Pyridazines as SARM1 inhibitors

Abstract

The present invention relates to novel pyridazine compounds as SARM1 inhibitors, pharmaceutical compositions containing said compounds, and methods of using said compounds and compositions for treating and preventing conditions involving axonal degeneration.

Description

[Technical Field]

[0001] The present invention relates to novel SARM1 inhibitors, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions to treat and prevent conditions involving axonal degeneration. [Background technology]

[0002] Axonal degeneration is a key feature of conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, hereditary neuropathies, traumatic brain injury, and glaucoma, which affect millions of patients and represent a significant economic burden worldwide.

[0003] Sterile Alpha and Toll / Interleukin receptor-1 (TIR) ​​motif-containing 1 (SARM1) has been identified as a central executioner in the injury-induced axonal death pathway known as Wallerian degeneration (O'Neill, LA & Bowie, AG, Nat. Rev. Immunol., 2007, 7, 353-364; Osterloh, JM, et al., Science, 2012, 337, 481-484; Gerdts, J., et al., J. Neurosci. 33, 2013, 13569-13580). Mechanistic studies have revealed that axonal injury-mediated activation of SARM1 or forced dimerization of the SARM1-TIR domain promotes rapid nicotinamide adenine dinucleotide (NAD+) consumption and leads to axonal degeneration (Gerdts, J., et al., Science, 2015, 348, 453-457). Genetic knockout of SARM1 allows axonal preservation more than 14 days after nerve transection (Osterloh, JM, 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 seen in pathologies such as chemotherapy-induced peripheral neuropathy. Loss of SARM1 prevents chemotherapy-induced peripheral neuropathy and inhibits both axonal degeneration and the hyperalgesia that develops after vincristine chemotherapy treatment (Geisler et al, Brain, 2016, 139, 3092-3108).

[0004] WO2021 / 142006A1 and WO2022 / 046606A1 disclose several compounds and methods that inhibit SARM1 and / or are useful for treating and / or preventing axonal degeneration.

[0005] Currently, there are no approved drugs for treating and / or preventing axonal degeneration. There is an unmet need for potent SARM1 inhibitors with improved metabolic profiles to treat and prevent conditions involving axonal degeneration. Summary of the Invention

[0006] The present invention provides novel SARM1 inhibitors for use in the treatment and prevention of conditions involving axonal degeneration. Furthermore, the present invention provides novel SARM1 inhibitors that have improved efficacy and are likely to result in reduced metabolic clearance.

[0007] Thus, the present invention provides compounds of formula III: [ka] or a pharmaceutically acceptable salt thereof [In formula: X is N and Y is CH, or X is CH and Y is N; R 5 are hydrogen, halogen, -NH2, -OC 1~3 C optionally substituted with alkyl and 1 to 3 halogen atoms, -OH, or -OCH 1~3 alkyl, selected from: R 5 is hydrogen, then ring A is The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from; R 5 But halogen, -NH2, -OC 1~3 C optionally substituted with alkyl and 1 to 3 halogen atoms, -OH, or -OCH 1~3 alkyl, when ring A is selected from The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from; R 1 and R 2together with the atoms to which they are attached form a 5-6 membered saturated heterocycle, in which one carbon atom may be optionally replaced by a heteroatom selected from oxygen and nitrogen, and in which one carbon atom is optionally replaced by a heteroatom selected from cyano, -OR d , or -NH2 or -OR d C, which may be optionally substituted with 1~3 alkyl, optionally substituted; R 3 is hydrogen and C 1~4 alkyl; R 4 is 1 to 3 R b phenyl, oxygen, nitrogen and sulfur, optionally substituted with 1 to 3 heteroatoms selected from b and 5-6 membered heteroaryl, which is fully or partially aromatic and contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1-3 R b a 9-10 membered bicyclic heteroaryl optionally substituted with R a are each independently hydrogen, halogen, cyano and halogen, -OR d , C optionally substituted with -NH or cyano 1~4 alkyl; R b are each independently a halogen, cyano, or C 1~4 Alkyl, -NH2, -OH, monohalomethyl, dihalomethyl, trihalomethyl, and -OC 1~4 alkyl; R c is halogen, cyano, R e -OC, which may be optionally substituted with 1~3 Alkyl, and halogen, -OR d , -NH2, or cyano optionally substituted C 1~4 alkyl; R d is hydrogen, C 1~4 alkyl and —CH2OP(O)(OH)2; Re has the following structure: [ka] Select from].

[0008] In one embodiment of the invention, X is N and Y is CH.

[0009] In a further embodiment, R 5 is hydrogen and ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] is selected from.

[0010] In other embodiments, R 5 are halogens, -NH2, -OC 1~3 C optionally substituted with alkyl and 1 to 3 halogen atoms, -OH, or -OCH 1~3 alkyl, and Ring A is selected from: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] is selected from.

[0011] In some embodiments, R 5 is selected from —CH 3 , —CH 2 OH, —NH 2 , —CH 2 F, and —OCH 3 .

[0012] In certain embodiments, the compound has formula IIIa: [ka] It is a compound represented by [In the formula, B is O, NH, CR 6 where R 6 is hydrogen, cyano, -OC 1~3 Alkyl, or -NH2 or -OR d C, which may be optionally substituted with 1~3 alkyl, and R 7 and R 8 is independently selected from hydrogen and —OH, and n is 0 or 1. In other embodiments, the compound has formula IIIa(i): [ka] It is a compound represented by [wherein n is 0 or 1].

[0013] In further embodiments, the compound has the formula IIIa(ii) to IIIa(xii): [ka] is selected from one of the following:

[0014] In a further embodiment, R 3 is hydrogen.

[0015] In certain embodiments, ring A is The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from R a are each independently selected from hydrogen, cyano, —CH3, —CH2OH, —CH2CH2OH, —CH2OCH3, —CH2CH2OCH3, —CH2CH2OCH2CH3, —CH2CN, —OCH3, —F, and —Cl.

[0016] In a further embodiment, ring A is The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and R c is cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, -Cl, as well as the following structures: [ka] is selected from.

[0017] In other embodiments, R 4 is 1 to 3 R b and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R b and 5-6 membered heteroaryl optionally substituted with R. 4 is 1 to 3 R b In another embodiment, R 4 contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and 1 to 3 R b In a further embodiment, R 4 is 1 to 3 R b In one embodiment, R 4 has the following structure: [ka] In some embodiments, R 4 is 1 to 3 R b is substituted with R b are each independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl. 4 has the following structure: [ka] is selected from.

[0018] The present invention further provides a compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is N and Y is CH, or X is CH and Y is N; R 5 is selected from hydrogen, and —OH, —NH, or —CH optionally substituted with 1 to 3 halogen atoms, wherein: R 5 C optionally substituted with -OH, -NH2, or 1 to 3 halogen atoms 1~3 When ring A is alkyl, it is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] is selected from. R 5 is hydrogen, then ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and; R 1 , R 2 and R 3are each independently hydrogen and C 1~4 alkyl, where R 2 and R 3 may optionally, together with the atoms to which they are attached, form a 3- to 6-membered saturated carbocyclic ring; R 4 is 1 to 3 R b phenyl, oxygen, nitrogen and sulfur, optionally substituted with 1 to 3 heteroatoms selected from b 5-6 membered heteroaryl optionally substituted with 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R b a 9-10 membered bicyclic heteroaryl, which is fully or partially aromatic, optionally substituted with R a is hydrogen, halogen, cyano, and C 1~4 alkyl; R b are each independently halogen, cyano, -OH, -NH2, C 1~4 Alkyl, monohalomethyl, dihalomethyl, trihalomethyl and -OC 1~4 alkyl; R c -OR d or R e -OC, which may be optionally substituted with 1~3 Alkyl, and -OR d or -C substituted with 1 to 3 halogen atoms 1~4 alkyl; R d is selected from H, —CH3, —CF3, —CHF2, and —CH2OP(O)(OH)2; R e has the following structure: [ka] Select from].

[0019] In one embodiment of the invention, X is N and Y is CH.

[0020] In a further embodiment, R 5 is C 1~3 alkyl, optionally substituted with -OH, -NH2, or 1 to 3 halogen atoms, and Ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] In some embodiments, R 5 is selected from -CH3, CH2OH, CH2F, and ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] is selected from.

[0021] In other embodiments, R 5 is hydrogen, and ring A has the following structure, in which one nitrogen atom is optionally substituted with —CH 2 OP(O)(OH) 2 : [ka] is.

[0022] In a further embodiment, R 1 , R 2 and R 3 are all hydrogen.

[0023] In certain embodiments, ring A is The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from R a is selected from hydrogen, cyano and —CH 3 .

[0024] In one embodiment, ring A has the following structure, in which one nitrogen atom is optionally substituted with —CH 2 OP(O)(OH): [ka] and R c is -OCH3, -CH2OCH3, -CH2CH2OCH3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2CH2OCHF2, -CH2CH2OCH2OP(O)(OH)2, as well as the following structure: [ka] is selected from.

[0025] In other embodiments, R 4 is 1 to 3 R b and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R b and 5-6 membered heteroaryl optionally substituted with R. 4 is 1 to 3 R b In another embodiment, R4 contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and 1 to 3 R b In a further embodiment, R 4 is 1 to 3 R b In one embodiment, R 4 has the following structure: [ka] In some embodiments, R 4 is 1 to 3 R b is replaced by R b are each independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl. 4 teeth: [ka] is selected from.

[0026] The present invention relates to compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is N and Y is CH, or X is CH and Y is N; Ring A has the following structure: [ka] Selected from; R 1 , R 2 and R 3 are each independently hydrogen and C 1~4 alkyl, where R 1 and R 2may optionally form, together with the atoms to which they are attached, a 5- to 6-membered saturated heterocycle, wherein one carbon atom may be optionally replaced with a heteroatom selected from oxygen and nitrogen, or wherein R 2 and R 3 may optionally, together with the atoms to which they are attached, form a 3- to 6-membered saturated carbocyclic ring; R 4 is 1 to 3 R b and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R b 5-6 membered heteroaryl optionally substituted with R a is hydrogen, halogen, cyano, and C optionally substituted with halogen, —OH, —NH or cyano; 1~4 alkyl; R b are each independently a halogen, cyano, or C 1~4 Alkyl, trihalomethyl and -OC 1~4 alkyl].

[0027] In one embodiment of the invention, X is N and Y is CH. In another embodiment, X is CH and Y is N.

[0028] In one embodiment of the invention, R 1 is hydrogen. In other embodiments, R 2 is hydrogen. In a further embodiment, R 3 is hydrogen. In certain embodiments, R 1 , R 2 and R 3 is hydrogen. In other embodiments, R 1 , R 2 and R 3 are each independently hydrogen and C 1~4 alkyl, where R 1 and R 2may optionally form, together with the atoms to which they are attached, a 5- to 6-membered saturated heterocycle, wherein one carbon atom may be optionally replaced with a heteroatom selected from oxygen and nitrogen, or wherein R 2 and R 3 may optionally be taken together with the atom to which they are attached to form a 3- to 6-membered saturated carbocyclic ring.

[0029] In other embodiments, the compound has Formula II: [ka] is a compound of [Wherein X, Y, ring A and R 4 is as defined above and Z is selected from CH2, O, NH or a bond. In some embodiments, Z is CH2. In other embodiments, Z is O. In other embodiments, Z is NH. In other embodiments, Z is a bond. In further embodiments, the compound has Formula IIa and Formula IIb: [ka] [ka] Selected from [Wherein X, Y, rings A, Z and R 4 is as defined above].

[0030] In another embodiment of the present invention, R a is hydrogen, cyano and C 1~4 In some embodiments, R a is hydrogen. In certain embodiments, R a is methyl. In other embodiments, R a is cyano.

[0031] In one embodiment of the invention, ring A has the following structure: [ka] is selected from.

[0032] In one embodiment of the invention, R b are each selected from halogen and cyano. b are each halogen. In yet another embodiment, R b are each selected from fluorine, chlorine, and bromine.

[0033] In another embodiment of the present invention, R 4 has the following structure: [ka] is selected from.

[0034] In a further embodiment, R 4 has the following structure: [ka] is selected from.

[0035] In one embodiment of the invention, the compound has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0036] The present invention provides pharmaceutical compositions comprising a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0037] The present invention provides a method for 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to any of the above embodiments.

[0038] The present invention also provides a method for treating or preventing a disease associated with SARM1 activation in a patient, the method comprising administering to a patient in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described in any of the above embodiments.

[0039] The present invention also provides a method for treating or preventing a disease in a patient selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy and chemotherapy-induced peripheral neuropathy, comprising administering to a patient in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to any of the above embodiments.

[0040] The present invention provides a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0041] Furthermore, the present invention provides a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease associated with axonal degeneration.

[0042] Furthermore, the present invention provides a compound according to any one of the above embodiments, or a 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.

[0043] The present invention provides the use of a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease associated with axonal degeneration.

[0044] Furthermore, the present invention provides the use of a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, 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.

[0045] As used herein, the term "alkyl," used alone or as part of a larger moiety, refers to a straight or branched chain saturated hydrocarbon group containing one or more carbon atoms.

[0046] As used herein, the term "bicyclic heteroaryl" refers to a chemical group consisting of two linked rings, at least one of which is a heterocyclic or heteroaromatic ring.

[0047] As used herein, the term "carbocycle" refers to a saturated ring system containing only carbon atoms.

[0048] As used herein, the term "heteroaryl" refers to an aromatic ring system group that contains one or more heteroatoms.

[0049] 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.

[0050] As used herein, the term "heterocycle" refers to a saturated ring system radical containing carbon atoms and one or more heteroatoms.

[0051] As used herein, the term "patient" refers to a human.

[0052] As used herein, the term "prevent" refers to preventing the onset of a disease or avoiding complications after its onset.

[0053] As used herein, the term "treating" includes slowing, arresting, or reversing the progression or severity of an existing condition or disorder.

[0054] As used herein, the term "effective amount" refers to an amount or dosage of a compound of the present invention, or a pharmaceutically acceptable salt thereof, that provides a desired effect in a patient in diagnosis or treatment, upon administration to the patient in a single dose or multiple doses.

[0055] The compound of the present invention is preferably formulated as pharmaceutical composition, which can be administered by any route that allows the bioavailability of compound, including oral administration route and transdermal administration route.Most preferably, this composition is for oral administration.This pharmaceutical composition and the process for preparing it are well known in the art (for example, see Remington: The Science and Practice of Pharmacy, A.Adejare, Editor, 23rd edition, Elsevier Academic Press, 2020).

[0056] Some compounds of the invention contain a nitrogen heteroaryl five-membered ring that can exist in several tautomeric forms. For the 1,2,4-triazole ring, there are three possible tautomeric forms: [ka]

[0057] There are two possible tautomeric forms for the pyrazole and imidazole rings: [ka]

[0058] These tautomeric forms are intended to be encompassed by the present disclosure and claims. When one nitrogen atom is substituted with -CH2OP(O)(OH)2, the aforementioned nitrogen heteroaryl five-membered ring can take any of the forms listed below: [ka]

[0059] 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 racemic forms of the formulae, substituents, fragments, and compounds described herein.

[0060] 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 understood in the art. For the steps of these preparations and examples, suitable reaction conditions are well known in the art, and appropriate substitution of solvents and co-reagents is within the skill of one of ordinary skill in the art. Similarly, it will be understood by those skilled in the art that synthetic intermediates may be isolated and / or purified by various well-known techniques, as necessary or desired, and that often various intermediates can be used directly in subsequent synthetic steps with little or no purification. By way of illustration, the compounds of the preparations and examples may be isolated, for example, by silica gel purification, directly by filtration, or by crystallization. Furthermore, those skilled in the art will understand that, in some conditions, the order in which moieties are introduced is not critical. The specific order of steps required to obtain the compounds of the present invention will depend on the particular compound being synthesized, the starting compound, and the relative liabilities of the moieties being substituted, and is well understood by those skilled in the art. All substituents, unless otherwise indicated, are as previously defined and all reagents are well known and understood in the art.

[0061] Some 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-butyllithium; "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 dicarbonate; "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 dimethylaminomethyl ether; "DMAc" refers to dimethylacetamide; "DMF" refers to dimethylformamide; "DMAP" refers to 4-dimethylaminopyridine; "DMSO" refers to dimethylsulfoxide; "DPPA" refers to diphenylphosphoryl azide; "ee" refers to "enantiomeric excess"; "EtN" or "TEA" refers to triethylamine; "EtOAc" refers to ethyl acetate; "EtOH" refers to ethyl alcohol; "EtSiH" 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 time; "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 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(triphenylphosphine)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-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; and "T3P" refers to propanephosphonic anhydride; "XPhos" refers to dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane.

[0062] In the scheme below, Rz is an alkyl group such as methyl or is hydrogen; Ar is aryl or heteroaryl; X is N or C.

[0063] [ka] Scheme 1: Step A illustrates the formation of compound (2) from compound (1) using propiononitrile as a reagent in a solvent such as THF containing a base such as LiHMDS. Step B illustrates the cyclization of compound (2) using EtOH and hydrazine hydrate solution and a base such as NaCO in a solvent such as AcOH to obtain compound (3). Step C illustrates the addition of (4-methoxybenzyl)hydrazine hydrochloride to compound (3) using an acid such as AcOH in a solvent such as EtOH to obtain compound (4). Step D illustrates the amide coupling of compound (4) with an arylpropanoic acid using a coupling agent such as HATU and a base such as DIPEA in a solvent such as DMA to obtain compound (5). Those skilled in the art will recognize that many other amide coupling agents, bases, and solvents can be used to perform this coupling. Step E illustrates the acid deprotection of compound (5) using an acid such as TFA in a solvent such as DCM to obtain compound (6).

[0064] [ka] Scheme 2: Step A illustrates the formation of compound (9) from compound (8) by the addition of hydrazine hydrate solution in a solvent such as EtOH. Step B illustrates the addition of methylcarbamimidothioate sulfate, hydrazine hydrate solution to compound (9) using a base such as NaOH to form compound (10). Step C illustrates the intramolecular cyclization of compound (10) using a base such as NaOH to give compound (11). Step D illustrates the coupling of compound (11) with bromopentanoic acid using a coupling agent such as TBTU and a base such as DIPEA in a solvent such as DMA to give compound (12). Those skilled in the art will recognize that many other amide coupling agents, bases, and solvents can be used to carry out this coupling. Step E illustrates a two-step reaction in which compound (12) undergoes acyl rearrangement followed by intramolecular cyclization under suitable conditions, such as in the presence of a base such as sodium hydride and a solvent such as DMF. The product is then reacted with SEM-Cl to protect the nitrogen on the triazole of compound 13 with SEM. Step F depicts the reaction of compound 13 with an aryl bromo compound, such as 1-(bromomethyl)-4-fluorobenzene, using a base, such as LiHMDS, in a solvent, such as THF, to form compound 14. Step G depicts the acid deprotection of compound 14, using an acid, such as TFA, in a solvent, such as DCM, to give compound 15.

[0065] [ka] Scheme 3: Step A illustrates the transformation of compound (16) via a Curtius rearrangement reaction using DPPA with a base such as EtN in a solvent such as tert-butanol to form compound (17). Step B illustrates the Suzuki coupling of compound (17) with methylboronic acid using a catalyst such as Pd(dppf)Cl and a base such as potassium carbonate in a solvent system such as dioxane and water to give compound (18). Those skilled in the art will recognize that there are many catalyst, ligand, base, and solvent combinations that may be utilized to perform this type of coupling. Step C illustrates the transformation of compound (18) to compound (19) using a catalyst system including PhP and Pd(OAc)2, EtSiH as the reducing agent, and EtN as the base. Step D illustrates the deprotection of compound (19) using an acid such as HCl in a solvent system such as dioxane and DCM to give compound (20). Step E illustrates the bromination of compound (20) using a reagent such as CuBr and tert-butyl nitrite in a solvent such as ACN to form compound (21). Step F illustrates 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 KPO to form compound (22). Step G illustrates the acid deprotection of compound (22) using an acid such as HCl in a solvent such as DCM and dioxane to give compound (23). Step H illustrates the amide coupling of compound (23) with arylpropanoic acid using a coupling agent such as HATU and a base such as DiPEA in a solvent such as DMA to give compound (24). Those skilled in the art will recognize that many other amide coupling agents, bases, and solvents can be used to carry out this coupling.

[0066] [ka] Scheme 4: Step A shows the formation of Weinreb amide from compound (25) using N,O-dimethylhydroxylamine hydrochloride in a solvent such as THF containing a base such as LiHMDS to obtain 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 obtain 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 obtain compound (28). Step D shows the cyclization of compound (28) with (4-methoxybenzyl)hydrazine hydrochloride using a base such as EtN in a solvent such as EtOH to obtain compound (29). Step E shows the base hydrolysis of compound (29) using NaOH in a solvent system such as THF, EtOH, and water to obtain compound (30). Step F illustrates the amide coupling of compound 30 with ammonium chloride using a coupling agent such as HATU and a base such as DIPEA in a solvent such as DMF to give compound 31. Those skilled in the art will recognize that many other amide coupling agents, bases, and solvents can be used to carry out this coupling. Step G illustrates the amide coupling of compound 31 with an arylpropanoic acid using a coupling agent such as HATU and a base such as DiPEA in a solvent such as DMA to give compound 32. Those skilled in the art will recognize that many other amide coupling agents, bases, and solvents can be used to carry out this coupling. Step H illustrates the acid deprotection of compound 32 using an acid such as TFA in a solvent such as DCM to give compound 33. Step I illustrates the dehydration of compound 33 using Burgess's reagent (methyl N-(triethylammoniumsulfonyl)carbamate) in a solvent such as DMF to give compound 34.

[0067] [ka] Scheme 5: Step A illustrates the conversion of 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, in a solvent such as THF. Step B illustrates the deprotection of compound 36 using HF.EtN in a solvent such as THF to give compound 37. Step C illustrates the oxidation of compound 37 using Dess-Martin reagent in a solvent such as DCM to give compound 38. Step D illustrates the reduction of compound 38 using NaBHCN in a solvent of AcOH and MeOH, followed by coupling with an amine, such as 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine, to give compound 39. Step E illustrates the conversion of compound (39) to compound (40) using HO and a base such as LiOH.HO in a solvent such as THF. Step F illustrates the intramolecular cyclization of compound (40) to compound (41) using a coupling agent such as T3P and a base such as DIPEA in a solvent such as DMA. Alternatively, Step G illustrates the intramolecular cyclization of compound (39) to compound (42) using a base such as LiOH.HO in a solvent system such as HO, water, and THF.

[0068] [ka] Scheme 6: Step A illustrates the reaction of compound 42a with hydrazine hydrate and an acid such as AcOH, followed by reaction of the intermediate with sodium nitrite to give compound 42b. Step B illustrates the reaction of compound 42b with tributyl(prop-1-yn-1-yl)stannane in a solvent such as toluene to give compound 42c. Step C illustrates 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 illustrates the protection of compound 42e with BocO using a base such as DMAP in a solvent such as DCM to give compound 42f. Step E illustrates the 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 illustrates the acid deprotection of compound (42g) using an acid such as HCl in a solvent such as dioxane to give compound (42h). Step G illustrates the Stille coupling of compound (43) with compound (42c) in a solvent such as DMF using a catalyst system such as Pd(PPh3)4 and CuI to give compound (44). Step H illustrates 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 K3PO4 to form compound (45). Step I illustrates the acid deprotection of compound (45) using an acid such as TFA in a solvent such as DCM to give compound (46).

