture of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- amine (7 g, 24.05 mmol) and Et3N (12.1 g, 120.27 mmol) in ACN (50 mL) was added 5- bromopentanoyl chloride (9.8 g, 48.11 mmol) dropwise. After stirring at ambient temperature for 12 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (5%) to give the title compound (8 g, 73%) as a yellow oil. ES / MS (m / z): 456 (M+H). Preparation 18bb 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-oneTo a solution of 5-bromo-N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)pentanamide (8 g, 17.5 mmol) in ACN (40 ml) was added K2CO3(12 g, 86.9mmol). The mixture was stirred at 90 °C for 8 hrs., cooled to ambient temperature, and filtered to remove solid. The filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (5%) to give the title compound (3.5 g, 54%) as a colorless oil. ES / MS (m / z): 374 (M+H). Preparation 18bc N-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(4-chloro-3- fluorophenyl)propenamideTo a solution of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- amine (5 g, 17.2 mmol) in DMA (30 mL) was added HATU (13 g, 34.4 mmol), 3-(4- chloro-3-fluorophenyl)propanoic acid (4.2 g, 20.6 mmol) and DIPEA (6.6 g, 51.5 mmol). After stirring at 120 °C for 12 hrs., the reaction mixture was cooled, water (100 ml) was added then extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (25%) to give the title compound (5.2 g, 64%) as a yellow oil. ES / MS m / z: 476 and 478 (M+H). The compound in Table 3m was prepared in a manner essentially analogous to that found in Preparation 18bc.Table 3mPreparation 18be 4-Bromo-N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)butanamideTo a solution of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- amine (85.00 g, 292.1 mmol) in DCM (800 mL) was added pyridine (69.23 g, 876.3 mmol) and 4-bromobutanoyl chloride (59.12 g, 321.3 mmol) at 0 °C under nitrogen. After stirring at ambient temperature for 2 hrs., the mixture was quenched with water (300 mL) and extracted with DCM (200 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude title compound (150.00 g, 99+%) as a yellow oil. The crude was used in next step directly. ES / MS (m / z): 440 (M+H).Preparation 18bf 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-oneTo a solution of 4-bromo-N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)butanamide (150.00 g, 340.1 mmol) in ACN (800 mL) was added potassium 2-methylpropan-2-olate (114.55 g, 1023.7 mmol) at 0 °C, and then stirred at 25 °C for 2 hrs. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude material. The crude material was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (13%) to give the title compound (46.00 g, 37%) as a yellow oil. ES / MS (m / z): 360 (M+H). Preparation 18bg 1-(3-Bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2- oneTo a solution of 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)pyrrolidin-2-one (50.60 g, 139.8 mmol) in ACN (600 mL) was added (1-chloromethyl- 4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (111.82 g, 349.5 mmol) and then stirred at 80 °C for 1.5 hrs. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude material. The crude was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (15%) to give the title compound (18.00 g, 34%) as a yellow oil. ES / MS (m / z): 378 (M+H).Preparation 19 tert-Butyl N-(3,6-dichloropyridazin-4-yl)carbamateTo a mixture of 3,6-dichloropyridazine-4-carboxylic acid (4 g, 20.76 mmol) in 1,4-dioxane (100 mL) was added Et3N (2.11 g, 20.8 mmol), DPPA (5.77 g, 20.76 mmol), and tert-butanol (26.6 mL), and the mixture was stirred at 110 °C for 3 hrs. The mixture was concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with EtOAc in petroleum ether (15:85) to give the title compound (4.31 g, 85%) as a white solid. ES / MS m / z 264.1 (M+H). Preparation 20 tert-Butyl N-(6-chloro-3-methyl-pyridazin-4-yl)carbamateTo a mixture of tert-butyl N-(3,6-dichloropyridazin-4-yl)carbamate (0.4 g, 1.52 mmol) in 1,4-dioxane : water (4:1) (15 mL) was added methylboronic acid (0.45 g, 7.58 mmol), Pd(dppf)Cl2(0.2 g, 0.3 mmol), and K2CO3(0.6 g, 4.55 mmol), and then stirred at 80 °C for 12 hrs. under N2atmosphere. The mixture was concentrated in vacuo. The crude was purified via silica gel flash chromatography eluting with EtOAc in petroleum ether (20:80) to give the title compound (0.25 g, 67%) as a yellow solid. ES / MS m / z 244.1 (M+H). Preparation 21 tert-Butyl N-(3-methylpyridazin-4-yl)carbamateTo a mixture of tert-butyl N-(6-chloro-3-methyl-pyridazin-4-yl)carbamate (5.1 g, 21 mmol) in EtOH (100 mL) was added Ph3P (0.5 g, 2.1 mmol), Pd(OAc)2(0.47 g, 2.1 mmol), Et3N (4.2 g, 42 mmol), and Et3SiH (7.3 g, 63 mmol). The mixture was stirred at 80 °C for 5 hrs. under N2atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with EtOAc in petroleum ether (80:20) to give the title compound (3.9 g, 89%) as a yellow solid. ES / MS m / z 210.1 (M+H). Preparation 22 3-Methylpyridazin-4-amineTo a mixture of tert-butyl N-(3-methylpyridazin-4-yl)carbamate (0.5 g, 2.40 mmol) in DCM (3 mL) was added HCl in 1,4-dioxane (4M, 3 mL) at 0 °C, and then stirred at ambient temperature for 12 hrs. The mixture was concentrated in vacuo to give the crude title compound (0.27 g, 99+%) as a yellow solid. ES / MS m / z 110.0 (M+H). Preparation 23 4-Bromo-3-methylpyridazineTo a mixture of 3-methylpyridazin-4-amine (0.2 g, 1.8 mmol) and CuBr2(1.63 g, 7.34 mmol) in ACN (10 mL) was added tert-butyl nitrite (0.38 g, 3.7 mmol), and then stirred at 65 °C for 30 min. The reaction mixture was concentrated in vacuo. Ammonia (15 wt.%, 50 mL) was added to the reaction which was then extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude title compound (0.1 g, 32%) as a brown oil. ES / MS m / z 173.1 (M+H).Preparation 23a Trimethyl(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)stannaneTo a solution of 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (5.5 g, 39 mmol) in dry THF (80 mL) was added n-BuLi in THF (23.4 mL, 2.5 molar, 58.5 mmol) slowly at - 78 °C under nitrogen. The mixture was stirred at -78 °C for 0.5 hr., and then trimethyltin chloride (8.6 g, 43 mmol) was added slowly. After stirring at -78 °C under nitrogen for 4 hrs., the mixture was quenched with saturated NH4Cl solution (100 mL), and then extracted with EtOAc (100 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (9.3 g, 70%) as a yellow oil.1H NMR (DMSO-d6): δ 4.52 (t, J = 4.4 Hz, 1H), 4.09 – 3.84 (m, 2H), 3.34 – 2.98 (m, 2H), 1.55 – 1.38 (m, 2H), 1.34 – 1.22 (m, 4H), 0.33– -0.40 (m, 9H). Preparation 23b 4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-5-(trimethylstannyl)pyridazineTo a solution of trimethyl(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1- yl)stannane (9.3 g, 31 mmol) in toluene (60 mL) was added 1,2,4,5-tetrazine (2.5 g, 31 mmol). The mixture was heated to 100 °C and stirred for 1 hr., and then cooled to ambient temperature, quenched by water (100 mL), and extracted with EtOAc (100 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (0 - 15%) to give the title compound (7.6 g, 59%) as a yellow oil. ES / MS (m / z): 359 (M+H).Preparation 24 tert-Butyl N-[1-(3-methylpyridazin-4-yl)pyrazol-4-yl]carbamateTo a mixture of tert-butyl N-(1H-pyrazol-4-yl)carbamate (0.2 g, 1 mmol) in DMF (10 mL) was added 4-bromo-3-methylpyridazine (0.38 g, 2 mmol), K3PO4(0.7 g, 3.3 mmol), CuI (0.2 g, 1 mmol), and N,N'-dimethyl-1,2-cyclohexanediamine (0.16 g, 1 mmol), and then stirred at 90 °C under N2atmosphere for 2 hrs. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (50 mL x 3). The combined EtOAc layers were concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with EtOAc in petroleum ether (80%) to give the title compound (50 mg, 16%) as a white solid. ES / MS m / z 276.3 (M+H). Preparation 25 1-(3-Methylpyridazin-4-yl)pyrazol-4-amineTo a mixture of tert-butyl N-[1-(3-methylpyridazin-4-yl)pyrazol-4-yl]carbamate (50 mg, 0.18 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (4 mol / L, 2 mL).The mixture was stirred at ambient temperature for 2 hrs., then concentrated in vacuo to give the title compound (50 mg, 99+%) as a yellow oil. ES / MS m / z 176.2 (M+H).Preparation 26 1-(5-Amino-3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-1-yl)-5-bromopentan-1-oneTo a mixture of 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine (3.1 g, 17.61 mmol) and 5-bromopentanoic acid (3.5 g, 19.38 mmol) in DMA (20 mL) was added DIPEA (5.7 g, 44.03 mmol) slowly at 0 °C, and then TBTU (8.5 g, 26.42 mmol) was added. The mixture was stirred for 4 hrs., at 10 °C, and then water (50 mL) was added. The resulting precipitate was filtered, and the filter cake was dried in vacuo to give the title compound (5 g, 85%) as a white solid. ES / MS m / z 341.1 (M+H). Preparation 27 1-(3-(5-Methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5- yl)piperidin-2-oneTo a solution of 1-(5-amino-3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-1-yl)-5- bromopentan-1-one (5 g, 14.79 mmol) in DMF (20 mL) was added NaH (1.18 g, 29.59 mmol) slowly at 0 °C, and then stirred for 4 hrs., at 0 °C. SEM-Cl (2.8 mL, 16.27 mmol) was added slowly at 0 °C, and then stirred for 1 hr. The mixture was added to water (100 mL) and it was then extracted with EtOAc (200 mL x 3). The combined organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, concentrated in vacuo, and purified via silica gel flash chromatography eluting with EtOAc inpetroleum ether (20: 80) to give the titled compound (2.6 g, 45%) as a brown oil. ES / MS m / z 389.2 (M+H). Preparation 28 3-(4-Fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-1,2,4-triazol-5-yl)piperidin-2-oneTo a solution of 1-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (388 mg, 1.0 mmol) in dry THF (10 mL) was added a solution of LiHMDS (1M in THF, 1.3 mL, 1.3 mmol) at -78 °C. After it was stirred for 30 min, a solution of 1-(bromomethyl)-4-fluorobenzene (189 mg, 1.0 mmol) in dry THF (5 mL) was added to the reaction mixture which was stirred at -78 ℃ for 1.5 hrs. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL x 2). The combined organic layer was dried and concentrated in vacuo and purified by Prep-HPLC (water: ACN = 30:1) to give the title compound (110 mg, 22%) as a white solid. ES / MS m / z 497.3 (M+H).Preparation 30a Di-tert-butyl ((5-(3-(3,4-difluorobenzyl)-2-oxopiperidin-1-yl)-3-(pyridazin-4-yl)-1H- 1,2,4-triazol-1-yl)methyl) phosphate (isomer 1)To a suspension of 3-(3,4-difluorobenzyl)-1-(5-(pyridazin-4-yl)-4H-1,2,4-triazol- 3-yl)piperidin-2-one (isomer 1 ) (1.00 g, 2.673 mmol), di-tert-butyl (chloromethyl) phosphate (1.383 g, 5.346 mmol) and cesium fluoride (2.030 g, 13.37 mmol) in dry DMF (40 mL) was stirred at ambient temperature for 16 hrs. The mixture was treated with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on reversed-phase column chromatography with a gradient of ACN / H2O (0-60%). The appropriate fractions were combined, concentrated in vacuo, and extracted with EtOAc. The organic layer was concentrated in vacuo to give title compound as a yellow solid (1.0 g, 60%). ES / MS (m / z): 593 (M+H). The compounds in Table 4a were prepared in a manner essentially analogous to that found in Preparation 30a.Table 4aPreparation 31 (R)-4-Benzyl-3-((R)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3- fluorobenzyl)pentanoyl)oxazolidin-2-oneA solution of (R)-4-benzyl-3-(5-((tert- butyldimethylsilyl)oxy)pentanoyl)oxazolidin-2-one (CAS Registry No.1353545-65-9 as prepared on Li et al. Tetrahedron (2012), 68(3), 846-850) (3 g, 7.67 mmol) in dry THF (30 mL) was cooled to -78 ℃ under N2and then a solution of NaHMDS in THF (2M, 4.2 mL, 8.44 mmol) was added dropwise, while keeping the temperature below -65 ℃. After the mixture was stirred for 2 hrs., a solution of 4-(bromomethyl)-1-chloro-2- fluorobenzene (4.3 g, 19.18 mmol) in dry THF (10 mL) was added. The mixture was stirred overnight while the temperature rose to ambient temperature slowly. The reaction mixture was cooled to -78 ℃, quenched with saturated NaHCO3(100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Sodium sulfate and concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with MeOH in DCM (5-10%) to give the title compound (3.0 g, 60%) as a yellow oil. ES / MS m / z 534 (M+H). The compounds in Table 5 were prepared in a manner essentially analogous to that found in Preparation 31.Table 5Preparation 35 (R)-4-Benzyl-3-((R)-2-(4-chloro-3-fluorobenzyl)-5-hydroxypentanoyl)oxazolidin-2-oneTo a solution of (R)-4-benzyl-3-((R)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro- 3-fluorobenzyl)pentanoyl)oxazolidin-2-one (1 g, 1.88 mmol) in dry THF (10 mL) was added HF.Et3N (3 g, 9.38 mmol) dropwise and then stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with 50-60% EtOAc in petroleum ether to give the title compound (0.65 g, 83%) as a white oil. ES / MS m / z 420 (M+H). The compounds in Table 6 were prepared in a manner essentially analogous to that found in Preparation 35. Table 6Preparation 39 (R)-5-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-4-(4-chloro-3-fluorobenzyl)-5-oxopentanalTo a mixture of (R)-4-benzyl-3-((R)-2-(4-chloro-3-fluorobenzyl)-5- hydroxypentanoyl)oxazolidin-2-one (1.85 g, 4.42 mmol) in DCM (25 mL) was added Dess-Martin reagent (2.81 g, 6.62 mmol), and then stirred at ambient temperature for 1 hr. The reaction mixture was quenched with saturated aqueous NaS2O3(30 mL) and saturated aqueous NaHCO3(30 mL) then extracted with EtOAc (100 mL x 5). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with 20-40% EtOAc in petroleum ether to give the title compound (1.2 g, 65%) as a white oil. ES / MS m / z 418 (M+H).The compounds in Table 7 were prepared in a manner essentially analogous to that found in Preparation 39.Table 7Preparation 43 (R)-4-Benzyl-3-((S)-2-(4-chloro-3-fluorobenzyl)-5-((1-(4-methoxybenzyl)-3-(5- methylpyridazin-4-yl)-1H-pyrazol-5-yl)amino)pentanoyl)oxazolidin-2-oneA mixture of 1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5- amine (700 mg, 2.4 mmol), (S)-5-((R)-4-benzyl-2-oxooxazolidin-3-yl)-4-(4-chloro-3- fluorobenzyl)-5-oxopentanal (1.0 g, 2.4 mmol), and AcOH (0.2 mL) in MeOH (10 mL) was stirred at ambient temperature for 2 hrs. Then NaBH3CN (302 mg, 4.8 mmol) was added. The mixture was stirred at ambient temperature for 12 hrs., and then concentrated in vacuo. Water was added (10 mL) which was extracted with EtOAc (50 mL x 2). The combined organics were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified via silica gel flash chromatography eluting with EtOAc in petroleum ether (1:5) to give the title compound (500 mg, 43%) as a yellow oil. ES / MS m / z 697 (M+H). The compound in Table 8 was prepared in a manner essentially analogous to that found in Preparation 43.Table 8Preparation 45 (R)-4-Benzyl-3-((S)-2-(4-chloro-3-fluorobenzyl)-5-((3-(5-methylpyridazin-4-yl)-1H- 1,2,4-triazol-5-yl)amino)pentanoyl)oxazolidin-2-oneThe mixture of 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine (300 mg, 1.7 mmol), (S)-5-((R)-4-benzyl-2-oxooxazolidin-3-yl)-4-(4-chloro-3-fluorobenzyl)-5- oxopentanal (714 mg, 1.7 mmol), and AcOH (0.2 mL) in MeOH (10 mL) was stirred at ambient temperature for 2 hrs. NaBH3CN (214 mg, 3.4 mmol) was added. The mixture was stirred at ambient temperature for 12 hrs., and then concentrated in vacuo. To the residue was added to water (5 mL) which was extracted with EtOAc (30 mL x 2). The combined organic layer was dried, concentrated in vacuo to give crude product, and purified via silica gel flash chromatography eluting with petroleum ether / EtOAc (5:1) to give the title compound (60 mg, 6%) as a yellow oil. ES / MS m / z 579 (M+H)+. The compounds in Table 8a were prepared in a manner essentially analogous to that found in Preparation 45.Table 8aPreparation 48a (R)-4-Benzyl-3-((S)-2-((6-chloro-5-fluoropyridin-3-yl)methyl)-5-((3-(5-methylpyridazin- 4-yl)-1H-pyrazol-5-yl)amino)pentanoyl)oxazolidin-2-oneTo a solution of (R)-4-benzyl-3-((S)-2-((6-chloro-5-fluoropyridin-3-yl)methyl)-5- ((1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5- yl)amino)pentanoyl)oxazolidin-2-one (1.35 g, 1.94 mmol) in DCM (10 ml) was added TFA (8 ml) at 0 °C. After stirring at ambient temperature for 6 hr., the reaction mixture was concentrated in vacuo. To the residue was added water (5 mL) and saturated NaHCO3(15 mL). The resulting precipitate was filtered and purified by pre-HPLC to give the title compound (120 mg, 11%) as a white solid. ES / MS (m / z): 578 (M+H). Preparation 49 (S)-2-(4-Chloro-3-fluorobenzyl)-5-((3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)amino)pentanoic acidA mixture of (R)-4-benzyl-3-((S)-2-(4-chloro-3-fluorobenzyl)-5-((3-(5- methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)amino)pentanoyl)oxazolidin-2-one (60 mg, 0.1 mmol) and H2O2(20 mg, 0.6 mmol) in THF / water (4 / 1, 3 mL) was stirred at ambient temperature for 10 min and then LiOH.H2O (13 mg, 0.3 mmol) was added. The mixture was stirred at ambient temperature for 16 hrs., and then quenched with aqueous Na2SO3(10 mL) and extracted with EtOAc (30 mL x 2). The combined organic layer was driedover anhydrous sodium sulfate, concentrated in vacuo, and purified by reverse phase chromatography (ACN in 10 mM NH4HCO3= 2-20%) to give the title compound (25 mg, 60%) as a white solid, which was used in the next step without further purification. ES / MS m / z 418 (M+H). The compound in Table 9 was prepared in a manner essentially analogous to that found in Preparation 49. Table 9Preparation 49c tert-Butyl 3-oxomorpholine-4-carboxylateTo a solution of morpholin-3-one (1 g, 10 mmol) in DCM (20 mL) was added Boc2O (4.3 g, 20 mmol) and DMAP (0.24 g, 2 mmol), and then stirred at ambient temperature for 1 hr. The mixture was concentrated in vacuo, and the residue was purifiedby silica gel flash chromatography eluting with MeOH in DCM (2: 98) to give the title compound (1.8 g, 90%) as a red solid. MS (m / z): 224 (M+Na)+. The compounds in Table 9a were prepared in a manner essentially analogous to that found in Preparation 49c. Table 9aPreparation 50 tert-Butyl 2-(4-chlorobenzyl)-3-oxomorpholine-4-carboxylateTo a mixture of tert-butyl 3-oxomorpholine-4-carboxylate (0.4 g, 2 mmol) (prepared as described in Arguello-Velasco, R. O., et al., J. Het. Chem., 2019, 56(7), 2068-2073) in THF (10 mL) was added LDA (1M in THF, 1.5 mL, 3 mmol) at -78 °C, and then stirred at -78 °C for 1 hr. The solution of 1-(bromomethyl)-4-chlorobenzene (0.49 g, 2.4 mmol) in THF (5 mL) was slowly added, and then stirred at -78 °C for 1 hr. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo, and purified via silica gel flash chromatography eluting with MeOH in DCM (0-2%) to give the title compound (0.3 g, 45%) as a yellow oil. ES / MS m / z 348.1 (M+Na).The compounds in Table 9b were prepared in a manner essentially analogous to that found in Preparation 50. Table 9bPreparation 51 2-(4-Chlorobenzyl)morpholin-3-oneA mixture of tert-butyl 2-(4-chlorobenzyl)-3-oxomorpholine-4-carboxylate (0.3 g, 0.9 mmol) and 4M HCl in 1,4-dioxane (5 mL) was stirred at ambient temperature for 2 hrs., and then concentrated in vacuo to give the title compound (0.2 g, 96%) as a yellow solid. ES / MS m / z 226.1 (M+H). Preparation 51a 1-Benzyl-4-(hydroxymethyl)pyrrolidin-2-oneTo a solution of methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate (5.00 g, 21.45 mmol) in MeOH (20 mL) was added NaBH4(1.80 g, 75 mmol) at 0 °C, and then stirred at 25 ℃ for 12 hrs., under nitrogen. The reaction mixture was quenched with H2O (100 mL) at 0 °C and extracted with EtOAc (40 mL x 3). The combined organic layers were washedwith saturated aqueous NaCl (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography eluting with DCM in MeOH (10: 1) to give the title compound (4.00 g, 91%) as a white solid. ES / MS (m / z): 206 (M+H). Preparation 51b 1-Benzyl-4-(methoxymethyl)pyrrolidin-2-oneTo a solution of 1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one (4.00 g, 19.5 mmol) in DMF (20 mL) was added NaH (1.60 g, 60% wt., 40 mmol) at 0 °C, and then stirred for 1 hr. The reaction mixture was added MeI (5.68 g, 40 mmol) at -40 °C, and then stirred at 0 °C for 2 hrs. The reaction mixture was quenched with H2O (100 mL) at 0 °C and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography eluting with DCM in MeOH (10:1) to give the title compound (3.00 g, 70%) as a white solid. ES / MS (m / z): 220 (M+H). The compound in Table 9b was prepared in a manner essentially analogous to that found in Preparation 51b. Table 9bPreparation 51d 1-Benzyl-3-(4-chloro-3,5-difluorobenzyl)-4-(methoxymethyl)pyrrolidin-2-oneTo a solution of 1-benzyl-4-(methoxymethyl)pyrrolidin-2-one (3.00 g, 13.5 mmol) in dry THF (10 mL) was added 1M LiHMDS in THF (17 mL, 17 mmol) dropwise at -78 °C under nitrogen. After stirring at -78 °C for 30 min, a solution of 5-(bromomethyl)-2- chloro-1,3-difluorobenzene (3.27 g, 13.5 mmol) in THF (6 mL) was added dropwise, and then stirred at -78 °C for 30 min. The reaction mixture was quenched with water (50 mL) and extracted with DCM (15 mL x 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAC in petroleum ether (1 :1) to give the title compound (1.9 g, 37%) as a yellow oil. MS (m / z): 380 (M+H). Preparation 51e 3-(4-Chloro-3,5-difluorobenzyl)-4-(methoxymethyl)pyrrolidin-2-oneThe mixture of 1-benzyl-3-(4-chloro-3,5-difluorobenzyl)-4- (methoxymethyl)pyrrolidin-2-one (1.90 g, 5.00 mmol) in CH3NO2(8 mL) was added KBr (595 mg, 5.00 mmol) and potassium peroxymonosulfate sulfate (4.61 g, 7.50 mmol), and then stirred for 96 hrs., at 80 °C. The mixture was cooled to ambient temperature, added to water (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1: 1) to give the title compound (900 mg, 62%) as a white solid. ES / MS (m / z): 290 (M+H).Preparation 51f 1-(2,4-Dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acidTo a solution of 2-methylenesuccinic acid (4.0 g, 31 mmol) in toluene (40 mL) was added (2, 4-dimethoxyphenyl)methanamine (5.7 g, 34 mmol), and then stirred at 110 °C for 16 hrs. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in LiOH solution (1 M, 70 mL) and extracted with EtOAc (50 mL x 3). The aqueous solution was acidified by adding diluted HCl solution to pH = 4 and extracted with EtOAc (80 mL x 3). The organic phases were combined, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (8.0 g, 89%) as a yellow oil. ES / MS (m / z): 280 (M+H). Preparation 51g 1-(2,4-Dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carboxylic acidTo a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (4.0 g, 14 mmol) in anhydrous THF (40 mL) was added the solution of LDA in THF (18 mL, 36 mmol) at -78 °C under nitrogen. After stirring for 45 min, the reaction mixture was added the solution of 5-(bromomethyl)-1,2,3-trifluorobenzene (3.5 g, 16 mmol) in anhydrous THF (2 mL) dropwise at -78 °C, and then stirred at -78 °C for 2 hrs. The mixture was added to water (40 mL). The pH value was adjusted to 6 with 1M HCl then extracted with EtOAc (70 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with DCM in MeOH (20:1) to give the title compound (3.0 g, 47%) as a yellow oil. ES / MS (m / z): 424 (M+H). Preparation 51h 1-(2,4-Dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carboxamideTo a solution of 1-(2,4-dimethoxybenzyl)-5-oxo-4-(3,4,5- trifluorobenzyl)pyrrolidine-3-carboxylic acid (3.5 g, 8.3 mmol) in ACN (30 mL) was added di-tert-butyl dicarbonate (5.4 g, 25 mmol), ammonium bicarbonate (3.3 g, 41 mmol) and pyridine (1.3 mL, 17 mmol), and then stirred at 25 °C for 2 hrs. Water (60 mL) was added and then extracted with EtOAc (80 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM in MeOH (30:1) to give the title compound (2.5 g, 68%) as a yellow solid. ES / MS (m / z): 423 (M+H). The compound in Table 9c was prepared in a manner essentially analogous to that found in Preparation 51h. Table 9cPreparation 51j 1-(2,4-Dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carbonitrileTo a solution of 1-(2,4-dimethoxybenzyl)-5-oxo-4-(3,4,5- trifluorobenzyl)pyrrolidine-3-carboxamide (4.5 g, 11 mmol) in DMF (30 mL) was added POCl3(4.9 g, 32 mmol), and then stirred at 25 °C for 2 hrs. The mixture was added to water (20 mL), adjusted pH = 8 with 10% NaHCO3solution, and then extracted with EtOAc (80 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel column chromatography eluting with n-hexane in EtOAc (2:1) to give the title compound (3.0 g, 66%) as a yellow solid. ES / MS (m / z): 405 (M+H) Preparation 51l 5-Oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carbonitrileTo a solution of 1-(2,4-dimethoxybenzyl)-5-oxo-4-(3,4,5- trifluorobenzyl)pyrrolidine-3-carbonitrile (2.5 g, 6.2 mmol) in TFA (20 mL) was added triflic acid (2.3 g, 15 mmol), and then stirred at 25 °C for 16 hrs. The reaction mixture was concentrated in vacuo. To the mixture was added saturated aqueous NaHCO3solution (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting withMeOH in DCM (2%) to give the title compound, which was purified further by reversed- phase chromatography (C18, Mobile Phase: A: water (10 mmol / L ammonium bicarbonate), B: ACN; B in A: 30% - 40%) to give the title compound (1.2 g, 75%) as a white solid. ES / MS (m / z): 255 (M+H). The compound in Table 9d was prepared in a manner essentially analogous to that found in Preparation 51l. Table 9dPreparation 51m tert-Butyl (2-bromo-5-methylphenyl)carbamateTo a solution of 2-bromo-5-methylaniline (3.00 g, 16.1 mmol) in THF (50 mL) was added 2M NaHMDS in THF (16.1 mL, 32.2 mmol) dropwise at -78 °C. After stirring for 0.5 hr., under nitrogen at -78 °C, added Boc2O (3.52 g, 16.1 mmol) in THF (10 mL) dropwise at -78 °C. After stirring for 3 hrs., under nitrogen at 25 °C, the reaction mixture was poured into saturated aqueous NaCl (200 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1:1) to give the title compound (4.3 g, 91.7%) as a yellow oil. ES / MS (m / z): 232.1 (M+H-56).Preparation 51n Ethyl (E)-3-(2-((tert-butoxycarbonyl)amino)-4-methylphenyl)acrylateTo a mixture of tert-butyl (2-bromo-5-methylphenyl)carbamate (1.24 g, 4.33 mmol) in 1,4-dioxane (10.8 mL) was added ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)acrylate (1.18 g, 5.20 mmol), sodium carbonate (1.38 g, 13.0 mmol), PdCl2(dppf) (317.0 mg, 0.43 mmol) and water (1.2 mL). After stirring at 90 °C under nitrogen for 16 hrs., the reaction mixture was cooled and filtered in vacuo. The mixture was added to water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (95:5) to give the title compound (1.183 g, 77%) as a white solid. ES / MS (m / z): 250 (M+H-tBu).Preparation 51o 5-Bromo-3-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridineTo a solution of (5-bromo-3-fluoropyridin-2-yl)methanol (1.00 g, 4.90 mmol) in THF (10 mL) was added 3,4-dihydro-2H-pyran (1.22 g, 14.7 mmol) and pyridinium p- toluenesulfonate (122 mg, 0.49 mmol). After stirring for 2 hrs., at 70 ℃ under nitrogen, the reaction mixture was cooled, diluted with EtOAc (30 mL), washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (1.49 g, 96%) as an orange oil. ES / MS (m / z): 206 and 208 (M+H-84). Preparation 52 4-Methyl-5-(trimethylstannyl)pyridazineA mixture of 4-bromo-5-methylpyridazine (1 g, 5.81 mmol), hexamethylditin (2.5 g, 7.56 mmol), and Pd(PPh3)4(335 mg, 0.29 mmol) in 1,4-dioxane (12 mL) was stirred at 95 ºC for 4 hrs., under nitrogen, and then filtered through diatomaceous earth. The filtrate was concentrated, and the residue purified by silica gel column chromatography eluting with EtOAc in petroleum ether (25-35%) to give the title compound (490 mg, 33%) as a black solid. ES / MS (ES) m / z 259 (M+H).Preparation 52a 4-(5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-5-methylpyridazineTo a mixture of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (100 mg, 0.27 mmol) in DMF (2 mL) was added 4-methyl-5-(trimethylstannyl)pyridazine (105 mg, 0.40 mmol), CuI (11 mg, 0.05 mmol), and Pd(PPh3)4(31 mg, 0.03 mmol), then stirred for 5 hrs. at 100 °C under N2atmosphere. The mixture was quenched with saturated aqueous KF (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with 0-5% MeOH in DCM to give the title compound (130 mg, 91%) as a yellow oil. ES / MS m / z 369.1 (M+H). Preparation 53 2-(4-Chlorobenzyl)-4-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)morpholin-3-oneTo a mixture of 2-(4-chlorobenzyl)morpholin-3-one (100 mg, 0.44 mmol) in 1,4- dioxane (2 mL) was added 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 3-yl)-5-methylpyridazine (245 mg, 0.67 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (63 mg, 0.44 mmol), K3PO4(94 mg, 0.44 mmol), and CuI (84 mg, 0.44 mmol). The mixture was stirred the mixture for 5 hrs. at 90 °C under nitrogen. The mixture was thenconcentrated in vacuo. The residue was purified by prep-HPLC (C18, ACN in 13 mL TFA = 65-95% in 17 min, rt = 8.9 min) to give the title compound (35 mg, 15%) as a white solid. ES / MS m / z 514.2 (M+H). Preparation 53a Benzyl 5-chloropentanoateTo a solution of 5-chloropentanoic acid (10.0 g, 73.2 mmol) in ACN (60 mL) was added (bromomethyl)benzene (13.8 g, 80.5 mmol) and potassium carbonate (12.1 g, 87.9 mmol) at ambient temperature. The reaction mixture was stirred at 80 °C for 16 hrs. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0- 15%) to give the title compound as a colorless oil (9.10 g, 41%).1H NMR (DMSO-d6) δ 7.41 – 7.30 (m, 5H), 5.09 (s, 2H), 3.64 (t, J = 6.3 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.77 – 1.62 (m, 4H). Preparation 54 Benzyl 5-chloro-2-((6-fluoropyridin-3-yl)(hydroxy)methyl)pentanoateTo a solution of LDA (12 mmol) in THF (24 mL) was added benzyl 5- chloropentanoate (2.9 g, 13 mmol) (prepared as described in Hoffman, M, et al., Chem. Med. Chem., 2018, 13(23), 2546-2557) at -78 °C which was stirred at -78 °C for 1 hr. A solution of 6-fluoronicotinaldehyde (1 g, 8 mmol) in THF (5 mL) was added at -78 °C. The reaction was stirred at -78 °C for another 3 hrs. The reaction was quenched by NH4Cl (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with 0-20%EtOAc in petroleum ether to give the title compound (2.5 g, 86%) as a light-yellow oil. ES / MS m / z 352 (M+H).The compounds in Table 9e were prepared in a manner essentially analogous to that found in Preparation 54.Table 9ePreparation 55 Benzyl (Z)-5-chloro-2-((6-fluoropyridin-3-yl)methylene)pentanoateA solution of benzyl 5-chloro-2-((6-fluoropyridin-3- yl)(hydroxy)methyl)pentanoate (1.5 g, 4.26 mmol) and TFA (2.2 g, 11 mmol) in DCM (25 mL) was stirred at ambient temperature overnight under nitrogen. DBU (3 g, 19 mmol) was added dropwise while keeping below 30 °C, and then stirred for 1 hr. The mixture was concentrated in vacuo, and the residue was purified via silica gel flash chromatography eluting with EtOAc / petroleum ether (0 to 20%) to give the title compound (0.9 g, 64%) as a light-yellow oil. ES / MS m / z= 334 (M+H). The compounds in Table 9f were prepared in a manner essentially analogous to that found in Preparation 55. Table 9fPreparation 56 5-Chloro-2-((6-fluoropyridin-3-yl)methyl)pentanoic acidTo a solution of benzyl (Z)-5-chloro-2-((6-fluoropyridin-3- yl)methylene)pentanoate (0.9 g, 2.7 mmol) in EtOH (30 mL) was added 10% Pd / C (200 mg) at ambient temperature which was then stirred under H2atmosphere at ambient temperature for 5 hrs. The mixture was filtered, and the filtrate was concentrated in vacuo to give crude title compound (650 mg, crude) as a colorless oil. ES / MS m / z= 246 (M+H); 1H NMR (CDCl3) δ 8.06 (d, J = 2.1 Hz, 1H), 7.65 (td, J = 8.0, 2.5 Hz, 1H), 6.90 (dd, J = 8.4, 2.6 Hz, 1H), 3.56 (dd, J = 11.8, 5.9 Hz, 2H), 2.98 (dd, J = 13.9, 8.9 Hz, 1H), 2.81 (dd, J = 14.1, 5.8 Hz, 1H), 2.67 (ddd, J = 13.9, 8.5, 5.7 Hz, 1H), 1.94 – 1.70 (m, 4H). The compounds in Table 9g were prepared in a manner essentially analogous to that found in Preparation 56. Table 9gPreparation 57 1-(5-Amino-3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-1-yl)-5-chloro-2-((6- fluoropyri din-3 -yl)methyl)pentan- 1 -oneTo a solution of 5-chloro-2-((6-fluoropyridin-3-yl)methyl)pentanoic acid (310 mg, 1.26 mmol) in DMF (10 mL) was added TBTU (810 mg, 2.5 mmol), DIPEA (489 mg, 3.79 mmol), DMAP (15 mg, 0.12 mmol), which was then stirred at ambient temperature for 1 hr., before adding 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine (233 mg, 1.32 mmol) stirring for 4 hrs. The mixture was quenched with water, and the resulting precipitate was collected by filtration to give the crude product, which was stirred inEtOAc in petroleum ether (1:1) and filtered to give the title compound (384 mg, 75%) as a white solid. ES / MS m / z 403 (M+H). The compound in Table 9ah was prepared in a manner essentially analogous to that found in Preparation 57. Table 9haPreparation 57a-a 5-Chloro-2-((6-fluoropyridin-3-yl)methyl)-N-(2-(pyridazin-4-yl)-2H-1,2,3-triazol-4- yl)pentanamideTo a solution of 5-chloro-2-((6-fluoropyridin-3-yl)methyl)pentanoic acid (260 mg, 1.06 mmol) in pyridine (6 mL) was added 2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-amine (257 mg, 1.59 mmol) and phosphorus oxychloride (325 mg, 2.12 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr. The solvent was removed in vacuum, the residue was diluted by water (3 mL) and extracted with EtOAc (3 mL x 3). The combined organic layer was washed with water (3 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-100%) to give the title compound as a yellow solid (150 mg, 35%). ES / MS (m / z): 390 (M+H). The compounds in Table 9d were prepared in a manner essentially analogous to that found in Preparation 57a-a.Table 9dPreparation 58 3-(4-Chloro-3-fluorophenyl)-N-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrazol-5-yl)propanamideTo a solution of N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)-3-(4-chloro-3-fluorophenyl)propanamide (1 g, 2 mmol) in DMF (10 ml) was added 4-methyl-5-(trimethylstannyl)pyridazine (0.65 g, 2.5 mmol), CuI (40 mg, 0.2 mmol) and Pd(PPh3)4(0.5g, 0.4mmol) under nitrogen. After stirring at 100 °C for 12 hrs., the reaction mixture was cooled to ambient temperature, quenched by adding saturated KF solution (30 ml) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude was purified by silica gel flash chromatography eluting with MeOH in CH2Cl2(7 %) to give the title compound (0.95 g, 92 %) as red oil. ES / MS (m / z): 490 (M+Na). Preparation 58a N-(3-(5-(Bromomethyl)pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 5-yl)-3-(4-chloro-3-fluorophenyl) propanamideTo a solution of 3-(4-chloro-3-fluorophenyl)-N-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)propanamide (0.8 g, 1.6 mmol) in ACN (10 mL) was added NBS (0.35 g, 2 mmol). After stirring at 25 °C for 2 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH in DCM (10%) to give the title compound (0.65 g, 70%) as a colorless oil. ES / MS (m / z): 568 (M+H).Preparation 58b 3-(4-Chloro-3-fluorophenyl)-N-(3-(5-(fluoromethyl)pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)propanamideTo a solution of N-(3-(5-(bromomethyl)pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(4-chloro-3-fluorophenyl) propanamide (0.65 g, 1.1 mmol) in THF (10 mL) was added 2.5M n-BuLi in THF (0.68 ml, 1.8 mmol) at -78 °C nitrogen. After stirring at -78 °C for 1 hr., added N- fluorobenzenesulfonimide (0.43g, 1.4 mmol) and then stirred at -78 °C for 1 hr. The reaction mixture was quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in petroleum ether (25%) to give the title compound (60 mg, 10%) as a colorless oil. ES / MS (m / z): 508 (M+H). Preparation 5ba 5-Bromo-N-(4-methoxybenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3- amineTo a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- triazole (13 g, 36 mmol) in N-methyl-2-pyrrolidone (100 mL) was added (4- methoxyphenyl)methanamine (6 g, 44 mmol) and solid K2CO3(15 g, 110 mmol). After stirring at 120 °C for 12 hrs., the reaction mixture was cooled, poured to water (300 ml)and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (5 %) to give the title compound (13 g, 71 %) as brown oil. ES / MS m / z: 413 (M+H) Preparation 58c N-(5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)-3-(4-chloro-3,5- difluorophenyl)-N-(4-methoxybenzyl)propanamideTo a solution of 5-bromo-N-(4-methoxybenzyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-amine (1.5 g, 3.62 mmol) in DMF (15 mL) was added NaH (0.29 g, 7.23 mmol) at 0 °C under nitrogen. After stirring at ambient temperature for 0.5 hr., added a solution of 3-(4-chloro-3,5-difluorophenyl)propanoyl chloride (1.04 g, 4.37 mmol) in DMF (5 mL) slowly at 0 °C. After stirring at ambient temperature for 2 hrs., the reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 7% MeOH in DCM to give the title compound (1.1 g, 49%) as a yellow solid. ES / MS (m / z): 615 / 617 (M+H).Preparation 58d 5-((tert-Butoxycarbonyl)amino)-2-(4-chloro-3-fluorobenzyl)pentanoic acidTo a solution of tert-butyl 3-(4-chloro-3-fluorobenzyl)-2-oxopiperidine-1- carboxylate (1.2 g, 3.5 mmol) in THF (20 mL) was added LiOH (0.22 g, 5.3 mmol) in H2O (5 mL) at 0 °C. After stirring at ambient temperature for 2 hrs., the reaction mixture was quenched with 1N HCl (6 mL, 6 mmol) dropwise at 0 °C, and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (1.2 g, 95%) as a colorless oil. ES / MS (m / z): 382 (M+Na). The compounds in Table 9e were prepared in a manner essentially analogous to that found in Preparation 58c. Table 9ePreparation 58h 5-Amino-2-(4-chloro-3-fluorobenzyl)pentanoic acid hydrochlorideTo a solution of 5-((tert-butoxycarbonyl)amino)-2-(4-chloro-3- fluorobenzyl)pentanoic acid (1.2 g, 3.3 mmol) in DCM (5 mL) was added 4M HCl in 1,4- dioxane (5 mL, 20 mmol). After stirring at ambient temperature for 2 hrs., the reaction mixture was concentrated in vacuo to give the title compound (1.2 g, 99+%) as a colorless oil. ES / MS (m / z): 260 (M+H). The compounds in Table 9f were prepared in a manner essentially analogous to that found in Preparation 58g. Table 9fPreparation 58l 5-((3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)-2-(4- chloro-3-fluorobenzyl)pentanoic acidTo a solution of 5-amino-2-(4-chloro-3-fluorobenzyl)pentanoic