[0069] [ka] Scheme 7: Step A illustrates the conversion of compound 47 to compound 48 by the addition of 6-fluoronicotinaldehyde using a strong base such as LDA in a solvent such as THF. Step B illustrates the reduction of compound 48 to compound 49 using Pd / C in the presence of H gas in a solvent such as EtOH. Step C illustrates the coupling of compound 49 with an amine compound such as 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine using a coupling agent such as TBTU and a base such as DIPEA in a solvent such as DMAP to give compound 50. Those skilled in the art will appreciate that many other amide coupling agents, bases, and solvents can be used to effect this coupling. Step D illustrates the conversion of compound 50 to compound 51 through a two-step reaction involving acyl transfer followed by intramolecular cyclization using a base such as t-BuOK in a solvent such as DMF.

[0070] In the following scheme, when n is 1, R 6 is H, OTBDPS, or OH; when n is 0, R 6 is H; Ar is aryl; Z is CH, N or CR c is. [ka]

[0071] Scheme 8: Step A illustrates 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 illustrates the amide coupling of compound 53 and acyl chloride 54 using a base such as TEA or pyridine in a solvent such as ACN / DCM to form compound 55. Step C illustrates the conversion of compound 55 to compound 58 using a base such as t-BuOK or KCO in a solvent such as ACN.

[0072] Alternatively, compound 58 can be prepared as shown in Step D, which depicts protecting compound 56 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 oxidizing compound 57 using reagents such as RuCl.HO and NaClO in a solvent such as EtOAc to form compound 58.

[0073] Step F shows the 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). 6 The TBDPS group in (59) may be optionally deprotected using TBAF in a solvent such as THF to generate an alcohol group. Step G illustrates the Stille coupling of compound (59) with a pyridazine tin compound in a solvent such as dioxane in a catalytic system such as Pd(tBuP) and CsF or Pd(PPh) to form compound (60). Alternatively, compound (59) can be coupled with bis(pinacolato)diboron in a solvent such as dioxane in a catalytic system such as Pd(dppf)Cl and a base such as KOAc. The boronate ester intermediate is then coupled with a pyridazine compound in a solvent such as dioxane in a catalytic system such as Pd(dppf)Cl and a base such as KCO to give compound (60). Step H illustrates the acid deprotection of compound (60) using 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 depicts the reaction of compound (61) with di-tert-butyl(chloromethyl)phosphate using a base such as CsCO or CsF in a solvent such as DMF to form isomeric compounds (62) and (63). Step J depicts the acid deprotection of compounds (62) and (63) using an acid such as TFA or AcOH in a solvent such as DCM or HO to give compounds (64) and (65).

[0074] [ka] Scheme 9: Step A illustrates the coupling of compounds (66) and (67) using a base such as KCO in a solvent such as ACN to give compound (68). Step B illustrates the dechlorination of compound (68) in a solvent such as EtOH in a catalytic system such as Pd(OAc) , PPh , and EtSiH and a base such as TEA to give compound (69). Step C illustrates the saponification of compound (69) using a base such as LiOH in a solvent such as THF and HO to give compound (70). Step D illustrates the reaction of compound (70) with DPPA using a base such as DiPEA in a solvent such as t-BuOH and dioxane to give compound (71). Step E illustrates the acid deprotection of compound (71) using an acid such as HFIP to give compound (72). Step F depicts the amide coupling of compounds (72) and (73) using a coupling agent such as POCl in a solvent such as pyridine to form compound (74). Step G depicts the cyclization reaction of compound (74) using a base such as KCO in a solvent such as ACN to give compound (75).

[0075] In the scheme below, R a is H or Cl. [ka] Scheme 10: Step A illustrates the chlorination of compound 76 with sulfuryl chloride in a solvent such as DCM to give compound 77. Step B illustrates the conversion of compound 77 to ester 78 with a base such as NaOH in a solvent such as MeOH. Step C illustrates the bromination of compound 78 with bromine in an acid solution such as AcOH to give compound 79. Step D illustrates the coupling of compounds 79 and 80 with a catalyst system such as CuI and N,N'-dimethyl-1,2-cyclohexanediamine in a solvent such as DMF using a base such as KPO to give compound 81. Step E illustrates the bromination of compound 81 with NBS in a solvent such as DCM to give compound 82. Step F illustrates the reaction of protecting compound (82) with SEM-Cl using a base such as NaH in a solvent such as THF to obtain compound (83). Step G illustrates the Stille coupling of compound (83) with a pyridazine tin compound in a catalyst system such as Pd(tBuP) and CsF in a solvent such as dioxane to form compound (84). Step H illustrates the saponification of compound (84) using a base such as LiOH in a solvent such as THF and HO to obtain compound (85). Step I illustrates the amide coupling of compound (85) with NH4Cl using a coupling agent such as HATU and a base such as DIPEA in a solvent such as DMF to form compound (86). Step J illustrates the conversion of the amide compound (86) to a nitrile using SOCl2 in a solvent such as DMF to obtain compound (87). Step K depicts the acid deprotection of compound (87) using an acid such as TFA in a solvent such as DCM to give compound (88).

[0076] [ka] Scheme 11: Step A illustrates the reaction of compound 89 with hydrazine in a solvent such as EtOH to give compound 90. Step B illustrates the intermolecular cyclization of compounds 90 and 91 in a solvent such as EtOH using a base such as KCO to form compound 92. Step C illustrates the dechlorination of pyrazidine compound 92 in a solvent such as MeOH using Pd / C and H gas to give compound 93. Step D illustrates the Sandmeyer reaction of compound 93 using tert-butyl nitrate and CuCl in a solvent such as ACN to give compound 94. Step E illustrates the saponification of compound 94 in a solvent such as THF and HO using a base such as LiOH to give compound 95. Step F illustrates the bromination of compound (95) using bromine and a base such as NaOH in a solvent such as HO to form compound (96). Step G illustrates the coupling reaction of compounds (96) and (97) in a solvent such as DMF using a base such as KPO in a catalyst system such as CuI and N,N'-dimethyl-1,2-cyclohexanediamine to give compound (98).

[0077] [ka] Scheme 12: Step A illustrates 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 illustrates the hydrogenation of compound 100 using Pd / C and H gas in a solvent such as MeOH to form compound 101. Step C illustrates the coupling of compounds 101 and 102 using a base such as pyridine in a solvent such as DCM, followed by a base such as KCO in a solvent such as MeOH to give compound 103. Step D illustrates the cyclization of compound 103 using a base such as KCO in a solvent such as ACN to give compound 104. Step E illustrates the reaction of compound 104 with an aryl bromo compound using a base such as LiHMDS in a solvent such as THF to give compound 105. Step F illustrates the acid deprotection of compound (105) using an acid such as TFA in a solvent such as DCM to form compound (106). Step G illustrates the iodination of compound (106) using NIS in a solvent such as ACN to form compound (107). Step H illustrates the reaction of compound (107) using NaSO in a solvent mixture such as EtOH, HO, and ACN to form compound (108). Step I illustrates the Stille coupling of compound (108) with pyridazine compound (109) in a catalyst system such as Pd(dba) and XPhos in a solvent such as DMF to form compound (110).

[0078] [ka] Scheme 13: Step A illustrates the reaction of compound 111 with an aryl bromo compound using a base such as LiHMDS in a solvent such as THF to form compound 112. Step B illustrates the acid deprotection of compound 112 using an acid such as HCl in a solvent such as dioxane to form compound 113. Step C illustrates the cyclization of compound 114 using an aryl amine compound in a solvent such as toluene to form compound 115. Step D illustrates the reaction of compound 115 with an aryl bromo compound using a base such as LDA in a solvent such as THF to form compound 116. Step E illustrates the conversion of the carboxylic acid compound 116 to an amide using BocO, NHHCO, and a base such as pyridine in a solvent such as ACN to form compound 117. Step F illustrates the conversion of amide compound (117) to a nitrile using POCl in a solvent such as DMF to give compound (118). Step G illustrates the acid deprotection of compound (118) using an acid such as triflic acid in a solvent such as TFA to give compound (113). Step H illustrates the coupling reaction of compounds (119) and (113) using a base such as KPO in a catalyst system such as CuI and N,N'-dimethyl-1,2-cyclohexanediamine in a solvent such as DMF to give compound (120). Step I illustrates the reduction of aldehyde compound (120) using a reducing agent such as NaBH in a solvent such as MeOH to give compound (121). Step J illustrates the acid deprotection of compound (121) using an acid such as TFA in a solvent such as DCM to give compound (122).

[0079] Modifier 1 2-Methyl-3-(5-methylpyridazin-4-yl)-3-oxopropanenitrile [ka] To a mixture of propiononitrile (500 mg, 9 mmol) in THF (10 mL) was slowly added LiHMDS (1.6 M / THF, 5.6 mL, 9 mmol) at -60 °C. The reaction mixture was stirred for 1 hour, and then a solution of ethyl 5-methylpyridazine-4-carboxylate (747 mg, 4.5 mmol) in THF (5 mL) was slowly added at -60 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (788 mg, crude). ES / MS m / z 176 (M+H).

[0080] The compounds listed in Table 1 were prepared by methods essentially similar to those found in Preparation 1. [Table 1]

[0081] Modifier 2a 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole [ka] To 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 h, and then 2-(chloromethoxyethyl)trimethylsilane (8.94 g, 53.6 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with ice water and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product as a yellow oil (9.50 g, crude). ES / MS (m / z): 233 (M+H).

[0082] Modifier 2b 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde [ka] To 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 minutes, and then DMF (14.9 g, 204 mmol) was added at the same temperature. The reaction mixture was stirred at −78° C. for 2 hours, then quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with EtOAc / petroleum ether (0–20%)) to give the title compound as a yellow oil (6.20 g, 53% for both steps). ES / MS (m / z): 233 (M-28+H).

[0083] Modifier 2c Ethyl 3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate [ka] To 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 h. The solvent was removed to give the crude product, which was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0-50%)) to give the title compound as a colorless oil (1.3 g, 98%). ES / MS (m / z): 305 (M+H).

[0084] Modulation 2e (3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)methanol [ka] To 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 LiAlH (3.2 mL, 6.4 mmol, 2M in THF). The mixture was stirred at 0 °C for 2 h. 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 under reduced pressure to give the title compound as a colorless oil (1.05 g, 93%). ES / MS (m / z): 263 (M+H).

[0085] Modifier 2j tert-Butyl 3-(4-chloro-3-fluorobenzyl)-2-oxopyrrolidine-1-carboxylate [ka] To a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (3 g, 16.2 mmol) in THF (15 mL) was added dropwise LiHMDS (21.1 mL, 1 M / THF, 21.1 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 hour, and 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 an additional 2 hours and then quenched with saturated NH4Cl (50 mL). The mixture was extracted with EtOAc (80 mL × 3). The combined organic layers were washed with water (50 mL) and saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / 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).

[0086] The compounds listed in Table 1c were prepared by essentially the same method as found in Preparation 2j. [Table 2] [Table 3]

[0087] Modifier 2aa 3-(4-chloro-3-fluorobenzyl)pyrrolidin-2-one [ka] To 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 (4 M in dioxane, 10 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure to give the title compound as a white solid (750 mg, 92%). ES / MS (m / z): 228 (M+H).

[0088] The compounds listed in Table 1d were prepared by methods essentially similar to those found in Preparation 2aa. [Table 4] [Table 5]

[0089] Modifier 2aq 1-(3-Bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-5-hydroxy-3-(3,4,5-trifluorobenzyl)piperidin-2-one [ka] To 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 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0-50%)) to give the title compound as a yellow oil (860 mg, 74%). ES / MS (m / z): 527 (M+H).

[0090] Modified 2au 1-Bromo-4-fluoro-2-(fluoromethyl)benzene [ka] To a solution of (2-bromo-5-fluorophenyl)methanol (CAS Registry Number: 202865-66-5) (3.00 g, 14.6 mmol) in DCM (30 mL) was added DAST (2.03 mL, 15.4 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 2 hours and then warmed to ambient temperature. The reaction was quenched with 1 N NaHCO (30 mL). The mixture was extracted with DCM (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0–3%)) to give the title compound as a colorless oil (2.86 g, 91.3%). 1 H 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).

[0091] The compounds listed in Table 1f were prepared by essentially the same method as found in Preparation 2au. [Table 6]

[0092] Modified 2aw 4-Fluoro-2-(fluoromethyl)benzaldehyde [ka] n-BuLi (2.125 mL, 2.5 M / 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 at −78° C. for 4 h. The reaction was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0–3%)) to give the title compound as colorless crystals (240 mg, 29.2%). 1 H 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).

[0093] Modifier 2ax 1-(Bromomethyl)-4-fluoro-2-(fluoromethyl)benzene [ka] To a solution of 4-fluoro-2-(fluoromethyl)benzaldehyde (400 mg, 2.28 mmol) in MeOH (4 mL) was added NaBH (173 mg, 4.56 mmol) at ambient temperature. After stirring at 25 °C for 1 h, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product.

[0094] To a solution of the crude product (385 mg, 2.43 mmol) in DCM (2 mL) was added PBr (1.36 g, 5.01 mmol) at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was quenched with saturated NaHCO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brownish oil (290 mg, 52% combined for two steps). 1 H 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).

[0095] The compounds listed in Table 1g were prepared by methods essentially similar to those found in Preparation 2ax. [Table 7]

[0096] 2bg of modifier tert-Butyl 3-hydroxy-2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidine-1-carboxylate [ka] To 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 dropwise NaHMDS (918 mg, 5.01 mmol) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 1 hour. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (1.01 g, 3.85 mmol) in THF (10 mL) was added dropwise to the mixture at −78° C. After stirring at −78° C. for 30 minutes, the reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (200 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0-20%)) to give the title compound as a white solid (500 mg, 18.9%). ES / MS (m / z): 290 (M+H).

[0097] Modifier 2bh 2-(Difluoromethyl)-4-fluoro-1-methylbenzene [ka] To 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 and stirred at ambient temperature for 16 h. The reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with petroleum ether (100%)) to give the title compound (5.00 g, 72%) as a colorless oil. ES / MS (m / z): 161 (M+H).

[0098] The compounds listed in Table 1h were prepared by essentially the same method as found in Preparation 2bh. [Table 8]

[0099] Modified 2bo Methyl 6-(difluoromethyl)nicotinate [ka] To a mixture of 5-bromo-2-(difluoromethyl)pyridine (2.00 g, 9.7 mmol) in DMF (10 mL) was added EtN (2.94 g, 29.1 mmol), MeOH (995 μL, 24.6 mmol), and Pd(OAc) (216 mg, 0.97 mmol). The reaction mixture was stirred at 75 °C under a CO atmosphere for 24 hours and then cooled to ambient temperature. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (1%)) to give the title compound (1.5 g, 82%) as a colorless oil. ES / MS (m / z): 188 (M+H).

[0100] The compounds listed in Table 1i were prepared by essentially the same method as found in Preparation 2bo. [Table 9]

[0101] Modulation 2bt (6-(difluoromethyl)pyridin-3-yl)methanol [ka] To a solution of methyl 6-(difluoromethyl)nicotinate (500 mg, 2.7 mmol) in THF (6 mL) was added a 1 M solution of LiAlH in THF (3.24 mL, 3.24 mmol) at ambient temperature, followed by stirring at 25 °C for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (40 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (170 mg, 40%) as a yellow oil. ES / MS (m / z): 160 (M+H).

[0102] The compounds listed in Table 1j were prepared by essentially the same method as found in Preparation 2bt. [Table 10]

[0103] Modified 2bv 5-(Bromomethyl)-2-(difluoromethyl)pyridine [ka] To 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, followed by stirring at 25 °C for 2 h. The reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (15 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with petroleum ether (100%)) to give the title compound (70 mg, 30%) as a colorless oil. ES / MS (m / z): 224 (M+H).

[0104] The compounds listed in Table 1k were prepared by essentially the same method as found in Preparation 2bv. [Table 11]

[0105] Modifier 3 4-Methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-amine [ka] To 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) at 80 °C for 16 h. The mixture was stirred at 80 °C for 16 h. Saturated aqueous NaCO solution was then added to the reaction mixture to adjust the pH to 8-9, and the organic solvent was then removed under reduced pressure. Water (20 mL) was added, and the mixture was stirred for 1 h. The resulting solid was filtered, and the cake was washed with water (10 mL × 2) and dried at 60 °C for 10 h to give the title compound (500 mg, 57%) as a brown solid. ES / MS m / z 176 (M+H).

[0106] The compounds listed in Table 2 were prepared by methods similar to those found in Preparation 3. [Table 12]

[0107] Modifier 4a Chloro-2-fluoro-4-iodo-5-methoxybenzene [ka] To 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 h, the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with DCM (100 mL), washed with sodium sulfite solution (100 mL × 2), saturated aqueous NaCl solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with 0-1% EtOAc / petroleum ether) to give the title compound as a colorless oil (8.00 g, 86.7%). 1 HNMR (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).

[0108] Modifier 4b 1-chloro-2-fluoro-5-methoxy-4-methylbenzene [ka] To 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 / 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 under nitrogen for 2 hours. After cooling to ambient temperature, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with EtOAc / petroleum ether (0-1%) to give the title compound as a colorless oil (880 mg, 36%). 1 HNMR (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).

[0109] Modifier 4c 1-(Bromomethyl)-4-chloro-5-fluoro-2-methoxybenzene [ka] To 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 under nitrogen for 16 h. After cooling to ambient temperature, the reaction mixture was quenched with water (15 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with sodium thiosulfate (20 mL × 2), saturated aqueous NaCl (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0–1%)) to give the title compound as a white solid (900 mg, 71%). 1 H 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).

[0110] The compounds listed in Table 2a were prepared by essentially the same method as found in Preparation 4c. [Table 13]

[0111] Modulation 4i tert-Butyl 5-chloropentanoate [ka] To 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, 65 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 3 hours. The mixture was poured into sodium bicarbonate solution (150 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with 1N HCl (200 mL), saturated aqueous NaCl (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound as a yellow oil (13.0 g, 73%). 1 H NMR (DMSO-d6) 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).

[0112] Modifier 4j tert-Butyl 5-chloro-2-(4-chloro-5-fluoro-2-methoxybenzyl)pentanoate [ka] To a solution of LDA (3.87 mL, 2M / 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) under nitrogen protection at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. 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 hours. The reaction mixture was quenched with ammonium chloride solution (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with saturated aqueous NaCl solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc / petroleum ether (0-5%)) to give the title compound as a yellow oil (770 mg, 28.3%).1 H 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).

[0113] The compounds listed in Table 2b were prepared by essentially the same method as found in Preparation 4j. [Table 14]

[0114] Modifier 4l 5-chloro-2-(4-chloro-5-fluoro-2-methoxybenzyl)pentanoic acid [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brown oil, which was used in the next step (660 mg, crude). ES / MS (m / z): 309 (M−H).

[0115] The compounds listed in Table 2c were prepared by essentially the same method as found in Preparation 4l. [Table 15]

[0116] Modifier 4n Methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate [ka] To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (3.0 g, 10.74 mmol) in MeOH (40 mL) was added SOCl (2.56 g, 21.48 mmol) at 0 °C, and the mixture was stirred at 70 °C for 16 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure to give the title compound as a colorless oil (2.9 g, 80%). ES / MS (m / z): 293 (M+H).

[0117] Modifier 4o 1-(2,4-Dimethoxybenzyl)-4-(hydroxymethyl)pyrrolidin-2-one [ka] To a solution of methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (2.50 g, 7.50 mmol) in MeOH (40 mL) was added NaBH (1.419 g, 37.50 mmol) at ambient temperature. The reaction mixture was stirred at 50 °C under nitrogen for 4 h. After cooling to ambient temperature, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with EtOAc / petroleum ether (0–100%)) to give the title compound as a yellow oil (2.1 g, 89%). ES / MS (m / z): 265 (M+H).

[0118] Modifier 4p 2-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole [ka] To 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 at 0 °C for 1 h, and then (2-(chloromethoxy)ethyl)trimethylsilane (16.22 g, 97.28 mmol) was added to the mixture at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (EtOAc / petroleum ether (0–25%)) to give the title compound as a yellow solid (20.0 g, 92%). ES / MS (m / z): 186 (M+H).

[0119] Modifier 4q 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-amine [ka] 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 at 25 °C with a hydrogen balloon attached for 16 h. The mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated to give the title compound as a black oil (16.8 g, 97%). ES / MS (m / z): 214 (M+H).

[0120] Modifier 4r 5-chloro-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pentanamide [ka] To 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 h, the reaction mixture was washed with saturated aqueous sodium bicarbonate (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (200 mL), and KCO (43.09 g, 311.8 mmol) was added. After stirring at 25 °C for 4 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (22.0 g, 84%). ES / MS (m / z): 332 (M+H).

[0121] Modifier 4s 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidin-2-one [ka] To 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 h. After cooling to ambient temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with MeOH / DCM (0-5%)) to give the title compound as a yellow oil (17.0 g, 96%). ES / MS (m / z): 296 (M+H).

[0122] 4t of modifier 3-(3,4-Difluorobenzyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidin-2-one [ka] To 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, 1 M / THF, 67.01 mmol) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 2 hours, and then a solution of 4-(bromomethyl)-1,2-difluorobenzene (2.428 g, 11.73 mmol) in THF (20 mL) was slowly added. After stirring at −78° C. for 1 hour, the reaction mixture was quenched with ammonium chloride (30 ml) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0-40%)) to give the title compound as a yellow oil (3.80 g, 51%). ES / MS (m / z): 422 (M+H).

[0123] Modified 4u 3-(3,4-Difluorobenzyl)-1-(1H-imidazol-2-yl)piperidin-2-one [ka] To 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 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (2.60 g, 98%). ES / MS (m / z): 292 (M+H).

[0124] Modified 4V 3-(3,4-Difluorobenzyl)-1-(4,5-diiodo-1H-imidazol-2-yl)piperidin-2-one [ka] To 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 slowly added a solution of 1-iodopyrrolidine-2,5-dione (2.26 g, 10.04 mmol) in ACN (20 mL) at 25 °C. After stirring at 25 °C for 2 hours, the reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was concentrated under reduced pressure to give the crude product as a brown oil (3.50 g, 65%). ES / MS (m / z): 544 (M+H).

[0125] The compounds listed in Table 2d were prepared by essentially the same method as found in Preparation 4v. [Table 16]

[0126] Modified 4x 3-(3,4-Difluorobenzyl)-1-(4-iodo-1H-imidazol-2-yl)piperidin-2-one [ka] A 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 h. After cooling to ambient temperature, the reaction mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with EtOAc / petroleum ether (0–15%)) to give the title compound (1.40 g, 67%) as a yellow oil. ES / MS (m / z): 418 (M+H).

[0127] The compounds listed in Table 2e were prepared by essentially the same method as found in Preparation 4x. [Table 17]

[0128] Modified 4z 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidine [ka] To 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 minutes, and then SEM-Cl (150 mL, 846.3 mmol) was added at 10 °C. The mixture was warmed and stirred at ambient temperature for 2 hours. Piperidine (340 mL, 3.438 mol) was added to the above solution at ambient temperature. The resulting mixture was heated to °C and stirred for 16 hours. The reaction mixture was poured into ice water (1.5 L) and extracted with EtOAc (1.5 L × 3). The combined organic layer was washed with 1N HCl, saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0-30%)) to give the title compound as a white solid (230 g, 96.6%). ES / MS (m / z): 363 (M+H).

[0129] The compounds listed in Table 2f were prepared by methods essentially similar to those found in Preparation 4z. [Table 18]

[0130] Modifier 4ac 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one [ka] To 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 minutes. 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 to ambient temperature and stirring for 16 hours, the mixture was filtered to remove solids. The filtrate was extracted with EtOAc (1 L × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography eluting with EtOAc / petroleum ether (0-30%) to give the title compound as a pale yellow oil (95 g, 75%). ES / MS (m / z): 375 (M+H)

[0131] The compounds listed in Table 2g were prepared by methods essentially similar to those found in Preparation 4ac. [Table 19]

[0132] Modified 4af 3,5-Dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole [ka] To 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. 1-Chloromethyl-4-methoxy-benzene (1.04 g, 6.61 mmol) was added to the mixture, which was stirred at ambient temperature for 16 hours, diluted with water (10 mL), and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (eluted with EtOAc / 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).

[0133] 4ag of modifier 3,5-Dibromo-4-methyl-1H-pyrazole [ka] To a solution of 3,4,5-tribromo-1H-pyrazole (5 g, 16.55 mmol) in THF (25 mL) was added n-BuLi (2.5 M / THF, 14.6 mL, 36.45 mmol) dropwise at −78° C. The mixture was stirred at −78° C. for 30 minutes, 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 an additional hour, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography and Prep-HPLC to give the title compound (1.52 g, 38.6%) as a white solid. ES / MS (m / z): 239 (M+H).

[0134] Modified 4ah 3,5-Dibromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] To a suspension of 3,5-dibromo-4-methyl-1H-pyrazole (1.52 g, 6.39 mmol) in THF (15 mL) was added NaH (60% / oil, 307 mg, 7.67 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 30 min, followed by the addition of SEM-Cl (1.06 g, 6.39 mmol) at 0 °C. After stirring at 0 °C for 2 h, the mixture was treated with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with EtOAc / 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).

[0135] Modified 4ai 1,2,4,5-tetrazine [ka] Formamidine acetate (60.0 g, 576.3 mmol) was cooled to 0°C in an ice-water bath, and then hydrazine hydrate (94.72 mL, 1.556 mol) was added dropwise. The reaction mixture was stirred at 25°C for 1 hour and then re-cooled to 0°C. Water (20 mL) was added to the reaction mixture, and the mixture was stirred at 0°C for an additional 1 hour. 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 portionwise to the reaction mixture at 0°C. After stirring at 0°C for 1 hour, the reaction was quenched with water (300 mL) and extracted with DCM (300 mL x 4). The organic layer was washed with saturated NaHCO3 until neutral, dried over MgSO4, filtered and concentrated under reduced pressure at 25 C to give the title compound as a red solid (7.41 g, 12.7%). 1 HNMR (CDCl3) δ 10.41 (s, 2 H).

[0136] Modulation 4aj 4-Methyl-5-(tributylstannyl)pyridazine [ka] To a stirred solution of tributyl(prop-1-yn-1-yl)stannane (182.9 g, 555.6 mmol) in toluene (1.5 L) at 120 °C, 1,2,4,5-tetrazine (38.00 g, 463.0 mmol) was slowly added. After stirring at 120 °C for 30 min, the mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0-10%)) to give the title compound as a yellow oil (151.0 g, 84%). ES / MS (m / z): 385 (M+H).

[0137] Modified 4ak (5-(trimethylstannyl)pyridazin-4-yl)methanol [ka] To 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 was stirred at 60° C. for 2 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated sodium carbonate solution (30 mL) and saturated aqueous NaCl solution (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a solid (528 mg, 71.2%): ES / MS (m / z): 275 (M+H).

[0138] Modified 4al 4-(Methoxymethyl)-5-(trimethylstannyl)pyridazine [ka] To 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, and then MeI (96.7 mg, 682 μmol) was added at the same temperature. After stirring at 0° C. for 6 h, the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with saturated aqueous NaCl solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brown oil. (120 mg, 46%): ES / MS (m / z): 289.0 (M+H).

[0139] Modified 4am (2-amino-4-chlorophenyl)methanol [ka] To a 1M solution of BH3 in THF (39.6 mL, 39.6 mmol), 2-amino-4-chlorobenzoic acid (2.00 g, 11.7 mmol) was added portionwise, followed by stirring at 25 °C for 3 days. The mixture was quenched with MeOH (200 mL) and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (1:1)) to give the title compound (1.40 g, 71%) as a white solid. ES / MS (m / z): 158 (M+H).

[0140] The compounds listed in Table 2h were prepared by methods essentially similar to those found in Preparation 4am. [Table 20]

[0141] Modified 4ao tert-Butyl (5-chloro-2-(hydroxymethyl)phenyl)carbamate [ka] To 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, followed by stirring at 50 °C under N2 for 2 days. The mixture was concentrated under reduced pressure to give the title compound (10.01 g, 99%+%) as a yellow oil. ES / MS (m / z): 184 (M+H-Boc). 1 H 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).

[0142] Modulation 4ap tert-Butyl (2-(bromomethyl)-5-chlorophenyl)carbamate [ka] To a solution of tert-butyl (5-chloro-2-(hydroxymethyl)phenyl)carbamate (5.00 g, 19.4 mmol) in THF (50 mL) were added triphenylphosphine (7.63 g, 29.1 mmol) and NBS (5.18 g, 29.1 mmol) in small portions. After stirring at 25 °C for 2 h, the reaction mixture was added to water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (9:1)) to give the title compound (5.9 g, 76%) as a yellow solid. ES / MS (m / z): 264 (M+Ht-Bu).

[0143] The compounds listed in Table 2i were prepared by methods essentially similar to those found in Preparation 4ap. [Table 21]

[0144] Modifier 5 5-Methylpyridazine-4-carbohydrazide [ka] To 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 at 120 °C for 2 h and then concentrated under reduced pressure to give the title compound (6 g, crude) as a yellow solid. ES / MS m / z 153 (M+H).

[0145] Modifier 6 2-(5-methylpyridazine-4-carbonyl)hydrazine-1-carboximidamide [ka] To a solution of the crude product, 5-methylpyridazine-4-carbohydrazide (6 g, 39.21 mmol) in water (20 mL), methylcarbamimidothioate sulfate (8.18 g, 58.82 mmol) and NaOH (1.17 g, 29.39 mmol) were added, and the mixture was stirred at ambient temperature for 16 hours. The resulting precipitate was filtered and dried under reduced pressure to give the title compound (4 g, 52.6%) as a yellow solid. ES / MS (m / z): 195 (M+H).

[0146] Modifier 7 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine [ka] To a solution of 2-(5-methylpyridazine-4-carbonyl)hydrazine-1-carboximidamide (4 g, 20.51 mmol) in 20 mL of HCl was added NaOH (8 mg, 0.2 mmol), and the solution was stirred at 100° C. for 16 h. The resulting solid was filtered and dried under reduced pressure to give the title compound (3.1 g, 85%) as a white solid. ES / MS m / z 177 (M+H).

[0147] Modified 8 1-(4-Methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-amine [ka] To a stirred mixture of crude 3-(5-methylpyridazin-4-yl)-3-oxopropanenitrile (10.3 g, 64 mmol) in EtOH (120 mL), AcOH (11.7 g, 192 mmol) was slowly added, followed by (4-methoxybenzyl)hydrazihydrochloride (18 g, 96 mmol), and the reaction mixture was then stirred at reflux overnight. The mixture was concentrated to dryness. The residue was purified by 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).

[0148] Modifier 8a 4-Methoxypyridazine [ka] To 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 warmed to ambient temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluting with MeOH / DCM (0-3%)) to give the title compound as a black oil (1.5 g, 68%). ES / MS (m / z): 111 (M+H).

[0149] Modifier 8b 4-Bromo-5-methoxypyridazine [ka] To 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 h. After cooling to ambient temperature, the reaction mixture was quenched with sodium sulfite solution (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with MeOH / DCM (0-3%)) to give the title compound as a brown oil (180 mg, 21.3%). ES / MS (m / z): 189 (M+H).

[0150] Modifier 8c 4-Methoxy-5-(trimethylstannyl)pyridazine [ka] To a solution of 4-bromo-5-methoxypyridazine (250 mg, 1.26 mmol) in 1,4-dioxane (5 mL) at ambient temperature, bis-(triphenylphosphino)-palladium chloride (88.3 mg, 126 μmol) and 1,1,1,2,2,2-hexamethyldistannane (824 mg, 2.52 mmol) were added. The reaction mixture was stirred at 100° C. under nitrogen for 16 hours. After cooling to ambient temperature, aqueous potassium fluoride (20 mL) was added to the reaction mixture. After stirring at 20° C. for 0.5 hours, the reaction mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (250 mg, 20.4%) as a brown oil. ES / MS (m / z): 275 (M+H).

[0151] Modulation 8d 3-chloro-5-hydrazinylpyridazine [ka] To a solution of 3,5-dichloropyridazine (10.0 g, 67.1 mmol) in EtOH (150 mL) was added dropwise hydrazine hydrate (4.30 g, 134 mmol) at 80° C. The mixture was stirred at 80° C. for 1 hour. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to give the crude title compound as a yellow solid (9.0 g, 78%). ES / MS (m / z): 145 (M+H).

[0152] Modifier 8e Ethyl 5-amino-1-(6-chloropyridazin-4-yl)-1H-pyrazole-4-carboxylate [ka] A mixture of 3-chloro-5-hydrazinylpyridazine (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 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), and water (100 mL) was added and separated. The aqueous layer was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluting with EtOAc / 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).

[0153] Modifier 8f Ethyl 5-amino-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylate [ka] A 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 with a hydrogen balloon attached for 3 h. After cooling to ambient temperature, the mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure. 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).

[0154] The compounds listed in Table 2h were prepared by essentially the same method as found in Preparation 8f. [Table 22]

[0155] Preparation 8h Ethyl 5-chloro-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylate [ka] A mixture of tert-butyl nitrite (0.79 g, 7.7 mmol) and CuCl (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 h, the reaction was cooled to ambient temperature, quenched with ammonium hydroxide (100 mL), and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0–30%)) to give the title compound as a yellow solid (1.2 g, 90%). ES / MS (m / z): 253 (M+H).

[0156] Modulation 8i 5-chloro-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylic acid [ka] To 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 hours, the pH of the reaction mixture was adjusted to 4 with HCl (2 M) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1 g, 90%) as a yellow solid. ES / MS (m / z): 225 (M+H).

[0157] The compounds listed in Table 2i were prepared by essentially the same method as found in Preparation 8i. [Table 23]

[0158] Modified 8k 4-(4-bromo-5-chloro-1H-pyrazol-1-yl)pyridazine [ka] To 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 h, the reaction mixture was treated with water (10 mL) and extracted with EtOAc (100 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0–30%)) to give the title compound (120 mg, 32%) as a yellow solid. ES / MS (m / z): 259 (M+H).

[0159] The compounds listed in Table 2j were prepared by essentially the same method as found in Preparation 8k. [Table 24]

[0160] Modified material 8m Methyl 2-(6-chloropyridazin-4-yl)-2H-1,2,3-triazole-4-carboxylate [ka] To a solution of methyl 2H-1,2,3-triazole-4-carboxylate (2.0 g, 15.7 mmol) in anhydrous 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 h. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluting with EtOAc / 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).

[0161] Modifier 8n Methyl 2-(pyridazin-4-yl)-2H-1,2,3-triazole-4-carboxylate [ka] To 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 EtSiH (1.4 g, 12 mmol), TEA (1.22 g, 12 mmol), PPh (157 mg, 0.6 mmol), and Pd(OAc) (135 mg, 0.6 mmol) at ambient temperature. After purging with N and degassing three times, the mixture was stirred at 60 °C under nitrogen for 2 h. After cooling to ambient temperature, the solution was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (eluting with 0–50% EtOAc / petroleum ether) to give the title compound as an off-white solid (1.2 g, 98%). ES / MS (m / z): 206 (M+H).

[0162] Modified 8o 2-(pyridazin-4-yl)-2H-1,2,3-triazole-4-carboxylic acid [ka] To 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·HO (901 mg, 21.5 mmol) at ambient temperature. After stirring at ambient temperature for 2 hours, the pH of the reaction mixture was adjusted to 3 with 1 N 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).

[0163] Modified 8p tert-Butyl (2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-yl)carbamate [ka] To 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 °C for 3 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (eluting with MeOH / DCM (0-10%)) to give the title compound as a brown solid (871 mg, 85%). ES / MS (m / z): 263 (M+H).

[0164] Modified 8q 2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-amine [ka] A 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 hours. The solvent was removed to give the crude product, which was washed with MeOH to give the title compound as a brown solid. ES / MS (m / z): 163 (M+H).

[0165] Modified 8r 4-Bromopyridazine [ka] To a suspension of copper 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 h, after which pyridazin-4-amine (19.00 g, 199.8 mmol) was added to the mixture. After stirring at 65 °C for 3 h, the reaction mixture was cooled to ambient temperature, quenched by the addition of ammonium hydroxide (100 mL), and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0–20%)) to give the title compound as a yellow solid (15 g, 44%). ES / MS (m / z): 161 (M+H).

[0166] Modified material 8s 4-(4-Bromo-1H-pyrazol-1-yl)pyridazine [ka] To 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 h, the reaction mixture was cooled to ambient temperature, quenched by the addition of water (100 mL), and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with EtOAc / petroleum ether (0–30%)) to give the title compound as a yellow solid (8 g, 50%). ES / MS (m / z): 227 (M+H).

[0167] The compounds listed in Table 2k were prepared by methods essentially similar to those found in Preparation 8s. [Table 25]

[0168] Modified 8u 4-Bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbaldehyde [ka] To 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 hour, after which DMF (2.93 g, 40.1 mmol) was added dropwise to the mixture. After stirring for 3 hours, the reaction was slowly quenched with water (50 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (1.00 g, 37.5%). ES / MS (m / z): 253 (M+H).

[0169] Modified 8V (4-Bromo-1-(pyridazin-4-yl)-1H-pyrazol-5-yl)methanol [ka] To a solution of 4-bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbaldehyde (1.00 g, 1.50 mmol) in MeOH (20 mL) at 20 °C was added NaBH (171 mg, 4.51 mmol). The reaction was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (eluting with MeOH / DCM (0-5%)) to give the title compound as a yellow solid (300 mg, 75.5%). ES / MS (m / z): 255 (M+H).

[0170] Modified 8w 4-(4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazol-1-yl)pyridazine [ka] To 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 h. After cooling to ambient temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (eluted with EtOAc / petroleum ether (0–20%)) to give the title compound as a white solid (320 mg, 73.3%). ES / MS (m / z): 369 (M+H).

[0171] Modified 8x (E)-3-Bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbaldehyde oxime [ka] To a mixture of 4-(3-bromo-1H-pyrazol-1-yl)pyridazine (760 mg, 3.32 mmol) in THF (20 mL) was added dropwise LDA (2.0 M / THF, 4.97 mmol) under nitrogen at −78° C. The mixture was stirred at −78° C. for 1 hour, and then DMF (485 mg, 6.63 mmol) was added. After stirring at −78° C. for 4 hours, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product.

[0172] To a suspension of the crude product (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 h and then filtered to remove inorganic salts. The filtrate was concentrated under reduced pressure. 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 under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with MeOH / DCM (0-3%)) to give the title compound as a brownish solid (290 mg, 80.9%). ES / MS (m / z): 268 (M+H).

[0173] Modified 8y 3-Bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbonitrile [ka] To 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) followed by TEA (509 mg, 5.03 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hours, and then oxalyl chloride (639 mg, 5.03 mmol) was added. After stirring at ambient temperature for 16 hours, the mixture was quenched with water (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with MeOH / DCM (0-2%)) to give the title compound as a brown solid (110 mg, 40.2%) ES / MS (m / z): 268 (M+H).

[0174] Modified 8z Ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate [ka] A solution of ethyl 3-oxobutanoate (30.0 g, 230.8 mmol) in DMF-DMA (50 mL) was stirred at 80 °C for 16 h. After cooling to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with EtOAc / petroleum ether (0-80%)) to give the title compound as a yellow oil (41.0 g, 96%). ES / MS (m / z): 186 (M+H).

[0175] Modified 8aa Ethyl 1-(6-chloropyridazin-4-yl)-5-methyl-1H-pyrazole-4-carboxylate [ka] To a solution of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (9.00 g, 48.6 mmol) in MeOH (30 mL) at ambient temperature was added 3-chloro-5-hydrazinylpyridazine (7.00 g, 48.6 mmol). The mixture was stirred at 80 °C for 16 h. 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 / petroleum ether (0-70%)) to give the title compound as a yellow oil (2.60 g, 20%). ES / MS (m / z): 267 (M+H).

[0176] Modifier 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-one [ka] To 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 at 70 °C for 2 h. EtOAc (20 mL) was added to the mixture, which was then washed with water (20 mL) and saturated aqueous NaCl (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with EtOAc / petroleum ether (0-100%)) to give the title compound (350 mg, 84%) as a yellow oil. ES / MS (m / z): 554 (M+H).

[0177] The compounds listed in Table 2l were prepared by essentially the same method as found in Preparation 8ab. [Table 26]

[0178] Modified 8ad 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-3-(4-fluoro-2-(fluoromethyl)benzyl)piperidin-2-one [ka] To 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 dropwise LiHMDS (3.88 mL, 1.0 M / THF, 3.88 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 1 hour, 1-(bromomethyl)-4-fluoro-2-(fluoromethyl)benzene (412 mg, 1.75 mmol) was added, followed by stirring at −78° C. for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with EtOAc / petroleum ether (0-30%)) to give the title compound as a colorless oil (460 mg, 46.0%). ES / MS (m / z): 515 (M+H).

[0179] The compounds listed in Table 2m were prepared by essentially the same method as found in Preparation 8ad. [Table 27] [Table 28] [Table 29] [Table 30]

[0180] Modified 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-one [ka] A 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 (×3) at ambient temperature, then heated to 100° C. and stirred for 2 h. After cooling to ambient temperature, the reaction mixture was quenched with saturated aqueous potassium fluoride (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with MeOH / DCM (0-3%)) to give the title compound as a yellow oil (14 mg, 62%). ES / MS (m / z): 515 (M+H).

[0181] The compounds listed in Table 2n were prepared by essentially the same method as found in Preparation 8bd. [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36] [Table 37]

[0182] Modifier 9 N-Methoxy-N,5-dimethyl-pyridazine-4-carboxamide [ka] A mixture of ethyl 5-methylpyridazine-4-carboxylate (1.2 g, 7.23 mmol), N,O-dimethylhydroxylamine hydrochloride (1.42 g, 14.46 mmol) and THF (20 mL) was stirred at -70 °C for 5 min. LiHMDS (1 M / THF, 50.6 mL, 50.6 mmol) was slowly added and stirred at -70 °C for 2.0 h. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with EtOAc / 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).

[0183] Modifier 10 Ethyl 3-(5-methylpyridazin-4-yl)-3-oxo-propanoate [ka] To a mixture of 1.37 g (15.6 mmol) of EtOAc in 20 mL of THF was slowly added a solution of LDA (1 M in THF, 15.6 mL) at −70° C., followed by stirring for 1.5 hours. A solution of N-methoxy-N,5-dimethyl-pyridazine-4-carboxamide (0.94 g, 5.2 mmol) in 8 mL of THF was slowly added, followed by stirring for 2.0 hours at −70° C. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with 1:1 EtOAc / petroleum ether) to give the title compound (0.53 g, 49.1%) as a yellow oil. ES / MS m / z 209 (M+H).

[0184] Modifier 11 Ethyl (Z)-3-amino-4,4,4-trichloro-2-(5-methylpyridazine-4-carbonyl)but-2-enoate [ka] To a mixture of ethyl 3-(5-methylpyridazin-4-yl)-3-oxopropanoate (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 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (1.08 g, crude) as a yellow oil. ES / MS m / z 352 (M+H).

[0185] Modifier 12 Ethyl 5-amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylate [ka] To a mixture of ethyl (Z)-3-amino-4,4,4-trichloro-2-(5-methylpyridazine-4-carbonyl)but-2-enoate (1.08 g, crude product) in EtOH (10 mL) was added EtN (0.77 g, 7.6 mmol) and (4-methoxybenzyl)hydrazine hydrochloride (0.58 g, 3.05 mmol), and the mixture was stirred at 65 °C for 2 h. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with EtOAc / 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).

[0186] Modified Material 13 5-Amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylic acid [ka] To 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 (4 mL), EtOH (4 mL), and water (2 mL) was added NaOH (118 mg, 2.94 mmol). The mixture was stirred at 75 °C for 4 hours, after which the reaction mixture was concentrated under reduced pressure. 1 M aqueous HCl was added to adjust the pH to 3-4. The resulting slurry was filtered, and the filter cake was washed with 20 mL of ice water and then dried under reduced pressure to give the title compound (350 mg, 70.1%) as a yellow solid. ES / MS m / z 340 (M+H).

[0187] Modifier 14 5-Amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxamide [ka] A 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 hours. The mixture was added to water (30 mL) and extracted with DCM (30 mL x 5). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (400 mg, crude) as a brown oil. ES / MS m / z 339 (M+H).

[0188] Modified 15 1-(4-Methoxybenzyl)-4-methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-amine [ka] To 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 h. The reaction mixture was adjusted to pH 8-9 by slowly adding saturated aqueous Na2CO3 and extracted with EtOAc (80 mL x 2). The combined organic layers were dried and concentrated under reduced pressure to give the crude product (1.8 g). This was purified by reverse-phase chromatography (ACN / 10 mM NH4HCO3 = 2-30%) to give the title compound (800 mg, 58%) as a brown solid. ES / MS m / z 310 (M+H).

[0189] Modifier 16 3-(6-chloro-5-fluoropyridin-3-yl)-N-(1-(4-methoxybenzyl)-4-methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)propanamide [ka] A 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 h. The mixture was added to water (10 mL) and then extracted with EtOAc (80 mL × 2). The combined organic layers were dried and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (ACN / 10 mM NH₄HCO₃ = 2-60%) to give the title compound (360 mg, 46%) as a pale yellow solid. ES / MS m / z 495 (M+H).

[0190] The compounds listed in Table 3 were prepared by methods essentially similar to those found in Preparation 16. [Table 38]

[0191] Modified 18 5-(3-(6-fluoropyridin-3-yl)propanamido)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxamide [ka] A 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 hours. The reaction mixture was concentrated under reduced pressure. To the residue, sodium bicarbonate solution was added to adjust the pH to approximately 8. The slurry was filtered, and the filter cake was washed with ice water (20 mL) and dried under reduced pressure to give the title compound (70 mg, crude) as a brown solid. ES / MS m / z 370 (M+H).

[0192] Modifier 18a 2,2,2-trichloro-1-(4-chloro-1H-pyrrol-2-yl)ethan-1-one [ka] To 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 chloride (15.25 g, 113.0 mmol) at 0 °C. The reaction mixture was stirred at 20 °C under a nitrogen atmosphere for 20 h. The mixture was diluted with DCM (100 mL) and poured into ice-water. The mixture was adjusted to pH > 7 with sodium bicarbonate and extracted with DCM (200 mL × 3). The combined organic layers were washed with water (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column silica gel chromatography (eluted with EtOAc / petroleum ether (0-20%)) to give the title compound as a white solid (12.20 g, 48%). ES / MS (m / z): 246 (M+H).