acid hydrochloride (0.5 g, 2 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was added 3,5-dibromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (0.68 g, 2 mmol) and K2CO3(1.33 g, 10 mmol). After stirring at 100 °C for 45 hrs., the reaction mixture was concentrated in vacuo. The mixture was added to water (25 mL), diluted with HCl (15 mL, 15 mmol) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH in DCM (1:9) to give the title compound (0.38g, 37%) as a brown oil. ES / MS (m / z): 535 / 537 (M+H). The compounds in Table 9g were prepared in a manner essentially analogous to that found in Preparation 58k.Table 9gPreparation 58p 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-3-(4-chloro-3- fluorobenzyl)piperidin-2-oneTo a solution of 5-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4- triazol-5-yl)amino)-2-(4-chloro-3-fluorobenzyl)pentanoic acid (0.5 g, 0.9 mmol) in DMF (10 mL) was added HATU (0.71 g, 1.9 mmol) and DIPEA (0.36 g, 2.8 mmol). After stirring at ambient temperature for 12 hrs., the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH in DCM (0-7%) to give the title compound (120 mg, 25%) as a brown oil. ES / MS (m / z): 517 (M+H). The compounds in Table 9h were prepared in a manner essentially analogous to that found in Preparation 58p.Table 9hPreparation 58s 1-(3-Bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(4-chloro- 3,5-difluorobenzyl)pyrrolidin-2-oneTo a solution of 1-(3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)pyrrolidin-2-one (17.00 g, 45.1 mmol) in THF (200 mL) was added 1M LiHMDS in THF (45.1 mL, 45.1 mmol) at -78 °C under nitrogen. After stirring for 1 hr., at -78 °C, added 5-(bromomethyl)-2-chloro-1,3-difluorobenzene (10.82 g, 45.1 mmol), and then stirred at -78 °C for 3 hrs., under nitrogen. The mixture was quenched with saturated NH4Cl solution (200 mL) and extracted with EtOAc (200 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel flash chromatography eluting with 15% EtOAc in petroleum ether to give the title compound (14.80 g, 61%) as a yellow oil. ES / MS (m / z): 538 (M+H) The compounds in Table 9i were prepared in a manner essentially analogous to that found in Preparation 58s.Table 9iPreparation 58z 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5- trifluorobenzyl)piperidin-2-oneTo a solution of 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)piperidin-2-one (3.2 g, 8.58 mmol) in dry THF (40 mL) was added 2M LDA in THF solution (6.4 mL, 12.87 mmol) dropwise while keeping the temperature below -65 °C under nitrogen. The mixture was stirred at -78 °C for 1 hr., and then 5-(bromomethyl)- 1,2,3-trifluorobenzene (1.91 g, 8.58 mmol) in dry THF (15 mL) was added slowly. The mixture was warmed up slowly to ambient temperature and stirred for 2 hrs. The mixture was cooled to -78 °C, quenched with saturated NH4Cl solution (100 mL). The aqueous solution was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (5- 15%) to give the title compound (2 g, 45%) as a yellow oil. ES / MS (m / z): 518 (M+H). The compounds in Table 9j were prepared in a manner essentially analogous to that found in Preparation 58z. Table 9jPreparation 59 Ethyl (E)-2-(7-chlorochroman-4-ylidene)acetateTo a solution of ethyl 2-(diethoxyphosphoryl)acetate (15.96 g, 71.19 mmol) in THF (100 mL) was added NaH (2.19 g, 60% wt, 54.76 mmol) in portions at 0 °C. After stirring at 0 °C for 30 min, a solution of 7-chlorochroman-4-one (10.00 g, 54.76 mmol) in THF (15 mL) was added dropwise, and then stirred at 0 °C for 1 hr., then at ambient temperature for another 16 hrs. The mixture was added to water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (9:1) to give the title compound (6.0 g, 43.4%) as a white solid. ES / MS (m / z): 253 (M+H).Preparation 59a Ethyl 2-(7-chlorochroman-4-yl)acetateTo a solution of ethyl (E)-2-(7-chlorochroman-4-ylidene)acetate (5.00 g, 19.79 mmol) in THF (50 mL) was added Pd / C (1.0 g, 10% wt, 0.94 mmol) at ambient temperature. After stirring under H2atmosphere at ambient temperature for 16 hrs., the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse chromatography on C18 column (Water: ACN = 4: 6) to give the title compound (3.13 g, 62.0%) as a white solid. ES / MS (m / z): 255 (M+H). Preparation 59b 2-(7-Chlorochroman-4-yl)acetic acidTo a solution of ethyl 2-(7-chlorochroman-4-yl)acetate (1.3 g, 5.1 mmol) in THF (10 mL) and water (1 mL) was added lithium hydroxide hydrate (0.86 g, 20 mmol) at ambient temperature, and stirred for 16 hrs. The reaction mixture was concentrated in vacuo. The mixture was added to water (10 mL) and adjusted to pH = 3-4 with 1N aqueous HCl. The resulting precipitate was filtered, and the filter cake was dried in vacuo to give the title compound (650 mg, 52.0%) as a white solid. ES / MS (m / z): 227 (M+H).Preparation 59c N-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2-(7-chlorochroman- 4-yl)acetamideTo a mixture of 2-(7-chlorochroman-4-yl)acetic acid (1.30 g, 5.74 mmol), 3- bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (1.51 g, 5.16 mmol) and pyridine (1.86 mL, 22.9 mmol) in DCM (15 mL) was added POCl3(1.14 g, 7.46 mmol) dropwise at 0 °C. The mixture was warmed to 20 °C and stirred for 3 hrs. The reaction mixture was quenched with water (30 mL) and extracted with DCM (100 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (10:1) to give the title compound (1.15 g, 34%) as a white solid. ES / MS (m / z): 502 (M+H). Preparation 59d 4-MethoxybutanamideTo a solution of 4-methoxybutanoic acid (2.00 g, 16.9 mmol) in ACN (150 mL) was added NH4HCO3(1.74 g, 22.0 mmol), pyridine (1.60 g, 20.3 mmol) and di-tert-butyl dicarbonate (4.43 g, 20.3 mmol). After stirring at 25 °C for 16 hrs., the reaction mixture was filtered, and the filtrate concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the titlecompound (1.98 g, 99.8%) as a white solid.1H NMR: (DMSO-d6) δ 7.27 (s, 1 H), 6.73 (s, 1 H), 3.28 (t, J = 6.4 Hz, 2 H), 3.21 (s, 3 H), 2.07 (t, J = 8 Hz, 2 H), 1.72-1.65 (m, 2 H). The compound in Table 9k was prepared in a manner essentially analogous to that found in Preparation 59d. Table 9kPreparation 59f 4-MethoxybutanenitrileTo a solution of 4-methoxybutanamide (1.33 g, 11.35 mmol) in THF (50 mL) was added Burgess reagent (5.40 g, 22.7 mmol). After stirring at 25 °C for 16 hrs., the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (538 mg, 47.9%) as a colorless oil.1H NMR: (DMSO-d6) δ 3.47 (t, J = 6 Hz, 2 H), 3.34 (s, 3 H), 2.50 (t, J = 7.2 Hz, 2 H), 1.90 - 1.84 (m, 2 H). The compound in Table 9l was prepared in a manner essentially analogous to that found in Preparation 59f.Table 9lPreparation 59h tert-Butyl (S)-2-((cyanomethoxy)methyl)morpholine-4-carboxylateTo a solution of tert-butyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate (5.00 g, 23.0 mmol) in ACN (100 mL) was added NaH (2.3 g, 57.5 mmol) at 0 °C, and then stirred for 1 hr. To the mixture was added 2-bromoacetonitrile (6.90 g, 57.5 mmol) at - 20 °C, and then stirred at -20 °C for 12 hrs. The mixture was quenched with MeOH (20 mL) and concentrated in vacuo to give the crude product. The crude material was purified by silica gel flash chromatography eluting with MeOH in DCM (0-5%) to give the title compound (5.00 g, 67%) as a yellow oil. ES / MS (m / z): 201 (M+H-tBu). The compounds in Table 9m were prepared in a manner essentially analogous to that found in Preparation 59h.Table 9mPreparation 59n tert-Butyl (2S)-2-((1-cyano-2-oxo-2-(pyridazin-4-yl)ethoxy)methyl)morpholine-4- carboxylateTo a solution of methyl pyridazine-4-carboxylate (2.77 g, 20.0 mmol) in THF (100 mL) was added 1M LiHMDS in THF (18.5 mL, 18.5 mmol) at -78 °C under nitrogen. After stirring for 1 hr., added a solution of tert-butyl (S)-2- ((cyanomethoxy)methyl)morpholine-4-carboxylate (5.00 g, 79% wt, 15.4 mmol) in THF (20 mL), and then stirred at -78 °C for 5 hrs. The reaction mixture was warmed to ambient temperature and concentrated in vacuo to give the title compound (11.00 g, crude) as a brown solid. ES / MS (m / z): 363 (M+H). The compounds in Table 9n were prepared in a manner essentially analogous to that found in Preparation 59n. Table 9nPreparation 59w tert-Butyl (S)-2-(((5-amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylateTo a solution of tert-butyl (2S)-2-((1-cyano-2-oxo-2-(pyridazin-4- yl)ethoxy)methyl)morpholine-4-carboxylate (11.00 g) in EtOH (200 mL) was added (4- methoxybenzyl)hydrazine hydrochloride (8.933 g, 47.35 mmol) and AcOH (2.7 mL, 47.35 mmol). After stirring at 80 °C for 12 hrs., the mixture was concentrated in vacuo. The residue was purified by reverse chromatography column (C18, 2 – 40% ACN in 10 mmol NH4HCO3) to give the title compound (3.60 g, 46%) as a yellow solid. ES / MS (m / z): 497 (M+H). The compounds in Table 9o were prepared in a manner essentially analogous to that found in Preparation 59w. Table 9oPreparation 59aa tert-Butyl (S)-2-(((5-bromo-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylateTo a mixture of copper (II) bromide (1.62 g, 7.25 mmol) in ACN (10 mL) was added tert-butyl nitrite (1.15 g, 11.1 mmol). After stirring at 65 °C for 15 min, added a solution of tert-butyl (S)-2-(((5-amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H- pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate (2.40 g, 4.83 mmol) in ACN (5 mL), and then stirred at 65 °C for 30 min. The mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silicagel flash chromatography eluting with EtOAc in petroleum ether (0-70%) to give the title compound (1.26 g, 42%) as a yellow solid. ES / MS (m / z): 560 / 562 (M+H).The compounds in Table 9p were prepared in a manner essentially analogous to that found in Preparation 59aa.Table 9pPreparation 59ae tert-Butyl 2-(((5-amino-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4- carboxylateTo a solution of tert-butyl 2-((1-cyano-2-oxo-2-(pyridazin-4- yl)ethoxy)methyl)morpholine-4-carboxylate (2.5g, 7 mmol) in EtOH (10 ml) was added N2H4.H2O (1 g, 21mmol) and AcOH (1.3 g, 21mmol). After stirring at 80 °C for 12 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography (C18, 40% ACN in 10 mmol NH4HCO3) to give the title compound (1 g, 38%) as a yellow solid. ES / MS (m / z): 377 (M+H). The compounds in Table 9q were prepared in a manner essentially analogous to that found in Preparation 59ae. Table 9qPreparation 59al 4-(4-Bromo-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-1-yl)pyridazineTo a solution of (4-bromo-1-(pyridazin-4-yl)-1H-pyrazol-5-yl)methanol (300 mg, 1.18 mmol) in ACN (10 mL) was added 3,4-dihydro-2H-pyran (989 mg, 11.8 mmol) and pyridine 4-methylbenzenesulfonate (29.6 mg, 118 µmol). After stirring at 75 °C for 5 hrs., cooled to ambient temperature, added water (20 mL) and extracted with EtOAc (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flashchromatography eluting with EtOAc in petroleum ether (6:1) to give the title compound (250 mg, 61%) as a white solid. ES / MS (m / z): 339 / 341 (M+H). Preparation 59am 4-(4-Bromo-5-(methoxymethyl)-1H-pyrazol-1-yl)pyridazineTo a solution of (4-bromo-1-(pyridazin-4-yl)-1H-pyrazol-5-yl)methanol (400 mg, 1.57 mmol) in THF (4 mL) and DMF (1 mL) was added NaH (94.1 mg, 60% wt., 2.35 mmol) at 0 °C. After stirring for 0.5 hr., at 0 °C, added a solution of MeI (267 mg, 1.88 mmol) in THF (1 mL), and then stirred at 20 °C for 5 hrs., under nitrogen. The mixture was added to water (20 mL) and extracted with EtOAc (100 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (6:1) to give the title compound (340 mg, 77%) as a white solid. ES / MS (m / z): 269 / 271 (M+H). Preparation 59an 3-Bromo-5-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carbaldehydeTo a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- carbaldehyde (3.7 g, 9 mmol) in dry DMF (200 mL) was added 4- (tributylstannyl)pyridazine (3.574 g, 9 mmol), CuI (0.092 g, 0.45 mmol) and Pd(PPh3)4(0.895 g, 0.72 mmol), and then stirred at 100 °C under nitrogen for 2 hrs. The reaction mixture was cooled to ambient temperature, then added aqueous KF solution (300 mL). After stirring at ambient temperature for 2 hrs., the mixture was filtered throughdiatomaceous earth, washing with EtOAc (400 mL). The filtrate was collected and extracted with EtOAc (300 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (1 : 1) to give the title compound (2.5 g, 67%) as a yellow solid. ES / MS (m / z): 383 / 385 (M+H).The compounds in Table 9r were prepared in a manner essentially analogous to that found in Preparation 59an.Table 9rPreparation 59au (5-Amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)methanolTo a solution of ethyl 5-amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H- pyrazole-4-carboxylate (1.5 g, 4.24 mmol) in THF (15 mL) was added 1M LiAH4in THF (4.7 mL, 4.7 mmol) at -5 °C, and then stirred at ambient temperature for 11 min under N2atmosphere. To the mixture was added saturated aqueous NH4Cl (40 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (7:93) to give the title compound (475 mg, 29%) as a yellow solid. ES / MS (m / z): 312 (M+H).Preparation 60 3-Bromo-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehydeTo a suspension of 3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (300 mg, 1.31 mmol) in 1,4-dioxane (5 mL) was added xantphos (76 mg, 0.13 mmol), 3,5-dibromo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde (553 mg, 1.44 mmol), Pd(OAc)2(11 mg, 0.06 mmol) and Cs2CO3(854 mg, 2.62 mol). After stirring at 100 ºC for 1 hr., under nitrogen atmosphere, the reaction mixture was cooled to ambient temperature, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (0-10%) to give the title compound (0.33 g, 47%) as a yellow oil. ES / MS (m / z): 554 (M+Na). The compounds in Table 9s were prepared in a manner essentially analogous to that found in Preparation 60. Table 9sPreparation 60g 1-(3-Bromo-4-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3- (3,4,5-trifluorobenzyl)pyrrolidin-2-oneTo a solution of 3-bromo-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde (7.9 g, 14.8 mmol) in THF (100 mL) was added NaBH4(1.12 g, 29.7 mmol) at ambient temperature. After stirring at ambient temperature for 30 min, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (EtOAc in petroleum ether (0-40%) to give the title compound (7.2 g, 86%) as a yellow oil. ES / MS (m / z): 558 (M+Na). The compounds in Table 9t were prepared in a manner essentially analogous to that found in Preparation 60g.Table 9tPreparation 60k 1-(4-(Hydroxymethyl)-3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [To a solution of 1-(3-bromo-4-(hydroxymethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2- one (2.50 g, 4.68 mmol) in toluene (40 mL) was added Pd2(dba)3(428 mg, 468 µmol), 4- (tributylstannyl)pyridazine (1.73 g, 4.68 mmol) and 2-(dicyclohexylphosphanyl)-2',4',6'- tris(isopropyl)biphenyl (446 mg, 936 µmol) at ambient temperature. After stirring at 100 °C under nitrogen for 16 hrs., the reaction mixture was cooled to ambient temperature, poured into water (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (0-80%) to give the title compound (1.7 g, 63%) as a brown solid. ES / MS (m / z): 534 (M+H). The compounds in Table 9u were prepared in a manner essentially analogous to that found in Preparation 60k.Table 9uPreparation 60p 2-Fluoro-4-((1-(4-formyl-5-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-3-yl)-2-oxopyrrolidin-3-yl)methyl)benzonitrileTo a solution of 3-bromo-5-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carbaldehyde (2 g, 5.2 mmol) in dry DMF (100 mL) was added 2-fluoro- 4-((2-oxopyrrolidin-3-yl)methyl)benzonitrile (1.22 g, 5.6 mmol), N1,N2- dimethylcyclohexane-1,2-diamine (1.31 g, 10.4 mmol), CuI (1.11 g, 5.2 mmol) and K3PO4(16.652 g, 74 mmol), and then stirred at 100 °C under nitrogen for 4 hrs. The mixture was cooled to ambient temperature and filtered in vacuo. The filtrate was added to water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (1:1) to give the title compound (866 mg, 32%) as a yellow oil. ES / MS (m / z): 521 (M+H). The compounds in Table 9v were prepared in a manner essentially analogous to that found in Preparation 60p.Table 9vPreparation 60x 2-Fluoro-4-((1-(4-(hydroxymethyl)-5-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-2-oxopyrrolidin-3- yl)methyl)benzonitrileTo a solution of 2-fluoro-4-((1-(4-formyl-5-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-2-oxopyrrolidin-3- yl)methyl)benzonitrile (970 mg, 1.9 mmol) in THF (10 mL) was added NaBH4(106 mg, 2.8 mmol) in portions, and then stirred at ambient temperature for 1 hr. The mixture was added to water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (932 mg, 95%) as a white solid. ES / MS (m / z): 523 (M+H). The compound in Table 9w was prepared in a manner essentially analogous to that found in Preparation 60x.Table 9wPreparation 60z 5-(3-(2-(Difluoromethyl)-4-fluorobenzyl)-2-oxopyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde [To a solution of 3-bromo-5-(3-(2-(difluoromethyl)-4-fluorobenzyl)-2- oxopyrrolidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde (300 mg, 95.78% wt., 526 µmol) in 1,4-dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridazine (217 mg, 1.05 mmol), PdCl2(dppf) (38.5 mg, 52.6 µmol), potassium carbonate (182 mg, 1.31 mmol) and water (0.5 mL), and then stirred at 100 °C for 2 hrs., under nitrogen. The reaction mixture was cooled to ambient temperature, added to water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with DCM in MeOH (10:1) to give the title compound (250 mg, 65.9%) as a yellow oil. ES / MS (m / z): 546 (M+H).The compounds in Table 9x were prepared in a manner essentially analogous to that found in Preparation 60z. Table 9xPreparation 60ac 3-(2-(Difluoromethyl)-4-fluorobenzyl)-1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-oneTo a solution of 5-(3-(2-(difluoromethyl)-4-fluorobenzyl)-2-oxopyrrolidin-1-yl)- 3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde (250 mg, 75.68% wt., 347 µmol) in MeOH (3 mL) was added NaBH4(26.2 mg, 693 µmol) at 0 °C, and then stirred at 0 °C for 0.5 hr. The reaction mixture was quenched with water (30 mL) at 0 °C and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography DCM in MeOH (10:1) to give the title compound (500 mg, 76.3%) as a brown oil. ES / MS (m / z): 548 (M+H). The compound in Table 9y was prepared in a manner essentially analogous to that found in Preparation 60ac. Table 9yPreparation 60af 1-(3-(5-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)piperidin-2-oneTo a solution of 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)-3-(3,4,5-trifluorobenzyl)piperidin-2-one (1.4 g, 2.71 mmol) in DMF (15 mL) was added 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5-(trimethylstannyl)pyridazine (1.0 g, 2.71 mmol), Pd(PPh3)4(313 mg, 0.27 mmol) and CuI (51 mg, 0.27 mmol) under nitrogen.After stirring at 100 °C for 12 hrs., the reaction mixture was cooled to ambient temperature, quenched with saturated aqueos KF solution (30 ml) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (75-85%) to give the title compound (750 mg, 44%) as a brown oil. ES / MS (m / z): 632 (M+H). The compound in Table 9z was prepared in a manner essentially analogous to that found in Preparation 60af.Table 9zPreparation 61 2-(4-Chlorobenzyl)-4-(5-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-3-yl)morpholin-3-oneTo a solution of 2-(4-chlorobenzyl)morpholin-3-one (100 mg, 0.44 mmol) in 1,4- dioxane (2 mL) was added 4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 5-yl)-5-methylpyridazine (245 mg, 0.67 mmol), K3PO4(94 mg, 0.44 mmol), N1, N2- dimethylcyclohexane-1,2-diamine (63 mg, 0.44 mmol) and CuI (84 mg，0.44 mmol), and then stirred for 5 hrs., at 90 °C under nitrogen. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep-HPLC (C18, ACN in 13 mmol TFA = 65-95% in 17 min, rt = 8.9 min) to give the title compound (35 mg, 15%) as a white solid. ES / MS (m / z): 514 (M+H). The compounds in Table 9aa were prepared in a manner essentially analogous to that found in Preparation 61. Table 9aaPreparation 61m 1-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-oneTo a mixture of 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (1.00 g, 1.99 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (757 mg, 2.98 mmol) in 1, 4-dioxane (15 mL) was added KOAc (389 mg, 3.98 mmol) and Pd(dppf)Cl2(146 mg, 0.2 mmol) in portions under nitrogen. After stirring at 100 ℃ for 2 hrs., under nitrogen, the reaction mixture was cooled to ambient temperature, added to water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with DCM in MeOH (20: 1) to give the title compound (400 mg, 43%) as an orange oil. ES / MS (m / z): 470 (M+H-82). The compound in Table 9ab was prepared in a manner essentially analogous to that found in Preparation 61m. Table 9abPreparation 61o 1-(3-(5-Aminopyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3- (3,4,5-trifluorobenzyl)pyrrolidin-2-oneTo a solution of 5-bromopyridazin-4-amine (258 mg, 1.49 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) was added K2CO3(618 mg, 4.47 mmol), Pd(dppf)Cl2(109 mg, 0.15 mmol) and 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2- one (700 mg, 1.49 mmol) in portions under nitrogen atmosphere. After stirring at 100 °Cfor 2 hrs., the reaction mixture was cooled to ambient temperature, added to water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM in MeOH (20:1) to give the title compound (280 mg, 36%) as a white solid. Es / MS (m / z): 519 (M+H). The compound in Table 9ac was prepared in a manner essentially analogous to that found in Preparation 61o. Table 9acPreparation 61q 1-(4-Bromo-3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3- (4-chloro-3,5-difluorobenzyl)pyrrolidin-2-oneTo a solution of 3-(4-chloro-3,5-difluorobenzyl)-1-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-one (1.22 g, 2.35 mmol) inDCM (20 mL) was added NBS (418 mg, 2.35 mmol). After stirring at 25 °C for 3 hrs., the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (50-60%) to give the title compound (1.3 g, 92%) as a brown oil. ES / MS (m / z): 598 (M+H).The compounds in Table 9ad were prepared in a manner essentially analogous to that found in Preparation 61q.Table 9adPreparation 61t (E)-3-(4-Chloro-3,5-difluorobenzyl)-1-(4-(2-ethoxyvinyl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-oneTo a solution of 1-(4-bromo-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(4-chloro-3,5- difluorobenzyl)pyrrolidin-2-one (1.30 g, 2.17 mmol) in 1,4-dioxane (20 mL) was added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (860 mg, 4.34 mmol), potassium carbonate (900 mg, 6.51 mmol), PdCl2(dppf) (159 mg, 0.2 mmol) and water (5 mL). After stirring at 100 °C for 12 hrs., under nitrogen, the reaction mixture was cooled to ambient temperature, added to water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (30-40%) to give the title compound (600 mg, 45%) as a brown oil. ES / MS (m / z): 590 (M+H). The compounds in Table 9ae were prepared in a manner essentially analogous to that found in Preparation 61t.Table 9aePreparation 61x 2-(5-(3-(4-Chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetaldehydeTo a solution of (E)-3-(4-chloro-3,5-difluorobenzyl)-1-(4-(2-ethoxyvinyl)-3- (pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-one (600 mg, 986 µmol) in THF (30 mL) was added 1N HCl (30 mL, 30 mmol). After stirring at 60 °C for 5 hrs., the reaction mixture was cooled to ambient temperature, added to water (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (600 mg, 50%) as a brown oil, which was used in the next step without further purification. ES / MS (m / z): 562 (M+H). The compound in Table 9af was prepared in a manner essentially analogous to that found in Preparation 61x. Table 9afPreparation 61z 2-(5-(3-(4-Chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetaldehyde oximeTo a solution of 2-(5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-3- (pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetaldehyde (600 mg, 0.49 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (51.2 mg, 0.74 mmol), Na2CO3(104 mg, 0.98 mmol) and water (2 mL). After stirring at 25 °C for 1 hr. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (420 mg, 98%) as a brown oil, which was used in the next step without further purification. ES / MS (m / z): 577 (M+H). The compound in Table 9ag was prepared in a manner essentially analogous to that found in Preparation 61z.Table 9agPreparation 61ab 2-(5-(3-(4-Chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetonitrileTo a solution of 2-(5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-3- (pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetaldehyde oxime (420 mg, 0.48 mmol) in ACN (12 mL) was added TEA (122 mg, 1.20 mmol) and oxalyl dichloride (73.2 mg, 0.58 mmol) at 0 °C. After stirring at 0 °C for 15 min and stirring at 25 °C for another 3 hrs., the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (300 mg, 82%) as a brown oil, which was used in the next step without further purification. ES / MS (m / z): 559 (M+H).Preparation 61ac 1-(4-(2-Ethoxyethyl)-3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol- 5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-oneTo a solution of (E)-1-(4-(2-ethoxyvinyl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2- one (50 mg, 0.09 mmol) in MeOH (20 mL) was added 10% Pd / C (10 mg) under nitrogen. After stirring at 25 °C for 2 hrs., under H2atmosphere, the reaction mixture was filtered and concentrated in vacuo to give the title (420 mg, 98%) as a brown oil, which was used in the next step without further purification. ES / MS (m / z): 577 (M+H). Preparation 61ad 2-(5-(2-Oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridin-4-yl)-1H-pyrazol-4- yl)acetaldehydeTo a solution of (E)-1-(4-(2-ethoxyvinyl)-5-(pyridin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2- one (945 mg, 1.65 mmol) in DCM (10 mL) was added TFA (8 mL, 110 mmol) dropwise. After stirring at 25 °C for 12 hrs., the mixture was concentrated in vacuo. The residue was added to water (30 mL), adjusted to pH 7 with saturated aqueous NaHCO3solution, and then extracted with DCM (50 mL x 3). The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (206 mg, 30%) as a white solid. ES / MS (m / z): 415 (M+H). Preparation 61ae 3-((6-Fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-oneTo a solution of 3-((6-fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)- 1H-1,2,4-triazol-5-yl)piperidin-2-one (500 mg, 1.36 mmol) in DMF (20 mL) was added t- BuOK (168 mg, 1.5 mmol) at ambient temperature. After stirring at ambient temperature for 15 min, SEM-Cl (250 mg, 1.5 mmol) was added, and then stirred at ambient temperature overnight. The reaction mixture was quenched with water (60 mL) and extracted with DCM (25 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 1% TEA in EtOAc to give the title compound (450 mg, 66%) as a brown oil. ES / MS (m / z): 498 (M+H) The compound in Table 9ai was prepared in a manner essentially analogous to that found in Preparation 61ae.Table 9aiPreparation 61ag 3-((6-Fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (Isomer 1) 3-((6-Fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (Isomer 2)The racemic 3-((6-fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (450 mg) was separated via SFC (Column: IG 20*250 mm, 10 um (Daicel), Mobile phase: CO2 / MeOH [0.2% NH3(7 mol / L in MeOH)] = 45 / 55) to give isomer 1 (140 mg, ee = 100%) and isomer 2 (95 mg, ee = 100%) as light brown oils. The compounds in Table 9aj were prepared in a manner essentially analogous to that found in Preparation 61ag.Table 9ajPreparation 62 (S)-5-((tert-Butyldimethylsilyl)oxy)-2-(4-chloro-3-fluorobenzyl)pentanoic acidTo a solution of (R)-4-benzyl-3-((S)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro- 3-fluorobenzyl)pentanoyl)oxazolidin-2-one (2.5 g, 4.69 mmol) in THF (10 mL) was added H2O2(957 mg, 28.14 mmol) at 0 ºC. After stirring for 10 min, the reaction mixture was added the solution of LiOH.H2O (844 mg, 14.07 mmol) in H2O (5 mL), and then stirred for 20 min. The reaction mixture was poured into NH4Cl solution (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with saturated aqueous NaCl, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (1.4 g, 80 %) as yellow oil. ES / MS (m / z): 375 (M+H). Preparation 62aa (S)-5-((tert-Butyldimethylsilyl)oxy)-2-(4-chloro-3-fluorobenzyl)-N-(1-(5- methylpyridazin-4-yl)-1H-pyrazol-4-yl)pentanamideTo a solution of (S)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3- fluorobenzyl)pentanoic acid (1.2 g, 3.2 mmol) in DMAc (4 mL) was added 1-(5- methylpyridazin-4-yl)-1H-pyrazol-4-amine (0.56 g, 3.2 mmol), DIPEA (1.24 g, 9.63 mmol) and the solution of T3P in EtOAc (3 g, 50 % wt., 4.7 mmol). After stirring at room temperature for 2 hrs., the reaction mixture was added water (50 mL) and extracted with EtOAc (50 x 3 mL). The combined organic phase was washed with saturated aqueousNaCl, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (7 %) to give the title compound (1.1 g, 62 %) as yellow oil. ES / MS (m / z): 532 and 534 (M+H). Preparation 62ab (S)-2-(4-Chloro-3-fluorobenzyl)-5-hydroxy-N-(1-(5-methylpyridazin-4-yl)-1H-pyrazol-4- yl)pentanamideTo a solution of (S)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3-fluorobenzyl)- N-(1-(5-methylpyridazin-4-yl)-1H-pyrazol-4-yl)pentanamide (1.1 g, 2.07 mmol) in dry THF (20 mL) was added dropwise Et3N.3HF (1.7 g, 10.6 mmol) at 0 ºC. After stirring at room temperature for 1 hr., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (0 – 50 %) to give the title compound (0.55 g, 64 %) as yellow oil. ES / MS (m / z): 418 and 420 (M+H). Preparation 62a 3-((6-Chloropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-oneTo a solution of 1-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (500 mg, 1.3 mmol)in dry THF (10 mL) was added 1M LiHMDS (1.7 mL, 1.7 mmol) at -78 °C, and then stirred for 30 min. To the reaction mixture was added a solution of 5-(bromomethyl)-2- chloropyridine (268 mg, 1.3 mmol) in dry THF (5 mL), and then stirred at -78 °C for 1.5 hrs. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase chromatography eluting with ACN in 10 mM NH4HCO3(2-50%) to give the title compound (110 mg, 16%) as a white solid. ES / MS (m / z): 514 (M+H). The compound in Table 9ak were prepared in a manner essentially analogous to that found in Preparation 62a. Table 9akPreparation 62d (S)-3-((6-Chloropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (isomer 2)The racemic of 3-((6-chloropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (530 mg, 1.0 mmol) was run SFC (AD 20*250mm, 10 um, CO2 / MeOH [0.2% NH3(7 M in MeOH) ] = 40 / 60) to give isomer 1 and isomer 2 (240 mg, 45%) as a white solid. The expected isomer was isomer 2 by compare with the authentic sample. Preparation 62e (S)-Di-tert-butyl ((5-(3-((6-chloropyridin-3-yl)methyl)-2-oxopiperidin-1-yl)-3-(5- methylpyridazin-4-yl)-1H-pyrazol-1-yl)methyl) phosphate (isomer 1) and (S)-di-tert- butyl ((3-(3-((6-chloropyridin-3-yl)methyl)-2-oxopiperidin-1-yl)-5-(5-methylpyridazin-4- yl)-1H-pyrazol-1-yl)methyl) phosphate (isomer 2)To a solution of (S)-3-((6-chloropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4- yl)-1H-pyrazol-5-yl)piperidin-2-one (800 mg, 2.1 mmol, ee = 100%) in dry DMF (80 ml) was added Cs2CO3(1.7 g, 5.3 mmol) and di-tert-butyl (chloromethyl) phosphate (1.4 g, 5.3 mmol). After stirring at ambient temperature for 48 hrs., the reaction mixture wasquenched with water (100 mL) and extracted with EtOAc (200 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed- phase column chromatography eluting with ACN in NH4HCO3solution (0-60%) to give the title compounds, isomer 1 (400 mg, 31%) as a white solid and isomer 2 (280 mg, 22%) as a white solid. ES / MS (m / z): 605 (M+H). Preparation 62f Di-tert-butyl ((5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-3- (pyridazin-4-yl)-1H-pyrazol-1-yl)methyl) phosphate (isomer 1) and Di-tert-butyl ((3-(3- (4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-5-(pyridazin-4-yl)-1H- pyrazol-1-yl)methyl) phosphate (isomer 2)To a solution of (isomer 1) 3-(4-chloro-3,5-difluorobenzyl)-1-(4-fluoro-5- (pyridazin-4-yl)-1H-pyrazol-3-yl)pyrrolidin-2-one (0.21 g, 0.5 mmol) in DMF (7 mL) was added Cs2CO3( 0.84 g, 2.6 mmol), NaI ( 0.08 g, 0.5 mmol) and di-tert-butyl (chloromethyl) phosphate (0.53 g, 2 mmol). After stirring at 35 °C for a week, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a mixture of the title compounds (0.46 g, 99+%) as a yellow oil. ES / MS (m / z): 630 (M+H).Preparation 62f N-(4-(Hydroxymethyl)-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3- (3,4,5-trifluorophenyl)propanamideTo a solution of 3-(3,4,5-trifluorophenyl)propanoic acid (374 mg, 1.83 mmol) in DMAc (8 mL) was added DIPEA (789 mg, 1.06 mL, 6.10 mmol) and the solution of T3P in EtOAc (971 mg, 50 % wt., 1.53 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was added (5-amino-1-(4-methoxybenzyl)-3- (pyridazin-4-yl)-1H-pyrazol-4-yl)methanol (475 mg, 1.53 mmol) at 0 °C, and then stirred at 20 °C for 3 hrs. The reaction mixture was added ice water (30 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with DCM in MeOH (93: 7) to give the title compound (340 mg, 44.8%) as yellow oil. ES / MS (m / z): 498 (M+H). Preparation 62h tert-Butyl 4-(2-hydroxyethyl)-3-(pyridazin-4-yl)-5-(3-(3,4,5-trifluorophenyl) propanamido)-1H-pyrazole-1-carboxylateTo a solution of N-(4-(2-hydroxyethyl)-5-(pyridazin-4-yl)-1H-pyrazol-3-yl)-3- (3,4,5-trifluorophenyl)propanamide (1.5 g, 3.83 mmol) in DMF (10 mL) was added TEA (1.1 mL, 7.67 mmol), DMAP (46.8 mg, 0.38 mmol) and (Boc)2O (0.9 mL, 3.83 mmol) at0 °C. After stirring at 20 °C for 1 hr., the reaction mixture was used in next step directly without further purification. ES / MS (m / z): 492 (M+H). Preparation 62i tert-Butyl 4-(2-(((di-tert-butoxyphosphoryl)oxy)methoxy)ethyl)-3-(pyridazin-4-yl)-5-(3- (3,4,5-trifluorophenyl)propanamido)-1H-pyrazole-1-carboxylateTo a mixture of tert-butyl 4-(2-hydroxyethyl)-3-(pyridazin-4-yl)-5-(3-(3,4,5- trifluorophenyl) propanamido)-1H-pyrazole-1-carboxylate in DMF (6 mL) was added Cs2CO3(2.5 g, 7.67 mmol) and di-tert-butyl (chloromethyl) phosphate (1.49 g, 5.75 mmol) at 0 ℃. After stirring at ambient temperature for 16 hrs., under nitrogen, the mixture was added to water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed- phase chromatography eluting with ACN in water (12.5mM NH4HCO3) (60-65%) to give the title compound (500 mg, 16.7%) as a yellow solid. ES / MS (m / z): 714 (M+H). Preparation 62j (2-(5-(Pyridazin-4-yl)-3-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4- yl)ethoxy)methyl dihydrogen phosphateTo a suspension of tert-butyl 4-(2-(((di-tert-butoxyphosphoryl)oxy) methoxy)ethyl)-3-(pyridazin-4-yl)-5-(3-(3,4,5-trifluorophenyl)propanamido)-1H- pyrazole-1-carboxylate (500 mg, 0.7 mmol) in H2O (2 mL) was added acetic acid (2.0 mL, 34.80 mmol). After stirring at 60 °C for 8 hrs., the reaction mixture was filtered at 60 °C. The filter cake was washed with H2O (2 mL) and dried in vacuo to give the title compound (71.7 mg, 20.4%) as a white solid. ES / MS (m / z): 502 (M+H). Preparation 62k tert-Butyl 2-(((3-(pyridazin-4-yl)-5-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol- 4-yl)oxy)methyl)morpholine-4-carboxylateTo a solution of tert-butyl 2-(((5-amino-3-(pyridazin-4-yl)-1H-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylate (0.5g, 1.3 mmol) in DMA (10 mL) was added 3-(3,4,5-trifluorophenyl)propanoic acid (0.35 g, 1.7mmol), a solution of T3P in EtOAc (1.7 g, 5.3 mmol) and DIPEA (0.51g, 4 mmol). After stirring at 100 °C for 12 hrs., the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (10%) to give the title compound (0.7 g, 93%) as a yellow oil. ES / MS (m / z): 563 (M+H). The compounds in Table 9am were prepared in a manner essentially analogous to that found in Preparation 62k.Table 9amPreparation 62s N-(4-(Morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5- trifluorophenyl)propenamideTo a solution of tert-butyl 2-(((3-(pyridazin-4-yl)-5-(3-(3,4,5- trifluorophenyl)propanamido)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate(0.7 g, 1.2 mmol) in DCM (5 mL) was added 4M HCl in 1,4-dioxane (5 mL, 20 mmol). After stirring at ambient temperature for 1 hr., the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (0.17, 30%) as a brown solid. ES / MS (m / z): 463 (M+H). Preparation 62t tert-Butyl 2-(((1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-5-(3-(3,4,5- trifluorophenyl)propanamido)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylateTo a solution of tert-butyl 2-(((5-amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)- 1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate (1.50 g, 3.02 mmol) in DMA (20 mL) was added 3-(3,4,5-trifluorophenyl)propanoic acid (802 mg, 3.93 mmol), N-ethyl-N- isopropylpropan-2-amine (1.95 g, 15.1 mmol) and the solution of T3P in EtOAc (3.84 g, 50% wt., 6.04 mmol). After stirring at 100 °C for 12 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (5%) to give the title compound (2.20 g, 93%) as a brown solid. ES / MS (m / z): 683 (M+H). The compounds in Table 9an were prepared in a manner essentially analogous to that found in Preparation 62t.Table 9anPreparation 62w N-(1-(4-Methoxybenzyl)-4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-3-(3,4,5-trifluorophenyl)propanamideTo a solution of tert-butyl 2-(((1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-5-(3- (3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4- carboxylate (2.10 g, 3.08 mmol) in DCM (15 mL) was added 4M HCl in 1,4-dioxane (5 mL, 20 mmol). After stirring at 25 °C for 5 hrs., the mixture was quenched 7M NH3in MeOH (10 mL, 70 mmol) and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (12%) to give the title compound (1.20 g, 48%) as a yellow solid. ES / MS m / z: 583 (M+H).Preparation 62x N-(1-(4-Methoxybenzyl)-4-((4-(methyl-d3)morpholin-2-yl)methoxy)-3-(pyridazin-4-yl)- 1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propanamideTo a solution of N-(1-(4-methoxybenzyl)-4-(morpholin-2-ylmethoxy)-3- (pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propanamide (500 mg, 0.86 mmol) in ACN (20 mL) was added K2CO3(356 mg, 2.57 mmol) and iodomethane-d3(149 mg, 1.03 mmol). After stirring at 25 °C for 12 hrs., the mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH in DCM (7%) to give the title compound (250 mg, 47%) as a yellow solid. ES / MS (ES): m / z = 600 (M+H). Preparation 63p 3-(2-(Difluoromethyl)-4-fluorobenzyl)-1-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (isomer 1) and 3-(2- (difluoromethyl)-4-fluorobenzyl)-1-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (isomer 2)The racemic 3-(2-(difluoromethyl)-4-fluorobenzyl)-1-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one was run by SFC(Column: IH 25*250mm, 10um (Daicel) Mobile phase: CO2 / MeOH[0.5%NH3(7M in MeOH) =90 / 10) to give isomer 1 and isomer 2 as light brown oil. ES / MS (m / z): 533 (M+H).Example 1 3-(6-Fluoropyridin-3-yl)-N-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)propanamideA mixture of 3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-amine (400 mg, 2.3 mmol), 3-(6-fluoropyridin-3-yl)propanoic acid (386 mg , 2.3 mmol), DIPEA (0.8 mL , 4.3 mmol) and T3P (1 g, 3.4 mmol) in DMA (5 mL) was stirred at ambient temperature for 2 hrs. The mixture was added to water (50 mL) which was extracted with EtOAc (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by Prep-HPLC (water / ACN=3 / 2) to give the title compound (227 mg, 30%) as a white solid. ES / MS m / z 327 (M+H).The compounds in Table 10 were prepared essentially the same as procedure for Example 1 using the appropriate starting materials and reagents.Table 10Example 8 3-(6-Chloropyridin-3-yl)-N-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)propenamideA mixture of 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine (300 mg, 1.7 mmol), 3-(6-chloropyridin-3-yl)propanoic acid (632 mg, 3.4 mmol), T3P (1.6 g, 5.1 mmol), and DIPEA (877 mg, 6.8 mmol) in DMA (6 mL) was stirred at 110 °C for 4 hrs. The mixture was added to water (30 mL) and EtOAc (30 mL). The resulting precipitate was filtered, and the filtrate dried over anhydrous sodium sulfate, concentrated in vacuo, slurried in MeOH, and filtered to give the title compound (364 mg, 63%) as a white solid. ES / MS m / z 344 (M+H). The compounds in Table 11 were prepared essentially the same as procedure for Example 8 using the appropriate starting materials and reagents.Table 11Example 14 3-(6-Chloro-5-fluoropyridin-3-yl)-N-(4-methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5- yl)propanamideA mixture of 3-(6-chloro-5-fluoropyridin-3-yl)-N-(1-(4-methoxybenzyl)-4- methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)propanamide (360 mg, 0.7 mmol) and TFA (3 mL) in DCM (3 mL) was stirred at ambient temperature for 4 hrs. Thereaction mixture was concentrated in vacuo to give a crude residue (600 mg). Water (3 mL) and saturated NaHCO3(20 mL) were added, and the mixture was extracted with EtOAc (80 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue (450 mg) was purified by prep-HPLC (C18, ACN in 10 mM NH4HCO3= 32-62% in 9 min, rt = 8.5 min) to give the title compound (208 mg, 76%) as a white solid. ES / MS m / z 375 (M+H). Example 15 N-(4-Cyano-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-3-(6-fluoropyridin-3- yl)propenamideA mixture of 5-(3-(6-fluoropyridin-3-yl)propanamido)-3-(5-methylpyridazin-4- yl)-1H-pyrazole-4-carboxamide (70 mg, 0.19 mmol) and methyl N- triethylammoniumsulfonyl(carbamate) (227 mg, 0.95 mmol) in DMF (2 mL) was stirred at ambient temperature for 2 hrs. The mixture was purified by Prep-HPLC (C18, ACN in 10 mM NH4HCO3= 20-50% in 9 min, rt = 7.4 min) to give the title compound (26 mg, 39.4%) as a white solid. ES / MS m / z 352 (M+H). Example 16 3-(4-Chloro-3-fluorophenyl)-N-(1-(3-methylpyridazin-4-yl)-1H-pyrazol-4- yl)propenamideTo a mixture of 1-(3-methylpyridazin-4-yl)pyrazol-4-amine (50 mg, 0.28 mmol), 3-(4-chloro-3-fluorophenyl)propanoic acid (87 mg, 0.43 mmol) in DMA (3 mL) was added HATU (326 mg, 0.86mmol) and DIPEA (180 mg, 1.43 mmol), which was thenstirred at 70 °C for 12 hrs. The mixture was purified by prep-HPLC (C18, ACN in 10 mmol NH4HCO3= 20-50% in 9 min) to give the product (21.8 mg, 21%) as a white solid. ES / MS m / z 360 (M+H). Example 17 3-(4-Fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-oneTo a mixture of 3-(4-fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (30 mg, 0.06 mmol) in DCM (2 mL) was added TFA (2 mL), and the mixture was stirred at ambient temperature for 3 hrs. The reaction mixture was concentrated in vacuo. Water (3 mL) and saturated NaHCO3(10 mL) were added to the residue which was extracted with EtOAc (30 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by Prep-HPLC (C18, ACN in 10 mM NH4HCO3= 20-50% in 9 min, rt = 7.4 min) to give the title compound (11 mg, 50%) as a white solid. ES / MS m / z 367 (M+H). The compounds in Table 12 was prepared essentially the same as described for Example 17 using the appropriate starting materials and reagents. Table 12Example 19 3-((6-Fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-oneTo a solution of 1-(5-amino-3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-1-yl)-5- chloro-2-((6-fluoropyridin-3-yl)methyl)pentan-1-one (150 mg, 0.37 mmol) in DMF (5 mL) was added t-BuOK (83 mg, 0.74 mmol) in several portions at ambient temperature, and then stirred at ambient temperature for 2 hrs. The reaction mixture was quenched by water (60 mL), and pH was adjusted to 6 to 7 with 1N HCl. The solid was collected by filtration, and dried in vacuo to give the crude material. The crude material was slurried in IPA and filtered to give the title compound (73 mg, 53%) as a white solid. ES / MS m / z 368 (M+H).The compound in Table 12a was prepared essentially the same as described for Example 19 using the appropriate starting materials and reagents. Table 12aExample 20 (S)-3-(4-Chloro-3-fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-oneA mixture of (S)-2-(4-chloro-3-fluorobenzyl)-5-((3-(5-methylpyridazin-4-yl)-1H- 1,2,4-triazol-5-yl)amino)pentanoic acid (25 mg, 0.06 mmol), T3P (38 mg, 0.12 mmol), and DIPEA (23 mg, 0.18 mmol) in DMA (2 mL) was stirred at ambient temperature for 3 hrs. The reaction mixture was purified by Prep-HPLC (C18, ACN in 10 mM NH4HCO3= 42-72% in 9 min, rt = 8.9 min) to obtain the title compound (6 mg, 42%) as a white solid. ES / MS m / z 401 (M+H). Example 21 2-(4-Chlorobenzyl)-4-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)morpholin-3-oneTo a mixture of 2-(4-chlorobenzyl)-4-(3-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)morpholin-3-one (70 mg, 0.13 mmol) in DCM (3 mL) was added TFA (1 mL) at 0 °C, which was then stirred at ambient temperature for 3 hrs. The mixture was concentrated in vacuo. To the residue was added saturated aqueous NaHCO3at 0 °C, and the resulting solid was filtered to give the title compound (35 mg, 67%) as a white solid. ES / MS m / z 384 (M+H). The compounds in Table 12b were prepared in a manner essentially analogous to that found in Example 21. Table 12bExample 22 (S)-3-(4-Chloro-3-fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5- yl)piperidin-2-oneA mixture of (R)-4-benzyl-3-((S)-2-(4-chloro-3-fluorobenzyl)-5-((3-(5- methylpyridazin-4-yl)-1H-pyrazol-5-yl)amino)pentanoyl)oxazolidin-2-one (150 mg, 0.26 mmol) and H2O2(53 mg, 1.56 mmol) in THF / H2O (4 / 1, 5 mL) was stirred at ambient temperature for 10 min. LiOH.H2O (33 mg, 0.78 mmol) was added, and then stirred at ambient temperature for 16 hrs. The reaction mixture was quenched with aqueous Na2SO3(20 mL) and extracted with EtOAc (30 mL x 2). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by Prep-HPLC (C18, ACN in 10 mM NH4HCO3= 48-78% in 9 min, rt = 8.9 min) to give the title compound (37.5 mg, 36%) as a white solid. The material was further purified by SFC [(Instrument: SFC-150 (Waters); Column: AS 20*250 mm, 10um (Daicel); Column temperature: 35 °C; Mobile phase: CO2 / MeOH [0.2%NH3 (7M in MeOH) ]= 60 / 40; Flow rate: 100 g / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 10.17 min)] and combined with a former batch (12.5 mg) to give the title isomer P3 (rt = 8.901 min) (24 mg, 48%) as a white solid. ES / MS m / z 400 (M+H). The compounds in Table 13 were prepared in a manner essentially analogous to that found in Example 22.Table 13Example 25 3-(4-Chloro-3-fluorobenzyl)-3-hydroxy-1-(2-(pyridazin-4-yl)-2H-1,2,3-triazol-4- yl)piperidin-2-oneTo a solution of 3-(4-chloro-3-fluorobenzyl)-1-(2-(pyridazin-4-yl)-2H-1,2,3- triazol-4-yl)piperidin-2-one (34 mg, 0.067 mmol, 76 wt%) in THF (2.5 mL) was added drop wise NaHMDS (16 mg, 0.087 mmol) at -78 °C under nitrogen. The reaction mixture was stirred at -78 °C for 1 hr.3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (18 mg, 0.067 mmol) in THF (0.5 mL) was added drop wise into the above mixture at -78 °C. After stirring at -78 °C for 30 minutes, the reaction was quenched by addition of water (50 mL)and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with saturated aqueous NaCl (50 mL x 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in petroleum ether = 0-20%) to give the title compound as a white solid (8.7 mg, 32%). ES / MS (m / z): 403 (M+H). The compound in Table 13a was prepared in a manner essentially analogous to that found in Preparation 63n. Table 13aExample 26 3-(4-Fluoro-2-(fluoromethyl)benzyl)-1-(3-(pyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-oneTo a solution of 3-(2-(difluoromethyl)-4-fluorobenzyl)-1-(3-(pyridazin-4-yl)-1- ((2-(trimethylsilyl) ethoxy) methyl)-1H-1,2,4-triazol-5-yl) piperidin-2-one (14 mg, 27 µmol) in DCM (1 mL) was added TFA (31 mg, 0.27 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hrs. The solvent was removed invacuo. The residue was dissolved in THF (2 mL) and purified by prep-HPLC (Column: Welch Xtimate 21.2*250mm C18, 10 um, Mobile Phase: A: water (0.2% Formic acid) B: ACN; gradient B%: 30%-70% in 15.0 min.). Appropriate fractions were combined, evaporated, and lyophilized to give the title compound as a white solid (2.14 mg, 20%) ES / MS (m / z): 385 (M+H).The compounds in Table 14 were prepared in a manner essentially analogous to that found in Example 26.Table 14Example 62 3-(4-Chloro-2-hydroxybenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-oneTo a solution of 3-(4-chloro-2-methoxybenzyl)-1-(3-(5-methylpyridazin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (100 mg, 184 µmol) in DCM (3 mL) was added boron tribromide (385 µL, 552 µmol) at 0 °C. After stirring at 25 °C for 3 hrs., the reaction was quenched by addition of saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with MeOH in DCM (0-10%) to give the title compound as a white solid (6.1 mg, 7.9%) ES / MS (m / z): 399 (M+H). The compounds in Table 15 were prepared in a manner essentially analogous to that found in Example 62.Table 15Example 68 1-(5-Chloro-1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2- oneTo a mixture of 4-(4-bromo-5-chloro-1H-pyrazol-1-yl)pyridazine (120 mg, 430 µmol) and 3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (98.6 mg, 430 µmol) in DMF (10 mL) was added potassium phosphate tribasic (274 mg, 1.29 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (122 mg, 860 µmol) and CuI (81.9 mg, 430 µmol) at ambient temperature under nitrogen. The reaction was stirred at 60 °C for 3 hrs. After cooling to ambient temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc in petroleum ether (0-30%) to give the title compound as a white solid (120 mg, 63.6%) ES / MS (m / z): 408 (M+H). The compounds in Table 16 were prepared in a manner essentially analogous to that found in Example 68. Table 16Example 72 3-((6-Fluoropyridin-3-yl)methyl)-1-(2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-yl)piperidin-2-To a solution of 5-chloro-2-((6-fluoropyridin-3-yl)methyl)-N-(2-(pyridazin-4-yl)- 2H-1,2,3-triazol-4-yl)pentanamide (140 mg, 359 µmol) in ACN (10 mL) was added potassium carbonate (149 mg, 1.08 mmol) at ambient temperature. The reaction mixture was stirred at 70 °C for 4 hrs. After cooling to ambient temperature, the reaction mixture was filtered and concentrated in vacuo. The crude material was purified by prep-HPLC (Column: Welch Xtimate 21.2*250mm C18, 10 um, Mobile Phase: A: water (10 mmol / L ammonium bicarbonate and 0.05% ammonium hydroxide) B: ACN; B%: 30%-70% in 15.0 min.) to give pure product solution which was lyophilized to give the title compound as a white solid (119 mg, 93%). ES / MS (m / z): 354 (M+H). The compounds in Table 17 were prepared in a manner essentially analogous to that found in Example 72. Table 17Example 75 5-Hydroxy-1-(3-(pyridazin-4-yl)-1H-1,2,4-triazol-5-yl)-3-(3,4,5- trifluorobenzyl)piperidin-2-oneTo a solution of 5-hydroxy-1-(1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-1,2,4- triazol-5-yl)-3-(3,4,5-trifluorobenzyl)piperidin-2-one (160 mg, 275 µmol) in TFA (2.00 mL, 26.2 mmol) was added trifluoromethanesulfonic acid (2.00 mL, 22.6 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated in vacuo, the residue was purified by prep-HPLC (Column: Welch Xtimate 21.2*250mm C18, 10 um, Mobile Phase: A: water (10 mmol / L ammonium bicarbonate and 0.05% ammonium hydroxide) B: acetonitrile; B%: 30%-70% in 15.0 min.). Appropriate fractions were combined, concentrated in vacuo, and lyophilized to give the title compound as a white solid (3.7 mg, 3.3%). ES / MS (m / z): 405 (M+H). Example 76 3-(3,4-Difluorobenzyl)-1-(4-(pyridazin-4-yl)-1H-imidazol-2-yl)piperidin-2-oneTo a mixture of 3-(3,4-difluorobenzyl)-1-(4-iodo-1H-imidazol-2-yl)piperidin-2- one (80 mg, 0.17 mmol) and 4-(tributylstannyl)pyridazine (81 mg, 0.21 mmol) in dry DMF (5 mL) was added XPhos (17 mg, 35 µmol) and Pd2(dba)3(16 mg, 17 µmol) at ambient temperature. The mixture was stirred for 1 hr., at 80 °C under nitrogen. After cooling to ambient temperature, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting withMeOH in DCM (0-5%) to give the title compound as a yellow solid (4.3 mg, 6.6%) ES / MS (m / z): 370 (M+H). The compounds in Table 18 were prepared in a manner essentially analogous to that found in Example 76. Table 18Example 79 5-(2-Oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1H-pyrrole-2- carbonitrileTo a solution of 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4- yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbonitrile (20 mg, 36 µmol) in DCM (3 mL) was added dropwise TFA (1 mL, 0.01 mol) at 20 °C. After stirring at 20 °C for 2 hrs., the reaction mixture was concentrated in vacuo to get the crude material. The crude material was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude was purified by prep-HPLC (Column: Welch Xtimate 21.2*250mm C18, 10 um, Mobile Phase: A: water (0.2% Formic acid) B: ACN; B%: 30%-70% in 15.0 min.). The appropriate fractions were combined and concentrated in vacuo to give the title compound as a grey solid (2.8 mg, 19%) ES / MS (m / z): 398 (M+H).The compounds in Table 19 were prepared in a manner essentially analogous to that found in Example 79.Table 19Example 87 (5-(3-(3,4-Difluorobenzyl)-2-oxopiperidin-1-yl)-3-(pyridazin-4-yl)-1H-1,2,4-triazol-1- yl)methyl dihydrogen phosphate (Isomer 1)To a solution of isomer 1 di-tert-butyl ((5-(3-(3,4-difluorobenzyl)-2-oxopiperidin- 1-yl)-3-(pyridazin-4-yl)-1H-1,2,4-triazol-1-yl)methyl) phosphate (isomer 1) (1.0 g, 2 mmol) in acetic acid (5 mL) was stirred at 40 °C for 16 hrs. The solvent was removed dried by nitrogen. The residue was triturated with ACN (10 mL) and water (1 mL), filtered, and dried in vacuo to give the title compound as a yellow solid (520 mg, 60%) ES / MS (m / z): 481 (M+H). The compounds in Table 20 were prepared in a manner essentially analogous to that found in Example 87.Table 20Example 92 (5-(3-(4-Chloro-3-fluorobenzyl)-2-oxopiperidin-1-yl)-3-(5-methylpyridazin-4-yl)-1H- 1,2,4-triazol-1-yl)methyl dihydrogen phosphate (isomer 2), ammonia saltTo a solution of di-tert-butyl ((5-(3-(4-chloro-3-fluorobenzyl)-2-oxopiperidin-1- yl) -3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-1-yl)methyl) phosphate (isomer 2) (300 mg, 0.482 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at ambient temperature for 2 hrs. The solvent was removed by evaporation and the residue was purified by prep-HPLC (0.1% NH4HCO3, 50% ACN increase to 80% within 8 min, stop at 16 min, flow rata: 30 mL / min, Rt: 8 min). The appropriate fractions were combined, evaporated, and lyophilized to give the title compound as a white solid (240 mg, 94%): ES / MS (m / z): 511 (M+H-NH3). The compound in Table 21 was prepared in a manner essentially analogous to that found in Example 92. Table 21Example 943-(2-(Difluoromethyl)-3,4-difluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4- triazol-5-yl)piperidin-2-one (isomer 1) and 3-(2-(difluoromethyl)-3,4-difluorobenzyl)-1- (3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (isomer 2)Racemic 3-(2-(difluoromethyl)-3,4-difluorobenzyl)-1-(3-(5-methylpyridazin-4- yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (100 mg) was purified by, Daicel ChiralPak IG (250*25 mm, 10um), mobile phase A: CO2, B: ( MEOH:ACN = 1:1), eluting 55% of B, flow rate: 100 mL / min. The eluent of the first peak was collected and lyophilized to give isomer 1 (16.9 mg, 16.9%, ee: 100.0%). ES / MS (m / z): 435 (M+H). The eluent of the second peak was collected and lyophilized to give isomer 2 (20.6 mg, 20.6%, ee: 100.0%). ES / MS (m / z): 435 (M+H). The compounds in Table 22 were prepared in a manner essentially analogous to that found in Example 94. Table 22Example 154 1-(4-(Hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl) pyrrolidin-2-oneTo a solution of 1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2- one (1.70 g, 3.19 mmol) in DCM (32 mL) was added TFA (8 mL, 0.1 mol) at ambient temperature. After stirring at ambient temperature for 16 hrs., the reaction mixture was concentrated in vacuo. The residue was basified by adding saturated aqueous NaHCO3solution to pH 8 at 0 °C. The aqueous solution was decanted. The remaining residue was purified by silica gel flash chromatography eluting with MeOH in DCM (0-10%) to give the title compound (1.1 g, 86%). ES / MS (m / z): 404 (M+H). The compounds in Table 23 were prepared in a manner essentially analogous to that found in Example 154. Table 23Example 159 2-Fluoro-4-((1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-oxopyrrolidin- 3-yl)methyl)benzonitrileTo a solution of 2-fluoro-4-((1-(4-(hydroxymethyl)-5-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-2-oxopyrrolidin-3- yl)methyl)benzonitrile (200 mg, 0.38 mmol) in DCM (2 mL) was added TFA (5 ml) dropwise, and then stirred at ambient temperature for 5 hrs. The reaction mixture was concentrated in vacuo. The residue was added to water (20 mL), adjusted to pH 7 with saturated aqueous NaHCO3solution, and then extracted with DCM (30 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by prep-HPLC (Column: Welch Xtimate 21.2*250 mm C18, 10 um, Mobile Phase: A: water (10 mmol / L ammonium bicarbonate) B: ACN; B%: 30%-70% in 15.0 min.) to give the title compound (101 mg, 66%) as a white solid. ES / MS (m / z): 393 (M+H).The compounds in Table 24 were prepared in a manner essentially analogous to that found in Example 159.Table 24Example 164 3-(2-(Difluoromethyl)-4-fluorobenzyl)-1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H- pyrazol-5-yl)pyrrolidin-2-oneTo a solution of 3-(2-(difluoromethyl)-4-fluorobenzyl)-1-(4-(hydroxymethyl)-3- (pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-one (500 mg, 57.97% wt., 529 µmol) in DCM (4 mL) was added 2,2,2-trifluoroacetic acid (302 mg, 2.65 mmol). The reaction mixture was stirred at 25 °C for 6 hrs., and then concentrated in vacuo to dryness. The crude was purified by prep-HPLC (gradient: 20- 50% ACN in water (10 mmol NH4HCO3) in 8 min, stop at 15 min; retention time: 12-13 min; flow rate: 30 mL / min; column: BOSTON pHlex ODS 10 um 21.2×250 mm 120 A) to give the title compound (130 mg, 58.8%) as a white solid. ES / MS (m / z): 418.3 [M+H]. The compounds in Table 24 were prepared in a manner essentially analogous to that found in Example 164. Table 24Example 167 1-(3-(5-(Hydroxymethyl)pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5- trifluorobenzyl)piperidin-2-oneTo a solution of 1-(3-(5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridazin -4-yl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)piperidin- 2-one (750 mg, 1.19 mmol) in DCM (8 mL) was added TFA (2 mL) at 0 °C, which was then stirred at ambient temperature for 4 hrs. The reaction mixture was concentrated in vacuo to dryness. To the residue was added saturated aqueous NaHCO3(15 mL) at 0 °C. The precipitate was filtered, washed with water (30 ml) and cold MeOH (0.5 mL) to give the title compound (258 mg, 52%) as a white solid. MS (m / z): 418 (M+H). The compounds in Table 25 were prepared in a manner essentially analogous to that found in Example 167. Table 25Example 187 3-(4-Chloro-3,5-difluorobenzyl)-4-(hydroxymethyl)-1-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)pyrrolidin-2-oneTo a solution of 3-(4-chloro-3,5-difluorobenzyl)-4-(methoxymethyl)-1-(3-(5- methylpyridazin-4-yl)-1H-pyrazol-5-yl)pyrrolidin-2-one (120 mg, 0.268 mmol) in dry DCM (5 mL) was added tribromoborane in DCM (0.1 mL, 17% wt., 1.34 µmol) dropwise at -78 °C under nitrogen, and then stirred at 25 °C for 16 hrs. The mixture was quenched with saturated aqueous NaHCO3(5 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Mobile Phase: A: Water (10 mM NH4HCO3); B: ACN; 15%-35% B in 8 min, stop at 15 min) to give the title compound (65 mg, 56%) as a white solid. ES / MS (m / z): 434 (M+H). The compound in Table 25a were prepared in a manner essentially analogous to that found in Example 187. Table 25aExample 188a 1-(3-(5-Aminopyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-oneTo a stirred solution of 1-(3-(5-aminopyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2- one (200 mg, 0.4 mmol) in DCM (2 mL) was added TFA (2 mL). After stirring for 2 hrs., at ambient temperature under nitrogen, the mixture was concentrated in vacuo. The residue was added NaHCO3solution (5 mL) and extracted with DCM (5 mL x 3). The combined DCM was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with MeOH (2 mL) and filtered to give the title compound (100 mg, 60%) as a white solid. ES / MS (m / z): 389 (M+H). The compounds in Table 25b were prepared in a manner essentially analogous to that found in Example 188a. Table 25bExample 189 2-(5-(3-(4-Chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-3-(pyridazin-4-yl)-1H- pyrazol-4-yl)acetonitrileTo a solution of 2-(5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-3- (pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetonitrile (300 mg, 0.39 mmol) in DCM (8 mL) was added TFA (2 mL). After stirring at 25 °C for 2 hrs., the reaction mixture was concentrated in vacuo. The residue was added to water (80 mL), adjusted pH 7-8 with saturated NaHCO3solution, and extracted with EtOAc (80 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by prep-HPLC (Boston pHlex ODS 21.2 x 250 mm, 10 µm, A: water (10 mM NH4HCO3), B: ACN 20-50% B in 10 min, stop at 15 min) to give the title compound (120 mg, 71.4%) as a white solid. ES / MS (m / z): 429 (M+H). The compounds in Table 25c were prepared in a manner essentially analogous to that found in Example 189. Table 25cExample 189c 3-(4-Chloro-3-fluorobenzyl)-1-(1-(5-methylpyridazin-4-yl)-1H-pyrazol-4-yl)piperidin-2- oneTo the mixture of 2-(4-chloro-3-fluorobenzyl)-5-hydroxy-N-(1-(5- methylpyridazin-4-yl)-1H-pyrazol-4-yl)pentanamide (470 mg, 1.13 mmol) and DIPEA (0.6 mL, 0.32 mmol) in ACN (6 mL) was added MsCl (154 mg, 1.35 mmol) at 0 °C under N2.After stirring at ambient temperature for 2 hrs., NaOAc (230 mg, 1.69 mmol) was added at 0 °C, and then heated to 70 °C for 2 hrs. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (110 mg, 24%) as a white solid. ES / MS (m / z): 400 [M+H]. Example 189d 1-(5-(Methoxymethyl)-1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-3-(3,4,5- trifluorobenzyl)pyrrolidin-2-oneTo a solution of 4-(4-bromo-5-(methoxymethyl)-1H-pyrazol-1-yl)pyridazine (27mg, 0.10 mmol) and 3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (23 mg, 0.10 mmol) inDMF (3 mL) was added K3PO4(64 mg, 0.30 mmol), N1, N2-dimethylcyclohexane-1,2- diamine (29 mg, 0.20 mmol), and CuI (29 mg, 0.15 mmol), and then stirred for 5 h at 90 °C under N2atmosphere. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by prep-HPLC (C18, ACN in 13 mmol TFA = 65-95% in 17 min, rt = 8.9 min) to give the title compound (13 mg, 31%) as a white solid. ES / MS (m / z): 418 (M+H). Example 190 3-((6-(Difluoromethyl)pyridin-3-yl)methyl)-1-(4-fluoro-3-(pyridazin-4-yl)-1H- pyrazol-5-yl)pyrrolidin-2-one (isomer 1) and 3-((6-(difluoromethyl)pyridin-3-yl)methyl)- 1-(4-fluoro-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)pyrrolidin-2-one (isomer 2)Racemic 3-((6-(difluoromethyl)pyridin-3-yl)methyl)-1-(4-fluoro-3-(pyridazin-4- yl)-1H-pyrazol-5-yl)pyrrolidin-2-one (100 mg) was purified by SFC, OX (4.6*100 mm, 5um), mobile phase A: CO2, B: (EtOH [1% NH3(7 M in MeOH)] ), eluting 45% of B, flow rate: 100 mL / min. The eluent of the first peak was collected and lyophilized to give isomer 1 (ee: 100.0%). ES / MS (m / z): 389 (M+H). The eluent of the second peak was collected and lyophilized to give isomer 2 (ee: 100.0%). ES / MS (m / z): 389 (M+H). The compounds in Table 26 were prepared in a manner essentially analogous to that found in Example 190. Table 26Example 287 1-(3-(5-(Fluoromethyl)pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5- trifluorobenzyl)pyrrolidin-2-oneTo a solution of 1-(3-(5-(hydroxymethyl)pyridazin-4-yl)-1H-pyrazol-5-yl)-3- (3,4,5-trifluorobenzyl)pyrrolidin-2-one (100 mg, 248 µmol) in DCM (2 mL) was added DAST (160 µL, 1.24 mmol) at 0 °C, and then stirred for 10 min at 0 °C under nitrogen atmosphere. The reaction was quenched with H2O (3 mL) at ambient temperature and extracted with DCM (5 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by Prep-HPLC (gradient: 25%-55% ACN in water (10mM NH4HCO3) in 10 min, stop at 15 min; retention time: 11-14 min; flow rate: 30 mL / min; column: Boston Phlex ODS 21.2 * 250 mm, 10 um) to give the title compound (3.2 mg, 3.2%) as a white solid. ES / MS (m / z): 406 (M+H). Example 291 1-(4-(2-Hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl) pyrrolidin-2-oneTo a solution of 2-(5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridin- 4-yl)-1H-pyrazol-4-yl)acetaldehyde (206 mg, 0.5 mmol) in MeOH (2 mL) was added NaBH4(38 mg, 1 mmol) slowly. After stirring at 25 °C for 1 hr., the reaction mixture was concentrated in vacuo. The residue was added to water (30 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by prep-HPLC (Column: Welch Xtimate 21.2 x 250 mm C18, 10 um, Mobile Phase: A: water (10mmol / L ammonium bicarbonate) B: ACN; B%: 30%-70% in 15.0 min.) to give the title compound (123 mg, 20%) as a white solid. ES / MS (m / z): 417 (M+H). Example 292 3-Hydroxy-1-(5-(methoxymethyl)-1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-3-(3,4,5- trifluorobenzyl)pyrrolidin-2-oneTo a solution of 1-(5-(methoxymethyl)-1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-3- (3,4,5-trifluorobenzyl)pyrrolidin-2-one (45 mg, 0.11 mmol) in THF (5 mL) was added the solution of LiHMDS in THF (0.16 mL, 0.16 mmol) at -75 °C. After stirring for 1 hr., at - 75 °C, the reaction mixture was added the solution of (1R)-(-)-(10- camphorsulfonyl)oxaziridine (37 mg, 0.16 mmol) in THF (1 mL) at -75 °C, and then stirred at -75 °C for 3 hrs., under nitrogen. The mixture was added to water (20 mL) and extracted with EtOAc (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (gradient: 25% - 55% ACN in water (10 mM NH4HCO3) in 8.0 min, stop at 24 min, RT = 10.3 min) to give the title compound (5 mg, 10%) as a yellow solid. ES / MS (m / z): 434 (M+H). Example 293 3-((6-Fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-one (isomer 1)To a solution of 3-((6-fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (isomer 1)(140 mg, 0.28 mmol) in DCM (1 mL) was added TFA (1 mL). After stirring at ambient temperature for 8 h, the reaction mixture was concentrated in vacuo. The residue was added to saturated NaHCO3solution (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (ACN in 10 mM NH4HCO3= 30 - 70%) to give the title compound (67 mg, 64%, ee = 99%) as a white solid. ES / MS (m / z): 368 (M+H). The compounds in Table 30 were prepared in a manner essentially analogous to that found in Example 293. Table 30Example 305 (S)-3-((6-Chloro-5-fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H-pyrazol- 5-yl)piperidin-2-oneTo a solution of (R)-4-benzyl-3-((S)-2-((6-chloro-5-fluoropyridin-3-yl)methyl)-5- ((3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)amino)pentanoyl)oxazolidin-2-one (120 mg, 0.21 mmol) in THF (3 ml) was added H2O2(42 mg, 1.25 mmol) at 0 °C. After stirring for 10 min, the reaction mixture was added to a solution of LiOH.H2O (26 mg, 0.62 mmol) in H2O (2 ml), and stirred for 20 min. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (50 mL x 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was slurried in MeOH (10 mL), and the solid was filtered and dried in vacuo to give the title compound (45 mg, 54%) as a white solid. ES / MS (m / z): 401 (M+H). The compound in Table 31 were prepared in a manner essentially analogous to that found in Example 305. Table 31Example 307 (S)-3-(4-Fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)piperidin-2-oneTo a solution of (R)-4-benzyl-3-((S)-2-(4-fluorobenzyl)-5-((3-(5-methylpyridazin- 4-yl)-1H-pyrazol-5-yl)amino)pentanoyl)oxazolidin-2-one (90 mg, 0.23 mmol) in DMAc (3 mL) was added DIPEA (0.1 ml, 0.59 mmol) and a solution of T3P in EtOAc (224 g, 0.35 mmol). After stirring at ambient temperature for 24 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (20 mg, 23%) as a white solid. ES / MS (m / z): 366 [M+H]. Example 308 (S)-(5-(3-((6-Chloropyridin-3-yl)methyl)-2-oxopiperidin-1-yl)-3-(5-methylpyridazin-4- yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphateTo a suspension of ((S)-di-tert-butyl ((5-(3-((6-chloropyridin-3-yl)methyl)-2- oxopiperidin-1-yl)-3-(5-methylpyridazin-4-yl)-1H-pyrazol-1-yl)methyl) phosphate (200 mg, 0.33 mmol) in water (3 mL) was added HOAc (3 mL). After stirring at 60 °C for 3 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase column chromatography eluting with ACN in NH4HCO3solution (0 - 40%) to give the title compound (95 mg, 58%) as a white solid. ES / MS (m / z): 493 (M+H).The compounds in Table 32 were prepared in a manner essentially analogous to that found in Example 308. Table 32Example 310 (5-(3-(4-Chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-3-(pyridazin-4-yl)- 1H-pyrazol-1-yl)methyl dihydrogen phosphate (Isomer 1-S1) and (5-(3-(4-chloro-3,5- difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-3-(pyridazin-4-yl)-1H-pyrazol-1- yl)methyl dihydrogen phosphate (Isomer 1-S2)To a suspension of isomer 1-di-tert-butyl ((5-(3-(4-chloro-3,5-difluorobenzyl)-2- oxopyrrolidin-1-yl)-4-fluoro-3-(pyridazin-4-yl)-1H-pyrazol-1-yl)methyl) phosphate and di-tert-butyl ((3-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-5- (pyridazin-4-yl)-1H-pyrazol-1-yl)methyl) phosphate (0.46 g, 0.7 mmol) in water (2 mL) was added AcOH (2 mL). After stirring at 40 °C for 48 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase column chromatography eluting with ACN in NH4HCO3solution (0 - 40%) to give the isomer 1-S1 (95 mg, 25%) as a white solid and isomer 1-S2 (42 mg, 11%) as a white solid. ES / MS (m / z): 518 (M+H).The compounds in Table 33 were prepared in a manner essentially analogous to that found in Example 310.Table 33Example 313 Disodium (2-(5-(pyridazin-4-yl)-3-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4- yl)ethoxy)methyl phosphateTo a solution of (2-(5-(pyridazin-4-yl)-3-(3-(3,4,5-trifluorophenyl)propanamido)- 1H-pyrazol-4-yl)ethoxy)methyl dihydrogen phosphate (71.7 mg, 0.14 mmol) in ACN (1 mL) was added NaOH (11.2 mg, 0.28 mmol) in water (1 mL) at 25 °C, and then stirred at 25 °C for 5 hrs. The reaction mixture was lyophilized to give the title compound (67.1 mg, 86%) as a white solid. ES / MS (m / z): 502 (M+H). Example 314 3-(4-Chloro-3,5-difluorophenyl)-N-(4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-1H- pyrazol-5-yl)propanamideTo a solution of tert-butyl 2-(((3-(3-(4-chloro-3,5-difluorophenyl)propanamido)- 5-(pyridazin-4-yl)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate (0.6 g, 1 mmol) in DCM (5 ml) was added the solution of HCl in 1,4-dioxane (5 mL, 20 mmol). After stirring at ambient temperature for 2 hrs., the reaction mixture was concentrated in vacuo to dryness. The residue was purified by prep-HPLC (C18, ACN in 10 mmol NH4HCO3) to give the title compound (0.15, 30 %) as white solid. ES / MS (m / z): 479 (M+H). The compounds in Table 34 were prepared in a manner essentially analogous to that found in Example 314.Table 34Example 316 N-(4-((4-Methylmorpholin-2-yl)methoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5- trifluorophenyl)propenamideTo a solution of N-(4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5- yl)-3-(3,4,5-trifluorophenyl)propenamide 0.17 g, 0.4 mmol) in formic acid (1 ml) was added formaldehyde (3 mL) at 0 °C. After stirring at 80 °C for 5 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (120 mg, 69%) as a white solid. ES / MS (m / z): 477 (M+H).Example 317 3-(4-Chloro-3-fluorophenyl)-N-(4-(2-hydroxyethoxy)-5-(pyridazin-4-yl)-1H-pyrazol-3- yl)propenamideTo a solution of 3-(4-chloro-3-fluorophenyl)-N-(4-(2-methoxyethoxy)-5- (pyridazin-4-yl)-1H-pyrazol-3-yl)propanamide (0.3 g, 0.7 mmol) in DCM (10 mL) was added 1M BBr3in DCM (3.5 mL, 3.5 mmol). After stirring at 60 °C for 12 hrs., the reaction mixture was cooled to ambient temperature, added MeOH (2 mL) dropwise, and then concentrated in vacuo. The crude material was purified by reverse chromatography column eluting with C18, 35% ACN in 10 mM NH4HCO3to give the title compound (95 mg, 32%) as a white solid. ES / MS (m / z): 406 (M+H). Example 318 N-(4-((4-(methyl-d3)morpholin-2-yl)methoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3- (3,4,5-trifluorophenyl)propenamideTo a solution of N-(1-(4-methoxybenzyl)-4-((4-(methyl-d3)morpholin-2- yl)methoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propanamide (0.25 g, 0.42 mmol) in DCM (5 mL) was added TFA (3.00 mL, 38.9 mmol) and triflic acid (0.20 mL, 2.3 mmol). After stirring at 25 °C for 3 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (0.12 g, 60%) as a white solid. ES / MS (m / z): 480 (M+H). The compounds in Table 35 were prepared in a manner essentially analogous to that found in Example 318.Table 35Example 321 N-(4-(Methoxymethyl)-5-(pyridazin-4-yl)-1H-pyrazol-3-yl)-3-(3,4,5- trifluorophenyl)propenamideTo a solution of N-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3- (3,4,5-trifluorophenyl)propanamide (76 mg, 0.2 mmol) in MeOH (8 mL) and DCM (2 mL) was added TFA (1 mL). After stirring at ambient temperature for 3 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (Water: ACN = 20:1) to give the title compound (20 mg, 25%) as a white solid. ES / MS (m / z): 392 (M+H).Example 322 3-(4-Chloro-1H-pyrrol-2-yl)-N-(5-(5-methylpyridazin-4-yl)-1H-pyrazol-3- yl)propanamideTo a solution of 1M TBAF in THF (5 mL, 5 mmol) was added 3-(4-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)-N-(5-(5-methylpyridazin-4-yl)-1H- pyrazol-3-yl)propenamide (0.15 g, 0.33 mmol). After stirring at 50 °C for 24 hrs., the reaction mixture was concentrated in vacuo. The residue was purified by reverse chromatography column eluting with 2-40% ACN in 10 mM NH4HCO3to give the title compound (27 mg, 25%) as a white solid. ES / MS (m / z): 331 (M+H). Example 323 N-(4-(2-(Difluoromethoxy)ethyl)-5-(pyridazin-4-yl)-1H-pyrazol-3-yl)-3-(3,4,5- trifluorophenyl)propenamideTo a solution of N-(4-(2-hydroxyethyl)-5-(pyridazin-4-yl)-1H-pyrazol-3-yl)-3- (3,4,5-trifluorophenyl)propanamide (500 mg, 1.28 mmol) in ACN (10 mL) was added CuI (48.7 mg, 256 µmol). The reaction mixture was heated to 50 °C, and then added 2,2- difluoro-2-(fluorosulfonyl)acetic acid (341 mg, 1.92 mmol) slowly. After stirring at 50 °C for 1 hr., under nitrogen, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (gradient: 30-60% ACN in water (0.01% TFA) in 8 min, stop at 14 min; retention time: 8.5 min; flow rate: 30 mL / min; column: BOSTON pHlex ODS 10 um 21.2×250 mm 120 A) to give the title compound (12 mg, 2.1%) as a white solid. ES / MS (m / z): 255 (M+H).Example 324 N-(4-(Hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5- trifluorophenyl)propanamideThe solution of N-(4-(hydroxymethyl)-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)- 1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propanamide (180 mg, 0.36 mmol) in DCM (1 mL) was added TFA (1 mL, 0.01 mol) at 0 °C, and then stirred at 20 °C for 16 hrs. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (C18, ACN in 10 mmol NH4HCO3) to give the title compound (15 mg, 11%) as white solid. ES / MS (m / z): 378 (M+H).ARM-SAM-TIR SARM1 IC50Assay This describes an assay of ARM-SAM-TIR NADase activity and use of this assay to measure the efficacy of compounds of the compounds of the present invention to block SARM1 mediated NAD+ cleavage. This assay was optimized in such a way as to characterize the efficacy of the compounds of the present invention to inhibit SARM1 activity and to calculate an IC50value for each compound. This assay makes use of full length SARM1, which encompasses the ARM, SAM and TIR domains. As demonstrated herein, expression of this fragment without the autoinhibitory N- terminal domain generates a constitutively active enzyme that cleaves NAD+. Preparation of ARM-SAM-TIR lysate (STL) NRK1-HEK293T cells were seeded onto 150 cm2plates at 20 x 106 cells per plate. The next day, the cells were transfected with 15 μg ARM-SAM-TIR expression plasmid (SEQ ID NO: 1 as disclosed in WO 2019 / 236879, Pages 77-81; Paragraph