[0193] Modifier 18b Methyl 4-chloro-1H-pyrrole-2-carboxylate [ka] To 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 hydride (5.293 g, 132.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluting with EtOAc / petroleum ether (0-20%)) to give the title compound as a white solid (4.96 g, 63%). ES / MS (m / z): 160 (M+H).

[0194] Modifier 18c Methyl 5-bromo-4-chloro-1H-pyrrole-2-carboxylate [ka] To a solution of 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 minutes. After cooling to ambient temperature, the reaction mixture was concentrated to give the crude product. The crude product was dissolved in water (10 mL), adjusted to pH > 7 with saturated sodium bicarbonate, and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluted with EtOAc / petroleum ether (0–20%)) to give the title compound as a white solid (1.2 g, 60%). ES / MS (m / z): 238 (M+H).

[0195] Modified material 18d Methyl 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1H-pyrrole-2-carboxylate [ka] To 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 in a sealed tube at 60 °C under nitrogen for 14 hours. After cooling to ambient temperature, the reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with EtOAc / petroleum ether (0-20%)) to give the title compound as a colorless oil (500 mg, 67.8%). ES / MS (m / z): 387 (M+H).

[0196] The compounds listed in Table 3a were prepared by essentially the same method as found in Preparation 18d. [Table 39]

[0197] Modifier 18f Methyl 3-bromo-4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1H-pyrrole-2-carboxylate [ka] To 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 h. The reaction was quenched by the addition of water (10 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with 0-20% EtOAc / petroleum ether) to give the title compound (300 mg, 58.6%) as a white solid. ES / MS (m / z): 467 (M+H).

[0198] The compounds listed in Table 3b were prepared by essentially the same method as found in Preparation 18f. [Table 40]

[0199] Modulation 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-carboxylate [ka] To 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) at 0° C. under nitrogen. The reaction was stirred at 20° C. for 5 minutes. SEM-Cl (107 mg, 644 μmol) was added to the mixture. After stirring at 20° C. for 5 hours, the reaction was quenched by the addition of water (20 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with saturated aqueous NaCl (10 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column silica gel chromatography (eluting with EtOAc / petroleum ether (0-20%)) to give the title compound as a white solid (200 mg, 76.8%). ES / MS (m / z): 617 (M+Na).

[0200] The compounds listed in Table 3c were prepared by essentially the same method as found in Preparation 18i. [Table 41]

[0201] Modifier 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) [ka] 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 to ambient temperature, the reaction was quenched with water (20 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with MeOH / DCM (0-3%)) to give the title compound 1 (100 mg, 26.1%) as a white solid: ES / MS (m / z): 561 (M+H), and the title compound 2 (100 mg, 26.4%) as a white solid: ES / MS (m / z): 595 (M+H).

[0202] The compounds listed in Table 3d were prepared by essentially the same method as found in Preparation 18k. [Table 42]

[0203] 18m of modifier 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) [ka] 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) at ambient temperature was added lithium hydroxide (17 mg, 0.71 mmol). The reaction was stirred at 60° C. for 3 hours. After cooling to ambient temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 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).

[0204] The compounds listed in Table 3e were prepared by essentially the same method as found in Preparation 18m. [Table 43]

[0205] Preparation 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) [ka] 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 (7 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 h, the reaction was quenched by the addition of water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (eluted with EtOAc / 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 the title compound 2 as a yellow solid (70 mg, 98%) ES / MS (m / z): 580 (M+H).

[0206] The compounds listed in Table 3f were prepared by essentially the same method as found in Preparation 18o. [Table 44]

[0207] Modified 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) [ka] 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 SOCl (27 mg, 0.22 mmol) dropwise at 0 °C. After stirring at 0 °C for 1 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (eluted with EtOAc / 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).

[0208] The compounds set forth in Table 3g were prepared by methods essentially similar to those found in Preparation 18r. [Table 45]

[0209] Modified 18V 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde [ka] To a solution of 1H-pyrrole-2-carbaldehyde (1.00 g, 10.5 mmol) in DMF (15 mL) was added NaH / oil (631 mg, 60 wt%, 15.8 mmol) at 0 °C. After stirring for 2 h, SEM-Cl (2.28 g, 13.7 mmol) was added at 0 °C, followed by stirring at 0 °C for 12 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (1:9)) to give the title compound (1.80 g, 49%) as a yellow oil. ES / MS (m / z): 226 (M+H).

[0210] Modified 18w 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (1:4)) to give a mixture of two isomers of the title compound (1.50 g, 23%) as a yellow oil. The crude product was used directly in the next step. ES / MS (m / z): 260 (M+H).

[0211] Modified 18x Ethyl (E)-3-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylate [ka] To 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-15-phosphanylidene)acetate (4.69 g, 13.5 mmol). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (1:10)) to give the title compound (0.47 g, 25%) as a yellow oil. ES / MS: (m / z) = 330 (M+H).

[0212] Modified 18y N-(2-bromo-5-fluoropyridin-3-yl)pivalamide [ka] To 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). After stirring at 25 °C for 5 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (95:5)) to give the title compound (10.0 g, 99%) as a yellow oil. ES / MS (m / z): 275 (M+H).

[0213] The compounds listed in Table 3h were prepared by essentially the same method as found in Preparation 18y. [Table 46]

[0214] Modified 18aa Ethyl (E)-3-(5-fluoro-3-pivalamidopyridin-2-yl)acrylate [ka] To 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), KCO (4.36 g, 31.5 mmol), and Pd(OAc) (0.71 g, 3.2 mmol) under nitrogen. After stirring at 120 °C for 3 h, the reaction mixture was cooled to ambient temperature and filtered. The filtrate was added to water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM (100%)) to give the title compound (857.0 mg, 15%) as a yellow solid. ES / MS (m / z): 295 (M+H).

[0215] The compounds listed in Table 3i were prepared by methods essentially similar to those found in Preparation 18aa. [Table 47]

[0216] Modifier 18ad Ethyl 3-(5-fluoro-3-pivalamidopyridin-2-yl)propanoate [ka] To 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 NaBH (165 mg, 14.37 mmol) in small portions at 0 °C. After stirring at 0 °C for 5 h, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (830 mg, 85%) as a yellow solid. ES / MS (m / z): 297 (M+H).

[0217] The compounds listed in Table 3j were prepared by essentially the same method as found in Preparation 18ad. [Table 48]

[0218] 18ag of modifier 3-(5-Fluoro-3-pivalamidopyridin-2-yl)propanoic acid [ka] To a solution of ethyl 3-(5-fluoro-3-pivalamidopyridin-2-yl)propanoate (830 mg, 2.8 mmol) in THF (6.4 mL) and HO (1.6 mL) was added a solution of lithium hydroxide monohydrate (235 mg, 5.6 mmol) in HO (1.5 mL). After stirring at 25 °C for 4 hours, 1 M HCl (6 mL) was added and the mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM / MeOH (95:5)) to give the title compound (608 mg, 76%) as a yellow oil. ES / MS (m / z): 269 (M+H).

[0219] The compounds listed in Table 3k were prepared by essentially the same method as found in Preparation 18ag. [Table 49]

[0220] Modified 18al Ethyl 3-(5-fluoro-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)propanoate [ka] To 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 at ambient temperature under a hydrogen atmosphere for 3 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.10 g, 95%) as an orange solid. ES / MS (m / z): 228 (M+H-84).

[0221] The compounds listed in Table 3l were prepared by methods essentially similar to those found in Preparation 18a1. [Table 50]

[0222] Modified 18an Ethyl 3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoate [ka] To 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 at ambient temperature under nitrogen for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was added to water (20 mL), basified to pH = 8 with saturated NaHCO3 solution, and extracted with DCM (20 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (800 mg, 91%) as an orange oil. ES / MS (m / z): 228 (M+H).

[0223] Modified 18ao Ethyl 3-(5-fluoro-6-formylpyridin-3-yl)propanoate [ka] To a solution of 3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoate (700 mg, 3.08 mmol) in DCM (10 mL) was added MnO (1.93 g, 22.2 mmol). After stirring at 40 °C under nitrogen for 2 h, the reaction mixture was diluted with DCM (30 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (650 mg, 94%) as an orange liquid. ES / MS (m / z): 254 (M+H).

[0224] Modifier 18ap Ethyl 3-(6-(difluoromethyl)-5-fluoropyridin-3-yl)propanoate [ka] To 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 at -78 °C under nitrogen for 10 minutes, the reaction mixture was stirred at ambient temperature under nitrogen for 2 hours. The reaction was quenched with HO (20 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (500 mg, 92%) as an orange liquid. ES / MS (m / z): 248 (M+H).

[0225] Adjustment item 18aq Diethyl 2-((2-chlorothiazol-5-yl)methyl)malonate [ka] To 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 small portions at 0 °C under nitrogen. After stirring at 0 °C under nitrogen for 2 h, the reaction mixture was quenched with HO (40 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (92:8)) to give the title compound (31.0 g, crude product) as a yellow oil. ES / MS (m / z): 292 (M+H).

[0226] Modulation 18ar 2-((2-chlorothiazol-5-yl)methyl)malonic acid [ka] To a solution of diethyl 2-((2-chlorothiazol-5-yl)methyl)malonate (31.0 g, crude product) in THF (100 mL) was added a solution of lithium hydroxide monohydrate (13.0 g, 0.31 mol) and HO (25 mL). After stirring at 20 °C for 9 h, the reaction mixture was concentrated under reduced pressure to remove the organic solvent. Water (40 mL) was added to the residue and washed with petroleum ether (120 mL × 3). The aqueous solution was used directly in the next step without further purification. ES / MS (m / z): 236 (M+H).

[0227] Modified material 18as 3-(2-chlorothiazol-5-yl)propanoic acid [ka] A solution of 2-((2-chlorothiazol-5-yl)methyl)malonic acid was acidified to pH 2-3 with sulfuric acid (4 M) and then stirred at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature and extracted with EtOAc (40 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (1:3)) to give the title compound (1.3 g, 28.6% over three steps) as a white solid. ES / MS (m / z): 192 (M+H).

[0228] Modified 18at 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] To 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 at 0 °C for 1 h, SEM-Cl (0.89 g, 5.4 mmol) was added, followed by stirring at 0 °C for 2 h. The mixture was quenched with cold water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1 g, 63%) as a colorless oil. ES / MS (m / z): 299 (M+H-58).

[0229] Modified 18au 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde [ka] To a solution of 3,4,5-tribromo-1H-pyrazole (90.0 g, 295 mmol) in THF (2 L) was added dropwise n-BuLi in THF (236 mL, 590 mmol) at −60° C. After stirring at −60° C. for 1 hour, DMF (114 mL, 1.48 mol) was added dropwise to the reaction mixture. The mixture was stirred at −60° C. for an additional hour and then at ambient temperature for 3 hours. SEM-Cl (78.4 mL, 443 mmol) was added dropwise to the mixture at ambient temperature, and the resulting mixture was stirred for 16 hours. The reaction mixture was poured into a NaHCO solution (1.5 L) and extracted with EtOAc (1.5 L × 3). The combined organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ester (0-10%) to give the title compound (50 g, 42%) as a yellow oil. 1 H NMR (DMSO-d6) δ 9.74 (s,1H),5.57 (s,2H),3.66 (t,2H),0.90 (t,2H),0.00 (s,9H).

[0230] Modified 18av 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol [ka] To 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 NaBH (2 g, 52 mmol) in small portions at −5° C., followed by stirring at −5° C. for 2 hours. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (7 g, 70%) as a white solid. ES / MS (m / z): 409 (M+Na).

[0231] Modified 18aw 3,5-Dibromo-4-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] To 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 °C, followed by MeI (7.37 g, 27.3 mmol). After stirring at 0 °C for 2 h, the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (1:1)) to give the title compound (2.1 g, 95%) as a yellow solid. ES / MS (m / z): 401 (M+H).

[0232] Modifier 18ax 3,5-Dibromo-4-fluoro-1H-pyrazole [ka] To a solution of 4-fluoro-1H-pyrazole (25 g, 290 mmol) in EtOH / HO (1:1.5) (400 mL) was added NaOAc (167 g, 2034 mmol) and Br (186 g, 1163 mmol) at 0 °C. The mixture was warmed and stirred at ambient temperature for 12 h. The mixture was combined and extracted with EtOAc (200 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (15%)) to give the title compound (18 g, 26%) as a colorless oil. ES / MS (m / z): 245 (M+H).

[0233] Modified 18ay 3,5-Dibromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] To 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) in small portions at 0 °C. After stirring for 1 h, SEM-Cl (15 g, 89 mmol) was added dropwise at 0 °C, followed by stirring at ambient temperature for 2 h. The mixture was quenched with water (400 mL) and extracted with EtOAc (200 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (eluted with EtOAc / 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)

[0234] Modified 18az 3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine [ka] To a solution of 3-bromo-1H-pyrazol-5-amine (10 g, 62.11 mmol) in anhydrous ACN (20 mL) cooled to 0 °C, NaH (60%, 3.7 g, 93.17 mmol) was slowly added. The mixture was stirred at 0 °C for 30 minutes, and then SEM-Cl (11.3 g, 68.32 mmol) was slowly added. After stirring at ambient temperature for 2 hours, the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (12%)) to give the title compound (7 g, 39%) as a yellow oil. ES / MS (m / z): 292 (M+H).

[0235] Modified 18ba 5-Bromo-N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pentanamide [ka] To a mixture of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (7 g, 24.05 mmol) and EtN (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 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (5%)) to give the title compound (8 g, 73%) as a yellow oil. ES / MS (m / z): 456 (M+H).

[0236] Modified 18bb 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)piperidin-2-one [ka] To 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, 86.9 mmol). The mixture was stirred at 90 °C for 8 h, cooled to ambient temperature, and filtered to remove solids. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (5%)) to give the title compound (3.5 g, 54%) as a colorless oil. ES / MS (m / z): 374 (M+H).

[0237] Modified 18bc N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(4-chloro-3-fluorophenyl)propenamide [ka] To a solution of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine (5 g, 17.2 mmol) in DMA (30 mL) were 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 h, the reaction mixture was cooled, water (100 mL) was added, and then extracted with EtOAc (100 mL×3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 25% EtOAc / petroleum ether) to give the title compound (5.2 g, 64%) as a yellow oil. ES / MS m / z: 476 and 478 (M+H).

[0238] The compounds listed in Table 3m were prepared by essentially the same method as found in Preparation 18bc. [Table 51]

[0239] Modified 18be 4-Bromo-N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)butanamide [ka] To 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 h, the mixture was quenched with water (300 mL) and extracted with DCM (200 mL × 2). The organic layers were combined, washed with saturated aqueous NaCl (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (150.00 g, 99% yield) as a yellow oil. The crude product was used directly in the next step. ES / MS (m / z): 440 (M+H).

[0240] Modified 18bf 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-one [ka] To 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., followed by stirring at 25° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (13%)) to give the title compound (46.00 g, 37%) as a yellow oil. ES / MS (m / z): 360 (M+H).

[0241] 18bg of modifier 1-(3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-one [ka] To 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), followed by stirring at 80 °C for 1.5 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluting with 15% EtOAc / petroleum ether) to give the title compound (18.00 g, 34%) as a yellow oil. ES / MS (m / z): 378 (M+H).

[0242] Modified Material 19 tert-Butyl N-(3,6-dichloropyridazin-4-yl)carbamate [ka] To a mixture of 3,6-dichloropyridazine-4-carboxylic acid (4 g, 20.76 mmol) in 1,4-dioxane (100 mL), EtN (2.11 g, 20.8 mmol), DPPA (5.77 g, 20.76 mmol), and tert-butanol (26.6 mL) were added, and the mixture was stirred at 110 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / 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).

[0243] Modified 20 tert-Butyl N-(6-chloro-3-methyl-pyridazin-4-yl)carbamate [ka] To 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), methylboronic acid (0.45 g, 7.58 mmol), Pd(dppf)Cl (0.2 g, 0.3 mmol), and KCO (0.6 g, 4.55 mmol) was added and stirred at 80 °C under a N atmosphere for 12 h. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (eluting with EtOAc / 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).

[0244] Modified Material 21 tert-Butyl N-(3-methylpyridazin-4-yl)carbamate [ka] To 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 PhP (0.5 g, 2.1 mmol), Pd(OAc) (0.47 g, 2.1 mmol), EtN (4.2 g, 42 mmol), and EtSiH (7.3 g, 63 mmol). The mixture was stirred at 80 °C under a N atmosphere for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / 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).

[0245] Modifier 22 3-Methylpyridazin-4-amine [ka] To a mixture of tert-butyl N-(3-methylpyridazin-4-yl)carbamate (0.5 g, 2.40 mmol) in DCM (3 mL) was added a solution of HCl in 1,4-dioxane (4 M, 3 mL) at 0 °C, followed by stirring at ambient temperature for 12 h. The mixture was concentrated under reduced pressure to give the crude title compound (0.27 g, 99% yield) as a yellow solid. ES / MS m / z 110.0 (M+H).

[0246] Modified Material 23 4-Bromo-3-methylpyridazine [ka] To a mixture of 3-methylpyridazin-4-amine (0.2 g, 1.8 mmol) and CuBr (1.63 g, 7.34 mmol) in ACN (10 mL) was added tert-butyl nitrate (0.38 g, 3.7 mmol), followed by stirring at 65 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure. Ammonia (15 wt%, 50 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (0.1 g, 32%) as a brown oil. ES / MS m / z 173.1 (M+H).

[0247] Modifier 23a Trimethyl(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)stannane [ka] To a solution of 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (5.5 g, 39 mmol) in anhydrous THF (80 mL) was slowly added a solution of n-BuLi in THF (23.4 mL, 2.5 mol, 58.5 mmol) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 0.5 h, and then trimethyltin chloride (8.6 g, 43 mmol) was slowly added. After stirring at −78° C. under nitrogen for 4 h, the mixture was quenched with saturated NH4Cl solution (100 mL) and then extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (9.3 g, 70%) as a yellow oil. 1 H 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).

[0248] Modified material 23b 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5-(trimethylstannyl)pyridazine [ka] To 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 h, then cooled to ambient temperature, quenched with water (100 mL), and extracted with EtOAc (100 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (0-15%)) to give the title compound (7.6 g, 59%) as a yellow oil. ES / MS (m / z): 359 (M+H).

[0249] Modifier 24 tert-Butyl N-[1-(3-methylpyridazin-4-yl)pyrazol-4-yl]carbamate [ka] To a mixture of tert-butyl N-(1H-pyrazol-4-yl)carbamate (0.2 g, 1 mmol) in DMF (10 mL), 4-bromo-3-methylpyridazine (0.38 g, 2 mmol), KPO (0.7 g, 3.3 mmol), CuI (0.2 g, 1 mmol), and N,N'-dimethyl-1,2-cyclohexanediamine (0.16 g, 1 mmol) were added and stirred at 90 °C under a N atmosphere for 2 h. The mixture was quenched with HO (20 mL) and extracted with EtOAc (50 mL × 3). The combined EtOAc layers were concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (80%)) to give the title compound (50 mg, 16%) as a white solid. ES / MS m / z 276.3 (M+H).

[0250] Modified 25 1-(3-methylpyridazin-4-yl)pyrazol-4-amine [ka] To 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 a solution of HCl in 1,4-dioxane (4 mol / L, 2 mL). The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure to give the title compound (50 mg, 99% yield) as a yellow oil. ES / MS m / z 176.2 (M+H).

[0251] Modified Material 26 1-(5-amino-3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-1-yl)-5-bromopentan-1-one [ka] To 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, followed by TBTU (8.5 g, 26.42 mmol). The mixture was stirred at 10 °C for 4 hours, after which water (50 mL) was added. The resulting precipitate was filtered, and the filter cake was dried under reduced pressure to give the title compound (5 g, 85%) as a white solid. ES / MS m / z 341.1 (M+H).

[0252] Modified Material 27 1-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one [ka] To 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., followed by stirring at 0° C. for 4 hours. SEM-Cl (2.8 mL, 16.27 mmol) was added slowly at 0° C., followed by stirring for 1 hour. The mixture was added to water (100 mL) and then extracted with EtOAc (200 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (20:80)) to give the title compound (2.6 g, 45%) as a brown oil. ES / MS m / z 389.2 (M+H).

[0253] Modified Material 28 3-(4-Fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one [ka] To 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 anhydrous THF (10 mL) was added a solution of LiHMDS (1 M / THF, 1.3 mL, 1.3 mmol) at −78° C. After stirring for 30 minutes, a solution of 1-(bromomethyl)-4-fluorobenzene (189 mg, 1.0 mmol) in anhydrous THF (5 mL) was added to the reaction mixture, which was stirred at −78° C. for 1.5 hours. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL×2). The combined organic layers were dried, concentrated under reduced pressure, and purified by preparative 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).

[0254] Modifier 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) [ka] 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 anhydrous DMF (40 mL) was stirred at ambient temperature for 16 hours. The mixture was treated with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (ACN / HO gradient (0–60%)). The appropriate fractions were combined, concentrated under reduced pressure, and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give the title compound as a yellow solid (1.0 g, 60%). ES / MS (m / z): 593 (M+H).

[0255] The compounds listed in Table 4a were prepared by essentially the same method as found in Preparation 30a. [Table 52]

[0256] Modified Material 31 (R)-4-Benzyl-3-((R)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3-fluorobenzyl)pentanoyl)oxazolidin-2-one [ka] A solution of (R)-4-benzyl-3-(5-((tert-butyldimethylsilyl)oxy)pentanoyl)oxazolidin-2-one (CAS Registry Number: 1353545-65-9 (prepared according to Li et al. Tetrahedron (2012), 68(3), 846-850)) (3 g, 7.67 mmol) in anhydrous THF (30 mL) was cooled to −78° C. under N2 conditions, and then a solution of NaHMDS in THF (2 M, 4.2 mL, 8.44 mmol) was added dropwise while maintaining the temperature below −65° C. The mixture was stirred for 2 hours, after which a solution of 4-(bromomethyl)-1-chloro-2-fluorobenzene (4.3 g, 19.18 mmol) in anhydrous THF (10 mL) was added. The mixture was stirred overnight, allowing the temperature to slowly rise to ambient temperature. The reaction mixture was cooled to -78 °C, quenched with saturated NaHCO3 (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (5-10%)) to give the title compound (3.0 g, 60%) as a yellow oil. ES / MS m / z 534 (M+H).

[0257] The compounds listed in Table 5 were prepared by methods essentially similar to those found in Preparation 31. [Table 53]

[0258] Modified 35 (R)-4-Benzyl-3-((R)-2-(4-chloro-3-fluorobenzyl)-5-hydroxypentanoyl)oxazolidin-2-one [ka] To 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 anhydrous THF (10 mL) was added HF.EtN (3 g, 9.38 mmol) dropwise, followed by stirring at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 50-60% EtOAc / petroleum ether) to give the title compound (0.65 g, 83%) as a white oil. ES / MS m / z 420 (M+H).