[0310] ). The cultures were supplemented with 1 mM NR at time of transfection to minimize toxicity from ARM-SAM-TIR overexpression. Forty-eight hrs., after transfection, cells were harvested, pelleted by centrifugation at 1,000 rpm (Sorvall ST 16R centrifuge, Thermo Fisher), and washed once with cold PBS (0.01 M phosphate buffered saline NaCl 0.138 M; KCl 0.0027 M; pH 7.4). The cells were resuspended in PBS with protease inhibitors (Complete™ protease inhibitor Cocktail, Roche product # 11873580001) and cell lysates were prepared by sonication (Branson Sonifer 450, output = 3, 20 episodes of stroke). The lysates were centrifuged (12,000×g for 10 min at 4°C) to remove cell debris and the supernatants (containing ARM-SAM-TIR protein) were stored at -80 °C for later use in the in vitro ARM-SAM-TIR NADase assay (see below). Protein concentration was determined by the Bicinchoninic (BCA) method and used to normalize lysate concentrations. ARM-SAM-TIR IC50 assay of Formula I compounds. The enzymatic assay was performed in a 384-well polypropylene plate in Dulbecco’s PBS buffer in a final assay volume of 20 µL. ARM-SAM-TIR lysate with a final concentration of 5 µg / mL was pre-incubated with the respective compound at 1% DMSO final assay concentration over 2 hrs. at ambient temperature. The reaction was initiated by addition of 5 µM final assay concentration of NAD+ as substrate. After a 2 hrs.ambient temperature incubation, the reaction was terminated with 40 µL of stop solution of 7.5% trichloroactetic acid in acetonitrile. The NAD+ and ADPR concentrations were analyzed by a RapidFire High Throughput Mass Spectrometry System (Agilent Technologies, Santa Clara, CA) using an API4000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA). Results are presented below in Tables 36A and 36B. Compounds having an activity designated as “A” provided an IC50< 50 nM; compounds having an activity designated as “B” provided an IC5051-100 nM; compounds having an activity designated as “C” provided an IC50101-500 nM; compounds having an activity designated as “D” provided an IC50501-1000 nM; compounds having an activity designated as “E” provided an IC50>1000 nM.Table 36A: HSARM1 IC50Assay (Part A)Table 36B: HSARM1 IC50Assay (Part B)The results shown in Tables 36A and 36B above demonstrate that the exemplified compounds possess hSARM1 inhibitory activity. List of embodiments 1. A compound of the formula, wherein X is N and Y is CH, or X is CH and Y is N; R5is selected from hydrogen, halogen, -NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, -OH, or -OCH3wherein when R5is hydrogen, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,and when R5is selected from halogen, -NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, -OH, or -OCH3, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,R1and R2together with the atoms they are attached to form a 5- to 6-membered saturated heterocyclic ring wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, and wherein one of the carbon atoms is optionally substituted with cyano, -ORd, or C1-3alkyl optionally substituted with -NH2, or -ORd; R3is selected from hydrogen and C1-4alkyl; R4is selected from phenyl optionally substituted with 1 to 3 Rb, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb, and 9- to 10-membered fully or partially aromatic bicyclic heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb; each Rais independently selected from hydrogen, halogen, cyano and C1-4alkyl optionally substituted with halogen, -ORd, -NH2or cyano; each Rbis independently selected from halogen, cyano, C1-4alkyl, -NH2, -OH, monohalomethyl, dihalomethyl, trihalomethyl, and -OC1-4alkyl; and Rcis selected from halogen, cyano, -OC1-3alkyl optionally substituted with Re, and C1-4alkyl optionally substituted with halogen, -ORd, -NH2, or cyano; and Rdis selected from hydrogen, C1-4alkyl and -CH2OP(O)(OH)2; Reis selected fromor a pharmaceutically acceptable salt thereof. 2. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof wherein X is N and Y is CH. 3. The compound according to embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof wherein R5is hydrogen and Ring A is selected from: optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2, optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2, optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,4. The compound according to embodiment 1 or embodiment 2 or a pharmaceutically acceptable salt thereof wherein R5is selected from halogen, - NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, - OH, or -OCH3and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2, optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,5. The compound according to embodiment 4 or a pharmaceutically acceptable salt thereof wherein R5is selected from -CH3, -CH2OH, -NH2, -CH2F, and -OCH3. 6. The compound according to any one of embodiments 1 to 5 or a pharmaceutically acceptable salt thereof which is:wherein B is selected from O, NH, C- R6, wherein R6is selected from hydrogen, cyano, -OC1-3alkyl, or C1-3alkyl optionally substituted with -NH2, or -ORd; R7and R8are independently selected from hydrogen and -OH, and n is 0 or 1, or a pharmaceutically acceptable salt thereof. 7. The compound according to embodiment 6 or a pharmaceutically acceptable salt thereof which is:wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.8. The compound according to embodiment 6 or 7 or a pharmaceutically acceptable salt thereof which is selected from:or a pharmaceutically acceptable salt thereof. 9. The compound according to any one of embodiments 1 to 8 or a pharmaceutically acceptable salt thereof wherein R3is hydrogen. 10. The compound according to any one of embodiments 1 to 9 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,and each Rais independently selected from hydrogen, cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, and -Cl. 11. The compound according to any one of embodiments 1 to 3 and 5 to 10 or a pharmaceutically acceptable salt thereof wherein Ring A is:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2, and Rcis selected from cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, - CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, -Cl,12. The compound according to any one of embodiments 1 to 11 or a pharmaceutically acceptable salt thereof wherein R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb. 13. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof wherein R4is phenyl optionally substituted with 1 to 3 Rb.14. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof wherein R4is 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb. 15. The compound according to embodiment 14 or a pharmaceutically acceptable salt thereof wherein R4is pyridine optionally substituted with 1 to 3 Rb. 16. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof wherein R4is selected from:17. The compound according to any one of embodiments 1 to 16 or a pharmaceutically acceptable salt thereof wherein R4is substituted by 1 to 3 Rband each Rbis independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl. 18. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof wherein R4is selected from:19. A compound of the formulawherein X is N and Y is CH, or X is CH and Y is N; R5is selected from hydrogen, and -CH3optionally substituted with -OH, -NH2, or 1-3 halogen atoms, wherein when R5is C1-3alkyl optionally substituted with -OH, -NH2, or 1-3 halogen atoms, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,and when R5is hydrogen, then Ring A is from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2; R1, R2and R3are each independently selected from hydrogen and C1-4alkyl, wherein R2and R3together with the atoms they are attached to may optionally form a 3- to 6-membered saturated carbocyclic ring; R4is selected from phenyl optionally substituted with 1 to 3 Rb, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb, 9- to 10-membered fully or partially aromatic bicyclic heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb; Rais selected from hydrogen, halogen, cyano, and C1-4alkyl; each Rbis independently selected from halogen, cyano, -OH, -NH2, C1-4alkyl, monohalomethyl, dihalomethyl, trihalomethyl and -OC1-4alkyl; Rcis selected from -OC1-3alkyl optionally substituted with -ORdor Re, and -C1-4alkyl substituted with -ORdor 1-3 halogen atoms; and Rdis selected from H, -CH3, -CF3, -CHF2, and -CH2OP(O)(OH)2; and Reis selected fromor a pharmaceutically acceptable salt thereof. 20. The compound according to embodiment 19 or a pharmaceutically acceptable salt thereof wherein X is N and Y is CH. 21. The compound according to embodiment 19 or embodiment 20 or a pharmaceutically acceptable salt thereof wherein R5is C1-3alkyl, optionally substituted with -OH, -NH2, or 1-3 halogen atoms, and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,22. The compound according to embodiment 21 or a pharmaceutically acceptable salt thereof wherein R5is selected from -CH3, CH2OH, CH2F and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,23. The compound according to embodiment 19 or a pharmaceutically acceptable salt thereof wherein R5is hydrogen, and Ring A is:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2. 24. The compound according to any one of embodiments 19 to 23 or a pharmaceutically acceptable salt thereof wherein R1, R2and R3are all hydrogen. 25. The compound according to any one of embodiments 19 to 22 and 24 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,and Rais selected from hydrogen, cyano and -CH3. 26. The compound according to any one of embodiments 19, 23 and 24 or a pharmaceutically acceptable salt thereof wherein Ring A is:optionally substituted at one nitrogen atom with -CH2OP(O)(OH), and Rcis selected from -OCH3, -CH2OCH3, -CH2CH2OCH3, -OCH2CH2OH, - OCH2CH2OCH3, -OCH2CH2OCHF2, -CH2CH2OCH2OP(O)(OH)2,27. The compound according to any one of embodiments 19 to 26 or a pharmaceutically acceptable salt thereof wherein R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb. 28. The compound according to embodiment 27 or a pharmaceutically acceptable salt thereof wherein R4is phenyl optionally substituted with 1 to 3 Rb. 29. The compound according to embodiment 27 or a pharmaceutically acceptable salt thereof wherein R4is 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb. 30. The compound according to embodiment 29 or a pharmaceutically acceptable salt thereof wherein R4is pyridine optionally substituted with 1 to 3 Rb. 31. The compound according to embodiment 27 or a pharmaceutically acceptable salt thereof wherein R4is selected from:32. The compound according to any one of embodiments 20 to 31 or a pharmaceutically acceptable salt thereof wherein R4is substituted by 1 to 3 Rband each Rbis independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl. 33. The compound according to embodiment 19 or a pharmaceutically acceptable salt thereof wherein R4is selected from:34. A compound of the formulawherein X is N and Y is CH, or X is CH and Y is N;Ring A is selected fromR1, R2and R3are each independently selected from hydrogen and C1-4alkyl, wherein R1and R2together with the atoms they are attached to may optionally form a 5- to 6-membered saturated heterocyclic ring wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, or wherein R2and R3together with the atoms they are attached to may optionally form a 3- to 6-membered saturated carbocyclic ring; R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6- membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb; Rais selected from hydrogen, halogen, cyano and C1-4alkyl optionally substituted with halogen, -OH, -NH2or cyano; each Rbis independently selected from halogen, cyano, C1-4alkyl, trihalomethyl and -OC1-4alkyl, or a pharmaceutically acceptable salt thereof. 35. The compound according to embodiment 34 or a pharmaceutically acceptable salt thereof wherein X is N and Y is CH. 36. The compound according to embodiment 34 or a pharmaceutically acceptable salt thereof wherein X is CH and Y is N. 37. The compound according to any one of embodiments 34 to 36 or a pharmaceutically acceptable salt thereof wherein R1, R2and R3are hydrogen. 38. The compound according to any one of embodiments 34 to 36 or a pharmaceutically acceptable salt thereof which is:wherein Z is selected from CH2, O, NH or a bond, or a pharmaceutically acceptable salt thereof.39. The compound according to embodiment 38 or a pharmaceutically acceptable salt thereof which is selected from:or a pharmaceutically acceptable salt thereof. 40. The compound according to any one of embodiments 34 to 39 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:41. The compound according to any one of embodiments 34 to 39 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:and Rais methyl. 42. The compound according to any one of embodiments 34 to 39 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:and Rais cyano. 43. The compound according to any one of embodiments 34 to 42 or a pharmaceutically acceptable salt thereof wherein R4is selected from:. 44. The compound according to embodiment 43 or a pharmaceutically acceptable salt thereof wherein Rbis halogen.45. The compound according to any one of embodiments 34 to 44 or a pharmaceutically acceptable salt thereof wherein R4is selected from:46. The compound according to embodiment 34 or a pharmaceutically acceptable salt thereof which is selected from:or a pharmaceutically acceptable salt thereof. 47. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 46 or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients. 48. A method of treating or preventing a disease associated with axonal degeneration in a patient, comprising administering to a patient in need of such treatment aneffective amount of a compound according to any one of embodiments 1 to 46 or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 47.49. A method of treating or preventing a disease associated with SARM1 activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of embodiments 1 to 46 or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 47.50. A method of treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy- induced peripheral neuropathy in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound thereof according to any one of embodiments 1 to 46 or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 47.51. A compound according to any one of embodiments 1 to 46 or pharmaceutically acceptable salt thereof for use in therapy.52. A compound according to any one of embodiment s 1 to 46 or pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease associated with axonal degeneration.53. A compound according to any one of embodiments 1 to 46 or pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy -induced peripheral neuropathy.