[0259] The compounds listed in Table 6 were prepared by methods essentially similar to those found in Preparation 35. [Table 54]

[0260] Modified 39 (R)-5-((R)-4-benzyl-2-oxooxazolidin-3-yl)-4-(4-chloro-3-fluorobenzyl)-5-oxopentanal [ka] To 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), followed by stirring at ambient temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaSO (30 mL) and saturated aqueous NaHCO (30 mL) and then extracted with EtOAc (100 mL × 5). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 20–40% EtOAc / petroleum ether) to give the title compound (1.2 g, 65%) as a white oil. ES / MS m / z 418 (M+H).

[0261] The compounds listed in Table 7 were prepared by methods essentially similar to those found in Preparation 39. [Table 55]

[0262] Modified Material 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-one [ka] A 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 hours. NaBHCN (302 mg, 4.8 mmol) was then added. The mixture was stirred at ambient temperature for 12 hours and then concentrated under reduced pressure. Water (10 mL) was added and the mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (1:5) to give the title compound (500 mg, 43%) as a yellow oil. ES / MS m / z 697 (M+H).

[0263] The compounds listed in Table 8 were prepared by methods essentially similar to those found in Preparation 43. [Table 56]

[0264] Modified 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-one [ka] A 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 hours. NaBHCN (214 mg, 3.4 mmol) was added. The mixture was stirred at ambient temperature for 12 hours and then concentrated under reduced pressure. Water (5 mL) was added to the residue and extracted with EtOAc (30 mL × 2). The combined organic layers were dried and concentrated under reduced pressure to give the crude product, which was purified by 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) + .

[0265] The compounds listed in Table 8a were prepared by essentially the same method as found in Preparation 45. [Table 57]

[0266] Modifier 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-one [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. To the residue was added water (5 mL) and saturated NaHCO (15 mL). The resulting precipitate was filtered and purified by preparative HPLC to give the title compound (120 mg, 11%) as a white solid. ES / MS (m / z): 578 (M+H).

[0267] Modified 49 (S)-2-(4-chloro-3-fluorobenzyl)-5-((3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)amino)pentanoic acid [ka] A 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 HO (20 mg, 0.6 mmol) in THF / water (4 / 1.3 mL) was stirred at ambient temperature for 10 min, after which LiOH.HO (13 mg, 0.3 mmol) was added. The mixture was stirred at ambient temperature for 16 h, then quenched with aqueous NaSO (10 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse-phase chromatography (ACN / 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).

[0268] The compounds listed in Table 9 were prepared by methods essentially similar to those found in Preparation 49. [Table 58]

[0269] Modifier 49c tert-Butyl 3-oxomorpholine-4-carboxylate [ka] To a solution of morpholin-3-one (1 g, 10 mmol) in DCM (20 mL) was added BocO (4.3 g, 20 mmol) and DMAP (0.24 g, 2 mmol), followed by stirring at ambient temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (2:98)) to give the title compound (1.8 g, 90%) as a red solid. MS (m / z): 224 (M+Na) + .

[0270] The compounds listed in Table 9a were prepared by essentially the same method as found in Preparation 49c. [Table 59]

[0271] Modified 50 tert-Butyl 2-(4-chlorobenzyl)-3-oxomorpholine-4-carboxylate [ka] To a mixture of tert-butyl 3-oxomorpholine-4-carboxylate (0.4 g, 2 mmol) (prepared as described in Arguello-Velasco, RO, et al., J. Het. Chem., 2019, 56(7), 2068-2073) in THF (10 mL) was added LDA (1 M / THF, 1.5 mL, 3 mmol) at -78 °C, followed by stirring at -78 °C for 1 h. A solution of 1-(bromomethyl)-4-chlorobenzene (0.49 g, 2.4 mmol) in THF (5 mL) was slowly added, followed by stirring at -78 °C for 1 h. 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 under reduced pressure, and purified by silica gel flash chromatography (eluting with MeOH / DCM (0-2%)) to give the title compound (0.3 g, 45%) as a yellow oil. ES / MS m / z 348.1 (M+Na).

[0272] The compounds set out in Table 9b were prepared by essentially the same method as found in Preparation 50. [Table 60]

[0273] Modified Material 51 2-(4-chlorobenzyl)morpholin-3-one [ka] A mixture of tert-butyl 2-(4-chlorobenzyl)-3-oxomorpholine-4-carboxylate (0.3 g, 0.9 mmol) and 4 M HCl in 1,4-dioxane (5 mL) was stirred at ambient temperature for 2 h and then concentrated under reduced pressure to give the title compound (0.2 g, 96%) as a yellow solid. ES / MS m / z 226.1 (M+H).

[0274] Modifier 51a 1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one [ka] To a solution of methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate (5.00 g, 21.45 mmol) in MeOH (20 mL) was added NaBH (1.80 g, 75 mmol) at 0 °C, followed by stirring at 25 °C under nitrogen for 12 h. The reaction mixture was quenched with HO (100 mL) at 0 °C and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with DCM / MeOH (10:1)) to give the title compound (4.00 g, 91%) as a white solid. ES / MS (m / z): 206 (M+H).

[0275] Modifier 51b 1-benzyl-4-(methoxymethyl)pyrrolidin-2-one [ka] To 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, followed by stirring for 1 hour. To the reaction mixture was added MeI (5.68 g, 40 mmol) at -40 °C, followed by stirring for 2 hours at 0 °C. The reaction mixture was quenched with HO (100 mL) at 0 °C and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (10:1)) to give the title compound (3.00 g, 70%) as a white solid. ES / MS (m / z): 220 (M+H).

[0276] The compounds listed in Table 9b were prepared by essentially the same method as found in Preparation 51. [Table 61]

[0277] Modified material 51d 1-benzyl-3-(4-chloro-3,5-difluorobenzyl)-4-(methoxymethyl)pyrrolidin-2-one [ka] To a solution of 1-benzyl-4-(methoxymethyl)pyrrolidin-2-one (3.00 g, 13.5 mmol) in anhydrous THF (10 mL) was added dropwise a solution of LiHMDS (1 M) in THF (17 mL, 17 mmol) at −78° C. under nitrogen at −78° C. After stirring for 30 minutes at −78° C., a solution of 5-(bromomethyl)-2-chloro-1,3-difluorobenzene (3.27 g, 13.5 mmol) in THF (6 mL) was added dropwise, followed by stirring at −78° C. for 30 minutes. The reaction mixture was quenched with water (50 mL) and extracted with DCM (15 mL×5). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAC / petroleum ether (1:1)) to give the title compound (1.9 g, 37%) as a yellow oil. MS (m / z): 380 (M+H).

[0278] Modifier 51e 3-(4-chloro-3,5-difluorobenzyl)-4-(methoxymethyl)pyrrolidin-2-one [ka] To a mixture of 1-benzyl-3-(4-chloro-3,5-difluorobenzyl)-4-(methoxymethyl)pyrrolidin-2-one (1.90 g, 5.00 mmol) in CHNO (8 mL) was added KBr (595 mg, 5.00 mmol) and potassium peroxymonosulfate (4.61 g, 7.50 mmol), followed by stirring at 80 °C for 96 h. The mixture was cooled to ambient temperature, added to water (30 mL), and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (1:1)) to give the title compound (900 mg, 62%) as a white solid. ES / MS (m / z): 290 (M+H).

[0279] Modifier 51f 1-(2,4-Dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid [ka] To 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), followed by stirring at 110 °C for 16 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was dissolved in LiOH solution (1 M, 70 mL) and extracted with EtOAc (50 mL × 3). Diluted HCl solution was added to acidify the aqueous solution to pH = 4, followed by extraction with EtOAc (80 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (8.0 g, 89%) as a yellow oil. ES / MS (m / z): 280 (M+H).

[0280] 51g of preparation 1-(2,4-Dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carboxylic acid [ka] To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (4.0 g, 14 mmol) in anhydrous THF (40 mL) was added a solution of LDA (18 mL, 36 mmol) in THF at −78° C. under nitrogen. After stirring for 45 minutes, a solution of 5-(bromomethyl)-1,2,3-trifluorobenzene (3.5 g, 16 mmol) in anhydrous THF (2 mL) was added dropwise to the reaction mixture at −78° C., followed by stirring at −78° C. for 2 hours. The mixture was added to water (40 mL). The pH was adjusted to 6 with 1 M HCl, followed by extraction with EtOAc (70 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (20:1)) to give the title compound (3.0 g, 47%) as a yellow oil. ES / MS (m / z): 424 (M+H).

[0281] Modified material 51h 1-(2,4-Dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carboxamide [ka] To 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), followed by stirring at 25 °C for 2 hours. Water (60 mL) was added, followed by extraction with EtOAc (80 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (30:1)) to give the title compound (2.5 g, 68%) as a yellow solid. ES / MS (m / z): 423 (M+H).

[0282] The compounds listed in Table 9c were prepared by essentially the same method as found in Preparation 51h. [Table 62]

[0283] Modifier 51j 1-(2,4-Dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carbonitrile [ka] To 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 POCl (4.9 g, 32 mmol), followed by stirring at 25 °C for 2 hours. The mixture was added to water (20 mL), and the pH was adjusted to 8 with 10% NaHCO solution, followed by extraction with EtOAc (80 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with n-hexane / EtOAc (2:1)) to give the title compound (3.0 g, 66%) as a yellow solid. ES / MS (m / z): 405 (M+H)

[0284] Modified material 51l 5-Oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carbonitrile [ka] To 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), followed by stirring at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Saturated aqueous NaHCO3 (50 mL) was added to the mixture, which was then extracted with EtOAc (80 mL × 3). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (2%)) to give the title compound, which was further purified by reverse-phase chromatography (C18, mobile phase: A: water (10 mmol / L ammonium bicarbonate), B: ACN; B / A: 30%-40%) to give the title compound (1.2 g, 75%) as a white solid. ES / MS (m / z): 255 (M+H).

[0285] The compounds listed in Table 9d were prepared by essentially the same method as found in Preparation 51l. [Table 63]

[0286] Modified material 51m tert-Butyl (2-bromo-5-methylphenyl)carbamate [ka] To a solution of 2-bromo-5-methylaniline (3.00 g, 16.1 mmol) in THF (50 mL) was added dropwise NaHMDS (2 M) / THF (16.1 mL, 32.2 mmol) at −78° C. After stirring under nitrogen at −78° C. for 0.5 h, a solution of BocO (3.52 g, 16.1 mmol) in THF (10 mL) was added dropwise. After stirring under nitrogen at 25° C. for 3 h, the reaction mixture was poured into saturated aqueous NaCl (200 mL) and extracted with EtOAc (200 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / 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).

[0287] Modifier 51n Ethyl (E)-3-(2-((tert-butoxycarbonyl)amino)-4-methylphenyl)acrylate [ka] To a mixture of tert-butyl (2-bromo-5-methylphenyl)carbamate (1.24 g, 4.33 mmol) in 1,4-dioxane (10.8 mL), 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), PdCl(dppf) (317.0 mg, 0.43 mmol), and water (1.2 mL) were added. After stirring at 90 °C under nitrogen for 16 h, the reaction mixture was cooled and filtered under reduced pressure. The mixture was added to water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / 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).

[0288] Modified material 51o 5-Bromo-3-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine [ka] To 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 at 70 °C under nitrogen for 2 h, the reaction mixture was cooled, diluted with EtOAc (30 mL), washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.49 g, 96%) as an orange oil. ES / MS (m / z): 206 and 208 (M+H-84).

[0289] Modified Material 52 4-Methyl-5-(trimethylstannyl)pyridazine [ka] A mixture of 4-bromo-5-methylpyridazine (1 g, 5.81 mmol), hexamethylpyridazine (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 °C under nitrogen for 4 h and then filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with 25-35% EtOAc / petroleum ether) to give the title compound (490 mg, 33%) as a black solid. ES / MS (ES) m / z 259 (M+H).

[0290] Modifier 52a 4-(5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-5-methylpyridazine [ka] To 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), followed by stirring at 100 °C under a N2 atmosphere for 5 h. The mixture was quenched with saturated aqueous KF solution (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 0–5% MeOH / DCM) to give the title compound (130 mg, 91%) as a yellow oil. ES / MS m / z 369.1 (M+H).

[0291] Modified Material 53 2-(4-chlorobenzyl)-4-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)morpholin-3-one [ka] To a mixture of 2-(4-chlorobenzyl)morpholin-3-one (100 mg, 0.44 mmol) in 1,4-dioxane (2 mL), 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), KPO (94 mg, 0.44 mmol), and CuI (84 mg, 0.44 mmol) were added. The mixture was stirred at 90 °C under nitrogen for 5 hours. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, ACN / 13 mL TFA = 65-95% (17 min), retention time = 8.9 min) to give the title compound (35 mg, 15%) as a white solid. ES / MS m / z 514.2 (M+H).

[0292] Modifier 53a Benzyl 5-chloropentanoate [ka] To a solution of 5-chloropentanoic acid (10.0 g, 73.2 mmol) in ACN (60 mL) at ambient temperature was added (bromomethyl)benzene (13.8 g, 80.5 mmol) and potassium carbonate (12.1 g, 87.9 mmol). The reaction mixture was stirred at 80 °C for 16 h. After cooling to ambient temperature, the solvent was removed under reduced pressure, and the residue was purified by flash silica gel chromatography (eluting with EtOAc / petroleum ether (0-15%)) to give the title compound (9.10 g, 41%) as a colorless oil. 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).

[0293] Modified Material 54 Benzyl 5-chloro-2-((6-fluoropyridin-3-yl)(hydroxy)methyl)pentanoate [ka] To a solution of LDA (12 mmol) in THF (24 mL) at −78 °C, benzyl 5-chloropentanoate (2.9 g, 13 mmol) (prepared as described in Hoffman, M, et al., ChemMed. Chem., 2018, 13(23), 2546-2557) was added and stirred at −78 °C for 1 hour. 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 an additional 3 hours. The reaction was quenched with NHCl (50 mL) and extracted with EtOAc (25 mL × 3). The combined organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 0-20% EtOAc / petroleum ether) to give the title compound (2.5 g, 86%) as a pale yellow oil. ES / MS m / z 352 (M+H).

[0294] The compounds listed in Table 9e were prepared by essentially the same method as found in Preparation 54. [Table 64]

[0295] Modified 55 Benzyl (Z)-5-chloro-2-((6-fluoropyridin-3-yl)methylene)pentanoate [ka] A 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 overnight at ambient temperature under nitrogen. DBU (3 g, 19 mmol) was added dropwise, maintaining the temperature below 30 °C, followed by stirring for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (eluting with EtOAc / petroleum ether (0-20%)) to give the title compound (0.9 g, 64%) as a pale yellow oil. ES / MS m / z = 334 (M+H).

[0296] The compounds listed in Table 9f were prepared by essentially the same method as found in Preparation 55. [Table 65]

[0297] Modified Material 56 5-chloro-2-((6-fluoropyridin-3-yl)methyl)pentanoic acid [ka] To 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, followed by stirring under an H atmosphere at ambient temperature for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the 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).

[0298] The compounds set forth in Table 9g were prepared by methods essentially similar to those found in Preparation 56. [Table 66]

[0299] Modified Material 57 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 [ka] To 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), and DMAP (15 mg, 0.12 mmol), followed by stirring at ambient temperature for 1 h. 3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-amine (233 mg, 1.32 mmol) was added and stirred for 4 h. The mixture was quenched with water, and the resulting precipitate was collected by filtration to give the crude product, which was stirred in 1:1 EtOAc / petroleum ether and filtered to give the title compound (384 mg, 75%) as a white solid. ES / MS m / z 403 (M+H).

[0300] The compounds listed in Table 9ah were prepared by methods essentially similar to those found in Preparation 57. [Table 67]

[0301] Modifier 57a-a 5-chloro-2-((6-fluoropyridin-3-yl)methyl)-N-(2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-yl)pentanamide [ka] To 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 h. The solvent was removed in vacuo, and the residue was diluted with water (3 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were washed with water (3 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluted with EtOAc / petroleum ether (0–100%)) to give the title compound (150 mg, 35%) as a yellow solid. ES / MS (m / z): 390 (M+H).

[0302] The compounds listed in Table 9d were prepared by essentially the same method as found in Preparation 57a-a. [Table 68]

[0303] Modified 58 3-(4-chloro-3-fluorophenyl)-N-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)propanamide [ka] To 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(PPh) (0.5 g, 0.4 mmol) under nitrogen. After stirring at 100 °C for 12 h, the reaction mixture was cooled to ambient temperature, quenched by the addition of saturated KF solution (30 mL), and extracted with EtOAc (50 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluting with MeOH / CH2Cl2 (7%)) to give the title compound (0.95 g, 92%) as a red oil. ES / MS (m / z): 490 (M+Na).

[0304] Modifier 58a N-(3-(5-(bromomethyl)pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(4-chloro-3-fluorophenyl)propanamide [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (10%)) to give the title compound (0.65 g, 70%) as a colorless oil. ES / MS (m / z): 568 (M+H).

[0305] Modifier 58b 3-(4-chloro-3-fluorophenyl)-N-(3-(5-(fluoromethyl)pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)propanamide [ka] To 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 a 2.5 M solution of n-BuLi in THF (0.68 mL, 1.8 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 1 hour, N-fluorobenzenesulfonimide (0.43 g, 1.4 mmol) was added, followed by stirring at −78° C. for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (20 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / petroleum ether (25%)) to give the title compound (60 mg, 10%) as a colorless oil. ES / MS (m / z): 508 (M+H).

[0306] Modified 5ba 5-Bromo-N-(4-methoxybenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-amine [ka] To 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 h, the reaction mixture was cooled, poured into water (300 mL), and extracted with EtOAc (200 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (5%)) to give the title compound (13 g, 71%) as a brown oil. ES / MS m / z: 413 (M+H)

[0307] Modifier 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)propanamide [ka] To 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 h, a solution of 3-(4-chloro-3,5-difluorophenyl)propanoyl chloride (1.04 g, 4.37 mmol) in DMF (5 mL) was added slowly at 0 °C. After stirring at ambient temperature for 2 h, the reaction mixture was quenched with HO (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with 7% MeOH / DCM) to give the title compound (1.1 g, 49%) as a yellow solid. ES / MS (m / z): 615 / 617 (M+H).

[0308] Modified material 58d 5-((tert-butoxycarbonyl)amino)-2-(4-chloro-3-fluorobenzyl)pentanoic acid [ka] To 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 a solution of LiOH (0.22 g, 5.3 mmol) in HO (5 mL) at 0 °C. After stirring at ambient temperature for 2 h, the reaction mixture was quenched by the dropwise addition of 1 N HCl (6 mL, 6 mmol) at 0 °C and extracted with EtOAc (20 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.2 g, 95%) as a colorless oil. ES / MS (m / z): 382 (M+Na).

[0309] The compounds listed in Table 9e were prepared by essentially the same method as found in Preparation 58c. [Table 69]

[0310] Modified material 58h 5-Amino-2-(4-chloro-3-fluorobenzyl)pentanoic acid hydrochloride [ka] To 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 HCl / 1,4-dioxane (4 M) (5 mL, 20 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was concentrated under reduced pressure to give the title compound (1.2 g, 99% yield) as a colorless oil. ES / MS (m / z): 260 (M+H).

[0311] The compounds listed in Table 9f were prepared by essentially the same method as found in Preparation 58g. [Table 70]

[0312] Modified material 58l 5-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)amino)-2-(4-chloro-3-fluorobenzyl)pentanoic acid [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. The mixture was added to water (25 mL), diluted with HCl (15 mL, 15 mmol), and extracted with EtOAc (30 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (1:9)) to give the title compound (0.38 g, 37%) as a brown oil. ES / MS (m / z): 535 / 537 (M+H).

[0313] The compounds set forth in Table 9g were prepared by essentially the same method as found in Preparation 58k. [Table 71]

[0314] Modified material 58p 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-3-(4-chloro-3-fluorobenzyl)piperidin-2-one [ka] To 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 h, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with MeOH / DCM (0–7%)) to give the title compound (120 mg, 25%) as a brown oil. ES / MS (m / z): 517 (M+H).

[0315] The compounds listed in Table 9h were prepared by methods essentially similar to those found in Preparation 58p. [Table 72]

[0316] Modified material 58s 1-(3-Bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(4-chloro-3,5-difluorobenzyl)pyrrolidin-2-one [ka] To 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 a 1 M solution of LiHMDS in THF (45.1 mL, 45.1 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 1 hour, 5-(bromomethyl)-2-chloro-1,3-difluorobenzene (10.82 g, 45.1 mmol) was added, followed by stirring at −78° C. under nitrogen for 3 hours. The mixture was quenched with saturated NH4Cl solution (200 mL) and extracted with EtOAc (200 mL × 2). The organic layers were combined, washed with saturated aqueous NaCl solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluting with 15% EtOAc / petroleum ether) to give the title compound (14.80 g, 61%) as a yellow oil. ES / MS (m / z): 538 (M+H)

[0317] The compounds listed in Table 9i were prepared by methods essentially similar to those found in Preparation 58s. [Table 73] [Table 74]

[0318] Modified material 58z 1-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)piperidin-2-one [ka] To 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 anhydrous THF (40 mL) was added dropwise a 2 M solution of LDA in THF (6.4 mL, 12.87 mmol) under nitrogen while maintaining the temperature below −65° C. The mixture was stirred at −78° C. for 1 hour, and then a solution of 5-(bromomethyl)-1,2,3-trifluorobenzene (1.91 g, 8.58 mmol) in anhydrous THF (15 mL) was added slowly. The mixture was allowed to warm slowly to ambient temperature and stirred for 2 hours. The mixture was cooled to −78° C. and quenched with saturated NH4Cl solution (100 mL). The aqueous solution was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with EtOAc / petroleum ether (5-15%)) to give the title compound (2 g, 45%) as a yellow oil. ES / MS (m / z): 518 (M+H).

[0319] The compounds listed in Table 9j were prepared by essentially the same method as found in Preparation 58z. [Table 75]

[0320] Modified Material 59 Ethyl (E)-2-(7-chlorochroman-4-ylidene)acetate [ka] To 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 small 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, followed by stirring at 0 °C for 1 h and then at ambient temperature for an additional 16 h. The mixture was added to water (50 mL) and extracted with EtOAc (30 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / 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).

[0321] Modifier 59a Ethyl 2-(7-chlorochroman-4-yl)acetate [ka] To 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 for 16 hours at ambient temperature under an H atmosphere, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (water:ACN=4:6) using a C18 column to give the title compound (3.13 g, 62.0%) as a white solid. ES / MS (m / z): 255 (M+H).

[0322] Modified material 59b 2-(7-chlorochroman-4-yl)acetic acid [ka] To 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 hours. The reaction mixture was concentrated under reduced pressure. The mixture was added to water (10 mL) and the pH was adjusted to 3-4 with 1N aqueous HCl. The resulting precipitate was filtered, and the filter cake was purified under reduced pressure to give the title compound (650 mg, 52.0%) as a white solid. ES / MS (m / z): 227 (M+H).

[0323] Modifier 59c N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2-(7-chlorochroman-4-yl)acetamide [ka] To 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 dropwise POCl (1.14 g, 7.46 mmol) at 0 °C. The mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (100 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (10:1)) to give the title compound (1.15 g, 34%) as a white solid. ES / MS (m / z): 502 (M+H).

[0324] Preparation 59d 4-Methoxybutanamide [ka] To a solution of 4-methoxybutanoic acid (2.00 g, 16.9 mmol) in ACN (150 mL) were 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 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (50 mL × 2). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.98 g, 99.8%) as a white solid. 1 H 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).

[0325] The compounds listed in Table 9k were prepared by essentially the same method as found in Preparation 59d. [Table 76]

[0326] Preparation 59f 4-Methoxybutanenitrile [ka] To 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 hours, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (50 mL×3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure 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).

[0327] The compounds listed in Table 9l were prepared by methods essentially similar to those found in Preparation 59f. [Table 77]

[0328] Preparation 59h tert-Butyl (S)-2-((cyanomethoxy)methyl)morpholine-4-carboxylate [ka] To 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, followed by stirring for 1 hour. 2-Bromoacetonitrile (6.90 g, 57.5 mmol) was added to the mixture at -20 °C, followed by stirring for 12 hours at -20 °C. The mixture was quenched with MeOH (20 mL) and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluted with MeOH / DCM (0-5%)) to give the title compound (5.00 g, 67%) as a yellow oil. ES / MS (m / z): 201 (M+H-tBu).

[0329] The compounds listed in Table 9m were prepared by essentially the same method as found in Preparation 59h. [Table 78]

[0330] Preparation 59n tert-Butyl (2S)-2-((1-cyano-2-oxo-2-(pyridazin-4-yl)ethoxy)methyl)morpholine-4-carboxylate [ka] To a solution of methylpyridazine-4-carboxylate (2.77 g, 20.0 mmol) in THF (100 mL) was added a 1 M solution of LiHMDS in THF (18.5 mL, 18.5 mmol) at −78° C. under nitrogen. After stirring for 1 hour, a solution of tert-butyl (S)-2-((cyanomethoxy)methyl)morpholine-4-carboxylate (5.00 g, 79 wt%, 15.4 mmol) in THF (20 mL) was added, followed by stirring at −78° C. for 5 hours. The reaction mixture was warmed to ambient temperature and concentrated under reduced pressure to give the title compound (11.00 g, crude) as a brown solid. ES / MS (m / z): 363 (M+H).

[0331] The compounds set forth in Table 9n were prepared by methods essentially similar to those found in Preparation 59n. [Table 79] [Table 80]

[0332] Preparation 59w tert-Butyl (S)-2-(((5-amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate TIFF2026504977000361.tif42164 To 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 h, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (C18, 2-40% ACN / 10 mmol NH4HCO3) to give the title compound (3.60 g, 46%) as a yellow solid. ES / MS (m / z): 497 (M+H).

[0333] The compounds listed in Table 9o were prepared by methods essentially similar to those found in Preparation 59w. [Table 81]

[0334] Preparation 59aa tert-Butyl (S)-2-(((5-bromo-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate [ka] To 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 minutes, 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) was added, followed by stirring at 65° C. for 30 minutes. The mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL×3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography eluting with EtOAc / 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).

[0335] The compounds listed in Table 9p were prepared by essentially the same method as found in Preparation 59aa. [Table 82]

[0336] Preparation 59ae tert-Butyl 2-(((5-amino-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate [ka] To a solution of tert-butyl 2-((1-cyano-2-oxo-2-(pyridazin-4-yl)ethoxy)methyl)morpholine-4-carboxylate (2.5 g, 7 mmol) in EtOH (10 mL) was added N2H4.HO (1 g, 21 mmol) and AcOH (1.3 g, 21 mmol). After stirring at 80 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (C18, 40% ACN / 10 mmol NH4HCO3) to give the title compound (1 g, 38%) as a yellow solid. ES / MS (m / z): 377 (M+H).

[0337] The compounds listed in Table 9q were prepared by methods essentially similar to those found in Preparation 59ae. [Table 83]

[0338] Preparation 59al 4-(4-bromo-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-1-yl)pyridazine [ka] To a solution of (4-bromo-1-(pyridazin-4-yl)-1H-pyrazol-5-yl)methanol (300 mg, 1.18 mmol) in ACN (10 mL) were 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 h, the mixture was cooled to ambient temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (50 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (6:1)) to give the title compound (250 mg, 61%) as a white solid. ES / MS (m / z): 339 / 341 (M+H).

[0339] Preparation 59am 4-(4-bromo-5-(methoxymethyl)-1H-pyrazol-1-yl)pyridazine [ka] To 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 at 0 °C for 0.5 h, a solution of MeI (267 mg, 1.88 mmol) in THF (1 mL) was added, followed by stirring at 20 °C under nitrogen for 5 h. The mixture was added to water (20 mL) and extracted with EtOAc (100 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (6:1)) to give the title compound (340 mg, 77%) as a white solid. ES / MS (m / z): 269 / 271 (M+H).

[0340] Preparation 59an 3-Bromo-5-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde [ka] To a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde (3.7 g, 9 mmol) in anhydrous DMF (200 mL) were 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), followed by stirring at 100 °C under nitrogen for 2 h. The reaction mixture was cooled to ambient temperature, and then aqueous KF solution (300 mL) was added. After stirring at ambient temperature for 2 h, the mixture was filtered through diatomaceous earth and washed with EtOAc (400 mL). The filtrate was collected and extracted with EtOAc (300 mL × 2). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with EtOAc / 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).

[0341] The compounds listed in Table 9r were prepared by methods essentially similar to those found in Preparation 59an. [Table 84]

[0342] Preparation 59au (5-amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)methanol [ka] To 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 LiAH / THF (1 M) (4.7 mL, 4.7 mmol) at -5 °C, followed by stirring at ambient temperature under a N atmosphere for 11 minutes. Saturated aqueous NHCl (40 mL) was added to the mixture, which was then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (7:93)) to give the title compound (475 mg, 29%) as a yellow solid. ES / MS (m / z): 312 (M+H).

[0343] Preparation 60 3-Bromo-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde [ka] To 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) (11 mg, 0.06 mmol), and CsCO (854 mg, 2.62 mol). After stirring at 100 °C under a nitrogen atmosphere for 1 h, the reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with EtOAc / petroleum ether (0–10%)) to give the title compound (0.33 g, 47%) as a yellow oil. ES / MS (m / z): 554 (M+Na).

[0344] The compounds set forth in Table 9s were prepared by methods essentially similar to those found in Preparation 60. [Table 85] [Table 86]

[0345] 60g of preparation 1-(3-Bromo-4-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] To 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 NaBH (1.12 g, 29.7 mmol) at ambient temperature. After stirring at ambient temperature for 30 minutes, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc / petroleum ether (0–40%)) to give the title compound (7.2 g, 86%) as a yellow oil. ES / MS (m / z): 558 (M+Na).

[0346] The compounds listed in Table 9t were prepared by essentially the same method as found in Preparation 60g. [Table 87]

[0347] Preparation 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 [ka] 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 Pd(dba) (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 h, the reaction mixture was cooled to ambient temperature, poured into water (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (0-80%)) to give the title compound (1.7 g, 63%) as a brown solid. ES / MS (m / z): 534 (M+H).

[0348] The compounds listed in Table 9u were prepared by essentially the same method as found in Preparation 60k. [Table 88]

[0349] Preparation 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)benzonitrile [ka] To a solution of 3-bromo-5-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde (2 g, 5.2 mmol) in anhydrous DMF (100 mL) was added 2-fluoro-4-((2-oxopyrrolidin-3-yl)methyl)benzonitrile (1.22 g, 5.6 mmol), N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (1.31 g, 10.4 mmol), CuI (1.11 g, 5.2 mmol), and KPO (16.652 g, 74 mmol) were added to the mixture, which was then stirred at 100 °C under nitrogen for 4 h. The mixture was cooled to ambient temperature and filtered under reduced pressure. The filtrate was added to water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (1:1)) to give the title compound (866 mg, 32%) as a yellow oil. ES / MS (m / z): 521 (M+H).

[0350] The compounds listed in Table 9v were prepared by methods essentially similar to those found in Preparation 60p. [Table 89] [Table 90]

[0351] Preparation 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)benzonitrile [ka] To 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 NaBH (106 mg, 2.8 mmol) in small portions, followed by stirring at ambient temperature for 1 hour. The mixture was added to water (100 mL) and extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (932 mg, 95%) as a white solid. ES / MS (m / z): 523 (M+H).

[0352] The compounds listed in Table 9w were prepared by methods essentially similar to those found in Preparation 60x. [Table 91]

[0353] preparation 60z 5-(3-(2-(difluoromethyl)-4-fluorobenzyl)-2-oxopyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde [ka] 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), PdCl(dppf) (38.5 mg, 52.6 μmol), potassium carbonate (182 mg, 1.31 mmol), and water (0.5 mL), followed by stirring at 100° C. under nitrogen for 2 hours. The reaction mixture was cooled to ambient temperature, added to water (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with DCM / MeOH (10:1)) to give the title compound (250 mg, 65.9%) as a yellow oil. ES / MS (m / z): 546 (M+H).

[0354] The compounds listed in Table 9x were prepared by methods essentially similar to those found in Preparation 60z. [Table 92]

[0355] preparation 60ac 3-(2-(difluoromethyl)-4-fluorobenzyl)-1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-one [ka] To 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 NaBH (26.2 mg, 693 μmol) at 0° C., followed by stirring at 0° C. for 0.5 h. The reaction mixture was quenched with water (30 mL) at 0° C. and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (DCM / MeOH (10:1)) to give the title compound (500 mg, 76.3%) as a brown oil. ES / MS (m / z): 548 (M+H).

[0356] The compounds listed in Table 9y were prepared by methods essentially similar to those found in Preparation 60ac. [Table 93]

[0357] preparation 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-one [ka] To 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 h, the reaction mixture was cooled to ambient temperature, quenched with saturated aqueous KF solution (30 mL), and extracted with EtOAc (50 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (75-85%)) to give the title compound (750 mg, 44%) as a brown oil. ES / MS (m / z): 632 (M+H).

[0358] The compounds listed in Table 9z were prepared by methods essentially similar to those found in Preparation 60af. [Table 94] [Table 95] [Table 96] [Table 97] [Table 98] [Table 99]

[0359] Preparation 61 2-(4-chlorobenzyl)-4-(5-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)morpholin-3-one [ka] A solution of 2-(4-chlorobenzyl)morpholin-3-one (100 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was added to 4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5-methylpyridazine (245 mg, 0.67 mmol), KPO (94 mg, 0.44 mmol), N 1 , N 2 -Dimethylcyclohexane-1,2-diamine (63 mg, 0.44 mmol) and CuI (84 mg, 0.44 mmol) were added, followed by stirring at 90 °C under nitrogen for 5 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 65-95% ACN / 13 mmol TFA in 17 min, retention time = 8.9 min) to give the title compound (35 mg, 15%) as a white solid. ES / MS (m / z): 514 (M+H).

[0360] The compounds set out in Table 9aa were prepared by methods essentially similar to those found in Preparation 61. [Table 100] [Table 101] [Table 102]

[0361] Preparation 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-one [ka] To 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)Cl (146 mg, 0.2 mmol) in small portions under nitrogen. After stirring at 100 °C under nitrogen for 2 h, the reaction mixture was cooled to ambient temperature, added to water (20 mL), and extracted with EtOAc (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (20:1)) to give the title compound (400 mg, 43%) as an orange oil. ES / MS (m / z): 470 (M+H-82).

[0362] The compounds listed in Table 9ab were prepared by methods essentially similar to those found in Preparation 61m. [Table 103]

[0363] Preparation 61o 1-(3-(5-aminopyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] To a solution of 5-bromopyridazin-4-amine (258 mg, 1.49 mmol) in 1,4-dioxane (8 mL) and HO (1 mL) under a nitrogen atmosphere, KCO (618 mg, 4.47 mmol), Pd(dppf)Cl (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) were added portionwise. After stirring at 100 °C for 2 h, the reaction mixture was cooled to ambient temperature, added to water (10 mL), and extracted with EtOAc (15 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (20:1)) to give the title compound (280 mg, 36%) as a white solid. ES / MS (m / z): 519 (M+H).

[0364] The compounds listed in Table 9ac were prepared by methods essentially similar to those found in Preparation 61o. [Table 104]

[0365] Preparation 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-one [ka] To 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) in DCM (20 mL) was added NBS (418 mg, 2.35 mmol). After stirring at 25 °C for 3 h, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (50-60%)) to give the title compound (1.3 g, 92%) as a brown oil. ES / MS (m / z): 598 (M+H).

[0366] The compounds listed in Table 9ad were prepared by methods essentially similar to those found in Preparation 61q. [Table 105]

[0367] Preparation 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-one [ka] To 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), PdCl(dppf) (159 mg, 0.2 mmol), and water (5 mL). After stirring at 100 °C under nitrogen for 12 hours, 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 under reduced pressure. The crude product was purified by silica gel flash chromatography (eluting with EtOAc / petroleum ether (30-40%)) to give the title compound (600 mg, 45%) as a brown oil. ES / MS (m / z): 590 (M+H).

[0368] The compounds listed in Table 9ae were prepared by methods essentially similar to those found in Preparation 61t. [Table 106]

[0369] Preparation 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)acetaldehyde [ka] To 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 hours, the reaction mixture was cooled to ambient temperature, added to water (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure 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).

[0370] The compounds listed in Table 9af were prepared by methods essentially similar to those found in Preparation 61x. [Table 107]

[0371] Preparation 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 oxime [ka] To 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 h, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure 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).

[0372] The compounds listed in Table 9ag were prepared by methods essentially similar to those found in Preparation 61z. [Table 108]

[0373] Preparation 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)acetonitrile [ka] To 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 for 15 min at 0° C. and an additional 3 h at 25° C., the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure 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).

[0374] 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-one [ka] To 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 under a H atmosphere for 2 h, the reaction mixture was filtered and concentrated under reduced pressure 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).

[0375] Preparation 61ad 2-(5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)acetaldehyde [ka] To 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 dropwise TFA (8 mL, 110 mmol). After stirring at 25 °C for 12 h, the mixture was concentrated under reduced pressure. The residue was added to water (30 mL), and the pH was adjusted to 7 with saturated aqueous NaHCO3, followed by extraction with DCM (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (206 mg, 30%) as a white solid. ES / MS (m / z): 415 (M+H).

[0376] 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-one [ka] To 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 minutes, SEM-Cl (250 mg, 1.5 mmol) was added, followed by stirring at ambient temperature overnight. The reaction mixture was quenched with water (60 mL) and extracted with DCM (25 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with 1% TEA / EtOAc) to give the title compound (450 mg, 66%) as a brown oil. ES / MS (m / z): 498 (M+H)

[0377] The compounds set forth in Table 9ai were prepared by methods essentially similar to those found in Preparation 61ae. [Table 109]

[0378] Preparation 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) [ka] The racemic mixture 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 (450 mg) was purified by SFC (column: IG 20 * Separation on a 250 mm, 10 μm (Daicel) column using a mobile phase of CO2 / MeOH [0.2% NH3 (7 mol / L in MeOH)] = 45 / 55 gave Isomer 1 (140 mg, ee = 100%) and Isomer 2 (95 mg, ee = 100%) as pale brown oils.

[0379] The compounds listed in Table 9aj were prepared by essentially the same method as found in Preparation 61ag. [Table 110] [Table 111] [Table 112]

[0380] Preparation 62 (S)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3-fluorobenzyl)pentanoic acid [ka] To 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 HO (957 mg, 28.14 mmol) at 0 °C. After stirring for 10 min, the reaction mixture was added to a solution of LiOH.HO (844 mg, 14.07 mmol) in HO (5 mL) and then stirred for 20 min. The reaction mixture was poured into NHCl solution (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (1.4 g, 80%) as a yellow oil. ES / MS (m / z): 375 (M+H).

[0381] Preparation 62aa (S)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3-fluorobenzyl)-N-(1-(5-methylpyridazin-4-yl)-1H-pyrazol-4-yl)pentanamide [ka] To 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 a solution of T3P in EtOAc (3 g, 50 wt%, 4.7 mmol). After stirring at room temperature for 2 h, the reaction mixture was added to water (50 mL) and extracted with EtOAc (50 × 3 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with MeOH / DCM (7%)) to give the title compound (1.1 g, 62%) as a yellow oil. ES / MS (m / z): 532 and 534 (M+H).

[0382] Preparation 62ab (S)-2-(4-chloro-3-fluorobenzyl)-5-hydroxy-N-(1-(5-methylpyridazin-4-yl)-1H-pyrazol-4-yl)pentanamide [ka] To 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 anhydrous THF (20 mL) was added EtN.3HF (1.7 g, 10.6 mmol) dropwise at 0 °C. After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with EtOAc / petroleum ether (0-50%)) to give the title compound (0.55 g, 64%) as a yellow oil. ES / MS (m / z): 418 and 420 (M+H).

[0383] 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-one [ka] To 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 anhydrous THF (10 mL) was added 1 M LiHMDS (1.7 mL, 1.7 mmol) at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added a solution of 5-(bromomethyl)-2-chloropyridine (268 mg, 1.3 mmol) in anhydrous THF (5 mL), followed by stirring at −78° C. for 1.5 hours. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (eluting with ACN / 10 mM NH4HCO3 (2-50%)) to give the title compound (110 mg, 16%) as a white solid. ES / MS (m / z): 514 (M+H).

[0384] The compounds set forth in Table 9ak were prepared by methods essentially similar to those found in Preparation 62a. [Table 113]

[0385] Preparation 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) [ka] The racemic mixture 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 added to SFC (AD 20 *Elution at 250 mm, 10 μm, with CO / MeOH [0.2% NH (7M / MeOH)] = 40 / 60] gave Isomer 1 and Isomer 2 (240 mg, 45%) as white solids. Comparison with an authentic sample revealed that the expected isomer was Isomer 2.

[0386] 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) [ka] 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 anhydrous DMF (80 mL) was added CsCO (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 h, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL × 2). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (eluting with ACN / NHHCO solution (0-60%)) to give the title compound, 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).

[0387] 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) [ka] (Isomer 1) To a solution of 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 CsCO (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 1 week, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound mixture (0.46 g, 99+%) as a yellow oil. ES / MS (m / z): 630 (M+H).

[0388] Preparation 62f N-(4-(hydroxymethyl)-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propanamide [ka] To a solution of 3-(3,4,5-trifluorophenyl)propanoic acid (374 mg, 1.83 mmol) in DMAc (8 mL) were added DIPEA (789 mg, 1.06 mL, 6.10 mmol) and a solution of T3P in EtOAc (971 mg, 50 wt%, 1.53 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes. To 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., followed by stirring at 20° C. for 3 hours. The reaction mixture was poured into ice water (30 mL) and extracted with DCM (20 mL × 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM / MeOH (93:7)) to give the title compound (340 mg, 44.8%) as a yellow oil. ES / MS (m / z): 498 (M+H).

[0389] Preparation 62h tert-Butyl 4-(2-hydroxyethyl)-3-(pyridazin-4-yl)-5-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazole-1-carboxylate [ka] To 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) at 0 °C. After stirring at 20 °C for 1 h, the reaction mixture was used in the next step without further purification. ES / MS (m / z): 492 (M+H).

[0390] 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-carboxylate [ka] To 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 CsCO (2.5 g, 7.67 mmol) and di-tert-butyl(chloromethyl)phosphate (1.49 g, 5.75 mmol) at 0 °C. After stirring at ambient temperature under nitrogen for 16 h, the mixture was added to water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (eluting with ACN / water (12.5 mM NHHCO) (60-65%)) to give the title compound (500 mg, 16.7%) as a yellow solid. ES / MS (m / z): 714 (M+H).

[0391] Preparation 62j (2-(5-(pyridazin-4-yl)-3-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4-yl)ethoxy)methyl hydrogen phosphate [ka] To 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 HO (2 mL) was added acetic acid (2.0 mL, 34.80 mmol). After stirring at 60 °C for 8 h, the reaction mixture was filtered at 60 °C. The filter cake was washed with HO (2 mL) and dried under reduced pressure to give the title compound (71.7 mg, 20.4%) as a white solid. ES / MS (m / z): 502 (M+H).

[0392] Preparation 62k tert-Butyl 2-(((3-(pyridazin-4-yl)-5-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate [ka] To a solution of tert-butyl 2-(((5-amino-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate (0.5 g, 1.3 mmol) in DMA (10 mL) were added 3-(3,4,5-trifluorophenyl)propanoic acid (0.35 g, 1.7 mmol), a solution of T3P in EtOAc (1.7 g, 5.3 mmol), and DIPEA (0.51 g, 4 mmol). After stirring at 100 °C for 12 h, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (10%)) to give the title compound (0.7 g, 93%) as a yellow oil. ES / MS (m / z): 563 (M+H).

[0393] The compounds listed in Table 9am were prepared by methods essentially similar to those found in Preparation 62k. [Table 114] [Table 115]

[0394] Preparation 62s N-(4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propenamide [ka] To 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 a 4 M solution of HCl in 1,4-dioxane (5 mL, 20 mmol). After stirring at ambient temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.17, 30%) as a brown solid. ES / MS (m / z): 463 (M+H).

[0395] 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-carboxylate [ka] To 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) were 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 a solution of T3P in EtOAc (3.84 g, 50 wt%, 6.04 mmol). After stirring at 100° C. for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluting with MeOH / DCM (5%)) to give the title compound (2.20 g, 93%) as a brown solid. ES / MS (m / z): 683 (M+H).

[0396] The compounds listed in Table 9an were prepared by methods essentially similar to those found in Preparation 62t. [Table 116]

[0397] Preparation 62w N-(1-(4-Methoxybenzyl)-4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propanamide [ka] To 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 a 4 M solution of HCl in 1,4-dioxane (5 mL, 20 mmol). After stirring at 25 °C for 5 h, the mixture was quenched with 7 M NH3 / MeOH (10 mL, 70 mmol) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (12%)) to give the title compound (1.20 g, 48%) as a yellow solid. ES / MS m / z: 583 (M+H).

[0398] 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)propanamide [ka] To 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 KCO (356 mg, 2.57 mmol) and iodomethane-d (149 mg, 1.03 mmol). After stirring at 25 °C for 12 h, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluted with MeOH / DCM (7%)) to give the title compound (250 mg, 47%) as a yellow solid. ES / MS (ES): m / z = 600 (M+H).

[0399] 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) [ka] The racemic mixture 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 was purified by SFC (column: IH 25 * Elution with a 250 mm, 10 μm (Daicel) mobile phase of CO₂ / MeOH [0.5% NH₃ (7M / MeOH) = 90 / 10] gave Isomer 1 and Isomer 2 as pale brown oils. ES / MS (m / z): 533 (M+H). [Table 117] [Table 118] [Example]

[0400] Example 1 3-(6-fluoropyridin-3-yl)-N-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)propanamide [ka] A 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 hours. The mixture was added to water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC (water / ACN = 3 / 2) to give the title compound (227 mg, 30%) as a white solid. ES / MS m / z 327 (M+H).

[0401] The compounds listed in Table 10 were prepared essentially similarly to the procedure of Example 1 using the appropriate starting materials and reagents. [Table 119] [Table 120]

[0402] Example 8 3-(6-chloropyridin-3-yl)-N-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)propenamide [ka] A 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 h. The mixture was added to water (30 mL) and EtOAc (30 mL). The resulting precipitate was filtered, and the filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, slurried in MeOH, and filtered to give the title compound (364 mg, 63%) as a white solid. ES / MS m / z 344 (M+H).