Claims

WE CLAIM:

1. A compound of the formulawherein X is N and Y is CH, or X is CH and Y is N; R5is selected from hydrogen, halogen, -NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, -OH, or -OCH3wherein when R5is hydrogen, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,and when R5is selected from halogen, -NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, -OH, or -OCH3, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,R1and R2together with the atoms they are attached to form a 5- to 6-membered saturated heterocyclic ring wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, and wherein one of the carbon atoms is optionally substituted with cyano, -ORd, or C1-3alkyl optionally substituted with -NH2, or -ORd; R3is selected from hydrogen and C1-4alkyl; R4is selected from phenyl optionally substituted with 1 to 3 Rb, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb, and 9- to 10-membered fully or partially aromatic bicyclic heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb; each Rais independently selected from hydrogen, halogen, cyano and C1-4alkyl optionally substituted with halogen, -ORd, -NH2or cyano;each Rbis independently selected from halogen, cyano, C1-4alkyl, -NH2, -OH, monohalomethyl, dihalomethyl, trihalomethyl, and -OC1-4alkyl; and Rcis selected from halogen, cyano, -OC1-3alkyl optionally substituted with Re, and C1-4alkyl optionally substituted with halogen, -ORd, -NH2, or cyano; and Rdis selected from hydrogen, C1-4alkyl and -CH2OP(O)(OH)2; Reis selected fromor a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is N and Y is CH.

3. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof wherein R5is hydrogen and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,4. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof wherein R5is selected from halogen, -NH2, -OC1-3alkyl, and C1-3alkyl optionally substituted with 1-3 halogen atoms, -OH, or -OCH3and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof wherein R5is selected from -CH3, -CH2OH, -NH2, -CH2F, and -OCH3.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof which is:wherein B is selected from O, NH, C- R6, wherein R6is selected from hydrogen, cyano, -OC1-3alkyl, or C1-3alkyl optionally substituted with -NH2, or -ORd; R7and R8are independently selected from hydrogen and -OH, and n is 0 or 1, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof which is:wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 6 or 7 or a pharmaceutically acceptable salt thereof which is selected from:or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof wherein R3is hydrogen.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at the nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,and each Rais independently selected from hydrogen, cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, and -Cl.

11. The compound according to any one of claims 1 to 3 and 5 to 10 or a pharmaceutically acceptable salt thereof wherein Ring A is:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2, and Rcis selected from cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, - CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, -Cl,12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof wherein R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof wherein R4is phenyl optionally substituted with 1 to 3 Rb.

14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof wherein R4is 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof wherein R4is pyridine optionally substituted with 1 to 3 Rb.

16. The compound according to claim 12 or a pharmaceutically acceptable salt thereof wherein R4is selected from:

17. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof wherein R4is substituted by 1 to 3 Rband each Rbisindependently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R4is selected from:

19. A compound of the formulawherein X is N and Y is CH, or X is CH and Y is N; R5is selected from hydrogen, and -CH3optionally substituted with -OH, -NH2, or 1-3 halogen atoms, wherein when R5is C1-3alkyl optionally substituted with -OH, -NH2, or 1-3 halogen atoms, then Ring A is selected from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2,and when R5is hydrogen, then Ring A is from:optionally substituted at one nitrogen atom with - CH2OP(O)(OH)2; R1, R2and R3are each independently selected from hydrogen and C1-4alkyl, wherein R2and R3together with the atoms they are attached to may optionally form a 3- to 6-membered saturated carbocyclic ring; R4is selected from phenyl optionally substituted with 1 to 3 Rb, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb, 9- to 10-membered fully or partially aromatic bicyclic heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb; Rais selected from hydrogen, halogen, cyano, and C1-4alkyl; each Rbis independently selected from halogen, cyano, -OH, -NH2, C1-4alkyl, monohalomethyl, dihalomethyl, trihalomethyl and -OC1-4alkyl;Rcis selected from -OC1-3alkyl optionally substituted with -ORdor Re, and -C1-4alkyl substituted with -ORdor 1-3 halogen atoms; and Rdis selected from H, -CH3, -CF3, -CHF2, and -CH2OP(O)(OH)2; and Reis selected fromor a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof wherein X is N and Y is CH.

21. The compound according to claim 19 or claim 20 or a pharmaceutically acceptable salt thereof wherein R5is C1-3alkyl, optionally substituted with -OH, -NH2, or 1-3 halogen atoms, and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,22. The compound according to claim 21 or a pharmaceutically acceptable salt thereof wherein R5is selected from -CH3, CH2OH, CH2F and Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,23. The compound according to claim 19 or a pharmaceutically acceptable salt thereof wherein R5is hydrogen, and Ring A is:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2.

24. The compound according to any one of claims 19 to 23 or a pharmaceutically acceptable salt thereof wherein R1, R2and R3are all hydrogen.

25. The compound according to any one of claims 19 to 22 and 24 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2,and Rais selected from hydrogen, cyano and -CH3.

26. The compound according to any one of claims 19, 23 and 24 or a pharmaceutically acceptable salt thereof wherein Ring A is:optionally substituted at one nitrogen atom with -CH2OP(O)(OH), and Rcis selected from -OCH3, -CH2OCH3, -CH2CH2OCH3, -OCH2CH2OH, - OCH2CH2OCH3, -OCH2CH2OCHF2, -CH2CH2OCH2OP(O)(OH)2,27. The compound according to any one of claims 19 to 26 or a pharmaceutically acceptable salt thereof wherein R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof wherein R4is phenyl optionally substituted with 1 to 3 Rb.

29. The compound according to claim 27 or a pharmaceutically acceptable salt thereof wherein R4is 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof wherein R4is pyridine optionally substituted with 1 to 3 Rb.

31. The compound according to claim 27 or a pharmaceutically acceptable salt thereof wherein R4is selected from:

32. The compound according to any one of claims 20 to 31 or a pharmaceutically acceptable salt thereof wherein R4is substituted by 1 to 3 Rband each Rbis independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl.

33. The compound according to claim 19 or a pharmaceutically acceptable salt thereof wherein R4is selected from:

34. A compound of the formulawherein X is N and Y is CH, or X is CH and Y is N; Ring A is selected fromR1, R2and R3are each independently selected from hydrogen and C1-4alkyl, wherein R1and R2together with the atoms they are attached to may optionally form a 5- to 6-membered saturated heterocyclic ring wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, or wherein R2and R3together with the atoms they are attached to may optionally form a 3- to 6-membered saturated carbocyclic ring; R4is selected from phenyl optionally substituted with 1 to 3 Rband 5- to 6- membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 Rb; Rais selected from hydrogen, halogen, cyano and C1-4alkyl optionally substituted with halogen, -OH, -NH2or cyano; each Rbis independently selected from halogen, cyano, C1-4alkyl, trihalomethyl and -OC1-4alkyl, or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 34 or a pharmaceutically acceptable salt thereof wherein X is N and Y is CH.

36. The compound according to claim 34 or a pharmaceutically acceptable salt thereof wherein X is CH and Y is N.

37. The compound according to any one of claims 34 to 36 or a pharmaceutically acceptable salt thereof wherein R1, R2and R3are hydrogen.

38. The compound according to any one of claims 34 to 36 or a pharmaceutically acceptable salt thereof which is:wherein Z is selected from CH2, O, NH or a bond, or a pharmaceutically acceptable salt thereof.

39. The compound according to claim 38 or a pharmaceutically acceptable salt thereof which is selected from:or a pharmaceutically acceptable salt thereof.

40. The compound according to any one of claims 34 to 39 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:

41. The compound according to any one of claims 34 to 39 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from:and Rais methyl.

42. The compound according to any one of claims 34 to 39 or a pharmaceutically acceptable salt thereof wherein Ring A is selected from: anad R is cyano.

43. The compound according to any one of claims 34 to 42 or a pharmaceutically acceptable salt thereof wherein R4is selected from:

44. The compound according to claim 43 or a pharmaceutically acceptable salt thereof wherein Rbis halogen.

45. The compound according to any one of claims 34 to 44 or a pharmaceutically acceptable salt thereof wherein R4is selected from:

46. The compound according to claim 34 or a pharmaceutically acceptable salt thereof which is selected from:or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.

48. A method of treating or preventing a disease associated with axonal degeneration in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 46 or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

49. A method of treating or preventing a disease associated with SARM1 activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 46 or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

50. A method of treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy- induced peripheral neuropathy in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound thereof according to any one of claims 1 to 46 or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

51. A compound according to any one of claims 1 to 46 or pharmaceutically acceptable salt thereof for use in therapy.

52. A compound according to any one of claims 1 to 46 or pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease associated with axonal degeneration.

53. A compound according to any one of claims 1 to 46 or pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy-induced peripheral neuropathy.

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