[0403] The compounds listed in Table 11 were prepared essentially similarly to the procedure of Example 8 using the appropriate starting materials and reagents. [Table 121] [Table 122] [Table 123] [Table 124]

[0404] Example 14 3-(6-chloro-5-fluoropyridin-3-yl)-N-(4-methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)propanamide [ka] A 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 h. The reaction mixture was concentrated under reduced pressure 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 × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (450 mg) was purified by preparative HPLC (C18, ACN / 10 mM NH4HCO3 = 32-62% for 9 min, retention time = 8.5 min) to give the title compound (208 mg, 76%) as a white solid. ES / MS m / z 375 (M+H).

[0405] Example 15 N-(4-cyano-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-3-(6-fluoropyridin-3-yl)propenamide [ka] A 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-triethylammonium sulfonylcarbamate (227 mg, 0.95 mmol) in DMF (2 mL) was stirred at ambient temperature for 2 h. The mixture was purified by preparative HPLC (C18, ACN / 10 mM NH4HCO3 = 20-50% 9 min, retention time = 7.4 min) to give the title compound (26 mg, 39.4%) as a white solid. ES / MS m / z 352 (M+H).

[0406] Example 16 3-(4-chloro-3-fluorophenyl)-N-(1-(3-methylpyridazin-4-yl)-1H-pyrazol-4-yl)propenamide [ka] To 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) and DMA (3 mL) was added HATU (326 mg, 0.86 mmol) and DIPEA (180 mg, 1.43 mmol), followed by stirring at 70 °C for 12 h. The mixture was purified by preparative HPLC (C18, ACN / 10 mmol NH4HCO3 = 20-50% over 9 min) to give the product (21.8 mg, 21%) as a white solid. ES / MS m / z 360 (M+H).

[0407] Example 17 3-(4-Fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one [ka] To 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 h. The reaction mixture was concentrated under reduced pressure. Water (3 mL) and saturated NaHCO3 (10 mL) were added to the residue, and the mixture was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative HPLC (C18, 20–50% ACN / 10 mM NH4HCO3 in 9 min, retention time = 7.4 min) to give the title compound (11 mg, 50%) as a white solid. ES / MS m / z 367 (M+H).

[0408] The compounds listed in Table 12 were prepared essentially similarly as described for Example 17 using the appropriate starting materials and reagents. [Table 125]

[0409] Example 19 3-((6-fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one [ka] To 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, followed by stirring at ambient temperature for 2 hours. The reaction mixture was quenched with water (60 mL) and the pH was adjusted to 6-7 with 1N HCl. The solid was collected by filtration and dried under reduced pressure to give the crude product. The crude product 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).

[0410] The compounds listed in Table 12a were prepared essentially similarly as described for Example 19 using the appropriate starting materials and reagents. [Table 126]

[0411] Example 20 (S)-3-(4-chloro-3-fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one [ka] A 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 h. The reaction mixture was purified by preparative HPLC (C18, 42–72% elution with ACN / 10 mM NH4HCO3 in 9 min, retention time = 8.9 min) to give the title compound (6 mg, 42%) as a white solid. ES / MS m / z 401 (M+H).

[0412] Example 21 2-(4-chlorobenzyl)-4-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)morpholin-3-one [ka] To 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, followed by stirring at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure. Saturated aqueous NaHCO3 was added to the residue at 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).

[0413] The compounds listed in Table 12b were prepared by methods essentially similar to those found in Example 21. [Table 127] [Table 128]

[0414] Example 22 (S)-3-(4-chloro-3-fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one [ka] A 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 HO (53 mg, 1.56 mmol) in THF / HO (4 / 1.5 mL) was stirred at ambient temperature for 10 min. LiOH.HO (33 mg, 0.78 mmol) was added, followed by stirring at ambient temperature for 16 h. The reaction mixture was quenched with aqueous NaSO (20 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (C18, ACN / 10 mM NH4HCO3 = 48-78% for 9 min, retention time = 8.9 min) to give the title compound (37.5 mg, 36%) as a white solid. The product was purified by SFC [apparatus: SFC-150 (Waters); column: AS20 * Further purification by column chromatography (250 mm, 10 μm, Daicel); column temperature: 35 °C; mobile phase: CO₂ / MeOH [0.2% NH₃ (7 M / MeOH)] = 60 / 40; flow rate: 100 g / min; back pressure: 100 bar; detection wavelength: 214 nm; cycle time: 10.17 min) and combination with the previous batch (12.5 mg) gave the title isomer P3 (retention time = 8.901 min) (24 mg, 48%) as a white solid. ES / MS m / z 400 (M+H).

[0415] The compounds listed in Table 13 were prepared by methods essentially similar to those found in Example 22. [Table 129]

[0416] Example 25 3-(4-chloro-3-fluorobenzyl)-3-hydroxy-1-(2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-yl)piperidin-2-one [ka] To 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 dropwise at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 1 hour. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (18 mg, 0.067 mmol) in THF (0.5 mL) was added dropwise to the above mixture at −78° C. After stirring at −78° C. for 30 minutes, the reaction was quenched with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with saturated aqueous NaCl (50 mL × 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Et0Ac / petroleum ether = 0-20%) to give the title compound as a white solid (8.7 mg, 32%). ES / MS (m / z): 403 (M+H).

[0417] The compounds listed in Table 13a were prepared by methods essentially similar to those found in Preparation 63n. [Table 130]

[0418] Example 26 3-(4-fluoro-2-(fluoromethyl)benzyl)-1-(3-(pyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one [ka] To 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) at ambient temperature was added TFA (31 mg, 0.27 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in THF (2 mL) and purified by preparative HPLC (column: Welch Xtimate 21.2 * Purification was performed on a 250 mm C18 column, 10 μm, mobile phase: A: water (0.2% formic acid) B: ACN; gradient B%: 30% to 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).

[0419] The compounds listed in Table 14 were prepared by methods essentially similar to those found in Example 26. [Table 131] [Table 132] [Table 133] [Table 134] [Table 135]

[0420] Example 62 3-(4-chloro-2-hydroxybenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one [ka] To 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 h, the reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with saturated aqueous NaCl (10 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with MeOH / DCM (0-10%)) to give the title compound as a white solid (6.1 mg, 7.9%) ES / MS (m / z): 399 (M+H).

[0421] The compounds listed in Table 15 were prepared by methods essentially similar to those found in Example 62. [Table 136]

[0422] Example 68 1-(5-chloro-1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] 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 to potassium phosphate tribasic acid (274 mg, 1.29 mmol), N 1 ,N 2-Dimethylcyclohexane-1,2-diamine (122 mg, 860 μmol) and CuI (81.9 mg, 430 μmol) were added. The reaction was stirred at 60 °C for 3 h. After cooling to ambient temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (eluted with EtOAc / petroleum ether (0–30%)) to give the title compound as a white solid (120 mg, 63.6%). ES / MS (m / z): 408 (M+H).

[0423] The compounds listed in Table 16 were prepared by methods essentially similar to those found in Example 68. [Table 137]

[0424] Example 72 3-((6-fluoropyridin-3-yl)methyl)-1-(2-(pyridazin-4-yl)-2H-1,2,3-triazol-4-yl)piperidin-2-one [ka] 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 hours. After cooling to ambient temperature, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Welch Xtimate 21.2 *Purification with 250 mm C18, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate and 0.05% ammonium hydroxide) B: ACN; B%: 30% to 70% in 15.0 min gave a solution of pure product, which was lyophilized to give the title compound as a white solid (119 mg, 93%). ES / MS (m / z): 354 (M+H).

[0425] The compounds listed in Table 17 were prepared by methods essentially similar to those found in Example 72. [Table 138]

[0426] Example 75 5-Hydroxy-1-(3-(pyridazin-4-yl)-1H-1,2,4-triazol-5-yl)-3-(3,4,5-trifluorobenzyl)piperidin-2-one [ka] To 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 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Welch Xtimate 21.2 * 250 mm C18, 10 μm, Mobile phase: A: Water (10 mmol / L ammonium bicarbonate and 0.05% ammonium hydroxide) B: Acetonitrile; B%: 30% to 70% in 15.0 min. Appropriate fractions were combined, concentrated under reduced pressure, and lyophilized to give the title compound as a white solid (3.7 mg, 3.3%). ES / MS (m / z): 405 (M+H).

[0427] Example 76 3-(3,4-Difluorobenzyl)-1-(4-(pyridazin-4-yl)-1H-imidazol-2-yl)piperidin-2-one [ka] To 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 anhydrous DMF (5 mL) was added XPhos (17 mg, 35 μmol) and Pd(dba) (16 mg, 17 μmol) at ambient temperature. The mixture was stirred at 80° C. under nitrogen for 1 hour. After cooling to ambient temperature, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with saturated aqueous NaCl (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with MeOH / DCM (0-5%)) to give the title compound as a yellow solid (4.3 mg, 6.6%) ES / MS (m / z): 370 (M+H).

[0428] The compounds listed in Table 18 were prepared by methods essentially similar to those found in Example 76. [Table 139]

[0429] Example 79 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4-yl)-1H-pyrrole-2-carbonitrile [ka] 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-carbonitrile (20 mg, 36 μmol) in DCM (3 mL) was added TFA (1 mL, 0.01 mol) dropwise at 20° C. After stirring at 20° C. for 2 hours, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with saturated aqueous NaCl solution (10 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Welch Xtimate 21.2 * Purification was performed on a 250 mm C18 column, 10 μm, mobile phase: A: water (0.2% formic acid) B: ACN; B%: 30% to 70% in 15.0 min. Appropriate fractions were combined and concentrated under reduced pressure to give the title compound as a gray solid (2.8 mg, 19%). ES / MS (m / z): 398 (M+H).

[0430] The compounds listed in Table 19 were prepared by methods essentially similar to those found in Example 79. [Table 140] [Table 141]

[0431] Example 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) [ka] 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 hours. The solvent was removed and dried with nitrogen. The residue was triturated with ACN (10 mL) and water (1 mL), filtered, and dried under reduced pressure to give the title compound as a yellow solid (520 mg, 60%). ES / MS (m / z): 481 (M+H).

[0432] The compounds listed in Table 20 were prepared by methods essentially similar to those found in Example 87. [Table 142]

[0433] Example 92 Ammonia salt of (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) [ka] To 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 h. The solvent was removed by evaporation, and the residue was purified by preparative HPLC (0.1% NH4HCO3, ACN ramped from 50% to 80% in 8 min, stopped at 16 min, flow rate: 30 mL / min, retention time: 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).

[0434] The compounds listed in Table 21 were prepared by methods essentially similar to those found in Example 92. [Table 143]

[0435] Example 94 3-(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) [ka] 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 added to a Daicel Chiralpak IG (250 * Purification was performed using a 25 mm, 10 μm column with a mobile phase of A:CO₂, B:(MEOH:ACN=1:1), with 55% B, at a flow rate of 100 mL / min. The first peak of eluate was collected and lyophilized to give Isomer 1 (16.9 mg, 16.9%, ee: 100.0%). ES / MS (m / z): 435 (M+H). The second peak of eluate was collected and lyophilized to give Isomer 2 (20.6 mg, 20.6%, ee: 100.0%). ES / MS (m / z): 435 (M+H).

[0436] The compounds listed in Table 22 were prepared by methods essentially similar to those found in Example 94. [Table 144] [Table 145] [Table 146] [Table 147] [Table 148] [Table 149] [Table 150] [Table 151] [Table 152] [Table 153] [Table 154] [Table 155] [Table 156]

[0437] Example 154 1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. At 0 °C, saturated aqueous NaHCO was added to the residue to basify it to pH 8. The aqueous solution was decanted. The residue was purified by silica gel flash chromatography (eluting with MeOH / DCM (0-10%)) to give the title compound (1.1 g, 86%). ES / MS (m / z): 404 (M+H).

[0438] The compounds listed in Table 23 were prepared by methods essentially similar to those found in Example 154. [Table 157]

[0439] Example 159 2-Fluoro-4-((1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-2-oxopyrrolidin-3-yl)methyl)benzonitrile [ka] To 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, followed by stirring at ambient temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was added to water (20 mL), and the pH was adjusted to 7 with saturated aqueous NaHCO3, followed by extraction with DCM (30 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Welch Xtimate 21.2 * Purification on a 250 mm C18 column, 10 μm, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: ACN; B%: 30% to 70% in 15.0 min afforded the title compound (101 mg, 66%) as a white solid. ES / MS (m / z): 393 (M+H).

[0440] The compounds listed in Table 24 were prepared by methods essentially similar to those found in Example 159. [Table 158]

[0441] Example 164 3-(2-(difluoromethyl)-4-fluorobenzyl)-1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)pyrrolidin-2-one [ka] To 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 hours and then concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (gradient: 20-50% ACN / water (10 mmol NH4HCO3) over 8 min, stopping at 15 min; retention time: 12-13 min; flow rate: 30 mL / min; column: BOSTON pHlex ODS 10 um 21.2 x 250 mm 120A) to give the title compound (130 mg, 58.8%) as a white solid. ES / MS (m / z): 418.3 [M+H].

[0442] The compounds listed in Table 24 were prepared by methods essentially similar to those found in Example 164. [Table 159]

[0443] Example 167 1-(3-(5-(hydroxymethyl)pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)piperidin-2-one [ka] To 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, followed by stirring at ambient temperature for 4 h. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added saturated aqueous NaHCO3 solution (15 mL) at 0 °C. The precipitate was filtered and washed with water (30 mL) and ice-cold MeOH (0.5 mL) to give the title compound (258 mg, 52%) as a white solid. MS (m / z): 418 (M+H).

[0444] The compounds listed in Table 25 were prepared by methods essentially similar to those found in Example 167. [Table 160] [Table 161] [Table 162]

[0445] Example 187 3-(4-chloro-3,5-difluorobenzyl)-4-(hydroxymethyl)-1-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)pyrrolidin-2-one [ka] To 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 anhydrous DCM (5 mL) was added dropwise a solution of tribromoborane in DCM (0.1 mL, 17 wt%, 1.34 μmol) at −78° C. under nitrogen, followed by stirring at 25° C. for 16 hours. The mixture was quenched with saturated aqueous NaHCO (5 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase: A: water (10 mM NH4HCO3); B: ACN; 15% to 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).

[0446] The compounds listed in Table 25a were prepared by methods essentially similar to those found in Example 187. [Table 163]

[0447] Example 188a 1-(3-(5-aminopyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] To 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 at ambient temperature under nitrogen for 2 hours, the mixture was concentrated under reduced pressure. The residue was added to NaHCO3 solution (5 mL) and extracted with DCM (5 mL x 3). The combined DCM was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 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).

[0448] The compounds listed in Table 25b were prepared by methods essentially similar to those found in Example 188a. [Table 164]

[0449] Example 189 2-(5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)acetonitrile [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. The residue was added to water (80 mL), and the pH was adjusted to 7-8 with saturated NaHCO3 solution, followed by extraction with EtOAc (80 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Boston pHlex ODS 21.2 × 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).

[0450] The compounds listed in Table 25c were prepared by methods essentially similar to those found in Example 189. [Table 165]

[0451] Example 189c 3-(4-chloro-3-fluorobenzyl)-1-(1-(5-methylpyridazin-4-yl)-1H-pyrazol-4-yl)piperidin-2-one [ka] To a 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 h, NaOAc (230 mg, 1.69 mmol) was added at 0 °C and then heated to 70 °C for 2 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (110 mg, 24%) as a white solid. ES / MS (m / z): 400 [M+H].

[0452] Example 189d 1-(5-(methoxymethyl)-1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] A solution of 4-(4-bromo-5-(methoxymethyl)-1H-pyrazol-1-yl)pyridazine (27 mg, 0.10 mmol) and 3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (23 mg, 0.10 mmol) in DMF (3 mL) was added to a solution of KPO (64 mg, 0.30 mmol), N 1 , N 2 -Dimethylcyclohexane-1,2-diamine (29 mg, 0.20 mmol) and CuI (29 mg, 0.15 mmol) were added, followed by stirring at 90 °C under a N2 atmosphere for 5 h. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, ACN / 13 mmol TFA = 65-95% (17 min), retention time = 8.9 min) to give the title compound (13 mg, 31%) as a white solid. ES / MS (m / z): 418 (M+H).

[0453] 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) [ka] 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 subjected to SFC, OX (4.6 * Purification was performed using a 100 mm column (5 μm) with a mobile phase of A: CO₂, B: (EtOH [1% NH₃ (7M / MeOH)]), eluting with 45% B, at a flow rate of 100 mL / min. The first peak of eluate was collected and lyophilized to give isomer 1 (ee: 100.0%). ES / MS (m / z): 389 (M+H). The second peak of eluate was collected and lyophilized to give isomer 2 (ee: 100.0%). ES / MS (m / z): 389 (M+H).

[0454] The compounds listed in Table 26 were prepared by methods essentially similar to those found in Example 190. [Table 166] [Table 167] [Table 168] [Table 169] [Table 170] [Table 171] Table 172 Table 173 Table 174 Table 175 Table 176 Table 177 Table 178 Table 179 Table 180 Table 181 Table 182 Table 183 Table 184 Table 185 Table 186 Table 187 Table 188 [Table 189]

[0455] Example 287 1-(3-(5-(fluoromethyl)pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] To 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., followed by stirring at 0° C. under a nitrogen atmosphere for 10 minutes. The reaction was quenched with HO (3 mL) at ambient temperature and extracted with DCM (5 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (gradient: ACN / water (10 mM NH4HCO3) 25% to 55% 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 μm) to give the title compound (3.2 mg, 3.2%) as a white solid. ES / MS (m / z): 406 (M+H).

[0456] Example 291 1-(4-(2-hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] To 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 NaBH (38 mg, 1 mmol) slowly. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was added to water (30 mL) and extracted with EtOAc (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Welch Xtimate 21.2 x 250 mm C18, 10 μm, Mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: ACN; B%: 30% to 70% in 15.0 min) to give the title compound (123 mg, 20%) as a white solid. ES / MS (m / z): 417 (M+H).

[0457] Example 292 3-Hydroxy-1-(5-(methoxymethyl)-1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one [ka] To 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 a solution of LiHMDS in THF (0.16 mL, 0.16 mmol) at −78° C. After stirring at −75° C. for 1 hour, the reaction mixture was added to a solution of (1R)-(−)-(10-camphorsulfonyl)oxaziridine (37 mg, 0.16 mmol) in THF (1 mL) at −75° C., followed by stirring at −75° C. under nitrogen for 3 hours. The mixture was added to water (20 mL) and extracted with EtOAc (30 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient: ACN / water (10 mM NHHCO) 25% to 55% in 8.0 min, stop at 24 min, retention time = 10.3 min) to give the title compound (5 mg, 10%) as a yellow solid. ES / MS (m / z): 434 (M+H).

[0458] 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) [ka] 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 under reduced pressure. The residue was added to saturated NaHCO3 solution (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (ACN / 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).

[0459] The compounds listed in Table 30 were prepared by methods essentially similar to those found in Example 293. [Table 190] [Table 191] [Table 192]

[0460] Example 305 (S)-3-((6-chloro-5-fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one [ka] To 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 HO (42 mg, 1.25 mmol) at 0 °C. After stirring for 10 min, the reaction mixture was added to a solution of LiOH.HO (26 mg, 0.62 mmol) in HO (2 mL) and stirred for 20 min. The reaction mixture was quenched with saturated aqueous NHCl and extracted with EtOAc (50 mL × 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was stirred in MeOH (10 mL) and the solid was filtered and dried under reduced pressure to give the title compound (45 mg, 54%) as a white solid. ES / MS (m / z): 401 (M+H).

[0461] The compounds listed in Table 31 were prepared by methods essentially similar to those found in Example 305. [Table 193]

[0462] Example 307 (S)-3-(4-Fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (20 mg, 23%) as a white solid. ES / MS (m / z): 366 [M+H].

[0463] 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 phosphate [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (eluting with ACN / NHHCO solution (0-40%)) to give the title compound (95 mg, 58%) as a white solid. ES / MS (m / z): 493 (M+H).

[0464] The compounds listed in Table 32 were prepared by methods essentially similar to those found in Example 308. [Table 194]

[0465] Example 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) [ka] To a suspension of the isomeric 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 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (eluting with ACN / NHHCO solution (0-40%)) to give 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).

[0466] The compounds listed in Table 33 were prepared by methods essentially similar to those found in Example 310. [Table 195]

[0467] Example 313 Disodium (2-(5-(pyridazin-4-yl)-3-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4-yl)ethoxy)methyl phosphate [ka] To 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 a solution of NaOH (11.2 mg, 0.28 mmol) in water (1 mL) at 25° C., followed by stirring at 25° C. for 5 hours. 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).

[0468] Example 314 3-(4-chloro-3,5-difluorophenyl)-N-(4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)propanamide [ka] To 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 a solution of HCl in 1,4-dioxane (5 mL, 20 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18, ACN / 10 mmol NH4HCO3) to give the title compound (0.15, 30%) as a white solid. ES / MS (m / z): 479 (M+H).

[0469] The compounds listed in Table 34 were prepared by methods essentially similar to those found in Example 314. [Table 196]

[0470] Example 316 N-(4-((4-methylmorpholin-2-yl)methoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propenamide [ka] To 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 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (120 mg, 69%) as a white solid. ES / MS (m / z): 477 (M+H).

[0471] Example 317 3-(4-chloro-3-fluorophenyl)-N-(4-(2-hydroxyethoxy)-5-(pyridazin-4-yl)-1H-pyrazol-3-yl)propenamide [ka] To 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 DC (10 mL) was added a 1 M solution of BBr3 in DCM (3.5 mL, 3.5 mmol). After stirring at 60 °C for 12 h, the reaction mixture was cooled to ambient temperature, MeOH (2 mL) was added dropwise, and then concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (C18, eluted with 35% ACN / 10 mM NH4HCO3) to give the title compound (95 mg, 32%) as a white solid. ES / MS (m / z): 406 (M+H).

[0472] Example 318 N-(4-((4-(methyl-d3)morpholin-2-yl)methoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propenamide [ka] To 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 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.12 g, 60%) as a white solid. ES / MS (m / z): 480 (M+H).

[0473] The compounds listed in Table 35 were prepared by methods essentially similar to those found in Example 318. [Table 197]

[0474] Example 321 N-(4-(methoxymethyl)-5-(pyridazin-4-yl)-1H-pyrazol-3-yl)-3-(3,4,5-trifluorophenyl)propenamide [ka] To 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 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (water:ACN=20:1) to give the title compound (20 mg, 25%) as a white solid. ES / MS (m / z): 392 (M+H).

[0475] Example 322 3-(4-chloro-1H-pyrrol-2-yl)-N-(5-(5-methylpyridazin-4-yl)-1H-pyrazol-3-yl)propanamide [ka] To a 1M solution of 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 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (eluted with 2-40% ACN / 10 mM NH4HCO3) to give the title compound (27 mg, 25%) as a white solid. ES / MS (m / z): 331 (M+H).

[0476] Example 323 N-(4-(2-(difluoromethoxy)ethyl)-5-(pyridazin-4-yl)-1H-pyrazol-3-yl)-3-(3,4,5-trifluorophenyl)propenamide [ka] To 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 2,2-difluoro-2-(fluorosulfonyl)acetic acid (341 mg, 1.92 mmol) was slowly added. After stirring at 50° C. under nitrogen for 1 hour, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL×3). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient: ACN / water (0.01% TFA) 30–60% in 8 min, stop at 14 min; retention time: 8.5 min; flow rate: 30 mL / min; column: BOSTON pHlex ODS 10 μm 21.2 × 250 mm 120A) to give the title compound (12 mg, 2.1%) as a white solid. ES / MS (m / z): 255 (M+H).

[0477] Example 324 N-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propanamide [ka] To a 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, followed by stirring at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, ACN / 10 mmol NH4HCO3) to give the title compound (15 mg, 11%) as a white solid. ES / MS (m / z): 378 (M+H).

[0478] ARM-SAM-TIR SARM1 IC 50 Assay This section describes an assay for ARM-SAM-TIR NADase activity and its use to measure the efficacy of compounds of the invention in blocking SARM1-mediated NAD+ cleavage. The assay was optimized to characterize the efficacy of compounds of the invention in inhibiting SARM1 activity, and the IC of each compound was determined. 50 The values ​​of α, β, and β were calculated. This assay utilized full-length SARM1, which encompasses the ARM, SAM, and TIR domains. As shown herein, expression of this fragment, lacking the autoinhibitory N-terminal domain, generates a constitutively active NAD+-cleaving enzyme.

[0479] Preparation of ARM-SAM-TIR lysate (STL) NRK1-HEK293T cells were cultured at 150 cm 2 Cells were seeded onto plates at 20 × 106 cells per plate. The next day, cells were transfected with 15 μg of ARM-SAM-TIR expression plasmid (SEQ ID NO: 1 (disclosed in WO2019 / 236879, pages 77-81; paragraph

[0310] )). At the time of transfection, 1 mM NR was added to the medium to minimize toxicity due to overexpression of ARM-SAM-TIR. Forty-eight hours after transfection, cells were harvested, pelleted by centrifugation at 1,000 rpm (Sorvall ST 16R centrifuge, Thermo Fisher), and washed once with ice-cold PBS (0.01 M phosphate-buffered saline, NaCl 0.138 M; KCl 0.0027 M; pH 7.4). Protease inhibitors (Complete TMCells were resuspended in PBS with a protease inhibitor cocktail (Roche product number: 11873580001), and cell lysates were prepared by sonication (Branson Sonifer 450, power = 3, 20 strokes). The lysates were centrifuged (12,000 × g, 10 min, 4°C) to remove cell debris, and the supernatant (containing ARM-SAM-TIR protein) was stored at -80°C for later use in the in vitro ARM-SAM-TIR NADase assay (see below). Protein concentrations were determined by the bicinchoninic (BCA) method and used to normalize lysate concentrations.

[0480] ARM-SAM-TIR IC of compounds of formula I 50 Assay Enzyme assays were performed in 384-well polypropylene plates containing 20 μL of Dulbecco's PBS buffer in a final assay volume. ARM-SAM-TIR lysate at a final concentration of 5 μg / mL was pre-incubated with each compound at a final assay concentration of 1% DMSO for 2 hours at ambient temperature. The reaction was initiated by adding NAD+ as a substrate at a final assay concentration of 5 μM. After 2 hours of incubation at ambient temperature, the reaction was terminated with 40 μL of stop solution (7.5% trichloroacetic acid / acetonitrile). 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).

[0481] The results are shown in Tables 36A and 36B below. Compounds with an activity designated "A" have an IC of less than 50 nM 50 compounds with activity designated "B" have an IC of 51-100 nM 50 compounds having an activity designated "C" have an IC of 101 to 500 nM 50compounds having an activity designated "D" have an IC of 501-1000 nM 50 compounds having an activity designated "E" have an IC of greater than 1000 nM 50 was provided. [Table 198] [Table 199] [Table 200] [Table 201] [Table 202] [Table 203] The "-" symbol indicates data that was not collected. The results shown above in Tables 36A and 36B demonstrate that the exemplified compounds have hSARM1 inhibitory activity.

[0482] List of embodiments 1. A compound of the formula: TIFF2026504977000576.tif37164 or a pharmaceutically acceptable salt thereof [In the formula, X is N and Y is CH, or X is CH and Y is N; R 5 are hydrogen, halogen, -NH2, -OC 1~3 C optionally substituted with alkyl and 1 to 3 halogen atoms, -OH, or -OCH 1~3 alkyl, wherein R 5 is hydrogen, then ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which the nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] is selected from R 5 But halogen, -NH2, -OC 1~3 C optionally substituted with alkyl and 1 to 3 halogen atoms, -OH, or -OCH 1~3 alkyl, when ring A is selected from: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which the nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from; R 1 and R 2 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring, wherein one carbon atom is optionally replaced with a heteroatom selected from oxygen and nitrogen, and wherein one carbon atom is optionally replaced with a heteroatom selected from cyano, -OR d , or -NH2 or -OR d C, which may be optionally substituted with 1~3 alkyl, optionally substituted; R 3 is hydrogen and C 1~4 alkyl; R 4 is 1 to 3 R b phenyl, oxygen, nitrogen and sulfur, optionally substituted with 1 to 3 heteroatoms selected from b and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R b a 9- to 10-membered aromatic bicyclic heteroaryl, which is fully or partially aromatic, optionally substituted with R a are each independently selected from hydrogen, halogen, and cyano, or halogen, -OR d , C optionally substituted with -NH or cyano 1~4 alkyl; R b are each independently a halogen, cyano, or C 1~4 Alkyl, -NH2, -OH, monohalomethyl, dihalomethyl, trihalomethyl, and -OC 1~4 alkyl; R c is halogen, cyano, R e -OC, which may be optionally substituted with 1~3Alkyl, and halogen, -OR d , -NH2, or cyano optionally substituted C 1~4 alkyl; R d is hydrogen, C 1~4 alkyl and —CH2OP(O)(OH)2; R e has the following structure: [ka] Select from]. 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is CH. 3. R 5 is hydrogen and ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which the nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from: A compound according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt thereof. 4. R 5 But halogen, -NH2, -OC 1~3 Alkyl, and C 1~3 C optionally substituted with 1 to 3 halogen atoms, -OH, or -OCH 1~3 alkyl, and ring A is selected from: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which the nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] or a pharmaceutically acceptable salt thereof. 5. R 5 is selected from —CH 3 , —CH 2 OH, —NH 2 , —CH 2 F, and —OCH 3 , or a pharmaceutically acceptable salt thereof. 6. The following structure: [ka] or a pharmaceutically acceptable salt thereof. [In the formula, B is O, NH, CR 6 where R 6 is hydrogen, cyano, -OC 1~3 Alkyl, or -NH2 or -OR d C, which may be optionally substituted with 1~3 alkyl; R 7 and R 8 is independently selected from hydrogen and —OH; n is 0 or 1]. 7. The following structure: [ka] or a pharmaceutically acceptable salt thereof. [wherein n is 0 or 1]. 8. The compound of embodiment 6 or 7, selected from the following structures: or a pharmaceutically acceptable salt thereof: TIFF2026504977000600.tif253153 9. R 3 9. The compound of any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. 10. Ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which the nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from R a are each independently selected from hydrogen, cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, and -Cl, or a pharmaceutically acceptable salt thereof. 11. Ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and R c are cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, -Cl, as well as the following structures: [ka] 11. The compound according to any one of embodiments 1 to 3 and 5 to 10, selected from: or a pharmaceutically acceptable salt thereof. 12. R 4 However, 1 to 3 R b and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R b 12. The compound of any one of embodiments 1 to 11, wherein the compound is selected from: 13. R 4 However, 1 to 3 R b or a pharmaceutically acceptable salt thereof. 14. R 4contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and 1 to 3 R b or a pharmaceutically acceptable salt thereof. 15. R 4 However, 1 to 3 R b or a pharmaceutically acceptable salt thereof. 16. R 4 has the following structure: [ka] 13. The compound of embodiment 12, selected from: 17. R 4 However, 1 to 3 R b is replaced by R b are each independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl, or a pharmaceutically acceptable salt thereof. 18. R 4 has the following structure: [ka] or a pharmaceutically acceptable salt thereof. 19. A compound of the formula: [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is N and Y is CH, or X is CH and Y is N; R 5 is selected from hydrogen, and —OH, —NH, or —CH optionally substituted with 1 to 3 halogen atoms, R 5 C optionally substituted with -OH, -NH2, or 1 to 3 halogen atoms 1~3 When ring A is alkyl, it is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from; R 5 is hydrogen, then ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and; R 1 , R 2 and R 3 are each independently hydrogen and C 1~4 alkyl, where R 2 and R 3 may optionally, together with the atoms to which they are attached, form a 3- to 6-membered saturated carbocyclic ring; R 4 is 1 to 3 R b phenyl, oxygen, nitrogen and sulfur, optionally substituted with 1 to 3 heteroatoms selected from b and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R b a 9- to 10-membered bicyclic heteroaryl which is fully or partially aromatic, optionally substituted with R a is hydrogen, halogen, cyano, and C 1~4 alkyl; R b are each independently halogen, cyano, -OH, -NH2, C 1~4 Alkyl, monohalomethyl, dihalomethyl, trihalomethyl and -OC 1~4 alkyl; R c -OR d or R e -OC, which may be optionally substituted with 1~3 Alkyl, and -OR d or -C substituted with 1 to 3 halogen atoms 1~4 alkyl; R d is selected from H, —CH3, —CF3, —CHF2, and —CH2OP(O)(OH)2; R e has the following structure: [ka] Select from]. 20. The compound of embodiment 19, wherein X is N and Y is CH, or a pharmaceutically acceptable salt thereof. 21. R 5 C optionally substituted with -OH, -NH2, or 1 to 3 halogen atoms 1~3 alkyl, and ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] 21. The compound according to embodiment 19 or embodiment 20, selected from: 22. R 5 is selected from -CH3, CH2OH, CH2F, and ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] and the following structure: [ka] 22. The compound of embodiment 21, selected from: 23. R 5 is hydrogen and ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH)2: [ka] 20. The compound of embodiment 19, wherein: 24. R 1 , R 2 and R 3 are all hydrogen; or a pharmaceutically acceptable salt thereof. 25. Ring A has the following structure, one nitrogen atom of which may be optionally substituted with —CH2OP(O)(OH)2: [ka] and the following structure: [ka] Selected from R a is selected from hydrogen, cyano, and —CH 3 , or a pharmaceutically acceptable salt thereof. 26. Ring A is: The following structure, in which one nitrogen atom is optionally substituted with -CH2OP(O)(OH): [ka] and R c -OCH3, -CH2OCH3, -CH2CH2OCH3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2CH2OCHF2, -CH2CH2OCH2OP(O)(OH)2, as well as the following structure: [ka] 25. The compound according to any one of embodiments 19, 23 and 24, selected from: 27. R 4 However, 1 to 3 R b and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R b 27. The compound of any one of embodiments 19 to 26, wherein the compound is selected from: 5-6 membered heteroaryl optionally substituted with 28. R 4 However, 1 to 3 R b 28. The com...

Claims

1. A compound of the formula: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [In the formula, X is N and Y is CH, or X is CH and Y is N; R ５ is hydrogen, halogen, -NH ２ , -OC １～３ Alkyl and 1 to 3 halogen atoms, —OH, or —OCH ３ C optionally substituted with １～３ alkyl, wherein R ５ is hydrogen, then ring A is: One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 2】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Transformation 3】 Nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 4】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Transformation 5】 and the following structure: 【Transformation 6】 is selected from R ５ is halogen, -NH ２ , -OC １～３ Alkyl and 1 to 3 halogen atoms, —OH, or —OCH ３ C optionally substituted with １～３ alkyl, then ring A is selected from: One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Transformation 7】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Transformation 8】 Nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 9】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 10】 and the following structure: 【Chemistry 11】 Selected from: R １ and R ２ together with the atoms to which they are attached form a 5- to 6-membered saturated heterocyclic ring, in which one carbon atom may be optionally replaced with a heteroatom selected from oxygen and nitrogen, and in which one carbon atom is optionally replaced with a heteroatom selected from cyano, —OR ｄ , or —NH ２ Or -OR ｄ C optionally substituted with １～３ alkyl, optionally substituted; R ３ is hydrogen and C １～４ alkyl; R ４ is 1 to 3 R ｂ phenyl, oxygen, nitrogen and sulfur, optionally substituted with 1 to 3 R ｂ and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｂ a 9-10 membered bicyclic heteroaryl, which is fully or partially aromatic, optionally substituted with R ａ are each independently selected from hydrogen, halogen, and cyano, or halogen, —OR ｄ , -NH ２ or C optionally substituted with cyano １～４ alkyl; R ｂ are each independently a halogen, a cyano, or a C １～４ Alkyl, —NH ２ , —OH, monohalomethyl, dihalomethyl, trihalomethyl, and —OC １～４ alkyl; R ｃ is halogen, cyano, R ｅ -OC, optionally substituted with １～３ Alkyl and halogen, —OR ｄ , -NH ２ or C optionally substituted with cyano １～４ alkyl; R ｄ is hydrogen, C １～４ Alkyl and —CH ２ OP(O)(OH) ２ Selected from: R ｅ has the following structure: 【Chemistry 12】 Selected from].

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

3. R ５ is hydrogen and ring A is: One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 13】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 14】 Nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 15】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 16】 and the following structure: 【Chemistry 17】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

4. R ５ is halogen, -NH ２ , -OC １～３ Alkyl and 1 to 3 halogen atoms, —OH, or —OCH ３ C optionally substituted with １～３ alkyl, and Ring A is selected from: One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: [Chemistry 18] One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 19】 Nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 20】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 21】 and the following structure: 【Chemistry 22】 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, selected from:

5. R ５ But -CH ３ , -CH ２ OH, —NH ２ , -CH ２ F, and -OCH ３ 5. The compound of claim 4, selected from:

6. The following structure: 【Chemistry 23】 The compound according to any one of claims 1 to 5, which is represented by the formula: or a pharmaceutically acceptable salt thereof. [In the formula, B is O, NH, CR ６ where R ６ is hydrogen, cyano, -OC １～３ Alkyl, or —NH ２ , or -OR ｄ C optionally substituted with １～３ alkyl; R ７ and R ８ is independently selected from hydrogen and —OH; n is 0 or 1.

7. The following structure: 【Chemistry 24】 7. The compound of claim 6, wherein: [wherein n is 0 or 1].

8. 8. The compound of claim 6 or 7, selected from the following structures, or a pharmaceutically acceptable salt thereof: 【Chemistry 25】

9. R ３ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

10. Ring A is: One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 26】 Nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 27】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 28】 and the following structure: 【Chemistry 29】 and R ａ are each independently hydrogen, cyano, or —CH ３ , -CH ２ OH, -CH ２ CH ２ OH, -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ , -CH ２ CN, -OCH ３ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from -F, -F, and -Cl.

11. Ring A is One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Transformation 30】 and R ｃ But cyano, -CH ３ , -CH ２ OH, -CH ２ CH ２ OH, -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ , -CH ２ CN, -OCH ３ , —F, —Cl, as well as the following structures: 【Chemistry 31】 11. The compound according to any one of claims 1 to 3 and 5 to 10, or a pharmaceutically acceptable salt thereof, selected from:

12. R ４ But 1 to 3 R ｂ and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｂ 12. The compound of any one of claims 1 to 11, wherein the compound is selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with

13. R ４ But 1 to 3 R ｂ 13. The compound of claim 12, wherein R is phenyl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

14. R ４ contains 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｂ 13. The compound according to claim 12, wherein R is 5 to 6-membered heteroaryl optionally substituted by R , or a pharmaceutically acceptable salt thereof.

15. R ４ But 1 to 3 R ｂ 15. The compound of claim 14, wherein R is an optionally substituted pyridine, or a pharmaceutically acceptable salt thereof.

16. R ４ but has the following structure: 【Chemistry 32】 13. The compound of claim 12, selected from:

17. R ４ But 1 to 3 R ｂ is substituted with R ｂ are each independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl, or a pharmaceutically acceptable salt thereof.

18. R ４ but has the following structure: 【Transformation 33】 2. The compound of claim 1, selected from:

19. A compound of the formula: 【Transformation 34】 or a pharmaceutically acceptable salt thereof [In the formula, X is N and Y is CH, or X is CH and Y is N; R ５ represents hydrogen, and —OH, —NH ２ or —CH optionally substituted with 1 to 3 halogen atoms ３ is selected from, where R ５ But -OH, -NH ２ or C optionally substituted with 1 to 3 halogen atoms １～３ When ring A is alkyl, one nitrogen atom is —CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 35】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Transformation 36】 and the following structure: 【Chemistry 37】 Selected from: R ５ is hydrogen, ring A has one nitrogen atom that is —CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Transformation 38】 and R １ , R ２ and R ３ are each independently hydrogen and C １～４ alkyl, where R ２ and R ３ may optionally, together with the atoms to which they are attached, form a 3- to 6-membered saturated carbocyclic ring; R ４ is 1 to 3 R ｂ phenyl, oxygen, nitrogen and sulfur, optionally substituted with 1 to 3 R ｂ and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｂ a 9-10 membered bicyclic heteroaryl which is fully or partially aromatic, optionally substituted with R ａ is hydrogen, halogen, cyano, and C １～４ alkyl; R ｂ are each independently a halogen, cyano, —OH, or —NH ２ , C １～４ Alkyl, monohalomethyl, dihalomethyl, trihalomethyl and —OC １～４ alkyl; R ｃ is -OR ｄ or R ｅ -OC, optionally substituted with １～３ alkyl, and —OR ｄ or —C substituted with 1 to 3 halogen atoms １～４ alkyl; R ｄ is H, -CH ３ , -CF ３ , -CHF ２ , and -CH ２ OP(O)(OH) ２ Selected from: R ｅ has the following structure: 【Chemistry 39】 Selected from].

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

21. R ５ But -OH, -NH ２ or C optionally substituted with 1 to 3 halogen atoms １～３ alkyl, and ring A is One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 40】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 41】 and the following structure: 【Chemistry 42】 21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt thereof, selected from:

22. R ５ But -CH ３ , C.H. ２ OH, CH ２ F, and ring A is selected from One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 43】 One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 44】 and the following structure: 【Chemistry 45】 22. The compound of claim 21 selected from: or a pharmaceutically acceptable salt thereof.

23. R ５ is hydrogen, and ring A is One nitrogen atom is -CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 46】 20. The compound of claim 19, wherein:

24. R １ , R ２ and R ３ The compound according to any one of claims 19 to 23, or a pharmaceutically acceptable salt thereof, wherein all of are hydrogen.

25. Ring A has one nitrogen atom that is —CH ２ OP(O)(OH) ２ The following structures, which may be optionally substituted with: 【Chemistry 47】 and the following structure: 【Chemistry 48】 and R ａ is hydrogen, cyano and -CH ３ 25. The compound according to any one of claims 19 to 22 and 24, or a pharmaceutically acceptable salt thereof, selected from:

26. Ring A has one nitrogen atom that is —CH ２ The following structure, optionally substituted with OP(O)(OH): 【Chemistry 49】 RRRR ｃ Yes, -OCH ３ 、-CH ２ OCH ３ 、-CH ２ CH ２ OCH ３ ,-OCH ２ CH ２ OH、-OCH ２ CH ２ OCH ３ ,-OCH ２ CH ２ OCHF ２ 、-CH ２ CH ２ OCH ２ O (O) (O) ２ 、 as well as the following structure: [Transformation 50] 25. The compound of any one of claims 19, 23 and 24, or a pharmaceutically acceptable salt thereof, selected from:

27. R ４ But 1 to 3 R ｂ and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｂ 27. The compound of any one of claims 19 to 26, wherein the compound is selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with

28. R ４ But 1 to 3 R ｂ 28. The compound of claim 27, wherein R is phenyl optionally substituted by R, or a pharmaceutically acceptable salt thereof.

29. R ４ contains 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｂ 28. The compound of claim 27, wherein R is 5 to 6-membered heteroaryl optionally substituted by R , or a pharmaceutically acceptable salt thereof.

30. R ４ But 1 to 3 R ｂ 30. The compound of claim 29, wherein R is an optionally substituted pyridine, or a pharmaceutically acceptable salt thereof.

31. R ４ but has the following structure: 【Chemistry 51】 28. The compound of claim 27, selected from: or a pharmaceutically acceptable salt thereof.

32. R ４ But 1 to 3 R ｂ is substituted with R ｂ are each independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl, or a pharmaceutically acceptable salt thereof.

33. R ４ has the following structure: 【Chemistry 52】 20. The compound of claim 19, selected from: or a pharmaceutically acceptable salt thereof.

34. A compound of the formula: 【Chemistry 53】 or a pharmaceutically acceptable salt thereof [In the formula, X is N and Y is CH, or X is CH and Y is N; Ring A has the following structure: 【Chemistry 54】 Selected from: R １ , R ２ and R ３ are each independently hydrogen and C １～４ alkyl, where R １ and R ２ may optionally form, together with the atoms to which they are attached, a 5- to 6-membered saturated heterocycle, wherein one carbon atom may be optionally replaced with a heteroatom selected from oxygen and nitrogen, or wherein R ２ and R ３ may optionally, together with the atoms to which they are attached, form a 3- to 6-membered saturated carbocyclic ring; R ４ is 1 to 3 R ｂ and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and 1 to 3 R ｂ 5-6 membered heteroaryl optionally substituted with R ａ is hydrogen, halogen, cyano, and halogen, —OH, —NH ２ or C optionally substituted with cyano １～４ alkyl; R ｂ are each independently a halogen, a cyano, or a C １～４ Alkyl, trihalomethyl and —OC １～４ alkyl].

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

36. 35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is N.

37. R １ , R ２ and R ３ 37. The compound of any one of claims 34 to 36, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

38. The following structure: 【Transformation 55】 The compound according to any one of claims 34 to 36, or a pharmaceutically acceptable salt thereof, wherein Z is CH ２ , O, NH or a bond.

39. The following structure: 【Transformation 56】 39. The compound of claim 38, selected from: or a pharmaceutically acceptable salt thereof.

40. Ring A has the following structure: 【Chemistry 57】 40. The compound of any one of claims 34 to 39, or a pharmaceutically acceptable salt thereof, selected from:

41. Ring A has the following structure: 【Chemistry 58】 and R ａ 40. The compound of any one of claims 34 to 39, or a pharmaceutically acceptable salt thereof, wherein is methyl.

42. Ring A has the following structure: 【Chemistry 59】 and R ａ 40. The compound of any one of claims 34 to 39, or a pharmaceutically acceptable salt thereof, wherein is cyano.

43. R ４ has the following structure: 【Transformation 60】 43. The compound of any one of claims 34 to 42, or a pharmaceutically acceptable salt thereof, selected from:

44. R ｂ 44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein is halogen.

45. R ４ has the following structure: 【Chemistry 61】 45. The compound of any one of claims 34 to 44, or a pharmaceutically acceptable salt thereof, selected from:

46. The following structure: 【Transformation 62】 【Transformation 63】 35. The compound of claim 34, selected from: or a pharmaceutically acceptable salt thereof.

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

48. A method for treating or preventing a disease associated with axonal degeneration in a patient, the method 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

49. A method for 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

50. 48. 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 according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

51. 47. A compound according to claims 1 to 46, or a pharmaceutically acceptable salt thereof, for use in therapy.

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

53. 47. The compound according to any one of claims 1 to 46, or a 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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